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Sixth Edition

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Neurology for the non-neurologist/editors, William J. Weiner ... [et al.].—6th ed.

p. cm.

Includes index.

ISBN 978-1-60547-239-3

1. Neurology. 2. Nervous system—Diseases. I. Weiner, William J.

RC346.N453 2010

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2010010048

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10 9 8 7 6 5 4 3 2 1

Contents

13. Hyperkinetic Movement Disorders

241

Gonzalo J. Revuelta, William J. Weiner, and Stewart A. Factor

14. Alzheimer Disease and Other Dementias

287

Neelum T. Aggarwal and Raj C. Shah

15. Behavioral Neurology

307

Robert S. Wilson and Christopher G. Goetz

16. Traumatic Brain Injury

324

Michael J. Makley

17. Neuromuscular Diseases

344

Dianna Quan and Steven P. Ringel

18. Peripheral Neuropathy

375

Joshua Gordon and Morris A. Fisher

19. Neurologic Evaluation of Low Back Pain

398

Megan M. Shanks

20. Dizziness and Vertigo

412

Robert K. Shin and Judd M. Jensen

21. An Approach to the Falling Patient

427

Kathryn A. Chung and Fay B. Horak

22. Neurotoxic Effects of Drugs Prescribed by Non-Neurologists

446

Katie Kompoliti

23. Neurologic Complications of Alcoholism

470

Allison L. Weathers

24. Central Nervous System Infections

486

Larry E. Davis

25. Neurologic Aspects of Cancer

499

Deborah Olin Heros

26. Eye Signs in Neurologic Diagnosis

516

Robert K. Shin and James A. Goodwin

27. Principles of Neurorehabilitation

551

David S. Kushner

28. Medicolegal Issues in the Care of Patients with Neurologic Illness

572

Maria R. Schimer and Lois Margaret Nora

Index

588

Contributors

Neelum T. Aggarwal, M.D.

Christopher G. Goetz, M.D.

Associate Professor of Neurological Sciences

Professor of Neurological Sciences and Pharmacology

Rush University

Rush University Medical Center

Clinical Core Leader, Rush Alzheimer’s Disease

Chicago, Illinois

Research Center

Rush University Medical Center

James A. Goodwin, M.D.

Chicago, Illinois

Associate Professor of Ophthalmology

University of Illinois at Chicago

Donna C. Bergen, M.D.

Director, Neuro-ophthalmology Service

Professor

University of Illinois Eye and Ear Infirmary

Department of Neurological Sciences

Chicago, Illinois

Rush University Medical Center

Chicago, Illinois

Joshua Gordon, M.D.

Assistant Professor of Neurology

Peter A. Calabresi, M.D.

Loyola University Medical Center

Professor of Neurology

Chicago, Illinois

The Johns Hopkins University School of Medicine

Assistant Professor of Neurology

Director, The Johns Hopkins Multiple Sclerosis Center

Edward Hines, Jr. VA Medical Center

Baltimore, Maryland

Hines, Illinois

Kathryn A. Chung, M.D.

Deborah Olin Heros, M.D.

Assistant Professor

Associate Professor of Clinical Neurology and

Department of Neurology

Neuro-Oncology

Oregon Health and Science University

University of Miami Leonard M. Miller

Portland, Oregon

School of Medicine Chief of Neurology

University of Miami Hospital

Larry E. Davis, M.D.

Miami, Florida

Professor of Neurology

University of New Mexico School of Medicine

Fay B. Horak, Ph.D., P.T.

Chief, Neurology Service, New Mexico VA Health

Research Professor

Care System

Department of Neurology

Albuquerque, New Mexico

Oregon Health and Science University

Portland, Oregon

Stewart A. Factor, D.O.

Professor of Neurology and Riley Family Chair in

Judd M. Jensen, M.D.

Parkinson's Disease

Penobscot Bay Medical Center

Emory University School of Medicine

Rockport, Maine

Director, Movement Disorders Program of Emory

University

Roger E. Kelley, M.D.

Atlanta, Georgia

Professor and Chair of Neurology

Tulane University School of Medicine

Morris A. Fisher, M.D.

New Orleans, Louisiana

Professor of Neurology

Loyola University Medical Center

Katie Kompoliti, M.D.

Maywood, Illinois

Associate Professor of Neurological Sciences

Acting Chief of Neurology

Rush University Medical Center

Edward Hines, Jr. VA Medical Center

Chicago, Illinois

Hines, Illinois

vii

Contributors

Ružica Kovaˇevi

´-Ristanovic´, M.D.

Neil C. Porter, M.D.

Clinical Associate Professor of Neurology

Assistant Professor of Neurology

University of Chicago Medical Center

University of Maryland School of Medicine

Chicago, Illinois

Baltimore, Maryland

Attending Medical Director, Sleep Disorders Center

Evanston Hospital

Dianna Quan, M.D.

Evanston, Illinois

Associate Professor of Neurology

University of Colorado Health Sciences Center

David S. Kushner, M.D.

Director, Electromyography Laboratory, University

Associate Professor of Rehabilitation Medicine

of Colorado Hospital

University of Miami Leonard M. Miller School

Denver, Colorado

of Medicine

Miami, Florida

Gonzalo J. Revuelta, D.O.

Movement Disorders Fellow, Department of

Tomasz J. Kuźniar, M.D., Ph.D.

Neurology

Assistant Professor of Medicine

Emory University School of Medicine

Northwestern University

Atlanta, Georgia

Chicago, Illinois

Attending Physician

Steven P. Ringel, M.D.

North Shore University Health System

Professor of Neurology

Evanston, Illinois

University of Colorado Health Sciences Center

Director, Neuromuscular Unit, University of

Steven L. Lewis, M.D.

Colorado Hospital

Professor and Associate Chairman

Denver, Colorado

Department of Neurological Sciences

Rush University Medical Center

Bradley J. Robottom, M.D.

Chicago, Illinois

Assistant Professor of Neurology

University of Maryland School of Medicine

Michael J. Makley, M.D.

Baltimore, Maryland

Assistant Professor of Neurology

University of Maryland School of Medicine

Joel R. Saper, M.D.

Director, Traumatic Brain Injury Unit, Kernan

Clinical Professor of Medicine-Neurology

Hospital

Michigan State University

Baltimore, Maryland

Director, Michigan Headache & Neurological

Institute

Alireza Minagar, M.D.

Ann Arbor, Michigan

Associate Professor of Neurology

Louisiana State University Health Sciences Center

Maria R. Schimer, M.P.H., J.D.

Shreveport, Louisiana

Associate Professor of Community Health

Sciences

Robert E. Morales, M.D.

Northeastern Ohio Universities Colleges of

Assistant Professor of Radiology

Medicine and Pharmacy

University of Maryland School of Medicine

Rootstown, Ohio

Director, Neuroimaging

University of Maryland Medical Center Baltimore,

Dishant G. Shah, M.D.

Maryland

Fellow, Diagnostic Neuroradiology

University of Maryland Medical Center

Scott D. Newsome, D.O.

Baltimore, Maryland

Assistant Professor of Neurology

The Johns Hopkins University School of Medicine

Raj C. Shah, M.D.

Baltimore, Maryland

Assistant Professor

Family Medicine and Rush Alzheimer’s Disease

Lois Margaret Nora, M.D., J.D.

Center

President and Dean, College of Medicine

Rush University Medical Center

Northeastern Ohio Universities Colleges of Medicine

Chicago, Illinois

and Pharmacy

Rootstown, Ohio

viii

Contributors

Megan M. Shanks, M.D.

Jordan L. Topel, M.D.

Assistant Professor

Associate Professor

Department of Neurological Sciences

Rush University Medical Center

Chicago, Illinois

Robert K. Shin, M.D.

Amy Wilcox Voigt, M.D.

Associate Professor of Neurology

Fellow

Associate Professor of Ophthalmology and Visual

Jefferson Headache Center

Sciences

Thomas Jefferson University

University of Maryland School of Medicine

Philadelphia, Pennsylvania

Director, Neuro-Ophthalmology, University

Eye Care

Allison L. Weathers, M.D.

Baltimore, Maryland

Assistant Professor

Department of Neurological Sciences

Lisa M. Shulman, M.D.

Rush University Medical Center

Eugenia Brin Professor of Parkinson's Disease and

Chicago, Illinois

Movement Disorders and

the Roslyn Newman Distinguished Scholar in

William J. Weiner, M.D.

Parkinson's Disease

Professor and Chairman

University of Maryland School of Medicine

Department of Neurology

Co-Director, Maryland Parkinson's Disease Center

University of Maryland School of Medicine

Baltimore, Maryland

Director,

Maryland Parkinson’s Disease and Movement

Madhu Soni, M.D.

Disorders Center

Assistant Professor

Baltimore, Maryland

Department of Neurological Sciences

Rush University Medical Center

Robert S. Wilson, M.D., Ph.D.

Chicago, Illinois

Professor of Neurological and Behavioral Sciences

Rush Alzheimer’s Disease Center

Tricia Y. Ting, M.D.

Rush University Medical Center

Assistant Professor of Neurology

Chicago, Illinois

University of Maryland School of Medicine

Director, Ambulatory Services

University of Maryland Epilepsy Center

Baltimore, Maryland

Preface

This sixth edition of Neurology for the Non-

Neuropathy, Neuromuscular Disease, Move-

Neurologist carries on a tradition of medical

ment Disorders, including Parkinson’s Disease,

education that began over 20 years ago with

Multiple Sclerosis, and Cerebrovascular Dis-

the first edition of this book. All editions have

ease, including stroke. We also cover topics

been anchored in an ongoing commitment to

based primarily on patient complaints: Vertigo

demystify neurology, so that its principles and

and Dizziness, Headaches, Low Back Pain, and

ever-growing knowledge base are accessible to

Falls. Most of these chapters stand as inde-

nonspecialists. Clearly, brain, spinal cord,

pendent discussions, but they are integrated

nerve, and muscle disorders are encountered by

with chapters that cross individual disease-

primary care physicians, including internists,

based categories and therefore have broad ap-

family practitioners, hospitalists, and pediatri-

plications to other chapters: Neuroradiology,

cians. Likewise, because of the interplay of

Behavioral Neurology, Drug-induced Disor-

brain and mind function as well as the neces-

ders, Medical-legal Issues, Neurologic Emer-

sary adaptations that patients endure from

gencies, Eye Signs in Neurologic Diagnosis,

neurologic disorders, psychiatrists also see

and Rehabilitation. With these different levels

many neurologic patients. As the core group of

and approaches, we hope to cover the major

physicians for whom this book is written, these

areas of neurology from the perspective of the

colleagues have embraced the former editions

non-neurologist who is likely to be the first-line

of Neurology for the Non-Neurologist, and we

physician with primary responsibility for man-

hope this new version will likewise meet their

aging neurologic problems within a full med-

educational and practice-based needs.

ical context.

Structurally, the new edition is similar to the

As editors, we have asked authors to follow

last edition, but with several significant addi-

a template that is consistent from chapter to

tions. The major neurologic disorders are cov-

chapter. Each chapter begins with a few Key

ered with an attention to the more commonly

Points that can be reviewed before launching

encountered diseases, but with careful signal-

into the full text. Each chapter presents the

ing to signs or symptoms that can suggest more

general pattern of neurologic signs pertinent to

unusual disorders. We begin the textbook with

the topic and this text is interspersed with high-

three overview chapters on Neurologic Symp-

lighted Special Clinical Points to focus the

toms, Neurologic Examination, and Diagnos-

reader on the most important details. Neurol-

tic Tests. These chapters orient readers to the

ogy is anchored in a two-part discipline of

significance of typical patterns of patient de-

defining the anatomy of a syndrome and then

scriptions, the different clustering of neuro-

establishing an etiology or cause. This principle

logic signs that help clarify diagnostic

is carried through each chapter text. Authors

categories, and the panoply of neurologic in-

alert readers to Special Considerations in the

vestigations available to define a likely single

Hospitalized Patient and When a Non-neurol-

diagnosis. Subsequent chapters focus on major

ogist Should Consider Referring to a Neurolo-

neurologic dilemmas that non-neurologists will

gist. Finally, we close each chapter with a

encounter, ranging from Epilepsy, Dementia,

section, termed Always Remember, to leave the

Infections, and Sleep Disorders to Peripheral

reader with a few important issues that can be

Preface

immediately applied in practice. We feel this

the senior editors will need to pass the baton

new arrangement helps to integrate the chap-

eventually if this book remains successful and

ters and allows busy practitioners to read the

if book publishing remains a viable educational

full text or to scan the chapters with these most

tool. Editorship requires an agile and harmo-

important highlights clearly marked. Updated

nious team that can work together and at the

references and a series of self-study questions

same time assume individual responsibility; we

close each chapter.

feel we have achieved both goals very comfort-

We are particularly proud of our list of re-

ably with the textbook edition. In an era when

cruited authors. Some have been part of this

North American practice patterns and health

textbook since the first edition, some have par-

care may rapidly evolve, we feel that Neurol-

ticipated in at least one earlier edition, and

ogy for the Non-Neurologist is particularly im-

some are new. Their commitment to education,

portant as an educational resource.

a clear writing style, and direct experience with

neurologic education have made the editorial

William J. Weiner, MD

management of this edition smooth and effi-

Christopher G. Goetz, MD

cient. We have also expanded our Editor team

Steven L. Lewis, MD

to four editors, with the long-term plan that

Robert K. Shin, MD

The Neurologic

Examination

ROBERT K. SHIN AND NEIL C. PORTER

key points

• The neurologic examination provides a comprehensive

assessment of the function of the human nervous system.

• When used in conjunction with the history, the

neurologic examination can provide information critical

to making a correct diagnosis.

• With practice, the neurologic examination can be

performed efficiently and quickly.

he neurologic

TABLE 1.1

examination is the foundation of the practice

Organization of the Neurologic

Examination

of neurology and an integral part of the physi-

cal examination. Unlike some medical disci-

Cognition

plines that may emphasize ancillary studies,

II. Cranial nerves

investigations in neurology are guided prima-

III. Motor function

rily by the information gleaned from the neuro-

IV. Deep tendon reflexes (DTR)

logic history and examination. Because the

V. Sensation

neurologic examination is often crucial in es-

VI. Coordination and gait

tablishing the correct diagnosis, all physicians

should be able to perform and document a

complete evaluation of the nervous system.

The neurologic examination is divided into sev-

At the same time, it is not always practical

eral parts (Table 1.1). These include assessment

to perform a detailed neurologic examination

of cognition, cranial nerves, motor function, re-

on every patient. A focused neurologic exami-

flexes, sensation, and coordination and gait.

nation should be influenced by the information

Each of these parts has multiple components

obtained from the interview and guided by the

with which all physicians should be familiar.

examiner’s clinical judgment.

■ SPECIAL CLINICAL POINT: Not every

MENTAL STATUS AND COGNITION

patient requires a detailed neurologic

examination, but physicians should at least

The cognitive examination provides an assess-

be familiar with each component of the

ment of the patient’s general mental status, eval-

comprehensive neurologic examination.

uating the integrity of the cerebral hemispheres.

Chapter 1

■ The Neurologic Examination

A comprehensive mental status examination

level of consciousness and cannot easily be

may begin with a general assessment of the pa-

aroused. An unconscious patient who cannot be

tient’s appearance, level of consciousness, and

fully aroused is stuporous. An unconscious pa-

mood and affect. Important primary cognitive

tient with no purposeful response to even nox-

domains to be tested include speech and lan-

ious stimuli is comatose.

guage, memory, visuospatial processing, and ex-

ecutive functioning

(including judgment and

Mood and Affect

insight). Disorders of perception or disorders of

thought form and content should be noted.

Mood refers to a person’s persistent emotional

state, while affect denotes more immediacy.

■ SPECIAL CLINICAL POINT: Important

Mood and affect can be assessed by observing

primary cognitive domains include speech and

the patient’s body language and behavior as

language, memory, visuospatial processing, and

executive functioning.

well as by verbal report. Depression is a state of

persistently low mood. A brief screen for de-

Often patients with cognitive problems will try

pression includes inquiries about reduced “spir-

to hide their deficiencies or may try to avoid di-

its,” reduced energy, poor self-attitude, poor

rectly answering questions. One can minimize

appetite, disturbed sleep, anhedonia, thinking

resistance to this testing by reassuring the pa-

difficulty, suicidal ideation, and psychomotor

tient that all of the questions are part of the

retardation. Conversely, mania is a state of per-

standard exam (e.g., “These are questions that

sistently elevated mood, increased energy, and

we ask everybody.”). Mistakes on the patient’s

heightened self-attitude, sometimes in associa-

part should be noted silently or corrected gen-

tion with delusions of grandeur, pressured

tly by the examiner in order to keep the patient

speech, and “flight of ideas.” Depression is seen

at ease.

in a number of neurologic disorders including

Parkinson disease, Huntington disease, and

strokes affecting the dominant hemisphere;

Appearance and Behavior

mania may be seen occasionally with cerebral

The patient’s appearance and general behav-

lesions of the nondominant hemisphere.

ior are important indicators of his or her

general level of function. The well-dressed,

Speech and Language

well- organized patient is likely functioning at

a higher level than the disheveled, unkempt pa-

Speech refers to the articulation of words,

tient. Additionally, a patient’s dress and de-

while language deals more with the structure

meanor are important indicators of underlying

and meaning of the spoken and written word.

psychiatric and psychological disturbances,

Both provide the examiner valuable insight

such as the patient who is inappropriately

into the patient’s mental state and can be as-

dressed for the weather or is clearly responding

sessed easily during the interview. Important

to unseen stimuli.

aspects of speech include the amplitude or

loudness, volume or amount (paucity vs. over-

abundance), and prosody or fluidity. Often pa-

Level of Consciousness

tients with end-stage dementia will have

Level of consciousness is a crucial part of the

paucity of speech. Patients with Parkinson dis-

mental status examination. One should note and

ease will often have hypophonic or soft speech.

document whether the patient is awake, alert,

Patients with cerebellar disorders may speak

and attentive versus unresponsive or drowsy. A

in a “choppy” ataxic manner. Speech may be

lethargic patient appears drowsy but is easily

slurred or dysarthric in a number of different

aroused. An obtunded patient has a reduced

clinical settings.

Chapter 1

■ The Neurologic Examination

A patient’s language capabilities can be as-

recall can be seen with lesions of the temporal

sessed quickly by evaluating spontaneous speech

lobe or thalami affecting the hippocampi or

and comparing it to comprehension of spoken

other structures within the Papez loop. The dis-

and written material. The presence of a language

tinction between “recent long-term memory”

disturbance or aphasia should be identified early,

(e.g., “What you had for breakfast this morn-

as it may preclude an adequate assessment of the

ing?”) versus “remote long-term memory” (e.g.,

rest of the mental status examination. An apha-

an event from childhood) is somewhat artificial.

sia may be expressive or receptive. An expressive

The use of the term short-term memory may

or nonfluent aphasia (e.g., Broca aphasia) is

be confusing as some use it to refer to working

characterized by difficulty producing speech

memory, while others use it to refer to recent

with intact comprehension, and typically results

long-term memory (see Chapter 15, Behavioral

from lesions in the inferior frontal region of the

Neurology).

dominant (usually left) hemisphere. In contrast,

a receptive or fluent aphasia

(e.g., Wernicke

Visuospatial Processing

aphasia) is characterized by poor comprehension

without difficulty producing speech. This may

Common tests of visuospatial processing include

result in the production of nonsensical speech

copying a complex figure or clock drawing. Pa-

(“word salad”) and is typically caused by lesions

tients can be asked to copy a design drawn by the

of the posterior temporal area of the dominant

examiner (e.g., a drawing of a cube, intersecting

hemisphere.

pentagons, or the façade of a house), or they may

Additonal localizing information can be

be asked to draw a clock face set to a particular

gleaned by assessing the patient’s ability to re-

time (e.g., “twenty after eight”). Patients with

peat and write.

parietal dysfunction may neglect to draw half of

the figure or may have trouble placing the num-

bers correctly on the clock face.

Memory

Two components of memory are commonly

Executive Function

assessed-working memory (also known as pri-

mary memory) and long-term memory (also

The integrity of the frontal lobes may be tested

known as secondary memory).

in several ways. Poor performance on tests of

Working memory is assessed by measuring

executive function, poor judgment and insight,

digit span (most patients can repeat strings of

or the presence of frontal release signs may all

approximately seven digits) or by backward

be evidence of frontal lobe impairment.

spelling (“Please spell WORLD backward.”),

Some simple tests of executive function in-

which are commonly interpreted as tests of

clude assessment of verbal fluency and oral

attention.

trail making. To assess verbal fluency, patients

Long-term memory is typically tested using

should be asked to generate a list of words

delayed word recall. Patients are given a list of

from a specific category

(e.g.,

“words that

three to five words (e.g., “cat, table, apple, pur-

begin with the letter F” or “all of the animals

ple, and bank”) and asked to repeat them back

you can think of”) in 1 minute. Although nor-

(registration). After being distracted by other

mative values vary based on age and level of

tasks (such as tests of working memory or visu-

education, most patients should be able to gen-

ospatial processing), the patient is asked to

erate 10 or more items for each list without

recall the list of words (retrieval). Clues or cues

much difficulty. Oral trail making involves

may be given (e.g., “One of the words was an

having the patient sequentially alternate be-

animal,” or “One of the words began with the

tween letters and numbers (“A-1-B-2-C-3-

letter C.”). Difficulty with this type of delayed

etc.”). Patients with frontal lobe dysfunction

Chapter 1

■ The Neurologic Examination

may perform poorly on these tests while doing

patient mistakes an object for something else,

surprisingly well on other components of the

such as a coat for an intruder. Both hallucina-

cognitive examination.

tions and illusions can be seen in patients who

A person’s judgment relies on the value sys-

are delirious or encephalopathic.

tem, making an assessment of judgment the

most subjective component of the mental sta-

Thought Form and Content

tus examination. Clinicians may ask questions

such as “What would you do if you found a

Abnormalities of thought form and content are

stamped envelope lying on the ground?” with

“psychotic features” associated with delirium,

the expected answer being, “Place the envelope

dementia, schizophrenia, and severe affective

in a mailbox.” Such questioning is probably

disorders. Abnormalities of thought content

most helpful in the patient who is demented or

consist of bizarre beliefs such as delusions, ob-

cognitively impaired. Insight refers to the pa-

sessions, compulsions, and phobias. Delusions

tient’s understanding of his or her condition.

are fixed, false, idiosyncratic beliefs tena-

The patient with Alzheimer disease, for exam-

ciously held by patients. Obsessions are intru-

ple, may have little awareness of memory loss,

sive, recurring thoughts that disturb patients.

often denying any problems in thinking.

Similarly, compulsions are acts that patients

When the frontal lobes are damaged due to

feel compelled to perform over and over again.

trauma, tumor, stroke, or dementia, primitive

Lastly, phobias are irrational fears held by pa-

reflexes may resurface. For example, the pres-

tients. These abnormalities of thought content

ence of a palmar grasp reflex (reflexive grip-

can be uncovered by simply asking the patient

ping of a finger or object stroking the palm)

if he or she has “any special powers,” or any

may signify a lesion of the contralateral frontal

strong beliefs or practices that others do not

lobe. An abnormal glabellar reflex (persistent

share. Paranoid delusions can be specifically

blinking in response to tapping of the fore-

detected by asking patients if “anyone is after

head) can be noted in the setting of frontal lobe

them” or if “anyone is out to get them.”

injury, although it may also be present in

Abnormalities of thought form consist of

parkinsonian disorders. Other frontal release

disordered thinking such as “thought block-

signs include the palmomental reflex (a twitch

ing,” “loosening of associations,” and “flight

of the corner of the mouth when the ipsilateral

of ideas.” Thought blocking is evident when

palm is stroked), rooting (turning toward the

patients are unable to complete their thoughts

cheek when stroked), and the snout reflex

while speaking. Loosening of associations is

(pursing of the lips when the lips are tapped

seen when patients jump from one subject to

lightly). The presence or absence of frontal re-

another with little connection. Similarly, flight

lease signs does not, however, correlate well

of ideas is manifested by patients speaking at a

with degree of dementia.

rapid pace, on any number of subjects, without

easily identifiable connections. Detecting ab-

normalities of thought form involves noting

Perceptual Disturbances

the manner in which patients volunteer infor-

Patients who are psychotic or delirious often

mation or respond to questions. Responses

report bizarre sensory experiences such as hal-

that are clear and concise are easily distinguish-

lucinations and illusions. Hallucinations are

able from answers that are difficult to follow.

perceptions in the absence of stimuli. These can

be elicited by asking the patient if he or she has

Mini-Mental Status Examination (MMSE)

seen

(or heard) things that

“weren’t really

there” or “that others couldn’t see (or hear).”

The MMSE is a commonly used screen for ab-

Illusions are misperceptions, whereby the

normalities of cognition. The MMSE is a 30-

Chapter 1

■ The Neurologic Examination

point instrument that assesses orientation, lan-

■ SPECIAL CLINICAL POINT: The MMSE

guage, recall, concentration, and some visu-

should not serve as a substitute for the full

ospatial skills. Ten points are awarded for

mental status evaluation, but it may be helpful

as a screening tool.

varying degrees of orientation in time and

space. Three points are given for registration

Other brief neuropsychological batteries have

(correctly repeating the names of three ob-

been developed which may be useful in the

jects). Five points are given for concentration,

clinical setting, such as the Montreal Cognitive

which is tested by having the patient spell

Assessment (MoCA), which includes measures

“WORLD” backward or sequentially subtract-

of frontal lobe/executive functioning in addi-

ing 7 from 100 five times (e.g., 100, 93, 86, 79,

tion to tests of memory, language, and visu-

72, 65). Three points are given for correctly

ospatial processing.

naming two objects and repeating the phrase

“No ifs, ands, or buts.” Three points are given

for following a three-step command. Three

CRANIAL NERVES

points are given for reading and enacting the

sentence “close your eyes,” writing a sentence,

There are 12 pairs of cranial nerves, each serv-

and copying a figure composed of two inter-

ing a specific function as illustrated in

locking pentagons. Finally, three points are

Table 1.2. A superficial examination of the cra-

given for recalling the three objects mentioned

nial nerves should be incorporated into any

for testing registration.

neurologic examination and can be completed

TABLE 1.2

Cranial Nerves and Their Functions

Cranial Nerve

Name of the Cranial Nerve

Function

Olfactory

Smell

Optic

Vision

III

Oculomotor

Elevation, depression, and adduction of the eye;

pupillary constriction

Trochlear

Depression of the adducted eye; intorsion of the

abducted eye

Trigeminal

Sensation of the face and motor control of the muscles of

mastication

Abducens

Abduction of the eye

VII

Facial

Muscles of facial expression, taste to the anterior two

thirds of the tongue

VIII

Vestibulocochlear

Hearing and balance

Glossopharyngeal

Taste of posterior one third of the tongue, sensation for

gag reflex

Vagus

Gag reflex motor to soft palate, pharynx, larynx;

autonomic fibers to esophagus, stomach, small intestine,

heart, trachea; sensation from ear; viscera

Spinal accessory

Motor control of the sternocleidomastoid and

trapezius muscles

XII

Hypoglossal

Motor control of the tongue

Chapter 1

■ The Neurologic Examination

in just a few minutes. Abnormalities found on

The pupillary light reflex is checked by hav-

the cursory examination may necessitate a

ing the patient look into the distance while

more detailed study of that area.

swinging a bright light from one eye to the

other. Normally, both pupils react equally to

■ SPECIAL CLINICAL POINT: A systematic

light shone in either eye (the “consensual re-

examination of the cranial nerves provides “top

sponse”). A lesion of one optic nerve may result

to bottom” information about the integrity of

in a weaker pupillary response from one eye

the brainstem. Remember the “4-4-4” rule: The

first four cranial nerves involve the “higher”

when compared to the other. When severe, such

subcortical structures or midbrain. The second

a relative afferent pupillary defect results in a

four cranial nerves generally localize to the

paradoxical dilation of the pupils when light is

pons. The final four cranial nerves originate

swung from the “good eye” to the “bad eye.”

from the medulla or upper cervical cord.

Visual fields can be easily tested in the office

or at the bedside by confrontation. The patient

should be asked to fixate on the examiner’s

CN I. The Olfactory Nerve

nose while covering one eye. The examiner

The olfactory nerve (cranial nerve I) is respon-

should hold up one, two, or five fingers in each

sible for the sense of smell. CN I is not tested

of the four quadrants of the visual field and ask

routinely during the screening neurologic ex-

the patient to count the fingers. One or multi-

amination, but should be assessed when pa-

ple trials can be conducted, depending on the

tients complain of loss of smell. Olfaction is

accuracy of the patient. The other eye should

assessed by having the patient identify a fra-

be tested in the same manner.

grant substance such as coffee or cloves. A

A visual field defect present only in one eye

small vial of the aromatic substance is held

suggests a lesion within that eye or of the optic

under one nostril, while the other nostril is oc-

nerve. Visual field defects present in both eyes

cluded. The patient is asked to breathe through

may suggest a lesion farther back along the vi-

the unobstructed nostril and identify the scent.

sual pathway. A bitemporal hemianopia (affect-

The exercise is repeated on the other side with

ing the temporal fields of both eyes) implies a

a different aromatic substance. Noxious sub-

lesion of the optic chiasm. Quadrantanopias,

stances such as ammonia or “smelling salts”

lesions of the same quadrant of both eyes

should be avoided because of the concomitant

(upper right, upper left, lower right, or lower

stimulation of cranial nerve V, the trigeminal

left), suggest a lesion of the optic radiations. A

nerve. Although reduced olfaction may be due

homonymous hemianopia, a field cut involving

to advanced age, pathologic states such as head

the same side of both eyes (meaning the tempo-

trauma, tumors affecting the base of the skull,

ral field of one eye and the nasal field of the

and certain inflammatory disorders such as sar-

other eye), suggests a lesion of the contralateral

coid should also be considered.

optic tract or occipital cortex. With experience,

additional visual field defects such as central sco-

tomas, macular sparing, or incongruous hemi-

CN II. The Optic Nerve

anopias can be detected as well (see Chapter 26,

The optic nerve (cranial nerve II) is responsible

Eye Signs in Neurologic Diagnosis).

for vision. Evaluation of the optic nerve in-

For many examiners, the funduscopic exam-

cludes examination of visual acuity, visual

ination is the most challenging aspect of the

fields, the pupillary light reflex, and fundus-

neurologic examination. Proficiency with oph-

copy. Visual acuity is typically tested using a

thalmoscopy requires careful instruction and

wall chart or handheld “near-card.” Each eye

practice. Items that can be evaluated with a di-

should be tested separately with contact lenses

rect handheld ophthalmoscope include the optic

or glasses in place (if needed).

disc, the retinal vessels that emanate from the

Chapter 1

■ The Neurologic Examination

disc, the macula, and the peripapillary retina.

be associated with eye movement abnormali-

The optic disc lies slightly nasal to midline and is

ties. Nystagmus may be noted during the eye

best visualized by approaching the patient

movement examination, which can suggest

slightly from the side with the same eye (i.e., use

vestibular or cerebellar dysfunction.

the right eye to look in a patient’s right eye, and

The third nerve also controls elevation of

the left eye to look in a patient’s left eye). Nor-

the upper eyelid (via the levator palpebrae su-

mally, the optic disc has a sharp border, but in

perioris) muscle and pupillary constriction via

the setting of papilledema or optic neuritis, the

parasympathetic fibers to the pupilloconstric-

margins appear blurred. Optic atrophy due to

tor and ciliary muscles. A complete lesion of

optic nerve damage results in a pale disc. Arter-

the cranial nerve III will result in ptosis and an

ies and veins generally run together, with veins

eye that is abducted and depressed (“down and

appearing thicker than arteries. The forklike

out”), with a dilated pupil (mydriasis). A lesion

branching of retinal arteries and veins “point

of cranial nerve VI will result in esotropia

to” the disc. A number of medical conditions,

(“crossed eyes”) and an inability to abduct the

such as diabetes and hypertension, produce

affected eye. A lesion of cranial nerve IV may

characteristic findings on the funduscopic ex-

result in the patient having a head tilt and head

amination. The macula can be visualized by ask-

turn away from the affected eye (see Chapter 26,

ing the patient to “look directly at the light.”

Eye Signs in Neurologic Diagnosis).

CN III. Oculomotor Nerve,

CN V. The Trigeminal Nerve

CN IV. Trochlear Nerve, and

The trigeminal nerve is responsible for sensory

CN VI. Abducens Nerve

information from the skin of the face and ante-

The oculomotor nerve

(cranial nerve III),

rior scalp, providing motor innervation to the

trochlear nerve (cranial nerve IV), and abducens

muscles of mastication (masseter, temporalis,

nerve (cranial nerve VI) control eye movements.

and pterygoid), and mediating the jaw jerk re-

The oculomotor nerve (CN III) supplies the su-

flex. The trigeminal nerve is divided into three

perior, inferior, and medial rectus muscles as

branches, V₁ (ophthalmic branch), V₂ (maxil-

well as the inferior oblique muscle. These mus-

lary branch), and V₃ (mandibular branch) (Fig.

cles elevate, depress, and adduct the eye. The

1.1). V₁ innervates the forehead and anterior

trochlear nerve supplies the superior oblique

scalp down to the lateral corner of the eye; V₂

muscle. Contraction of this muscle results in de-

innervates the cheek down to the corner of the

pression of the adducted eye and intorsion of

mouth; and V₃ innervates the jaw including the

the abducted eye. The abducens nerve supplies

underside of the chin, but excluding the angle

the lateral rectus muscle. Contraction of this

of the jaw.

muscle results in abduction of the eye.

The sensory function of the trigeminal nerve

These three cranial nerves are assessed to-

can be tested using a safety pin for pain sensa-

gether during testing of eye movements. The

tion, a cool tuning fork for temperature sensa-

patient should follow the examiner’s finger or

tion, and a fingertip or cotton swab for light

pen vertically and horizontally into the cardi-

touch. The corneal reflex also can be used to

nal directions of gaze

(up, down, left, and

evaluate CN V, particularly in an unresponsive

right). Normally, the eyes should move to-

patient. To test the corneal reflex, the examiner

gether (conjugate gaze). A monocular limita-

touches a wisp of cotton to the cornea over the

tion of abduction may suggest a sixth palsy. A

iris, avoiding the pupil or central visual axis.

monocular limitation in vertical gaze could be

Jaw strength can be tested by asking the pa-

consistent with a third or fourth nerve palsy.

tient to forcibly clench his or her teeth against

Myasthenia gravis and thyroid eye disease can

the resistance of the examiner or by forcibly

Chapter 1

■ The Neurologic Examination

FIGURE 1.1 Distribution of the three divisions of the trigeminal nerve. The sensory portion of the

trigeminal nerve has three divisions: I, ophthalmic; II, maxillary; III, mandibular. Their approximate

locations are illustrated. (From members of the Department of Neurology, Mayo Clinic, and Mayo

Foundation for Medical Education and Research. Clinical Examinations in Neurology. 6th ed. St. Louis:

Mosby Year Book; 1991:270, with permission.)

opening the jaw against resistance. The jaw jerk

sagging cheek (flattened nasolabial fold), or

reflex is mediated solely by the trigeminal nerve

sagging lower eyelid (widened palpebral fis-

and is elicited by placing one’s index finger

sure) are all indicators of facial weakness. Pe-

across the relaxed jaw of the patient and tap-

ripheral lesions of the facial nerve produce

ping that finger with a reflex hammer. A normal

eyelid retraction and not ptosis, so that the eye

response is a brisk but slight contraction of the

on the affected side appears “larger” than the

muscles of mastication causing partial jaw clo-

normal eye. Facial weakness can occur on

sure. An exaggerated response may be a sign of

the basis of disturbances in the central or pe-

cerebral pathology (an upper motor neuron sign

ripheral nervous systems. Involvement of the

originating above the foramen magnum), but an

frontalis muscles (responsible for wrinkling the

absent response has little clinical significance.

forehead) can reliably distinguish between these

two possibilities. The forehead is spared with

central lesions such as strokes but is affected by

CN VII. The Facial Nerve

peripheral lesions as in Bell palsy.

The facial nerve provides innervation to the

The sense of taste may be affected by a pe-

muscles of facial expression and also supplies

ripheral disturbance if the lesion is proximal

taste to the anterior two thirds of the tongue via

to the chorda tympani. To test the sense of

the chorda tympani. Integrity of the facial nerve

taste, the patient is asked to protrude his or

can be assessed by having the patient perform

her tongue and identify sweet or sour sub-

various maneuvers such as forcibly closing his

stances, although this is not commonly tested

or her eyes, smiling, puffing air into the cheeks,

as a part of a routine neurologic examination.

and wrinkling the forehead muscles. Weakness

is indicated by an inability to “bury” the eye-

CN VIII. The Vestibulocochlear Nerve

lashes, an asymmetric smile, inability to hold

air fully in the cheeks, and reduced forehead

The vestibulocochlear, or acoustic, nerve (cra-

wrinkling. Facial weakness also can be assessed

nial nerve VIII) is a compound nerve composed

by simple observation. A downturned mouth,

of the cochlear nerve, responsible for hearing,

Chapter 1

■ The Neurologic Examination

and the vestibular nerve, involved in balance.

a gag response is elicited by stimulation of ei-

Although a number of techniques can be used

ther side. A unilateral cranial nerve lesion may

to assess hearing, a simple screen consists of

suppress the gag reflex on one side. A wide

gently rubbing one’s fingers together near the

range of variability exists for the normal gag

patient’s ear to check for gross hearing defects.

reflex. Some patients will start to gag as soon

Additional methods to test function of cra-

as they see the tongue blade, while others will

nial nerve VIII include the Rinne and Weber

have no gag reflex. In the appropriate clinical

tests. In the Rinne test, the base of a vibrating

setting (e.g., the patient with swallowing diffi-

tuning fork (256 Hz) is held against the mastoid

culties), an apparently abnormal gag reflex

bone. When the sound disappears, the head of

may assume greater significance. Oftentimes

the tuning fork then is placed beside the pa-

clinicians forgo formal testing of the gag re-

tient’s ear. Normally, air conduction is greater

flex, assessing simply the motor aspect by hav-

than bone conduction. If bone conduction is

ing the patient say “aah.”

greater than air conduction, a blockage of the

Normally, the soft palate and uvula elevate

external ear or a defect within the middle ear

symmetrically with stimulation of the soft

should be suspected. In the Weber test, a vibrat-

palate or when a subject says “aah.” With a

ing tuning fork is pressed firmly against the mid-

unilateral lesion of the vagus nerve, the uvula

dle of the patient’s forehead. Normally, sound is

and palate deviate away from the lesion. With

perceived equally in both ears and the sound of

bilateral lesions, no movement may be seen.

the vibration is appreciated as being in the mid-

line. With conductive hearing loss, the sound

CN XI. Spinal Accessory Nerve

lateralizes to the abnormal ear. In contrast, with

sensorineural hearing loss, the sound lateralizes

The accessory nerve innervates the trapezius

to the opposite ear with the intact nerve.

and sternocleidomastoid muscles. It arises

Dysfunction of the vestibular component of

from the upper five cervical segments of the

the acoustic nerve is suggested by complaints

spinal cord, ascends through the foramen mag-

of vertigo and a unidirectional jerk nystagmus

num, and exits through the jugular foramen.

on examination of eye movements. Advanced

The accessory nerve is tested by having the pa-

testing of vestibular function might include the

tient shrug his or her shoulders or turn his or

head thrust maneuver and testing of dynamic

her head against resistance

(the examiner’s

visual acuity.

hand pressed against the subject’s jaw). A uni-

lateral lesion causes weakness of shoulder

shrugging on the same side or impaired head

CN IX. Glossopharyngeal Nerve

turning toward the opposite side.

and CN X. Vagus Nerve

The glossopharyngeal nerve is responsible for

CN XII. Hypoglossal Nerve

providing sensation to the pharynx and taste to

the posterior tongue. The vagus nerve performs

The hypoglossal nerve (cranial nerve XII) pro-

a number of functions within the body, includ-

vides motor innervation to the tongue. Testing

ing supplying parasympathetic innervation to

of CN XII includes examination of the bulk of

the heart and gut and contributing to the nor-

the tongue, the ability of the patient to pro-

mal motor function of the oropharynx.

trude the tongue in the midline, and the ability

Cranial nerve IX mediates the sensory limb

of the patient to rapidly move the tongue from

of the gag reflex, and cranial nerve X mediates

side to side. Normally, the tongue should ap-

its motor limb. Typically, a gag reflex is

pear symmetrical and the patient should be

elicited by gently stimulating the soft palate

able to protrude the tongue straight ahead and

with a cotton swab or tongue blade. Normally,

move the tongue rapidly from side to side.

Chapter 1

■ The Neurologic Examination

With unilateral lesions of CN XII, the tongue

motor neuron signs (decreased tone, muscle

may appear atrophied with evident fascicula-

atrophy and fasciculations, depressed reflexes)

signify pathology of the peripheral nervous

tions (muscle twitches) on one side. Further-

system (nerve roots or peripheral nerves). A

more, on protrusion, the tongue will deviate

mix of upper and lower motor neuron signs

toward the weak side.

may be seen in motor neuron disease (e.g.,

amyotrophic lateral sclerosis) or in spinal cord

lesions that involve the anterior horn.

MOTOR EXAMINATION

Muscle power or strength refers to the force

The motor examination consists of assessment

that muscles are able to generate. The exam-

of muscle bulk, tone, strength, and dexterity,

iner assesses muscle strength through manual

with notation of any abnormal movements.

muscle testing. Proper technique dictates that

Muscle bulk simply refers to the normal size

the examiner “isolate” the muscle being tested,

and contour of the muscle and is assessed by

using two hands to “stabilize” the limb proxi-

simple inspection. Muscle wasting or atrophy

mal to the joint of interest and apply force to

is a “lower motor neuron sign” seen in disor-

the limb distal to that joint. One should avoid

ders of the peripheral nervous system such as

testing across multiple joints to guard against

radiculopathies and neuropathies; muscle hy-

involving unwanted muscles. Sufficient force

pertrophy is rarely seen, but may be noted in

must be applied to detect even mild weakness,

specific disorders

(e.g., calf hypertrophy in

yet not hurt the patient. Muscles that are com-

Duchenne muscular dystrophy).

monly tested in the upper extremities include

Muscle tone is defined as the resistance to

the deltoids, biceps, triceps, wrist extensors

passive movement. In the arm, one assesses

and flexors, and finger flexors and extensors.

muscle tone by supporting the patient’s re-

In the lower extremities, the hip flexors, knee

laxed upper arm, grasping the patient’s fin-

flexors and extensors, and ankle dorsiflexors

gers, and then quickly flexing, extending,

and plantarflexors are commonly tested.

pronating, and supinating the arm at the

Muscle strength is graded on a scale from 0

elbow. Normal tone is negligible, but in-

to 5: 0 = absence of movement; 1 = a flicker of

creased tone can be appreciated as marked re-

movement; 2 = movement in the horizontal

sistance to movement. The increased tone may

plane, removing the effect of gravity; 3 = move-

have a “ratchety” quality that is intermittent

ment against gravity; 4 = movement against

(i.e., “cogwheel” rigidity of Parkinson disease),

some resistance; and

5 = normal strength

a give-way quality reminiscent of one opening a

(Table 1.3). Various patterns of weakness help

pocket or “clasp knife” (i.e., spasticity seen in

one determine the origin of the disturbance.

upper motor neuron lesions), or a more diffuse,

persistent quality (i.e., “lead-pipe” rigidity seen

with disorders of the basal ganglia). In the leg,

TABLE 1.3

one assesses tone with the patient supine and

Medical Research Council (MRC)

relaxed. The examiner grasps the patient’s knee

Grading of Muscle Strength

with two hands and quickly lifts the knee into

the air noting whether the patients heel drags

0/5

No movement

along the bed (normal) or comes off the bed (in-

1/5

Flicker of movement

dicative of increased tone).

2/5

Moves with gravity removed but not

against gravity

■ SPECIAL CLINICAL POINT: Upper motor

3/5

Moves against gravity

neuron signs (increased tone, brisk reflexes,

4/5

Movement against resistance

Babinski sign) signify pathology of the central

5/5

Normal strength

nervous system (brain or spinal cord). Lower

Chapter 1

■ The Neurologic Examination

Weakness of muscle groups on one side of the

The afferent limb of each reflex is composed of

body would suggest a cerebral disturbance.

sensory nerves that transmit information from

Weakness of the proximal muscles suggests a

the muscle spindles to the anterior horn cells

myopathy, while weakness of distal muscles

within the spinal cord. The efferent limb is

suggests a neuropathic process (see Chapter 17,

composed of motor nerves running from the

Neuromuscular Disorders).

spinal cord back to the original muscle. Al-

Testing for a pronator drift is an easy method

though a number of DTRs have been de-

to detect subtle arm weakness. The patient holds

scribed, only a few are routinely tested in the

up both arms, extended at the elbows, with the

neurologic examination. These reflexes are the

palms facing upward. When the patient closes

biceps, brachioradialis, and triceps reflexes in

his or her eyes, both arms should stay in place,

the upper extremities and the patellar (knee

next to each other. In the case of subtle arm

jerks) and Achilles reflexes (ankle jerks) in the

weakness, however, the weaker arm will begin

lower extremities.

to pronate and drop toward the ground. A

■ SPECIAL CLINICAL POINT: The segmental

pronator drift is an extremely sensitive test, es-

representation of the commonly tested deep

pecially for subtle weakness of central origin.

tendon reflexes can be remembering the “1-to-

To test the speed and dexterity of movement,

8” rule: The Achilles tendon reflex or “ankle

patients are asked to open and close their hands

jerk” is mediated by fibers from the S1 and S2

rapidly, to tap their index finger and thumb to-

nerve roots. The patellar reflex or “knee jerk”

gether, or to pat their feet on the floor. The ex-

is mediated by fibers from the L3 and L4 nerve

aminer is looking for the speed, amplitude, and

roots. The biceps reflex is mediated by the C5

regularity of these movements. Slowed move-

and C6 nerve roots. The triceps reflex is

mediated by the C7 and C8 nerve roots.

ments suggest a problem within the pyramidal

tracts or the extrapyamidal system.

The Achilles reflex (ankle jerk) is elicited by

Abnormal movements such as chorea and

striking the Achilles tendon just proximal to

tremor are observed while the patient is at rest

the heel and monitoring for subsequent plan-

and while his or her hands are outstretched.

tarflexion. The patellar reflex

(knee jerk) is

These abnormal movements will be discussed in

elicited by striking the patellar tendon just

chapter 13, Hyperkinetic Movement Disorders.

below the kneecap. The biceps reflex is elicited

by having the examiner strike his or her own

finger that is pressed against the patient’s bi-

DEEP TENDON REFLEXES (DTRs)

ceps tendon within the antecubital fossa. The

The DTRs, or muscle stretch reflexes, are

triceps reflex is elicited by striking the triceps

monosynaptic reflexes responsible for prevent-

tendon within the olecranon fossa, just above

ing overstretching of the muscles and hyperex-

the elbow.

tension of the corresponding joints (Table 1.4).

DTRs may be graded numerically (Table 1.5).

Absent reflexes are graded as 0, reduced reflexes

TABLE 1.4

Segmental Innervation of the Various

TABLE 1.5

Deep Tendon Reflexes

Deep Tendon Reflex Grading

S1, S2

Achilles reflex

1+ Reduced

(L2) L3, L4

Patellar reflex

2+ Normal

C5, C6

Biceps reflex

3+ Increased

(C6) C7, C8

Triceps reflex

4+ Pathologically increased, clonus

Chapter 1

■ The Neurologic Examination

as 1+, normal reflexes as 2+, and brisk reflexes

toe with downward curling of the toes. In the

as 3+. When clonus is elicited (rhythmic, oscil-

setting of a central or upper motor neuron dis-

latory movements of the joint), a grade of 4+ is

order, Babinski sign may be noted, in which the

given. Unfortunately, the determination of

great toe extends and the toes fan outward.

“normal” versus “reduced” versus “brisk” is

subjective. To increase reliability, some authors

SENSORY TESTING

promote the convention of using

3+ when

“spread” is seen, whereby the testing of one re-

The sensory examination is the most subjec-

flex elicits responses in multiple reflex arcs

tive portion of the neurologic examination, re-

(e.g., striking the biceps tendon elicits a triceps

lying heavily on accurate reporting by the

reflex). Similarly, the grade of 1+ could be re-

patient. If the patient is confused, demented,

served for instances in which “augmentation”

aphasic or delirious, the responses may be in-

is necessary (e.g., the patient is asked to “bite

valid and this portion of the examination may

down” while the reflex is being elicited to re-

need to be omitted.

duce the threshold for the response).

The primary sensory modalities consist of

Hyperactive reflexes are considered an

light touch, pain and temperature sensation, vi-

“upper motor neuron sign” seen in central

bratory sensation, and proprioception. More

nervous system disturbances of the brain or

complex cortical sensory processing includes

spinal cord. Examples of such disorders in-

stereognosis, graphesthesia, and appreciation

clude strokes, brain tumors, or spinal cord in-

of double simultaneous simulation.

juries. Somewhat brisk reflexes, however, can

The primary sensory modalities are carried on

be seen in otherwise healthy young people. Re-

two separate sets of nerve fibers. In the periph-

duced reflexes are seen in disorders of the pe-

eral nervous system, vibratory sensation and

ripheral nervous system and are considered a

proprioception are carried by

“large-fiber”

“lower motor neuron sign.” Asymmetric de-

nerves, while pain and temperature sensation are

crease or loss of a particular reflex may be seen

carried by “small-fiber” nerves. This dichotomy

with focal lesions such as radiculopathies, plex-

is preserved within the spinal cord where vibra-

opathies, or mononeuropathies. For example, a

tion and proprioception are conveyed by un-

lesion of the sixth cervical root may lead to ipsi-

crossed fibers in the dorsal columns, while pain

lateral loss of the biceps and brachioradialis re-

and temperature sensation are carried by crossed

flexes, while a femoral neuropathy may result in

spinothalamic tracts. The two pathways eventu-

loss of the knee reflex. Symmetrical loss of re-

ally converge at the thalamus, which then sends

flexes implies a more generalized process. For

projections to the primary sensory cortex within

example, bilaterally decreased or absent DTRs

the parietal lobe. In diabetes and other small-

in the legs suggest a peripheral neuropathy, and

fiber neuropathies, pain and temperature sensa-

generalize areflexia is often seen with Guillain-

tion may be more diminished than vibration and

Barré syndrome (see Chapter 18, Peripheral

proprioception. In large-fiber neuropathies or

Neurologic Disorders).

dorsal column disease, as in vitamin B₁₂ defi-

Assessment of the plantar response is in-

ciency, the opposite pattern of sensory loss is

cluded under reflex testing. The plantar re-

seen with vibration sensation and propriocep-

sponse is obtained most commonly by stroking

tion being disproportionately affected.

the lateral sole of the foot, starting at the heel,

Cortical sensory modalities are the products

and then coming across the ball of the foot.

of the integrated primary sensory modalities.

This maneuver can be performed with a blunt

Cortical sensory loss can be evaluated only in the

but rigid object such as a key, a tongue depres-

presence of intact primary sensory modalities.

sor broken lengthwise, or even one’s finger. The

Disturbances in the cortical sensory modalities

normal plantar response is flexion of the great

imply a dysfunction within the parietal lobes.

Chapter 1

■ The Neurologic Examination

FIGURE 1.2 Peripheral distribution of sensory nerves with the dermatomes on the right and

cutaneous nerves on the left. (From House EL, Pansky B. A Functional Approach to Neuroanatomy. New

York: McGraw-Hill; 1960:286, with permission.)

The primary sensory modalities should be

the level of the peripheral nerve, plexus, or

evaluated in an organized fashion. Pain sensa-

nerve root (dermatomal) sensory loss (Fig. 1.2).

tion is most reliably assessed with a disposable,

Temperature sensation can be quickly tested

sharp implement such as a safety pin. A quick

using a cool tuning fork. As with assessment of

assessment of side-to-side and proximal versus

pain, side-to-side and proximal versus distal

distal comparisons usually suffices unless the

differences should suffice. To test propriocep-

patient specifically complains of a region of re-

tion, the examiner grasps the subject’s distal

duced sensation. If a particular area of de-

phalanx (tip of the great toe or index finger) on

creased sensation is identified, careful attention

the sides of the digit while stabilizing the prox-

to its boundaries may suggest a disturbance at

imal digit. The examiner moves the finger or

Chapter 1

■ The Neurologic Examination

toe upward or downward, asking the patient to

motor and sensory testing argues strongly for a

correctly identify the direction of movement

disorder in cerebellar function. The cerebellum

without looking. The examiner assesses the pa-

integrates proprioceptive information with in-

tient’s threshold for detection by initially mov-

formation from muscles to allow smooth limb

ing the digit slightly and then progressively

and truncal movements. Cerebellar dysfunc-

using larger movements until the patient can

tion often results in ataxia. A unilateral lesion

consistently answer correctly. For vibratory

within the cerebellum produces dysfunction on

testing, the examiner sets the base of a vibrat-

the same side of the body.

ing tuning fork against a bony portion of the

Tests of coordination include finger-to-nose

patient’s digit or more proximal joint.

and heel-to-shin testing, evaluation of rapid al-

Testing of cortical sensory functions (graph-

ternating movements, station, and gait. The

esthesia, stereoagnosia, and double simultane-

finger-to-nose and heel-to-shin tests assess for

ous stimulation) can reveal information about

limb (appendicular) ataxia as opposed to trun-

parietal lobe function, but only when the pri-

cal ataxia. In finger-to-nose testing, the patient

mary sensory modalities are intact. Graphesthe-

is asked to guide his or her finger back and

sia is the ability to recognize by touch a number

forth from the examiner’s finger to his or her

“written” on the skin. With the patient’s eyes

own nose with eyes open. The patient should

closed, the examiner traces numbers on the pa-

be forced to fully extend his or her arm to

tient’s palm using a finger or blunt object. Stere-

touch the examiner’s finger so that any tremor

ognosis is the ability to recognize objects by

at the extreme of arm extension can be seen.

touch alone. Various items such as safety pins,

Heel-to-shin testing is performed by having the

keys, coins, or pencils are placed in the patient’s

patient run the heel of one foot along the shin,

hand with the patient’s eyes closed. He is al-

from the knee to the ankle, of the other leg.

lowed to move the object around in his hand to

Rapid alternating movements can be tested

fully appreciate the size, shape, and texture. If

by asking the patient to pat the front and then

the hand is paretic, stereognosis still can be eval-

back of his or her hand into the palm of the

uated by moving the object around in the pa-

other hand or onto the thigh in a rapid, rhyth-

tient’s palm. Double simultaneous stimulation is

mic fashion. Because rhythmic movements re-

useful for detecting hemispatial neglect. The

quire an intact cerebellum, difficulty with this

examiner alternately touches body parts (e.g.,

task suggests ipsilateral cerebellar dysfunction.

hand, face, or leg) on one side at a time, then on

The inability to perform this specific task is

both sides simultaneously, asking the patient to

known as dysdiadochokinesia.

identify which side has been touched. Patients

Midline cerebellar dysfunction often pro-

with neglect may be able to appreciate sensation

duces ataxia of the trunk, resulting in difficulties

on both sides of the body when each side is

with standing or walking. To test stance, the pa-

tested separately, but will extinguish sensation

tient first is asked to arise from a chair. A patient

on one side of the body when both sides are

with hip weakness may require the use of his or

touched simultaneously.

her hands, while an ataxic patient may require

the assistance of another individual. Next, the

examiner assesses the patient’s stance, noting

the subject’s posture, stability, and foot position.

COORDINATION AND GAIT

Normally, the patient should stand erect with

Coordinated movements require the integrated

feet slightly separated. A patient with Parkinson

workings of a number of neurologic systems

disease may exhibit a stooped posture, while a

including the sensory pathways, vestibular sys-

patient with cerebellar disease may have a

tem, pyramidal tracts, and extrapyramidal

widened stance and marked truncal instability.

system, including the basal bangia and cere-

The examiner can further assess postural stabil-

bellum. Incoordination in the setting of intact

ity by gently pulling backward or forward on

Chapter 1

■ The Neurologic Examination

the patient’s shoulders, guarding against the

Optional tests include assessment of the pa-

possibility of a fall. Normally, the patient should

tient’s heel-walking, toe-walking, and tandem

be able to quickly regain their stance, requiring

gait. Heel-walking and toe-walking, as their

no more than one or two steps. Patients with

names imply, are performed by having patients

truncal instability, however, may need multiple

walk on their heels and toes, respectively, test-

steps to avoid falling or have no capacity to

ing the strength of foot dorsiflexion and plan-

catch themselves.

tarflexion. Tandem gait is assessed by having

Although often described as a test of bal-

patients walk “heel to toe” as if walking on a

ance, Romberg test is actually an assessment of

tightrope. Impairment of tandem gait may be

proprioception. Patients are asked to stand

seen with mild ataxia and leg weakness.

with their feet together, and then asked to close

their eyes. Patients may sway slightly, but they

THE NEUROLOGIC EXAMINATION

should not fall over or step to the side to catch

IN PEDIATRIC NEUROLOGY

their balance. Romberg test is positive when

the patients lose their balance with their eyes

Performing age-appropriate examinations of

closed, implying dysfunction of the dorsal

infants and children can be a daunting task,

columns or proprioceptive fibers. If a patient is

given the amazing developmental changes that

unable to maintain balance with the eyes open

occur in early childhood. Infants and young

(e.g., in the setting of vestibular dysfunction),

children require adaptations of the routine

then Romberg test cannot be performed.

adult neurologic examination including the use

of more functional tasks to assess performance.

■ SPECIAL CLINICAL POINT: If a patient

A good working knowledge of normal gross

cannot stand with feet together and eyes open,

motor, fine motor, and language development is

he or she may have cerebellar or vestibular

dysfunction. If a patient can stand with feet

essential. As with other pediatric disciplines,

together and eyes open but falls with eyes

the child’s parents can be enlisted to assist with

closed (a positive Romberg test), then the

examination. For small children and infants,

problem is likely proprioceptive.

much of the examination can be performed on

the parent’s lap to ensure the comfort and

Finally, the patient’s ambulation is analyzed for

safety of the child. Unpleasant tests such as the

speed, stride length, turning, and associated

testing of pain sensation (i.e., with a pin) should

movements, with particular attention being paid

be avoided unless there is a specific need.

to any asymmetry. Gait testing can be per-

formed in the examination room or the adjacent

■ SPECIAL CLINICAL POINT: The neurologic

examination of children must be tailored to a

hallway. Normally, the patient should exhibit a

child’s age, abilities, and temperament. In order

smooth stride with a narrow base and normal

to be most effective, one must establish rapport

sway of the arms. Patients with a cerebellar dis-

with the child, be creative in testing, and make

ease may have an ataxic gait with a wide-based

the examination fun!

wobbly, off-balance ambulation that looks

“drunk.” Patients with upper motor neuron dis-

Mental Status

ease may have gait spasticity, exhibiting stiffness

while walking reminiscent of “Frankenstein’s

The mental status examination often centers

monster.” Patients with weakness of one side

around the child’s behavior with respect to the

may have a hemiparetic gait, favoring one side,

parents and surroundings. Assessment of re-

or perhaps associated with hip hiking or circum-

ceptive and expressive language skills can yield

duction of the leg to overcome a unilateral foot

insight into the child’s cognitive abilities even

drop. A patient with early Parkinson disease or

in infancy. Knowledge of normal developmen-

mild unilateral arm weakness may have a de-

tal milestones allows the examiner to relate a

creased arm swing on one side with ambulation.

child’s abilities to the normal population.

Chapter 1

■ The Neurologic Examination

Cranial Nerves

Deep Tendon Reflexes

Most cranial nerves can be tested easily with

Testing of DTRs in children requires no special

creative techniques in children. Visual acuity

accommodations other than gentleness, with

can be assessed roughly by holding colorful or

the major exception being that the ankle jerks

bright objects of varying sizes within an in-

are better elicited in infants by grasping the in-

fant’s field of vision. For example, one can

fant’s foot and gently tapping on the bottom of

offer a toddler a small wad of paper within

that foot. Along similar lines, the Babinski re-

one’s hand. The examiner can test visual fields

flex can be elicited with one’s finger in younger

and eye movements by holding attractive ob-

children and infants. Remember that an exten-

jects in the periphery of the child’s vision and

sor plantar response (an upgoing toe) is normal

then having the child follow those objects with

in infants up to 1 year of age.

his or her eyes. Visual threat also can be used

to test visual fields in infants older than

Sensory

months of age, but this technique may be con-

sidered too threatening if not performed in a

Vibratory sensation can be tested reliably in

sufficiently playful manner. The funduscopic

older but not younger children. Proprioception

examination can be challenging but not impos-

is tested more reliably in children because the

sible. The pupillary light reflex can be tested in

outcomes are directly observable by the exam-

standard fashion in all age groups. The corneal

iner. Temperature sensation can be tested with

reflex can be tested in young infants but may

a cool tuning fork. Testing of pin sensation

be unacceptably irksome to older children. Al-

should be avoided because of the inherently

though not technically proper, a quick puff of

uncomfortable nature of the test.

air into the eye is better tolerated than a cotton

swab. The examiner can assess facial asymme-

Coordination

try by observing the child’s repertoire of facial

expressions. Observing how children respond

Age-appropriate testing of coordination is

to sounds made outside of their field of view

straightforward. Infants older than a few

can be used to assess hearing. As with the

months can reach for colorful objects. Toddlers

corneal reflex, testing of the gag reflex is well

can be assessed for their ability to walk and

tolerated only by very young infants and older

reach for things. Older children can be asked to

children. On the other hand, most children rel-

run, jump, and hop or stand on one leg.

ish the opportunity to protrude their tongues at

an adult.

Motor

Always Remember

Assessment of muscle bulk in children is no dif-

• General principles of organization (e.g.,

ferent than in adults except that young infants

peripheral vs. central, motor vs. sensory, and

may have more superficial adipose tissue. Tone

proximal vs. distal) allow lesion localization

can be assessed easily in older children if they

that aids in the differential diagnosis of

are at ease or distracted. Assessment of power

neurologic disorders.

in infants usually is restricted to opposing their

• A focused neurologic examination should be

volitional movements. In young children, one

guided by clinical judgment.

must rely on functional assessment of strength,

• The neurologic examination should be a

observing the child perform playful tasks.

helpful tool, not a painful burden to be

Older children, however, are usually very coop-

avoided by nonneurologists.

erative in testing “how strong they are.”

Chapter 1

■ The Neurologic Examination

Guillain-Barré syndrome is an acute or sub-

QUESTIONS AND DISCUSSION

acute process characterized by hyporeflexia or

areflexia. Ptosis is not a recognized feature.

1. A 62-year-old man complains of a 3-week

Sensory complaints are usually present.

history of generalized weakness, difficulty

chewing and swallowing, and a change in

2. A 55-year-old woman has noticed gradual

the quality of speech. Further questioning

loss of dexterity of her left hand and

reveals that he has been suffering from

increasing difficulty with ambulation.

intermittent diplopia and drooping of one

Examination discloses an atrophied left hand

eyelid for the past year. The examination

and bilateral lower-extremity spasticity. The

reveals ptosis of the left eyelid, impaired

left lower extremity is weaker than the right,

abduction of the left eye, weakness of jaw

whereas pinprick is better perceived on that

opening, and nasal speech. The gag reflex

same side. The decrease in sensation to

is present, but the soft palate elevates

pinprick on the right side extends to the

poorly. Weakness is generalized, affecting

upper trunk. There are no cranial nerve

both proximal and distal muscles. There

findings, and cognitive function is intact. The

are no cognitive findings (including no

likely site of the lesion is:

emotional lability) and no sensory

A. An asymmetrical neuropathy affecting

findings. Reflexes are normal and

the left median nerve and both sciatic

symmetrical, plantar responses are flexor,

nerves

and tone is normal. The likely site of the

B. A compressive lesion of the cervical cord

lesion is:

C. Generalized motor neuron disease

A. Both cerebral hemispheres

(amyotrophic lateral sclerosis)

B. The neuromuscular junction

D. A lesion of the right cerebral hemisphere

C. The brainstem affecting cranial nerves

III, V, VI, IX, and X

The correct answer is B. This patient harbors

D. The peripheral nerves in a diffuse

a clinical picture consistent with Brown-Se-

fashion as seen in Guillain-Barré

quard syndrome, most likely due to cord

syndrome

compression. Originally seen with traumatic

hemisection of the spinal cord, Brown-Se-

The correct answer is B. Myasthenia gravis is

quard syndrome is characterized by weak-

the most commonly seen disease of the neuro-

ness and dorsal column dysfunction

muscular junction. Myasthenia gravis can pro-

ipsilateral to the lesion and spinothalamic

duce generalized weakness of the limbs as well

dysfunction contralateral to the lesion. Addi-

as weakness of the face, eyes, and neck. Upper

tionally, upper motor neuron signs are seen

motor neuron signs and sensory findings

ipsilaterally below the level of the lesion,

should be absent.

while lower motor neuron signs (e.g., atro-

Bilateral hemispheric disturbances should

phy) are seen at the level of the lesion. In

be associated with cognitive changes and even

this case, the precise location of the lesion is

a reduced level of consciousness. Additionally,

given by the hand wasting, suggesting in-

one should see bilateral upper motor neuron

volvement of the lower motor neurons at the

signs such as hyperreflexia, increased tone,

C8 or T1 root levels.

and extensor plantar responses, all of which

Polyneuropathy does not cause spasticity,

are lacking in this case.

which is an upper motor neuron sign. Motor

A brainstem event large enough to affect

neuron disease can present with a combina-

this many cranial nerves should be associated

tion of upper and lower motor neuron signs as

with upper motor neuron signs and sensory

is seen in this case, but sensory involvement

abnormalities.

should be absent.

Chapter 1

■ The Neurologic Examination

3. A 35-year-old woman complains of painful,

20/80 on the left, corrected by glasses,

burning feet and difficulty ambulating. On

and 20/15 in the right eye. The left pupil

physical examination, she has severe loss of

dilates when a light is swung from the

proprioception and vibratory sensation in

right eye to the left eye. The visual field of

the lower extremities (distal more than

the right eye is full. The patient has a

proximal), lower-extremity spasticity,

subtle central scotoma in the left eye.

hyperreflexia, and abnormal Babinski

Funduscopic examination is normal in

responses. The upper extremities show a

both eyes. There are no other findings on

similar sensory deficits but to a milder

neurologic examination. The likely site of

degree. Cranial nerves and cognition are

the lesion is:

intact. The likely site of the lesion is:

A. The optic chiasm as a result of

A. The dorsal columns and corticospinal

compression by a pituitary gland tumor

tracts at the level of the spinal cord

B. The right occipital lobe or right optic

B. The peripheral nerves, particularly the

radiations

large myelinated fibers that conduct

C. The anterior chamber of the eye from an

proprioceptive information

attack of acute glaucoma

C. The brainstem, affecting the

D. The left optic nerve

proprioceptive fibers (medial lemnisci)

The correct answer is D. The presentation is

and corticospinal tracts

typical of acute optic neuritis: a decrease of

D. Bilateral spinothalamic tracts within the

central vision in one eye, associated with an

spinal cord

afferent pupillary defect with minimal to no

The correct answer is A. The loss of proprio-

changes of the optic disc.

ception can be caused by a peripheral neu-

Although the patient’s amenorrhea war-

ropathy affecting large myelinated fibers or to

rants investigation, a lesion at the level of the

a disturbance of the dorsal columns in the

optic chiasm is commonly associated with bi-

spinal cord. The concurrent presence of upper

lateral visual field defects (e.g., a bitemporal

motor neuron signs (spasticity, hyperreflexia,

hemianopsia).

and Babinski responses) points to the spinal

A lesion of the right occipital lobe or the

cord as the site of pathology.

optic radiations would cause a loss of vision

A peripheral neuropathy could be associ-

in the nasal field of the right eye and the tem-

ated with selective loss of proprioception and

poral field of the left eye (i.e., a left homony-

vibratory sensation but not upper motor neu-

mous hemianopsia).

ron findings. The patient does not have evi-

Sudden loss of vision as a result of an acute

dence of cranial nerve involvement to suggest

attack of glaucoma would be associated with

a disturbance in the brainstem.

severe eye pain, redness, and possibly an unre-

active pupil. The patient’s positive family his-

4. A 25-year-old woman with myopia

tory for glaucoma proves to be a red herring

presents with a 3-day history of blurred

rather than a clue in this particular case.

vision and mild pain on eye movements in

the left eye. Past history reveals that she

has been experiencing amenorrhea for the

SUGGESTED READING

preceding 6 months. There is a very

strong family history of glaucoma. The

Adams RD, Victor M. Principles of Neurology. 5th ed.

extraocular movements are intact, and

New York: McGraw-Hill; 1993:5-9.

there is no ptosis. The eye examination

De Myer WE. Technique of the Neurological Examina-

discloses no overt abnormalities of the

tion: A Programmed Text. 4th ed. New York:

cornea, iris, or lens. Visual acuity is

McGraw-Hill; 1994.

An Approach

to Neurologic

Symptoms

STEVEN L. LEWIS

key points

• A careful neurologic history is the cornerstone of

neurologic diagnosis.

• The goal of the neurologic history, followed by the

examination and appropriate diagnostic studies, is to

determine, first, where in the nervous system the

dysfunction lies and, next, how that dysfunction occurred.

• Using neurologic terminology to describe the likely site

of neurologic dysfunction can be very helpful in

categorizing patients’ symptoms and signs.

• Even a very basic and simplified understanding of

neuroanatomy can be of great benefit in neurologic

diagnosis.

• Recognizing the temporal course of a patient’s

neurologic illness is critical in determining the likely

disease mechanism.

n neurologic diagnosis,

COMMON NEUROLOGIC TERMS

individual symptoms and constellations of

symptoms can be of telling diagnostic impor-

Before proceeding with a discussion of specific

tance both anatomically and etiologically.

neurologic symptoms, it is worthwhile to de-

Thus, a detailed neurologic history that puts

fine some terms that can be useful in character-

together various symptoms and their temporal

izing neurologic symptom complexes. These

development can help to define neurologic en-

words are used to indicate certain localizations

tities with significant precision; the role of the

of pathology (Table 2.1).

subsequent neurologic examination is to look

Encephalopathy means disease of the brain.

for evidence to support, or refute, the diagnos-

Although theoretically the term encephalopa-

tic hypothesis that was generated by analysis of

thy could refer to any process involving any

the careful neurologic history.

Chapter 2

n An Approach to Neurologic Symptoms

TABLE 2.1

These generic terms are very helpful to the

Common Terms Used to Describe

clinician in categorizing sites of pathology or

Localizations of Neurologic Dysfunction

dysfunction. A specific causative lesion, or

causative process, is not conveyed by any of

Term

Meaning

these terms. Unless there is a preceding adjec-

tive (e.g., compressive myelopathy or demyeli-

Encephalopathy

Disease of brain (usually refers

native polyneuropathy), a cause or mechanism

to diffuse brain dysfunction)

Myelopathy

Disease of spinal cord

is not implied. Likewise, substitution of the

Radiculopathy

Disease of nerve root

suffix -itis for -pathy (e.g., myositis instead of

Neuropathy

Disease of nerve

myopathy) implies, specifically, an inflamma-

Myopathy

Disease of muscle

tory process, rather than an as-yet-unknown

process affecting that region of the nervous

system.

part of the brain, it generally is used to mean

dysfunction that involves the entirety of both

cerebral hemispheres. Thus, the terms en-

AN APPROACH TO SPECIFIC

cephalopathy and diffuse encephalopathy are

NEUROLOGIC SYMPTOM COMPLEXES

synonymous. An example of a common type of

The essential elements of the neurologic diag-

encephalopathy is a metabolic encephalopathy,

nostic process are an accurate and detailed

such as that caused by hepatic, uremic, or other

history, followed by a neurologic examina-

metabolic dysfunction.

tion. Imaging and laboratory studies follow,

Myelopathy means disease of the spinal

as appropriate.

cord. A patient with any symptoms or signs

that are caused by spinal cord dysfunction has

n SPECIAL CLINICAL POINT: The goals of

a myelopathy. An example of a common type

neurologic diagnosis are to determine, first,

of myelopathy is a compressive myelopathy

where in the nervous system the problem lies,

caused by a tumor or other mass lesion com-

and, next, to determine how the dysfunction

pressing the spinal cord, causing weakness,

occurred.

sensory loss, and spasticity below the level of

This section discusses the “where” part of the

the compression.

neurologic formulation using the history and

Radiculopathy, disease of the nerve roots

examination to evaluate several specific symp-

(radix is Latin for root; a radish is a root veg-

tom complexes (mental status changes, weak-

etable), is the term used for any process in-

ness, sensory symptoms, and gait disorders).

volving single or multiple nerve roots in the

Using the temporal course of the evolution of

cervical, thoracic, or lumbar spine. For exam-

symptoms to help determine the mechanism of

ple, a herniated lumbar disc between the

dysfunction (the “what” part) will be discussed

fourth and fifth lumbar spine might cause an

later in this chapter.

L5 radiculopathy; Guillain-Barré syndrome

would cause a polyradiculopathy as a result of

dysfunction of multiple nerve roots.

MENTAL STATUS CHANGES

Neuropathy means disease of a nerve. The

term means dysfunction of one (mononeuro-

When confronted with a patient who has had a

pathy), several

(mononeuropathy multiplex),

mental status change, the clinician should try

or many/diffuse

(polyneuropathy) peripheral

to determine whether there is an alteration in

nerves. Dysfunction of a cranial nerve would be

the level of consciousness or an alteration of

called a cranial neuropathy. Myopathy refers to

the content of consciousness. Alterations in the

any disease of muscle.

level of consciousness manifest in the contin-

Chapter 2

n An Approach to Neurologic Symptoms

uum between drowsiness and coma. They re-

their deficit (anosagnosia) because of the non-

sult either from dysfunction of both cerebral

dominant hemisphere dysfunction.

hemispheres, dysfunction of the upper brain-

stem, or a combination of hemispheric and

WEAKNESS

upper brainstem dysfunction. The clinical ap-

proach to the patient who presents with an al-

“Weakness” as a patient complaint may have

teration in level of consciousness is discussed in

several possible meanings, besides the usually

more detail in Chapter 5.

presumed meaning of a decrease in motor func-

tion in one or several extremities. The clinician

n SPECIAL CLINICAL POINT: A major goal

should keep in mind that some patients might

of the neurologic examination of patients with

use the term “weakness” to describe general-

an alteration of the level of consciousness is

ized fatigue, malaise, or asthenia. Some pa-

determining whether there is evidence for focal

tients might even describe a symptom such as

brainstem dysfunction.

the generalized bradykinesia of parkinsonism

If brainstem function is intact, the cause of the

(Chapter 10) as weakness. As in all neurologic

problem is unlikely to be the result of a focal

diagnosis, an accurate history and examination

structural brainstem process; it is more likely

should help clarify what symptoms the patient

the result of a diffuse encephalopathic process.

is actually describing. Muscular fatigue, al-

The actual processes that may affect the level

though very nonspecific, suggests the possibil-

of consciousness are vast and are discussed in

ity of a disorder of the neuromuscular junction,

more detail in Chapter 5.

such as myasthenia gravis (see Chapter 19), or

Neurologic processes can affect the mental

a disease of muscle (myopathy), in addition to

status of patients, however, by affecting the

the many primarily nonneurologic processes

content of consciousness without necessarily

that can cause generalized malaise and fatigue.

altering the level of consciousness. Alterations

The following are definitions of some com-

in the content of consciousness are exempli-

mon terms used to describe decreases in motor

fied by psychiatric disorders or by neurologic

function. Paresis refers to muscular weakness

disorders that affect memory, language,

but not complete paralysis. Plegia is the term

awareness, or global intellectual functioning.

used to describe complete paralysis. Mono-

Patients with chronic dementing illnesses

paresis and monoplegia are terms sometimes

(Chapter 16) usually have normal alertness de-

used to describe weakness or paralysis in one

spite the deterioration in cognitive function-

extremity. Hemiparesis and hemiplegia refer to

ing. Patients with aphasia—particularly those

weakness or paralysis in the arm and leg on

with fluent aphasias—often appear to be con-

one side of the body. Paraparesis and paraple-

fused. More careful attention to the patient’s

gia describe weakness or paralysis in both legs,

speech pattern to determine the presence of

and quadriparesis and quadriplegia (sometimes

paraphasic errors and neologisms

(“new

alternatively called tetraplegia) denote weak-

words” without meaning) often will help the

ness or paralysis in all four extremities.

clinician determine that the “confused” patient

Muscular weakness can occur as a result of

is actually aphasic; the presence of aphasia is

dysfunction at any level of the central or periph-

usually a clue to focal dysfunction in the dom-

eral nervous system. To illustrate this, it is worth

inant (usually left) hemisphere. Patients with

considering the neuroanatomic pathway for

lesions affecting the right hemisphere also may

muscle movement. The pathway for muscle

appear to be “confused,” neglectful, and un-

movement begins in nerve cells that are located

aware, whereas they actually have neglect of

on the precentral gyrus of each frontal lobe (the

the left side of space and may be oblivious of

upper motor neurons). The axons from these

Chapter 2

n An Approach to Neurologic Symptoms

nerve cells comprise the corticospinal tract. The

weakness, include increased or pathologic re-

corticospinal tracts travel through the white

flexes, and increased tone and spasticity in

matter of each cerebral hemisphere, through the

chronic lesions. It also should be recognized

internal capsule, and further downward into the

that these classic findings of upper motor neu-

brainstem, where each corticospinal tract

ron dysfunction might not always be evident.

crosses in the low medulla to the opposite side.

Upper motor neuron syndromes can result

From the medulla, the corticospinal tracts travel

from lesions of the corticospinal tract at vari-

downward through each side of the spinal cord.

ous levels of the central nervous system. Fur-

Within the spinal cord, the corticospinal

ther clinical details help to specify whether the

tract on each side synapses with nerve cells in

lesion is cortical, subcortical, or in the spinal

the anterior horns located in the spinal cord

cord. When symptoms of transient motor dys-

gray matter (the lower motor neurons). Axons

function occur that have resolved by the time

from these second-order neurons become the

of the examination, however, no abnormalities

cervical, thoracic, and lumbosacral nerve

would be expected on examination, and the

roots. The cervical nerve roots then form the

site of the lesion must be inferred by the pa-

brachial plexus, and the nerves that are formed

tient’s description of the areas of transient

in the brachial plexus travel into the upper ex-

weakness and associated symptoms.

tremities and innervate the muscles of the

Hemispheric motor cortex lesions involv-

upper extremities. The lumbar nerve roots

ing the cortical motor neurons of the lateral

travel downward within the lumbar spinal

surface of one hemisphere usually cause upper

canal as the cauda equina, before exiting and

motor neuron weakness of the contralateral

forming the lumbosacral plexus and ultimately

face and arm, with less weakness of the leg. A

forming the nerves that innervate the lower-

lesion in this region, like all corticospinal tract

extremity musculature.

lesions, often will cause predominant weak-

ness in the extensors of the arm and flexors of

n SPECIAL CLINICAL POINT: A lesion at any

the leg, with relative preservation of strength

level of the upper and lower motor neuron

in arm flexors and leg extensors. As such, the

pathway, from the cerebral cortex to the

affected arm is held mildly flexed while walk-

muscles themselves, can cause weakness.

ing and the leg is overextended, causing it to

The location of this lesion causing weakness, or

drag stiffly, sometimes catching the toe.

a history of weakness, is not always immedi-

Hemispheric motor cortex lesions involving

ately obvious, even to an experienced clinician

the medial aspect of one frontal lobe will pre-

who has performed an accurate history and ex-

dominantly cause contralateral leg weakness.

amination. However, there are typical, or clas-

Weakness resulting from cortical lesions often

sic, patterns of muscle weakness that lesions at

is also accompanied by other signs of cortical

various levels of the pathway for motor function

dysfunction, giving a clue to the localization of

usually will produce. Recognition of these typi-

the problem. For example, left hemisphere cor-

cal patterns can be very helpful in attempting to

tical lesions often are accompanied by abnor-

decide on possible localizations of pathology in

malities of language function. Right hemisphere

patients who present with motor weakness.

cortical lesions often are accompanied by de-

nial of the left-sided weakness (anosagnosia)

or even unawareness of the presence of the left

Upper Motor Neuron Lesions

extremities (asomatagnosia). Any complex be-

Lesions that cause dysfunction of the corti-

havioral change of these types suggests that

cospinal tracts are called upper motor neuron

the upper motor neuron lesion is cortical. Cor-

lesions; their distinctive features, in addition to

tical lesions causing weakness are often also

Chapter 2

n An Approach to Neurologic Symptoms

accompanied by some contralateral sensory

An example would be a right peripheral facial

disturbance because of the proximity of the

palsy and left body weakness as a result of a

cortical sensory neurons to the motor cortex.

right pontine lesion. In addition, because both

Deep hemispheric or internal capsule lesions

the right and the left corticospinal tracts are

also will cause weakness of the contralateral

relatively close together in the brainstem, bilat-

body, but without accompanying signs of corti-

eral extremity weakness can be seen in brain-

cal dysfunction. Lesions affecting the corti-

stem disease.

cospinal tract fibers in the posterior limb of the

Lesions of the corticospinal tracts in the

internal capsule may produce a characteristic

spinal cord cause weakness below the level of

pure motor hemiparesis (or hemiplegia) involv-

the spinal cord lesion. Although it is possible

ing the contralateral face, arm, and leg. This is

to have unilateral weakness resulting from a

characterized by significant weakness of one

spinal cord lesion, many lesions affecting the

side of the body without sensory disturbance

spinal cord cause bilateral weakness because

or signs of cortical dysfunction such as apha-

of involvement of the corticospinal tracts on

sia. This distinctive form of isolated weakness

both sides of the cord. The level of the spinal

occurs because the corticospinal fibers from a

cord lesion causing the weakness is not always

large area of the motor cortex all lie close to-

immediately obvious to the examiner, how-

gether in the internal capsule, segregated from

ever. The corticospinal fibers destined for arm

the sensory fibers, and deep to the cortical

function end in the lower cervical/first tho-

structures. In contrast, a hemispheric lesion

racic portion of the spinal cord. The corti-

that would be large enough to cause significant

cospinal tract fibers for leg function need to

weakness of an entire side of the body most

pass through the cervical and thoracic por-

likely also would involve sensory signs or

tions of the spinal cord before ending in the

symptoms and signs of cortical dysfunction.

lumbosacral cord. Therefore, weakness of the

Brainstem lesions that involve the corti-

upper and lower extremities, when the result

cospinal tract on one side also will cause weak-

of a single lesion, must be due to a lesion at

ness of the contralateral side of the body. Some

least as high as the cervical spinal cord. How-

unilateral ventral pontine lesions—affecting

ever, weakness of the legs without weakness of

only the corticospinal tract but no other brain-

the arms is not necessarily the result of a lesion

stem pathways—may even produce an isolated

below the neck; a partial or early process af-

pure motor hemiparesis clinically indistin-

fecting the cervical spinal cord could poten-

guishable from an internal capsular lesion.

tially cause dysfunction primarily affecting

However, many brainstem processes producing

that portion of the corticospinal tract destined

weakness also produce brainstem signs or

for lower-extremity function, without obvi-

brainstem symptoms such as diplopia, vertigo,

ously affecting those fibers involved in upper-

nausea, and vomiting, or cranial nerve palsies,

extremity function. This has important

which are clues to the brainstem localization of

implications in the imaging of patients with

the process.

suspected spinal cord lesions.

n SPECIAL CLINICAL POINT: One of the

pillars of neurologic localization is that a

Lower Motor Neuron Lesions

brainstem lesion can cause weakness of the

Lower motor neuron dysfunction occurs when

contralateral body (as a result of involvement

there is dysfunction at the level of the anterior

of the corticospinal tract) and dysfunction of

horn cell, motor nerve root, plexus, peripheral

an ipsilateral cranial nerve (as a result of

involvement of a cranial nerve nucleus, or

nerve, or neuromuscular junction. Lesions of

the cranial nerve itself, before it exits the

the lower motor neuron may cause, in addition

brainstem).

to weakness, decreased reflexes in the involved

Chapter 2

n An Approach to Neurologic Symptoms

limb, if a clinically testable reflex is subserved

lar pain (see later), when present, are helpful

by the nerve in question. In chronic lesions,

diagnostic clues to the presence of a radicular or

lower motor neuron dysfunction may lead to

polyradicular localization.

atrophy and fasciculations of muscle because

Disease of muscle (myopathy) is suggested

of the trophic influence the lower motor neu-

when a patient presents with weakness that is

ron plays in muscle maintenance. In these

predominantly proximal in distribution. How-

cases, patients may complain that their muscles

ever, proximal weakness is not pathognomonic

are shrinking and have small, visible twitches.

for myopathy and also can be seen, for exam-

Lower motor neuron weakness may be the re-

ple, in some myelopathic and radiculopathic

sult of either a focal or diffuse process.

processes. It also should be noted that some

Clinical localization of the source of a pa-

myopathies cause unusual patterns of weak-

tient’s weakness to a particular focal lower

ness (e.g., inclusion body myositis) or even pre-

motor neuron lesion mainly rests in the find-

dominantly distal weakness

(e.g., myotonic

ing of muscle dysfunction that appears to fit

dystrophy). Sometimes myopathies cause pain

the territory of a specific nerve root (radicu-

and tenderness in the involved muscles, espe-

lopathy), region of plexus (plexopathy), or pe-

cially in inflammatory conditions.

ripheral nerve distribution

(neuropathy). In

addition, when such a lesion also is affecting

PAIN AND SENSORY SYNDROMES

sensory fibers (as do most lower motor neuron

lesions that are distal to the anterior horn cell),

Arguably one can consider all pain to be neu-

the concomitant sensory dysfunction also can

rologic in origin because any pain must be

be an important clue to the localization of the

transmitted through sensory fibers and per-

problem.

ceived in central nervous system structures.

Examples of common diffuse lower motor

However, primary neurologic pain and other

neuron processes include processes that simulta-

neurologic abnormalities of sensation are dis-

neously affect multiple peripheral nerves

cussed here and can be defined as pain and

(polyneuropathies) or multiple nerve roots

other sensory symptoms that are the direct re-

(polyradiculopathies). Diffuse polyneuropathies

sult of dysfunction of nervous system struc-

typically predominantly affect the most distal

tures. Back pain is discussed in Chapter 21 and

extremities, causing weakness that often is lim-

headache is discussed in Chapter

7—these

ited to the distal fingers and foot muscles. Dis-

topics therefore will not be addressed specifi-

tal reflexes (specifically, the ankle jerks) usually

cally in this section.

are diminished or lost, fairly symmetrically. In

Patients often report “numbness” as a neu-

most diffuse polyneuropathies, such as diabetic

rologic symptom. However, this term has

neuropathy, the sensory symptoms are more

many potential meanings, including the ex-

prominent than the distal motor findings, at

pected sensory symptoms of decreased sensa-

least initially. Multifocal, rather than diffuse,

tion (hypoesthesia or anesthesia), a tingling/

polyneuropathies are characterized as a mono-

pins and needles sensation (paresthesias), or

neuropathy multiplex. This would be seen clini-

very uncomfortable/burning sensations (dyses-

cally by dysfunction in the territories of two or

thesias). Patients, however, sometimes use the

more peripheral nerves. Polyradiculopathic

word numbness to describe weakness or other

processes clinically resemble (and may be diffi-

nonsensory symptoms. A careful history, specif-

cult to initially distinguish from) the diffuse

ically asking the patient to explain the symp-

polyneuropathies but are suggested by the pres-

tom of numbness in more detail, usually will

ence of motor dysfunction that appears to in-

suffice for clarification.

volve multiple motor nerve root territories.

The pathways for cutaneous sensation will

Concomitant sensory symptoms such as radicu-

be summarized here. Sensation starts in the

Chapter 2

n An Approach to Neurologic Symptoms

peripheral nerve endings and travels up the

radiculopathies are less common and may

sensory nerves to the dorsal nerve roots and

produce radiating pain, paresthesias, or severe

into the spinal cord. In the spinal cord, the

dysesthesias in the territory of one or several

sensory pathways ascend as the spinothala-

thoracic nerve roots. Causes of thoracic radicu-

mic tract (mainly subserving pain and tem-

lopathies include herpes zoster, diabetic tho-

perature sensation) and the posterior columns

racic radiculopathies, or structural lesions.

(mainly subserving vibration and propriocep-

Thoracic radiculopathies may mimic serious

tive sensation). These ascending sensory tracts

systemic processes such as intra-abdominal or

in the spinal cord synapse in the thalamus.

cardiac pathology. A clue to the primary neu-

From the thalamus, thalamocortical projec-

rologic, radicular cause of the patient’s symp-

tions send the sensory information to the cere-

toms would be the presence of clear-cut

bral cortex.

cutaneous hypoesthesia or dysesthesia on the

surface of the skin, conforming to a thoracic

n SPECIAL CLINICAL POINT: Abnormalities

dermatomal distribution.

at any level of the sensory pathway—peripheral

Spinal cord lesions (myelopathies) that af-

sensory nerve, nerve root, spinal cord,

fect the ascending sensory tracts cause sensory

thalamus, or sensory cortex—may produce

symptoms

(hypoesthesia and paresthesias)

sensory symptoms.

below the level of the lesion. Total interrup-

Lesions at some of these levels, particularly the

tion of these sensory fibers at any level of the

sensory nerve, nerve root, or thalamus, also

cord would cause complete anesthesia below

may produce pain.

that level. Myelopathies may cause Lhermitte

The sensory symptoms of peripheral nerve

sign, which is an uncomfortable feeling of

lesions generally consist of hypoesthesia, pares-

electricity, vibration, or tingling that radiates

thesias, or dysesthesias conforming to the terri-

down the neck and/or back and sometimes

tory of the nerve. When this occurs focally, as a

into the extremities, occurring on neck flexion.

result of a focal peripheral nerve process, the

Lhermitte sign is caused by dysfunction of

area of numbness is usually well circumscribed,

nerve fibers in the posterior columns. Al-

corresponding to a particular peripheral nerve

though it can be seen in multiple sclerosis, it

distribution. When the peripheral nerve process

can occur as a result of any process affecting

is diffuse and symmetric, such as in a distal

the cord, including compressive lesions. There-

polyneuropathy, the area of sensory distur-

fore, when a patient reports a Lhermitte sign,

bance characteristically occurs in a stocking or

it can be a helpful clue to a spinal cord local-

stocking-glove pattern.

ization of pathology.

Like peripheral neuropathic lesions, radicu-

Thalamic lesions may cause decreased sen-

lopathies may cause paresthesias or hypoesthe-

sation and paresthesias over the contralateral

sia in the territory of a nerve root. However,

body. This may be quite marked, and some pa-

these nerve root lesions often cause character-

tients with thalamic strokes, for example, may

istic radiculopathic pain, characterized by sharp

have severe sensory dysfunction over an entire

shooting pain, radiating proximally to distally

half of the body up to the midline. Thalamic le-

in the distribution of the root. Radicular pain

sions, particularly chronic ones, sometimes

resulting from cervical or lumbar root processes

also cause severe dysesthesias (thalamic pain)

can occur even in the absence of obvious neck

in addition to the cutaneous sensory loss. Cor-

or back pain. The possibility of a cervical or

tical lesions involving the sensory cortex may

lumbar radiculopathic localization of a pa-

cause paresthesias or hypoesthesia in the re-

tient’s symptoms is often apparent given the

gions of the contralateral body corresponding

characteristic symptoms. However, thoracic

to the cortical territory involved. Such sensory

Chapter 2

n An Approach to Neurologic Symptoms

cortical lesions also may be associated with

ple steps needed for turns, which may be ac-

motor abnormalities or other signs of cortical

companied by impairment of postural reflexes.

dysfunction.

Patients may complain that they have a diffi-

cult time stopping their forward progress while

walking (festination of gait).

GAIT DISORDERS

Disorders of the cerebellum or cerebellar

pathways (e.g., in the brainstem) produce an

Disorders of gait and balance may be caused by

ataxic gait. This is a wide-based unsteady gait

nonneurologic or neurologic problems. Non-

indistinguishable from the gait disorder of

neurologic causes of gait dysfunction are pri-

acute alcohol intoxication.

marily the result of orthopedic problems such

Unilateral corticospinal tract disease will

as spine, pelvic, hip, or knee problems. Gait

produce a hemiparetic gait, often with charac-

dysfunction resulting from pain in a lower ex-

teristic circumduction of the stiff, overex-

tremity is called an antalgic gait. It is usually,

tended, hemiparetic leg, pivoting around the

although not always, evident from the history

axis of the strong leg. Bilateral corticospinal

and examination that a disorder of gait is re-

tract disease such as myelopathy can occur as a

lated to an orthopedic, rather than a primary

result of spinal cord lesions, causes both legs to

neurologic, process.

be stiff, and the resulting spastic gait may in-

The neurologic structures that control gait

clude a scissoring motion of each leg around

and balance include the frontal lobes, basal

the other while moving forward.

ganglia, cerebellum, and the pathways for

Disorders of the lower motor neuron, or the

motor and sensory function.

muscles, of the lower extremities also can af-

n SPECIAL CLINICAL POINT: Gait problems

fect the gait. The resulting gait abnormality de-

can occur as a result of dysfunction in any of the

pends on the muscles that are weakened. When

regions that control gait and balance, each of

there is weakness of extension at the knee joint,

which cause characteristic abnormalities

the patient may lose the ability to lock the

evident on examination.

knee, and this may cause buckling and falling.

Frontal lobe disorders, as can be seen as a re-

This may be most bothersome in maneuvers

sult of hydrocephalus or bifrontal mass lesions

that require the knee to lock for stabilization,

or as an accompaniment of aging or dementia

and patients therefore may note buckling of a

in some patients, cause a characteristic diffi-

leg particularly when walking down stairs.

culty with initiation of gait. Patients may com-

Weakness of foot dorsiflexion may cause the

plain that their feet are “glued” to the floor.

patients to complain of tripping over their toes

The resulting gait disorder is very similar to a

(foot drop). Severe foot dorsiflexion weakness

parkinsonian gait, with very short steps, al-

therefore will produce a steppage gait, with the

though the way the feet appear to be nearly

leg lifted higher than normal to avoid tripping

stuck to the floor, and the absence of other

over the toes of the weak foot.

parkinsonian features, help in distinguishing

Patients with severely impaired sensation in

this from parkinsonism. Patients with a frontal

the lower extremities also may complain of dif-

lobe gait disorder may or may not have other

ficulty with gait, even in the absence of motor

symptoms of frontal lobe dysfunction such as

impairment. Examples include severe periph-

incontinence or dementia.

eral neuropathies or other disorders affecting

When the basal ganglia dysfunction of

proprioceptive sensory function in the legs, as

Parkinson disease (see Chapter 10) affects walk-

can be seen, for example, from vitamin B₁₂ de-

ing, it causes a characteristic flexed posture and

ficiency. These patients may not realize that

a slow, shuffling, bradykinetic gait, with multi-

there is an underlying disorder of extremity

Chapter 2

n An Approach to Neurologic Symptoms

sensation, and may present to the physician

the compressive mechanism would include

specifically with the complaint of a gait prob-

such diverse disease processes as a subdural

lem, especially when paresthesias or dysesthe-

hematoma causing mass effect on the brain, a

sias are not prominent. When patients have

benign or malignant tumor (with or without

such a severe loss of proprioceptive sensation in

associated edema) compressing or infiltrating

the feet, the resulting wide-based gait disorder

brain tissue, or a cervical disc compressing the

is called a sensory ataxia. These patients need

spinal cord. In addition, single pathologic

to look at their feet while walking, and they

processes can produce clinical symptoms via

often describe a particular tendency to fall

different potential mechanisms; for example, an

when visual cues are lost, such as when stand-

intracerebral aneurysm may produce disease

ing in the dark or when closing their eyes in the

because of hemorrhage or because of compres-

shower (Romberg sign).

sion of important structures (e.g., a posterior

communicating artery aneurysm causing a

compressive oculomotor nerve palsy).

ROLE OF THE TEMPORAL COURSE

Consideration of the temporal pattern of

OF NEUROLOGIC ILLNESS IN

symptom development, although not specific

NEUROLOGIC DIAGNOSIS

for a single mechanism, can be most helpful in

including or excluding some of these mecha-

An accurate and detailed neurologic history is

nisms; other clues from the history and exami-

the cornerstone of neurologic diagnosis. In ad-

nation then can be incorporated to narrow the

dition to learning the patient’s specific symp-

choices of mechanism and specific disease

toms, another important aspect of the history

process. The following discussion presents

is the elucidation of the temporal pattern of the

some common temporal patterns of sympto-

neurologic symptoms.

matology and the disease mechanisms they par-

n SPECIAL CLINICAL POINT: The time

ticularly suggest.

course of neurologic symptoms can give the

clinician important clues as to the probable

n SPECIAL CLINICAL POINT: Transient focal

mechanism of nervous system dysfunction.

neurologic symptoms, which may or may not

be recurrent, usually are seen as a result of

In neurologic diagnosis, it is usually most

ischemia, migraine, or seizure.

helpful to try to decide which general mecha-

nism of disease is most likely to be present be-

Although these three mechanisms may seem to

fore proceeding further diagnostically. Most

be quite different from each other, they are not

neurologic disease processes can be catego-

always easy to distinguish. Ischemic symptoms,

rized as producing their dysfunction through

when transient, can produce focal neurologic

one of these general mechanisms: compressive,

dysfunction lasting from seconds to hours. Mi-

degenerative, epileptic, hemorrhagic, infec-

grainous brain dysfunction can produce a vari-

tious, inflammatory (including demyelinative),

ety of focal neurologic manifestations (even

ischemic, migrainous, metabolic

(including

without headache). In addition to the visual

toxic), or traumatic. (Some congenital neuro-

scintillations of classic migraine, other neuro-

logic processes also may produce disease that

logic symptoms can be seen as migrainous

results from the congenital absence of certain

phenomena, including weakness, paresthesias,

normal structures or tissues—whether on a

and aphasia. These migrainous symptoms typ-

subcellular or macroscopic level—thereby lead-

ically progress and spread over a period of

ing to abnormal neurologic function.)

minutes (e.g., 15 to 30 minutes) before resolv-

These mechanisms of acquired neurologic

ing. In contrast, the focal neurologic symptoms

disease are generic and inclusive; for example,

of seizures tend to spread somewhat more

Chapter 2

n An Approach to Neurologic Symptoms

quickly. The patient’s age, associated medical

conditions, and other clues from the history

Always Remember

and examination may also assist in the delin-

• A detailed and thoughtful neurologic history

eation of the likely mechanism of transient

is always the first step in neurologic diagnosis.

focal neurologic dysfunction. It should be

• As you take your patient’s history and

noted that demyelinating disease (specifically

perform your patient’s examination, keep

multiple sclerosis) causes focal neurologic dys-

basic neuroanatomic concepts in mind.

function that can resolve and then recur in a

• Use the clues from the history and

different region of the central nervous system.

examination to determine first the most likely

However, the symptoms of an acute attack of

location of the neurologic problem and

multiple sclerosis usually last at least days to

second the likely cause of the problem.

weeks before improving, unlike the more tran-

• Recognition of specific patterns of neurologic

sient symptoms of ischemia, migraine, or

symptoms and signs and their temporal

epilepsy. Some patients with multiple sclerosis

development can be very helpful in

do experience very brief (as short as seconds),

neurologic diagnosis.

repetitive, stereotypical, paroxysmal neuro-

logic symptoms. This is presumably because of

“short circuits”

(ephaptic transmission) be-

tween adjacent demyelinated axons in an acute

QUESTIONS AND DISCUSSION

multiple sclerosis plaque, and the resulting very

1. A 35-year-old man presents to the

brief paroxysmal event simply can be consid-

emergency room with a 3-day history of

ered a kind of white matter electrical event.

numbness and tingling from his mid chest

Sudden-onset neurologic symptoms suggest

down to his legs, and mild weakness in

ischemia or hemorrhage. A progressive focal

both legs. He describes an unusual

neurologic symptom primarily suggests a com-

sensation like an electric shock whenever

pressive lesion, but ischemic, inflammatory, or

he flexes his neck forward. He also has

focal infectious processes can progress gradually

some urinary urgency. Examination shows

as well. Degenerative diseases also may produce

normal mental status and cranial nerves.

progressive focal neurologic dysfunction, but

There is mild weakness in both legs (4/5).

the dysfunction is usually more diffuse, even if

Sensory examination shows that pinprick is

not symmetric. Ischemic or compressive lesions

diminished below the level of the nipples,

also can cause waxing and waning focal neuro-

including the lower chest, abdomen, and

logic symptoms. More diffuse waxing and wan-

legs. Reflexes are normal in the arms but

ing symptoms also would be expected in some

are brisk in the legs. Babinski signs are

toxic or metabolic processes.

present bilaterally. Which of the following

Progressive diffuse neurologic symptoms

terms best describes the localization of this

are most suggestive of degenerative processes,

patient’s clinical syndrome?

infectious or inflammatory processes, or meta-

A. Encephalopathy

bolic abnormalities. The specific time course in

B. Myelopathy

question can be quite helpful. For example, dif-

C. Radiculopathy

fuse neurologic dysfunction that has been pro-

D. Neuropathy

gressing over days would more likely be

E. Myopathy

ascribed to a metabolic or infectious process,

whereas the same kind of symptoms progress-

The correct answer is B (myelopathy). This

ing over years would be more likely caused by

patient has symptoms of spinal cord (myelo-

a degenerative disease.

pathic) dysfunction. Clues to a spinal cord

Chapter 2

n An Approach to Neurologic Symptoms

localization of his symptoms include the bi-

Sensory testing shows that she has severe

lateral motor dysfunction in the legs as well

discomfort when the skin under the right

as the bilateral sensory dysfunction with a

breast and below the right scapula is

sensory level over the trunk. There are also

touched with either a cotton swab or the

brisk reflexes in both legs and bilateral

point of a pin. This area of sensory

Babinski signs, suggestive of bilateral upper

abnormality is a strip about 2 cm in height

motor neuron (corticospinal tract) dysfunc-

extending from the right mid/upper

tion. Although brainstem lesions similarly

thoracic spine posteriorly to the lower

can cause bilateral motor and sensory symp-

sternum anteriorly. Reflexes are 1+ and

toms, the absence of cranial nerve abnormali-

symmetric, and Babinski signs are absent.

ties is evidence that the lesion is below the

Which of the following terms best describes

level of the brainstem. Urinary symptoms, in-

the localization of this patient’s pain

cluding urgency, are also commonly associ-

syndrome?

ated with spinal cord processes. This patient

A. Encephalopathy

also describes Lhermitte sign, an electric-like

B. Myelopathy

sensation on neck flexion, a finding sugges-

C. Radiculopathy

tive of a spinal cord process affecting the pos-

D. Neuropathy

terior columns. This patient’s clinical

E. Plexopathy

symptoms and signs are not suggestive of

The correct answer is C (radiculopathy). This

pathology in the brain (encephalopathy),

patient has characteristic symptoms and signs

nerve root (radiculopathy), nerve (neuropa-

of a thoracic radiculopathy. The major clue to

thy), cervical or lumbosacral plexus (plexopa-

a probable nerve root localization of her dis-

thy), or muscle (myopathy). Although the

ease process is the distribution of her sensory

cause of this patient’s spinal cord dysfunction

symptoms and sensory findings to the cuta-

is not yet clear, the clinical recognition that

neous territory of a particular nerve root. In

his symptoms are likely myelopathic is impor-

this case, her findings map out the territory of

tant and will guide the clinician to the appro-

either the right T5 or T6 root. Another clue to

priate choice of imaging and other studies.

a radicular localization of her symptoms is the

2. A 72-year-old woman with a 2-year history

occasional proximal-to-distal shooting pains in

of diabetes mellitus comes to the office

the territory of a right thoracic nerve root. The

because of 4 weeks of severe pain. She

generic diagnosis of a thoracic radiculopathy

describes the pain as a severe, sharp,

does not in itself give a specific clinical diagno-

burning sensation that begins in her medial

sis for this patient. However, the recognition

scapula and radiates around her trunk to

that this is the likely localization of her prob-

beneath her right breast. The pain is not

lem allows the physician to narrow the

worse with breathing, but she notes that

causative possibilities, and to reasonably ex-

the skin in this area is very uncomfortable

clude other possibilities, prior to further inves-

to touch. Her only medication is an oral

tigation. Recognition that this patient’s

hypoglycemic agent. She has seen multiple

cutaneous sensory symptoms and signs are

physicians and has undergone extensive

most compatible with a thoracic radicular

gastrointestinal and cardiac evaluations for

process, and not a visceral process, might have

the pain, which were unrevealing. Her

saved her from some unnecessary investiga-

general physical examination is normal,

tion. One caveat, though, is that visceral dis-

and there is no skin rash. Neurologic

ease can cause referred pain syndromes

examination shows normal mental status,

suggestive of neurologic or spinal processes,

cranial nerves, and muscle strength.

such as mid- or low-back pain from deep

Chapter 2

n An Approach to Neurologic Symptoms

chest, abdominal, or retroperitoneal processes.

tion; however, it should always be performed

In this patient, the most likely cause of her

only after the history has been obtained. The

thoracic radicular syndrome is a diabetic tho-

results of ancillary laboratory tests, although

racic radiculopathy. Herpes zoster (shingles) in

often very important in excluding or con-

this distribution would cause similar symp-

firming specific diagnostic considerations,

toms, but it is less likely given the absence of

should be ordered and interpreted in light of

herpetic skin lesions.

the clinical history (first) and the neurologic

examination (second). Clinical interpretation

3. Your office nurse tells you that your next

of a patient’s diagnostic studies without re-

patient is complaining of intermittent

gard to the findings of history and examina-

episodes of dizziness that have been

tion is fraught with potential hazard. Just as

occurring for the last 2 months. The patient

incidental abnormalities may be overinter-

is a 54-year-old woman who you have been

preted for clinical importance (red herrings),

following for general medical care. She has

the clinician also might get false reassurance

a history of hypertension but no other

from the results of normal studies that do not

previous significant illnesses. Prior to

answer the appropriate clinical question

coming to your office today, the patient had

at hand.

a few tests done by another physician,

including a magnetic resonance imaging

4. A 25-year-old woman comes to the office

scan of the brain and a 24-hour ambulatory

because of a 5-year history of intermittent

heart monitor test. Which of the following

episodes of face and arm numbness and

choices would be the most appropriate first

difficulty with vision and speech. The

step in your evaluation of this patient?

attacks are all very similar, and she has had

A. Review the results of the previous

about two attacks per year. Her symptoms

workup.

begin with a visual disturbance, which she

B. Take a history from the patient.

describes as difficulty seeing the right side

C. Perform a general physical examination.

of people’s faces or the right side of a page,

D. Perform a general neurologic

“as if they are covered by heat waves.”

examination.

This then is followed within a few minutes

E. Check for orthostatic hypotension, and

by numbness and tingling in her right hand.

perform a bedside maneuver for

This numb sensation then gradually

positional vertigo.

ascends over the next 15 minutes to involve

the right arm and cheek. During the

The correct answer is B (take a history from

attacks, she has difficulty with speech,

the patient). Although all of the choices are

which she describes as a feeling, “I know

important and may be helpful, the first step

what I want to say, but I can’t get the

in any neurologic evaluation should be a

words out.” The symptoms last a total of

thorough history. Once the neurologic his-

about 30 minutes then resolve and usually

tory is obtained, the clinician usually should

are followed by a moderately severe

have enough clues to determine the likely

throbbing headache over her left temple.

locations of the lesion (the where part of the

Although the majority of her episodes have

neurologic diagnostic process) and the possi-

involved her right vision and body, she

ble disease mechanisms involved (the what

recalls having had a few episodes that

part of the diagnostic process). The neuro-

involved only the left side of her vision,

logic examination can be a very helpful

face, and arm, but without the speech

adjunct to the neurologic history, and in

disturbance. She has no significant past

many cases it will help exclude or include

medical history except for additional

certain processes that are under considera-

Chapter 2

n An Approach to Neurologic Symptoms

occasional headaches that occur about once

possible, it is a less likely cause of this patient’s

a month, located over either or both

symptoms because of the migrainous quality of

temples and relieved by over-the-counter

her symptoms, the number of episodes she has

analgesics. Her neurologic examination is

had over many years without obvious sequelae,

normal. Which of the following general

and her age. A focal seizure is also possible, but

mechanisms of neurologic dysfunction is

it is less likely because of the slow tempo of

the most likely cause of this patient’s

progression and the fact that her symptoms

symptoms?

have occurred on either side. Demyelinating

A. Demyelinative

disease is an unlikely cause of this patient’s

B. Epileptic

symptoms, as attacks of demyelinating disease

C. Ischemic

typically cause neurologic dysfunction lasting

D. Metabolic

at least days to weeks.

E. Migrainous

The answer is E (migrainous). This patient has

SUGGESTED READING

recurrent episodes of transient focal neurologic

dysfunction, most likely of migrainous etiology.

Brazis PW, Masdeu JC, Biller J. Localization in Clinical

Recurrent transient focal neurologic symptoms

Neurology. 5th ed. Philadelphia, PA: Lippincott

Williams & Wilkins; 2006.

are usually the result of ischemia, epilepsy, or

migraine. In this case, migraine is the most

Campbell WW. DeJong’s the Neurologic Examination.

6th ed. Philadelphia, PA: Lippincott Williams &

likely cause of her visual symptoms, which

Wilkins; 2005.

sound typical of migraine auras. Her other neu-

Gelb DJ. Introduction to Clinical Neurology. 3rd ed.

rologic symptoms, which occur subsequent to

Boston, MA: Butterworth-Heinemann; 2005.

the onset of her visual symptom, suggest the

Gilman S, Newman SW. Manter & Gatz’s Essentials of

focal neurologic symptomatology that migraine

Clinical Neuroanatomy and Neurophysiology. 10th

sometimes can produce, and they progress with

ed. Philadelphia, PA: FA Davis; 2002.

a typical migrainous tempo. The subsequent

Goetz CG. Textbook of Clinical Neurology. 3rd ed.

headache after the neurologic disturbance

Philadelphia, PA: Saunders; 2007.

is also suggestive of migraine, although

Lewis SL. Field Guide to the Neurologic Examination.

migrainous neurologic symptoms sometimes

Philadelphia, PA: Lippincott Williams & Wilkins;

can occur without headache, and headache can

2004.

occur with other neurologic processes, includ-

Patten JP. Neurological Differential Diagnosis. 2nd ed.

ing ischemia and epilepsy. Although ischemia is

London: Springer-Verlag; 1998.

Clinical Use

of Neurologic

Diagnostic Tests

MADHU SONI

key points

• Computed tomography (CT) is preferred over magnetic

resonance imaging (MRI) to visualize hemorrhage and

bony structures.

• Posterior fossa structures, such as the brainstem and

cerebellum, are not visualized well by CT.

• A routine EEG may be normal in some patients with

epilepsy.

• An MRI should not be performed in patients with

pacemakers or ferromagnetic devices.

• Nephrogenic systemic fibrosis may occur with MRI dye

in patients with renal dysfunction.

• Nerve biopsy is most useful in evaluation of vasculitic

neuropathy.

• Ultrasound, computed tomographic angiography, and

magnetic resonance angiography have significantly

reduced the need for conventional angiography in the

routine evaluation of carotid stenosis.

impressions. This chapter will highlight the

INTRODUCTION

major neurodiagnostic studies, focusing on

their indications, benefits, and potential risks

Although the history and physical examination

(Table 3.1). These tests can be organized into

remain the foundation upon which neurologic

four general categories: neuroimaging tests, vas-

localization and diagnoses are made, neurolo-

cular imaging studies, neurophysiologic tests,

gists have an armamentarium of diagnostic

and fluid/tissue studies.

tests available to help confirm their clinical

Chapter 3

n Clinical Use of Neurologic Diagnostic Tests

TABLE 3.1

Calcifications in the brain parenchyma, blood

Neurodiagnostic Studies

vessels, choroid plexus, pineal gland, and

within cystic, neoplastic, or infectious lesions

Neuroimaging tests

are well differentiated on CT. The advent of

Computed tomography

spiral CT technology also allows three-dimen-

Magnetic resonance imaging

sional reformatted images of the spine. CT ad-

Myelography

ditionally provides useful information about

Vascular imaging studies

ventricular size, the presence of communicat-

Ultrasound

ing or obstructive hydrocephalus, large mass

Carotid Doppler

Transcranial Doppler

lesions, and integrity of hemispheric midline

Computed tomographic angiography

structures. Adjacent sinus structures are also

Magnetic resonance angiography

visualized on head CT and may provide a clue

Magnetic resonance venography

to the source of a patient’s headache or facial

Catheter angiography

pain. Additionally, sinus abnormalities may

Neurophysiologic tests

suggest a site of contiguous spread in the set-

Electroencephalography

ting of central nervous system infections. Ded-

Electromyography

icated imaging of the sinuses, however, may be

Evoked potentials

necessary.

Visual

Brainstem

n SPECIAL CLINICAL POINT: With CT,

Somatosensory

there are limitations in visualizing posterior

Fluid and tissue studies

fossa structures such as the brainstem and

Lumbar puncture

cerebellum and other neuroimaging techniques

Tissue biopsy

like MRI are preferred for identifying problems

Brain

related to these areas.

Nerve

Muscle

If MRI evaluation is not immediately available

or when patients are unable to tolerate MRI,

requesting thin CT slices through the posterior

fossa may be helpful. Due to the associated ra-

diation exposure, CT is not recommended in

NEUROIMAGING TESTS

pregnancy. However, in emergent situations, it

Computed Tomography (CT)

may be performed while shielding the ab-

domen from radiation exposure. The use of

Perhaps one of the oldest imaging modalities of

contrast dye is helpful in evaluating suspected

those that will be described in this chapter,

breaches in the blood-brain barrier as can

CT remains an important diagnostic tool in

occur with primary or metastatic brain tu-

the setting of neurologic emergencies. It is

mors, meningitis, encephalitis, abscesses and

widely available, generally accessible in most

other infections, and active areas of demyeli-

medical centers at any hour (based on techni-

nation or inflammation. CT contrast may also

cian availability), and can be performed

help in the evaluation of vascular conditions.

relatively quickly. Compared to magnetic reso-

In ischemic stroke, a filling defect may be seen

nance imaging (MRI), CT is easier to perform

due to a thrombosed artery, or in patients with

in those with claustrophobia or with confu-

increased intracranial pressure, the classic

sional states.

“empty delta sign” indicates a clot at the con-

fluence of venous sinuses. Aneurysms and ar-

n SPECIAL CLINICAL POINT: CT is

preferred over MRI to screen for acute

teriovenous malformations (AVMs) are better

hemorrhage and to visualize bony structures.

delineated with the use of contrast and may

Chapter 3

n Clinical Use of Neurologic Diagnostic Tests

be missed with a noncontrast study. It is not

Orbital MRI is utilized to visualize the optic

advisable to administer iodinated contrast to

nerve and extraocular muscles. To optimally

pregnant women, those with renal insuffi-

visualize these structures, it is important to

ciency, or if there is an allergy to the contrast

specify that the study is done with fat suppres-

agent. If use of contrast is necessary in patients

sion. This eliminates the bright artifact from

with renal impairment, acetylcysteine and hy-

fat within the orbit.

dration should be used as prophylaxis in at-

n SPECIAL CLINICAL POINT: Patients with

tempts to protect the kidneys. Some patients

pacemakers, mechanical heart valves, brain or

with myasthenia gravis may have an exacerba-

spinal cord stimulators, retained bullet or

tion of their weakness after the use of CT or

shrapnel fragments, and other ferromagnetic

MRI contrast and therefore should be moni-

material should not be placed in a magnetic

tored closely if use of contrast is necessary.

field due to risk of device malfunction and

movement of the metal that may result in

serious injury or death.

Magnetic Resonance Imaging

Aneurysm clips in the current era are designed

The advent of MRI has provided increased reso-

so that they are compatible with MRI imaging.

lution in imaging structures such as soft tissue,

It is best, however, to verify compatibility prior

cerebral gray and white matter, the brainstem,

to ordering an MRI in these patients.

cerebellum, spinal cord, cranial nerves, spinal

As mentioned earlier, the use of contrast is

nerve roots, peripheral nerves, and muscle with-

helpful if a breach of the blood-brain barrier is

out traditional radiation exposure. Generally

suspected.

speaking, T1-weighted images are useful in eval-

uating the normal anatomy, and cerebrospinal

n SPECIAL CLINICAL POINT: Although

fluid (CSF) appears black. On T2-weighted im-

traditionally thought to be safer than iodine-

based contrast dye, gadolinium has been

ages, the CSF is white and this sequence high-

associated with nephrogenic systemic fibrosis

lights abnormalities in the brain or spinal cord

(NSF; also known as nephrogenic fibrosing

parenchyma. In particular, areas of increased

dermopathy) when administered to patients

water content or edema look bright, or white.

with renal dysfunction.

Fluid attenuated inversion recovery

(FLAIR)

sequences also highlight pathology, but the CSF

This condition causes fibrosis of the skin and

is black, allowing better contrast for lesions

other organs. It is, therefore, essential to weigh

around the ventricles, such as in multiple

the risk of NSF and renal failure against the di-

sclerosis, and near the cortical surface. Diffu-

agnostic necessity of using dye in these patients.

sion-weighted imaging (DWI) has become an

important tool in identifying acute stroke and is

Myelography

based on the diffusion properties of water mole-

cules through normal and injured tissue. Al-

Evidence for spinal cord or nerve root com-

though not specific to acute stroke, patterns of

pression may be evaluated by myelography in

restricted water molecule diffusion will appear

patients who are unable to undergo an MRI.

bright on the DWI sequence. The apparent dif-

Vascular malformations of the cord may also

fusion coefficient (ADC) is a measure of the mo-

be seen. A lumbar or cervical puncture is per-

bility of water and if mobility is reduced, as in

formed under fluoroscopic guidance and an io-

injured tissue, the corresponding area will ap-

dinated water-soluble contrast agent is injected

pear dark. Therefore, an area that is bright on

into the subarachnoid space. X-rays are ob-

DWI and dark on ADC corresponds to an area

tained to visualize the opaque column of dye

of acute to subacute injury. These changes may

and to see if there is a block or indentation

persist for 2 weeks.

in the column that may signify an area of

Chapter 3

n Clinical Use of Neurologic Diagnostic Tests

compression. Generally, CT is performed after

comparable to MRA (see below). In detecting

myelography to identify what is causing the

occlusive disease, CTA and carotid Doppler

compression (i.e., herniated disc, osteophyte,

studies have the same sensitivity but the speci-

mass) and to increase the diagnostic yield of

ficity is greater for CTA. The intracranial circu-

the procedure. As with lumbar puncture (LP), a

lation is better visualized and in a shorter period

post-dural-puncture headache may occur after

of time with CTA compared to MRA.

myelography. Arachnoiditis and idiosyncratic

adverse reactions to the dye may occur.

Magnetic Resonance Angiography and

Magnetic Resonance Venography (MRV)

VASCULAR IMAGING STUDIES

Arterial and venous vessels may be evaluated

without the invasive risks associated with

Ultrasound

catheter angiography. MRA refers to MRI of

Ultrasonography remains a very useful tool in

arterial vessels, and MRV evaluates venous

the evaluation of patients with transient is-

structures. Small aneurysms (3 mm or less),

chemic attacks and stroke, particularly in the

however, may not be seen with MRA, and arte-

evaluation of the extracranial carotid circula-

rial stenosis may be overestimated.

tion. It provides valuable information about

the presence of arterial stenosis by evaluating

Catheter Angiography

flow velocities. This imaging modality is

portable, widely available, and can be per-

Angiography is the gold standard for evaluat-

formed relatively quickly. Although not as well

ing arterial and venous structures. This diag-

known, transcranial Doppler (TCD) offers an

nostic study is utilized in the evaluation of

evaluation of the intracranial circulation. Per-

cerebral or spinal ischemia due to thrombotic

formance of the study relies on sonography

disease or dissection, and in subarachnoid or

through bony windows and may be technically

intracerebral hemorrhage when an aneurysm

limited by cranial hyperostosis. Carotid and

or AVM is suspected. The procedure is also

TCD studies can help confirm findings on mag-

used for endovascular coiling of aneurysms,

netic resonance angiography (MRA) and vice

embolization of AVM feeder vessels, intra-

versa, as areas of high-grade stenosis may be

arterial administration of thrombolytic agents,

overestimated with either modality alone. TCD

angioplasty, and stent placement. However, the

is also utilized in monitoring for vasospasm

interventional nature of this procedure is not

after subarachnoid hemorrhage and can help

without risk. These risks include hematoma

determine the need for transfusion in sickle cell

formation at the site of arterial puncture, vas-

anemia children when the middle cerebral ar-

cular injury with a tear in the vessel wall,

tery flow velocity escalates.

stroke due to plaque embolism, and an adverse

reaction to the contrast agent, including renal

dysfunction.

Computed Tomographic

Angiography (CTA)

n SPECIAL CLINICAL POINT: Noninvasive

tests such as ultrasound, computed tomographic

Computed tomographic angiography utilizes

angiography (CTA), and magnetic resonance

spiral CT and allows noninvasive imaging of ex-

angiography (MRA) have decreased the need

tracranial and intracranial vessels in a two- and

for conventional angiography in the evaluation

three-dimensional format, utilizing less dye, less

of cerebral ischemia, particularly when at least

time, and less risk compared to conventional an-

two of the noninvasive studies show concordant

results.

giography. In carotid artery assessment, CTA is

Chapter 3

n Clinical Use of Neurologic Diagnostic Tests

Individual patient comorbidities, such as car-

in metabolic and infectious encephalopathies.

diopulmonary status and chronic illness, should

For example, bilateral triphasic waves classi-

be considered when deciding whether to accept

cally are seen with hepatic or renal dysfunction.

the risk of conventional arteriography.

This wave pattern, however, is not specific and

may be seen in any condition that causes severe

slowing of cerebral activity. Periodic sharp

NEUROPHYSIOLOGIC TESTS

wave complexes in the temporal and frontal

lobe regions may be seen with herpes encephali-

Electroencephalography (EEG)

tis or other acute insult. Creutzfeldt-Jakob dis-

ease due to prion infection is associated with

Electroencephalography is ordered in patients

generalized sharp waves occurring approxi-

with spells and altered mental status when

mately every second, but this may not be seen

there is a concern for seizures. Electrodes are

until later stages of the disease. EEG may also

attached with removable adhesive to the scalp

be used as a confirmatory test in evaluating

and the brain’s electrical activity is recorded.

brain death. As with other diagnostic testing

Activating procedures such as hyperventilation

methods, clinical correlation is essential in in-

and photic stimulation are utilized in attempts

terpreting the significance of electroencephalo-

to trigger a typical spell and increase diagnostic

graphic findings.

yield. In patients with pulmonary or cardiac

conditions in which hyperventilation is con-

traindicated, specification should be made not

Electromyography (EMG)

to perform the activating procedure. Epilepti-

This electrodiagnostic study is used as an ex-

form activity may in some cases only be seen

tension of the clinical exam to evaluate the pe-

during sleep and thus, it is important to record

ripheral nervous system including the spinal

the EEG during both wakefulness and sleep. To

roots, nerves, neuromuscular junction, and

ensure sleep is attained, it is recommended that

muscle. Although the entire test is generically

patients limit their sleep prior to the test to half

referred to as “EMG,” the study consists of

of their usual amount the day before the test.

two parts: a nerve conduction study (NCS) and

n SPECIAL CLINICAL POINT: A routine EEG

needle EMG.

may be normal in some patients with epilepsy

The NCS is performed by applying an electri-

given the short duration of the study and the

cal impulse over nerve landmarks, recording the

paroxysmal nature of epileptic spells that

generated waveform on a computer screen and

typically do not occur during the EEG. Further,

analyzing it to determine conduction velocity

if an epileptic focus is located too deep for

and amplitude, measures of peripheral myelin,

detection by the recording scalp electrodes, the

and axon integrity, respectively. Both sensory

EEG will be normal.

and motor nerves are tested. Patients should not

Therefore, the decision to treat patients with

wear lotions, oils, or ointments to the test as

anticonvulsants must be based on the clinical

these interfere with the contact between the elec-

syndrome. In patients with nonepileptic spells

trodes and skin and may result in suboptimal or

or pseudoseizures, the EEG is normal during a

absent waveforms. The presence of edema also

typical spell. It is important to verify that the

technically limits the ability to obtain nerve re-

event is a characteristic one and may require

sponses. Nerve conduction slows down with

discussion with family members who have wit-

cooler temperatures, so if the patient’s limb is

nessed the spells. Prolonged ambulatory EEG

cold, appropriate measures must be taken in the

may be necessary to capture these events. Cer-

lab to warm the limb before

interpreting the

tain EEG patterns may provide etiologic clues

results. Repetitive nerve stimulation studies are

Chapter 3

n Clinical Use of Neurologic Diagnostic Tests

useful in detecting defects in neuromuscular

cortex. A lesion in the brainstem would result

junction transmission as occurs in myasthenia

in absence/abnormality of the SSEP waveform

gravis, botulism, and Lambert-Eaton myas-

at that level and at the subsequent cortical level

thenic syndrome. EMG involves insertion of a

with preservation of the others. In general,

thin needle electrode into individual muscles to

evoked potentials are no longer commonly or-

look for signs of denervation as can occur in

dered except for the SSEP in intraoperative

motor neuron disease, radiculopathy, plexopa-

monitoring, particularly for spine surgery.

thy, or neuropathy. Primary muscle disorders

Prior to the availability of MRI, VEPs and

have characteristic patterns that help differenti-

BAERs were commonly done when multiple

ate them from neurogenic conditions. Diagnos-

sclerosis was clinically suspected, to look for

tic changes on the needle study may not be seen

evidence of optic nerve dysfunction and multi-

immediately.

focal central lesions. There is still a potential

role for these tests in patients who are unable

n SPECIAL CLINICAL POINT: Because some

to have MRIs due to pacemakers or other

diagnostic EMG abnormalities take time to

metal implants. VEPs are also useful to look

develop, it is best to order the test after the

for subclinical optic nerve dysfunction in pa-

patient has had the symptoms for at least

tients suspected of having Devic disease (also

3 weeks.

called neuromyelitis optica), an aggressive de-

Nerve conduction and electromyographic stud-

myelinating condition generally isolated to the

ies will be normal in conditions isolated to the

spinal cord and optic nerve.

central nervous system.

FLUID AND TISSUE STUDIES

Evoked Potentials

Lumbar Puncture

The three most common evoked potential stud-

ies are the visual evoked potential

(VEP),

n SPECIAL CLINICAL POINT: Although the

brainstem auditory evoked response or brain-

availability of MRI has significantly decreased

stem auditory evoked potential (BAER, BAEP),

the need for diagnostic LPs in patients with

and somatosensory evoked potential (SSEP).

multiple sclerosis, analysis of the cerebrospinal

These diagnostic studies evaluate the electrical

fluid (CSF) for the presence of increased

intracranial pressure, subarachnoid

signals generated by the sensory pathways for

hemorrhage, infectious or neoplastic meningitis

vision, hearing, and somatic sensation, respec-

continues to be an important indication for

tively. Sensory stimuli are provided relevant to

lumbar puncture.

the test being performed, for example, a

checkerboard pattern for the VEP, auditory

Cerebrospinal fluid analysis is also used to sup-

clicks for the BAER, and electrical stimulation

port or confirm the clinical suspicion of inflam-

of a peripheral nerve for the SSEP. Electrodes

matory demyelinating conditions affecting the

are strategically placed over the peripheral

central and peripheral nervous system. For ex-

nerve, spine, scalp, etc. Waveforms are ana-

ample, the presence of oligoclonal bands and in-

lyzed from the cranial (optic nerve for VEP,

trathecal immunoglobulin synthesis, in the

vestibulocochlear nerve for BAER) or periph-

absence of a serologic monoclonal gammopathy,

eral nerve (SSEP) to the cerebral cortex. Abnor-

aids the diagnostic probability of multiple sclero-

malities in the waveforms help localize a

sis in patients with a suggestive clinical history

problem to the peripheral or central nervous

and exam findings. An elevated CSF protein

system. Using the SSEP as an example, separate

with normal cell count (cytoalbuminologic dis-

waveforms are present for the peripheral nerve,

sociation) is pathognomonic for Guillain-Barré

plexus, spinal cord, brainstem, and parietal

syndrome in patients presenting with acutely

Chapter 3

n Clinical Use of Neurologic Diagnostic Tests

progressive limb, facial or oropharyngeal weak-

Hydration, caffeine, and rest are recom-

ness, and areflexia. Chronic inflammatory de-

mended for management of these headaches. A

myelinating polyradiculoneuropathy (CIDP) is

blood patch may be required for refractory

generally associated with an elevated CSF pro-

post-LP headaches. This procedure is generally

tein, which differentiates it from multifocal

performed by an anesthesiologist. Approxi-

motor neuropathy in the appropriate clinical

mately 10 cc of the patient’s own blood is in-

and electrodiagnostic setting. Neuroimaging

jected into the epidural space at the same level

studies may not detect small areas of subarach-

where the LP was performed. The goal is to

noid hemorrhage and it is therefore imperative

create a mechanical seal of the dural tear cre-

to perform an LP, if the head CT is normal, to

ated by the LP and stop the CSF leak. Patients

confirm this suspicion in patients presenting

generally experience prompt relief if the seal is

with a sudden, severe, “worst headache of my

successful. Rarely after LP, epidermoid tumors

life.” Prior to performing an LP, it is generally

may form in the spinal canal if epithelial cells

recommended that a CT or an MRI of the

from the skin accompany the spinal needle into

brain be performed to exclude a contraindica-

the subarachnoid space. It is, therefore, impor-

tion to the procedure, such as the presence of a

tant to make sure that while performing an LP,

structural lesion causing elevated intracranial

the spinal needle is always inserted and ad-

pressure and risk of cerebral or cerebellar her-

vanced with the stylet in place.

niation. Additionally, patients should be evalu-

ated for the presence of a coagulopathy by

Tissue Biopsy

checking the PT/INR, PTT, and CBC. Signifi-

cantly abnormal coagulation studies and

Brain Biopsy Biopsy of brain tissue is consid-

thrombocytopenia increase the risk of superfi-

ered when noninvasive studies are insufficient

cial and deep hematomas, including in the

in providing a definitive diagnosis, and patient

epidural and subdural space, which can lead to

management would be altered by the results.

nerve root or cord compression. Preparation

Neoplastic disease, infection, vasculitis, and

for LP requires use of sterile technique to mini-

rapidly progressive degenerative conditions are

mize the risk of skin, epidural, subdural, or sub-

situations in which biopsy of a specific brain le-

arachnoid infection. For patients with local

sion, the meninges, or functionally affected

back tenderness, fluctuance, fever, history of

parenchyma may be considered. Selection of

substance use, or any other “red flags” that raise

biopsy site is critical to minimize potential loss

the concern for a local infection, an imaging

of function. For example, in cases with multi-

study of the spine (preferably, contrasted MRI if

ple lesions, the one most accessible at the sur-

no contraindication) should be performed prior

face should be chosen and the language center

to performing or ordering an LP due to the risks

should be avoided. Computer-assisted stereo-

of spreading infection by inadvertent needle

tactic biopsy allows for tissue retrieval through

puncture through an abscess, or adjacent area of

a burr hole with less risk compared to an open

discitis or osteomyelitis. A post-dural-puncture

biopsy via craniotomy. As with all invasive

or low-CSF-pressure headache may occur in

tests, risks and benefits must be weighed and

patients after LP, particularly when large di-

discussed with patients and/or family members

ameter spinal needles are used. Occurrence of

before proceeding.

the headache is not associated with the

amount of fluid removed or with the duration

Nerve/Muscle Biopsy Nerve or muscle biopsy

the patient is kept supine after the procedure.

may be a helpful diagnostic tool in cryptogenic

Clinically, patients are asymptomatic while

cases of neuropathy and myopathy, respec-

supine (position of highest CSF pressure) and

tively. Nerve biopsy is an acceptable diagnostic

the headache develops when they sit or stand.

study if there is a clinical suspicion of an in-

Chapter 3

n Clinical Use of Neurologic Diagnostic Tests

flammatory, infiltrative, or infectious etiology

mildly weak (i.e., grade 4 out of 5 on the Med-

that would alter management.

ical Research Council Scale). Biopsy of a se-

verely affected muscle increases the chance of

n SPECIAL CLINICAL POINT: Nerve biopsy

detecting endstage, fibrotic changes that are

is most useful in suspected cases of vasculitis

diagnostically nonspecific. Needle EMG can

which can present as a mononeuritis multiplex

with asymmetric involvement of individual

help identify the site for biopsy. In patients

nerves sequentially or at the same time.

with symmetric weakness, the biopsy site

should be contralateral to the studied muscle

According to a recent practice parameter from

to avoid needle artifact in the submitted speci-

the American Academy of Neurology, there is

men. It is helpful to let the electromyographer

insufficient evidence to recommend when a

know to test only one side if a biopsy is being

nerve biopsy would be beneficial in the more

contemplated.

common presentation of a symmetric, distal

polyneuropathy. A punch biopsy of the skin has

been used to evaluate the intraepidermal nerve

fiber density, which is reduced in polyneuropa-

thy, including small fiber neuropathy.

Always Remember

n SPECIAL CLINICAL POINT: Routine

• CT is preferred over MRI to screen for acute

nerve conduction studies only evaluate large

hemorrhage and to visualize bony structures.

nerve fiber function and will be normal in

• CT is not adequate to visualize the brainstem

pure small fiber neuropathy cases, in which

and cerebellum.

pain and temperature abnormalities are found

• Check renal function before ordering

with preservation of proprioception and

contrast for CT or MRI.

vibration.

• Although traditionally thought to be safer

A skin biopsy is therefore helpful in diagnosing

than iodine-based contrast dye, gadolinium

small fiber neuropathies but its specific role in

has been associated with nephrogenic

the routine evaluation of neuropathy has yet to

systemic fibrosis when administered to

be established.

patients with renal dysfunction.

Muscle biopsy is utilized in cases of inflam-

• Patients with pacemakers, mechanical heart

matory myopathy to differentiate inclusion

valves, brain or spinal cord stimulators,

body myositis from polymyositis and der-

retained bullet or shrapnel fragments, and

matomyositis. There are distinguishing patho-

other ferromagnetic material should not be

logic features in each of these conditions and

placed in a magnetic field due to risk of device

correct classification is important for manage-

malfunction and movement of the metal that

ment and prognostication. For example, der-

may result in serious injury or death.

matomyositis requires periodic surveillance

• An area that is bright on DWI MRI sequences

for an underlying malignancy, polymyositis

and dark on ADC corresponds to an area of

may be associated with interstitial lung disease

acute to subacute injury.

and connective tissue disease, and there is no

• A normal EEG does not exclude the

specific treatment for inclusion body myositis.

diagnosis of epilepsy.

Muscle biopsy is also helpful in evaluating po-

• Routine nerve conduction studies only

tential toxic, metabolic, and infectious causes

evaluate large nerve fiber function and will be

of otherwise undiagnosed myopathic condi-

normal in pure small fiber neuropathy.

tions. Typical muscles used for biopsy are the

• To enhance the yield of the EMG study, it is

quadriceps, deltoid, and biceps. The chosen

best to perform the test no sooner than

muscle should be clinically or electrodiagnosti-

3 weeks after symptom onset.

cally affected. Ideally, the muscle should be

Chapter 3

n Clinical Use of Neurologic Diagnostic Tests

seizures. Awareness is retained in simple par-

QUESTIONS AND DISCUSSION

tial seizures. An abnormal routine EEG is not

required to make the diagnosis of epilepsy as

1. A 40-year-old woman presents to the

scalp electrodes may not pick up a deep or

emergency room with the sudden onset of

small focus, particularly during the relative

the worst headache of her life. Head CT is

short recording time. The diagnosis of

normal. What is the most appropriate

epilepsy is a clinical one requiring paroxys-

next step?

mal, stereotypical spells.

A. Send the patient home with pain

medication.

3. Which of the following statements is true

B. Perform a lumbar puncture.

about magnetic resonance imaging?

C. Order a brain MRI.

A. It is safe with certain types of

D. Administer subcutaneous sumatriptan.

pacemakers.

E. Consult a neurointerventionalist to

B. It may be performed if aneurysm clips

perform a cerebral angiogram.

are ferromagnetic.

The correct answer is B. In patients with sudden

C. It may cause nephrogenic systemic

onset of a new, severe headache, it is imperative

fibrosis if gadolinium is used in the

to evaluate for subarachnoid hemorrhage

setting of renal dysfunction.

(SAH). A noncontrast head CT is the appropri-

D. It is readily available and easier to

ate emergent initial diagnostic study. Approxi-

perform than CT in patients with altered

mately 10% of hemorrhages, however, either

mental status.

based on size or location, may be missed on CT.

E. It is better than CT for detecting acute

MRI is also not 100% sensitive in detecting

blood.

SAH. In such cases, lumbar puncture is essential

The correct answer is C. Gadolinium may in-

to further evaluate the clinical suspicion. Send-

duce nephrogenic systemic fibrosis in patients

ing the patient home or administering a potent

with renal insufficiency. MRI is contraindicated

vasoconstrictor such as sumatriptan could po-

in patients with all types of pacemakers and

tentially be catastrophic. A cerebral angiogram

ferromagnetic material due to the risk of device

would be appropriate to look for an aneurysm

malfunction and movement that may be fatal.

if the CSF shows evidence for SAH.

CT is more readily available than MRI and

may be performed quicker in confused patients

2. A 23-year-old man presents with recurrent

as it does not require the same degree of immo-

1 to 2 minute episodes of speech arrest and

bility and cooperation. CT is the imaging study

right facial twitching. He is completely

of choice for acute hemorrhage.

aware of what happens. Which of the

following is required to diagnose epilepsy

4. A 35-year-old woman with hepatitis C

in this patient?

presents with painful, burning feet.

A. Paroxysmal, stereotypical spells

Examination reveals symmetric, stocking

B. Loss of consciousness

distribution of sensory loss to pain and

C. An abnormal EEG

temperature. Position and vibration are

D. Convulsions

normal. EMG and nerve conduction studies

E. Tongue biting

are normal. Which of the following

The correct answer is A. Since the brain has

conditions is most likely in this patient?

localized areas of function, seizures may fo-

A. Lumbar polyradiculopathy

cally emanate from and remain confined to an

B. Large fiber polyneuropathy

area outside the motor strip and therefore, not

C. Mononeuritis multiplex

cause convulsions. Loss of consciousness and

D. Small fiber neuropathy

tongue biting do not occur with all types of

E. Myositis

Chapter 3

n Clinical Use of Neurologic Diagnostic Tests

The correct answer is D. The patient presents

or with the duration the patient is kept supine

clinically with a small fiber neuropathy. Pro-

after the procedure. Clinically, patients are

prioception and vibration perception are trans-

asymptomatic while supine (position of high-

mitted by large caliber nerve fibers. Of the

est CSF pressure) and the headache develops

answers listed, the best choice is small fiber

when they sit or stand. Hydration, caffeine,

neuropathy as dysfunction of these nerve fibers

and rest are recommended for management

is not detected on routine nerve conduction/

of these headaches. A blood patch may be

EMG studies.

required for refractory post-LP headaches.

5. Which of the following features is most

consistent with a post-lumbar-puncture

SUGGESTED READING

headache?

A. It worsens when patients lie down.

Bradley WG, Daroff RB, Fenichel GM, et al. Neurology

in Clinical Practice. Volume I: Principles of Diagnosis

B. It promptly improves or resolves with

and Management. 5th ed. Philadelphia, PA: Butter-

standing.

worth, Heinemann, Elsevier; 2008.

C. A blood patch may be necessary for

Ellenby MS, Tegtmeyer K, Lai S, et al. Videos in clinical

treatment.

medicine. Lumbar puncture. N Engl J Med.

D. The CSF opening pressure is high.

2006;355:e12.

E. It is more likely to occur with use of a

England JD, Gronseth GS, Franklin G, et al. Practice pa-

small diameter needle.

rameter: evaluation of distal symmetric polyneuropa-

thy: role of autonomic testing, nerve biopsy, and skin

The correct answer is C. A post-dural-

biopsy (an evidence-based review). Neurology.

puncture or low-CSF-pressure headache may

2009;72:1-8.

occur in patients after lumbar puncture, par-

Goetz CG. Textbook of Clinical Neurology. 3rd ed.

ticularly when large diameter spinal needles

Philadelphia, PA: Saunders, Elsevier; 2007.

are used. Occurrence of the headache is not

Osborn AG. Diagnostic Neuroradiology. St. Louis, MO:

associated with the amount of fluid removed

Mosby-Yearbook, Inc.; 1994.

Fundamentals of

Neuroradiology

ROBERT E. MORALES AND DISHANT G. SHAH

key points

• Neuroradiologic images must always be evaluated in a

systematic fashion with an understanding of

fundamental neuroimaging concepts. Otherwise, not

only can certain findings be overlooked, but one may

quickly proceed down the wrong diagnostic path.

• Only after these basic concepts are understood, should

one focus on specific imaging features of particular

disease processes.

• Once a lesion is identified, it should be initially

characterized by its location and by the type of edema

that may be present. Only after these features are

analyzed, should the CT density characteristics, MR

signal characteristics, and possible contrast

enhancement patterns be considered.

euroradiology

This chapter will review some of the funda-

has come a long way from the days when in-

mental principles of neuroimaging. Initially, the

tracranial lesions were indirectly imaged. Air

individual modalities of CT and MRI as well as

was placed into ventricles and contrast was in-

the utility of contrast administration will be dis-

jected into vessels to look for mass effect on

cussed. Basic topics will then be reviewed that

these structures that would then suggest adja-

form the foundation of image interpretation.

cent intracranial pathology. Fortunately, how-

These include the imaging findings of herniation

ever, times have changed. We now have

and mass effect, hydrocephalus and volume

advanced tools to image lesions directly and

loss, cytotoxic and vasogenic edema, and intra-

less invasively. Magnetic resonance imaging

axial and extra-axial masses. A brief discussion

(MRI) and computed tomography (CT) have

of spinal imaging will follow. Finally, due to

become powerful instruments that not only de-

their relatively common occurrence and particu-

pict these lesions but also can further charac-

larly critical clinical implications, intracranial

terize them. Often an abbreviated differential

hemorrhage and cerebral ischemia/infarction

diagnosis can be suggested.

will be specifically addressed.

Chapter 4

■ Fundamentals of Neuroradiology

nullifies the bright CSF signal (free water) on

COMPUTED TOMOGRAPHY VERSUS

the T2-weighted images, hence turning the

MAGNETIC RESONANCE IMAGING

CSF into a dark signal. Thus, pathology seen

on T2-weighted images may be more conspic-

The physics of CT and MRI is complex and be-

uous on this sequence. This is particularly evi-

yond the scope of this chapter. In its most basic

dent in the periventricular white matter and at

form, CT uses ionizing radiation to generate

the cortex where, on T2-weighted images, the

cross-sectional images from x-ray absorption

lesions may be somewhat obscured by the

of the tissues examined. MR images are gener-

bright signal in the ventricles and sulci, respec-

ated using principles of in vivo magnetism and

tively (Fig. 4.1).

capturing signal from water and organic mole-

cules that produce a magnetic field.

■ SPECIAL CLINICAL POINT: A useful

When discussing CT, structures are character-

approach when interpreting an MRI study is

ized with regard to their density or attenuation

to initially utilize the T1-weighted images to

(of the x-ray beam), just as in the interpreta-

evaluate the anatomy and underlying structure

tion of plain x-ray films. Metal, bone, and cal-

of the brain including the ventricles and CSF

cification are densest (brightest), acute blood is

spaces. Since many pathologic processes result

in surrounding edema, which is very high in

denser than soft tissue, water is denser than fat,

signal and more conspicuous on the

and air is the least dense (darkest). The density

T2-weighted images, this sequence is then utilized

is measured in Hounsfield units (HU) with water

to evaluate for underlying subtle pathology. If a

having a HU of zero. Higher HU are meas-

lesion is detected, the signal characteristics on

ured in bone, blood, and soft tissue, whereas

the T1- and T2-weighted images, as well as the

fat and air have HU in the negative range. This

possible presence and pattern of contrast

is an important fact to remember as HU meas-

enhancement, are then evaluated to more

urement and density characteristics are often

specifically characterize the lesion.

reported in radiology reports while characteriz-

ing findings on CT.

The T1- and T2-weighted pulse sequences are

In MRI, structures are characterized with re-

essentially the foundation of MRI. Other se-

gard to their signal or intensity. There are now

quences such as FLAIR and diffusion-weighted

more than 20 sequences used in MRI for tissue

imaging have been developed to increase the sen-

characterization. In general, the basic sequences

sitivity of detecting lesions and to add more in-

are T1 and T2. T1-weighted images are superior

formation when characterizing them.

in depicting anatomic detail. Postcontrast images

Diffusion-weighted imaging has revolution-

are nearly always T1-weighted images. Bright

ized the ability to image acute infarction. This se-

T1 signal is seen in fat, subacute hemorrhage

quence detects the change in Brownian motion

(intracellular and extracellular methemoglobin),

of water molecules in injured tissue. Restricted

proteinaceous fluid, melanin, occasionally calci-

diffusion signifies cell injury and appears as

fication and with the use of contrast (gadolin-

bright signal on the diffusion-weighted images

ium). Bright T2 signal is seen in substances or

(with corresponding dark signal on apparent dif-

tissue with relative higher watercontent such as

fusion coefficient [ADC] map images). This se-

cerebrospinal fluid (CSF), edematous/inflamed

quence generally takes less than a minute to

tissue, gliotic/encephalomalacic tissue, certain

obtain and is highly sensitive in acute infarction.

stages of hemorrhage (oxyhemoglobin and ex-

For all practical purposes, diffusion restriction

tracellular methemoglobin), and occasionally fat

can be seen essentially at the time of onset of an

(if a fast technique of obtaining the T2-weighted

acute infarct. Although diffusion-weighted imag-

images is utilized). FLAIR

(fluid attenuated

ing is usually utilized to evaluate for acute infarc-

inversion recovery) sequence in basic terms,

tion, other lesions/substances, including highly

Chapter 4

■ Fundamentals of Neuroradiology

FIGURE 4.1 MR and CT evaluation of a right frontal meningioma. A: On T1-weighted MRI, the CSF

is low in signal intensity. The white matter is higher in signal intensity than the cortex. The dural-based

lesion (arrow) is subtle. B: On T2-weighted MRI, the CSF is high in signal intensity. The cortex is higher

in signal intensity than the white matter. The lesion (long arrow) is lower in signal than the adjacent

CSF. A small nonspecific subcortical white matter lesion (short arrow) is questioned although this may

also represent a sulcus. C: MR FLAIR imaging is similar to T2-weighted imaging except that free

water (CSF) is suppressed and is low in signal intensity. The lesion (long arrow) is more conspicuous

and the white matter lesion (short arrow) is confirmed since the CSF in the sulci is low in signal.

D: Postcontrast T1-weighted MRI demonstrates enhancement of the lesion (arrow), confirming it is

solid. The mass is much more conspicuous. E: A CT image with bone windowing demonstrates

hyperostosis (arrows) of the inner and outer tables of the calvarium adjacent to the mass suggesting

a meningioma.

cellular tumors and purulent material can also

MRI has superior contrast resolution com-

restrict diffusion. These characteristics can be

pared to CT, and in all but a few instances, it is

particularly helpful when evaluating for possible

superior to CT in evaluating the soft tissues of

underlying intracranial abscess or purulent

the central nervous system (CNS). CT is, how-

collection.

ever, much better in detecting and characterizing

Chapter 4

■ Fundamentals of Neuroradiology

osseous abnormalities. CT is superior to MRI in

guidelines when performing CT and MRI in

evaluating cortical bone and is used commonly

pregnant patients.

in evaluating trauma patients for underlying

MRI is also usually contraindicated in pa-

fractures. In contrast, MRI is more sensitive in

tients with implanted electronic devices such as

evaluating the marrow spaces for underlying

cardiac pacemakers, defibrillators, cochlear im-

edema or other infiltrating processes. As a result,

plants, and nerve stimulators. It is also con-

it is useful in the imaging of infection and neo-

traindicated if the patient has ferromagnetic

plasms. For all practical purposes, CT has better

clips or foreign bodies that lay on or in close

spatial resolution than MR and can be used in

proximity to delicate structures such as the

evaluating structures as small as 0.625 mm with

globes, brain, spinal cord, and nerves. There are

current multislice detector scanners.

resources, including websites, that can be used

as a source of reference to determine if a specific

■ SPECIAL CLINICAL POINT: Although MRI

device is MR compatible. All patients need to be

is superior to CT at imaging nearly all the

screened prior to MRI to ensure safety.

nonosseous components of the central nervous

Current scanner and postprocessing tech-

system, CT remains the imaging study of choice

nologies have enabled us to further advance

in the evaluation of acute intracranial

our abilities to detect CNS pathology. CT an-

hemorrhage, particularly acute subarachnoid

giography (CTA) and MR angiography (MRA)

hemorrhage. MRI, however, is probably more

sensitive if the onset of symptoms was a few

have become essential tools in the imaging

days prior.

evaluation of neurovascular disorders such as

in the work-up for infarcts, vascular injury,

Given the increased availability of CT scan-

and vascular lesions, such as arteriovenous

ners, faster turnaround time in obtaining the

malformations (AVM) and aneurysms. Con-

study, and cheaper cost, CT remains the main-

ventional angiography continues to remain the

stay of emergent imaging.

gold standard for neurovascular evaluation if

In a few instances, MRI is the initial study of

noninvasive techniques do not provide ade-

choice. Since MRI is much better in evaluating

quate information. CT and MR perfusion ima-

the thecal sac and spinal cord, emergent MRI

ging are being used more in the setting of acute

of the spine is indicated for the work-up of pos-

stroke to evaluate for salvageable tissue. MR

sible cord compression or intrinsic cord lesion as

perfusion data can also be helpful in distin-

well as in the evaluation for spinal infection. In

guishing recurrent neoplasm from radiation

some institutions, MRI with limited sequences,

necrosis in neuro-oncology. Advanced MR

including diffusion-weighted imaging, is per-

techniques such as MR spectroscopy, func-

formed emergently as part of the stroke center

tional MRI, and diffusion tensor imaging are

“brain attack” protocol.

now often being used in daily clinical practice

Although both CT and MRI have tremendous

to answer specific questions. The ability to

use in the work-up of neurologic disorders, one

detect and characterize CNS pathology rapidly

must be aware of the potential disadvantages

continues to improve with advances in techno-

and contraindications when ordering a study.

logy and with the development of newer pulse

CT uses ionizing radiation, and cumulative

sequences. The trend is always toward obtain-

doses over time may increase the risk of

ing superior images with faster imaging.

developing cancer. This risk is higher in the

pediatric population due to growing cell lines.

Every institution has specific imaging proto-

CONTRAST VERSUS NONCONTRAST

cols, which use lower radiation in the pediatric

population; however, this risk must be kept in

The question of whether to administer contrast

mind while ordering any study with

is a common one. Contrast agents used in CT

ionizing radiation. Likewise, there are also

and MRI have risk factors, and screening for

Chapter 4

■ Fundamentals of Neuroradiology

possible adverse events must be done before or-

characterization of a stenosis or lesion is war-

dering a study with contrast.

ranted. Another use of contrast is in CT myel-

ography where contrast is injected into the

■ SPECIAL CLINICAL POINT: Contrast is not

thecal sac followed by CT of the spine. This is

typically necessary when evaluating for acute

particularly useful when MRI is contraindi-

ischemia or in the setting of trauma. Contrast

cated or in the postsurgical patient where MRI

should be considered when an underlying

can be limited due to metallic artifact of under-

infectious/inflammatory process or neoplasm is

lying hardware.

suspected.

Iodinated contrast agents used with CT have the

HERNIATION AND MASS EFFECT

potential to elicit allergic reactions and can be

nephrotoxic in patients with poor renal function.

The first step in evaluating the brain is to deter-

Preventive measures including steroid pretreat-

mine if there is impending herniation that

ment, in patients with a known contrast allergy,

would indicate emergent intervention. On

and hydration, in patients with compromised

axial imaging, it is useful to evaluate the ventri-

renal function, are often performed. The con-

cles and basal cisterns to determine whether

trast agents used for MRI are molecular forms of

they are effaced (compressed), suggesting mass

gadolinium. Although gadolinium-based con-

effect or herniation. Sagittal and coronal re-

trast agents have a lower propensity to cause al-

constructions can often also be performed to

lergic reactions, recent literature has associated

directly visualize the degree of herniation.

nephrogenic systemic fibrosis (NSF) with expo-

Effacement of the fourth ventricle is a marker

sure to gadolinium in patients with renal impair-

for tonsillar herniation, particularly if the

ment. As a result, an accurate medical history

process is supratentorial (a lesion in the cerebel-

and renal function tests (blood urea nitrogen and

lum can efface the fourth ventricle without nec-

creatinine) are often indicated prior to contrast

essarily resulting in overt tonsillar herniation).

administration of either iodinated CT contrast

Evaluation of the posterior fossa with newer CT

or gadolinium-based contrast agents.

technology is much better than on older scan-

ners where the foramen magnum was obscured

■ SPECIAL CLINICAL POINT: Enhancement

by streak artifact. In addition, if there is any

in abnormal tissue is related to breakdown of

question, sagittal reconstructions can be per-

the blood-brain barrier with leakage of

formed to directly visualize the tonsils. Efface-

contrast. Almost any lesion can demonstrate

ment of the quadrigeminal plate cistern (behind

an element of enhancement, particularly mild,

the superior and inferior colliculi) is a marker

linear enhancement along its periphery.

for transtentorial herniation. If the lesion is

However, nodular, solid enhancement is more

supratentorial, it signifies downward herniation

suggestive of an underlying neoplasm.

across the tentorium. If the lesion is infratentor-

There are, of course, exceptions as certain

ial, it signifies upward herniation across the ten-

nonneoplastic lesions can have nodular enhance-

torium. Effacement of the suprasellar cistern is a

ment such as tumefactive multiple sclerosis. In

marker for uncal herniation

(another form

addition, not all neoplasms enhance. Specifically,

of transtentorial herniation), where the medial

low-grade astrocytomas typically do not enhance.

temporal lobe protrudes into the suprasellar

As discussed in the section on CT versus

cistern, over the tentorium. Shift of the midline

MRI, CTA and MRA are also used to evaluate

structures and septum pellucidum is usually

the vasculature. Of note, MRA can be done

more obvious with displacement of the lateral

without contrast using time of flight (TOF)

ventricles/third ventricle across the midline. This

technique. Contrast-enhanced MRA can be

represents subfalcine herniation. When this is

performed in cases where the TOF technique

more advanced, the foramen of Monro becomes

is limited due to artifact or more accurate

effaced, and dilatation of the contralateral

Chapter 4

■ Fundamentals of Neuroradiology

FIGURE 4.2 Comparison of normal anatomy with herniation in a patient with a large subdural

hemorrhage. Normal images are on top of each figure. A: Tonsillar herniation is evidenced by

effacement and obliteration of the fourth ventricle (arrow). B: Transtentorial herniation is noted by

effacement of the quadrigeminal plate cistern (arrow). C: Subfalcine herniation is noted by shift of the

lateral and/or third ventricle across the midline. Enlargement of the contralateral lateral ventricle

(arrowheads) indicates entrapment due to obstruction at the foramen of Monro.

lateral ventricle develops (ventricular trapping)

adjacent cisterns or portions of the ventricles. Al-

(Fig. 4.2).

though this may be a subtle finding, it is impor-

Herniation is problematic for a variety of rea-

tant as it may be the only clue to suggest adjacent

sons. Parenchyma and other neural structures

pathology that is not otherwise directly visual-

can be compressed, and vessels can be compro-

ized. Mass effect in general indicates that the un-

mised. Tonsillar herniation compresses the

derlying process is active. For example, edema

medulla and can depress the centers for respira-

and gliosis/encephalomalacia will both demon-

tion and cardiac rhythm control. Transtentorial

strate decreased density on CT, decreased signal

herniation can compress the posterior cerebral

on T1-weighted MRI, and increased signal on

arteries and cause infarction. It can also result in

T2-weighted MRI. Edema, however, will result

midbrain compression and hemorrhages, likely

in mass effect with displacement/compression

from tearing of small parenchymal vessels

of adjacent structures. Gliosis/encephalomalacia

(Duret hemorrhage) (Fig. 4.3).

will result in the opposite effect with widening of

The mass effect may not be severe enough to

the adjacent CSF spaces due to the loss of

result in herniation but can efface local sulci and

parenchymal volume.

Chapter 4

■ Fundamentals of Neuroradiology

FIGURE 4.3 Sequelae of transtentorial herniation. A: A diffusion-weighted image demonstrates

acute posterior circulation infarcts in a patient with transtentorial herniation, and compression of the

vessels, due to a subdural hemorrhage. There are bilateral posterior cerebral artery territorial infarcts,

within the occipital cortex, and bilateral thalamic infarcts. B: Gradient echo MRI at the level of the

pons demonstrates linear area of susceptibility artifact. This is consistent with a Duret hemorrhage

with the low signal due to blood products.

cephalus where the obstruction of CSF drainage

HYDROCEPHALUS VERSUS

is along the ventricular outflow. Typically this is

VOLUME LOSS

at the cerebral aqueduct or foramen of Monro,

due to the smaller caliber of these passages.

After determining whether the ventricles and

Communicating hydrocephalus refers to ob-

sulci are effaced or displaced, signifying mass

struction at the level of the arachnoid villi as the

effect, one should make a judgment as to

CSF drains into the dural venous sinuses. This

whether the ventricles and sulci in general are

can be due to such etiologies as infectious/in-

normal in size. When the ventricles are en-

flammatory meningitis, subarachnoid hemor-

larged, it can be due to volume loss or hydro-

rhage

(SAH), and neoplasm (carcinomatous

cephalus. If the ventricles are enlarged and the

meningitis). In communicating hydrocephalus,

sulci are also enlarged, it suggests volume loss

all of the ventricles are enlarged.

either due to atrophy or lack of development of

Once hydrocephalus is diagnosed, a quick

the parenchyma (in pediatric patients). In the

method of evaluating for obstructive versus

closed intracranial system, when there is loss of

communicating hydrocephalus is to evaluate

volume of the parenchyma, the CSF spaces dif-

the fourth ventricle. If the fourth ventricle is

fusely must widen to compensate for the space

normal in size, there is likely obstructive hy-

previously taken up by the parenchyma. If the

drocephalus (Fig. 4.5). If the fourth ventricle is

ventricles are enlarged but the sulci are not

also dilated, communicating hydrocephalus is

widened, or especially when they are narrow, it

more likely. Obstructive hydrocephalus from

suggests hydrocephalus with the enlarged ven-

obstruction at the foramen of Luschka and

tricles taking up space and causing effacement

Magendie will result in an enlarged fourth ven-

of the surrounding sulci (Fig. 4.4).

tricle, but this is uncommon. Normal pressure

If hydrocephalus is established, the next step

hydrocephalus appears similar to communicat-

is to determine whether the cause is noncom-

ing hydrocephalus. Often it is difficult to deter-

municating

(obstructive) or communicating.

mine whether there is an element of mild

Obstructive hydrocephalus refers to hydro-

Chapter 4

■ Fundamentals of Neuroradiology

FIGURE 4.4 Atrophy versus hydrocephalus. A: A CT image of the head demonstrates cerebral

atrophy as noted by prominence of the ventricles and sulci. The CSF spaces diffusely enlarge to occupy

the space formed by the parenchymal loss. B, C: CT images in a different patient demonstrate

widening of the ventricles with effacement of the sulci. The ventricles are enlarged due to

communicating hydrocephalus caused by poor functioning arachnoid villi/granulations in this patient

with subarachnoid hemorrhage.

communicating hydrocephalus or central vol-

CYTOTOXIC VERSUS

ume loss. Widening of the temporal horns, a

VASOGENIC EDEMA

convex margin of the lateral walls of the third

ventricle, and a stretched appearance of the

The identification of edema indicates an acute

corpus callosum are more suggestive of under-

or active process. It is critical to determine

lying hydrocephalus.

whether cytotoxic edema, vasogenic edema or

FIGURE 4.5 Aqueductal stenosis. A: An axial T2-weighted image demonstrates widening of the

lateral (long arrow) and third (short arrow) ventricles and effacement of the sulci, suggesting

hydrocephalus. B: A sagittal T1-weighted image demonstrates the fourth ventricle (long arrow) to be

normal in size, suggesting obstructive hydrocephalus at the level of the cerebral aqueduct of Sylvius.

The aqueduct (short arrow) is noted to be widened at its superior aspect but narrowed inferiorly

without evidence of an underlying mass. This is consistent with aqueductal stenosis.

Chapter 4

■ Fundamentals of Neuroradiology

FIGURE 4.6 Cytotoxic edema. A, B: CT images from two patients with acute cerebral infarctions

(arrowheads in A) demonstrate cytotoxic edema as noted by “loss of the gray-white matter

differentiation,” sulcal effacement and also a component of vasogenic edema, with low density within

the underlying white matter.

both are present. In its simplest form, cytotoxic

any underlying insult. However, if the cortex is

edema implies cell injury to the cell body of the

involved (cytotoxic edema), the differential di-

neuron in the cortex with failure of the

agnosis is much more limited. Diagnostic con-

sodium-potassium pump and cell swelling. Va-

siderations in this category most commonly

sogenic edema implies breakdown of the

include infarction and encephalitis. Although

blood-brain barrier with fluid extending to the

encephalitis is much less common, it is an im-

interstitial space and is much less specific with

portant process to always consider. In the right

regard to the etiology of the insult.

clinical context, posttraumatic cortical contu-

Cytotoxic edema is swelling of the neurons in

sion, edema from seizure activity, and an under-

the cortex. Normally, the cortex is slighter hyper-

lying glioma also can have this appearance. If

dense relative to the underlying white matter. On

the etiology of the cytotoxic edema is unclear,

CT , cytotoxic edema causes the cortical density

and nearly in all cases when vasogenic edema

to decrease, approaching that of the underlying

alone is identified, contrast should be adminis-

white matter. This is classically described as

tered in order to evaluate for an underlying le-

“loss of the gray-white matter differentiation”

sion and to better characterize the findings.

(Fig. 4.6). When there is cytotoxic edema, there

is also often a component of vasogenic edema.

Vasogenic edema is interstitial edema within

INTRA-AXIAL VERSUS EXTRA-AXIAL

the white matter usually due to breakdown of

the blood-brain barrier. The overlying cortex is

If an intracranial mass is identified, the first step

spared since the neuron itself is not directly in-

is to determine whether it is intra-axial or extra-

jured. On CT , vasogenic edema appears as de-

axial in location. Intra-axial refers to the lesion

creased density of the fluid tracking along the

being located within the brain parenchyma.

white matter. This is classically described as a

Extra-axial refers to the lesion being outside the

“finger-in-glove” appearance (Fig. 4.7).

brain but within the confines of the calvarium.

Since many pathologic processes result in

In general, intra-axial lesions are surrounded by

breakdown of the blood-brain barrier, resulting

brain parenchyma, whereas extra-axial lesions

in interstitial edema, vasogenic edema is non-

displace brain parenchyma (Fig. 4.8). Intra-axial

specific and can be associated with essentially

lesions rarely produce changes in the adjacent

Chapter 4

■ Fundamentals of Neuroradiology

FIGURE 4.7 Vasogenic edema. A: A CT image demonstrates vasogenic edema (arrows) as

evidenced by a “finger-in-glove” pattern where the edema is within the white matter, sparing the

overlying cortex. B: A contrast-enhanced CT image in the same patient demonstrates an intensely

enhancing mass as the underlying etiology for the vasogenic edema in the left hemisphere. An

additional lesion was present in the contralateral hemisphere. These represented metastatic lesions.

calvarium, whereas extra-axial lesions can occa-

hance, it is typically either an arachnoid cyst, epi-

sionally thin or even thicken it. Meningiomas

dermoid/dermoid, or lipoma, unless hematoma

can cause hyperostosis and thickening of the ad-

or other fluid collection, including an infected

jacent osseous cortex as well as thickening of the

collection, is suspected. If it enhances, in a solid

adjacent dura (dural tail).

fashion, it is typically either a meningioma,

Accurately locating the lesion is essential as

schwannoma, meningeal-based metastasis/lym-

the differential diagnosis is dependent on this

phoma, or occasionally an inflammatory mass

feature. If a lesion is extra-axial, the differential

from perhaps granulomatous disease. Metastases

diagnosis is much more limited. If it does not en-

and lymphoma are often considered together in

FIGURE 4.8 Intra-axial versus extra-axial masses. A: A postcontrast T1-weighted image demonstrates

an enhancing intra-axial mass (glioma) (arrow) within the left occipital lobe. The mass is surrounded by the

parenchyma. B: A postcontrast T1-weighted image demonstrates a heterogeneously enhancing extra-axial

mass (meningioma) (long arrow) within the interhemispheric fissure, displacing the frontal lobes bilaterally.

The anterior cerebral arteries (short arrows) are displaced posteriorly.

Chapter 4

■ Fundamentals of Neuroradiology

neuroimaging since they are typically included in

from compression by adjacent degenerative

the differential diagnosis of any enhancing lesion

changes, is of course specific to the spine.

throughout the CNS.

CT is particularly useful for evaluating the

If the lesion is intra-axial, then the differen-

osseous structures, in the setting of trauma, and

tial diagnosis is much more extensive with

for evaluating surgical hardware in postopera-

regard to neoplastic, infectious/inflammatory,

tive patients. MRI is the study of choice when

congenital, metabolic, posttraumatic and vas-

evaluating the spinal cord and nonosseous sur-

cular processes. In all of neuroradiology, accu-

rounding structures of the spine such as the in-

rate location of a lesion is perhaps the single

tervertebral discs, ligaments, and epidural space.

most important factor in developing an appro-

Contrast is useful if infection, neoplasm, or an

priate differential diagnosis. This is particu-

underlying vascular lesion is suspected. If there

larly evident in imaging the spine where the

has been prior surgery, contrast can help distin-

differential diagnosis can be significantly nar-

guish between epidural scar formation, which

rowed once an accurate location of the lesion is

enhances, and recurrent disc herniations, which

determined.

typically do not. This is more of an issue within

the lumbar spine since significant scar forma-

tion is less common within the cervical spine.

SPINE IMAGING

Imaging of the spine is discussed briefly. The

INTRACRANIAL HEMORRHAGE

spinal cord is essentially an extension of the

brain so the differential diagnosis of in-

Evaluating for the presence of intracranial hem-

tramedullary (intra-axial) and extramedullary

orrhage is a common task in neuroimaging. The

(extra-axial) lesions is similar. Since the most

four types of hemorrhage, originating from su-

common lesions of the spine are related to de-

perficial to deep, include epidural, subdural, sub-

generative changes and trauma to the spinal

arachnoid, and intraparenchymal hemorrhage.

column, which lie outside of the dura, the ex-

Epidural hematomas are located outside the

tramedullary compartment is further divided

dura. Subdural hematomas are located between

into two components, the extramedullary in-

the dura and arachnoid membranes. Subarach-

tradural and the extradural spaces. Extradural

noid hemorrhage (SAH) is located between the

pathology includes posttraumatic lesions, de-

arachnoid and pia mater, within the CSF space.

generative changes such as osteophytic spurs

Intraparenchymal hemorrhage is located within

and disc herniations, osseous neoplasms, and

the parenchymal substance of the brain.

epidural masses and collections. The ex-

Epidural and subdural hemorrhages are typi-

tramedullary intradural lesions are the same le-

cally due to trauma. The classic epidural

sions considered in the intracranial extra-axial

hematoma is due to a temporal bone fracture,

space. Lesions within the cord itself are consid-

with injury to the middle meningeal artery. Ve-

ered intramedullary in location (Fig. 4.9).

nous epidural hematoma formation can occur if

The differential diagnosis of intramedullary

the dural venous sinuses are torn. This is report-

lesions of the spinal cord is similar to the intra-

edly more common in pediatric patients. Sub-

axial lesions in the brain, although neoplasms

dural hemorrhages are typically due to a tear in

are less common within the spinal cord than

perforating veins. They are more prone to tearing

within the brain. Spinal cord neoplasms usu-

after less severe trauma if they are already

ally enhance; in contrast, nonenhancing glial

“stretched” due to the presence of volume loss

tumors are common in the brain. Demyelinating

or a preexisting subdural collection. Epidural

disease is relatively common in the spinal cord,

hematomas exist between the calvarium and the

whereas infarcts are much less common than in

dura with the dura being stripped away from the

the brain. Parenchymal signal abnormality,

overlying bone. It usually takes some force to

Chapter 4

■ Fundamentals of Neuroradiology

FIGURE 4.9 Intramedullary, extramedullary/intradural, and extradural spine lesions. A: A sagittal

T2-weighted image demonstrates an intramedullary lesion (astrocytoma) (arrow) expanding the cord.

B, C: A sagittal T1-weighted image (B) and an axial image from a CT myelogram (C), demonstrate

an extramedullary, intradural mass (meningioma) (long arrow) displacing the cord (black arrow in C)

and widening the immediately adjacent subarachnoid space (short arrows in B and C) as the dura

stays on the outside of the lesion. D: A sagittal T2-weighted image demonstrates an extradural lesion

(osseous metastasis) (arrow) displacing the cord and effacing the thecal sac.

accomplish this, with the underlying hematoma

the arachnoid. Since this type of hematoma can

being under an element of pressure. As a result,

more easily extend along this potential space, it

this type of hematoma usually has a convex

usually maintains a concave border along the

margin against the brain (Fig. 4.10). Epidural

brain (Fig. 4.11). Since they are deep to the dura,

hematomas can cross the midline but typically

they can cross the sutures, but they are limited by

do not cross the sutures, where the dura is adher-

the dural reflections of the falx and tentorium.

ent to the calvarium. Subdural hematomas exist

They do not cross the midline and instead extend

within the potential space between the dura and

along the falx.

Chapter 4

■ Fundamentals of Neuroradiology

FIGURE 4.11 CT demonstrates a large layering

FIGURE 4.10 CT demonstrates an epidural

subdural hematoma with a concave margin along the brain

hematoma (arrow) in the right frontal region with a

parenchyma.

convex margin along the brain parenchyma.

Epidural hematomas tend to cause more

cular or neoplastic lesion, however, should

focal, local mass effect due to their shape and

always be considered. If the patient is young

resistance to diffuse spread. They also can

or without significant medical history, an un-

grow rapidly as the patient goes from the

derlying AVM needs to be excluded.

“lucid interval” to losing consciousness. How-

In any intraparenchymal hemorrhage, the

ever, the overall volume of a subdural hemor-

differential diagnoses to consider include con-

rhage along one hemisphere is typically larger

tusion (if there is a history of trauma and par-

and can be underestimated. Even a thin layer of

ticularly if the hemorrhage is located in the

hemorrhage extending along the whole hemi-

anterior/inferior frontal lobes or anterior tem-

sphere cumulatively can result in a large vol-

poral lobes), hypertensive hemorrhage (again

ume of blood.

particularly within the basal ganglia and thal-

SAH is most commonly caused by trauma.

amus) (Fig. 4.13), hemorrhagic conversion of

In cases of spontaneous SAH, aneurysm rup-

arterial or venous infarcts, underlying vascular

ture is the most likely etiology. Since the vast

majority of aneurysms are located near the cir-

cle of Willis, SAH aneurysm rupture usually

presents with some component of the hemor-

rhage extending into the suprasellar cistern

(Fig.

4.12). This is the star-shaped cistern

above the sella (pituitary fossa) where the circle

of Willis is located.

Intraparenchymal hemorrhage is hemor-

rhage within the substance of the brain. The

etiology for this hemorrhage is more exten-

sive than other types of hemorrhage. If the

hemorrhage originates particularly within the

basal ganglia or thalamus, or occasionally

within the pons or cerebellum, a hypertensive

etiology may be initially suspected in the ap-

FIGURE 4.12 CT demonstrates subarachnoid

propriate clinical setting. An underlying vas-

hemorrhage (arrow) within the suprasellar cistern.

Chapter 4

■ Fundamentals of Neuroradiology

rhage may not only be the cause of the neuro-

logic deficit, but may also likely alter therapy.

Due to ongoing improvements in developing

“stroke centers,” the treatment strategies have

become more sophisticated, and so have the

imaging tools. The goal is to have patients ar-

rive for treatment and be evaluated, as rapidly

as possible, for time sensitive treatment. These

therapeutic interventions include intravenous

tissue plasminogen activator (TPA), intra-arte-

rial thrombolytic therapy, and intra-arterial

mechanical thrombectomy.

Although treatment paradigms continue to

FIGURE 4.13 CT demonstrates a right thalamic

intraparenchymal hemorrhage that has extended into the

change and develop, there are basic principles.

ventricular system.

Initially, if intravenous TPA is to be considered,

the main function of imaging (CT) is to exclude

intracranial hemorrhage and to see if an infarct

lesion

(including AVM, cavernous angioma,

is visible in order to determine its size. If the

and aneurysm), underlying neoplasm, amy-

patient is beyond the intravenous therapeutic

loid angiopathy (if the patient is elderly and

window and/or intra-arterial therapy is con-

has evidence of chronic hemorrhages else-

templated, one of the roles of imaging is to es-

where (best seen with special MR sequences

timate the risk of hemorrhage after potential

[gradient echo])), underlying coagulopathy,

clot lysis/mechanical removal and to determine

and encephalitis.

the ischemic penumbra (viable, potentially sal-

One must also keep in mind that the jet of

vageable tissue). With regard to an increased

blood from a ruptured aneurysm can dissect

risk of hemorrhage in general, thrombolysis is

into the parenchyma and also result in an intra-

often not performed in patients with completed

parenchymal hematoma. Typically, in this lat-

infarcts of greater than one third the MCA ter-

ter scenario, there is also a component of SAH.

ritory or of significant portions of the basal

Occasionally although this is very minimal

ganglia.

such as when a temporal lobe hematoma is

Currently the treatment protocols are struc-

caused by a ruptured middle cerebral artery

tured around designated time intervals from the

(MCA) aneurysm that is embedded in the syl-

onset of symptoms. The goal, however, is to

vian fissure.

eventually base treatment plans around the

physiology of the injured brain parenchyma.

For example, hopefully someday treatment deci-

sions will be based on whether there is ischemia

INFARCT EVALUATION

to the underlying parenchyma versus com-

AND VASCULAR IMAGING

pleted, irreversible infarction as opposed to the

Prior to the advent of MRI, cerebrovascular in-

exact time of the onset of the neurologic deficit.

farcts were often difficult to visualize within

Although the current technique of diffusion-

the first 24 hours. From a basic patient man-

weighted MRI can now effectively determine

agement point of view, CT is still the preferred

whether an infarct has occurred, almost imme-

initial study, not only due to the speed and rel-

diately, it is the task of CT and MR perfusion to

ative ease of acquiring these images, but be-

estimate the ratio of completed infarction to

cause the initial primary diagnostic dilemma is

penumbra. If the volume of parenchyma that

to exclude intracranial hemorrhage. Hemor-

has gone on to completed infarction is relatively

Chapter 4

■ Fundamentals of Neuroradiology

small and there is a lot of tissue that is ischemic

imaging, one must rely on the presence or ab-

and still viable but at risk for infarction, the in-

sence of mass effect when determining whether

terventionalist will likely be more aggressive in

an infarct is recent or chronic, respectively.

pursuing intra-arterial therapy.

Edema from recent infarction and gliosis/

Understanding the utility of CT and MRI in

encephalomalacia from chronic infarction have

evaluating infarcts can be complicated, but

similar density

(CT) and signal intensity

there are a few basic principles. Infarcts may be

(MRI). Edema, however, takes up space and

invisible on CT within the first 24 hours. There

results in mass effect, whereas gliosis/en-

are some early signs of infarction that can be

cephalomalacia results in loss of volume, with

visualized. The “insular ribbon sign” illustrates

compensatory widening of the surrounding CSF

early cytotoxic edema of the insular cortex

spaces

(Fig.

4.15). With diffusion-weighted

such that there is loss of the normal gray-white

imaging, however, new small infarcts can be

matter differentiation between it and the un-

identified essentially immediately and can

derlying external capsule. Thrombus can also

be easily separated from chronic infarcts (Fig.

occasionally be seen within the affected vessel

4.16).

as the “hyperdense MCA sign.” With improve-

CT perfusion imaging can be performed to

ments in scanner technology thrombus can

not only evaluate for infarction but also is-

now occasionally be seen within smaller MCA

chemia. In this technique, a bolus of contrast

branches.

is tracked as it courses through the brain vas-

With the advent of the diffusion-weighted

culature. Parameters such as mean transit

pulse sequence of MRI, acute infarcts are much

time, time to peak, cerebral blood flow, and

more easily detected (Fig. 4.14). This utilizes

cerebral blood volume can be deduced, and

the parameter of restricted diffusion of water

maps can be obtained, depicting areas of in-

across the cell membrane of acutely infarcted

farction and ischemia. MR perfusion serves a

tissue. Without the use of diffusion-weighted

similar role.

FIGURE 4.14 Acute cerebral infarction. A: CT demonstrates somewhat subtle loss of gray-white

differentiation and sulcal effacement in the left frontal-temporal region (arrowheads).

B: Diffusion-weighted MRI clearly shows the area of infarction appearing as markedly hyperintense.

C: Corresponding apparent diffusion coefficient (ADC) map shows this area to be darker than

surrounding normal brain, thus confirming the finding of true restricted diffusion in this acute infarct.

Chapter 4

■ Fundamentals of Neuroradiology

After establishing the presence of possible

technique is performed by imaging the region of

cerebral ischemia or infarction, the vasculature

interest as the contrast bolus traverses the arte-

will need to be evaluated for underlying throm-

rial system. The contrast bolus is administered

bus, stenosis, or occlusion. This can be per-

intravenously, similar to any other CT study.

formed with magnetic resonance angiography

The contrast column is directly visualized, like

(MRA), computed tomography angiography

conventional angiography, and is not affected

(CTA), ultrasound, and/or with conventional an-

by flow-related artifacts, like MRA.

giography. Although conventional angiography

In general, due to its higher spatial resolution,

remains the gold standard in the evaluation of

CTA typically provides a more detailed anatomic

the vasculature, it carries with it a small but def-

evaluation of the vascular system than MRA,

inite risk of infarction and vascular injury.

other than occasionally at the skull base or

With MRA and CTA, numerous sequential

where there is marked vascular calcification. It

axial images are obtained maximizing the con-

does, however, utilize iodinated contrast and ra-

trast between the vessels and the surrounding

diation. Since CTA, at this time, is performed by

tissues. These “raw data” images can then be

imaging typically during a single vascular phase

manipulated by subtracting out the adjacent tis-

(e.g., the arterial phase), flow mechanics cannot

sues and leaving only the vessels. These are then

be evaluated. Flow across luminal narrowing

displayed, and can be rotated, in three dimen-

from a dissection or stenosis cannot be charac-

sions

(Figs.

4.17 and 4.18). Although CTA

terized. Visualization of an early filling vein, to

requires the administration of intravenous con-

suggest an underlying fistula or AVM, also can-

trast, MRA can be performed without contrast.

not be confidently diagnosed. For this type of

It can be easily incorporated as part of a com-

evaluation, angiography is still often necessary.

prehensive study of the brain and vasculature in

Newer scanners, however, are now fast enough

the patient with possible ischemic symptoms or

to image multiple vascular phases. Certain scan-

a questioned underlying vascular lesion. If,

ners can now image a volume of tissue multiple

however, more accurate, detailed evaluation of a

times, although contrast is in the arterial, capil-

stenosis or vascular lesion, such as an aneurysm,

lary, and venous phase, after the administration

is necessary, CTA should be considered. This

of a single bolus.

FIGURE 4.17 MR angiography. A: A single axial image from the MR angiographic raw data

demonstrates increased signal within the patent internal carotid and basilar arteries (arrows). The

remainder of the surrounding parenchyma demonstrates relatively low signal. B: A three-dimensional

reconstructed image of this raw data reveals the circle of Willis.

Chapter 4

■ Fundamentals of Neuroradiology

FIGURE 4.18 CT angiography. A: A single axial image from the CT angiographic raw data, at the

level of the neck, demonstrates dense contrast timed within the arterial structures with a

pseudoaneurysm (arrow) on the left. B: A two-dimensional maximum intensity projection (MIP)

image, in the oblique sagittal plane, better demonstrates the extent of the pseudoaneurysm (arrow).

C: A three-dimensional reconstructed image demonstrates the morphology of the pseudoaneurysm

(arrow). Also notice the detailed anatomy of the osseous structures.

■ SPECIAL CLINICAL POINT: Conventional

angiography is still necessary if the smallest

Always Remember

vessels need to be evaluated, such as in the

• When evaluating a radiologic study, proceed

work-up of certain aneurysms or when

in a systematic fashion and review the study

vasculitis is strongly suspected.

in the same manner every time. This will

decrease the possibility of failing to evaluate a

CONCLUSION

certain anatomic region and overlooking a

lesion. One must not jump immediately to

Neuroradiology is a rapidly changing field; yet,

the pathologic lesion, ignoring the rest of the

the fundamental principles of image interpreta-

study, or hastily come to a diagnosis.

tion remain the same. Detecting a lesion, local-

• Although a lesion may be obvious, sometimes

izing it to a specific anatomic region within the

only subtle signs of mass effect, such as

CNS, characterizing it with regard to its den-

effacement of sulci, ventricles, or other CSF

sity, signal intensity and the presence or lack of

spaces, are present to suggest an underlying

contrast enhancement, and finally developing a

lesion.

differential diagnosis is a common pathway for

• Although the imaging appearance of a lesion

all image interpretation. As one becomes more

can occasionally suggest a specific diagnosis,

experienced, the differential diagnosis be-

one should always entertain other differential

comes more refined, and when the clinical in-

possibilities.

formation is applied, a specific diagnosis can

often be obtained.

Chapter 4

■ Fundamentals of Neuroradiology

A. Territorial infarcts typically have

QUESTIONS AND DISCUSSION

components of both cytotoxic and

vasogenic edema

1. Regarding CT and MRI, which of the

B. Metastatic disease typically demonstrates

following is true?

only vasogenic edema

A. MRI is always better than CT in

C. Encephalitis can have cytotoxic edema,

evaluating for central nervous system

vasogenic edema, or both

pathology

D. Loss of the “gray-white junction/

B. A patient with a metallic hip

interface” implies vasogenic edema

replacement can have an MRI

C. FLAIR imaging can demonstrate

The correct answer is D. Loss of the “gray-

infarcts earlier than all other MR pulse

white junction/differentiation” suggests cyto-

sequences

toxic edema. On CT, the cortex and deep gray

D. Both MRI and CT utilize ionizing

matter structures are more dense than the adja-

radiation

cent white matter. When there is cytotoxic

edema, the relative increased density of the cor-

The correct answer is B. Patients with metal

tex is lost, as the cortex becomes lower in den-

that is screwed into bone, such as with hip

sity to match the underlying white matter.

and knee implants and spinal fusion hard-

ware are able to safely have an MRI study.

4. Regarding intracranial hemorrhage, which

MRI is better than CT at evaluating most

of the following is false?

CNS pathology outside of the osseous struc-

A. Subdural hematomas do not typically

tures; however, CT is the imaging study of

cross the midline as they are limited by

choice in evaluating for acute subarachnoid

the dural reflection of the falx

hemorrhage. CTA also typically gives a more

B. Aneurysm rupture typically results in

detailed evaluation of the vascular system

subarachnoid hemorrhage

than MRA. MR diffusion-weighted imaging

C. The temporal lobe is a typical location

demonstrates infarcts almost as soon as they

for a hypertensive intraparenchymal

happen, earlier than on FLAIR images,

hemorrhage

T2-weighted images or CT.

D. A vascular or neoplastic lesion underlying

an intraparenchymal hematoma may be

2. Regarding hydrocephalus and volume loss,

initially obscured by the hemorrhage

which of the following is false?

A. Widening of both the ventricles and sulci

The correct answer is C. Although hyperten-

is suggestive of volume loss

sive hemorrhages can occur anywhere, they

B. In aqueductal stenosis, the fourth

are typically located in the basal ganglia or

ventricle is typically normal in size

thalamus as well as occasionally in the brain-

C. In communicating hydrocephalus, the

stem and cerebellum. An underlying lesion

fourth ventricle is typically normal in

should always be considered, however, espe-

size

cially when the clinical history is inconsistent.

D. Meningitis and subarachnoid

In addition to the multiple etiologies resulting

hemorrhage can cause communicating

in intracranial hemorrhage, the temporal lobe

hydrocephalus

is a relatively common site for posttraumatic

hemorrhagic contusion, hemorrhagic venous

The correct answer is C. In patients with com-

infarction from transverse sinus thrombosis

municating hydrocephalus, the obstruction is

and occasionally from a ruptured middle cere-

at the level of the arachnoid villi. As a result,

bral artery aneurysm, where the jet of blood

the fourth ventricle is also enlarged.

can be directed predominantly into the

3. Regarding patterns of edema, which of the

parenchyma. Herpes encephalitis can also

following is false?

result in petechial hemorrhage.

Chapter 4

■ Fundamentals of Neuroradiology

5. Regarding extra-axial lesions, which of the

SUGGESTED READING

following is false?

A. Epidermoids typically contain fat

Barkovich AJ, Moore KR, Jones BV, et al. Diagnostic

B. Meningiomas can be relatively dark on

Imaging Pediatric Neuroradiology. Canada: Amirsys;

T2-weighted images, dense on

2007.

noncontrast CT images and demonstrate

Castillo M. Neuroradiology Companion: Methods,

hyperostosis and thickening of the

Guidelines, and Imaging Fundamentals. 3rd ed.

Philadelphia, PA: Lippincott Williams & Wilkins;

adjacent osseous cortex.

2006.

C. Arachnoid cysts should appear similar to

Grossman RI, Yousem DM. Neuroradiology: The Requi-

CSF on all pulse sequences

sites. 2nd ed. Philadelphia, PA: Mosby; 2003.

D. Schwannomas are suggested when a

Harnsberger HR, Osborn AG, Macdonald A, et al. Diag-

mass extends along the expected course

nostic and Surgical Imaging Anatomy: Brain, Head &

of a cranial nerve

Neck, Spine. Philadelphia, PA: Lippincott Williams &

Wilkins; 2006.

The correct answer is A. Epidermoids do

not contain fat. If an extra-axial lesion is

Osborn AG, Blaser SI, Salzman KL, et al. Diagnostic Im-

aging Brain. Canada: Amirsys; 2007.

composed solely of fat, it is likely a lipoma.

If it is heterogeneous with fat, areas of typi-

Ross JS, Brant-Zawadzki M, Moore KR, et al. Diagnostic

Imaging Spine. Canada: Amirsys; 2007.

cally nonenhancing soft tissue and occasion-

ally calcification, a dermoid should be

Willing SJ. Atlas of Neuroradiology. Philadelphia, PA:

W.B. Saunders Company; 1995.

considered.

Neurologic

Emergencies

TRICIA Y. TING AND LISA M. SHULMAN

key points

• Status epilepticus may present with convulsions or

nonconvulsive altered mental status. Treatment must be

rapidly initiated to achieve early seizure termination for

best outcome.

• Delirium, or encephalopathy, may be caused by acute

medical conditions that demand emergency medical or

surgical treatment for infection (i.e., herpes

encephalitis), structural abnormalities (i.e., intracranial

hematoma, cerebellar stroke), or toxic-metabolic

etiologies (i.e., drug intoxication, thiamine deficiency).

• Other central nervous system emergencies that may

require neurosurgical intervention include acute

intracranial hypertension and spinal cord compression.

• Increasing weakness in peripheral nervous system

disorders, such as myasthenia gravis and Guillain-Barré

syndrome, carries the risk of acute respiratory failure.

For this reason, inpatient observation and treatment are

warranted.

• Neuroleptic malignant syndrome is best treated by

discontinuation of dopamine-blocking antipsychotic

medications.

e u r o l o g i c

CENTRAL NERVOUS SYSTEM

emergencies are encountered frequently in the

practice of medicine, and, if unrecognized, they

Status Epilepticus

may progress rapidly to permanent neurologic

Most epileptic seizures are self-limiting, lasting

disability or death. The topics included in this

only seconds to minutes. Seizures that become

chapter represent the more common and treat-

prolonged or repetitive with impaired recovery

able conditions that non-neurologists may

of consciousness are at risk of evolving into sta-

likely encounter. Cerebrovascular emergencies

tus epilepticus (SE), a serious medical emergency.

are discussed separately in Chapter 7.

Chapter 5

■ Neurologic Emergencies

SE is not uncommon, affecting approximately

Nonconvulsive SE is a more heterogeneous

50 patients per 100,000 population yearly with

category that includes absence SE and complex

a mortality rate estimated at up to 20% in

partial SE. Both forms of nonconvulsive SE are

adults. Long-term morbidity from SE includes

characterized by confusion or other altered

chronic epilepsy, cognitive dysfunction, and

mental status with minimal motor manifesta-

focal neurologic deficits.

tions. Patients may exhibit blinking, automa-

The point at which a seizure may be defined

tisms, or fluctuating bizarre behavior. Evidence

as SE has been a matter of debate over the past

from an electroencephalogram (EEG) is impor-

decade. Physiologic evidence for neuronal dam-

tant to support the diagnosis of nonconvulsive

age in animal studies formerly led to the defini-

SE and sometimes, but not always, can help dif-

tion of SE as any seizure or intermittent seizures

ferentiate between absence and complex partial

without recovery of consciousness lasting for

SE. EEG findings may vary from generalized

30 minutes or longer. More recently, however,

epileptiform discharges to focal discharges or

clinical experience has broadened the definition

generalized activity with a focal predominance.

of SE to continuous or repeated seizure activity

Absence SE is believed to have little long-term

without return of consciousness for longer than

neurologic sequelae. Whether complex partial

5 minutes. The shortened time frame reflects a

SE carries a risk of significant neurologic mor-

general push for initiating treatment earlier to

bidity remains controversial. Although several

minimize the potential morbidity and mortality.

series documented no lasting neurologic deficits

Longer seizure duration has been associated

in patients following complex partial SE, there

with a poorer outcome, and the longer a seizure

are others that reported long-term morbidity,

remains untreated, the more difficult it becomes

particularly in those whose seizures were pre-

to abort.

cipitated by acute neurologic disorders. Never-

theless, there is widespread agreement that

■ SPECIAL CLINICAL POINT: To optimize

patients with nonconvulsive SE should be

patient outcome by earlier treatment, the

treated quickly and aggressively to avoid poten-

working definition of SE should be ongoing or

tial adverse outcomes.

repetitive seizures without recovery of

Morbidity and mortality from SE are a result

consciousness for >5 minutes.

of multiple factors including central nervous

The most common type of SE carrying the

system (CNS) damage from the causative illness

greatest risk of morbidity and mortality is gen-

or acute insult that precipitated SE, the meta-

eralized convulsive SE. The seizures are usually

bolic consequences of prolonged convulsive SE,

easy to recognize clinically as tonic-clonic con-

and the neuronal excitotoxic effects of pro-

vulsions of the extremities with complete loss

longed electrical seizure activity. It is recognized

of consciousness. However, generalized con-

that continuous electrical activity for more than

vulsive SE may progress over time from overt

60 minutes, even while correcting for SE-associ-

convulsions to more subtle physical activity

ated metabolic derangements, can result in hip-

such as mild focal twitching or ocular devia-

pocampal damage and probably in more

tion before further evolving to only general-

widespread brain damage as well. Excitotoxic

ized electrical activity with persistent loss of

neuronal injury may be compounded by signif-

consciousness but absence of all physical man-

icant systemic manifestations including hypox-

ifestations. There is a risk of delayed recogni-

emia, metabolic and respiratory acidosis,

tion of generalized SE when patients present

hyperglycemia, hyperthermia, and blood pres-

to the emergency room without overt tonic-

sure fluctuation. With more prolonged SE,

clonic movements, so clinicians must be aware

rhabdomyolysis from prolonged muscle activity

of the signs of nonconvulsive as well as con-

and significant sodium and potassium derange-

vulsive SE.

ments may develop along with renal failure.

Chapter 5

■ Neurologic Emergencies

Cardiac arrhythmias may occur from CNS dys-

abort continued seizure activity after initial

regulation, electrolyte abnormalities, or even

dosing, but activation of emergency services

medications used in the treatment of SE. Labo-

and transfer to an emergency department

ratory investigations commonly demonstrate a

should then be considered in such cases.

peripheral leukocytosis, an acidotic pH, and a

mild cerebrospinal fluid (CSF) pleocytosis.

■ SPECIAL CLINICAL POINT: Rescue

therapy that patients can take at home, such a

The general principles to minimize the mor-

benzodiazepine, can be prescribed for patients

bidity and mortality associated with SE are early

with epilepsy who are at high risk for prolonged

diagnosis, early intervention, and prompt iden-

or acute repetitive seizures and SE.

tification and management of concurrent med-

ical and surgical conditions, including potential

Generalized convulsive SE is a medical emer-

etiologies. The three most common precipitants

gency and should be managed in the emergency

of SE in adults are withdrawal from anticonvul-

department or intensive care unit (ICU) where

sive medications, alcohol withdrawal, and cere-

aggressive measures to provide life support and

bral infarction. Metabolic derangements such as

terminate seizure activity may be best per-

hyponatremia, hyperglycemia or hypoglycemia,

formed. The first steps are to assess vital signs

hypocalcemia, hepatic failure, and renal failure

and evaluate oxygenation. An oral or nasopha-

account for 10% to 15% of the cases reported.

ryngeal airway is inserted, nasotracheal suction

Other recognized etiologies of SE include

is performed, and supplemental oxygen is ad-

anoxia, hypotension, CNS infections (meningi-

ministered if necessary. Oxygenation is evalu-

tis, abscess, encephalitis), tumors, trauma, and

ated by clinical examination, pulse oximetry,

drug overdose.

and arterial blood gas determination. Establish-

ing two intravenous (IV) lines is the next prior-

ity, providing a backup IV access as well as

Treatment of SE

allowing parallel delivery of IV glucose, med-

It has been established that earlier treatment of

ications, and fluids with IV anticonvulsant ther-

SE leads to better patient outcome. To this end,

apy. Simultaneously, venous blood is drawn for

the past decade has seen many options investi-

a complete blood count, electrolytes, glucose,

gated for the prehospital treatment of SE and

calcium, magnesium, blood urea nitrogen, liver

acute repetitive seizures by first-responders—

function tests, anticonvulsant drug levels, toxi-

medical personnel and family members of at-risk

cology screen, and ethanol level. An IV bolus of

patients. Concern for respiratory compromise

50 mL of 50% glucose and thiamine (1 mg/kg)

from treatment administered out of the hospital,

is administered as soon as the IV access is estab-

moreover, has not been substantiated in clinical

lished. Electrocardiographic (ECG) monitoring

trials. In fact, a prehospital SE study found the

is instituted immediately, and vital signs are

rates of respiratory or circulatory complications

monitored throughout the treatment protocol.

after treatment were highest in a placebo group.

Electrographic seizure activity may persist in up

Accepted prehospital options for early SE

to 15% of patients even after anticonvulsant

therapy are currently limited to a rectal benzo-

therapy has suppressed all signs of clinical

diazepine gel (diazepam), particularly for non-

seizure activity. Moreover, seizure activity be-

medically trained persons, and intravenous (IV)

comes difficult to assess clinically when patients

benzodiazepine administration by health care

receive long-acting neuromuscular paralytic

professionals (Table 5.1). Alternative routes of

agents for endotracheal intubation or when

drug administration, including intramuscular

anesthesia is induced for treatment of refrac-

(midazolam), buccal, and nasal routes, are

tory SE. EEG monitoring, therefore, should

under investigation. Prehospital benzodiazepine

begin at the earliest possible opportunity. It

dosing should be repeated once if necessary to

should be emphasized, however, that lack of

Chapter 5

■ Neurologic Emergencies

TABLE 5.1

Management of Status Epilepticus

Objectives

Time Frame

Intervention

Prehospital treatment

>5 minute

1. Recognize SE or acute repetitive seizures

(nonmedical persons)

2. Safety measures, lie patient on side, nothing

inserted in mouth

3. Check blood glucose if appropriate

4. Treat with rescue benzodiazepine:

Adults: Diazepam 10 mg rectally

Children: Diazepam 0.5 mg/kg rectally

Repeat once if needed and activate emergency services

for continued seizure activity

Prehospital (medical

5 to 20 minute

1. Recognize SE

personnel) or initial

2. Assess vital signs and oxygenation

in-hospital treatment

3. Insert oral airway and administer oxygen if necessary

4. Establish two IV lines

5. Draw blood for CBC, electrolytes, glucose, calcium,

magnesium, BUN, LFTs, anticonvulsant levels, toxicology

screen, and ethanol level

6. Begin ECG and EEG^a monitoring

7. Administer IV bolus of thiamine 1 mg/kg and 50 mL

of 50% glucose

8. Treat with benzodiazepine:

Adults: Lorazepam IV 4 mg bolus or Diazepam

IV 10 mg

Children: Lorazepam IV 0.1 mg/kg (maximum

4 mg) or

Diazepam IV 0.3 mg/kg (maximum 10 mg)

In-hospital treatment/ED

20 to 60 minute

1. Treat with longer-acting AED:

setting (second stage SE)

Fosphenytoin IV 15-18 mg PE/kg at a rate of

150 PE/min or Phenytoin IV 15-18 mg/kg at

maximum rate of 50 mg/min,

or in children, Phenobarbital^b IV 15-20 mg/kg at

maximum rate of 100 mg/min

2. Monitor blood pressure, ECG, and respirations

immediate EEG monitoring should never delay

tionally phenytoin IV. Phenytoin IV should be

therapy for suspected SE.

infused at a rate no faster than 50 mg/min

Termination of seizure activity is the focus

because of the risk of hypotension and cardiac

of SE treatment, and benzodiazepines, gener-

dysrhythmias. ECG and frequent blood

ally lorazepam or diazepam, are the first-line

pressure monitoring are essential. If hypoten-

agents

(Table

5.1 details drug dosing). Lo-

sion or bradycardia develops, the rate of

razepam is preferable to diazepam because of a

administration can be decreased or the infusion

longer duration of action and, consequently, a

can be held until the vital signs stabilize.

lower seizure-relapse rate. Benzodiazepine

Phenytoin IV should never be delivered by an

therapy is often followed by treatment with a

automatic infusion pump to an unattended

longer-acting antiepileptic drug (AED), tradi-

patient. Phosphenytoin, a prodrug that is

Chapter 5

■ Neurologic Emergencies

TABLE 5.1

Management of Status Epilepticus (continued)

Objectives

Time Frame

Intervention

Treatment of refractory

>60 minute

1. If seizures persist, consider transfer to an intensive

SE/ICU setting

care unit. Perform elective endotracheal intubation

2. Treat with general anesthesia:

Midazolam, 0.2 mg/kg boluses, maximum 2 mg/kg

then, infusion rate 0.05-2 mg/kg/hr, or in adults:

Propofol, 1-2 mg/kg boluses, maximum

10 mg/kg, then infusion rate 2-10 mg/kg/hr, or

Pentobarbital, 10-15 mg/kg, then infusion rate

0.5-1 mg/kg/hr, or

Thiopental, 3-5 mg/kg bolus, then infusion rate,

3-5 mg/kg/hr

3. Titrate anesthetic to burst-suppression pattern on EEG

for 24 to 48 hours, then gradually taper infusion rate

while monitoring for seizure activity

4. If clinical or electrographic seizure activity is observed,

repeat the anesthetic induction

Prevention and treatment

Throughout

1. Monitor vital signs

of complications of SE

2. Monitor volume status

3. Maintain airway and prevent aspiration

4. Review laboratory information and treat accordingly

Identification of cause of SE

Throughout

1. Obtain history from relatives and friends

2. Obtain head CT, when indicated

3. Perform lumbar puncture, when indicated

4. Initiate IV antibiotic or antiviral coverage when meningitis

or encephalitis is suspected

Prevention of recurrence

Following cessation

1. Monitor anticonvulsant levels

of SE

of seizure activity

2. Initiate daily therapy with appropriate anticonvulsant(s)

3. Educate patient and family to ensure medication

compliance

CBC, complete blood count; BUN, blood urea nitrogen; LFTs, liver function tests; SE, status epilepticus; ICU, intensive care unit; PE, phosphenytoin

sodium equivalents.

^aAt earliest availability.

^bThird-line therapy (after anesthetics) in some protocols.

converted to phenytoin, has gained favor over

Absence of these side effects allows for a faster

parenteral phenytoin where available. Dosage

rate of infusion of phosphenytoin, up to 150

is expressed in phosphenytoin sodium equiva-

mg PE/min, with peak concentrations within 10

lents (PE) for ease of transition from more fa-

minutes after infusion. Phosphenytoin offers

miliar phenytoin dosing. By virtue of its

the additional advantage of intramuscular in-

solubility, phosphenytoin does not require the

jection in those patients without IV access; ther-

addition of propylene glycol as a vehicle, which

apeutic plasma concentrations are reached

is thought to cause most of the clinically signif-

within 30 minutes by this route. Phosphenytoin

icant hypotension, arrhythmias, and local injec-

is considerably more expensive than phenytoin,

tion reactions of phenytoin administration.

but, in fact, may be more cost-effective as a

Chapter 5

■ Neurologic Emergencies

result of a reduced need for adverse event

of refractory SE has not been standardized,

management.

anesthetics typically are titrated to produce a

If seizures persist, phenobarbital IV tradition-

burst-suppression pattern on the EEG for 24 to

ally has been used as a second-line agent, after

48 hours. After this time, the infusion rate is de-

benzodiazepines and phenytoin have failed.

creased gradually. If electrographic or clinical

However, phenobarbital may result in respira-

seizures emerge, induction is repeated at pro-

tory depression, prolonged sedation, or severe

gressively longer intervals.

hypotension. This adverse side effect profile has

The prevention and management of compli-

relegated the barbiturate to the status of a third-

cations of SE is ongoing throughout the treat-

line agent in some SE treatment algorithms. If

ment protocol. Hypertension, hyperthermia,

phenobarbital IV is used, elective endotracheal

and acidosis require attention, but effective

intubation is recommended before initiation of

treatment of SE should reverse these problems.

the infusion. Valproate IV has become available

Hypotension can be a direct consequence of

for use in treating SE, with loading doses of 15 to

prolonged SE or, alternatively, the effect of an-

20 mg/kg infused at a rate of 3 to 6 mg/kg/min.

ticonvulsant medication, volume depletion,

Its safety profile suggests usefulness as a second-

trauma, or cardiovascular disease. The poten-

line agent, particularly in patients who are he-

tial risks of rhabdomyolysis, aspiration pneu-

modynamically unstable. However, clinical

monia, or traumatic injury as a result of

experience with valproate in this capacity re-

seizure activity also must be recognized and

mains limited, and it is absent from many stan-

prevented if possible.

dard SE treatment protocols.

The management of SE cannot be separated

Approximately 30% of patients with SE will

from the exigency of identifying the underlying

have ongoing seizures resistant to standard

cause. Obtaining historical information from

loading doses of anticonvulsant medications,

the patient’s family, friends, or medical records

thus requiring therapy for

“refractory SE.”

may reveal a pattern of noncompliance with

Anesthetic doses of benzodiazepines, short-act-

medication or a recurrent history of alcohol

ing barbiturates, or propofol are the third-line

withdrawal. Reports of acute neurologic

agents used to treat refractory SE, although

deficits or febrile illness may further help guide

some investigators have proposed resorting to

appropriate diagnostic evaluation. A head

these drugs as second-line agents in place of phe-

computed tomography (CT) should be consid-

nobarbital IV. Midazolam is a well-tolerated,

ered, with and without contrast (if renal func-

short-acting benzodiazepine that causes fewer

tion and allergies permit), to exclude the

problems with hypotension. An alternative to

possibilities of neoplasm, cerebrovascular in-

more costly midazolam is propofol, a nonbarbi-

farction, intracerebral hemorrhage, and trau-

turate, anesthetic agent. A disadvantage of this

matic injury. Following CT, lumbar puncture

therapy is the potential for developing “propo-

may be indicated. It should be noted that the

fol-infusion syndrome,” characterized by hy-

CSF can reveal a moderate pleocytosis (up to

potension, lipidemia, metabolic acidosis, renal

150 white blood cells) and an increase in CSF

failure, and cardiovascular collapse. Finally,

protein (up to 100 mg/dl) following persistent

pentobarbital and thiopental sodium are short-

seizure activity. Nonetheless, if there is any sus-

acting barbiturates that may be used in treating

picion of meningitis, antibiotic therapy should

refractory SE. Prolonged elimination and the

be started promptly and appropriate cultures

potential immunosuppressive propensity of

should be sent for evaluation.

these agents are potential disadvantages.

Upon successful treatment of SE, careful at-

EEG monitoring is important in the manage-

tention to initiating a daily dosing schedule of

ment of refractory SE. Although the necessary

one or more anticonvulsants and monitoring

depth and duration of anesthesia for treatment

the total and free serum drug levels will help

Chapter 5

■ Neurologic Emergencies

prevent recurrence of seizure activity. In the

even in patients with known psychiatric illness,

coming years, the development of novel routes

several evaluations of possible causes of delirium

of administration for established drugs as well

are important to perform. The differential diag-

as new anticonvulsant and neuroprotective

nosis of delirium is extensive and can be divided

agents holds promise for further reducing the

into several broad etiologic categories: infec-

morbidity and mortality of SE.

tions, structural lesions, toxic-metabolic causes

(drug-related, hypoxia, hypoglycemia, hepatic

and renal disease, electrolyte abnormalities, thi-

ACUTE ALTERATION

amine deficiency, etc.), and postictal states. The

OF MENTAL STATUS

term “encephalopathy” is frequently substituted

An acute alteration of mental status is the most

for delirium to describe diffusely abnormal brain

common neurobehavioral disorder seen in hos-

function from a medical cause (i.e., toxic-meta-

pitalized patients. It is characterized by a sudden

bolic encephalopathy). A psychiatric disorder

change in cognition with impaired attention

should only be considered after underlying, po-

that may fluctuate; it is potentially reversible;

tentially life-threatening, medical causes are

and it is not a result of preexisting dementia.

properly excluded. Several of the more impor-

A well-known form of acute alteration of

tant causes of altered mental status that require

mental status is delirium. The Diagnostic and

special attention are discussed below.

Statistical Manual of Mental Disorders, 4th edi-

Herpes simplex encephalitis (HSE) is one of the

tion (DSM IV), delineates the following clinical

most common, potentially fatal infections of the

criteria for the diagnosis of delirium: inatten-

brain associated with an acute altered mental state.

tion, change in cognition, acute and fluctuating

HSE is usually associated with herpes simplex virus

course, and evidence of a medical cause. Sub-

(HSV)-1 in adults and children from either primary

types of delirium have been described and cate-

infection or virus reactivation. The virus causes in-

gorized by overall psychomotor activity and

flammation of the brain parenchyma, necrosis, and

arousal level. These subtypes include hyperactive,

hemorrhage, particularly in the temporal and or-

hypoactive, and mixed delirium. Hyperactive

bitofrontal lobes. Patients are often ill-appearing

delirium is dominated by hyperarousal, halluci-

with fever, headache, meningitis, focal neurologic

nations, and agitation, whereas hypoactive

deficits such as hemiparesis and aphasia, confusion,

delirium is characterized by lethargy, confusion,

and seizures (both partial and secondarily general-

and sedation. Although specific etiologies do

ized). The clinical course of a patient with HSE

not consistently coincide with certain subtypes,

may decline precipitously to obtundation, coma,

there do appear to be some trends associating

and death if left untreated. For this reason, treat-

causes with clinical subtypes. For instance, pa-

ment with IV acyclovir (10 mg/kg every 8 hours for

tients with alcohol and benzodiazepine with-

at least 14 days) should be initiated promptly in

drawal typically appear more hyperaroused,

anyone suspected of having HSE. The risk of acy-

whereas those with a metabolic disorder tend

clovir is low but does include bone marrow sup-

toward hypoactivity. Categorizing patients into

pression, liver and renal toxicities.

general subtypes may be helpful prognostically.

Investigators found that patients with hypoac-

■ SPECIAL CLINICAL POINT: In patients

suspected of having herpes simplex encephalitis

tive delirium had longer hospitalizations with

(HSE), empiric treatment with acyclovir, even

increased risk of developing pressure ulcers,

prior to completion of diagnostic testing, is

whereas their hyperactive counterparts in-

warranted due to the high risk of morbidity and

curred an increased risk of falls.

mortality from delayed treatment.

An unexplained acute alteration of mental

status due to a medical condition (delirium) must

Diagnostic testing for HSE should include a

be differentiated from a psychiatric disorder, and

brain magnetic resonance imaging

(MRI)

Chapter 5

■ Neurologic Emergencies

(or HCT if not available) and CSF sampling

in the context of cerebrovascular disease (see

(including HSV PCR analysis). MRI may show

Chapter 7).

edema particularly in the temporal and frontal

Chronic subdural hematomas, especially in

regions, often with associated hemorrhage.

older patients, may result from blunt head

Opening pressure of the lumbar puncture may

trauma and develop slowly over weeks to

be elevated, and the CSF may mimic an aseptic

months, presenting clinically with cognitive

meningitis with a mildly decreased glucose,

decline that can be easily mistaken for demen-

mildly elevated protein, pleocytosis (with lym-

tia. Like the elderly, patients with coagu-

phocytes and some neutrophils) as well as

lopathies and alcoholism have a higher risk for

many red blood cells (RBCs) and xanthrochro-

subdural hematomas. Acute epidural and sub-

mia due to hemorrhagic necrosis of the brain

dural hematomas may develop within just min-

parenchyma. A traumatic lumbar puncture

utes to hours after head trauma. Younger

may falsely elevate RBCs in the CSF; therefore,

patients and those with skull fractures are at

cell counts should be sent on the first and last

greater risk for epidural hematomas, most com-

tubes collected to aid interpretation. The sensi-

monly from tearing arterial vessels. Headache,

tivity and specificity of PCR of CSF for HSV is

vomiting, seizures, and focal deficits may

high. It is, therefore, appropriate to consider

progress rapidly to bradycardia, apnea, and

discontinuation of acyclovir initiated empiri-

coma in a patient with an expanding epidural

cally in patients who are later found to have a

hematoma coinciding with increasing intracra-

negative PCR result.

nial pressure and cerebral herniation.

An EEG is frequently indicated in patients

with HSE exhibiting overt seizures or an alter-

■ SPECIAL CLINICAL POINT: A falsely

ation in their mental status without return to

reassuring “lucid interval” may be seen

their baseline. Seizures are particularly com-

following head injury in a patient with an

epidural hematoma who has a transient

mon with temporal lobe lesions, such as seen

recovery of mental status after initial impact,

with HSE. The EEG may show areas of focal

only to have rapid neurologic decline minutes

slowing or focal epileptiform discharges with

to hours later with hematoma expansion.

temporal predominance, often superimposed

upon an abnormal diffusely slowed back-

Patients, thus, presenting after head injury with

ground. Classically, the focal sharp wave ab-

headache or altered mental status should have

normalities in HSE are periodic, lateralized,

an unenhanced head CT as soon as possible

epileptiform discharges (PLEDs), though this is

and be kept under close surveillance with fre-

not specific for HSE. Patients who recover

quent neurologic evaluations. If necessary,

from HSE are at somewhat higher risk for later

emergency transfer to a trauma center for de-

developing epilepsy. AED therapy is appropri-

compression should be arranged.

ate in the management of HSE for the treat-

Cerebellar stroke, either infarction or hem-

ment of seizures and in those at high risk for

orrhage, is an acute structural lesion not to be

seizures based on the EEG.

overlooked due to the potentially devastating

Intracranial hematoma should be consid-

neurologic outcome. Patients may present with

ered in any patient with a recent history of

any combination of headache, nausea, vomit-

head trauma and an acute change in mental

ing, vertigo, clumsiness, ataxia, and dysarthria,

status, particularly with headache or focal neu-

or may present early on in coma. The difficulty

rologic deficits. A patient with a spontaneous

in managing acute cerebellar stroke lies in pre-

intracerebral or subarachnoid hemorrhage

dicting who will deteriorate, deciding which

may have a similar acute presentation requir-

treatment options are needed, and electing

ing emergency intervention. These neurologic

when to proceed with surgery. There is as yet

emergencies, however, are more aptly discussed

no definitive protocol for the management of

Chapter 5

■ Neurologic Emergencies

patients with acute cerebellar stroke. Clinicians

basic mechanisms: deficiency of a necessary

generally must rely upon both the overall clini-

metabolic substrate (e.g., hypoglycemia), dis-

cal picture as well as neuroimaging features to

ruption of the internal environment of the

guide their decision-making. A deteriorating

brain (e.g., dehydration), or the presence of a

level of consciousness, gaze palsy, or signs of

toxin or accumulation of a metabolic waste

herniation along with findings on HCT (i.e.,

product (e.g., drug intoxication or uremia).

effacement of the fourth ventricle, presence

Hepatic and uremic encephalopathies are com-

of hydrocephalus, size of cerebellar hemor-

mon metabolic causes of mental status change

rhage, and evidence of brainstem infarction)

in hospitalized patients. Disorders of glucose

may help determine the primary mechanism(s)

regulation; osmolarity/sodium homeostasis;

of clinical decline and, thus, the best therapeu-

and derangement of calcium, magnesium, and

tic approach.

phosphorous levels are also frequent offenders.

Endocrine encephalopathies seen in Cushing

■ SPECIAL CLINICAL POINT: An

syndrome, Addison disease, and thyroid dis-

observation period of 72 to 96 hours in a

ease are less common and may be overlooked.

neurologic intensive care unit is generally

A patient with a metabolic encephalopathy

recommended for patients with acute

may evolve through stages of inattentiveness,

cerebellar stroke to enable early detection of

disturbed memory, and confusion to lethargy,

a deterioration in neurologic status and, if

somnolence, obtundation, and coma. The ear-

necessary, emergency surgical intervention.

lier stages of encephalopathy may go unrecog-

Several mechanisms may account for the neuro-

nized because of a patient’s concurrent loss of

logic deterioration seen in cerebellar stroke.

insight and judgment. Of note, an alteration of

These include obstructive hydrocephalus from

personality, behavior, cognitive function, or

fourth ventricle compression, direct brainstem

level of alertness may be the only symptom that

compression from mass effect, upward hernia-

brings a patient with a metabolic derangement

tion of the cerebellar vermis through the tento-

to medical attention.

rial

notch, and irreversible brainstem

Drug intoxication and withdrawal are par-

infarction. In cases of acute hydrocephalus

ticularly common causes of acute alteration in

without brainstem compression (clinically or

mental status. At-risk patients typically are

on imaging), ventriculostomy alone may be ad-

taking drugs that have anticholinergic proper-

equate. However, if there is no clinical im-

ties, including many antidepressants, neurolep-

provement, a posterior fossa decompressive

tics, antihistamines, antiparkinsonian agents,

craniectomy may be required as a staged ap-

and over-the-counter cold preparations. High-

proach following ventriculostomy. In cases of

dose steroids, narcotic pain medications, and

direct brainstem compression or when there is

sedatives also may cause acute alterations in

a rapid neurologic decline, a suboccipital

mental status, especially in elderly patients.

craniectomy with hematoma evacuation or

Abused street drugs associated with violent

resection of infarcted tissue is indicated.

delirium include amphetamines, cocaine, hallu-

Additionally, cerebellar hemorrhages more

cinogens, tranquilizers, sedatives, and alcohol.

than 3 cm in diameter usually require surgical

Alcoholic patients commonly present to the

evacuation.

emergency department with mental status

Metabolic encephalopathies are common

alteration, which should be distinguished clini-

acquired causes of acute alteration in mental

cally from intoxication. A blood ethanol level

status, a diverse group of neurologic disorders

of 80 to 100 mg/dl correlates with a change in

defined by an alteration of mental status result-

mental status. Sharp declines in blood ethanol

ing from failure of organs other than the brain.

levels 12 to 24 hours after intake can result in

Cerebral dysfunction may result from three

tremulousness followed by alcohol withdrawal

Chapter 5

■ Neurologic Emergencies

seizures. These seizures are usually brief with

especially in the setting of chronic alcohol use,

return to normal neurologic function. Pro-

requires immediate treatment with thiamine

(IV or IM) for Wernicke encephalopathy to

longed or focal seizures, a prolonged postictal

prevent permanent brain injury and coma.

state, or a focally abnormal neurologic examina-

tion should initiate a search for other causes of

The general approach to the patient with an

seizures. Alcoholic patients are particularly prone

acute alteration in mental status involves identi-

to head injury, and brain imaging may reveal

fication and treatment of the underlying cause,

epidural or subdural hematomas, intraparenchy-

environmental modification, and symptomatic

mal hemorrhage, or traumatic subarachnoid

treatment. Historical information should be

hemorrhage. CNS infection also should be con-

sought about systemic illness, drug or alcohol

sidered, potentially warranting a diagnostic

use, recent trauma, toxin exposure, baseline

lumbar puncture. Coexistent hepatic failure,

mental status, and the temporal course of

hypoglycemia, hyponatremia, or drug ingestion

symptoms. A history of dementia, mental retar-

should be screened with appropriate testing.

dation, or pre-existing brain injury may predis-

Likewise, nonconvulsive SE should prompt

pose a patient to acute mental status alteration,

EEG monitoring when suspected.

particularly in the face of undue physical or

The clinician should be particularly alert to

psychological stress. Unfamiliar surroundings

the possibility of Wernicke encephalopathy, a

with loss of daily routine, disruption of sleep-

manifestation of thiamine deficiency. It is clini-

wake cycles, and sensory understimulation or

cally characterized by an apathetic-confusional

overstimulation are common precipitants for

state, oculomotor dysfunction

(at times evi-

these patients. Both the very old and the very

denced by a subtle nystagmus), and ataxia. Thi-

young are at special risk, especially older pa-

amine should be administered routinely, before

tients with hip fractures (up to 65% incidence)

glucose, at 100 mg/day IV to prevent precipita-

because these patients tend to be more frail; ad-

tion and progression of Wernicke encephalopa-

vanced in age; taking multiple medications; and

thy to irreversible amnesia. B vitamins also

sensitive to electrolyte or metabolic distur-

should be supplemented because many patients

bances, infection, and hypotension.

have concurrent nutritional compromise. Ben-

A thorough physical examination includes in-

zodiazepines are the mainstay of management

spection for stigmata of hepatic, renal, or en-

of both alcoholic withdrawal and alcoholic

docrine disorders. Scrutiny of the state of

seizures. Although chlordiazepoxide, diazepam,

hydration and nutrition provides important in-

and lorazepam commonly are used, oxazepam

formation. Alterations in vital signs may provide

may be preferable in patients with liver insuffi-

clues to a wide diversity of problems, ranging

ciency because its clearance is less dependent on

from hypoxia to sepsis to elevated intracranial

hepatic metabolism than other benzodiazepines.

pressure. Signs of head trauma should be sought

Patients should be evaluated for dehydration,

in the obtunded or comatose patient.

hypomagnesemia, and other electrolyte distur-

Examination of mental status should be per-

bances. Hyponatremia should be corrected

formed in a reproducible manner to guide subse-

slowly, at a rate no faster than

0.5 to

1.0

quent reevaluations of progression and efficacy

meq/L/hr, with not more than 12 meq/L correc-

of therapy. A patient’s level of consciousness is

tion in 24 hours because rapid correction may

best described with a few well-recognized de-

lead to the development of central pontine

scriptors, such as alert, lethargic (easily aroused),

myelinolysis.

stuporous (difficult to arouse), and comatose

(little response to external stimulation). Docu-

■ SPECIAL CLINICAL POINT: A triad of

mentation of patient performance on standard-

acute confusion, ophthalmoplegia (eye

ized tests of arousability, orientation, attention,

paralysis) or nystagmus, and gait ataxia,

and memory are more reproducible and allow

Chapter 5

■ Neurologic Emergencies

for quantitative comparison. The Folstein Mini-

pressure or focal abnormalities. Patients with

Mental Status Examination or the alternative

fluent aphasias from dominant temporopari-

Montreal Cognitive Assessment (MoCA), and

etal lesions or with nondominant parietal in-

the Glasgow Coma Scale are convenient quanti-

jury can be misdiagnosed as psychotic in the

tative scales for this purpose.

absence of appropriate brain imaging. CSF ab-

The neurologic examination includes tests

normalities are rare in metabolic en-

of pupillary response and ocular motility as

cephalopathies. Nevertheless, there should be a

well as motor responses to stimulation. Ocu-

low threshold for performing a lumbar punc-

locephalic reflexes, oculovestibular reflexes,

ture to rule out meningitis or encephalitis when

and respiratory patterns should be noted in

previous evaluations have failed to reveal a

comatose patients. Demonstration of intact

cause or when there is clinical suspicion of a

brainstem function makes a structural lesion

CNS infection. Brain imaging is recommended

of the brainstem, including elevation of in-

prior to lumbar puncture to evaluate for in-

tracranial pressure, less likely. Hyperreflexia

creased intracranial pressure as a result of the

may be seen in association with metabolic en-

risk of provoking herniation.

cephalopathy, but other evidence of upper

An EEG can be helpful in patients with

motor neuron dysfunction is usually not

metabolic encephalopathy or altered mental

demonstrated until advanced stages of dis-

status of uncertain etiology. It can provide an

ease. Asterixis, generalized tremor, and spon-

objective evaluation of the degree of CNS dys-

taneous myoclonus often are observed. Toxic

function. Loss of the normal EEG patterns and

encephalopathies should be considered in pa-

generalized slowing are the most commonly ob-

tients with dysarthria, nystagmus, ataxia,

served changes. Seizure activity, particularly

tremor, or dilated pupils.

nonconvulsive SE, as well as focal abnormalities

Diagnostic testing can screen for metabolic

may be identified. Often, serial EEG studies are

abnormalities and toxin exposure. Laboratory

valuable to quantitatively and objectively

tests should include a blood count, platelet

gauge the degree of cerebral dysfunction.

count, prothrombin time, partial thromboplas-

Prognostically, background reactivity on EEG

tin time, chemistry profile (electrolytes, glucose,

may suggest, in some instances, a potentially

blood urea nitrogen, creatinine, calcium, mag-

reversible encephalopathic process.

nesium, phosphorous), liver function tests, am-

monia level, thyroid function tests, arterial

Treatment of Delirium

blood gas, urinalysis, and drug and toxicology

screen. Drug levels of prescription medications

The management of acute alteration in mental

that may alter mental status should be checked

status requires medical or surgical treatment

(e.g., anticonvulsants, lithium, theophylline,

targeted at the identified etiologic process.

barbiturates, digoxin). Information gathered

Even with appropriate therapy, mental status

during the history and physical examination

alterations, when reversible, can take weeks to

will guide the choice of additional studies:

months to improve. Controlling a patient’s en-

serum osmolality, plasma cortisol level,

vironment can facilitate reorientation. Envi-

syphilis serology, erythrocyte sedimentation

ronmental modifications include instituting

rate, antinuclear antibody, vitamin B₁₂, folate,

regular wake and sleep schedules, diurnal ex-

human immunodeficiency virus, ceruloplas-

posure to natural and artificial light, use of

min, serum copper, urinary copper, and urinary

clocks and calendars, and frequent reorienta-

porphobilinogen.

tion by staff and visitors.

Neuroimaging is recommended following an

Patients with disorientation, emotional labil-

acute change in mental status to exclude a struc-

ity, delusions, hallucinations, paranoid ideation,

tural lesion resulting in increased intracranial

or intoxication may be agitated, aggressive,

Chapter 5

■ Neurologic Emergencies

violent, and resistant to medical evaluation and

excluded. In some situations, the patient’s be-

treatment. Although it is best to avoid the use

havior may be a critical index of disease pro-

of drugs that may result in sedation and CNS

gression, and the use of physical restraints is

depression in these patients, symptomatic ther-

preferable to sedation.

apy for delirium is warranted in instances

Although the diagnosis and treatment of

where behavior poses a significant risk to pa-

delirium may be challenging and difficult in pa-

tient or staff safety.

tients with multiple system failure or irre-

Pharmacologic intervention should be indi-

versible brain injury, a significant proportion

vidualized and directed at the specific problem

of these patients are found to have reversible

(anxiety, depression, insomnia, disturbance of

processes. These encounters, when approached

sleep-wake cycles, agitation, hallucinations,

with proficiency, can be especially rewarding.

delusions, and aggression). The most com-

monly used agents are benzodiazepines and

ACUTE INTRACRANIAL HYPERTENSION

neuroleptics. Neuroleptics should be avoided

in long-term management of behavior because

The main components of volume in the skull

of the risk of developing irreversible tardive

are the brain (1,400 mL), blood (1,400 mL),

dyskinesia. Moreover, clinicians should be

and CSF (150 mL). Any increase in the volume

watchful for the symptoms of neuroleptic ma-

of one of these components without a corre-

lignant syndrome, a rare but potentially fatal

sponding decrease in the volume of the other

idiosyncratic drug reaction

(see section on

two will result in increased intracranial pres-

Neuroleptic Malignant Syndrome, p. 83). For

sure (ICP), or intracranial hypertension. Be-

the patient with acute agitation with psychotic

cause volume in the cranium cannot change, any

features, haloperidol may be administered in a

volume increase will result initially in a compen-

dosage of 5 mg intramuscularly (IM) every 4

satory reduction in intracranial blood volume

to 8 hours to a maximum of 15 to 30 mg/day.

and displacement of CSF into the lumbar cis-

Neuroleptic-induced extrapyramidal symp-

tern. Once brain compliance is exhausted, small

toms are a significant risk in all patients, par-

increases in ICP will result in herniation of the

ticularly the elderly. The atypical neuroleptics,

brain through the foramen magnum. The

including quetiapine and olanzapine, are less

prompt recognition and treatment of acutely

likely to precipitate parkinsonism, acute dys-

raised intracranial pressure is, thus, vital to pre-

tonic reaction, or tardive syndromes (quetiap-

serve brainstem function and life.

ine 25 to 300 mg/day, olanzapine 2.5 to 10

Intracranial hypertension poses a risk of

mg/day). When the predominant feature is

cerebral hypoperfusion as well as herniation.

anxiety, benzodiazepines (e.g., diazepam, 5 to

Cerebral blood flow (CBF) normally is main-

10 mg IM) are often sufficient. Rarely, patients

tained over a wide range of cerebral perfusion

may develop paradoxical agitation with

pressures (CPPs). CPP is defined as the differ-

benzodiazepines, requiring withdrawal of

ence between mean arterial blood pressure

medication.

(MAP) (normally 50 to 150 mm Hg) and ICP

Neuroleptics should be used cautiously in

(normally 3 to 15 mm Hg). A CPP greater than

patients with mental status alteration, particu-

or equal to 70 mm Hg ensures adequate cere-

larly when the underlying etiology is unclear

bral perfusion. In disease states, the CPP will

because these drugs can mask evidence of clin-

approximate the CBF in a linear fashion as a

ical deterioration. Sedation should be, likewise,

result of loss of vascular autoregulation; there-

avoided especially when a patient’s level of

fore, any elevation of ICP or decrease in MAP

consciousness is worsening. Intoxication and

will result in cerebral hypoperfusion.

drug overdose, structural lesions with elevated

Understanding the neuroanatomic shifts

intracranial pressure, and infections should be

that evolve with progressive increases in ICP

Chapter 5

■ Neurologic Emergencies

enables better clinical recognition of pending

less reactive pupil on that side. Hemiparesis

herniation. The cranial vault is divided incom-

may occur ipsilateral to the herniating uncus

pletely into compartments by thick, fibrous

because of the compression of the contralateral

bands of dura mater. The tentorium cerebelli is

cerebral peduncle against the far edge of the

clinically the most important of these struc-

tentorial notch as the midbrain is displaced

tures. It separates the lower brainstem and

laterally

(Kernohan notch syndrome). More

cerebellum from the cerebral hemispheres and

commonly, however, the hemiparesis is con-

diencephalon, delineating the infratentorial

tralateral to the herniating uncus. In either case,

and supratentorial spaces. The midbrain lies

hemiparesis is not a good clinical sign for local-

within an opening in the tentorium called the

izing the side of the herniation. The abducens

tentorial notch and is bound laterally by fasci-

nerve (sixth cranial nerve), by virtue of its ex-

cles of the oculomotor nerve and the medial

tensive intracranial course, is particularly sus-

portion of the temporal lobes

(the uncus).

ceptible to traction injury when the intracranial

Under conditions of increased intracranial

pressure is elevated. Therefore, sixth nerve

pressure, the downward displacement and her-

palsies with inward eye deviation are frequently

niation of the midbrain and uncus can result in

seen but have little localizing value. A dilated

compression of the brainstem, compromising

pupil (third nerve palsy) is ipsilateral to the her-

vital functions including respiration, mainte-

niation 95% of the time and is a more reliable

nance of consciousness, and cardioregulation.

clinical indicator.

Coma and death may ensue.

Unlike the situation that occurs with mass

The two main types of herniation syndromes

lesions, raised ICP can be distributed equally

are uncal and central. Central herniation occurs

among the intracranial compartments with lit-

when diffusely raised supratentorial pressure

tle risk of herniation and brainstem compres-

compresses central brainstem structures and

sion. Some of the more common causes of

produces a progressive impairment of con-

diffuse intracranial hypertension are listed in

sciousness, respiratory irregularities, abnormal

(Table 5.3).

motor responses (posturing), and symmetric

Symptoms and signs of intracranial hyper-

midposition unreactive pupils. Uncal hernia-

tension are variable and depend on both the

tion, however, occurs as a unilateral supraten-

etiology and the rapidity with which the pres-

torial mass lesion displaces the medial temporal

sure increase develops. Intracranial pressure

lobe toward the tentorial notch. Some of the

may increase gradually over an extended

mass lesions that can lead to herniation are

listed in (Table 5.2). Early on, the oculomotor

(third cranial) nerve becomes compressed be-

TABLE 5.3

Causes of Diffuse Intracranial

tween the encroaching uncus and the edge of

Hypertension with Less Risk

the tentorial opening, producing a larger and

of Herniation

Hypoxia

TABLE 5.2

Meningitis

Mass Lesions Associated with

Encephalitis

Brain Herniation

Head trauma without subdural or epidural

Neoplasm

hematoma

Subdural hematoma

Subarachnoid hemorrhage

Epidural hematoma

Malignant hyperthermia

Intraparenchymal hemorrhage

Cerebral-vein thrombosis

Abscess

Pseudotumor cerebri

Infarction

Lead encephalopathy

Chapter 5

■ Neurologic Emergencies

period or suddenly in a matter of minutes.

cerebral blood volume and intracranial pres-

Headache is more likely to be a prominent

sure. Excessive hypocarbia may cause deleteri-

symptom in more acute problems, whereas pa-

ous vasoconstriction. It is also important not to

pilledema may be present in subacute or

compress the jugular veins with the tape used to

chronic conditions. Patients with large acute

secure the endotracheal tube.

hemispheric infarctions may develop signs of

Osmotic agents such as mannitol are given

herniation between 2 and 5 days of stroke

to reduce the water content of the brain. The

onset, when brain edema typically peaks.

starting dose is 500 mL of 20% mannitol given

IV for

20 to

30 minutes

(approximately

1 mg/kg). A urinary catheter is recommended.

Treatment of Acute Intracranial

Serum electrolytes and osmolality are moni-

Hypertension

tored closely, using the latter as a guide to fur-

The primary goal in the management of raised

ther dosing. A mannitol dose of 100 to 250 mg

ICP is to reduce ICP while maintaining an ade-

(0.25 mg/kg) can be given every 4 hours as nec-

quate CPP (70 mm Hg). Therefore, judicious

essary to maintain serum osmolality at 300 to

manipulations of systemic MAP are warranted,

320 milliosmoles (mOsm) per liter.

as well as reliable measurements of ICP.

Corticosteroids may be administered if vaso-

Although estimations of ICP can be deduced

genic edema is present. Vasogenic edema occurs

from clinical signs, this is unreliable. The gold

in conditions with breakdown of the blood-

standard for ICP monitoring is by direct ven-

brain barrier and often is seen with brain neo-

tricular pressure measurement through a ven-

plasms. Steroids are generally not effective for

triculostomy. This method is precise and

the type of edema that accompanies cerebral in-

allows for therapeutic CSF drainage to reduce

farction (cytotoxic edema) and thus are not in-

ICP. There are risks, however; parenchymal

dicated in large hemispheric strokes. Steroids

damage may result from direct penetration

do not begin working for several hours, so they

during placement of the ventriculostomy, and

usually are given concurrently with hyperventila-

there is a high incidence of infectious ventri-

tion and hyperosmolar agents in acute situations.

culitis with prolonged insertion of ventricular

Methylprednisolone (Solu-Medrol) 250 mg or

catheters

(particularly after

5 days). Other

dexamethasone (Decadron) 10 mg IV can be

methods are safer, with fewer infectious com-

used immediately, followed by dexamethasone

plications, but also less precise. They include

4 mg IV every 6 hours.

subarachnoid bolts, epidural transducers, and

In situations with rapidly progressing in-

intraparenchymal fiberoptic transducers. Non-

tracranial hypertension, emergency neuro-

invasive methods with transcranial Doppler

surgery may be necessary. Sizable cerebellar

are promising but not yet reliable.

hemorrhages or rapidly expanding epidural or

The evaluation of patients with suspected in-

subdural hematomas often require lifesaving

tracranial hypertension should begin with a

evacuation and surgical decompression. Ven-

brief history from available informants and a

tricular drainage of CSF can also rapidly de-

brief physical examination. Patients who are un-

crease ICP and may be performed at the

responsive and in danger of herniation should

bedside. Decompressive craniotomy for cere-

be intubated immediately, and emergency treat-

bral edema in acute ischemic infarction has

ment should be initiated before diagnostic inves-

shown promise for markedly reducing mortal-

tigation. Mechanical hyperventilation is the

ity and morbidity from an otherwise devastat-

fastest way of reducing intracranial pressure.

ing condition. Randomized controlled clinical

It is desirable to keep the PaCO₂ between 25

trials of this treatment are under way to pro-

and 30 mm Hg. The decreased PaCO₂ causes

vide more definitive evidence of efficacy.

cerebral vasoconstriction, thereby reducing

Moderate hypothermia (33 to 36°C) also has

Chapter 5

■ Neurologic Emergencies

been shown to reduce ICP and improve mor-

ACUTE SPINAL CORD COMPRESSION

tality in patients following massive middle

cerebral artery infarction. However, increased

Acute compression of the spinal cord often

ICP may rebound with rewarming. Pentobar-

presents insidiously with pain, mild sensory

bital-induced coma may be helpful in the

disturbance, weakness, or sphincter or sexual

management of refractory intracranial hyper-

dysfunction, but it may progress rapidly to ir-

tension; but potential adverse effects, including

reversible paralysis if not corrected. Spinal

hypotension, reduced cardiac performance, and

cord compression is a common complication of

severe infection, limit its use.

metastatic disease, affecting 5% to 10% of pa-

There are a number of other general thera-

tients with cancer, but it also occurs with other

peutic measures that should be undertaken.

conditions

(Table

5.4). The most frequent

IV or enteral fluids should be isotonic or hy-

metastatic tumors causing spinal cord com-

pertonic. Hypotonic solutions such as

pression include multiple myeloma; lym-

dextrose or half-normal (0.45) saline can ag-

phoma; and carcinomas of the prostate, lung,

gravate cerebral edema. Serum osmolarity of

breast, kidney, and colon.

less than 280 mOsm/L should be corrected,

Pain is the earliest symptom in the vast ma-

and mild hyperosmolarity greater than

jority of patients and may be localized to the

300 mOsm/L is desired. The composition of

involved spinal area (96%) or may radiate in a

fluids replenished is a greater determinant of

dermatomal pattern (90%) if the dorsal spinal

cerebral edema than the amount of fluids.

roots are also involved. Pain may be intensified

Blood pressure should be modified to main-

by actions that increase intrathoracic pressure

tain a CPP of 70 to 120 mm Hg. When CPP is

and consequently CSF pressure, such as cough-

greater than 120 and ICP is greater than 20,

ing, sneezing, or straining at stool. Percussion

short-acting antihypertensive medications

tenderness over the spine is often a valuable

such as labetalol should be used. Nitroprus-

clinical sign aiding localization. Thoracic cord

side may worsen cerebral edema by dilating

compression is the most frequent site of in-

the cerebral vasculature. In patients with in-

volvement (70%) because it is the narrowest

creased ICP and low CPP, an adequate MAP

area of the spinal canal. It is followed in fre-

should be maintained to avoid hypoxic-

quency by the lumbosacral (20%) and cervical

ischemic injury. Vasopressors sometimes are

(10%) areas. Up to one fifth of patients have

used in this situation. Sedation may be

multiple sites of cord compression.

needed in ventilated patients who become ag-

The development of weakness, sensory loss,

itated. In these patients, raised intrathoracic

or erectile or sphincter dysfunction may progress

pressure may elevate ICP by increasing ve-

quickly. The distribution of weakness can aid

nous resistance to CSF outflow. Short-acting

in localizing the level of the lesion. Typically,

sedatives are preferred; propofol is gaining

lesions in the cervical spine region result in

popularity in this setting because of its very

paralysis of the legs and varying degrees of

short half-life, which allows rapid discontin-

uation, and thus reliable, serial neurologic

examinations.

TABLE 5.4

Only after the patient’s clinical status has

Common Causes of Acute Spinal

been stabilized should further evaluation with

Cord Compression

a head CT scan proceed. Because of the risk of

Metastatic cancer

precipitating herniation, a lumbar puncture

Herniated disc

generally should be avoided in a patient sus-

Abscess

pected of having increased ICP until a mass

Hematoma

lesion is excluded by neuroimaging.

Chapter 5

■ Neurologic Emergencies

weakness in the upper extremities. Less com-

at 24 mg IV every 6 hours for 24 hours, and

monly, patients may exhibit weakness that is

then it is tapered over the next 48 hours to 6 mg

disproportionately more impaired in the upper

every 6 hours, until more definite treatment is

extremities than in the lower extremities with

completed. Lower doses may be as effective.

bladder dysfunction and varying degrees of

Gastric prophylaxis should be provided con-

sensory loss characteristic of an acute central

currently. An indwelling bladder catheter

cervical spinal cord injury. This lesion often re-

should be inserted. Bladder and bowel function

sults from traumatic hyperextension of the

should be monitored, with stool softeners and

neck causing anterior and posterior cord com-

laxatives given as needed. Patients may require

pression within the spinal canal and subse-

management in the ICU in cases with pul-

quent injury to the central substance of the

monary, cardiac, or blood pressure instability.

cervical spinal cord.

Specific treatment directed at the underlying

A rapid diagnosis of acute spinal cord com-

process can begin once the etiology and loca-

pression is essential for appropriate manage-

tion are defined. In metastatic disease, radia-

ment and optimal prognosis. This begins with

tion therapy is started immediately and is

a detailed clinical examination, cervical spinal

especially valuable for the more radiosensitive

x-rays to assess vertebral column injury in

tumors such as multiple myeloma and lym-

cases of trauma, and timely MRI of the spinal

phoma. Surgical decompression is the treat-

cord directed at the suspected lesion level(s) to

ment of choice for disc disease, epidural

evaluate for intrinsic injury or compression.

abscess, and hematoma, and it sometimes is in-

Plain x-rays of the spine are abnormal in 84%

dicated for metastatic disease in situations in

to 94% of cases and may show evidence of

which a tissue diagnosis is needed, spinal stabi-

bony erosion from metastatic disease, particu-

lization is necessary, or further radiotherapy is

larly loss of vertebral pedicles; however, they

not warranted. For acute central cervical spinal

are of little help in imaging the soft-tissue

cord injury, surgical reduction is warranted for

structures that are invading the epidural or

fracture-dislocation injuries, but the benefit of

subdural spaces and compressing the spinal

early decompressive surgery is still under inves-

cord. MRI is the procedure of choice for visu-

tigation. The use of moderate systemic hy-

alizing the extent of anatomic involvement and

pothermia (between 33.5 and 34.5° C) to treat

spinal cord compression. It is superior to myel-

acute spinal cord injuries has shown some

ography in most instances because it is nonin-

promise but has not been proven in controlled

vasive and yields better resolution of anatomic

clinical trials.

structures. Spinal CT and bone scans play an

The prognosis for meaningful functional re-

important role in the diagnostic evaluations of

covery depends in large part on the functional

these patients as well.

state of the patient at presentation. Whereas

80% of patients who are able to walk when

they come to medical attention remain ambula-

Treatment of Acute Spinal

tory after treatment, only 30% to 40% of non-

Cord Compression

ambulatory persons with antigravity leg

Treatment should be started at the first sign of

function regain ambulation, and only 5% of

myelopathy. A very high dose of cortico-

people without antigravity leg strength are able

steroids, such as dexamethasone 100 mg IV, is

to walk after therapy.

given immediately to reduce the edema caused

A high index of suspicion is required to

by the compressing lesion, and this often pro-

make the diagnosis of a spinal epidural abscess,

vides dramatic pain relief and return of some

and a history of recent bacteremia or IV drug

neurologic function. In metastatic epidural

use often is obtained. The patient may or may

cord compression, dexamethasone is continued

not appear septic at the time of presentation. If

Chapter 5

■ Neurologic Emergencies

epidural abscess is a possibility, high-dose IV

TABLE 5.5

Drugs That May Exacerbate the

antibiotics should be given immediately (after

Weakness of Myasthenia Gravis

sending blood and other appropriate cultures

for analysis), while awaiting radiologic proce-

Aminoglycoside antibiotics

dures and surgical decompression.

Quinine

Cardiac antiarrhythmics (e.g., quinidine,

■ SPECIAL CLINICAL POINT: If a spinal

procainamide, propranolol, lidocaine)

epidural abscess is suspected, a routine “blind”

Polymyxin

lumbar puncture (without myelography or

Colistin

enhanced spinal MRI) should be deferred due

to the risk of precipitating meningitis or

downward spinal coning.

precipitant is identified. A crisis may also be

caused by overmedication with anti-

PERIPHERAL NERVOUS SYSTEM

cholinesterase agents, the so-called “choliner-

gic crisis.’’ A cholinergic crisis may be heralded

Myasthenic Crisis

by an increase in muscarinic symptoms such as

Myasthenia gravis is an autoimmune disorder

abdominal colic and diarrhea, with more se-

directed against the postsynaptic acetylcholine

vere muscarinic signs such as vomiting,

receptor of striated muscle. Neuromuscular

lacrimation, hypersalivation, and miosis indi-

transmission is impaired resulting in weakness

cating impending danger. The differentiation of

and fatigability of voluntary muscles. Classi-

myasthenic from cholinergic crisis may be

cally, a diurnal variation in strength is noted,

more academic than practical, however, be-

with strength waning as the day progresses.

cause the emergency management is the

Diplopia or ptosis is the initial symptom in

same—protect the airway and maintain ade-

about one half of the cases. Dysphagia, chew-

quate ventilation. Following respiratory stabi-

ing difficulty, nasal speech, and regurgitation

lization, medications may be adjusted and

of fluids are the presenting features in one third

precipitating factors may be investigated further.

of patients, reflecting the involvement of bul-

Hospitalization, preferably in an intensive

bar musculature. Proximal limb weakness,

care setting, should be considered in any patient

without bulbar or ocular involvement, is the

with myasthenia who complains of shortness of

least common presentation and is easily misdi-

breath or difficulty swallowing. Frequent mon-

agnosed. The outpatient diagnosis and man-

itoring of the vital capacity is important, with

agement of myasthenia gravis is described in

endotracheal intubation performed when the

detail in Chapter

17. This chapter focuses,

vital capacity is <800 to 1,000 mL (<1 L) or <

rather, on the emergency management of myas-

15 mL/kg, or if dysphagia is so severe that there

thenic crisis.

is a serious risk of aspiration. Maximal inspira-

Myasthenic crisis occurs when muscle

tory and expiratory pressures are more sensi-

weakness interferes with vital functions such as

tive for detecting ventilatory weakness than

breathing and swallowing. Emergency inter-

vital capacity. A reduction of maximal inspira-

vention is required. The mortality rate remains

tory pressure to less than 30% of that predicted

approximately 5% to 6%, with cardiac com-

for age and weight should alert the physician to

plications and aspiration pneumonia being the

impending respiratory failure and the need for

leading causes of death. A crisis may be precip-

mechanical ventilation. Arterial blood gases are

itated most commonly by infection, but emo-

not good predictors for when to begin mechan-

tional stress, hypokalemia, thyroid disease, or

ical ventilation in a myasthenic crisis because

(rarely) certain drugs (Table 5.5) may trigger a

they may be normal up to the onset of respira-

crisis; however, in one third of patients, no

tory failure.

Chapter 5

■ Neurologic Emergencies

■ SPECIAL CLINICAL POINT: A forced vital

this reason, corticosteroids initially should be

capacity (FVC) below 1 L should raise concern

administered in a hospital setting, particularly

for the need for intubation. A good bedside

if a high-dose regimen is elected. Because

estimate of FVC can be made by having the

steroids usually are required for several weeks

patient count out loud to 25 on one breath.

or more following a crisis exacerbation, alter-

Counting to 25 approximates an FVC of about

nate-day steroid therapy is recommended to

2 L while counting to 10 approximates an FVC

minimize long-term side effects. Prednisone

of only about 1 L.

100 mg, or its equivalent, is given on alternate

When endotracheal intubation is required,

days, with a gradual taper beginning after the

nondepolarizing muscle relaxants should be

patient’s status is clearly stabilized, usually sev-

avoided in patients with myasthenia who often

eral weeks after the crisis is over. Some authors

have marked sensitivity to these agents leading

favor giving high-dose IV corticosteroids on a

to difficulty weaning from the ventilator. For

daily basis early in the course before switching

this reason, some anesthesiologists depend on

to alternate-day prednisone therapy.

deep inhalational anesthesia (i.e., halothane,

Intravenous immune globulins

(IVIG) or

isoflurane, or sevoflurane) for tracheal intuba-

plasmapheresis are useful adjunctive therapies

tion. An alternative to mechanical ventilation,

in myasthenic crisis. Plasmapheresis is directed

bilevel positive airway pressure (BiPAP), may

at removing the acetylcholine receptor antibody

be a useful noninvasive option for the manage-

that causes myasthenia gravis. However, for un-

ment of acute respiratory failure in patients

clear reasons, even patients seronegative for the

with myasthenia. Preliminary data suggest that

acetylcholine receptor antibody may improve

BiPAP may prevent intubation in patients with

with plasmapheresis. The effects of plasma-

myasthenia who are not hypercapnic (PaCO₂

pheresis alone are temporary, rarely persisting

>50 mm Hg). In addition to respiratory moni-

more than 4 to 11 weeks, and may not occur

toring, oral anticholinesterase agents should be

for several days. Thus, concomitant immuno-

discontinued in all patients and withheld for

suppressive therapy usually is recommended for

48 hours even if cholinergic crisis is not sus-

more lasting treatment effect. Although

pected. An increased response to these drugs

plasmapheresis is generally safe, potential com-

may occur after this “drug holiday,” and often

plications include hemodynamic instability,

less medication may be needed once resumed.

hypocalcemia, and dilutional coagulopathy.

IVIG is administered at 400 mg/kg daily for

3 to 5 consecutive days. It has complex im-

Treatment of Myasthenic Crisis

mune-modulating effects, potentially involving

Treatment begins with a shorter-acting drug,

downregulation of antibody production.

neostigmine, 0.5 mg IM or 15 mg per nasogas-

Plasma exchange and IVIG are both effective

tric tube every 2 to 3 hours using the vital ca-

treatments, but the ease of administration of

pacity or muscle strength as a guide to dosage

the latter makes it the more commonly used

titration. Once the optimal dose of neostigmine

modality. Although IVIG is expensive, costs are

is found, the switch to the longer-acting agent

comparable with plasma exchange. Moreover,

pyridostigmine can be made. Approximately

IVIG may be a safer alternative in patients with

four times the neostigmine dose is required

hypotension, sepsis, or autonomic instability.

every 3 to 4 hours. Corticosteroids also may be

Potential complications of IVIG include hyper-

helpful in ending myasthenic crisis, but they

viscosity with possible cardiac or cerebral is-

should be used cautiously in the presence of in-

chemia, mild aseptic meningitis, acute renal

fection. Moreover, steroids initially may

failure, or an allergic reaction. It is important to

worsen weakness and result in respiratory fail-

draw serologic titers before IVIG administra-

ure, particularly in the first few days of use. For

tion because many of these will be altered by

Chapter 5

■ Neurologic Emergencies

the administration of pooled IVIG. In particu-

the lower extremities (10% begin in the upper

lar, quantitative immune globulins should be

extremities) and progresses upward, with the

drawn because IgA-deficient individuals can be-

maximum deficit attained by

4 weeks and

come sensitized and develop adverse responses

partial or complete recovery occurring over

to repeat administration of IVIG. Plasma ex-

weeks to months. In contrast to other more

change has been associated with a better out-

slowly progressive polyneuropathies in which a

come compared to IVIG. However, plasma

distal weakness predominates, the greatest

exchange carries a slightly higher complication

weakness in GBS is in proximal muscles.

rate, especially in hemodynamically unstable

Areflexia is the rule and may precede weakness.

patients, and the trend of IVIG use has, in fact,

Many patients complain of distal paresthesias

increased compared to plasma exchange.

or dysesthesias initially, but formal testing

Because any infection may precipitate a cri-

rarely demonstrates a significant sensory loss.

sis, an infectious source should be sought and

Facial weakness is seen in about one half of the

treated aggressively. Many patients with myas-

cases. A prior history of a recent

(within

thenia are iatrogenically immunosuppressed

4 weeks) respiratory or gastrointestinal illness

and are highly susceptible to infection. If an in-

is obtained in about one half of the patients;

fection is suspected, empiric therapy with

however, a fever at onset is atypical. A previous

broad-spectrum antibiotics is started at once

inoculation, surgery, hematologic malignancy,

after cultures have been sent. The change to

and hepatitis B or mycoplasma infection also

more specific drugs is made when the cultures’

have been associated with the syndrome. CSF

sensitivities are available. The aminoglycosides

analysis within the first week may be normal—

are known to interfere with neuromuscular

the classic albuminocytologic dissociation (ele-

transmission but may be used when necessary.

vated CSF protein and <10 mononuclear cells)

Chest roentgenogram and blood, urine, and

usually appears after the second week of illness.

sputum cultures on all patients with myasthe-

■ SPECIAL CLINICAL POINT: The hallmark

nia presenting with exacerbation should be

presentation of GBS is ascending symmetric

checked routinely. In addition, a diligent search

weakness with loss of deep tendon reflexes.

for infections is required in elderly or steroid-

treated patients who may not manifest the

Nerve conduction studies may be entirely

usual systemic signs of infection.

normal early in the course if the proximal root

segments are not studied. The F and H re-

sponses, measuring the motor and sensory prox-

imal segments, respectively, may be the only

GUILLAIN-BARRÉ SYNDROME

abnormality noted early on. Profound slowing of

Acute inflammatory polyradiculoneuropathy,

nerve conduction velocity may appear on routine

commonly referred to as the Guillain-Barré syn-

studies after several weeks of illness. Those cases

drome (GBS), is a rapidly progressive, demyeli-

that show evidence of secondary axonal degener-

nating polyneuropathy. This disorder is further

ation with denervation on an electromyogram

described in Chapter 18 within the context of

generally will have a more protracted recovery.

peripheral neuropathies. In its most fulminant

GBS should be differentiated from other

form, GBS may lead to sudden respiratory fail-

causes of rapidly progressive flaccid paralysis

ure and autonomic instability. It, therefore,

(Table 5.6). A brief description of these disor-

should be considered a neurologic emergency.

ders and their general management follows.

The mortality rate remains at 3% to 5% despite

Acute intermittent porphyria can cause a rap-

modern intensive care management.

idly ascending flaccid paralysis with respiratory

The classic presentation is a symmetric, as-

and autonomic involvement, but it usually is as-

cending, flaccid paralysis that usually begins in

sociated with severe abdominal pain, seizures,

Chapter 5

■ Neurologic Emergencies

Tick-bite paralysis is caused by a natural en-

TABLE 5.6

Disorders That Can Mimic

dotoxin that interferes with the release of

Guillain-Barré Syndrome

acetylcholine at the neuromuscular junction. It

Acute intermittent porphyria

presents as a rapidly ascending paralysis with

Diphtheria neuropathy

respiratory and bulbar involvement. A dra-

Botulism

matic improvement can occur after removal of

Tick-bite paralysis

the offending tick.

Poliomyelitis

Poliomyelitis can produce a flaccid paralysis

Arsenic intoxication

with respiratory involvement. However, the

weakness of poliomyelitis is characteristically

asymmetric, and the disease usually presents as

and psychosis. Urine porphobilinogen and

a febrile illness with gastrointestinal symptoms,

delta-aminolevulinic acid are elevated. Unlike in

myalgias, meningismus, and a CSF pleocytosis.

GBS, the CSF protein is usually normal. Attacks

Arsenical neuropathy can present as rapidly de-

of acute intermittent porphyria may be precipi-

veloping weakness and areflexia, with CSF and

tated by certain drugs such as barbiturates,

nerve conduction studies indistinguishable

phenytoin, sulfonamides, and some benzodi-

from those of GBS. However, the neuropathy

azepines. Acute attacks are managed support-

usually is accompanied by gastrointestinal, he-

ively. A high carbohydrate intake may help

patic, and hematologic manifestations of ar-

further by suppressing porphyrin synthesis.

senic poisoning. The patient with arsenical

Diphtheric neuropathy occurs 1 to 2 months

neuropathy often complains of burning dyses-

after a characteristic pharyngitis. The onset of

thesia, a feature not common in GBS.

weakness usually follows pronounced cranial

nerve involvement by several weeks, and it may

Treatment of Guillain-Barré Syndrome

be associated with myocarditis. Unfortunately,

by the time neurologic symptoms appear, spe-

GBS is a neurologic emergency because of the

cific therapy with antitoxin is ineffective. Thus,

life-threatening complications of respiratory

the mainstays of treatment are respiratory sup-

failure and cardiovascular collapse that

port and good nursing care.

sometimes occur within 24 hours of symptom

Botulism may present early on, with blurred

onset. The patient, therefore, should be moni-

vision and diplopia as well as gastrointestinal

tored in an ICU or an intermediate care unit

symptoms. Unlike in GBS, pupillary reflexes

until the plateau phase of maximal deficit is

are lost and the CSF is normal. Sensation re-

reached. The vital capacity should be checked

mains intact. The diagnosis is supported by

every 4 to 6 hours (see Special Clinical Point in

nerve conduction studies with reduced ampli-

the Myasthenia Gravis section above); if it is

tude of compound muscle action potentials

less than 60% of the predicted value (generally

and an incremental response following rapid

below 1 L), endotracheal intubation should be

repetitive nerve stimulation. Specific treatment

considered. Artificial ventilation may be re-

with trivalent botulinum antitoxin is recom-

quired in up to 23% of patients. Autonomic

mended. Nasogastric suctioning and enemas

instability may be severe, with marked fluctua-

may help remove toxin from the gastrointesti-

tions in blood pressure, tachycardia, and malig-

nal tract early in the illness. Wound botulism is

nant arrhythmias. Cardiac arrhythmias are

managed with surgical debridement and peni-

probably the main cause of death in the acute

cillin. In food-borne botulism, the role of an-

period, thus warranting continuous cardiac

tibiotics is controversial because of the concern

monitoring. Hypotension is usually mild and

that rapid bacterial destruction might increase

can be controlled with IV fluids; vasopressor

the release of toxin.

agents rarely are needed. Extreme caution

Chapter 5

■ Neurologic Emergencies

should be used when treating hypertension. Be-

degeneration, which carries a poorer progno-

cause of the marked lability in blood pressure,

sis. Positive anti-ganglioside autoantibodies

only short-acting, easily titrated drugs such as

(anti-GMl IgG), IgG1 subclass, are typically as-

IV nitroprusside should be used. Sustained

sociated with the axonal variant that appears

tachycardia can be treated with small doses of

to correlate with slower recovery and more se-

beta blockers if necessary. Corticosteroids, pre-

vere residual disability.

viously widely used in the acute phase of GBS,

are no longer advocated because of compelling

NEUROLEPTIC MALIGNANT

evidence of slower recovery and an increased

SYNDROME

relapse rate associated with steroid use. How-

ever, methylprednisolone in combination with

NMS is a potentially lethal complication asso-

IVIG has shown promise in GBS therapy.

ciated with the use of dopamine-blocking

IVIG remains the cornerstone of treatment

agents that act in the CNS. Although NMS is

for GBS. Studies comparing high-dose IVIG

not exclusively associated with neuroleptic

with plasma exchange indicated a beneficial ef-

drugs, phenothiazines, buty-rophenones, and

fect from prompt institution of IVIG, compara-

thioxanthenes are the most commonly impli-

ble to that seen with plasmapheresis. IVIG has

cated agents (Table 5.7). In general, drugs with

become the treatment of choice for GBS in many

greater dopamine-blocking potency harbor a

centers because of its ease of administration,

greater potential for inducing NMS. Thus,

safety profile, and comparable cost. Despite

haloperidol, chlorpromazine, and fluphenazine

concerns of early recurrences with IVIG treat-

have been associated more frequently with

ment (compared with plasmapheresis), most

NMS than other less potent dopamine-

centers use IVIG as initial treatment of GBS.

blocking agents. Even olanzapine, an atypical

Plasmapheresis, if performed within 2 weeks

antipsychotic, has been reported, infrequently,

of the onset of symptoms, can significantly

to induce NMS. In addition, the use of a

shorten the time it takes to attain a functional

dopamine-depleting agent such as tetra-

recovery; however, it does not decrease the inci-

benazine as well as the abrupt discontinuation

dence of respiratory failure. It is, moreover,

of antiparkinsonian dopaminergic medication

contraindicated in patients with severe auto-

rarely has been associated with NMS.

nomic instability. Thus, plasmapheresis often is

used in patients who do not respond first to

IVIG. Waiting 2 weeks before changing to the

TABLE 5.7

Causes of Neuroleptic

alternative modality is recommended because

Malignant Syndrome

the effects of either may not be immediately

apparent.

Dopamine-blocking agents

GBS is a self-limiting disease with many pa-

Haloperidol (Haldol)

tients attaining full recovery; however, some

Chlorpromazine (Thorazine)

suffer severe residual disabilities including loss

Fluphenazine (Prolixin)

of independent ambulation. Studies have iden-

Clozapine (Clozaril)

Thioridazine (Mellaril)

tified several clinical predictors of poor out-

Thiothixene (Navene)

come for GBS, including advanced age,

Trifluoperazine (Stelazine)

preceding Campylobacter jejuni gastrointesti-

Metaclopramide (Reglan)

nal illness or cytomegalovirus infection, venti-

Dopamine-depleting agents (tetrabenazine)

lation requirement, and low compound muscle

Abrupt discontinuation of antiparkinsonian

action potential amplitudes. Whereas the ma-

dopaminergic medications

jority of patients with GBS have a demyelinat-

Lithium

ing polyneuropathy, a minority develop axonal

Chapter 5

■ Neurologic Emergencies

The risk of NMS is related neither to the

are discontinued. Symptoms may persist two

duration of exposure to neuroleptics nor to

to three times longer with depot preparations

toxic overdoses of neuroleptics; however, nu-

of neuroleptics.

merous predisposing factors in affected pa-

Although NMS is largely a clinical diagno-

tients have been identified. NMS is associated

sis, laboratory investigations can provide sup-

with the initiation of neuroleptic medications

portive data and reveal metabolic alterations

at high doses, the rapid upward titration of

that mandate diligent monitoring and treat-

dose, as well as the use of long-acting depot

ment. An elevation of the blood creatinine

neuroleptic preparations. Metabolic factors

phosphokinase (CPK) level and a polymor-

such as dehydration, physical exhaustion,

phonuclear leukocytosis are consistently

and acute agitation with excessive sympa-

found. White blood cell counts between

thetic discharge also have been implicated.

10,000 and 30,000 cells/mm³ are present in the

The four cardinal features of NMS are hyper-

majority of cases. Electrolyte levels may reveal

thermia, muscle rigidity, altered mental sta-

dehydration. Lumbar puncture, when per-

tus, and autonomic instability. Hyperthermia

formed, demonstrates either normal CSF pa-

is present in all cases of NMS; however, the

rameters or nonspecific changes. CT of the

height of the temperature elevation is vari-

head is typically negative, and EEG studies are

able:

>38°C (100.4°F) in 92% and >40°C

either normal or consistent with a nonspecific

(104°F) in 40% of patients with NMS. Mus-

encephalopathy.

cular rigidity, commonly described as “lead

The differential diagnosis of NMS includes

pipe” rigidity, is typically generalized and

CNS infection (meningitis, encephalitis, postin-

may be severe enough to compromise chest

fectious encephalomyelitis), malignant hyper-

wall compliance, causing hypoventilation

thermia

(an inherited response to general

and the need for ventilatory support. Dyspha-

anesthesia) or heatstroke, anticholinergic toxi-

gia may occur as a result of the rigidity of the

city, and idiopathic malignant catatonia (ad-

pharyngeal musculature, placing the patient

vanced progression of a psychotic disorder).

at risk for aspiration. Other commonly re-

NMS, essentially a drug-induced malignant

ported motor abnormalities include immobil-

catatonia, may be difficult to distinguish from

ity or slowness of movement, and involuntary

idiopathic malignant catatonia. Nevertheless,

movements, such as tremor and dystonia.

discontinuation of antipsychotics is necessary

Mental status changes, often described as

in both. Other disorders with a similar presen-

fluctuating states of consciousness, occur in

tation include thyrotoxicosis, heat stroke,

75% of affected patients. Progression through

tetanus, and drug-induced parkinsonism.

stages of agitation to alert mutism, stupor,

and coma may be observed. Autonomic dys-

Treatment of Neuroleptic

function is universal. Frequently reported

Malignant Syndrome

manifestations are tachycardia, diaphoresis,

blood pressure instability, urinary inconti-

Management of NMS begins as soon as the di-

nence, cardiac dysrhythmias, and pallor or

agnosis is suspected with the immediate with-

flushing of the skin. Infrequent findings in-

drawal of neuroleptic medications or other

clude Babinski sign, hyperreflexia, seizures,

dopamine antagonists. In the acute setting, IV

opisthotonos (body spasm with arching of

fluids may be indicated for volume repletion,

the back), oculogyric crisis, chorea, and tris-

and metabolic abnormalities may need correc-

mus (jaw muscle spasm). The clinical features

tion. Ice packs and cooling blankets can aid in

of NMS typically develop over a 24- to 72-

reducing hyperthermia. In most cases, discon-

hour period and continue for approximately

tinuation of antipsychotic medication is suffi-

5 to 10 days even when the offending agents

cient as NMS is usually self-limited.

Chapter 5

■ Neurologic Emergencies

Pharmacologic therapy has not been fully es-

and

cardiovascular collapse may be seen. There

tablished by controlled trials due to the rarity

is a significant risk of renal failure as a result of

and heterogenous nature of NMS. For patients

the combined effects of volume depletion and

with milder and primarily catatonic NMS, lo-

myoglobinuria due to rhabdomyolysis.

razepam (1 to 2 mg every 4 to 6 hours IM or IV)

Mortality may result from the cumulative ef-

may be used as a first-line treatment. The most

fects of medical complications. Morbidity and

commonly used medications for NMS are

mortality from NMS have decreased over the

dopaminergic drugs, bromocriptine and aman-

years: reports document a mortality rate of 25%

tadine, and dantrolene sodium. Bromocriptine

before 1984 and 11.6% since 1984. The im-

(initiated at 2.5 mg PO every 8 hours, up to a

provement in prognosis is attributed more to

total daily dose of 45 mg as needed) may worsen

early recognition and treatment of the syndrome

psychosis and hypotension. Dantrolene (1 to

than to the use of any specific therapeutic agent.

2.5 mg/kg IV every 6 hours for 48 hours, then

Because many patients who recover from

tapered), a muscle relaxant, should not be ad-

NMS continue to require the use of dopamine-

ministered with calcium channel blockers due to

blocking agents, the safety of reintroducing

cardiovascular risks. These medications used

neuroleptics often is raised. Studies have

alone or in combination promote a reduction of

demonstrated that a recurrence of NMS can

body temperature and serum CPK by reducing

best be avoided by waiting for a complete reso-

skeletal muscle rigidity. If NMS is caused by

lution of NMS before reintroducing low doses

orally administered neuroleptics, treatment with

dantrolene and/or bromocriptine should be con-

tinued for at least 10 days because recurrence

Always Remember

may develop with early treatment withdrawal.

• Early anticonvulsant treatment is associated

Treatment may even be required for

2 to

with the best prognosis for recovery from

3 weeks if depot neuroleptics were used.

status epilepticus. Treatment should start if a

The psychiatry literature also supports the

seizure or series of seizures continue for

use of ECT as second-line treatment for NMS

>5 minutes.

when drug therapy has failed. Recommended

• The risk of acute respiratory failure calls for

ECT regimen (with caution in succinylcholine

special observation in patients presenting with

use for those with rhabdomyolysis) includes

GBS or an exacerbation of myasthenia gravis.

6 to 10 bilateral treatments.

• If a diagnosis of herpes encephalitis is

suspected in a patient with an acute change

■ SPECIAL CLINICAL POINT: The primary

in mental status, empiric acyclovir treatment

treatment for NMS is discontinuation of

should be initiated even before the diagnostic

antipsychotics and supportive care.

testing is completed.

Benzodiazepines, dopaminergic drugs

• Empiric thiamine therapy for Wernicke

(amantadine or bromocriptine), and dantrolene

encephalopathy should be considered in any

are not proven but may be helpful in NMS and

should be tapered to avoid rebound symptoms.

patient presenting with a change in mental

status and a history of alcohol use.

Approximately

40% of patients with NMS

• Neurosurgical consultation is generally

suffer from medical complications. Respiratory

warranted in a patient presenting with a

complications arising from diminished chest

neurologic emergency that may require

wall compliance and prolonged immobility

urgent surgical intervention, such as in the

include ventilatory failure, aspiration pneumo-

case of intracranial hematoma, cerebellar

nia, pulmonary edema, and pulmonary em-

hemorrhage, increased ICP, or spinal cord

bolism. Cardiovascular complications such as

compression.

phlebitis, dysrhythmias, myocardial infarction,

Chapter 5

■ Neurologic Emergencies

of low-potency neuroleptics and ensuring that

pleocytosis may not occur until after a few

the patient is well hydrated and metabolically

weeks of illness.

stable. Rechallenge with antipsychotics should

2. The next day, she complains of difficulty

be delayed for at least 2 weeks after recovery

in walking and on examination shows a

from NMS.

pulse of 120, diffuse areflexia, and

The diagnosis of NMS should come to mind

bilateral proximal lower-extremity

when encountering any individual taking neu-

weakness. The best management at this

roleptics who develops unexplained fever with

time would be:

muscle rigidity. Although there are numerous al-

A. Admit her to an ICU for cardiac

ternate diagnoses, the life-threatening danger of

monitoring, frequent vital capacities,

NMS demands that treatment should not be de-

and lumbar puncture.

layed if there is significant clinical suspicion.

B. Observe her in a general medical ward

with daily vital capacities and steroids.

C. Admit her to an ICU for cardiac

QUESTIONS AND DISCUSSION

monitoring, with monitoring of the vital

capacity only if respiratory problems

1. A 21-year-old woman is seen in the

occur.

emergency room complaining of a feeling

D. Admit her to an ICU for vital capacity

of tingling in her feet and hands for 1 day.

and cardiac monitoring, and give high-

She has no other neurologic complaints.

dose steroids.

She denies shortness of breath, exposure to

drugs or toxins, or a recent viral illness. An

The correct answer is A. With weakness now

examination reveals diffuse hyporeflexia

developing, it is clear that the patient has GBS.

with absent ankle jerks. Very careful

She should be monitored in an ICU setting, and

sensory testing is normal despite the

she should be watched closely for the develop-

patient’s complaints. The best course of

ment of cardiac arrhythmias and respiratory

action would be:

compromise. Vital capacities should be checked

A. Discharge the patient with the diagnosis

every 4 to 6 hours, with intubation done if

of “functional disorder” because of a

there is less than 60% predicted value. Steroids

paucity of objective findings.

have not been shown to be effective in GBS.

B. Admit her to the hospital for close

3. Which of the following statements about

observation, watching carefully for signs

generalized SE is true?

of developing weakness or respiratory

A. Generalized SE should be diagnosed in a

difficulty.

patient who within a 2-hour period has

C. Perform a lumbar puncture in the

a series of seizures, between which he is

emergency room, suspecting early GBS,

fully oriented and able to clearly state

with plans to discharge the patient if the

his medications and dosages.

results are normal.

B. A patient presents to the clinic with a

D. Order a brain MRI to rule out a cerebral

normal mental status but continuous

mass lesion or stroke.

involuntary twitching of his left thumb,

The correct answer is B. Paresthesias with-

consistent with a diagnosis of

out objective sensory findings occur com-

generalized SE.

monly and early in GBS, often before clinical

C. A patient in generalized SE should be

weakness develops. The key features in this

immediately intubated and paralyzed

case are the sensory complaints in the pres-

with neuromuscular blockade to prevent

ence of diffuse hyporeflexia. The typically

rhabdomyosis from intense muscular

high CSF protein concentration without

contractions.

Chapter 5

■ Neurologic Emergencies

D. Generalized SE should be treated with a

intravenous fluids, while considering the

fast-acting benzodiazepine followed

need for neuroimaging and lumbar

immediately by a loading dose of a long-

puncture.

acting anticonvulsant.

D. Order serial neurologic examinations to

be done by nursing staff while

The correct answer is D. Generalized SE is

attempting to contact family members

defined by prolonged seizure activity with

for further historical information.

loss of consciousness or repeated seizures

without recovery of consciousness between

The correct answer is C. This patient presents

episodes. Statement (A) better describes acute

with the classic triad of clinical features for

repetitive seizures that may evolve into gener-

Wernicke encephalopathy—ophthalmoplegia,

alized SE in some patients if left untreated.

ataxia, and confusion. Immediate infusion of

Focal motor SE, or epilepsia partialis con-

thiamine is warranted because the symptoms

tinua, described in statement (B) does not

are potentially reversible with early treatment.

carry the same morbidity or urgency as gen-

Glucose should be administered for potential

eralized SE, may persist for weeks without

hypoglycemia, but it should be given only

evolving further, and can be very resistant to

after thiamine because of the risk of precipi-

seizure therapy. Neuromuscular blockade (C)

tating encephalopathy in those with border-

will abolish the motor activity but will not

line nutritional status. Pursuing additional

treat the underlying electrical seizure activity.

evaluative testing including neuroimaging,

Following preservation of an airway, drawing

lumbar puncture, EEG, and cervical spine

labs, and the establishment of intravenous

plain film series may be warranted based on

access, first-line therapy is aimed at abolish-

the clinical picture but should not delay early

ing electrographic seizure activity with anti-

administration of thiamine.

convulsants.

4. A 45-year-old man presents to the

emergency department confused with an

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Examination of

the Comatose

Patient

JORDAN L. TOPEL AND STEVEN L. LEWIS

key points

• Coma is not an independent disease entity but a

reflection of an underlying disease process.

• Coma results from bilateral, diffuse cerebral hemisphere

dysfunction or brainstem (midbrain or pons)

involvement of the ascending reticular activating system,

or a combination of the two.

• Metabolic or systemic disorders generally cause

depressed consciousness without focal neurologic

findings.

• Proper management of the unconscious patient

includes an aggressive pursuit of the medical history.

• The goal of the neurologic examination of the

comatose patient is to determine the presence,

location, and nature of the underlying process

creating the decreased level of consciousness and

also to determine the prognosis of the patient’s

condition.

• Following the establishment of an airway with

stabilization of respiration and maintenance of

circulation, certain laboratory tests and therapeutic

measures are undertaken that can occur concurrently

with the acquisition of a pertinent history and a

neurologic examination.

Chapter 6

n Examination of the Comatose Patient

and decerebrate responses), and deep coma, in

DEFINITIONS AND CLINICAL

which there is no response to painful stimuli.

SYNDROMES

Psychogenic unresponsiveness

(hysterical

coma) is a psychiatric phenomenon in which

A discussion of the evaluation and treatment of

the patient appears unresponsive but is physio-

the comatose patient requires one to define cer-

logically awake. The heart and respiratory

tain terms regarding different states and levels of

rates are usually normal. The patient lies with

consciousness and unconsciousness. The exami-

the eyes closed, and the eyelids are frequently

nation and diagnostic studies must be carried

difficult to separate (forced eye closure). Mus-

out in an organized and systematic manner with

cle tone is normal. Although there may be little

documentation that is clear to all members of

resistance to passive movement, suspending the

the health team. The definitions of different lev-

patient’s hand over his or her face usually re-

els of consciousness are, by themselves, often

sults in its falling to the side instead of directly

confusing and misleading. When one physi-

downward. Pupils are equal and reactive unless

cian’s understanding of terms (e.g., lethargy,

certain eyedrops have been used. Ice water

stupor, or obtundation) differs from that of his

caloric testing produces nystagmus, a sign seen

or her colleagues, one may think that a patient’s

only in awake patients. The electroencephalo-

condition has deteriorated, although only the

gram (EEG) reveals a waking record.

terminology has changed between the observers.

The “locked-in” syndrome is an important

It is better to specifically describe a patient’s

condition to recognize. The patient appears to

movements, and reactions to painful stimuli, for

be in a coma but has essentially all higher men-

example, rather than to categorize the patient as

tal activities intact. The syndrome most fre-

being lethargic, semicomatose, or stuporous.

quently is related to pontine infarction due to

Consciousness is defined as the awareness of

basilar artery thrombosis or embolism. There is

one’s self and the environment. This is a poor

an interruption of the descending corticobulbar

definition, however, because one can argue that

and corticospinal tracts, resulting in quadriple-

a sleeping person is unconscious—that is, un-

gia and paralysis of lower cranial nerves. The

aware of himself or herself and his or her envi-

patient is unable to talk, breathe, or move his or

ronment. Clinically, however, no one regards a

her extremities. Because the ascending reticular

sleeping person as unconscious: he or she can

activating system is spared, however, arousabil-

be aroused to appropriate physical and mental

ity and wakefulness are present. There also is

activity with appropriate, non-noxious stimuli.

sparing of fibers controlling eye blinking and

Consciousness comprises a continuum from

vertical eye movements, though horizontal eye

full alertness to deep coma, or total unrespon-

movements are almost always impaired. Thus,

siveness. Drowsiness or lethargy is character-

the patient’s only means for communication

ized by easy arousal with light stimuli. There

may be using eye blinks (Morse code). The ram-

may be a verbal response or appropriate limb

ifications of not recognizing this disturbing

movements to pain. Stupor reflects arousability

clinical condition are obvious.

by persistent or vigorous stimuli only, and the

arousal is incomplete. There is little verbal re-

n SPECIAL CLINICAL POINT: Every patient,

sponse, but limb movements still may be ap-

no matter how deep in coma he or she appears

propriate to the stimulus. Mental and physical

to be, should be asked to open and close the

activities are reduced to a minimum. Coma re-

eyes and to move them up and down, to assess

flects the state in which the patient cannot be

for the locked-in syndrome.

aroused to make purposeful responses. This is

subgrouped into light coma, in which there

The vegetative state is somewhat clinically op-

may be reflex, primitive, or disorganized re-

posite of the “locked-in” syndrome. The patient

sponses to noxious stimuli (e.g., decorticate

appears to be awake with intermittent eye

Chapter 6

n Examination of the Comatose Patient

opening but is unable to attain higher mental

Coma is unusual with unilateral cerebral

functions. Simply stated, there is arousal but no

hemisphere disease unless there is a dysfunc-

awareness. There is no language comprehension

tion of the other hemisphere or secondary

or intelligible speech nor responses to visual or

pressure or destruction of brainstem struc-

auditory stimuli. Sleep-wake cycles may return,

tures. Most large cerebral hemisphere infarc-

but there is no return of higher mental activity.

tions will result in a slightly decreased level of

consciousness, but the patient still can be

n SPECIAL CLINICAL POINT: The vegetative

aroused to elicit some purposeful movements

state occurs in the setting of severe cortical

or higher mental activity. Rare exceptions may

dysfunction with relative brainstem sparing, such

be patients with large, acute lesions affecting

as in patients who survive a cardiopulmonary

the dominant cerebral hemisphere. In contrast,

arrest with consequent severe cerebral anoxia.

profound coma may result from very small in-

The term “persistent vegetative state” implies

that the patient has been in a clinical vegetative

farctions in the brainstem affecting the ascend-

state for more than 30 days.

ing reticular activating system.

A unilateral hemispheral mass lesion,

n SPECIAL CLINICAL POINT: The minimally

such as a tumor, abscess, or expanding hem-

conscious state is seen in patients with marked

orrhage, frequently will present with unilat-

impairment of consciousness but who have

eral focal neurologic symptoms and signs.

evidence of any awareness of the environment.

On continued enlargement of the mass, there

Patients in the minimally conscious state can ex-

may be a compression of the contralateral

hibit some deliberate or cognitively mediated be-

cerebral hemisphere or a downward hernia-

havior. This may be manifested by the ability to

tion of the ipsilateral temporal lobe, creating

follow very simple commands, show some pur-

distortion and compression of the brainstem

poseful behavior, or have minimal verbalization.

(transtentorial herniation). At this point,

It is not uncommon for patients with acute

coma will ensue. There is also the suggestion

onset of global aphasia to be diagnosed ini-

that horizontal displacement of the brain at

tially as being in coma. The patient is indeed

the level of the pineal body may correlate

unable to comprehend, communicate, or carry

more closely with levels of consciousness

out simple verbal commands. The diagnosis

than downward displacement with brainstem

may be established by noting that the patient

compression.

appears to be awake and alert, often with

Metabolic processes usually affect both

deviation of the eyes to the left with a right

brainstem and cerebral hemispheres to produce

hemiplegia.

coma. This likely reflects a direct interference

of the metabolic activity of the neurons. Ini-

tially, the patient is drowsy, but coma ensues as

COMA

the metabolic process worsens.

Anatomy

In the evaluation of the comatose patient, it is

ETIOLOGY

necessary to consider the physiologic and

n SPECIAL CLINICAL POINT: Coma is not an

anatomic abnormalities that result in decreased

independent disease entity but a reflection of

level of consciousness.

an underlying disease process.

n SPECIAL CLINICAL POINT: Coma results

The causes of coma can be divided into two

from bilateral, diffuse cerebral hemisphere

dysfunction or brainstem (midbrain or pons)

main categories: (1) those of primary central

involvement of the ascending reticular

nervous system (CNS) disease and (2) those of

activating system, or a combination of the two.

metabolic or systemic depression (Table 6.1).

Chapter 6

n Examination of the Comatose Patient

TABLE 6.1

Common Causes of Coma

Cause

Comments

Coma Secondary to Primary Brain Injury or Disease

Infection

Bacterial meningitis

Nuchal rigidity; CSF shows pleocytosis, increased protein; glucose may be

decreased; meningeal enhancement on MRI

Viral encephalitis

May have focal findings; CSF shows increased lymphocytes, increased

protein, normal or slightly decreased glucose; positive PCR for HSV;

possible focal abnormalities on MRI

Abscess

Focal findings; positive CT or MRI scan; history of ear or sinus infection

or HIV or endocarditis; CSF shows mildly increased protein, increased

cells, negative cultures

Tumor

Primary or metastatic

Focal findings; progressive course; may have papilledema

Cerebral infarction

Basilar occlusion or bilateral

Usually no coma unless bilateral or acute, large dominant hemisphere, or

internal artery occlusion

involving brainstem reticular activating system

Cerebral hemorrhage

Subarachnoid

Sudden onset; headache, nuchal rigidity, vomiting; positive CT scan (95%);

bloody CSF

Intracerebral

Sudden onset; headache, nuchal rigidity, vomiting; focal findings; abnormal

CT scan (100%); history of hypertension or coagulopathy or

anticoagulation

Hydrocephalus

May result from subarachnoid

Decreasing level of consciousness; enlarging ventricular size on CT scan

hemorrhage or meningitis

Trauma

Concussion, contusion

Positive history, evidence of injury on examination; uncomplicated

concussion leaves no residual

Subdural hematoma

Depressed level of consciousness can occur before focal findings; may

have trivial or no trauma history

Epidural hematoma

Lucid interval; skull fracture over middle meningeal artery

Seizures

Generalized or focal seizures

Convulsive or nonconvulsive status epilepticus; postictal progressive

improvement in level of consciousness unless other factors are involved

The latter group contains the more common

only one side, or asymmetric reflexes. A previ-

causes of a depressed level of consciousness.

ous neurologic injury, however, may render cer-

Primary central nervous system disorders

tain neurons more susceptible to a metabolic

may or may not produce focal abnormalities

insult and accentuate clinical signs related to the

on examination.

older injury. A metabolic encephalopathy in a

patient with an old stroke that had fully re-

n SPECIAL CLINICAL POINT: Metabolic or

solved thus could produce a reemergence of the

systemic disorders generally cause depressed

former weakness in a focal pattern, even though

consciousness without focal neurologic findings.

the cause of the current coma is a metabolic one.

In these instances, the clinician does not expect

With correction of the metabolic abnormality,

to find unequal pupils, signs of weakness on

the focal signs would be expected to disappear

Chapter 6

n Examination of the Comatose Patient

TABLE 6.1

Common Causes of Coma (continued)

Cause

Comments

Coma Secondary to Metabolic and Systemic Diseases

Exogenous substances

Sedatives, hypnotics,

Positive blood or urine screens; may cause pupillary abnormalities

antidepressants

(opiates cause miosis and anticholinergics cause mydriasis)

Alcohol

Breath odor may not be apparent; withdrawal seizures 8 to 48 hours

after last drink

Methyl alcohol

Metabolic acidosis; visual symptoms

Heavy metals, cyanide

Lead encephalopathy common in children, not in adults

arsenic, lead, salicylates

Endogenous substances

Hepatic coma

Fetor hepaticus, jaundice, ascites, asterixis; triphasic waves on

electroencephalogram

Uremic coma

Uriniferous breath; seizures; asterixis

CO₂ narcosis

Increased P

; abnormal physical chest findings; abnormal electrolytes

CO2

Endocrine-pituitary, thyroid,

Urine and serum osmolalities; thyroid function studies;

pancreas (diabetes), adrenal glands

focal seizures with hyperglycemic nonketotic coma

Hypoxia

Pulmonary disease, carbon

Abnormal blood gases; elevated carboxyhemoglobin, cherry red lips

monoxide intoxication, anemia

Decreased cardiac output

Hypotension, congestive heart failure, myocardial infarction,

arrhythmia, cardiopulmonary arrest

Hypertensive encephalopathy

Papilledema; proteinuria; headaches; seizures; posterior reversible

encephalopathy syndrome

Hypoglycemia

Suspect in all comatose patients

Reversed with D50 unless prolonged coma

Thiamine deficiency

Wernicke encephalopathy

Potentially reversible with IV thiamine

Electrolyte imbalance

Often multifactorial

Water, sodium, acidosis, alkalosis, calcium

Temperature regulation

Hypothermia

Exposure; myxedema; circulatory failure

Hyperthermia

Heat stroke; neuroleptic malignant syndrome with muscle rigidity and

elevated CK; infection

CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; HSV, herpes simplex virus; CT, computed

tomography; HIV, human immunodeficiency virus; CK, creatine kinase.

again, unless there was further focal damage

“obvious” cause from the history obtained

superimposed.

does not change the patient’s clinical status.

n SPECIAL CLINICAL POINT: Aggressive

HISTORY AND EXAMINATION

management of the unconscious patient

includes an aggressive pursuit of the history.

A history should be taken, but unfortunately

this is often incomplete, nonexistent, or mis-

For example, metabolic abnormalities most

leading. A search for “less likely” causes for

often are associated with subacute onset of

coma is necessary when treatment for the

coma, whereas a history of a more rapid course

Chapter 6

n Examination of the Comatose Patient

is suggestive of cardiac or cerebrovascular cause

to apnea. The periods of apnea may last up to

or drug overdose.

30 seconds or more and may be accompanied

There should be a search for evidence of

by decreased responsiveness and miosis. It is be-

trauma. Battle’s sign (purple and blue discol-

lieved that Cheyne-Stokes respiration relates to

oration of the mastoid skin area), blood in the

an abnormal response of carbon dioxide-sensi-

external auditory canal, or blood noted behind

tive respiratory brain centers. There is an in-

the tympanic membranes may signify a tempo-

creased ventilatory response to carbon dioxide

ral bone or basal skull fracture. Raccoon eyes

stimulation, creating hyperpnea. After the con-

(purple discoloration of the eyelid and orbital

centration of carbon dioxide drops below the

regions) may signify orbital or basal skull frac-

level at which the centers are stimulated, the

tures. Cerebrospinal fluid rhinorrhea or otor-

apnea phase appears and continues until the car-

rhea also suggests a skull fracture.

bon dioxide reaccumulates and the cycle repeats

One should check carefully for nuchal

itself. Because sleep induces further cerebral-

rigidity, but several factors must be considered

depressing mechanisms, Cheyne-Stokes respira-

in doing so. If there is any suspicion of a cervi-

tion may be seen in some patients during sleep,

cal neck fracture, there should be no manip-

whereas they exhibit normal breathing patterns

ulation of the neck. In deep coma, nuchal

while awake. Cheyne-Stokes respiration is, by

rigidity may be lacking despite its presence in a

itself, not a serious prognostic sign. Although it

lighter level of consciousness. Finally, some

can be seen in focal primary CNS problems, it

patients with a CNS infection or subarachnoid

also can be seen early in many metabolic and

hemorrhage may not manifest nuchal rigidity

systemic problems.

initially in the course of their illness.

Central neurogenic hyperventilation ap-

The odor of the patient’s breath may indi-

pears when lower brain centers are involved; it

cate the cause for the coma. Alcohol gives its

is noted with dysfunction at the midbrain or

characteristic smell; hepatic coma is often asso-

the upper pons and often is associated with

ciated with a musty odor; and a fruity or ace-

pulmonary edema. There are continuous,

tone smell is characteristic of ketoacidosis.

regular, and rapid respirations up to 40 or 50

After a screening, general physical examina-

times per minute. Arterial blood gases reveal a

tion, an orderly, systematic neurologic exami-

respiratory alkalosis with decreased PCO2 and

nation, is undertaken.

increased pH. The PO2 must be greater than 70

or 80 mm Hg. If the PO2 is not higher than that

n SPECIAL CLINICAL POINT: The goal of the

level, it raises the possibility of an extracerebral

neurologic examination is to determine the

cause (hypoxemia) for the respiratory problem.

presence, location, and nature of the underlying

In reality, most cases of sustained hyperventila-

process creating the decreased level of

consciousness and also to determine the

tion in comatose patients are not central neuro-

prognosis of the patient’s condition.

genic hyperventilation. Cardiac, pulmonary,

and metabolic (e.g., diabetes, uremia, hepatic,

Respiratory patterns yield information re-

salicylates) problems must be ruled out as pos-

garding the activity of different cerebral

sible causes of the hyperventilation.

areas. When one develops bilateral cerebral

Apneustic respiration, noted in lower pon-

hemisphere dysfunction

(essentially, func-

tine lesions, consists of a prolonged inspiratory

tioning at the diencephalic level), Cheyne-

phase with a pause at full inspiration. Cluster

Stokes respiration may occur. This respiratory

breathing (short-cycle Cheyne-Stokes respira-

pattern is associated with periods of hyperpnea

tion), also signifying lower pontine damage, is

alternating with periods of apnea. There is a reg-

characterized by a disorderly sequence of closely

ularity to the respirations: first a gradual

grouped respirations followed by apnea.

buildup of respirations to the level of hyperpnea

Ataxic respirations signify a lower pontine

and then a gradual tapering off of respirations

or medullary respiratory center problem. The

Chapter 6

n Examination of the Comatose Patient

breathing pattern is chaotic and haphazard

quently present. Because the oculomotor nerve

with irregular pauses. It may, and usually does,

is strategically situated at the temporal incisura,

lead to gasping and eventual cessation of

temporal lobe herniation may result in a widely

breathing. Ataxic breathing is a forewarner of

dilated, fixed pupil and possibly total cranial

respiratory arrest, and prompt endotracheal in-

nerve III paralysis.

tubation is necessary at the time of its discovery.

Pinpoint (1 mm) pupils are seen with pon-

An examination of the pupillary responses,

tine damage but may be a transient finding for

eye movements, and fundus must be under-

only the first 24 or 48 hours. The pupils are

taken. In a patient with a decreased level of

small and can be seen occasionally to react

consciousness, but who is not yet in coma, vi-

slightly to light if viewed through a magnifying

sual threat (forceful movements of the hand to-

glass. This is thought to relate to damage of the

ward either side of the eyes) may be helpful.

descending sympathetic tracts. Frequently,

Blinking in response to a threat from one side,

however, midposition and fixed pupils may be

but not from the other side, suggests a hemi-

noted with pontine dysfunction.

anopsia. The abnormality thus would be in the

In general, metabolic causes of coma do not

cerebral hemisphere opposite to the side that

alter pupillary response until late in their course,

did not blink. A funduscopic examination may

if at all. For example, a deeply comatose patient

reveal papilledema or retinal hemorrhages sug-

with no spontaneous or reflex movements and

gesting increased intracranial pressure or ma-

no respirations, but with reactive pupils, must

lignant hypertension.

be considered to be in metabolic coma until

The pupillary response should be assessed.

proven otherwise. However, certain drugs can

The light reflex is mediated, in succession,

alter pupillary size and response. Opiates char-

through the optic nerve, the optic chiasm, the

acteristically produce pinpoint pupils (reversed

optic tract, the posterior diencephalon, and the

with naloxone). Atropine may result in widely

Edinger-Westphal nuclei of the midbrain and

dilated and fixed pupils. Various eyedrops also

then to the sphincter pupillae by way of the

may alter pupillary size and reaction.

parasympathetic nerve fibers in the oculomo-

The position and movements of the eyes are

tor nerve (cranial nerve III). Thus, it is not sur-

observed, and certain procedures are under-

prising that the most significant abnormalities

taken to evaluate cerebral hemisphere and

of the pupils are seen with dysfunction at the

brainstem integrity. The neural pathways for the

level of the midbrain or oculomotor nerve.

control of horizontal conjugate eye movements

Diencephalic pupils, the result of bilateral

are outlined in Figure 6.1. Cortical control orig-

hemispheral dysfunction, are small and reactive.

inates in the frontal gaze centers (Brodmann’s

The small size likely reflects sympathetic nerve

area 8). Descending fibers controlling horizon-

dysfunction at the level of the takeoff of the

tal conjugate gaze cross the midline in the lower

sympathetic fibers from the hypothalamus.

midbrain region and descend to the paramedian

Midposition, unreactive (4 to 7 mm) pupils

pontine reticular formation (PPRF) in the pons.

result from direct midbrain

(tectal region)

The PPRF is thus the major area of confluence

damage. The pupillary size likely reflects in-

of pathways controlling horizontal eye move-

volvement of both the descending sympathetic

ments. Neurons from the PPRF project to the

fibers and the parasympathetic fibers of the

nearby abducens nerve (cranial nerve VI) nu-

oculomotor complex.

cleus and thereby stimulate movement in the

A widely dilated, fixed pupil usually is seen

lateral rectus muscle of the eye ipsilateral to the

as a result of direct oculomotor nerve involve-

PPRF and contralateral to the frontal gaze cen-

ment, with unopposed dilator sympathetic

ter. In addition, impulses from the abducens

tone. In addition to the pupillary abnormalities,

nerve nucleus cross the midline and ascend the

ptosis and extraocular muscle paralysis (espe-

median longitudinal fasciculus to the medial

cially paralysis of adduction of the eye) are fre-

rectus nucleus of the oculomotor nerve (cranial

Chapter 6

n Examination of the Comatose Patient

FIGURE 6.1 Diagram of the conjugate vision pathways

(nuclei and paths are shaded to include those important to

left conjugate gaze). Fibers from the right frontal cortex

descend and cross the midline, and they synapse in the left

paramedian pontine reticular formation (PPRF). Fibers then

travel to the nearby left cranial nerve VI nucleus (to move

the left eye laterally) and then cross the midline to rise in

the right medial longitudinal fasciculus (MLF) to the right

cranial nerve III nucleus (to move the right eye medially). In

addition to the cortical influence on the left PPRF, there is

vestibular influence. With vestibular activation from the right,

the left PPRF is stimulated, and the eyes conjugatively move

to the left. Instillation of ice water into the right ear canal will

test the integrity of this vestibular-PPRF-cranial nerve-VI-

cranial nerve-III circuit, and if the eyes move to vestibular

stimulation, the brainstem from medulla to midbrain must

be functioning.

nerve III) in the midbrain. This stimulates ad-

hemispheral lesion and “look” away from the

duction of the eye ipsilateral to the frontal gaze

resulting hemiplegia.

center. Horizontal conjugate gaze thus is com-

By contrast, a destructive left pontine lesion,

pleted.

for example, will damage the left PPRF. The

By following these pathways, it can be seen

eyes, therefore, cannot go to the left and will

that stimulation of fibers from the frontal gaze

tend to deviate to the right. Because descending

center of one cerebral hemisphere results in

pyramidal tract fibers cross the midline in the

horizontal, conjugate eye movements to the

medulla, damage to the pyramidal tract fibers

contralateral side. If one frontal gaze center or

in the pons on the left results in a right hemi-

its descending fibers are damaged, the eyes will

plegia. Thus, the eyes “look” away from a de-

tend to “look” toward the involved cerebral

structive pontine lesion but “look” toward the

hemisphere because of unopposed action of the

hemiplegia.

remaining frontal gaze center. For example, a

If the abducens nerve or nucleus is destroyed,

destructive lesion in the right cerebral hemi-

there will be a loss of abduction of the ipsilateral

sphere, involving descending motor fibers and

eye (cranial nerve VI palsy). With destruction of

frontal gaze fibers, will cause a left hemiplegia

the tract of the medial longitudinal fasciculus,

with head and eyes deviated to the right. In

disconjugate gaze results, with loss of adduction

other words, the eyes “look” at a destructive

of the ipsilateral eye (same side as the tract of the

Chapter 6

n Examination of the Comatose Patient

medial longitudinal fasciculus). Abduction of the

think of this as an indirect means of stimulating

contralateral eye is preserved, but there is nystag-

the ipsilateral PPRF. Hence, after cold water in-

mus. This type of disconjugate gaze abnormality

stillation, there is a slow, tonic, conjugate devia-

also is termed “internuclear ophthalmoplegia”

tion of the eyes toward the irrigated ear. In a

(see Chapter 22). The pathways for vertical eye

waking patient, there is a correction of the eyes

movements are less well understood. Lower cen-

to the opposite side, resulting in a fast nystag-

ters likely exist in the midbrain (pretectal and tec-

mus away from the stimulated ear. In an uncon-

tal) regions. Integrity of vertical eye movements

scious patient, there is a loss of the fast-phase

can be tested in some patients by gently moving

nystagmus, and only tonic deviation of the eyes

the head back and forth in the vertical plane.

is seen if appropriate pontine-midbrain areas

If a patient cannot follow verbal commands,

are intact. Thus, if nystagmus is noted in a seem-

two tests are used to determine brainstem

ingly unconscious patient, the patient is either in

integrity. An oculocephalic (doll’s head) maneu-

a very light coma or psychogenic unresponsive-

ver is performed by turning the patient’s head

ness. It is important to be vigilant when per-

rapidly in the horizontal or vertical planes and

forming caloric testing in these states because

by noting the movement or position of the eyes

the stimulation is potentially noxious and can

relative to the orbits. This maneuver should not

induce vomiting; making certain that the patient

be performed if a cervical neck fracture is sus-

is safely positioned so that vomiting would not

pected. If the pontine (horizontal) or midbrain

cause aspiration is paramount.

(vertical) gaze centers are intact, the eyes should

A lack of oculovestibular responses thus sug-

move in the orbits in the direction opposite to

gests pontine-midbrain dysfunction. Ice water

the turning head. An abnormal response (no eye

calorics can help to differentiate between the con-

movement with doll’s head maneuver) implies

jugate gaze weakness or paralysis caused by ei-

pontine or midbrain dysfunction and is charac-

ther cortical (cerebral hemisphere) or brainstem

terized by no movement of the eyes relative to

(pontine) damage. Oculovestibular responses

the orbits or by an asymmetry of movement.

should not be altered in patients with only hemi-

Horizontal oculocephalic maneuvers are a

spheral pathology. Movement of the ipsilateral

relatively weak stimulus for horizontal eye

eye toward the irrigated ear, but no movement of

movements. If a doll’s head maneuver is present,

the contralateral eye, suggests an abnormality of

it is not necessary to continue with oculovestibu-

the contralateral medial longitudinal fasciculus.

lar testing. If, however, a doll’s head response is

Severe metabolic coma (e.g., after barbiturate

lacking, ice water calorics should be performed

overdose) may result in a lack of oculocephalic

because it is a stronger stimulus than oculo-

and oculovestibular responses. Reactive pupils

cephalic maneuvers.

may signify that the coma is of metabolic origin.

Oculovestibular responses (ice water calorics)

Ocular bobbing is characterized by a rapid

are reflex eye movements in response to irriga-

downward eye movement with a slow return

tion of the external ear canals with cold water.

to the horizontal plane. This is seen most often

The head is raised to 30 degrees relative to the

in pontine destruction and is thought to relate

horizontal plane, and the external canals are in-

to the loss of horizontal eye movements with

spected for the presence of cerumen or a perfo-

preservation of midbrain-mediated vertical eye

rated tympanic membrane. Fifty to 100 mL of

movement pathways. Sustained down gaze

cold water is instilled into the canal (waiting

can be seen with lesions of the thalamus or

5 minutes between ears), and the resulting eye

pretectum or after cerebral hypoxia.

movements are noted. Ice water produces a

Roving eye movements signify intact brain-

downward current in the horizontal semicircu-

stem mechanisms for horizontal gaze. The

lar canal and decreases tonic vestibular input to

movements should be distinguished from those

the contralateral PPRF. Simplistically, one can

seen in patients with seizures. In the latter, the

Chapter 6

n Examination of the Comatose Patient

eye movements are of a jerking quality and fre-

pronation of the arms. There may be opistho-

quently tend to lateralize to one side. Referring

tonic posturing of the neck. The movement of

to Figure 6.1, it can be seen that an irritative cor-

the lower extremities is similar to that seen in

tical focus in the area of the frontal gaze center

decorticate posturing. Although not completely

will deviate the eyes away from the side of

anatomically specific, bilateral decerebrate pos-

the lesion (and possibly toward a hemiplegia).

turing often is seen in lesions of the midbrain and

Oculovestibular responses usually will be able

pons, whereas decorticate posturing often im-

to overcome the eye deviations because of the

plies a higher corticospinal tract lesion. Decere-

strong direct input into the pons, “bypassing”

brate posturing is generally a poorer prognostic

the cortical effects on eye movements.

sign than decorticate posturing. However, decer-

Asymmetric corneal reflexes may be present

ebrate posturing also occasionally can be seen in

in both cortical and brainstem lesions. Meta-

the setting of severe, although potentially re-

bolic abnormalities and hypoxia can suppress

versible, metabolic encephalopathies.

corneal reflexes. It should be noted, however,

A common mistake regarding the interpre-

that corneal responses can be decreased or ab-

tation of motor responses is that of relating a

sent in waking elderly patients.

withdrawal response in the legs as representing

Motor movements may be spontaneous, in-

an appropriate cortical response. When the

duced, reflex, or totally absent. It is important

bottom of the foot is stroked, or a noxious

to note not only the type of response but also the

stimulus is applied to the leg, there may be hip

symmetry of response. An asymmetric, induced

flexion, knee flexion, and dorsiflexion of the

motor movement may be the only indication of

foot

(triple flexor response). This signifies

an underlying focal problem. Asymmetric mus-

spinal cord reflex integrity and does not signify

cle tone may also suggest a focal process.

an intact cerebral response.

It may be necessary to observe the patient for

Asymmetric extensor toe signs (i.e., flexion

several minutes to note the presence or lack of

on one side, extensor response on the other)

spontaneous or reflex motor movements. The

are of moderate value in localizing a focal

position of the extremities (e.g., a persistent ex-

cerebral lesion. Bilateral extensor toe signs

ternally rotated leg secondary to weakness of

(Babinski signs) can be seen in any form or at

that extremity) may indicate focal pathology.

any level of coma and are, by themselves, nei-

The most favorable prognostic sign related to

ther prognostic nor localizing. For example,

the motor system is symmetric, spontaneous

transient extensor toe signs are common in

movements of all four extremities. Appropriate

hypertensive encephalopathy.

motor response to noxious stimuli (e.g., pain)

The Glasgow Coma Scale (Table 6.2) is the

signifies that sensory pathways are functional

most widely used clinical scale for assessment

and there is at least partial integrity of corti-

of comatose patients. Although it initially was

cospinal tracts. It is not necessary to use unusu-

designed for trauma cases, it is also used now

ally noxious stimuli, but rather mild supraorbital

for other causes of coma. It measures the “best

pressure or pinching of the skin of the neck.

responses” of eye opening, motor response,

Reflex motor movements frequently can be

and verbal response. A lower score usually sig-

elicited by light, painful stimuli or flexion of the

nifies a more serious neurologic problem and

neck or during routine care of the patient, such

possibly a poorer prognosis. However, there

as tracheal suctioning. Decorticate posturing

can be falsely low scores such as in patients

consists of flexion of the arms, wrists, and fin-

who cannot speak because of mechanical ven-

gers and adduction of the upper arms. In the

tilation or aphasia. Recently the FOUR (Full

legs, there is extension, internal rotation, and

Outline of UnResponsiveness) score has been

plantar flexion. Decerebrate (extensor) postur-

developed which includes examination of the

ing consists of extension, adduction, and hyper-

brainstem reflexes and respiration (Table 6.3).

Chapter 6

n Examination of the Comatose Patient

TABLE 6.2

TABLE 6.3

Glasgow Coma Scale

The FOUR (Full Outline of

UnResponsiveness) Score

Eye opening

Spontaneous

Eye response

To speech

4 = eyelids open or opened, tracking, or blinking

To pain

to command

None

3 = eyelids open but not tracking

Motor response

2 = eyelids closed but open to loud voice

Obeys

1 = eyelids closed but open to pain

Localizes

0 = eyelids remain closed with pain

Withdraws (flexion)

Motor response

Abnormal reflex (flexion)

4 = thumbs-up, fist, or peace sign

Extension

3 = localizing to pain

None

2 = flexion response to pain

Verbal response

1 = extension response to pain

Oriented

0 = no response to pain or generalized myoclonus

Confused

status

Inappropriate

Brainstem reflexes

Incomprehensible

4 = pupil and corneal reflexes present

None

3 = one pupil wide and fixed

2 = pupil or corneal reflexes absent

Adapted from Jennett B, Teasdale G, Braakman R, et al. Prognosis

1 = pupil and corneal reflexes absent

of patients with severe head injury. Neurosurgery. 1979;4:283.

0 = pupil, corneal, and cough reflexes absent

Respiration

Although this may be a more accurate coma

4 = not intubated, regular breathing pattern

scale, it is not yet extensively used.

3 = not intubated, Cheyne-Stokes breathing

pattern

2 = not intubated, irregular breathing

LABORATORY EVALUATION

1 = breathes above ventilator rate

AND TREATMENT

0 = breathes at ventilator rate or apnea

Initial emergency treatment for a comatose

Adapted from Wijdicks EFM, Bamlet WR, Maramattrom BV, et al.

Validation of a new coma scale: the FOUR score. Ann Neurol.

patient is the same as for all other medical

2005;58:585, with permission of Mayo Foundation for Medical

emergencies. An adequate airway should be

established. Endotracheal intubation and arti-

ficial ventilation may be necessary. The cardio-

history and the performance of the neurologic

vascular status must be evaluated promptly,

examination.

and shock and blood pressure should be

controlled. The temperature should be noted

Blood is drawn for a complete blood count

because hypothermia or hyperthermia may

(CBC), electrolyte, glucose, calcium, blood

play a prominent role in the identification of

urea nitrogen (BUN), and creatinine determina-

the underlying problem.

tions, liver function tests, prothrombin time

(PT), partial thromboplastin time (PTT), arterial

n SPECIAL CLINICAL POINT: Following the

blood gas determinations, and a drug/toxin

establishment of an airway with stabilization of

screen. Urinalysis and urine drug screening

respiration and maintenance of circulation,

certain laboratory tests (Table 6.4) and

are performed. An electrocardiogram and chest

therapeutic measures (Table 6.5) should be

roentgenograms are obtained. If hypoglycemia

undertaken. These measures can occur

is suspected, or if the cause of the coma is

simultaneously with the acquisition of a medical

uncertain, 50 mL (25 g) of 50% dextrose in

100

Chapter 6

n Examination of the Comatose Patient

TABLE 6.4

tremia) must be undertaken. Suspected bacterial

Tests in the Evaluation of the

meningitis should be treated empirically with

Comatose Patient

appropriate antibiotics

(e.g., ceftriaxone and

Blood tests

vancomycin), and patients suspected of viral en-

Complete blood count

cephalitis should be given acyclovir. If there is

Glucose, electrolytes, calcium, blood urea nitrogen,

significant evidence for increased intracranial

and creatinine

pressure, intubation with hyperventilation and

Liver function studies and serum ammonia

the use of mannitol or hypertonic saline must be

Coagulation studies (PT and PTT)

considered. Corticosteroids may be beneficial to

Arterial blood gases

reduce vasogenic edema related to neoplasms,

Drug/toxin screen

but their effect is not immediate. Neurosurgical

Thyroid function studies

intervention should be considered for insertion

Adrenal function studies

of an intracranial pressure monitor or possibly

Magnesium

surgical decompression. Hypothermia has been

Serum osmolality

Carboxyhemoglobin

shown to improve neurologic outcome and de-

Blood cultures

crease mortality in postventricular fibrillation

Urine tests

cardiac arrest patients if started immediately

Urinalysis

after the patient is stabilized.

Drug/toxin screen

Seizure activity may be generalized or focal

Urine osmolality

and necessitates prompt treatment and a search

Urine culture

for a cause. Nonconvulsive status epilepticus

Electrocardiogram

needs to be considered if the patient does

Imaging studies

not awaken after appropriate treatment with

Chest x-ray

anticonvulsant drugs. Myoclonus (symmetric

Computed tomography (CT) brain scan

or asymmetric rapid, brief movements of the

Magnetic resonance imaging scan of the brain

Lumbar puncture, if indicated

extremities) is frequently seen in metabolic

encephalopathies and is common following

PT, prothrombin time; PTT, partial thromboplastin time;

anoxia

(e.g., after cardiac arrest). Unfortu-

CT, computed tomography.

nately, myoclonus in the setting of severe

anoxic coma is often difficult to treat, and its

water is given intravenously (IV). Hypoglycemia

appearance, especially if multifocal, following

is an extremely important, potentially reversible

anoxia is a poor prognostic sign.

cause of coma that, if not treated promptly, will

It is urgently necessary to proceed with fur-

lead to irreversible cerebral damage. For sus-

ther neurologic studies if the cause of the coma

pected opiate overdose, naloxone 0.4 mg IV is

remains unclear. Computed tomography (CT)

given and is repeated every 5 to 15 minutes as

will demonstrate intracerebral or extracerebral

needed. Repeated infusions should be instituted

blood, mass lesions, hydrocephalus, cerebral

if the response to glucose or naloxone is incom-

infarctions

(though not always immediately),

plete. Other medications can be given for spe-

and abscesses as well as skull fractures. Magnetic

cific drug overdoses when appropriate, such as

resonance imaging (MRI) will show the brain in

intravenous flumazenil for benzodiazepine over-

greater detail and may reveal abnormalities ear-

dose. If chronic or acute ingestion of alcohol is

lier than a CT scan, but it is often difficult to

suspected, or if there is any suggestion of malnu-

obtain an MRI on a comatose patient. Patients

trition, 100 mg of thiamine should be given IV

who are unstable will also need to be left unat-

to treat or prevent the Wernicke-Korsakoff syn-

tended for a longer scanning time with MRI than

drome. Thiamine should be given prior to glu-

with CT. If a CNS infection or subarachnoid

cose administration. Correction of any other

hemorrhage is suspected, a lumbar puncture is

underlying metabolic process

(e.g., hypona-

indicated, although a CT scan will identify most

101

Chapter 6

n Examination of the Comatose Patient

TABLE 6.5

Treatment of the Comatose Patient

Problem

Comment

Respiration

Immediately obtain an airway and consider intubation; early intubation

prevents aspiration, decreases risk of transferring patient to other

hospital areas, and allows for more aggressive treatment of seizures

Blood pressure

Hypotension

Treat with fluids, volume expanders, or pressors; treat sepsis if present

Hypertension

Aggressiveness of treatment depends on etiology and level of elevation of

blood pressure; different treatments for ischemic infarction or

intracerebral hemorrhage; may need IV labetalol or nicardipine

Arrhythmias

May point to etiology of coma or can be a secondary factor; continuous

cardiac monitoring is necessary

Hypoglycemia

50 mL of 50% dextrose in water; risk of worsening hyperglycemia

outweighed by benefits of treating hypoglycemia

Thiamine deficiency

To be considered in alcoholic patients or patients who are chronically

malnourished or postgastric bypass; glucose load may precipitate Wernicke

encephalopathy and thus give thiamine 100 mg IV prior to giving glucose

Drug overdose

Obtain urine and blood toxicology screens; for suspected narcotic overdose,

give naloxone IV (see text for details); use of other specific antidotes

depends on history, clinical examination, and results of toxin screens

Increased intracranial pressure

Worsening level of coma, focal abnormalities, change in respiratory pattern,

pupillary dilatation; intubation, hyperventilation, and mannitol or

hypertonic saline infusion; possible intracranial pressure monitoring and

assessing the need for neurosurgical intervention

Infection

Ceftriaxone and vancomycin for bacterial meningitis; acyclovir for herpes

simplex encephalitis

Seizures

Correct any underlying metabolic or systemic problem; treat status

epilepticus with lorazepam or diazepam; loading dose of phenytoin or

fosphenytoin IV for long-term anticonvulsant effect; if seizures not

controlled, consider barbiturates, valproate, levetiracetam; midazolam or

propofol for refractory status epilepticus (see Chapter 25 for doses)

Post-cardiac arrest

If global ischemia from cardiac arrest, immediately institute therapeutic

hypothermia

General medical and nursing care

Fluids and acid-base balance, electrolytes, observation of metabolic status;

watch and treat changes in temperature (hyperthermia or hypothermia),

agitation, and infections; prevent corneal abrasions and decubiti; correct

any underlying metabolic or systemic problem

Modified from Weiner WJ, Shulman LM, eds. Emergent and Urgent Neurology. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 1999.

subarachnoid hemorrhages sufficient to cause

ness (normal EEG). It is especially important in

coma. A CT scan should be obtained prior to the

assessing for subclinical seizure activity (non-

lumbar puncture to rule out a focal mass lesion

convulsive status epilepticus) as a cause for pro-

or increased intracranial pressure.

longed, unexplained coma. An EEG with no

The EEG may be helpful in the diagnosis

evidence of cerebral activity can be reversibly

of an overdose from sedatives (excessive fast

noted secondary to barbiturate intoxication

activity), hepatic or uremic encephalopathy

(and occasionally other drugs) and also with

(triphasic waves), or psychogenic unresponsive-

hypothermia.

102

Chapter 6

n Examination of the Comatose Patient

based solely on the level of consciousness. For

PROGNOSIS

example, patients with barbiturate overdose in

deep coma may have no spontaneous respira-

Overall prognosis for survival and functional

tion, absent oculovestibular responses, and

cerebral recovery is dependent upon the etiol-

absent cerebral activity on the EEG, yet have a

ogy of the coma as well as the depth and dura-

complete neurologic recovery.

tion of the insult and the patient’s clinical

course. For example, coma related to meta-

bolic problems typically carries a better prog-

nosis than that due to structural lesions.

WHEN TO REFER THE PATIENT

Several studies that have dealt with

TO A NEUROLOGIST

postanoxic coma have revealed that the prog-

nosis is generally better for the patient with

A neurologist should be consulted for almost

spontaneous motor movements or appropri-

all comatose patients, especially when the eti-

ate movements in response to noxious stimuli

ology of the coma is uncertain. The neurolo-

and those with intact pupillary reactions and

gist will aid in arriving at a diagnosis, localize

oculocephalic or oculovestibular responses.

the abnormalities, and assist in the treatment

Patients studied after cardiopulmonary arrest

of the underlying cause of coma. In addition,

reveal that depth and duration of postarrest

the neurologist will be able to help assess

coma correlated significantly with poor neu-

prognosis for survival and functional recov-

rologic outcome. Motor unresponsiveness,

ery (e.g., ability to function independently).

lack of pupillary responses, and lack of

This information also will enable the family

oculocephalic and oculovestibular responses

and all treating physicians to make important

were associated with a poor prognosis for

further decisions regarding the patient’s med-

neurologic functional recovery. In addition,

ical care.

the prediction of survival and outcome could

be based on a loss of consciousness alone

within 3 days after cardiopulmonary arrest.

Always Remember

Those patients not awakening within 72 hours

had the worst prognosis.

• Coma occurs due to bilateral, diffuse cerebral

Overall, however, it appears that the most

hemisphere dysfunction, upper brainstem

specific findings on examination for poor

dysfunction, or a combination of the two.

prognosis are absent or extensor

(decere-

• The goal of the neurologic examination is to

brate) motor responses and absent pupillary

determine the presence, location, and nature

or corneal responses on day 3. Myoclonic

of the underlying process creating the

status epilepticus also appears to signify a

decreased level of consciousness and also to

similar poor prognosis. Elevated blood levels

aid in prognostication.

of neuron-specific enolase

(NSE) and the

• Every patient who appears to be in coma

absence of somatosensory evoked potentials

should be assessed for the possibility of the

also have been found to suggest very poor

locked-in syndrome.

outcomes.

• Overall prognosis for survival and functional

Recent studies show that early induced

cerebral recovery is dependent upon the

hypothermia following cardiac arrest improves

etiology of the coma, the severity and

survival and function at 6 months.

duration of the insult, and the patient’s clinical

Prognosis for patients with metabolic en-

course.

cephalopathies or drug overdose cannot be

103

Chapter 6

n Examination of the Comatose Patient

The correct answer is C. Eyes “look toward” a

QUESTIONS AND DISCUSSION

destructive hemispheral lesion. Caloric responses

are preserved because the pathway for the

1. A 24-year-old man is brought to the

oculovestibular responses does not involve hemi-

emergency room with a decreased level of

spheral connections. Eyes “look away” from the

consciousness that developed over several

side of a destructive pontine lesion.

hours. On arrival, he is intubated for

diminished respirations. Examination

3. A 64-year-old man suffers a 10-minute

reveals no response to verbal command,

out-of-hospital cardiac arrest. Examination

including the command to blink his eyes.

2 days after the event shows that he is

He has small, reactive pupils (2 mm), intact

comatose, with no response to commands.

horizontal oculocephalic reflexes, and no

He has roving horizontal eye movements,

motor response to painful stimuli. Which

intact pupillary responses, and bilateral

of the following is the most likely etiology

decorticate posturing to noxious stimuli.

of this patient’s condition?

Which of the following is the most likely

A. Left middle cerebral artery infarct

localization of his neurologic dysfunction?

B. Metabolic encephalopathy

A. Bilateral cerebral hemispheres

C. Pontine hemorrhage

B. Medulla

D. Pontine infarction

C. Midbrain

E. Right hemispheric intracerebral

D. Pons

hemorrhage

E. Right cerebral hemisphere

The correct answer is B. Metabolic en-

The correct answer is A. This patient’s examina-

cephalopathies can cause profound coma with

tion is consistent with intact brainstem function

preserved pupillary responses. The gradual

but severely impaired bilateral hemispheric dys-

onset of coma is also consistent with a meta-

function, typical of patients after severe anoxic-

bolic process but is not specific for this cause.

ischemic encephalopathies due to cardiac arrest.

A pontine lesion could also cause small reactive

4. A 76-year-old woman develops the sudden

pupils but would typically be associated with

onset of unresponsiveness while eating

impaired horizontal eye movements. In addi-

dinner with her family. Examination in the

tion to the profound coma with preserved

emergency department shows small reactive

pupillary reflexes, the lack of other lateralizing

pupils, brisk spontaneous downward

findings makes other structural lesions unlikely.

movements of her eyes, absent

2. Which of the following findings is most

oculocephalic reflexes, and bilateral

likely to be seen in a patient with a right

decerebrate (extensor) posturing. She

hemispheral destructive lesion?

appears to blink her eyes to command.

A. Lack of caloric responses, eyes conjugately

Which of the following is the most likely

deviated to the left, and left hemiplegia

etiology of her condition?

B. Right eye deviated to the right, left eye

A. Diffuse cerebral anoxia

midline, and left hemiplegia

B. Hypoglycemia

C. Eyes conjugately deviated to the right,

C. Left middle cerebral artery infarct

left hemiplegia, and intact caloric

D. Pontine infarct

responses

E. Right basal ganglia hemorrhage

D. Ocular bobbing and left hemiplegia

The correct answer is D. This patient’s signs

E. Present caloric responses, eyes conjugately

and symptoms are most compatible with the

deviated to the left, and left hemiplegia

“locked-in” syndrome due to a high pontine

104

Chapter 6

n Examination of the Comatose Patient

lesion (typically an infarct) causing quadriple-

Jennett B, Teasdale G, Braakman R, et al. Prognosis of

patients with severe head injury. Neurosurgery.

gia and impaired lateral eye movements; these

1979;4:283.

patients are actually awake and alert but can

Levy DE, Caronna JJ, Singer BH, et al. Predicting out-

communicate only with vertical eye move-

come from hypoxic-ischemic coma. JAMA.

ments and blinking. This patient’s finding of

1985;253:1420.

ocular bobbing is also commonly seen in this

Lewis SL, Topel JL. Coma. In: Weiner WJ, Shulman LM,

condition.

eds. Emergent and Urgent Neurology. 2nd ed.

Philadelphia: Lippincott Williams & Wilkins; 1999.

Posner JB, Saper CB, Schiff ND, et al. Plum and Posner’s

Diagnosis of Stupor and Coma. 4th ed. New York:

SUGGESTED READING

Oxford University Press; 2007.

Bates D. Predicting recovery from medical coma. Br J

Rabinstein AA, Atkinson JL, Wijdicks EF. Emergency

Hosp Med. 1985;33:276.

craniotomy in patients worsening due to expanded

cerebral hematoma: to what purpose? Neurology.

Bernard SA, Gray TW, Buist MD, et al. Treatment of

2002;58(9):1367.

comatose survivors of out-of-hospital cardiac arrest

with induced hypothermia. N Engl J Med.

Wijdicks EFM, Bamlet WR, Maramattom BV, et al. Vali-

2002;346:557.

dation of a new coma scale: the FOUR score. Ann

Neurol. 2005;58:585.

Buettner WW, Zee DS. Vestibular testing in comatose pa-

tients. Arch Neurol. 1989;46:561.

Wijdicks EFM, Hijdra A, Young GB, et al. Practice pa-

rameter: prediction of outcome in comatose survivors

Fisher CM. The neurological examination of the coma-

after cardiopulmonary resuscitation (an evidence-

tose patient. Acta Neurol Scand. 1969;45(suppl 36):1.

based review): report of the Quality Standards Sub-

Hamel MB, Goldman L, Teno J, et al. Identification of

committee of the American Academy of Neurology.

comatose patients at high risk for death or severe dis-

Neurology. 2006;67:203.

ability. JAMA. 1995;273:1842.

Wijdicks EFM, Parisi JE, Sharbrough FW. Prognostic

Hoesch RE, Geocadin RG. Therapeutic hypothermia for

value of myoclonus status in comatose survivors of

global and focal ischemic brain injury—a cool way to

cardiac arrest. Ann Neurol. 1994;35:239.

improve neurologic outcomes. Neurologist.

Young GB, Ropper AH, Bolton CF. Coma and Impaired

2007;13:331.

Consciousness. New York: McGraw-Hill; 1998.

Hoffman RS, Goldfrank LR. The poisoned patient with

altered consciousness: controversies in the use of a

“coma cocktail.” JAMA. 1995;274:562.

Cerebrovascular

Disease

ROGER E. KELLEY AND ALIREZA MINAGAR

key points

• Stroke is easily recognized in the older patient with risk

factor who presents with sudden onset of a focal

neurologic deficit.

• Stroke prevention remains the most effective

management since interventional therapy in acute

ischemic stroke (the most common type) remains limited.

• Recent antiplatelet trials advanced an evidence-based

approach toward secondary stroke prevention.

• Anticoagulant therapy is primarily utilized for deep

venous thrombosis prophylaxis in patients with acute

ischemic stroke.

• Anticoagulant therapy has a potential role in ischemic

stroke prevention if there is a documented

cardioembolic source, in hypercoagulable conditions, in

cerebral sinovenous thrombosis, and perhaps in

cerebrovascular dissection.

• There is a growing literature on interventional therapy in

acute ischemic stroke, but intravenous recombinant tissue

plasminogen activator, initiated within 3 hours of

presentation, remains the only FDA-approved medication.

• Endovascular techniques are becoming increasingly

utilized for cerebrovascular anomalies such as

aneurysms and arteriovenous malformations.

erebrovascular

infarction, vascular dissection-induced infarc-

disease includes both primary ischemic stroke

tion, and sinovenous thrombotic infarction) and

(large artery thrombotic, e.g., lacunar-type, em-

hemorrhagic stroke (primary intracerebral hem-

bolic, and hemodynamic, small artery throm-

orrhage [ICH] and subarachnoid hemorrhage

botic, e.g., watershed-type, vasculitis-induced

[SAH]). In addition, one can see hemorrhagic

105

106

Chapter 7

n Cerebrovascular Disease

TABLE 7.1

Major Etiologies of Stroke

Primary Ischemic

Primary Hemorrhagic

Thrombotic

Hypertensive hemorrhage

Large artery

Aneurysmal rupture

Small artery (lacunar)

Bleeding from an AVM

Sinovenous thrombosis

Bleeding diathesis

Vascular dissection

Bleeding related to neoplasm

Mechanical obstruction, e.g., surgical complication

Cerebral amyloid angiopathy

Hemodynamic, e.g., hypotension

Iatrogenic, i.e., related to antithrombotic therapy

Embolic

Septic aneurysm

Cardiogenic

Aortic arch atheromata

Artery-to-artery

Arteritis

transformation of an initially ischemic stroke

embolism related to an atrial septal defect, and

and this is one of the major concerns with the

vascular dissection (which often has trauma as

use of either recombinant tissue plasminogen

an initiating factor).

activator (rt-PA) or anticoagulant therapy in

Roughly 80% to 85% of all stroke is primary

acute ischemic stroke. Stroke, which is a

ischemic and 15% to 20% is primary hemor-

generic term for damage to the central nervous

rhagic. Of the ischemic strokes, approximately

system (CNS) on a vascular basis, is a common

50% to 60% are large artery thrombotic; 20%

presentation in the emergency department.

are small artery thrombotic

(lacunar-type);

Most strokes are readily diagnosed on the basis

15% to 20% are cardiogenic or artery-to-artery

of a sudden constellation of neurologic deficits

emboli; and 5% to 10% are less common eti-

in a patient with well-recognized risk factors

ologies such as vasculitis, dissection, septic or

for cerebrovascular disease.

nonseptic emboli, or sinovenous occlusive dis-

It is estimated that there are roughly

ease. Approximately 5% to 6% of all strokes

750,000 first or recurrent strokes in the United

are SAH, usually related to rupture of a cere-

States per year. This translates to approximately

bral aneurysm or bleeding from an arteriove-

250 stroke patients per 100,000 per year. The

nous malformation (AVM), whereas 10% to

frequency of stroke type varies depending on

15 % are primary ICH. The major stroke eti-

the patient population. For example, a retire-

ologies are listed in Table 7.1.

ment community is more likely to have patients

n SPECIAL CLINICAL POINT: Determination

of advanced age with a relatively high inci-

of stroke mechanism is important since it has a

dence of atherosclerotic disease seen in tandem

direct impact on management.

with hypertension, diabetes mellitus, hyperlipi-

demia, and coronary artery disease. A hospital

in a community of young and middle-aged peo-

IDENTIFICATION OF THE

ple will tend to see more esoteric causes of

STROKE-PRONE INDIVIDUAL

stroke, such as lupus vasculitis, hypercoagula-

ble states, sinovenous occlusive disease as a

It has become increasingly important to identify

complication of pregnancy, stroke related to

patients with risk factors for stroke (Table 7.2)

oral contraceptive use, paradoxical cerebral

because there is an increasing armamentarium of

107

Chapter 7

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TABLE 7.2

Risk Factors for Stroke

Major Risk Factors

Minor Risk Factors

Age

Hypercholesterolemia

Sex

Oral contraceptives

Race

Migraine

Genetic predisposition

Obesity

TIA/prior stroke

Physical inactivity

Hypertension

Mitral valve prolapse

Acute myocardial infarction

Patent foramen ovale

with thrombus

Bacterial endocarditis

Diabetes mellitus

Marantic endocarditis

Cigarette smoking

Sick sinus syndrome

Valvular heart disease

Aortic arch atheromatia

Atrial fibrillation

Polycythemia

Dilated cardiomyopathy

Bleeding diathesis

Peripheral vascular disease

Sympathomimetic agents including cocaine

Sickle cell anemia

Hyperhomocysteinemia

Hypercoagulable state

Thrombocytosis

potential therapies to reduce stroke risk. Con-

The risk of stroke increases exponentially with

versely, the interventional therapies for acute

age, and the risk is higher for males. African

stroke remain quite limited. Transient ischemic

Americans appear to be more susceptible to

attack (TIA) is a warning of ischemic stroke, and

stroke than Caucasians. For example, intracra-

it can precede up to 15% of all stroke. It repre-

nial stenosis, which can account for up to 10%

sents an opportunity to identify a patient who is

of all ischemic stroke, tends to be more prevalent

at particular risk for ischemic stroke in an effort

in African Americans, Hispanics, and Orientals.

to institute effective prevention. Prior stroke and

In contrast to African Americans, Caucasians

TIA are major identifiers of stroke-prone indi-

appear to be more susceptible to symptomatic

viduals. In a study of patients with TIA present-

extracranial carotid stenosis. Naturally, the

ing to the emergency room (ER), 10.5% of

presence of contributing factors to atheroscle-

patients returned to the ER within 90 days with

rosis, such as hypertension, hyperlipidemia, di-

a stroke and half of these events occurred within

abetes mellitus, familial predisposition, and

2 days of the TIA. The risk of recurrent stroke is

smoking consumption impact on stroke type

very much reflective of the stroke mechanism

and frequency. In addition, cumulative car-

and how aggressively risk factors are managed.

diac factors can play a major role in predispo-

The risk of recurrent stroke is 10% to 12% per

sition to cardioembolic stroke. An example of

year, but this can be impacted by optimal blood

this is atrial fibrillation. Lone atrial fibrilla-

pressure management, aggressive control of hy-

tion (AF) in a person under 60 years of age is

perlipidemia, smoking cessation, and an effective

not a significant risk factor for stroke. How-

diet and exercise programs.

ever, the coexistence of AF with such factors

as valvular heart disease, ischemic cardiomy-

n SPECIAL CLINICAL POINT: A transient

opathy, hypertension, or prior embolic events

ischemic attack (TIA), when properly

recognized, represents an important opportunity

translates into a much greater risk of car-

to effectively intervene before the stroke occurs.

dioembolic stroke.

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Chapter 7

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n SPECIAL CLINICAL POINT: So-called “lone

atrial fibrillation” (atrial fibrillation in a patient

less than 60 years of age with a structurally

normal heart and no risk factors for stroke) is

associated with a stroke risk that is essentially

that of an age-matched individual without atrial

fibrillation.

CLINICAL EVALUATION

The history is obviously a vital aspect of the di-

agnostic assessment of patients presenting with

stroke-like symptoms. The most common pres-

entation for stroke is the sudden onset of focal

neurologic deficit(s) in a patient with risk fac-

tors for stroke, with increasing age being a par-

ticularly important indicator. The term “stroke

in the young” promotes recognition of patients

45 years of age or younger who do not have a

readily identifiable predisposing factor. In such

circumstances, more esoteric explanations for

the stroke should be sought such as lupus vas-

culitis, primary CNS vasculitis, drug-induced

vascular compromise, moyamoya disease,

FIGURE 7.1 Noncontrast CT brain scan which

sickle cell disease, paradoxical cerebral embo-

demonstrates an infarct (arrow) that has already evolved.

lus, meningovascular syphilis, and sinovenous

This would mitigate against the use of recombinant

thrombosis and hypercoagulable conditions.

tissue plasminogen activator (rt-PA) in such a

circumstance, as there is already hypodensity implying

Proper recognition of stroke has become even

already infarcted tissue and the onset would be

more important with the advent of thrombolytic

presumably well beyond 3 hours based on this scan. The

therapy, specifically rt-PA, which must be admin-

distribution of the infarct is the left watershed region

istered intravenously within 3 hours of symptom

between the middle cerebral artery and posterior

onset. This is the only agent presently available

cerebral artery that can imply a hemodynamic

for acute ischemic stroke. To be eligible for rt-

mechanism.

PA, patients need to be assessed, have certain

blood tests performed, and have a noncontrast

computed tomography (CT) brain scan per-

ically unaffected. For example, if they woke up

formed within the 3-hour time window before

with a stroke at 6 AM and were last awake at 11

the agent can be infused (Fig. 7.1). The initial his-

PM the evening before, then it has to be assumed

tory must place emphasis on determination of

that the stroke occurred just after 11 PM. How-

the exact time that the symptoms began and

ever, if the patient had gone to the bathroom at 5

pertinent past medical factors such as prior

AM, and they were perfectly fine, and then went

bleeding, recent surgery, or trauma that might

back to bed and awakened at 6 AM with the

enhance the bleeding complication rate with rt-

stroke, it can be assumed that the stroke oc-

PA. It is important to note that patients who

curred just after 5 AM. This would translate into

wake up with their deficits have to have the onset

a 2-hour window of opportunity for treatment

assigned to the time that they were last neurolog-

with rt-PA (i.e., 6 to 8 AM).

109

Chapter 7

n Cerebrovascular Disease

The use of rt-PA mandates a more stan-

Institutes of Health (NIH) Stroke Scale is used

dardized approach to the neurologic evalua-

to provide such standardization. This is in

tion for a patient with acute stroke, and this,

recognition that rt-PA should only be consid-

fortunately, has been extended to most stroke

ered for patients with a significant neurologic

patients even if they are not candidates for the

deficit at the time of presentation; rt-PA should

medication. For example, it is important to

not be used if the patient is rapidly improving.

obtain a CT brain scan at the time of presenta-

There are potentially greater risks of complica-

tion to readily distinguish a primary ischemic

tions of rt-PA and a reduced chance of benefit

stroke from a primary hemorrhagic stroke.

from therapy when the patient has a high score

Generally, contrast is not necessary unless

on their NIH Stroke Scale. This scale correlates

there are clinical concerns that the patient

with severity of neurologic deficit.

might have a tumor or abscess instead of a

stroke. It is important to recognize that the CT

n SPECIAL CLINICAL POINT: The greater

the time from the onset of stroke, the greater

brain scan has a sensitivity of 90% to 95% for

the evolution of an infarction pattern by CT

the detection of SAH. Therefore, clinical suspi-

brain scan, the greater the degree of neurologic

cion for SAH, even with a negative CT brain

deficit, the poorer the control of blood

scan, mandates the performance of a lumbar

pressure, the higher the admission blood

puncture unless there are contraindications.

glucose, as well as possibly the greater the age

In addition to the CT brain scan, routine im-

of the patient, the greater the likelihood of

mediate blood work includes a complete

hemorrhagic transformation with rt-PA.

blood count (CBC), platelet count, metabolic

profile, prothrombin time (PT)/international

There are certain presentation characteristics

normalization ratio (INR), and partial throm-

that help identify the stroke mechanism (Table

boplastin time (PTT).

7.3). For example, cerebral embolus, as opposed

Furthermore, a more standardized approach

to thrombosis, tends to occur with maximum

to the neurologic examination has been

neurologic deficit at onset. There can be syn-

adopted to quantitate the degree of deficit in a

cope and/or seizure at the time of presentation

more objective and reproducible pattern. This

due to the sudden cessation of the circulation.

is especially pertinent for patients who are

Involvement of different vascular territories and

potentially eligible for rt-PA. The National

a documented source of cardiogenic embolus

TABLE 7.3

Features of Thrombotic Versus Embolic Stroke

Thrombotic

Embolic

Stepwise progression

Sudden onset of maximal deficit

Premonitory TIA

Source of cardiogenic embolus

Atherosclerotic disease

Multiple vascular territory involvement

Carotid distribution infarct

Association with syncope at onset

Middle cerebral artery

Association with seizure at onset

Anterior cerebral artery

Hemorrhagic transformation of the infarct

Penetrating artery distribution, i.e., lacunar-type

Branch occlusion pattern on brain scan or angiography

Other evidence of large vessel disease

Embolic involvement of other organs

Severe deficit at onset followed by rapid resolution

110

Chapter 7

n Cerebrovascular Disease

are other features strongly supportive of an

The same is true for relatively minor stroke

embolic mechanism. Conversely, thrombotic

associated with resolution of signs and symp-

stroke tends to occur in a stepwise fashion, is

toms within days to weeks. However, there is

reported to be more commonly associated with

usually little to offer the patient who is mori-

premonitory TIA, and is associated with risk

bund from a stroke.

factors for atherosclerosis or lipohyalinosis.

n SPECIAL CLINICAL POINT: It is important

Embolic events tend to result in cerebral artery

to determine whether or not particular testing

branch occlusions.

will impact management. This will help avoid

unnecessary costs as well as testing that may be

associated with risks that are best avoided.

DIAGNOSTIC EVALUATION

The CT brain scan is often the only neuroimag-

Table 7.4 outlines the first-, second-, and third-

ing study that is necessary for acute stroke eval-

tier diagnostic studies that are part of the

uation. Contrast is usually not necessary, and

stroke evaluation. The first tier represents the

this represents a practical and cost-effective ap-

routine studies that are performed on any pa-

proach for most patients. However, there are

tient presenting with symptoms of TIA or

certain patients in whom a magnetic resonance

stroke. Obviously the clinical picture will affect

imaging (MRI) brain scan may provide worth-

the choice and speed with which the study is

while information that may affect patient man-

performed. For example, a patient presenting

agement—for example, in the patient with an

with new-onset TIA should undergo immediate

atypical or fluctuating clinical picture with evi-

evaluation of the potential ischemic mechanism

dence of brainstem or cerebellar involvement

in an effort to intervene before a stroke occurs.

an MRI typically provides a much better image

TABLE 7.4

Hierarchy of Studies in Acute Ischemic Stroke

First tier

Third tier (if clinically indicated)

Noncontrast CT brain scan

Cardiac stress test

CBC, platelet count, PT, INR, and PTT

Transesophageal echocardiogram

Serum chemistry profile EKG

Cerebral arteriography

Fasting lipid profile

HIV test

Syphilis testing

Second tier (if clinically indicated)

Sickle cell prep

Contrast-enhanced CT brain scan

Bleeding time

MRI brain scan

Platelet function studies

Carotid/vertebral duplex scan

Special clotting studies

Transcranial Doppler ultrasonography

Fasting homocysteine level

Transthoracic echocardiogram

C-reactive protein

Holter monitor

Proteins C and S levels

Magnetic resonance angiography and/or

Proteins C and S levels

venography vs. CT angiography

Antiphospholipid antibodies

Blood cultures

Genetic testing for MELAS (mitochondrial myopathy,

ESR

lactic acidosis, and stroke-like episodes), Fabry

Lumbar puncture

disease, CADASIL (cerebral autosomal-dominant

Urine drug screen

arteriopathy with subcortical strokes and

leukoencephalopathy), etc.

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Chapter 7

n Cerebrovascular Disease

Diffusion-weighted imaging

(DWI) as a

component of the MRI brain scan in acute is-

chemic stroke allows detection of cellular in-

jury and cytotoxic edema

(Fig.

7.3). MR

perfusion imaging can identify brain tissue that

is susceptible to infarction but that is in a po-

tentially salvageable state. Thus, a so-called

“perfusion-diffusion mismatch” might be of

value in identifying acute ischemic stroke pa-

tients who are most likely to respond to rt-PA.

However, such an approach requires ready

availability of these MRI techniques and imme-

diate reading of images. Any delay associated

with obtaining these studies further prolongs

the initiation of rt-PA, which limits the useful-

ness of perfusion-diffusion images. In situa-

tions in which there is some difficulty in

distinguishing an ischemic stroke from another

process, the finding of hypointensity on the

FIGURE 7.2 T2-weighted MRI brain scan that

demonstrates signal hyperintensity with the anterior

arrow pointing to a right brainstem infarct and the

posterior arrow showing infarction within the

cerebellum.

of this area and can help to confirm the clinical

impression (Fig. 7.2). Other potential advan-

tages of MRI include the greater safety of using

contrast-enhanced MRI, as opposed to con-

trast-enhanced CT scan. In addition, magnetic

resonance angiography (MRA) and venogra-

phy (MRV) have the ability to provide a reason-

ably accurate view of the extracranial and

intracranial circulation, which often provides

information complementary to the MRI. CT

angiography (CTA) appears to have better defi-

nition than MRA in most circumstances. How-

ever, CTA requires intravenous infusion of

iodine-based contrast. These less-invasive stud-

ies vary in quality between institutions and do

not yet have the accuracy of the “gold stan-

dard” for the evaluation of the cerebral circula-

FIGURE 7.3 Diffusion-weighted MRI brain scan that

tion, which remains intra-arterial cerebral

demonstrates an acute left hemispheric superficial

arteriography.

cortical infarct (arrow).

112

Chapter 7

n Cerebrovascular Disease

apparent diffusion coefficient

(ADC) image

An erythrocyte sedimentation rate can be use-

that correlates with hyperintensity on the DWI,

ful for the detection of endocarditis, atrial

in the same region, supports acute ischemia (see

myxoma, or a vasculitic process. Syphilis serol-

Chapter 4, Fundamentals of Neuroradiology).

ogy and human immunodeficiency virus testing

Cardiac evaluation is of value in the assess-

also can be important in susceptible individuals

ment of potential cardiogenic sources of em-

presenting with stroke-like symptoms.

bolism. This can include imaging of the aortic

Evaluation for a hypercoagulable state is

arch where atheromata have the potential to

predicated on the clinical picture of prior

break off and enter the brain circulation. How-

thromboembolic events, a positive family his-

ever, one must factor in the costs versus benefits

tory, a history of spontaneous abortions, and

of extensive cardiac evaluation unless the results

unexplained ischemic stroke in a young per-

are going to definitely affect management of the

son. Antiphospholipid antibody titers are

patient. Specifically, transesophageal echocar-

particularly important when there is a well-

diography (TEE) and long-term cardiac monitor-

documented hypercoagulable state or in pa-

ing are reserved for patients with a reasonable

tients with systemic lupus erythematosus in

chance of having a potential cardiogenic source

association with ischemic stroke. Protein C,

of embolism and who should be considered for

protein S, and antithrombin III deficiencies

anticoagulant therapy. The potential coexis-

are evaluated in young patients with unex-

tence of coronary artery disease in patients

plained stroke, but the yield tends to be quite

with ischemic stroke must be considered be-

low unless there is a history of thromboem-

cause this association is not uncommon. Car-

bolic events and/or a positive family history.

diac stress testing might be appropriate in some

Thrombocythemia, with a platelet count

patients with cerebral events.

greater than 1,000,000/μL, polycythemia, and

sickle cell disease are additional hematologic

n SPECIAL CLINICAL POINT: There is clearly

factors associated with ischemic stroke. Con-

an indication for cardiac evaluation in stroke

versely, a low platelet count or factor defi-

since it can impact management and has the

ciency can result in a bleeding diathesis with

distinct potential to prevent recurrent stroke.

secondary ICH.

Cryptogenic stroke might require assessment

Noninvasive vascular imaging includes

with longer term cardiac telemetry in an effort to

carotid and vertebral duplex ultrasound, which

identify paroxysmal AF. TEE usually is restricted

combines the anatomic information of B-mode

to patients who have unexplained stroke (i.e.,

scanning with the physiologic information of

with no risk factors for stroke). TEE is useful

Doppler and transcranial Doppler ultrasonog-

when there is concern about a possible patent

raphy (TCD), which allows assessment of the

foramen ovale in a patient with the possibility of

flow velocities of the intracranial major arter-

paradoxical cerebral embolus. TEE is useful to

ies, as well as MRA and CTA. However, routine

assess the left atrium and left atrial appendage

intra-arterial cerebral arteriography remains

and to more effectively assess the aortic arch for

the “gold standard” for the most accurate in-

atheromata. Vegetations, either septic or nonsep-

formation about the extracranial and in-

tic, as well as thrombus formation tend to be bet-

tracranial circulation. This is useful for the

ter detected with TEE. Concern about possible

detection of intracranial or extracranial vas-

bacterial endocarditis mandates blood cultures.

cular stenosis, possible vasculitis, vascular

dissection, the presence of an aneurysm, or

n SPECIAL CLINICAL POINT: Bacterial

the presence of an AVM. Moyamoya disease,

endocarditis is in the differential diagnosis of

stroke especially in patients who are at

with progressive occlusion of the intracranial

increased risk and for stroke patients with a

vasculature, is another entity that requires as-

fever and/or newly detected heart murmur.

sessment with angiography.

113

Chapter 7

n Cerebrovascular Disease

Second- and third-tier studies are performed

Middle cerebral artery (MCA) infarction typ-

in an effort to prevent a subsequent event. The

ically results in contralateral weakness with

plasma homocysteine level and C-reactive pro-

greater involvement of the face and arm than

tein (CRP) level also can help to identify indi-

the leg. Involvement of the dominant hemi-

viduals with an enhanced risk of ischemic

sphere is often associated with aphasia. Expres-

stroke. Both elevated levels of homocysteine

sive aphasia (Broca) is related to involvement of

and CRP have been implicated. The finding of

the foot of the inferior frontal gyrus of the dom-

a relationship between CRP levels and stroke

inant hemisphere, which abuts the motor strip.

risk raises the possibility that inflammation is a

Expressive aphasia is usually associated with

potential mechanism for ischemic events.

significant contralateral hemiparesis. On the

other hand, receptive aphasia (Wernicke) is re-

lated to involvement of the posterior aspect of

CLINICAL ASPECTS OF ISCHEMIC

the superior temporal gyrus of the dominant

STROKE AND TIA

hemisphere. It is uncommon to have contralat-

eral weakness with involvement of this vascular

Presentation and Localization

territory and the patient will present with im-

Of particular importance is the distinction be-

paired comprehension and with speech output

tween carotid distribution versus vertebrobasilar

that can have a “word salad” quality. Involve-

distribution ischemia. Carotid endarterectomy is

ment of the superior and inferior division of the

of value for stroke prevention in symptomatic

MCA, usually seen with MCA stem involve-

patients when carotid stenosis ipsilateral to the

ment, will typically result in a global or so-called

involved cerebral hemisphere is demonstrated.

“mixed” aphasia with pronounced contralateral

However, it is not expected that prophylactic

hemiparesis and hemisensory deficit. Involve-

carotid endarterectomy would be of any value

ment of the anterior cerebral artery typically

for a patient presenting with vertebrobasilar dis-

causes contralateral hemiparesis with the leg

tribution symptoms who also was found to have

more involved than the arm or face. Involve-

moderate or severe carotid stenosis. The features

ment of the posterior cerebral artery territory re-

that help to distinguish carotid distribution

sults in contralateral homonymous hemianopsia

symptoms of stroke or TIA from vertebrobasilar

often with little, if any, associated motor or sen-

distribution are outlined in Table 7.5.

sory findings.

TABLE 7.5

Carotid Versus Vertebrobasilar Distribution of Stroke/TIA Symptoms

Carotid Distribution

Vertebrobasilar Distribution

Aphasia

Bilateral visual loss

Transient monocular blindness

Ataxia

(amaurosis fugax)

Quadriparesis

Hemiparesis

Perioral numbness

Hemiparesis

“Crossed” sensory or motor deficits

Hemisensory deficit

Two or more of the following:

Homonymous hemianopsia in combination

Vertigo, syncope, diplopia, nausea, dysarthria, and

with motor or sensory deficit

dysphagia

Drop attack especially when seen in association

with a sensory or motor deficit

114

Chapter 7

n Cerebrovascular Disease

Vertebrobasilar arterial involvement can

sensory stroke. A clue to pure motor stroke re-

be recognized by so-called “crossed” findings

lated to lacunar-type infarction of the posterior

such as involvement of one side of the face and

limb of the internal carotid artery is a con-

the other side of the body. Isolated symptoms

tralateral symmetrical pure motor involvement

such as vertigo or diplopia rarely represent

with relatively equal involvement of the face,

vertebrobasilar stroke, but a constellation of

arm, trunk, and leg.

findings such as dysarthria, ataxia, and gaze

n SPECIAL CLINICAL POINT: Lacunar-type

paresis are typical findings of vertebrobasilar

stroke accounts for up to 20% of stroke and is

insufficiency in susceptible individuals.

primarily an in situ thrombotic process that

Small vessel thrombotic

(lacunar-type)

does not necessarily require an extensive

stroke (Fig. 7.4) can have a number of presen-

evaluation of a cardiogenic source of embolus

tations. However, the most common include

or evaluation for carotid surgery.

five so-called “classic” lacunar presentations:

pure motor stroke, pure sensory stroke, hemi-

paresis-hemiataxia, clumsy-hand dysarthria,

OPTIMIZATION OF ISCHEMIC

and sensorimotor. The hallmark is lack of cor-

STROKE PREVENTION

tical involvement, and there are characteristic

locations such as the posterior limb of the in-

Atherosclerosis is a primary factor in the

ternal capsule for pure motor stroke and the

pathogenesis of ischemic stroke. It has been

thalamus or the centrum semiovale for pure

clearly established that the formation of ather-

osclerotic plaque correlates with stroke risk.

Measures that interfere with the deposition of

plaque material are the most effective means

for reducing the incidence of stroke and TIA.

Lipohyalinosis of the small penetrating arteries,

with secondary occlusion, is the most common

mechanism of lacunar-type stroke. Effective

blood pressure control is of particular impor-

tance for both primary and secondary stroke

prevention. Two agents identified for their

potential in preventing secondary stroke are

ramipril and perindopril plus a diuretic.

Statins are established for the primary pre-

vention of stroke in certain high-risk patients.

Statins, and other lipid-lowering agents, have

been associated with a 25% relative risk reduc-

tion in fatal and nonfatal stroke. However,

there has been an increase in the risk of pri-

mary hemorrhagic stroke with lipid lowering

associated with statin therapy. Smoking cessa-

tion is of utmost importance.

Antithrombotic agents can be of benefit in

stroke prevention, as well as in acute ischemic

stroke treatment, but one must weigh risk ver-

FIGURE 7.4 T2-weighted MRI brain scan that

sus benefit in terms of choice of therapy. For ex-

demonstrates bilateral thalamic lacunar-type infarcts

ample, aspirin was not found to be of benefit in

(arrows).

the primary prevention of stroke in middle-aged

115

Chapter 7

n Cerebrovascular Disease

healthy men. However, some benefit was ob-

TABLE 7.6

served in women for primary stroke prevention.

Pharmacologic Treatment Approaches

for Stroke Prevention

Warfarin is recognized as the agent of choice in

the primary prevention of stroke in patients

Antihypertensives

with a documented source of cardioembolic

Ramipril

source such as higher risk AF. Warfarin also has

Perindopril with diuretic

a place in the management of certain conditions

Alternative antihypertensives

associated with a hypercoagulable state.

Antiplatelet agents

Aspirin is the first line of antiplatelet ther-

Aspirin 81 mg to 325 mg/day

Clopidogrel 75 mg/day

apy for protection against ischemic stroke in

Ticlopidine 250 mg with meals b.i.d.

patients with symptoms of stroke who do not

Aspirin/dipyridamole 25/200 mg b.i.d.

have a cardiogenic source of embolism or a hy-

Anticoagulant therapy

percoagulable state. For patients who are

Warfarin

symptomatic on aspirin (aspirin failures), alter-

Lipid-lowering agents

native antiplatelet agents should be considered.

Statins

The choices may include combination of low-

Cholestyramine

dose aspirin-high-dose dipyridamole (25/200

Ezetimibe

mg twice a day) or clopidogrel at 75 mg/day.

Fenofibrate

The decision about substituting an antiplatelet

Chlofibrate

agent, and which agent to use, often is based

Niacin

Gemfibizol

on several factors including cost, purported ef-

Fenofibrate

ficacy, and risk of side effects. In a recent study,

Colesvelam

there was no evidence of superiority of low-

Colestipol

dose aspirin-long-acting higher-dose dipyri-

Smoking cessation agents

damole over clopidogrel in prevention against

Buproprion

recurrent ischemic stroke. In terms of clopido-

Varenicline

grel, which has marginal superiority over as-

Nicotine administration devices

pirin, at best, for ischemic stroke prevention,

two studies of the combination of aspirin and

clopidogrel revealed no benefit for stroke pre-

benefits of endarterectomy do not justify the

vention and an enhanced risk of bleeding com-

risks.

plications. Table

7.6 outlines the potential

prophylactic medications available.

Carotid endarterectomy is the most effective

ACUTE ISCHEMIC STROKE

means of preventing stroke in patients with

INTERVENTION

symptomatic high-grade carotid stenosis. There

is possibly some potential benefit for patients

rt-PA is approved for acute ischemic stroke in

with 50% to 69% symptomatic stenosis, but

patients who fulfill the criteria for its use

the greatest benefit is in those with 70% to

(Table 7.7). It is associated with a 30% in-

99% stenosis. Careful patient selection and risk

creased chance of full neurologic recovery at 3

versus benefit analysis is required. Carotid an-

and 12 months compared to placebo. It is most

gioplasty is an option for patients who have un-

effective when given early, and the more nor-

acceptable surgical risk but who clearly may

mal the CT brain scan, the more likelihood of

benefit from correction of their stenosis. This is

benefit. Conversely, the greater the evolution

an evolving procedure, but it may be particu-

of the infarct by CT brain scan, the less likeli-

larly attractive for certain patients with asymp-

hood of a good response and the greater the

tomatic carotid stenosis where the potential

chance of ICH as a complication. This is seen

116

Chapter 7

n Cerebrovascular Disease

TABLE 7.7

Indications and Contraindications to the Use of Recombinant Tissue Plasminogen

Activator for Acute Ischemic Stroke

Indications

Contraindications

Evaluation and management within 3 hours

Hemorrhage on CT brain scan

Persistent significant neurologic deficit on exam

Uncontrolled hypertension with persistent systolic

Absence of severe anemia, severely abnormal blood

BP >185 and diastolic BP >110 mm Hg

glucose, or other severe metabolic disturbance

History of prior intracranial hemorrhage

History of bleeding diathesis

Platelet count <100,000 mL

Patient or caregiver amenable to treatment with

Active anticoagulant therapy

rt-PA which may include informed consent

Active internal bleeding

No associated seizure activity at onset

Recent serious head trauma

No recent arterial or lumbar puncture

Recent ischemic stroke

Recent intracranial surgery

Clinical suspicion for subarachnoid hemorrhage

Recent myocardial infarction

in approximately 6.4% of patients treated with

of hemorrhagic transformation of the initially is-

rt-PA for acute ischemic stroke. The percentage

chemic infarct (Fig. 7.5). The primary indication

might be higher in older individuals, but bene-

for anticoagulant therapy in acute ischemic stroke

fit can still be seen (Flow Chart 7.1).

is for deep venous thrombosis prevention related

Aspirin at a dose of 160 to 300 mg/day ap-

to immobility from the stroke.

pears indicated in acute ischemic stroke as long as

n SPECIAL CLINICAL POINT: The use of 160

there is no medical contraindication. The primary

to 320 mg/day of aspirin is recognized as having

benefit is to reduce the risk of early recurrent

the potential to positively impact outcome.

stroke. Of note, neither aspirin nor anticoagulant

therapy should be given within 24 hours of the

There are certain standard measures for acute

use of rt-PA to help protect against the 6.4% risk

stroke management (Table 7.8). These include

FLOW CHART 7.1. APPROACH TO USE OF RECOMBINANT TISSUE PLASMINOGEN

ACTIVATOR IN ACUTE ISCHEMIC STROKE.

Presentation → Initial assessment → Review of potential → Dosing

contraindications

Within 3 hours

Noncontrast CT brain scan, CBC, platelet count, PT/INR, PTT, and EKG

No bleed by CT scan, No bleeding diathesis, No recent MI or stroke,

No prior intracerebral hemorrhage, No severe hyper- or hypoglycemia,

No recent surgical intervention, No seizure at onset

0.9 mg/kg up to 90 mg IV with 10% over

1 minute and the rest over 1 hour, no

antiplatelets or anticoagulants for 24 hours

117

Chapter 7

n Cerebrovascular Disease

systolic blood pressures of 160 ± 20 mm Hg and

diastolic blood pressure of 100 ± 10 mm Hg are

not usually treated in the first several days to

weeks of the acute event. This is in recognition

of the potential for sudden drops in blood pres-

sure to reduce cerebral perfusion and cause ex-

tension of the infarction related to disruption of

cerebral autoregulation in acute stroke. It is also

well recognized that elevated blood glucose can

have a deleterious effect on stroke outcome and

enhances the risk of complications with rt-PA.

n SPECIAL CLINICAL POINT: It is

FIGURE 7.5 A: Noncontrast CT brain scan that

important to avoid aggressive blood pressure

reveals an acute right middle cerebral artery distribution

control in acute ischemic stroke as this can

infarct (arrow). B: Follow-up of noncontrast CT brain

promote cerebral hypoperfusion with

scan several days later that reveals hemorrhagic

extension of the infarction.

transformation of the infarct (area) with increased

density now observed reflecting blood.

INTRACEREBRAL HEMORRHAGE

protection of the airway with aspiration precau-

tions, careful monitoring of the vital signs, and

Clinical Approach

early mobilization if at all possible. In acute is-

The most common causes of ICH are listed in

chemic stroke, it is important not to be overly

Table 7.9. Hypertensive ICH most commonly

aggressive with blood pressure control, and

affects the basal ganglionic-thalamic region;

pontine hemorrhage and cerebellar hemor-

TABLE 7.8

rhage are other common locations. The patient

Guidelines for the General Management

typically presents with maximal deficit at

of the Patient with Acute Stroke

1. Stability of vital signs

2. Avoidance of aggressive blood pressure control

TABLE 7.9

in acute ischemic stroke

Causes of Spontaneous Intracerebral

3. Avoidance of glucose- or dextrose-containing

Hemorrhage

intravenous fluids in acute ischemic stroke

4. Initiation of aspirin therapy in acute ischemic

1. Hypertension

stroke if no contraindication

2. Intracranial aneurysm

5. Protection of airway with aspiration precautions

3. Arteriovenous malformation

6. Assessment of swallowing capacity

4. Bleeding diathesis

7. Early mobilization as clinically indicated

5. Complication of anticoagulant therapy

8. Bowel program

6. Illicit drug use (e.g., cocaine)

9. Prevention of pressure sores

7. Mycotic aneurysm

10. Antiembolus measures

8. Hemorrhagic metastasis

11. Rehabilitation therapy evaluation as indicated by

9. Bleeding into a primary brain tumor

the deficit

10. Bleeding into a brain abscess

12. Social service evaluation

11. Arteritis (primary, connective tissue disorder,

13. Assessment for evidence of poststroke

syphilitic, etc.)

depression

12. Amyloid angiopathy

14. Long-term management of risk factors for stroke

13. Hemorrhagic leukoencephalopathy

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Chapter 7

n Cerebrovascular Disease

onset, and a patient who complains of sudden

Certain drugs including cocaine and am-

severe headache followed by obtundation and

phetamines promote ICH. Such agents, with a

focal neurologic deficit, in association with a

sympathomimetic effect, can cause a sudden

markedly elevated blood pressure, usually is

increase in blood pressure that can “unmask” a

found to have ICH rather than ischemic

preexisting cerebrovascular anomaly such as

stroke. However, small hematomas can pres-

an AVM or aneurysm. There also can be a vas-

ent with minor deficit; this is why it is impor-

culitic effect with so-called “beading” of the

tant to obtain a CT brain scan immediately at

cerebral blood vessels similar to what one can

presentation because this distinguishes an in-

see with a connective tissue disorder such as

tracerebral hematoma from an evolving in-

systemic lupus erythematosus and polyarteritis

farct. It is important to recognize that acute

nodosa. Phenylpropanolamine, a sympath-

bleeding is visible immediately on CT brain

omimetic agent, which, until recently, was

scan, whereas it takes 3 to 6 hours or longer

commonly found in cough and cold over-the-

for an acute ischemic stroke to evolve on the

counter preparations and in appetite suppres-

CT brain scan.

sants, has been implicated as a factor in ICH.

Lobar hematomas are less likely associated

n SPECIAL CLINICAL POINT: The urine

with a hypertensive mechanism; other etiolo-

drug screen (UDS) is an important part of the

gies need to be considered. Roughly one half of

evaluation of unexplained stroke and can help

all lobar hematomas are not attributable to hy-

to explain an intracerebral hemorrhage.

pertension. Alternative explanations include

cerebral amyloid angiopathy. This is typically

Bleeding into a primary CNS neoplasm or

seen in patients older than 60 and/or is charac-

metastatic disease can occur. The most likely

terized by lobar hematoma, dementia, and con-

metastatic lesions associated with ICH include

gophilic (amyloid) angiopathy on pathologic

lung, breast, thyroid, renal cell, and melanoma.

specimen. This entity is important to recognize

Bleeding related to septic embolism from

clinically because surgical evacuation should

bacterial endocarditis as well as nonseptic

be avoided. The involved vessels tend to be

embolism from marantic endocarditis is possi-

quite friable, and this can be associated with an

ble. It is also possible to have bleeding into a

unexpected challenge in terms of control of

brain abscess.

bleeding. Vascular anomalies such as AVMs

and aneurysms are also in the differential diag-

Treatment

nosis of lobar hemorrhage.

A platelet count below 30,000/μL can be as-

In hypertensive ICH, bleeding can persist for

sociated with brain hemorrhage as can factors

6 hours, which can produce major deleterious

VIII and IX deficiency, with the latter two enti-

outcomes. There has been controversy about

ties being familial in nature. Routine PT, PTT,

what degree of blood pressure control is de-

and bleeding time obtained in patients with

sirable in the acute setting. There has been

ICH can be useful to assess platelet dysfunc-

concern that aggressive reduction of a

tion. Hypofibrinogenemia is another potential

markedly elevated blood pressure can lead to

hematologic explanation for ICH. In addition,

secondary hypoperfusion of brain tissue sur-

the presence of fibrinogen degradation prod-

rounding the hematoma and lead to worsen-

ucts with fragmented erythrocytes suggests dis-

ing of the outcome. However, this has not

seminated intravascular coagulation. Acquired

been demonstrated. It is recognized that ex-

immune deficiency syndrome can have a multi-

pansion of the hematoma to a critical level,

tude of effects that can promote ICH; one of

related to persistent intracranial bleeding,

them is severe thrombocytopenia. Meningo-

can accurately identify those patients with no

vascular syphilis also remains in the differential

hope for meaningful recovery. It appears that

diagnosis of ICH.

aggressive blood pressure management, with

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Chapter 7

n Cerebrovascular Disease

FLOW CHART 7.2. APPROACH TO PATIENT WITH INTRACEREBRAL HEMORRHAGE

Presentation →

Assessment →

Management →

Postmanagement factors

Typically a precipitous neurologic in patient with long-standing poorly controlled hypertension

CT brain scan without contrast and with contrast to identify possible vascular anomaly

or tumor coagulation studies

Aggressive blood pressure control with an agent such as

labetalol or nicardipine with nitroprusside if necessary

Assessment for

hematoma expansion

Assessment for

intraventricular

extension with potential

for obstructive

hydrocephalus

agents such as nicardipine or labetalol, can

critical area of the brain, such as the speech area,

reduce expansion of the hematoma, and limit

is not going to be severely compromised by the

end organ damage to other areas such as the

intervention. Acute obstructive hydrocephalus

heart and kidneys (Flow Chart 7.2). ICH as-

related to intraventricular extension of the

sociated with severely elevated blood pres-

hematoma may respond effectively to placement

sure can be treated with sodium nitroprusside

of an intraventricular drain and a ventricular

because of its effectiveness in rapidly lower-

shunt may become necessary. However, the risks

ing the blood pressure. However, this agent

versus the benefits of such a procedure, in such a

can increase cerebral blood flow and promote

clinical setting, remain controversial. Recent re-

increased intracranial pressure.

ports suggest that the prognosis for recovery is

improved with thrombolytic therapy through

n SPECIAL CLINICAL POINT: The consensus

the ventricular drain to help clear clot formation

is for effective management of acute blood

and restore normal CSF flow pathways.

pressure for hypertensive intracerebral

hemorrhage, although the degree of control

n SPECIAL CLINICAL POINT: Surgical

remains controversial.

intervention may be indicated in cerebellar

hematoma, particularly with evidence of

Surgical evacuation of primary ICH remains

pressure on the brainstem.

controversial especially for those involving the

basal ganglia or thalamus. However, there is

ICH related to the use of unfractionated he-

clearly a benefit for surgical removal of a cerebel-

parin requires immediate discontinuation of

lar hematoma that is associated with any evi-

the heparin infusion and infusion of protamine

dence of pressure effect on the brainstem. In

sulfate. Warfarin-related ICH is managed most

addition, cerebral lobar hematoma resulting in

effectively with fresh frozen plasma. It can take

significant mass effect with resultant worsening

vitamin K up to 8 to 24 hours to correct a pro-

of the neurologic condition is probably best

longed prothrombin time, which is far too long

managed with surgical evacuation as long as a

in such an emergency setting.

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Chapter 7

n Cerebrovascular Disease

SUBARACHNOID HEMORRHAGE

Intracranial Aneurysm

Aneurysmal SAH has an annual incidence in

the United States of roughly 1 in 10,000 peo-

ple. It is estimated that 0.5% to 1% of adults

have an incidental aneurysm. Each year, new

aneurysms may develop in up to 2% of pa-

tients with previously ruptured aneurysms,

and the rupture rate is up to 6 per 10,000 per

year. The risk of aneurysmal rupture is associ-

ated with female sex, age, amount of cigarettes

smoked, hypertension, moderate-to-heavy alco-

hol consumption, and ingestion of sympath-

omimetic agents. Genetic factors include Marfan

syndrome, autosomal-dominant polycystic kid-

ney disease, Ehlers-Danlos syndrome Type IV,

and neurofibromatosis type 1.

Aneurysmal rupture has a mortality rate

that approaches 50%. It is extremely impor-

tant to recognize that a “warning leak” can

precede a major rupture in up to 25% of pa-

tients and that recognition of this premonitory

syndrome can be life saving. Patients present-

FIGURE 7.6 Large middle cerebral artery aneurysm

ing with an atypical or particularly severe

(arrow) demonstrated on an intra-arterial cerebral

headache, especially when there is clinical ev-

arteriogram.

idence of meningeal irritation, are most wor-

risome. The CT brain scan has a sensitivity

of roughly 90% to 95% during the initial

locations, and they typically are seen at branch-

24 hours of the bleed, whereas the lumbar

ing points of the major cerebral arteries

puncture has essentially

100% sensitivity.

(Fig. 7.6). MRA and spiral CTA have value for

Thus, the lumbar puncture is indicated even if

noninvasive

“screening” purposes. Roughly

the CT brain scan appears to be completely

80% to 85% of cerebral aneurysms are seen in

negative, but there is clinical suspicion for an

the anterior circulation, with the most common

aneurysmal bleed.

locations at the junction of the internal carotid

artery and the posterior communicating artery,

n SPECIAL CLINICAL POINT: It is important

in the region of the anterior communicating ar-

to recognize the potential of a “warning leak”

tery, and at the trifurcation of the MCA. Poste-

in patients presenting with atypical or severe

rior circulation aneurysms most commonly are

“thunderclap”-type headache even if the CT

found at the tip of the basilar artery or at the

brain scan does not clearly demonstrate

evidence of subarachnoid blood.

junction of a vertebral artery with the posterior

inferior cerebellar artery.

Cerebral arteriography remains the definitive

The clinical manifestations of a ruptured

study for documentation of an aneurysm or

cerebral aneurysm typically reflect its location.

aneurysms because they can be in multiple

Most patients have a severe headache with

121

Chapter 7

n Cerebrovascular Disease

clinical evidence of meningeal irritation (i.e.,

induces electrothrombosis, and obliteration, of

neck stiffness and pain), which is aggravated

the aneurysmal sac. A recent follow-up to this

by neck motion. Some patients have syncope as

study demonstrated similar benefits to surgical

the primary manifestation, with headache as a

clipping over 10 years of follow-up.

more minor component of the presentation.

Subhyaloid hemorrhage on funduscopic exami-

n SPECIAL CLINICAL POINT: There is

increasing use of endovascular intervention

nation can be an important clue. So-called

with aneurysmal subarachnoid hemorrhage.

“classic” presentations include the patient stat-

However, potential risks versus benefits,

ing they are experiencing the “worst headache”

including the expertise of the particular

of their life with no localizing neurologic fea-

interventionalist versus the neurosurgeon

tures or having a severe headache with a third

performing clipping of the aneurysm, must be

cranial nerve palsy. The third nerve palsy iden-

factored into the decision-making process.

tifies the location of the aneurysm at the junc-

tion of the internal carotid artery with the

Another complication is vasospasm. This tends

posterior communicating artery in the vicinity

to correlate with the amount of subarachnoid

where the third cranial nerve is traversing from

blood present, and it is most commonly seen 3

the midbrain toward the eye.

to 15 days after the initial rupture. Nimodip-

The major therapeutic approach is to have

ine, a calcium channel blocker, is available to

early surgical clipping, or endovascular coiling,

help prevent aneurysmal rupture-induced va-

of the ruptured aneurysm as soon as possible

sospasm. Some centers now are using endo-

in an effort to prevent further bleeding. There

vascular balloon angioplasty or intravascular

are a number of potential complications of

infusion of vasodilating agents, such as vera-

the initial rupture (Table 7.10), and rebleeding

pamil, in an effort to protect against hypoper-

is the most worrisome. Up to 10% to 20% of

fusion, with secondary cerebral infarction, that

patients will suffer rebleeding if early interven-

can be seen as a consequence of vasospasm.

tion, within the first 48 to 72 hours of presenta-

In an effort to serially monitor for potential

tion, cannot be performed. The International

vasospasm in a noninvasive fashion, transcra-

Subarachnoid Aneurysm Trial

(ISAT) found

nial Doppler is often used to detect elevation

that endovascular coiling of an aneurysm that

of the mean flow velocity, which reflects nar-

has bled, when accessible to such a coiling pro-

rowing of the intracranial vessel diameter.

cedure, was just as efficacious as and safer than

This can be useful for guidance in terms of

surgical clipping. In this procedure, the place-

more aggressive approaches toward evolving

ment of endovascular coils within the aneurysm

vasospasm.

Arteriovenous Malformation

TABLE 7.10

Complications of Aneurysmal Rupture

An AVM is an anomaly of embryonal develop-

1. Rebleeding

ment in which there is a conglomeration of ar-

2. Vasospasm with secondary ischemia

teries and veins with no intervening capillaries.

3. Hydrocephalus

The prevalence of AVM in the general popula-

a. Obstructive

tion is estimated at 0.14%, and most remain

b. Communicating

clinically silent throughout life. They are re-

4. Diffuse cerebral edema

ported to be twice as common in men as in

5. Chemical meningitis

6. Subdural hematoma

women. Although present at birth, they tend to

7. Intracerebral hematoma

become clinically evident most commonly be-

tween the ages of 10 and 40 years.

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Chapter 7

n Cerebrovascular Disease

Approximately 50% of people who become

tor. The purpose is to focus the radiotherapy at

symptomatic from an AVM present with either

the vascular supply of the AVM in an effort to

ICH, SAH, or both. It is the second most com-

promote occlusive vascular injury, over multi-

mon cause of spontaneous SAH after aneurys-

ple courses of therapy, in an effort to thrombose

mal rupture. Approximately 30% of patients

the involved vessels. Theoretically, radiother-

with AVM present with seizures; the remaining

apy, also known as radiosurgery, can obliterate

20% present with headache, focal neurologic

the AVM in a best-case scenario and remove its

deficit, or cognitive impairment. Roughly 25%

risk of ever bleeding or rebleeding. It is impor-

of patients with ICH secondary to AVM suffer

tant to point out that both radiotherapy and

serious morbidity or death. Overall, the first

endovascular occlusion are in the developmen-

bleed is fatal in 4.6% of patients. In a population-

tal stages, and it is expected that outcome will

based long-term follow-up study, the risk of

improve as these techniques are perfected.

first hemorrhage is lifelong and increases with

age. The recurrence rate for brain hemorrhage

is roughly 7% for the first year following the

WHEN TO REFER TO A NEUROLOGIST

initial bleed. Of the patients with AVM who

The edict “time is brain” is particularly impor-

present with seizure, 1% will suffer ICH within

tant in patients with acute ischemic stroke who

1 year. The headache that is associated with

present within the timeframe for rt-PA. Expert-

AVM can be very difficult to distinguish from

ise in the use of rt-PA enhances outcome. Neu-

migraine, and there is always the possibility

rologic expertise is also of value in patients

that the two coexist.

who require a more sophisticated opinion in

Fortunately, the risk of rebleeding from an

reference to recurrent symptoms of stroke or

AVM is not similar to that of aneurysmal rup-

TIA. This can include optimal choice of an-

ture. The most effective course is to surgically

tiplatelet therapy versus anticoagulant therapy.

remove the AVM, if feasible. However, not all

In terms of symptomatic carotid stenosis, the

AVMs can be resected because of the extent of

neurologist can provide expertise and experi-

the vascular supply, the location, or both.

ence in terms of risks versus benefits of proce-

AVMs located within the deep brain structures

dures such as carotid endarterectomy versus

or those involving vital brain function areas

carotid angioplasty with stenting. They can

are the most challenging from a surgical ap-

also provide a perspective on optimal choice of

proach. In an effort to reduce the vascular sup-

imaging such as carotid ultrasound versus

ply of the AVM, endovascular occlusion has

MRA versus CTA versus routine intra-arterial

been used. With the use of superselective vas-

cerebral angiography. One can also obtain in-

cular catheterization, one can insert a perma-

formed opinions about the evaluation and

nent balloon, sclerosing drugs, quick-acting

management of the patient with unexplained

glues, or thrombosing coils to interrupt the

ICH as well as the optimal approach to the pa-

vascular supply. In certain instances, these en-

tient with aneurysmal rupture and the patient

dovascular procedures can obliterate the

with an AVM.

AVM. However, the usual purpose is to allow

the AVM to be more effectively, and safely,

managed from a surgical standpoint. This is in

SPECIAL CHALLENGES FOR

recognition of the proposed surgical risk of ex-

HOSPITALIZED PATIENTS

tirpation based on size of the lesion, type of

venous drainage, and location.

It is important to recognize that patients pre-

Radiotherapy is an alternative to more inva-

senting with acute stroke or new-onset TIA re-

sive approaches. It can involve the use of

quire immediate evaluation and management.

gamma knife, proton beam, or linear accelera-

The sooner the mechanism of the ischemia is

123

Chapter 7

n Cerebrovascular Disease

determined, the better to make an informed

choice in terms of optimal management. Pa-

Always Remember

tients who are neurologically unstable should

• Transient ischemic attack is a medical

be admitted to an intensive care unit. This is

emergency that requires expeditious

particularly important for monitoring after

evaluation and management.

having received rt-PA. Noninvasive vascular

• Time is of the essence in the evaluation of

imaging (MRA and CTA) has become quite

the patient with acute ischemic stroke who is

good. However, there continue to be challenges

a potential candidate for tissue plasminogen

in terms of the accuracy of less-invasive imag-

activator.

ing studies, including carotid and vertebral ul-

• It is best to avoid aggressive blood pressure

trasound and transcranial Doppler, compared

treatment in patients with acute ischemic

to routine cerebral angiography. Outside of a

stroke, as this can promote extension of the

routine electrocardiogram (EKG) on admission,

infarct.

along with transthoracic echocardiography

• Most evidence suggests that more aggressive

when appropriate, cardiac monitoring can be

blood pressure control is indicated for patients

especially important for patients who are at

presenting with intracerebral hemorrhage.

significant risk for cardiac arrhythmia as an ex-

• The primary indication for anticoagulant

planation for their symptoms. TEE might also

therapy in the acute ischemic stroke period is

be useful, but it might also cloud the picture

for deep venous thrombosis prophylaxis.

when there is the not uncommon finding of a

• Aspirin tends to improve outcome in acute

patent foramen ovale or mitral valve prolapse.

ischemic stroke with the recommended dose

Many medical centers now have stroke units

of 160 to 325 mg/day as long as there is no

available, which allow a multidisciplinary ap-

contraindication to the use of aspirin.

proach toward the various special needs of the

• The CT brain scan is not 100% sensitive for

patient with acute stroke. These include nurs-

the detection of minor bleeding that can

ing staff with special expertise in neurologic

occur with rupture of an intracranial

monitoring of patients with stroke; supervision

aneurysm. A lumbar puncture is indicated if

by neurologists with special expertise in stroke;

there is any clinical support for this diagnostic

and a dedicated stroke rehabilitative staff to

possibility.

address communication disorders secondary

to stroke, cognitive dysfunction, psychologic

sequelae including depression, swallowing, and/

A. A CT brain scan that reveals no evidence

or respiratory impairment. The staff also can

of intracerebral hemorrhage

assess and treat motor dysfunction, incoordi-

B. Routine blood work that reveals no

nation, and gait impairment.

significant metabolic disturbance such

as severe hypoglycemia or

hyperglycemia

QUESTIONS AND DISCUSSION

C. A CT brain scan that reveals a

hyperdense middle cerebral artery

1. A 67-year-old right-handed male presents

reflective of a clot within the involved

to your ER complaining of aphasia, right

middle cerebral artery

homonymous hemianopsia, and right

D. An INR of 1.1

hemiparesis. He noted the symptoms upon

E. An inability to pinpoint the time of

awakening at 7 AM, and it is now 9 AM.

symptom onset

Which of the following would be a

contraindication to administration of rt-PA

The correct answer is E. This patient would

in this case?

be a potential candidate for rt-PA if he

124

Chapter 7

n Cerebrovascular Disease

presents with an ischemic stroke within 3

B. Evaluate for possible intracranial

hours of onset and with enough time to ex-

occlusive disease with conventional

clude contraindications to the use of this

4-vessel cerebral arteriography

drug. A CT brain scan is mandatory to ex-

C. Order a transesophageal ECHO (TEE)

clude intracerebral hemorrhage or evolution

to rule out a cardiac source of embolism

of the infarct to the point that there is al-

D. EEG to evaluate for possible focal

ready significant tissue damage present,

seizure activity

which would raise serious questions about

E. Substitution of low-dose aspirin-high-

the exact onset of the ischemic insult and

dose long-acting dipyridamole for the

would increase the likelihood of hemor-

present aspirin dose

rhagic transformation as a complication of

The correct answer is D. Two recent studies

the therapy. Patients also must have enough

showed absolutely no benefit from the combi-

of a deficit to warrant the use of this agent,

nation of aspirin and clopidogrel for ischemic

and they should not be demonstrating signif-

stroke protection with an increased risk of

icant spontaneous resolution of their signs

bleeding complications. This patient might

and symptoms during the evaluation period

have significant intracranial artery stenosis as

because this contraindicates the need for this

an explanation for her recurrent symptoms,

potentially dangerous agent. One must ex-

despite aspirin, and guidance for alternative

clude a severe metabolic derangement, such

therapy might be aided by such documenta-

as a very low or very high blood glucose,

tion with noninvasive imaging (e.g., transcra-

which can produce focal neurologic deficit.

nial Doppler study, MRA, or CTA) before

It is also important to exclude focal seizure

risking conventional angiography. Although it

activity as part of the presentation because

is possible that she has a transient cardiac ar-

this can contribute to the neurologic deficit.

rhythmia, such as atrial fibrillation, or valvu-

Contraindications include a clinically signifi-

lar disease as an explanation for her recurrent

cant bleeding diathesis or anticoagulant ther-

symptoms, cardioembolism is unlikely to re-

apy that is in a therapeutic range. In this

sult in six identical transient ischemic attacks.

specific case, the time that the patient was

On the other hand, focal seizure activity is fre-

last asymptomatic (presumably when he

quently stereotyped and can mimic TIA. It is

went to sleep) must be determined.

currently not clear that substitution of low-

2. A 73-year-old right-handed woman

dose aspirin-high-dose long-acting dipyri-

presented to the local hospital ER several

damole is superior to aspirin for stroke

weeks ago with an episode of left-sided

prophylaxis.

numbness and weakness that lasted

for 5 to 10 minutes before resolving

3. A 35-year-old right-handed woman presents

completely. She has minor bilateral

to your ER with a several hour history of

stenosis by carotid ultrasound, a normal

progressive aphasia and right hemiparesis.

MRI brain scan, a normal EKG, and a

She has no history of hypertension,

normal routine blood work. She is placed

diabetes, or hypercholesterolemia. The CT

on aspirin 81 mg/day and comes to your

brain scan reveals an evolving left middle

office for follow-up 1 month later and

cerebral artery distribution infarct. She has

reports having five identical episodes

been on an oral contraceptive for the past

since the initial presentation. Which of

6 months but is on no other medications.

the following would be most appropriate

She does not smoke and has no family

at this time?

history of vascular disease. Review of

A. Add clopidogrel to the aspirin

systems is significant for occasional dull

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Chapter 7

n Cerebrovascular Disease

headaches without associate symptoms, but

negative CT brain scan, and was sent

she reports that she recently returned from

home with a diagnosis of “migraine.”

a business trip to Thailand. Which of the

However, she has no history of significant

following is most likely to have caused her

headache prior to these two episodes. She

stroke?

is afebrile with normal vital signs. Her

A. Use of oral contraception

neurologic exam is normal. You elect to

B. Complicated migraine

obtain a noncontrast CT brain scan, and

C. Parasitic infection

it is officially read as normal. Which

D. Paradoxical embolus associated with the

diagnostic test should be performed

presence of a patent foramen ovale

before she is sent home?

E. Giant cell arteritis

A. An MRI brain scan

B. An EEG

The correct answer is E. The risk of stroke

C. A serum protein electrophoresis

related to oral contraceptives is low, but it is

D. A lumbar puncture

enhanced in older patients, those who

E. An ESR

smoke, those with other risk factors for vas-

cular disease as well as those with a strong

The correct answer is D. A patient presenting

family history of early vascular disease. Mi-

to the ER with a severe headache is always a

grainous infarction is felt to be a not uncom-

cause for concern, especially if it is called

mon cause of “stroke in the young.” This

“the worst headache of my life.” Atypical

small, but real, risk can be potentially en-

headaches also should raise particular con-

hanced by oral contraceptive use as a con-

cern so that one does not miss the so-called

tributing factor, as oral contraceptives have

“warning leak” of subarachnoid hemorrhage

the potential to exacerbate migraine, as well

or an early meningitis or encephalitis. The CT

as increase the risk of stroke, and this com-

brain scan has sensitivity of the order of 90%

bination might be a particularly important

to 95% within the first day of an aneurysmal

factor in migraine with aura. In this case,

subarachnoid hemorrhage, and, thus, it does

however, the patient’s history does not sug-

not fully exclude the possibility of such a life-

gest migraine, and she does not have signifi-

threatening bleed. The MRI brain scan is not

cant vascular risk factors. Although the

clearly superior to CT brain scan in the acute

patient reports travel overseas, a parasitic in-

setting for the detection of blood. To com-

fection is unlikely as an explanation for her

pletely exclude this possibility, when there is

stroke. But it is now well recognized that pro-

any clinical suspicion, one must perform a

longed air travel can promote deep venous

lumbar puncture. An ESR is an important test

thrombosis of the legs. This, in association

for the older patient presenting with headache

with the not uncommon finding of a patent

to help in the evaluation for possible tempo-

foramen ovale, can lead to what has been

ral arteritis. In this particular patient, it is im-

termed “paradoxical cerebral embolism.”

portant to keep in mind that migraine often

The patient is not likely to have giant cell

presents itself by the time patients reach the

arteritis, a disease of the elderly.

age of 35.

4. A 38-year-old right-handed woman

presents to your ER with severe headache

and is found to have some pain on motion

SUGGESTED READING

of her neck. She experienced a similar, but

Adams HP Jr. Secondary prevention of atherothrombotic

milder, headache 1 week earlier. She was

events after ischemic stroke. Mayo Clin Proc.

evaluated at a different ER, had a

2009;84:43.

Headache

Disorders

AMY WILCOX VOIGT AND JOEL R. SAPER

key points

• Primary headache disorders reflect intrinsic, possibly

genetically determined vulnerability to recurring

headaches.

• Secondary headaches can mimic the primary disorders,

thus justifying aggressive diagnostic pursuit for patients

with frequent or changing headache patterns or those

with neurologic symptoms or findings.

• Progression from intermittent migraine to daily or

almost daily chronic migraine results from a variety of

factors, such as genetic, hormonal, psychological, and

metabolic, including obesity.

• Acute medication overuse exceeding 3 days a week,

week after week, and month after month is a major

cause of progression from intermittent headache to

more frequent headache referred to as medication

overuse headache.

• Effective headache treatment requires individualized

programs, using abortive (acute) and preventive

medications and occasionally, if appropriate, behavioral

therapy. Intractable cases must be referred to advanced

systems of care, including specialists and comprehensive

headache programs.

• Chronic administration of opioids for frequent

headaches is discouraged.

worldwide. The lifetime prevalence of common

INTRODUCTION

headache disorders can be more than 78%,

Primary headache disorders are highly preva-

with migraine prevalence greater than 20% in

lent conditions affecting tens of millions of U.S.

adult females. The economic and quality-of-life

citizens and hundreds of millions of individuals

burden of migraine alone is substantial, with

127

128

Chapter 8

■ Headache Disorders

the most disabled half of migraine sufferers ac-

TABLE 8.2

counting for more than 90% of migraine-

Secondary Headache Conditions

related work loss. Barriers to successful care

More than 300 conditions can produce

include failure to diagnose properly, underesti-

secondary headaches. Among the conditions

mation by both the professional and public do-

are the following:

mains of the morbidity of these conditions, and

Cerebrovascular/cardiovascular ischemia

denied access to appropriate treatment.

Metabolic disorders

Intracranial mass lesions

CSF hypotension/hypertension

Infectious disorders (systemic,

PRIMARY AND SECONDARY

intracranial)

HEADACHES

Endocrine dysfunction

Primary headaches include those in which in-

Cervical (neck) disorders

Temporomandibular/dental disorders

trinsic dysfunction of the nervous system, often

genetic in origin, predisposes to increased vul-

CSF, cerebrospinal fluid.

nerability to headache attacks. Examples in-

clude cluster headache and migraine. Secondary

headaches are those in which the headache is

accompaniments. These can precede, accompany,

secondary to an organic or physiologic process,

or follow the headache itself.

intracranially or extracranially.

Table 8.1 is a short overview version of the In-

Migraine is classified into three major subtypes:

ternational Headache Society’s (IHS) classifica-

1. Migraine with aura—characterized by herald-

tion of primary headaches. Table 8.2 lists some

ing neurologic events lasting 30 minutes to

of the more frequently occurring categories of ill-

1 hour and preceding the head pain attacks

nesses that produce secondary headaches.

(only 15-20% of migraine attacks). A migraine

aura should last longer than 5 minutes and

less than 60 minutes. If an aura is consistently

MIGRAINE

less than 5 minutes in duration, then a “sec-

■ SPECIAL CLINICAL POINT: Migraine is a

ondary aura” should be suspected (arteriove-

complex neurophysiologic disorder characterized

nous malformation, epileptic aura). If an aura

by episodic and progressive forms of head pain

lasts longer than 60 minutes in duration, it is

in association with numerous neurologic and

termed a “prolonged aura,” and an underly-

nonneurologic (autonomic, psychophysiologic)

ing coagulopathy or other cerebral pathology

should be ruled out.

2. Migraine without aura—in which attacks of

migraine and accompaniments occur with-

TABLE 8.1

out clear-cut preheadache neurologic symp-

Abbreviated International Headache

Society Classification for Primary

tomatology. This is the most common form

Headache Disorders

of migraine (80% to 85%). A prodrome is a

period of time, up to 24 hours or so, prior

Episodic migraine

to the aura or headache phase in which

With aura (including basilar [brainstem] migraine)

mental or physiologic events herald the next

Without aura

phases of migraine. The prodrome may con-

Chronic migraine (new IHS criteria)

Cluster headache (episodic/chronic)

sist of subtle or less than subtle phenomena,

Tension-type headache (episodic/chronic)

such as excessive yawning, food cravings,

and mental changes, such as excitability,

IHS, International Headache Society.

anxiety, elation, or even depression. Many

129

Chapter 8

■ Headache Disorders

have misinterpreted the prodrome as a

TABLE 8.3

“trigger” phenomenon for the headache,

Key Concepts in Migraine Pathogenesis

but in actuality the prodrome represents the

Trigeminal-mediated perivascular (neurogenic)

earliest phases of the ensuing attack.

inflammation resulting in painful vascular and

3. Chronic or transformed migraine—

meningeal tissue

frequently a progressive form of migraine in

The perivascular release of vasoactive neuropeptides,

which intermittent attacks occur at increas-

particularly calcitonin gene-related peptide (CGRP)

ing frequency, eventually reaching 15 or

The development of allodynia and central sensitization

as attacks progress

more days per month. By definition, chronic

The presence of an active “modulator zone” in the

migraine occurs on a backdrop of episodic

dorsal raphe nucleus of the midbrain during

migraine without aura, often accompanied

migraine attacks

by comorbid neuropsychiatric phenomena.

Activation and threshold reduction of neurons in

Chronic migraine frequently is associated

the descending trigeminal system and dorsal horn

with medication overuse and “rebound.”

of upper spinal cord (C2-C3)

The deposition of nonheme iron in the brainstem,

■ SPECIAL CLINICAL POINT: Comorbid

roughly correlated to increasingly frequent attacks

conditions associated with migraine,

A yet-to-be-defined relationship with nitrous oxide

particularly chronic migraine, include

depression, anxiety and panic disorders, bipolar

disorder, obsessive-compulsive disorder,

character disorders, and perhaps fibromyalgia.

Pathophysiology of Migraine

■ SPECIAL CLINICAL POINT: Migraine is a

Migraine—Clinical Symptoms

brain disorder that renders the brain

“hypersensitive” and overresponsive to a

Between 80% and 90% of patients with mi-

variety of internal and external stimuli.

graine have a family history. In childhood,

Trigeminal/cervical connections and cervical

there is a ratio of 1:1, males to females, but in

activation may be important phenomena in the

adulthood a 3:1 female-to-male gender ratio

clinical manifestations, pathogenesis, and

occurs. This is primarily thought to result from

treatment. The key features of current

the adverse influence on the headache mecha-

pathophysiologic understanding are identified in

nism by estrogen. At older ages, the gender

Table 8.3.

ratio again declines to almost 1:1, further sug-

gesting that estrogen is likely to be influential.

Each attack generally lasts between 4 and

TENSION-TYPE HEADACHE

72 hours and can be accompanied by a wide

range of autonomic and cognitive symptoms.

This controversial disorder is classified into

In complex cases, particularly in chronic mi-

both episodic and chronic forms. Episodic

graine, a likely association with several neu-

forms have certain features that overlap with

ropsychiatric comorbid disorders, including

migraine without aura, although there is a

depression, panic/anxiety syndromes, sleep dis-

general absence of throbbing pain and auto-

turbance, obsessive-compulsive disorder, and

nomic accompaniments. Chronic tension-type

others, occurs. Predisposed individuals are par-

headache overlaps in clinical features with

ticularly vulnerable to provocation (triggering)

chronic migraine. Both forms of tension-type

by certain extrinsic and intrinsic events, includ-

headache may be present in patients who have

ing hormonal fluctuation, weather changes,

otherwise typical migraine headaches. Some

certain foods, delayed meals and fasting, extra

authorities believe that these disorders are

sleeping time, stress, and others.

variant forms of migraine.

130

Chapter 8

■ Headache Disorders

TABLE 8.4

CHRONIC DAILY HEADACHE

Features of MOH

Chronic daily headache is a frequency-based de-

• Weeks to months of excessive use of abortive

scriptive term that embodies four overlapping

agents, with usage exceeding 2-3 days/week

clinical subtypes. These include the following:

• Insidious increase of headache frequency

• Dependable and predictable headache,

1. Chronic/transformed migraine, with or

corresponding to an irresistible escalating use of

without medication overuse (see below).

offending agents at regular, predictable intervals

2. Chronic tension-type headache, with or

• Evidence of psychological and/or physiologic

without medication overuse.

dependency

3. New daily persistent headache—sudden

• Failure of alternate acute or preventive

medications to control headache attacks

onset followed by persistent head pain

• Reliable onset of headache within hours to days

without the progressive features of chronic

following the last dose of symptomatic treatment

migraine but that often is associated with

comorbid and medication misuse features.

MOH, medication overuse headache.

New daily persistent headache, while con-

sidered by some to be a primary headache

disorder, may actually be a secondary

headache to daily headache, and ultimately has

headache entity, the etiology of which is

toxic and perhaps fatal implications because of

uncertain at this time.

the compulsive and often physiologically depend-

4. Hemicrania continua—unilateral, generally

ent features that reflect this medication/headache

persistent hemicranial discomfort with

cycle. Also, MOH imposes a refractoriness to

some features of migraine and cluster

otherwise appropriate treatment, thereby forcing

headache and that in 20% of cases appears

the discontinuation of these drugs before more

to arise as a consequence of head trauma.

appropriate medication treatment will be effec-

This entity also may actually represent a

tive. The authors of this chapter believe that there

secondary headache disorder.

are certain behavioral underpinnings to the de-

velopment of MOH in some, but not all, patients.

Addressing these, if present, is essential in order

MEDICATION OVERUSE HEADACHE

TABLE 8.5

(FORMERLY CALLED REBOUND

New International Headache Society

HEADACHE)

Criteria for Headache Attributed to

Medication Overuse

■ SPECIAL CLINICAL POINT: Medication

overuse headache (MOH), formerly referred

A. Headache present on >15 days/month

to as rebound headache, is a self-sustaining

B. Regular overuse of one or more acute/

headache condition characterized by

symptomatic treatment drugs

persisting and recurring headache (usually

1. Ergotamine, triptans, opioids, or combination

migraine forms) against a background of

analgesic medications ≥10 days/month on a

chronic, regular use of centrally acting

regular basis for >3 months

analgesics, ergotamine tartrate, or triptans.

2. Simple analgesics or any combination of

The descriptive features of this condition are

ergotamine, triptans, or analgesic opioids on

noted in Table 8.4. Table 8.5 reflects the

>15 days/month on a regular basis for >3

current IHS criteria for MOH.

months without overuse of any single class

alone

Among the most important clinical concerns is

C. Headache has developed or markedly worsened

that MOH can be a progressive disorder, per-

during medication overuse

haps prompting the conversion of intermittent

131

Chapter 8

■ Headache Disorders

to remedy the acute problem and maintain pre-

45 minutes). The attacks are associated with

vention in the long run.

focal orbital or temporal pain, which is always

unilateral, is of extremely severe intensity, and

is accompanied by lacrimation, nasal drainage,

pupillary changes, and conjunctival injection.

CLUSTER HEADACHE AND

Attacks of headache commonly occur during

ITS VARIANTS

sleeping times or napping and can be pro-

Cluster headache is a relatively rare disorder

voked by ingestion of alcohol or nitroglycerin.

that affects more men than women in a ratio of

It is interesting that a high likelihood of blue

3:1. Current concepts of pathophysiology sug-

or hazel-colored eyes; ruddy, rugged, lionized

gest disturbances within the hypothalamus

facial features; and a long history of smoking

with relevant involvement of autonomic sys-

and excessive alcohol intake characterize the

tems and alterations in melatonin function.

majority of men with cluster headache. Table

Melatonin “fine-tunes” endogenous cerebral

8.6 lists the clinical distinctions between clus-

rhythms and homeostasis.

ter headache and migraine.

The clinical features of cluster headache

Cluster headache may occur in its episodic

include the presence of headache cycles or

form (bouts or cycles of recurring headaches

bouts (clusters) lasting weeks to months and

followed by a period of no headache [remis-

occurring one or more times per year or less.

sion], lasting weeks to years) or in a chronic

During these periods, repetitive attacks of

form without an interim period, with headache

short- lasting headache occur daily. Individual

attacks daily for years without interruption.

attacks of headache last 1 to 3 hours (averaging

Treatment differences may exist.

TABLE 8.6

Clinical Features Distinguishing between Cluster and Migraine Headaches

Feature

Cluster

Migraine

Location of pain

Always unilateral, periorbital;

Unilateral and bilateral

sometimes occipital referral

Age at onset (typical)

Onset 20 years or older

10-50 years (can be younger or older)

Gender difference

Majority male

Majority female in adulthood

Time of day

Frequently at night, often same

Any time

time each day

Frequency of attacks

1-6 per day

1-10 per month in episodic form

Duration of pain

30-120 minutes

4-72 hours

Prodromes

None

Often present

Nausea and vomiting

20%

85%

Blurring of vision

Infrequent

Frequent

Lacrimation

Frequent

Infrequent

Nasal congestion/drainage

70%

Uncommon

Ptosis

30%

1%-2%

Polyuria

40%

Family history of similar

90%

headaches

Miosis

50%

Absent

Behavior during attack

Pacing, manic, and agitation

Resting in quiet, dark room

132

Chapter 8

■ Headache Disorders

TABLE 8.7

TABLE 8.8

Trigeminal Autonomic Cephalgias

Therapeutic Categories of Treatment

for Primary Headache

Cluster headache

Chronic and episodic paroxysmal hemicrania

• Nonpharmacologic treatment, including

SUNCT (short-lasting unilateral neuralgiform

behavioral therapy

headaches with conjunctival injection and tearing)

• Pharmacologic treatment (acute and preventive)

syndrome

• Interventional procedures, including:

Cluster-tic syndrome (the association of cluster

• Neuroblockade (nerve, facet, epidural space)

headache with trigeminal neuralgia

• Neurotoxin treatment (botulinum toxin)

symptomatology)

• Radiofrequency and cryolysis procedures

• Neurostimulation

• Hospital/rehabilitational programs

In addition to cluster headache, several short-

lasting headache entities are recognized and cur-

rently are classified with cluster headache in a

• Hormonal disturbances

category referred to as the trigeminal autonomic

• Use of or exposure to toxic substances

cephalgias. These disorders are characterized pri-

• Others

marily by the presence of short-lasting headaches

• Identifying previous treatment successes

of variable duration—seconds

(short-lasting

and failures

unilateral neuralgiform headaches with con-

junctival injection and tearing

[SUNCT]) to

Treatment Modalities

3 hours (cluster headache). The attacks are asso-

Numerous treatment modalities are available

ciated with autonomic features. Table 8.7 lists

(Table 8.8). Nonpharmacologic treatments can

the current members of the trigeminal auto-

be very helpful, particularly when combined

nomic cephalgia group.

with pharmacologic therapy. Behavioral modifi-

cation, biofeedback, exercise, and dietary ma-

nipulation add a dimension of help beyond the

TREATMENT OF PRIMARY HEADACHES

administration of medications and also pro-

AND RELATED PHENOMENA

vide patients a method of helping themselves.

The following represents the key principles in

Pharmacologic therapy provides the essential

the approach to treatment of primary headaches

treatment for the majority of patients with pri-

and related phenomena. These key treatment

mary headache. Increasing attention has focused

principles include the following:

on the important contribution that interven-

tional treatment may provide patients with pri-

• Diagnosing the specific primary headache

mary headache. Occipital nerve blocks, although

entity

not reversing the primary problem, can be par-

• Determining attack frequency and severity

ticularly useful for symptomatic treatment.

• Establishing the presence or absence of

comorbid illnesses (e.g., psychiatric,

Nonpharmacologic Treatments

neurologic, medical)

for Primary Headaches

• Identifying confounding factors, includ-

ing external or internal phenomena, such

A variety of factors related to health, habits, and

as the following:

education can assist patients with headache. Ed-

• MOH

ucation on headache triggers and eliminating

• Psychological and behavioral illness

headache-producing behaviors can be essential.

and medication factors (e.g., estrogen

Reduction of medication use and the treatment

replacement, nitroglycerin, etc.)

of rebound provide a fundamental and critical

133

Chapter 8

■ Headache Disorders

element to the treatment of patients with chronic

of “detoxification” headache, emotional events

headache when medication overuse phenomena

escalate and patients often become desperate in

exist. Discontinuing smoking, establishing regu-

their search for calming agents and the treat-

lar eating and sleeping patterns, and getting regu-

ment of pain. Many cases can be treated in an

lar exercise are reported as helpful by many

outpatient setting or in an infusion center,

patients with headache. Biofeedback and behav-

where IV therapies can be administered during

ioral treatment, together with cognitive behav-

the day. More severe and complex cases require

ioral therapy, may be of value in many cases and

hospitalization during which 24-hour fluid re-

essential in some.

placement, IV protocols to treat the pain, and

supportive measures can be provided in an

acute care setting with 24-hour nursing supervi-

Treatment of MOH

sion and monitoring. Hospitalization is gener-

MOH requires treatment because continued

ally required in patients with behavioral and/or

use of the medication renders patients refrac-

psychological confounding factors or when

tory to effective treatment. Outpatient and in-

complex drug regimens, including opioids and

patient strategies are available, depending on

others, add additional layers of complexity to

the intensity of medication usage and the char-

the case. Emotional support as well as behav-

acteristics of the case. Table 8.9 identifies im-

ioral treatment are necessary both on an inpa-

portant general principles in the treatment of

tient and on an outpatient level of care.

rebound or medication misuse headache.

Table 8.10 identifies some of the IV medica-

tions that are used in intravenously adminis-

■ SPECIAL CLINICAL POINT: MOH, which

tered treatment protocols to address acute

most likely results from chronic changes to

headache and treat medication overuse during

receptors, must be distinguished from

the withdrawal phases. Patients are also pro-

headaches resulting from toxic substances or

vided both preventive and other orally or par-

other exposure to agents or drugs.

enterally administered acute treatments. Among

These have a direct provocative influence. The

those acute treatments that will not cause MOH

discontinuation of offending medication is

when given more than 3 days/week (which is

often a challenging process. During the period

often necessary in the acute phases of treatment

TABLE 8.10

Parenteral Regimens to Treat

TABLE 8.9

Intractable Headaches

General Principles in the Treatment

of MOH

• Dihydroergotamine (0.25-1 mg IV or IM, t.i.d.)

• Diphenhydramine (25-50 mg IV or IM, t.i.d.)

Discontinuation of offending agent (taper if contain

(Swidan et al., 2005)

opioid or barbiturate)

• Various neuroleptics (i.e., chlorpromazine 2.5-10 mg

Aggressive treatment of resulting severe

IV, t.i.d.; droperidol 0.325-2.5 mg IV, t.i.d.)

“withdrawal” headache

• Ketorolac (10 mg IV, t.i.d.; 30 mg IM, t.i.d.)

Hydration, including intravenous fluids and support

• Valproic acid (250-750 mg IV, t.i.d.)

in severe cases (treat nausea)

• Magnesium sulfate (1 g IV, b.i.d.)

The development of pharmacologic prophylaxis

• Hydrocortisone (100 mg t.i.d. for 3 days)

Implementation of behavioral therapies

• Sumatriptan (4-6 mg s.c., cannot use more than

Use of outpatient infusion or hospitalization

2 days/week)

techniques for advanced and severe conditions

IV, intravenous; IM, intramuscular; t.i.d., three times a day; b.i.d., two

MOH, medication overuse headache.

times a day; s.c., subcutaneous.

134

Chapter 8

■ Headache Disorders

of MOH) are hydroxyzine, nonsteroidal anti-in-

TABLE 8.12

flammatory agents, baclofen, neuroleptics, and

Categories of Medications Used in

the Acute Treatment of Migraine

others. Steroids might also be used for short-

term intervention.

Simple and combined analgesics (acetaminophen,

excedrin, nonsteroidal anti-inflammatory drugs,

Pharmacologic Treatment of Migraine

and others)

Mixed analgesics (barbiturate and simple analgesics,

The pharmacologic treatment of headache in-

such as aspirin ± acetaminophen ± caffeine)—

volves the use of abortive (acute) and preven-

often avoided because of the likelihood of

tive medications. Abortive treatments are

dependency and misuse

used to terminate evolving or existing at-

Ergot derivatives, including dihydroergotamine

Triptan medications, including the following:

tacks. Preventive treatment is implemented to

Sumatriptan

reduce the frequency of attacks and prevent

Naratriptan

overuse of acute medications. Most patients

Almotriptan

require combination treatment. Preemptive

Rizatriptan

treatment is a short-term preventive course of

Zolmitriptan

therapy used in anticipation of a predictable

Frovatriptan

event, such as a menstrual period, or vaca-

Eletriptan

tion-related headache. There is a wide variety

of pharmacologic agents used in headache

management. Table 8.11 lists various routes

of delivery that can be utilized in the treat-

to migraine pathogenesis. Table 8.12 lists the

ment of headache.

various categories of abortive agents.

The triptans represent narrow-spectrum, re-

Acute Treatment of Migraine

ceptor-specific (serotonin [5-HT₁]) agonists that

stimulate the 5-HT₁ receptors to reduce neuro-

There are numerous agents used for the acute

genic inflammation. The ergot derivatives are

treatment of migraine. Some agents, such as

broader spectrum agents affecting the sero-

analgesics, are of general value for pain,

toninergic receptors and also alpha-adrenergic

whereas others, such as the ergots and triptan

and dopamine receptors (and others).

medications, are specific and influence receptor

and transmitter systems thought to be relevant

■ SPECIAL CLINICAL POINT: Whereas many

patients respond well to the triptans, others

appear to require the additional use of ergot

derivatives.

TABLE 8.11

Routes of Delivery of Medications

Experienced clinicians are adept at administering

• Oral

several of the triptans as well as the ergots.

• Nasal spray (sumatriptan/zolmitriptan/DHE)

Short-acting, rapidly effective triptans include al-

• Rectal (neuroleptics, indomethacin)

motriptan, sumatriptan, rizatriptan, zolmitrip-

• Transdermal (lidocaine)

tan, and eletriptan, whereas naratriptan and

• Parenteral

frovatriptan have the longest half-lives. Several

Subcutaneous (sumatriptan/DHE)

delivery formulations are available in addition

Intramuscular (DHE, ketorolac, diphenhydramine,

hydroxyzine, neuroleptics, etc.)

to tablets: injection (sumatriptan), nasal spray

Intravenous (DHE, ketorolac, valproic acid,

(sumatriptan and zolmitriptan), and rapidly dis-

steroids, magnesium sulfate, neuroleptics)

solving forms (zolmitriptan and rizatriptan).

Patients who have not responded to less po-

DHE, dihydroergotamine.

tent medications require triptans or ergots for

135

Chapter 8

■ Headache Disorders

maximum benefit. It is imperative that the trip-

TABLE 8.13

tans, and probably the ergot derivatives as well,

Guidelines for Determining the

Need for Preventive Treatment

be administered to patients in the early phases

of an ensuing headache attack, at the first sign

1. Disability from migraine headaches (loss of time

of a migraine aura or at the onset of headache

at work or at home)

pain, to bring about maximum benefit and re-

2. Migraine headaches occurring 2 or more days

duce the possibility of recurrence (the return of

per week

headache within the same

24-hour period).

3. Patient is overusing acute medication (analgesic-

rebound headache)

Acute medications are used in conjunction with

4. Risk of persistent neurologic dysfunction

antinauseants and in combination with each

because of the headache condition (hemiplegic

other for maximum efficiency (do not combine

migraine, migraine with prolonged aura)

ergots and triptans). Clinicians must be familiar

5. Acute medications are contraindicated or

with important contraindications and safety

ineffective

warnings of each of these medication groups as

6. Patient preference, provided clinical justification

well as adverse effects and influence on hepatic

exists

metabolism, particularly when these drugs are

used in combination with others.

Finally, for reasons that are not fully under-

preventive treatment of migraine in those pa-

stood but perhaps related to the cervical/trigem-

tients who do not have contraindications or

inal connections, occipital nerve blocks may

restrictions to either medication. Calcium chan-

relieve acute migraine attacks in some individu-

nel blockers are generally not as effective. The

als. This method has been used historically by

anticonvulsants have considerable value and are

anesthesiologists but is increasingly used by

particularly useful in the presence of neuropsy-

neurologists and others treating headache.

chiatric comorbidities or other conditions, such

Long-term value is rare, but short-term relief

frequently is seen, and an adjunctive value is

widely appreciated.

TABLE 8.14

Categories of Preventive Medications

Preventive Treatment of Migraine

Tricyclic antidepressants (particularly amitriptyline,

nortriptyline, and doxepin)

Many agents are available for the prevention of

Beta-adrenergic blockers (particularly propranolol

migraine. However, the clinician must deter-

and nadolol)

mine when preventive pharmacotherapy

Calcium channel blockers (verapamil)

should be introduced. Table 8.13 lists certain

Anticonvulsants (valproic acid, gabapentin,

clinical guidelines that can be used to make this

topiramate)

determination.

Ergot derivatives (methylergonovine and

The categories of medications useful in pre-

methysergide)^a

vention are listed in Table 8.14. A wide range of

Monoamine oxidase inhibitors (for refractory cases)

therapies is available, and increasingly useful are

Others

those that appear to work on specific neuro-

Selective serotonin reuptake inhibitors

transmitter systems. The reader will note that

Neuroleptics

Tizanidine

several of these categories do not relate to vascu-

Botulinum toxin

lature or blood flow, suggesting that the primary

Riboflavin

pathogenesis of migraine seems more likely to

involve neuronal rather than vascular dynamics.

^aAfter 4 to 6 months of daily use of ergot derivatives, diagnostic

pursuit of evidence of cardiac, pulmonary, or retroperitoneal

Tricyclic antidepressants and beta blockers

fibrosis must be undertaken.

are well-established, first-line medications for

136

Chapter 8

■ Headache Disorders

as seizures or bipolar disorders, which might ac-

TABLE 8.15

company migraine.

Acute Treatment of Cluster Headache

The selective serotonin reuptake inhibitors

Oxygen inhalation (8-10 L/min 100% oxygen via

(SSRIs) and serotonin norepinephrine reuptake

non-rebreather face mask)

inhibitors (SNRIs) are helpful for neuropsychi-

Triptans/dihydroergotamine (limit 1-2 dosages/day,

atric comorbidities, such as depression and

2-3 days/week)

panic and anxiety disorders, but generally do

Occipital nerve blocks

not have a strong antimigraine influence,

although venlafaxine (an SNRI) and fluoxetine

(an SSRI) do have supportive data in episodic

(one to eight), the use of abortive medications is

migraine and/or chronic migraine. Some pa-

limited to only a few agents that are safe for

tients with migraine-related headaches benefit

such frequent use. Unlike migraine, preventive

from the antidopaminergic influence of the

therapy is necessary for cluster headache unless

new neuroleptics, although the potential for

the typical cluster cycle is 2 weeks in duration

adverse effects limits their widespread use.

or less.

Tizanidine, an alpha-adrenergic agonist, has

Table 8.15 lists the agents useful in the acute

been shown effective in an adjunctive, preven-

management of cluster headache, which is lim-

tive role. Botulinum toxin increasingly is admin-

ited by the need to use medications up to several

istered for the prevention of chronic migraine,

times a day when effective preventive is not

but not intermittent migraine. Numerous un-

available or has not yet become effective. Many

controlled studies support efficacy, but there is a

clinicians have found that occipital nerve blocks,

paucity of controlled data at this time, although

with or without steroids, may not only terminate

supportive data may be available shortly. If

an acute cluster attack but may prevent subse-

botulinum toxin is shown to work for chronic

quent attacks, at least for a day or longer.

migraine, it is likely to work through a central

Table

8.16 lists the available preventive

mechanism and not through a primary muscu-

agents for the treatment of cluster headache. The

lar influence.

most reliable agents for prevention are the

The treatment of chronic migraine is similar

steroids, but because of their inherent risks with

to that of episodic migraine. Treatment is di-

long-term usage, they are inappropriate except

rected at both the daily or almost daily pain

in transitional regimens. Steroids can be used,

and periodic attacks. Because of the likely pres-

for example, at the onset of treatment while

ence of a progressive course, medication over-

other preventive agents are being titrated up-

use, and neuropsychiatric comorbidities in this

ward; during particularly vulnerable times, such

population, a more comprehensive approach

as when traveling; or when other medications

beyond medications alone is required. This in-

cludes cognitive behavioral therapy and other

forms of psychotherapy and family therapy.

TABLE 8.16

Organic illness must be ruled out with appro-

Preventive Agents for Cluster Headache

priate testing in patients with frequent or daily

Steroids

headache and in those with neurologic findings

Lithium carbonate

(see later).

Verapamil

Valproic acid

Treatment of Cluster Headache

Topiramate

Baclofen

Cluster headache responds and is treated differ-

Melatonin

ently than migraine. Because cluster headache

Indomethacin

attacks generally occur numerous times daily

137

Chapter 8

■ Headache Disorders

TABLE 8.17

conditions in patients with recurring or persist-

Recommended 7-Day Prednisone

ent headache. Diagnostic testing includes a wide

Program

range of studies, including the investigation of

metabolic, endocrinologic, toxic, dental, trau-

Day Breakfast (mg) Lunch (mg) Dinner (mg)

matic, cervical, and infectious disorders and

space-occupying lesions. Disturbances of cere-

20 (4 pills)

brospinal fluid (CSF) pressure, ischemic disease,

15 (3 pills)

and allergic conditions must be considered.

10 (2 pills)

Table 8.18 lists diagnostic tests that are among

those that should be considered in intractable or

5 (1 pill)

variant cases.

Important specific conditions to consider

include those of the temporomandibular or

Available as 5 mg tablets; 60 tablets should be dispensed.

dental structures, sphenoid sinuses

(must

specifically image and evaluate for sphenoid

are in transition. Table 8.17 lists a recommended

sinus disease), carotid and vertebral dissec-

prednisone protocol.

tion syndromes, and cerebral venous occlu-

For intractable cases, hospitalization is rec-

sion. Table

8.19 lists some of the disease

ommended. In some cases surgical intervention

categories that must be considered. Because of

is required, but surgical treatment is limited be-

the relevance of the cervical spine to the de-

cause of the likelihood of postsurgical painful

scending trigeminal system and headache

sequelae. Occipital nerve injection is effective

physiology

(trigeminal cervical connection),

in treating some acute attacks, and subcuta-

disturbances at the level of the upper cervical

neous occipital stimulation has been reported

spine and its nerves and joints have become

as anecdotally effective. Recently hypothala-

mic stimulation has been shown effective in

desperate clinical circumstances.

TABLE 8.18

Diagnostic Tests to Consider in

Refractory Cases

Treatment of Other Primary

Physical examination

Headache Disorders

Metabolic evaluation

Chronic paroxysmal hemicrania (CPH) and

Hematologic

episodic paroxysmal hemicrania (EPH), as well

ESR/CRP

as hemicrania continua, are characteristically

Endocrinologic

Chemistry

sensitive to treatment with indomethacin at a

Toxicology (drug screens)

dose of 25 to 50 mg three times a day. SUNCT

Standard x-rays

syndrome may respond to lamotrigine, topira-

Neuroimaging

mate, or gabapentin.

MRI/MRA/MRV

CT/CTA/CTV

Arteriography

DIAGNOSTIC TESTING AND

Dental and otologic examination

Lumbar puncture

SECONDARY HEADACHE DISORDERS

Diagnostic blockades

More than 300 entities may produce symptoms

ESR

of headache, many of which mimic the primary

CRP

headache disorders. The clinician has the burden

ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.

of ruling in and ruling out potentially relevant

138

Chapter 8

■ Headache Disorders

TABLE 8.19

TABLE 8.20

Secondary Headache Disorders

Possible Reasons for Intractability

• Traumatic disease (cryptic or obvious)

•

“Rebound” (medication overuse headache) or

• Carotid/vertebral dissection syndromes

excessive medication overuse, toxicity, etc.

• CSF disturbances (CSF leak syndromes,

• Wrong diagnosis (wrong primary or undetected

intracranial hypertension)

secondary causes) or nondiagnosis

• Toxic or environmental exposure syndromes

• Medication selection not proper/dosages not

• Nasal/dental/temporomandibular conditions

adequate

• Ocular disturbances

• Psychological barriers

• Metabolic/hormonal disturbances

• More aggressive treatment required:

• Alterations of sleep-wake cycle

hospitalization

• Intracranial pathology

• Current or previous use of opioids

• Vascular/ischemic/hemorrhage/vasculitis

• Requires interventional therapy

• Tumor, mass lesions, AV malformations

• Beyond current pathophysiologic understanding

• Infectious (encephalitis, meningitis)

• Obstructive/structural disorders (Arnold-Chiari

malformation)

• Connective tissue disorders

symptomatology have reached an intensity and

• Disorders of the upper cervical spine

complexity that make outpatient therapy no

CSF, cerebrospinal fluid; AV, arteriovenous.

longer appropriate.

Hospitalization

important targets for the treatment of other-

Many patients with intractable headache can

wise pharmacologically resistant headaches.

and do respond to the more aggressive thera-

Premature or excessive use of interventional

peutic environment and milieu in specialty in-

procedures is unwarranted, but when selective

patient programs when outpatient therapy

and expertly administered, they clearly have a

has failed to establish efficacy. Recently Lake

role in the overall spectrum of diagnosis and

and Saper (2009) have published outcome data

treatment for headache conditions. Treat-

on 276 consecutive patients admitted to the

ments such as implantable stimulators are on

Michigan Head Pain & Neurological Institute,

the horizon.

demonstrating that 75% of these intractable

patients reported moderate to significant

headache reduction at the time of discharge.

Inpatient programming provides for the ability

REFERRAL AND HOSPITALIZATION

to address pain, toxic, physiologic, and behav-

ioral issues, while at the same time observing

There are indeed patients who are intractable

various patient pain patterns and patient be-

to standard primary and secondary level care.

haviors, which can be very informative and in-

Table 8.20 lists some possible reasons for in-

fluential in treatment strategies. Table

8.21

tractability. It is advisable to refer patients with

lists the criteria that can be used when hospital-

intractable headache to specialists, specialized

ization is considered.

clinics, and tertiary centers.

Hospitalization for acute and prolonged

■ SPECIAL CLINICAL POINT: Hospitalization

headache is a complex undertaking because it

is required for many complex patients whose

must address not only the refractoriness of the

medication misuse or the presence of

symptoms, the often-present confounding

intractable pain and behavioral/ neuropsychiatric

influence of MOH (rebound), but also the

139

Chapter 8

■ Headache Disorders

TABLE 8.21

Criteria for Hospitalization

1. Moderate to severe intractable headache, failing to respond to appropriate and aggressive outpatient or

emergency department services and requiring repetitive, sustained, parenteral treatment

2. The presence of continuing nausea, vomiting, and diarrhea

3. The need to detoxify and treat toxicity, dependency, or rebound phenomena and require monitoring services

against withdrawal symptoms, including seizures

4. The presence of dehydration, electrolyte imbalance, and prostration, requiring monitoring and intravenous

fluids for the presence of unstable vital signs

5. The presence of repeated previous emergency department treatments

6. The presence of serious concurrent disease (e.g., SAH, intracranial infection, cerebral ischemia, severe

hypertension or hypotension, etc.)

7. To simultaneously develop an effective pharmacologic prophylaxis in order to sustain improvement achieved

by parenteral therapy

8. To acutely address other comorbid conditions contributing or accompanying the headache, including medical

or psychological illness

9. Concurrent medical and/or psychological illness requiring careful monitoring in high-risk situations (i.e., severe

hypotension, coronary artery disease, etc.)

SAH, subarachnoid hemorrhage.

behavioral and psychological factors that often

is overused and that requires discontinuation,

influence these dilemmas. Discontinuation of

the amount of pain and its duration during this

medication and the weaning process bring with

weaning process, the behavioral issues that

them a predictable escalation of headache and

emerge, and the confounding factors that often

the emotional factors that are characteristic to

are present in patients with these symptoms. De-

that patient. The principles of hospitalization

veloping a preventive treatment during this time

are listed in Table 8.22.

is difficult because it takes time for medications

Hospitalization length of stay varies, depend-

to work and because generally patients are in a

ing on the intensity and type of medication that

refractory period that may last up to weeks to

months after discontinuation of the offending

agents.

TABLE 8.22

Principles of Inpatient Care

When and When Not to Administer Opioids

Interrupt daily/intractable headache with parenteral

■ SPECIAL CLINICAL POINT: Experience

protocols

and evidence support the avoidance of

Discontinue offending analgesic medications if

sustained opioid administration in the chronic

rebound is present

headache population.

Implement preventive pharmacotherapy

Identify effective abortive therapy

Administration of opioids in acute situations

Treat behavioral and neuropsychiatric

when other treatments are contraindicated or

comorbidities

established to be ineffective remains appropri-

Use interventional modalities when indicated

ate in selected cases, but dose and amounts of

Educate

prescriptions should be limited and monitored

Discharge and outpatient planning along with case

carefully to avoid misuse. Sustained opioid ad-

management

ministration should be extremely limited and

140

Chapter 8

■ Headache Disorders

considered only in the following selected cir-

cumstances:

Always Remember

When all else fails, following a full range

• Primary headaches, particularly migraine, are

of advanced services, including detoxifi-

considered potentially life-long disorders and

cation

require not only aggressive treatment but

maintenance therapy that changes over the

When standard agents are contraindicated

course of a patient’s life.

In the elderly or during pregnancy

• In patients with migraine and cluster

Saper et al. (2008) provide detailed criteria for

headache, headaches due to secondary

the administration of sustained opioid therapy

causes can emerge, and therefore the clinician

in the headache population.

must be alert to the possibility that there is a

Experience suggests that, although some

superimposed condition, thus justifying

patients with difficult headache problems

vigilance and appropriate testing whenever

initially respond to sustained opioid therapy,

patterns change, new symptoms develop, or

there is significant risk for untoward reactions

unexplained phenomena occur.

and confounding of the already complex prob-

• A range of treatments is available from

lem. Sustained opioid therapy for intractable

medications to behavioral therapy to

headache should not be started on a primary

rehabilitative approaches. Patients with

care level, and patients who do not respond

intractable symptoms should be referred to

to standard treatment should be referred to

advanced programs for comprehensive

specialists and/or centers where more complex

treatment approaches.

regimens of treatment can be offered, where

• Opioids are generally discouraged in the

rebound and the underlying behavior can be

treatment of chronic headaches. Chronic

treated, and where psychological influences on

administration for maintenance treatment

headache refractoriness can be most effectively

has shown to both be counterproductive

addressed.

and contribute to the progression of

headache conditions.

■ SPECIAL CLINICAL POINT: Use of opioids

in the treatment of headache should be

severely restricted, and if used, must be

carefully monitored by those who administer

the medication. If opioids are prescribed,

QUESTIONS AND DISCUSSION

measures must be in place to ensure that

1. A 36-year-old woman develops onset of

multiple doctors are not writing prescriptions

severe right-sided orbital pain lasting 2 to

for these drugs.

3 hours. The attacks may occur three times

Those who choose to administer chronic

a day, and each attack is associated with

opioids must be prepared to calculate appro-

conjunctival injection, tearing, and nasal

priate dosages, see patients frequently, per-

drainage. During each attack, the patient

form appropriate urine drug screens, and

paces and at times pounds her fists in pain.

monitor usage carefully through collaboration

Alcohol is reliably able to provoke an

with other treating physicians and collateral

attack.

sources, such as spouses. Unfortunately, this is

Which of the following is the likely diagnosis?

not always the case, and many of the problems

A. Cluster headache

associated with opioid use have resulted from

B. Migraine with aura

failure to carefully select appropriate patients

C. Migraine without aura

and effectively monitor those prescribed these

D. Chronic paroxysmal hemicrania

medications.

E. Tension-type headache

141

Chapter 8

■ Headache Disorders

Which is likely to apply to this condition?

parasympathetic disturbances, including eye

A. The patient is a cigarette smoker.

tearing, nasal drainage, and other autonomic

B. Menstrual periods affect the attack.

symptoms, although in cluster headache these

C. The patient would feel better if she

are more reliable and diagnostic in their pres-

sought a quiet, cool, dark room.

entation. In migraine they may not occur in

D. Physical therapy would be of benefit.

dramatic form.

E. Antidepressants are likely to be helpful.

Estrogen is influential in migraine but not

in cluster headache, a predominantly male ill-

The answer to the first part of the question is

ness. Migraine is more common in females,

A and the answer to the second part of the

but cluster headache is much more common

question is also A. Cluster headache is the di-

in males. Migraine averages 4 to 72 hours,

agnosis, and the case description is quite char-

whereas cluster headache lasts no more than

acteristic of a cluster attack.

3 hours. Migraine often has its onset in ado-

Alcohol can be provocative in both disor-

lescence, whereas cluster headache generally

ders, but the distinct combination of conjunc-

starts later in life.

tival injection, tearing, nasal drainage, pacing,

and duration of attacks is much more likely in

cluster headache than in migraine. By defini-

tion migraine lasts at least 4 hours.

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Swidan SZ, Lake AE III, Saper JR. Efficacy of intravenous

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diphenhydramine versus intravenous DHE-45 in the

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strual periods, do not generally pace, rarely if

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cept that lithium can be helpful and does have

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Argoff CE. A focused review of the use of botulinum tox-

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Bartsch T, Goadsby PJ. Stimulation of the greater occipi-

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C. Both have attacks averaging 4 to

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Epilepsy

DONNA C. BERGEN

key points

• Seizures are diagnosed by taking a careful history from

the patient and/or a witness of the attacks.

• A single electroencephalogram may be normal in

patients with epilepsy.

• Onset of epilepsy is most common in children and in

the elderly, but may occur at any age.

tonic-clonic

remodeling, excessive excitatory activity, and

seizure may occur acutely at any time of life as a

other chronic cortical changes all may play a part

result of trauma, metabolic disturbances,

in producing an acquired epileptogenic focus.

stroke, alcohol withdrawal, substance abuse, or

other causes. Approximately 6% of the popula-

tion has an afebrile seizure at some point in their

TYPES OF SEIZURES

lives. The recurring seizures of the chronic disor-

der called epilepsy also may begin at any time of

The diagnosis of epilepsy is made on the

life and include various other types of seizures.

basis of the clinical history of the seizures

The prevalence of epilepsy in the United States is

taken from the patient and often from a wit-

about 0.5%, making it one of the most common

ness. The prototypical seizure, the tonic-

neurologic disorders. Incidence across the lifes-

clonic seizure (previously called grand mal

pan is a U-shaped curve, with the first year of

seizure), often starts with sudden loss of con-

life and old age being times of highest risk.

sciousness, with the patient falling stiffly (the

Epilepsy is a disorder primarily of the cere-

tonic phase); this is followed by rhythmic

bral cortex, with seizures occurring when popu-

jerking of the limbs and torso

(the clonic

lations of neurons discharge in abnormal

phase), which slows and then stops abruptly.

patterns. The pathophysiology of epileptic dis-

Such seizures usually last only 60 to 90 seconds.

orders is not well understood, and varies de-

The patient awakens after a period of postic-

pending on seizure type and epilepsy syndrome

tal stupor, which usually lasts less than

(see Types of Seizures). Many of the genetically

15 minutes, but confusion may persist con-

determined epilepsies, for example, have been

siderably longer. Such seizures coincide with

shown to be the result of channelopathies or in-

very rapid, abnormal cortical and subcortical

born structural abnormalities of neurotransmit-

neuronal activity, which is recruited so rap-

ter receptors. The many animal models of focal

idly that it appears synchronously in all

epilepsies, however, suggest that glial prolifera-

brain areas when recorded on an electroen-

tion, loss of inhibitory neuronal activity, cortical

cephalogram (EEG).

143

144

Chapter 9

■ Epilepsy

The physiologic abnormalities that may

■ SPECIAL CLINICAL POINT: An aura

accompany these attacks include apnea, hy-

represents the beginning of a seizure, and its

poxemia, acidosis, and autonomic disruptions

nature is determined by the site of onset in the

cerebral cortex.

such as cardiac arrhythmias and hyperten-

sion. Pulmonary edema can occur and may

There are also less dramatic seizure types,

play a role in the syndrome of sudden death

many occurring more commonly in children

that occurs occasionally even in young, other-

than in adults. An absence seizure (previously

wise healthy patients with epilepsy. Other

called petit mal seizure) refers to a brief episode

physical complications may include disloca-

of loss of awareness, occuring without warn-

tion of the shoulder, vertebral collapse, and

ing, lasting for a few seconds, and ending with

aspiration pneumonia.

immediate resumption of consciousness. The

Focal or partial seizures begin in a local-

patient usually stops what she is doing; the eyes

ized cortical area, with the clinical ictal phe-

remain open or may blink rapidly, but the pa-

nomena being determined by the brain region

tient does not fall. Absences may occur many

involved. For example, seizures beginning

times per day. Patients often are unaware of

with abnormal neuronal activity in primary

them, and they commonly are noted first by

motor cortex may cause initial twitching of

family members or teachers.

the face or limb, depending on the exact site

Another brief seizure type is the myoclonic

of onset. The patient with an occipital ictal

seizure, which consists of sudden, brief single

focus may report flashing lights or globes,

or repetitive jerks of the limbs without warn-

often in the visual field contralateral to the

ing. Myoclonic seizures occur without warning

focus. Foci in the temporal lobes often pro-

and generally last only a few seconds. Con-

duce autonomic symptoms such as nausea or

sciousness sometimes is impaired, but like the

complex psychic experiences such as intense

absence seizure, the myoclonic seizure is fol-

feelings of familiarity (déjà vu) or feelings of

lowed by immediate return to full awareness

strangeness. Such recalled seizure onsets com-

without a postictal state.

monly are called auras; although commonly

Less common are the brief atonic or akinetic

construed as warnings of seizures they actu-

seizures, which consist of sudden falls without

ally reflect the beginnings of the seizures

warning, usually but not always with loss of

themselves. The duration of focal seizures is

consciousness. Although brief, these seizures

generally 30 to 60 seconds.

can be very dangerous, with patients often suf-

Focal seizures that end without impairment

fering injuries to the face or skull.

of consciousness are termed simple partial

seizures. Whether they begin with an aura or

with sudden loss of awareness, focal seizures

EPILEPSY SYNDROMES

that at some time impair consciousness are

called complex partial seizures. A witness typ-

The primary generalized epilepsies are a group of

ically reports that the patient stares and be-

disorders which usually present in childhood, re-

comes unreactive, and that the patient may

spond well to treatment, and may have high rates

carry out simple motor activities such as pick-

of remission. They generally are considered ge-

ing at the clothes, walking about, or most typ-

netic in origin, most having nonspecific inheri-

ically smacking the lips. Complex partial

tance patterns but definite family clustering. The

seizures also last about a minute and may or

seizure types seen in these syndromes vary and

may not be followed by postictal confusion.

may include generalized tonic-clonic seizures,

Both simple and partial seizures may spread

absence seizures, and myoclonic seizures.

throughout the brain, developing into a typical

Patients with primary generalized epilepsies

tonic-clonic seizure.

usually have normal neurologic examinations,

145

Chapter 9

■ Epilepsy

are of normal intelligence, and give no history

use commonly triggers seizures. The EEG shows

suggesting preexisting brain pathology. The

characteristic polyspike-and-wave discharges

EEG shows normal background activity, often

elicited by strobe lights. The seizures themselves,

interrupted by bursts of generalized spike-and-

however, are not sensitive to flashing lights. This

wave discharges. Primary generalized epilepsies

type of epilepsy persists for decades or may even

make up 30% to 40% of childhood epilepsies.

be lifelong.

Virtually all of the primary generalized

epilepsies are age related, beginning and often

■ SPECIAL CLINICAL POINT: Juvenile

myoclonic epilepsy is one of the most common

remitting at specific times of life. The most

types of epilepsy, and though generally responsive

common syndrome is that of febrile seizures,

to treatment, may require lifelong therapy.

which occur in nearly 5% of children, generally

between the ages of 1 and 3 years. Uncompli-

In contrast to the previously mentioned seizure

cated febrile seizures stop by the age of 5 years

types, almost all adult epilepsies, as well as the

and are not associated with an increased risk of

majority beginning in childhood, are focal or

seizures in later life. On the contrary, when the

localization-related epilepsies, with focal or par-

seizures are prolonged (30 minutes or more),

tial seizures. The occurrence of focal seizures

repeated, or followed by postictal hemiparesis

implies the existence of focal brain pathology.

(Todd’s paralysis), children do have an in-

An almost unlimited variety of clinical seizure

creased risk of developing a chronic seizure dis-

phenomena may occur, depending on the site of

order, which sometimes appears years later in

brain injury.

the form of complex partial or other seizure

In the diagnosis of all forms of epilepsy, tak-

types. Such syndromes are called complicated

ing a meticulous history from the patient as

febrile seizures.

well as from witnesses to the seizures is essen-

Childhood absence epilepsy usually begins

tial. The precise sequence of events making up

between the ages of 4 and 10 years with the ap-

the attacks reveals the site of seizure onset in

pearance of absence seizures. In 30% to 40% of

the brain and the route and extent of seizure

cases, tonic-clonic seizures appear around the

propagation through the brain. For example, a

time of puberty. Seizures usually respond easily

patient with a meningioma growing over the

to medical treatment, and the remission rate by

right cerebral hemisphere may present with

young adulthood may reach 80% to 90%. Be-

focal motor seizures of the left leg resulting

fore treatment, the EEG usually shows normally

from irritation of nearby cerebral motor cortex

developed background activity interrupted by

by the tumor. Such an attack may spread down

hyperventilation-induced three per second spike-

along the precentral

(motor) gyrus, sequen-

and-wave activity

(see Diagnosing Epilepsy),

tially involving the cortex controlling the left

which is characteristic and helpful for diagnosis.

arm. If the patient remains conscious through-

Juvenile myoclonic epilepsy is one of the

out the seizure, the episode is called a simple

most common genetically based epilepsies, with

partial seizure. Commonly, however, intrinsic

onset between the ages of 10 and 20 years. Pa-

cerebral inhibitory mechanisms fail to keep the

tients usually present with a tonic-clonic seizure

seizure localized, and the electrical discharge

occurring without warning, often in the early

may spread suddenly into thalamic and other

morning. If specifically asked, they also give a

brain structures with strong, widespread corti-

history of recent involuntary jerks of the limbs

cal projections. In this case, a generalized

or dropping of objects from the hands. These

tonic-clonic seizure ensues. Unless the clini-

myoclonic seizures also occur most commonly

cian obtains the history of focal onset of such

in the morning and often immediately precede

an attack, a mistaken diagnosis of primary gen-

the “big” seizure that usually brings them to

eralized epilepsy may be made, and a search for

medical attention. Sleep deprivation or alcohol

localized brain disease may be left undone.

146

Chapter 9

■ Epilepsy

A completely different symptom complex

The clinical picture becomes even more

may be reported by the patient with temporal

complex in the patient with multifocal or dif-

lobe injury, such as that following encephalitis,

fuse brain injury. Such a person may be sub-

anoxia, or complicated febrile convulsions. A

ject to two or sometimes three seizure types.

complex partial seizure often begins with a sub-

Generalized motor convulsions, focal seizures

jective experience such as a sudden feeling of

of any type, or absence attacks all may occur

strangeness or an abrupt sensation of nausea

chronically. Additional patterns also may be

moving upward from the epigastrium. If the

present, often as fragments (tonic seizures) or

seizure discharges remain confined to a small

distinctive types of episodes such as sudden

area of the temporal lobe, the attack may not

losses of muscle tone with falling (akinetic

proceed further and may end in 30 to 60 sec-

seizures). Patients with these multiple seizure

onds. If, however, the seizure spreads throughout

types nearly always bear other stigmata of se-

both sides of the limbic system, consciousness

rious cerebral injury such as mental retarda-

may be altered or lost. The patient may stare va-

tion or cerebral palsy. In such cases, seizures

cantly or may appear to look about, becoming

are often difficult if not impossible to control

unresponsive and often making simple move-

with drugs, are almost always lifelong, and

ments (automatisms) such as lip smacking, gri-

are best handled with the help of a neurologist

macing, or hand wringing. He may stand or sit

or epileptologist.

still or may walk about aimlessly. Because of the

Epilepsy takes a heavy toll on many aspects

intimate relationship between limbic cortical

of patients’ lives. Although prejudicial atti-

structures and the hypothalamus, autonomic

tudes are softening gradually, epilepsy is still a

signs and symptoms such as piloerection, change

condition often hidden from those outside the

in skin color, borborygmus, or an urge to urinate

family. Social stigmatization is still surpris-

are common in complex partial seizures. If the

ingly high, often affecting employment, insur-

seizure stops at this point, the altered behavior

ability, and self-esteem. When the condition is

also stops abruptly, but the patient may remain

poorly controlled, it can dominate and define

confused for several minutes or longer. If the

relationships between parents, children,

seizure has started in the speech-dominant hemi-

spouses, and siblings. Children may be shel-

sphere, language function may be temporarily

tered excessively by parents and teachers,

impaired postictally. If the ictal activity spreads

which may cause social maturation to be de-

further, however, a full-fledged tonic-clonic

layed or prevented. Depression and anxiety

seizure occurs. Patients may be able to describe

are very common and underdiagnosed in

vividly the onset or aura of such attacks, but

those with epilepsy, and suicide rates are

many subjects with temporal lobe seizures have

above average. Learning difficulties in chil-

no recall of events before loss of consciousness,

dren with epilepsy are common and some-

and the physician must rely on witnesses for a

times overlooked.

full description of the episodes.

■ SPECIAL CLINICAL POINT: Mood disorders

Focal epilepsy, with or without secondary

occur in many patients with epilepsy and are

generalization of the attacks, is by far the most

often missed unless sought for by physicians.

common form of seizure disorder seen by the

primary care physician and by most neurolo-

Details of state regulations vary, but usually the

gists. Within this category, complex partial

patient with epilepsy who cannot demonstrate

seizures are the most prevalent type. Many pa-

complete, long-term control of the attacks is

tients with partial seizures find complete relief

prohibited from driving. Public transportation

from attacks with medication, but about 30%

and car pools are often inadequate solutions for

continue to have some seizures even with com-

day-to-day autonomy. Because a diagnosis of

petent medical advice and optimal therapy.

epilepsy has far-reaching implications for the

147

Chapter 9

■ Epilepsy

life of the patient, it is essential that the diagno-

of seizure. The details of such seizures are cru-

sis be neither missed nor misapplied.

cial in discussing safety issues such as driving.

Discriminating between absence and com-

plex partial seizures sometimes may be a di-

agnostic hurdle. The latter is much more

DIAGNOSING EPILEPSY

common than the former, especially in adults.

Epilepsy is diagnosed through the patient’s his-

Making the correct diagnosis is important be-

tory—not by head scans, EEGs, or the neurologic

cause only complex partial seizures imply the

examination. In cases when a seizure disorder is

presence of focal brain disease and the thera-

suspected, the physician must spend adequate

pies for the two types vary somewhat. If a re-

time with the patient and often with witnesses to

liable witness can be found, the two seizure

the attacks to make a reliable diagnosis.

types can be distinguished accurately by the

In most cases, asking the patient for a de-

duration of the attack. Almost all absence

tailed account of the last episode, or of the last

seizures last less than 15 seconds, and many

one the patient recalls well, often evokes pre-

are shorter. However, most complex partial

cise details and a coherent impression. Physi-

seizures continue for more than 30 seconds,

cians should ask what the patient was doing

with many lasting 1 to 1.5 minutes. Auras,

when the attack began. They should inquire

automatisms, and postictal confusion are

about the first thing that occurred when the at-

common with complex partial seizures but

tack started and what happened next. They

are not characteristic of absence seizures.

also should ask how the patient felt after the

Postictal language difficulty or other focal

episode ended and if any focal weakness or

neurologic signs may be reported after a com-

speech difficulty was present, details that might

plex partial seizure.

reveal the focal nature of the seizure.

An EEG almost always demonstrates ab-

The stereotypy of the attacks is an impor-

normal, repetitive neuronal discharges (spikes)

tant diagnostic point, because for the individ-

during a seizure. In the far more usual case,

ual patient, seizures are highly consistent

when seizures are not occurring, interictal

events. Even when there is more than one

EEGs often show single spikes that often are

seizure type, each type has its own stereotypy.

reported as “epileptiform discharges” on EEG

Significant variation in the pattern of attacks

reports. Such discharges may be focal or dif-

argues against epilepsy.

fuse (“generalized”), depending on the type of

The duration of seizures is generally invari-

epilepsy. Some are so characteristic of specific

ant. Except for brief absence or myoclonic

epilepsy syndromes that an expert electroen-

seizures, which generally last 5 to 15 seconds,

cephalographer may be able to corroborate

most focal or tonic-clonic seizures last 30 to

the likely clinical diagnosis very specifically,

90 seconds. The postictal recovery period de-

given an adequate history. This rule is particu-

pends on the type of seizure, but actual seizure-

larly true in patients with childhood absence

like episodes that last many minutes to hours

epilepsy where the EEG shows characteristic

are usually not epileptic.

three per second discharges and in subjects

Finally, a brief history from a witness is

with complex partial seizures associated with

often crucial. What does the witness see and

focal spikes over the temporal lobe.

how does the attack begin? Patients with com-

Epilepsy, however, cannot be diagnosed by

plex partial seizures sometimes recall the aura

the EEG alone. Although the typical abnormal-

that begins the seizure, but are unaware of the

ity is seen in more than 80% of untreated pa-

subsequent loss of awareness. A witness may

tients with absence seizures, there is a dismaying

provide the crucial description of the blank

50% false-negative rate in a single EEG in pa-

stare and unresponsiveness typical of this type

tients with focal seizures. In addition, the EEG

148

Chapter 9

■ Epilepsy

may be falsely positive in up to 5% to 10% of

■ SPECIAL CLINICAL POINT: Syncope is

children, that is, epileptiform discharges are

easily diagnosed because of the typical

seen although the child does not have nor will

prodrome or trigger and often includes brief

myoclonic jerking.

develop epilepsy. This is seen especially in those

with a family history of epilepsy. Focal epilepti-

Cardiogenic or Stokes-Adams attacks also

form discharges in adults are much more spe-

must be differentiated from seizures. Most pa-

cific, however, occurring in fewer than 2% to

tients with this syndrome are late middle aged

3% of those without active epilepsy or a history

or elderly. The patient usually loses conscious-

of epilepsy.

ness without warning or after brief palpita-

When a diagnosis of epilepsy is made, and

tions. The patient usually falls suddenly and

even after a single first seizure, magnetic reso-

limply to the ground. Syncope from cardiac ar-

nance scanning of the head with infusion is indi-

rhythmias rarely causes incontinence or tongue

cated, unless a specific genetically determined,

biting. The attacks are usually short, and con-

nonfocal epilepsy syndrome is identified with

sciousness is regained quickly and completely.

some assurance. Most patients, even those with

Panic attacks sometimes are mistaken for

focal epilepsy, have normal scans, but up to

seizures, particularly if they include an element

30% demonstrate focal pathology such as corti-

of dissociation reported as altered conscious-

cal migrational abnormalities, mesial temporal

ness. The typical symptom complex of fear,

sclerosis, vascular malformations, infarctions,

chest pain, dyspnea, numbness (especially in

or neoplasms.

the fingertips and lips as a result of hyperventi-

lation), and weakness is not typical of seizures.

Pseudoseizures or psychogenic seizures usually

DIFFERENTIAL DIAGNOSIS

present as seizure-like attacks that do not respond

to antiepileptic drug (AED) treatment. Like true

Neurocardiogenic (vasovagal) syncope is gen-

seizures, pseudoseizures vary from convulsive-like

erally easily diagnosed, because the typical pro-

episodes to transient alterations in consciousness

drome almost always is remembered vividly by

or sensation, but the astute clinician may note in-

the patient. Giddiness, weakness, sweating,

congruous or atypical elements in the history. For

nausea, and fading or graying-out of vision are

example, the person with pseudoseizures resem-

highly suggestive of true syncope. Urinary in-

bling tonic-clonic seizures may report continuing

continence is not rare in syncope; tongue bit-

awareness of surroundings even during the throes

ing, however, is rare and usually implies a

of an attack. Symptoms may vary from episode to

convulsion.

episode. Urinary incontinence and even bodily in-

Witnesses report the victim of syncope as

jury occur with surprising frequency in pseudo-

crumpling or sliding to the ground, whereas

seizures and do not rule out the diagnosis. A firm

the patient with convulsions usually falls stiffly.

diagnosis can be made only with the help of the

Consciousness is regained very quickly after

EEG (see Management of Epilepsy). Pseudo-

syncope, whereas confusion or somnolence is

seizures and true epileptic seizures occasionally

common after seizures. The diagnosis of neuro-

occur in the same patient, making diagnosis and

cardiogenic syncope may be made more diffi-

treatment particularly difficult.

cult by the occurrence of a few myoclonic jerks

during the syncope, which may be reported by

witnesses as seizure activity (so-called “convul-

MANAGEMENT OF EPILEPSY

sive syncope”). A history of the typical pro-

drome and syncopal triggers

(dehydration,

Medical therapy is begun once a diagnosis of

overheating, prolonged standing, micturition)

epilepsy has been firmly established, that is,

will prevent confusion.

after at least two unprovoked seizures (Flow

149

Chapter 9

■ Epilepsy

Chart). The goal of treatment should be com-

TABLE 9.1

plete control of seizures, and the ideal ther-

Treatment of Common Seizure Types

apy is a single drug without side effects. This

Partial (focal) seizures

goal is initially achievable in 70% of patients.

Phenytoin (Dilantin, Phenytek)

Eventually, a substantial minority of patients

Carbamazepine (Tegretol, Carbatrol)

(10% to 30%) will demonstrate refractori-

Valproate (Depakote)

ness to drug therapy, however (see Surgical

Primidone (Mysoline)

Therapies).

Phenobarbital

Gabapentin (Neurontin)

Epilepsy is a fearsome diagnosis for most pa-

Lamotrigine (Lamotrigine)

tients or parents, so the physician should be pre-

Topiramate (Topamax)

pared to spend some time dispensing information

Tiagabine (Gabitril)

about the disorder, its prognosis, expectations of

Oxcarbazepine (Tripleptal)

therapy, problems relating to pregnancy, and

Zonisamide (Zonegran)

safety measures. Informational pamphlets can be

Levetiracetam (Keppra)

acquired from a local or regional Epilepsy Foun-

Pregabalin (Lyrica)

dation office; the phone number for the national

Lacosamide (Vimpat)

office is

800-332-1000, and the Web site is

Absence seizures

www.epilepsyfoundation.org.

Ethosuximide (Zarontin)

The choice of initial treatment depends

Valproate

on an accurate diagnosis of seizure type(s).

Lamotrigine

Absences and myoclonic seizures, for example,

Zonisamide

respond to valproate, lamotrigine, zonisamide,

Levetiracetam

levetiracetam, and topiramate, and these drugs

Myoclonic seizures

also prevent tonic-clonic and focal seizures.

Valproate

Ethosuximide, however, will stop absence

Lamotrigine

seizures but not other seizure types. Most other

Zonisamide

AEDs are effective against the most common

Levetiracetam

seizure types

(i.e., focal seizures and tonic-

Drugs are listed in order of FDA approval, not necessarily by

clonic seizures) (Table 9.1). Treatment of the

preference.

patient with mental retardation, cerebral palsy,

FLOW CHART FOR EPILEPSY EVALUATION AND TREATMENT

Diagnosis of epilepsy: careful history and review of step-by-step events of episodes

Identification of seizure type and syndrome

EEG to confirm diagnosis and/or epilepsy syndrome

MR scan of brain in adults and in children with focal seizures or abnormal

neurologic examination

Initiation of AED

Monitoring patient for seizures, mood disorders, and drug toxicity

150

Chapter 9

■ Epilepsy

or structural cerebral pathology who has multi-

SERUM ANTIEPILEPTIC DRUG LEVELS

ple seizure types or akinetic seizures is particu-

larly challenging and usually requires the

Recommended “therapeutic” serum levels of

assistance of a neurologist or epileptologist.

AEDs are values below which patients have been

Because many AEDs cause side effects if in-

observed to be at risk for seizures, and above

troduced too quickly, standard practice is to

which many patients complain of dose-related

start the chosen AED strictly according to in-

side effects. It is prudent to titrate doses of carba-

structions on the package insert, or even

mazepine, phenytoin, valproate, and the barbi-

slower. This practice involves starting with a

turates to within the usual therapeutic levels.

low dosage and building to a recommended ef-

Optimal therapeutic levels for the other AEDs

fective dose or serum level. An exception is

have not been well established, although clinical

phenytoin, which generally is started at a full,

laboratories provide estimates, and these AEDs

usually well-tolerated, adult daily dosage of

usually are increased to a therapeutic dosage

300 mg/day. In emergency situations such as

(Table 9.2). If seizures or side effects occur, an

initial multiple seizures, intravenous loads with

AED dosage may be increased or decreased care-

phenytoin, valproate, or levetiracetam are all

fully within or even sometimes outside normal

well tolerated.

levels or dosages. If the first AED fails to control

The effective dose of many AEDs is often

the seizures, a second drug may be added; when

very close to the dose that causes side effects,

the dosage is stable, the first, ineffective drug can

and interactions among AEDs themselves and

then be withdrawn slowly.

between some AEDs and other drugs are com-

Serum AED levels also can aid decision mak-

mon. Careful attention to the pharmacokinetics

ing when a patient taking more than one drug

of the AED is essential, and the physician man-

becomes toxic. Drug levels may be helpful if

aging epilepsy must be aware of all drugs that

patient adherence is questionable. When drawn

the patient chronically or intermittently ingests

at the same time of day, and without interfer-

(Table 9.2).

ence from other medications or illness (e.g.,

TABLE 9.2

Properties of AEDs

AED

Plasma Half-Life

% Protein Bound

Target Levels (μg/mL)

Ethosuximide

30-60

<10

40-100

Gabapentin

5-9

4-16

Lamotrigine

15-24^a

55^a

2-20

Levetiracetam

<10

20-60

Oxcarbazepine

10-15

5-50

Phenobarbital

65-110

10-30

Phenytoin

10-24

10-20

Primidone

8-15

<20

4-8

Tiagabine

2-9

5-70

Topiramate

12-30

2-25

Valproate

5-15

70-90

50-150

Zonisamide

50-70

10-40

^a60 hours when used with valproate.

AED, antiepileptic drug.

151

Chapter 9

■ Epilepsy

gastrointestinal upsets), AED levels are usually

always be aware of possibly significant pharma-

remarkably stable from sample to sample.

cologic interactions with other drugs (e.g., war-

farin [Coumadin], certain antimicrobials). These

drugs reduce the serum levels of valproate, lamot-

rigine, topiramate, tiagabine, zonisamide, oxcar-

SOME INDIVIDUAL

bazepine, and each other.

ANTIEPILEPTIC DRUGS

Valproate is generally tolerated well, but side

Although some general principles govern their

effects such as weight gain and tremor are com-

use, individual AEDs vary enough in their metab-

mon, and alopecia can present a problem. Fatal

olism, side effects, and interactions with other

toxic hepatitis has been reported, mainly in

drugs to require separate comment. Carbamazepine,

young children on polytherapy during the first

especially in one of its long-acting forms, is an

6 months of use; the drug is not recommended

older AED still used commonly for focal or tonic-

for children younger than 2 years of age. Blood

clonic seizures. A readily reversible rash occurs in

levels tend to vary more than they do with other

about 3% to 5% of patients, but serious hypersen-

anticonvulsants, so they are less useful. Drug in-

sitivity reactions are rare. Early, mild leucopenia

teractions with valproate may be significant: it is

may be seen but is generally reversible and is only

an inhibitor of certain liver metabolic pathways,

rarely a significant problem. Predictable, re-

and the drug dramatically raises the serum level

versible, dose-related side effects are blurred vi-

of lamotrigine. Valproate’s metabolism may be

sion, diplopia, and nausea. Chronic side effects

enhanced by enzyme-inducing medications in-

may include macrocytosis, low-normal serum

cluding phenytoin and carbamazepine.

levels of folate, and hyponatremia.

Since 1993 many new AEDs, most of them

Despite common long-term side effects,

pharmacologically unrelated to older AEDs, have

phenytoin is still often prescribed. It is avail-

become available for treatment of seizure disor-

able in a parenteral form, a loading dose is well

ders

(i.e., lamotrigine, topiramate, gabapentin,

tolerated, and most adults achieve a therapeu-

tiagabine, zonisamide, oxcarbamazepine, leve-

tic blood level on a “standard” 300 mg/day

tiracetam, pregabalin, and lacosamide). All are

dosage. Dose-related toxicity typically includes

U.S. Food and Drug Administration-approved as

nystagmus, tremor, and ataxia. Elevated serum

treatment of focal

(partial) and tonic-clonic

alkaline phosphatase, macrocytosis, and low

seizures. All but gabapentin, pregabalin, tiagabine,

serum T₄ (but normal thyroid-stimulating hor-

and lacosamide have been successfully used for

mone) are common and require no action. The

treatment of absence and myoclonic seizures

metabolism of phenytoin is saturable, so that

as well. The “therapeutic” blood levels of these

small increases in dosage within the therapeu-

AEDs show much wider variation than those of

tic range may cause disproportionately large

the older drugs and may not be as clinically useful.

increases in serum levels. Therefore, changes in

Many of these drugs offer some advantages in

daily doses should be no more than 25 to 50

terms of fewer drug interactions. All are consider-

mg at one time. The common long-term cos-

ably more costly than the older AEDs, but most

metic effects of phenytoin, which include acne,

are available as generic preparations.

hirsutism, gingival hyperplasia, and possibly

Gabapentin and pregabalin are derivatives

coarsening of facial features may be significant,

of gamma-aminobutyric acid

(GABA), the

especially in children.

main inhibitory neurotransmitter of the brain.

Both carbamazepine and phenytoin, along

They demonstrate no interactions with other

with the now little used phenobarbital and primi-

drugs and are therefore very useful in the eld-

done, are powerful inducers of certain P450 he-

erly, who are often taking a variety of other

patic enzymes, and phenytoin is strongly protein

pharmaceuticals. The most common dose-re-

bound, so physicians prescribing these drugs must

lated side effect is drowsiness. Patients should

152

Chapter 9

■ Epilepsy

be warned that weight gain is common with

tion deficit disorder is a frequent accompani-

chronic use.

ment in children, and learning disorders are

Lamotrigine must be introduced very slowly

common and generally underdiagnosed.

to reduce the incidence of skin rash to a tolerable

Long-term use of the enzyme-inducing

3% to 4%. Titration and doses must be moder-

AEDs has convincingly been shown to increase

ated, when valproate also is used, because of

the risk of bone thinning and folate deficiency.

pharmacokinetic interactions. It is generally well

Relatively higher serum cholesterol levels, and

tolerated, although insomnia may limit its use.

low levels of folate, have consistently been ob-

Dose-limiting side effects include diplopia, nau-

served as well. The metabolism of some B vita-

sea, and dizziness.

mins may also be increased. Similar adverse

Levetiracetam can be introduced at a thera-

effects on bone metabolism have been shown

peutically effective dose of 1000 mg/day. It is

with valproate. For these reasons, patients on

generally well tolerated, although high doses

enzyme-inducing AEDs or valproate should be

can be associated with changes in mood or

given supplemental calcium with vitamin D

even cognition.

(e.g., 500 mg twice a day), and those on en-

Oxcarbazepine is a derivative of carbamazepine,

zyme inducers should take a daily multivita-

with the advantage of fewer drug interactions

min. Early bone density scans for both men

and with a similar side effect profile. Hypona-

and women are increasingly recommended.

tremia may be a problem, especially in the eld-

■ SPECIAL CLINICAL POINT: Standard

erly or in those with already low serum sodium.

practice is to add a multivitamin and

Topiramate and zonisamide are sulfonamide

supplemental calcium with vitamin D when

derivatives, with topiramate especially requiring

patients take valproate or an enzyme-

slow dose titration to minimize cognitive and

inducing AED.

behavioral side effects. Weight loss with chronic

For “rescue” therapy in patients with clusters

use may be considerable. The concomitant use

of seizures, prepackaged syringes of diazepam

of hepatic enzyme-inducing drugs such as

gel for rectal use are safe for home use and are

phenytoin or carbamazepine significantly low-

very effective. Oral lorazepam (usually 1-2 mg

ers the blood level of these drugs. Nephrolithia-

for adults) can also be used, but takes longer to

sis has been reported.

be effective.

Tiagabine is another GABA agonist, whose

metabolism is briskly enhanced by enzyme-in-

ducing drugs, and its dose must be managed

SURGICAL THERAPIES

accordingly. Twice-a-day dosing has been

shown to be effective.

A novel treatment for drug-resistant epilepsy is

vagus nerve stimulation, shown to be effective

in treating partial and tonic-clonic seizures.

This pacemaker-like device is implanted subcu-

COMPLICATIONS OF EPILEPSY

taneously, and it operates both by programmed,

AND ANTIEPILEPTIC DRUGS

intermittent stimulation and by being switched

The psychosocial complications of epilepsy may

on when a seizure is felt or seen to begin.

be significant, even in the absence of other obvi-

Although about 30% of patients improve with

ous cerebral pathology. The prevalence of major

vagus nerve stimulation, it is always used with

depression and anxiety is high; the incidence

concomitant AEDs, and complete cessation of

of suicide is about double that in the general

seizures is unusual.

population. Complaints of significant memory

If three appropriate AEDs at therapeutic

deficits for recent events are almost universal in

dosages fail to control epilepsy in adults or

those with focal limbic system epilepsy and can

children, the possibility of surgical therapy

worsen if uncontrolled seizures persist. Atten-

should be considered because continued drug

153

Chapter 9

■ Epilepsy

resistance to multiple therapies is likely. The

hanced by phenytoin, carbamazepine, and

most common procedure is temporal lobectomy,

the barbiturates. Because inadequate mater-

which has a low morbidity and a high probabil-

nal folate has been associated with spinal bi-

ity of complete cessation of seizures, particularly

fida, supplemental folic acid should be given

in patients with mesial temporal sclerosis.

to all women of reproductive capacity taking

these drugs.

All of the AEDs that have been studied

STOPPING ANTIEPILEPTIC DRUGS

have been shown to increase the rate of fetal

malformations by about a factor of 2, and all

Many epilepsies, particularly those beginning

AEDs are category C or D drugs in preg-

in childhood, eventually go into remission. The

nancy. Valproate has been associated with a

point at which AEDs may be safely stopped in

significant increased risk of midline neural

well-controlled patients is debatable. A seizure-

tube defects. Because of the serious risks of

free period of 2 years in children and 3 years in

seizures during pregnancy, however, most

adults is considered a reasonable time at which

women with epilepsy continue to use an AED

to consider a trial without drugs. Permanent

when pregnant. Stopping or changing an

remission rates in children with absence

AED after pregnancy is discovered generally

epilepsy reach 80% to 90%, but relapse is the

is not advised. Serum AED levels characteris-

rule in juvenile myoclonic epilepsy. Drug with-

tically fall during pregnancy and need careful

drawal fails in the more common adult focal

monitoring.

epilepsies in 30% to 50% of cases.

SPECIAL CHALLENGES FOR

DIETARY AND ALTERNATIVE OR

MANAGING HOSPITALIZED PATIENTS

REHABILITATIVE TREATMENTS

Patients with epilepsy who are admitted to

The ketogenic diet and its variants are high-

hospital for other conditions should have their

fat, low-protein/carbohydrate diets sometimes

routine AEDs continued. Currently, the only

used for short periods in children with in-

chronically used AEDs available in parenteral

tractable epilepsy. It customarily is initiated

form are phenytoin, valproate, levetiracetam,

and supervised by a pediatric neurologist, usu-

phenobarbital, and lacosamide. If patients

ally with the assistance of a dietitian experi-

cannot take their usual AED by mouth for

enced in its use. No other dietary changes,

herbs, or supplements have been found to help

in the treatment of epilepsy.

Always Remember

Hypnosis has been successful in isolated

cases but is not customarily used. In the absence

• Epilepsy is diagnosed by taking a careful

of complications, no specific physical or occu-

history.

pational rehabilitation is necessary in treating

• Almost all adult onset epilepsies are focal in

epilepsy.

nature, so MR scanning of the brain is

essential.

• Complete cessation of seizures using a single

WOMEN AND EPILEPSY

AED without side effects is the goal of

therapy for all patients.

Phenytoin, carbamazepine, the barbiturates,

• Failure of two AEDs suggests that the

and topiramate all enhance the metabolism

diagnosis may be incorrect or that the patient

of oral contraceptive hormones; high-dose

has intractable epilepsy requiring referral to a

preparations with 50 g of estradiol are rec-

neurologist.

ommended. Folate metabolism also is en-

154

Chapter 9

■ Epilepsy

more than 24 hours, a parenteral AED should

The correct answer is A. In focal epilepsy,

be used, preferably with the help of a neurolo-

groups of hyperirritable neurons, perhaps

gist. Many surgical procedures will interrupt

affected by loss of inhibitory input, excessive

oral AED therapy by less than a day, and the

excitatory activity, and anatomic distortions,

usual drug simply may be resumed as soon as

overact and are able to hypersynchronize the

the patient is able to take it.

activity of other neuronal populations. This

activity spreads and causes focal or even

generalized seizures.

WHEN TO REFER THE PATIENT

3. High blood levels of phenytoin usually are

TO A NEUROLOGIST

accompanied by:

Although most patients with epilepsy are helped

A. Somnolence

to achieve substantial control of seizures, at

B. Hair loss

least 10% to 30% of patients on optimal drug

C. Ataxia

therapy continue to have seizures serious or fre-

D. Pulmonary edema

quent enough to cause major disruptions to life.

E. Weakness

If seizures have not been completely controlled

The correct answer is C. Ataxia is much more

after 2 years, or if the patient has failed to re-

common than somnolence. Sedation is caused

spond to two AEDs, such patients should be re-

by phenytoin only at extremely high levels, as

ferred to a neurologist or epilepsy center. Some

would be caused by deliberate overdosing.

of these patients turn out to have disorders other

Hair loss may occur with valproate but not

than epilepsy; some have types of seizures re-

with phenytoin. Neither pulmonary edema

sponsive to more appropriate AEDs; others are

nor muscle weakness is typical of phenytoin

appropriate for surgical therapy.

effect. Ataxia is seen in most patients with

blood levels higher than 30 mg/dL.

4. The true statement about vagal nerve

QUESTIONS AND DISCUSSION

stimulation for epilepsy control is:

A. Approximately 30% of patients

1. Patients with primary generalized epilepsy

undergoing this procedure improve.

may have which of the following types of

B. The aim of vagal nerve stimulation is to

seizures?

eliminate AEDs.

A. Absence

C. The treatment is not useful to treat

B. Myoclonic

partial and tonic-clonic seizures.

C. Grand mal

D. The stimulator is limited because

D. All of the above

patients cannot turn on the stimulator at

E. None of the above

the time of their seizure onset, even if

The correct answer is D. Patients may have

they have a well-defined aura.

any combination of these seizures. Sometimes

The correct answer is A. A novel treatment

grand mal attacks are preceded or led into by

for drug-resistant epilepsy is vagus nerve

clusters of absence or myoclonic spells.

stimulation, shown to be effective in treating

2. The physiologic substrate of clinical seizure

partial and tonic-clonic seizures. This

activity is:

pacemaker-like device is implanted subcuta-

A. Abnormal neuronal discharge

neously, and it operates both by programmed,

B. Hyperactive glial potentials

intermittent stimulation and by being

C. Repeated disturbances in cerebral blood

switched on when a seizure is felt or seen to

flow

begin. Although about 30% of patients im-

D. Excessive gabaergic activity

prove with vagus nerve stimulation, it is

155

Chapter 9

■ Epilepsy

always used with concomitant AEDs, and

Duncan JS, Sander JW, Sisodiya SM, et al. Adult epilepsy.

Lancet. 2006;367:1087-1100.

complete cessation of seizures is unusual.

French JA, Pedley TA. Initial management of epilepsy. N

Engl J Med. 2008;359:155-176.

SUGGESTED READING

Haut SR, Shinnar S. Considerations in the treatment of

a first unprovoked seizure. Semin Neurol. 2008;28:

Amar AP. Vagus nerve stimulation for the treatment of

289-296.

intractable epilepsy. Expert Rev Neurother. 2007;7:

1763-1773.

LaFrance WC Jr, Kanner AM, Hermann B. Psychiatric co-

morbidities in epilepsy. Int Rev Neurobiol. 2008;83:

Arif H, Hirsch LJ. Treatment of status epilepticus. Semin

347-383.

Neurol. 2008;28:342-354.

Sirven JI. Acute and chronic seizures in patients older

Brodie MJ, French JA. Management of epilepsy in adoles-

than 60 years. Mayo Clin Proc. 2001;76:175-183.

cents and adults. Lancet. 2000;356:323-329.

Tomson T, Hiilesmaa V. Epilepsy in pregnancy. Brit Med

Cross JH, Jayakar P, Nordli D, et al.; International

J. 2007;335:769-773.

League against Epilepsy, Subcommission for Paediatric

Epilepsy Surgery; Commissions of Neurosurgery and

Wyllie E, Gupta A, Lachhwani DK. The Treatment of

Paediatrics. Proposed criteria for referral and evalua-

Epilepsy: Principles and Practice. 4th ed. Philadelphia:

tion of children for epilepsy surgery: recommendations

Lippincott Williams & Wilkins; 2005.

of the Subcommission for pediatric epilepsy surgery.

Epilepsia. 2006;47(6):952-959.

Sleep Disorders

RUŽICA KOVA

EVIC´ -RISTANOVIC´

AND TOMASZ J. KUZ´NIAR

key points

• Insufficient sleep time and sleep apnea are the two

most common causes of excessive daytime sleepiness.

• Obstructive sleep apnea is suspected on the basis of

snoring and excessive daytime sleepiness.

• Obstructive sleep apnea may be associated with

significant morbidity related to sleepiness and

morbidity/mortality related to its cardiovascular effects.

• Taking a good sleep history is a key to diagnosis and

the first step to successful treatment of insomnia.

• Narcolepsy typically presents in an adolescent/young

adult with excessive sleepiness, sleep attacks, and

cataplexy.

leep is a subject

neurons [TMN] projecting widely to the cor-

that has fascinated physicians and the public

tex). Structures found to facilitate waking are

since antiquity. A search for a “sleep center” in

wake-promoting hypocretin

(orexin) system

the brain has demonstrated the complexity of

and the ascending reticular-activating system

the sleep process, the multiplicity of structures

of the pons and midbrain and posterior hypo-

involved in sleep, and the reciprocal interac-

thalamus. The role of the hypothalamus has

tions necessary for the initiation and mainte-

been revised recently since the discoveries of

nance of this behavior.

sleep-promoting GABA/galanin activity in the

The structures found to facilitate sleep are

VLPO and wake-promoting hypocretin (orexin)

the basal forebrain (i.e., the preoptic area of

system activity in the dorsolateral hypothalamus

the hypothalamus, specifically the ventrolat-

around the perifornical nucleus. Although no di-

eral preoptic nucleus [VLPO], promoting sleep

rect interaction between the VLPO and hypocre-

via gamma-aminobutyric acid [GABA]/galanin

tin systems is reported, both systems innervate

activity), the area surrounding the solitary

the main components of ascending arousal sys-

tract in the medulla, and the midline thala-

tems such as adrenergic locus coeruleus (LC),

mus. It has been proposed that the sleep-

serotonergic dorsal raphe (DR), dopaminergic

promoting role of the anterior hypothalamus

ventrotegmental area (VTA), and histaminergic

results from its inhibitory action on the pos-

TMN. The VLPO (GABA/galanin) system inhibits

terior hypothalamic awakening neurons nu-

and the dorsolateral hypothalamic (hypocretin

clei (mainly tuberomammillary histaminergic

[orexin]) system activates these “arousal” systems.

156

157

Chapter 10

n Sleep Disorders

Destruction of the VLPO system results in in-

Most current treatments for sleep disorders do

somnia, whereas destruction of the hypocretin

not relate to the known neurochemical sub-

system results in narcolepsy

(hypersomno-

strates for sleep. Even more important, the myr-

lence/sleep attacks and cataplexy). The control

iad effects of currently used medications on

of alternating sleep stages (NREM [nonrapid

sleep (those used to alter sleep and those used

eye movement]/REM [rapid eye movement]

for an unrelated purpose) should be understood.

cycling) is attributed to interaction between an-

The important clinical, diagnostic, and ther-

tagonistic aminergic and cholinergic systems in

apeutic features of some sleep disorders are de-

the brainstem. The aminergic and cholinergic

scribed in this chapter. Useful guidelines for

systems also are involved in the process of cor-

diagnosis and therapy also are presented, al-

tical activation of arousal. In addition to the

though there are few universally accepted

previously mentioned systems, the dopaminer-

treatments for common sleep complaints.

gic system is involved in control of alertness as

well, especially the ventral tegmental area

SLEEP ARCHITECTURE

(A10). Dopaminergic neurons of the VTA but

not substantia nigra

(SN) are excited by

Because the workup of many patients with

hypocretins, and there is a greater hypocretin

sleep disorders involves the use of a sleep labo-

innervation of the VTA than SN. Dopaminer-

ratory, it is important to understand the tests

gic neurons in the ventral periaqueductal gray

available and the parameters measured. A por-

(PAG) also are activated during wakefulness.

tion of the sleep recording, referred to as a

The dopaminergic system, including the de-

polysomnogram (PSMG) of a normal subject, is

scending A11 projection, may be particularly

shown in Figure 10.1. Three basic parameters

important for sleep disorders accompanied by

are needed to define the stage of sleep: an elec-

anomalies of sleep-related motor control (cata-

troencephalogram (EEG), an electro-oculogram

plexy and periodic limb movement [PLM] dis-

(EOG), and an electromyogram (EMG). The

order). Circadian sleep rhythm is modulated by

normal EEG of an alert, resting subject with

the hypothalamic suprachiasmatic nucleus

closed eyes shows an 8- to 12-Hz posterior ac-

(SCN). The SCN sets the body clock period to

tivity known as alpha. Two major sleep stages

approximately 25 hours, with the light and

are distinguished: NREM and REM sleep; the

schedule cues (zeitgebers, “time givers”) entrain-

nomenclature of NREM sleep has recently

ing it to 24 hours. The retinohypothalamic tract

changed. Electroencephalographically NREM

conveys light stimuli to the SCN that directly

sleep has three stages. Stage N1 sleep is the

influences its activity. Melatonin has been im-

stage of NREM sleep that directly follows the

plicated as a modulator of light entrainment be-

awake state. An EEG shows a low-voltage trac-

cause it is secreted maximally during the night by

ing of mixed frequencies predominantly in the

the pineal gland (hormone of darkness). Thus,

theta band with alpha activity less than 50%,

the anterior hypothalamus may serve as a center

vertex sharp activity, and slow eye movements.

for “sleep switch” under the influence of the cir-

Stage N2 sleep is the stage of NREM sleep that

cadian clock.

is characterized by the presence of sleep spin-

Understanding the neurochemistry of sleep is

dles (12 to 14 Hz) and K-complexes against a

important for practical reasons. The discovery

relatively low-voltage, mixed-frequency back-

of the involvement of different neurotransmit-

ground. High-voltage delta waves may consti-

ters and neuromodulators in control of arousal

tute up to

20% of N2 sleep. In the new

and sleep has raised the possibility of more

diagnostic description of stage N3 of NREM

specific treatments of sleep disorders

(e.g.,

sleep, at least 20% of the period consists of

hypocretin agonists and/or GABA/galanin an-

EEG waves less than 2 Hz; this stage is com-

tagonists for treatment of excessive sleepiness).

monly referred to as slow wave sleep. Stage N3

158

Chapter 10

n Sleep Disorders

FIGURE 10.1 A typical eight-channel polysomnogram recorded from a normal adult man in stage 2

of nonrapid eye movement sleep. Electro-oculogram (ROC/LOC) recorded from right outer canthus

referred to left outer canthus; electroencephalogram (EEG) (C4/A2) recorded from the right central

lead referred to the right mastoid; electromyogram (EMG) recorded from the submental musculature;

arterial oxygen saturation (O2SAT) transduced by an ear oximeter; nasal and oral airflow (N/OT)

recorded by a thermocouple mounted in a plastic respiratory mask; thoracic movement (TSG) recorded

by a strain gauge; heart rate recorded by a cardiotachometer; electrocardiogram (ECG) recorded from

V5 referred to the left mastoid.

sleep occurs predominantly in the first third of

ratory rate, heart rate, and blood pressure, and,

the sleep period (Fig. 10.2).

more importantly, much more pronounced

REM sleep alternates with the NREM sleep

variability throughout the REM period. In

at about 90-minute intervals in adults and

about 80% of awakenings from REM sleep,

60-minute intervals in infants. The EEG pattern

people recall vivid dreams, compared to only

during REM sleep resembles stage 1 sleep but is

5% of awakenings from NREM sleep. How-

accompanied by REMs. In addition, EMG ac-

ever, in about

60% to 80% of awakenings

tivity is low. There is a general activation of the

from NREM sleep, people may recall thought-

autonomic system, with a higher average respi-

like fragments. Population studies have shown

159

Chapter 10

n Sleep Disorders

FIGURE 10.2 The sleep architecture of a normal adult man. The progression of electroencephalogram

(EEG) stages of sleep demonstrates a concentration of stages 3 and 4 within the first half of the sleep

period. Episodes of rapid eye movement (REM) sleep occur at approximately 90-minutes intervals, and

the majority of REM appears within the latter half of the sleep period. Waking arousals are few.

that the percentage of time spent in each stage

will result in improved classification along the

varies with age and sex. Figures 10.1 and 10.2

lines of pathology.

represent a sleep PSMG and architecture plot

from a normal adult.

SLEEP DISORDERS ASSOCIATED

WITH INSOMNIA

CLASSIFICATION OF SLEEP

Insomnia is a perception of inadequate, dis-

ABNORMALITIES

turbed, insufficient, or nonrestorative sleep

The recently updated international classifica-

despite an adequate opportunity to sleep,

tion of sleep disorders (International Classifi-

accompanied by daytime consequences of

cation of Sleep Disorders-2, ICSD-2) divides

inadequate sleep. A Gallup phone survey

sleep disorders into (a) insomnias, (b) sleep-

found that

36% of Americans suffer from

disordered breathing,

some type of sleep disorders. Occasional in-

central origin, (d) circadian rhythm disorders,

somnia was reported by 27% of respondents,

(e) sleep-related movement disorders, and (f)

and chronic insomnia was reported by 9%.

parasomnias. The most common clinical cor-

Among the intrinsic sleep disorders are psy-

relates of these disorders are insomnia and

chophysiologic insomnia, sleep-state misper-

excessive daytime sleepiness, although some

ception

(paradoxical insomnia), restless legs

sleep disorders do not cause any daytime

syndrome and idiopathic insomnia, all of

symptoms. Future advances in the understand-

which produce the complaint of insomnia.

ing of the pathophysiology of sleep disorders

Similarly, many extrinsic sleep disorders such

160

Chapter 10

n Sleep Disorders

as inadequate sleep hygiene, environmental

A conditioned internal factor also may develop

sleep disorder, altitude insomnia, adjustment

in the form of apprehension about unsuccessful

sleep disorder, limit-setting sleep disorder, food

and excessive efforts to sleep. Conscious efforts

allergy insomnia, hypnotic-dependent sleep

to fall asleep result in CNS arousal. These pa-

disorder, alcohol-dependent sleep disorder,

tients consider themselves

“light sleepers.”

and sleep-disordered breathing are likely to be

They often have multiple somatic complaints

accompanied by insomnia. Among circadian

such as back pains, headaches, and palpitations

rhythm sleep disorders, delayed sleep-phase

that lead to occasional abuse of alcohol, barbi-

syndrome is associated with a complaint of

turates, minor tranquilizers, and hypnotics. The

sleep-onset delay, whereas advanced sleep-

sleep of such patients in the sleep laboratory is

phase syndrome is accompanied by a complaint

usually better than at home because the condi-

of early awakening. In general, the pattern of

tioning factors that are active at home are

insomnia may be primarily (a) difficulty falling

reduced in the laboratory. Multiple specific psy-

asleep

(sleep-onset delay, sleep-onset insom-

chiatric illnesses associated with anxiety, such

nia),

(b) early morning arousal

(premature

as personality disorders (e.g., anxiety and panic

awakening, terminal insomnia), or (c) prema-

disorders, hypochondriasis, obsessive-compul-

ture awakening(s), sleep fragmentation with

sive disorders), and schizophrenia, also can be

inability to fall asleep again (sleep-maintenance

associated with sleep-onset difficulty.

insomnia).

Drugs also can compromise the initiation of

Insomnias can be transient or acute (lasting

sleep. When obtaining a history, the physician

less than 3 to 4 weeks) or chronic (lasting longer

should inquire specifically about possible pre-

than that). Multiple factors can trigger transient

cipitants of drug-induced insomnia. In addition

insomnia, including life stress, brief illness,

to steroids and dopaminergic agents, xanthine

rapid change of time zones, drug withdrawal,

derivatives (e.g., caffeine and theophylline) may

use of central nervous system (CNS) stimulants,

cause sleep disruption. A frequently overlooked

and pain. Transient insomnia is experienced by

class of agents is the beta-adrenergic agonists,

everyone, and recovery usually is rapid.

such as terbutaline and phenylethylamine deriv-

Chronic insomnia may be lifelong. It usually

atives

(used as stimulants, appetite suppres-

is related to chronic psychophysiologic arousal,

sants, and decongestants). If such medications

psychiatric disorders, use of drugs and alcohol,

are taken late in the day, and in increasing

and other medical, toxic, and environmental

amounts because of the development of toler-

conditions. However, it also may represent a

ance, they easily can cause sleep-onset delay as

primary sleep disorder in the form of sleep

well as sleep fragmentation and “lightening” of

apnea syndrome, alveolar hypoventilation syn-

sleep. Such inadequate sleep provokes daytime

drome, PLMs of sleep, and RLS.

symptoms such as sleepiness, which is responsi-

ble for a further increase of ingestion of the

drug to promote alertness.

In addition to the psychologic and drug-

SLEEP-ONSET DELAY

induced causes of sleep-onset delay, patients

Sleep-onset delay is a common problem and

who have a disturbed circadian rhythm may

probably accounts for most patients who pres-

have the same sleep complaint. In delayed

ent with a complaint of insomnia. It usually has

sleep-phase syndrome, patients naturally fall

psychogenic causes. Sleeplessness may develop

asleep at 2 or 3 AM or later. They cannot fall

from a continued association with stimulating

asleep if they go to bed at conventional times.

practices and objects at bedtime. Such patients

If they must get up for a job or school at 6 AM,

sleep better away from their bedrooms and

they will be sleepy in the morning. However,

usual routines, for example, while on vacation.

they have no trouble going to sleep and getting

161

Chapter 10

n Sleep Disorders

full rest if they can go to bed late and sleep

apnea, aging, and alteration in the circadian

until midday. This pattern is characteristic (and

rhythm. Treatment then should be based on

probably physiological) in late adolescence and

concurrent problems, age, and hepatic and

early adulthood. A change in lifestyle and a

renal function. The mainstay of treatment is

course of chronotherapy at a sleep disorder

the exploration and correction of maladaptive

center can correct this problem. Delayed sleep-

nighttime behaviors. This behavioral therapy,

phase syndrome may also be treated with a

typically involving a series of meetings with

morning session of bright light, which may be

the managing physician or therapist can be

combined with an early evening dose of mela-

supplemented with carefully chosen, typically

tonin. Similarly, evening exposure to bright

short-term, pharmacological therapy. Specific

light and light restriction in the morning (wear-

interventions that are typically used in this set-

ing dark goggles) may be useful in treatment of

ting are discussed below.

advanced sleep-phase disorder. Chronother-

n SPECIAL CLINICAL POINT: In treating

apy, an individually designed sleep schedule

sleep-onset delay, pharmacologic treatment

consisting of a gradual sleep-onset time delay

should be used judiciously and should be

until a desired time is reached, may also help

combined with nonpharmacologic treatments.

patients with irregular sleep-wake patterns,

who sleep for short and variable periods

Counseling plays an important role in the ther-

throughout the 24 hours. These people have

apy of sleep disorders. If the physician spends

difficulty falling asleep at conventional times

time talking with these patients, he or she may

because they have napped recently. Shift work-

find that they actually are attempting to discuss

ers and those who travel frequently across time

problems that they find difficult to raise, such as

zones often experience sleep-onset delay (in ad-

impotence, marital discord, or alcoholism in a

dition to jet lag) and may also benefit from a

family member. The complaint may be resolved

combined bright light-melatonin treatment.

if attention is given to these problems, regardless

Similar delay in sleep onset may result from

of whether sleep behavior actually is altered.

misalignment between the natural body’s circa-

Sleep hygiene includes setting a fixed hour

dian rhythm and work schedule (shift work

for retiring each night, eliminating daytime

disorder). Other conditions that may induce

naps, avoiding drinking caffeine-containing

similar clinical presentation of troubles falling

beverages and engaging in anxiety-producing

asleep and/or sleepiness include jet lag disorder,

activities at night, and ensuring that the bed-

and irregular circadian rhythm sleep disorders,

room is quiet, dark, and comfortable. Because

related to either lack of sleep hygiene. Infre-

patients may not think of over-the-counter

quent free-running circadian sleep rhythm dis-

preparations as drugs, mentioning the need to

order is most frequently seen in blind persons;

avoid sympathomimetic substances may prove

lack of entrainment of the circadian rhythm re-

fruitful. Physical exercise is advised, if taken at

sults in non-24-hour rhythm.

least a few hours before bedtime.

Only a few practical points concerning be-

havioral therapies need to be reviewed here.

Treatment

Techniques that attempt to increase relaxation,

The treatment of chronic insomnia is a signifi-

either through biofeedback or more conven-

cant challenge. It is highly individualized, and

tional learning paradigms, may be valuable if

no uniform approach can be recommended.

they are aimed at a specific physiologic distur-

The physician should first identify any underly-

bance. For example, a patient whose PSMG in-

ing conditions, which may include psychiatric

dicates a large amount of muscle activity prior

disorders such as depression, alcohol or sub-

to falling asleep might benefit from EMG

stance abuse, chronic medical disorders, sleep

biofeedback. These techniques generally will

162

Chapter 10

n Sleep Disorders

require the facilities of a sleep laboratory. At-

notic drug should decrease sleep latency and

tempts at operant and classic conditioning as

increase the total sleep time. The value of a

aids in treating insomnia also have had some

hypnotic depends on the balance of its efficacy

limited success. A widely accepted behavioral

and side effects. The efficacy is defined by its

modification technique—stimulus control—is

ability to induce and maintain sleep, and it di-

especially useful in correcting maladaptive as-

rectly depends on the drug’s dose, absorption,

sociation of arousal with bedtime routine.

and duration of action. Thus, an efficacious

Other techniques aimed at reducing tension in-

hypnotic is absorbed rapidly and has duration

clude progressive muscular relaxation and au-

of action consistent with the sleep period (usu-

togenic training.

ally around 8 hours). Ideally, such a hypnotic

Sleep restriction relies on restricting time

has no adverse effects. However, hypnotics

spent in bed to the estimated sleep time the

with duration of action that exceeds the sleep

patient accumulates during the night, as docu-

period usually lead to residual sedation during

mented by sleep logs, and then gradually in-

daytime. In contrast, use of short-acting hyp-

creasing it until an optimal sleep time is

notics in doses higher than required often is as-

achieved. This treatment is based on the obser-

sociated with major adverse effects such as

vation that insomniacs spend too much time in

rebound insomnia and anterograde amnesia.

bed in an attempt to obtain more sleep. Reduc-

Dependence is also an undesirable possibility

tion of time spent in bed leads to a state of mild

with the use of hypnotics. This possibility can

sleep deprivation, which is likely to result in

be minimized by the intermittent use of low

faster sleep onset, improved sleep continuity,

doses, together with limited duration of drug

and deeper sleep. Stimulus control therapy is a

intake and gradual withdrawal if treatment has

formal set of behavioral advices and entails

been continuous for more than a month. The

going to bed only if sleepy, getting out of bed

available drugs have a surprisingly heteroge-

when unable to sleep, using the bed and bed-

neous set of effects on sleep architecture.

room for sleep only, arising at the same time

Although almost all agents used as hyp-

every morning, and avoiding naps.

nosedatives will suppress REM sleep when given

Cognitive therapy focuses on maladaptive

in sufficiently large quantities, two patterns of

thoughts that produce an emotional arousal,

effects are seen at lower doses. Barbiturates,

such as unrealistic expectations about sleep re-

chloral hydrate, anticholinergics, tricyclics, and

quirements, negative consequences of insom-

ethanol demonstrate REM suppression, whereas

nia, and misattributions of daytime difficulties

most benzodiazepines decrease stage N3 sleep.

to poor sleep.

They all appear to decrease sleep latency and re-

Pharmacologic treatment can be used in the

duce the number of spontaneous awakenings.

management of insomnia; however, the use of

Although the drugs that have the least effect on

medications must be considered carefully.

sleep architecture may offer a theoretic advan-

These medications are most helpful when their

tage in the therapy of insomnia, there is no clear

use is self-limited, such as during acute hospi-

demonstration that they induce “better” sleep.

talization or as part of a more comprehensive

Data on commonly used sleep-promoting med-

program of sleep hygiene. In the latter case,

ications and some miscellaneous agents are sum-

they may allow the physician time to explore

marized in Table 10.1.

the roots of the sleep disturbance more thor-

Sleep latency usually is decreased with these

oughly and implement behavioral treatments.

agents, and there is seldom a reason to use more

The choice of a sedative agent is dictated

than a single agent in the treatment of insom-

primarily by the duration of clinical sedation;

nia. A failure to obtain an adequate response on

ideally, the hypnosedative effect should cease

the first night does not imply a need to increase

by the time the patient arises. An effective hyp-

the dosage immediately; a trial of at least two

163

Chapter 10

n Sleep Disorders

TABLE 10.1

Commonly Used Sleep-Promoting Medications

Initial

Maintenance

Drug Name

Dose (mg)

Drug Interactions

Temazepam^a

7.5-15

15-30

Combination contraceptives may stimulate

glucuronide conjugation of temazepam

Estazolam^a

1-2

Ketoconazole inhibits CYP 450 3A and 2C family of

enzymes

Triazolam^a

0.125

Usually 0.25

Drugs inhibiting cytochrome P450 CYP 3A such as

ketoconazole, itraconazole and nefazodone, and

erythromycin

Lorazepam^a

1-2

Combination contraceptives may increase

glucuronidation; quetiapine reduces the clearance

Alprazolam

0.25

0.5

Drugs that inhibit alprazolam’s metabolism via CYP

450 3A including fluoxetine, propoxyphene,

diltiazem, isoniazid, and macrolide antibiotics

Clonazepam

0.5-1

1-2

Cytochrome P450 inducers such as phenytoin,

carbamazepine, and phenobarbital cause a 30%

decrease in plasma clonazepam levels; inhibitors of

P450 family of enzymes, such as oral antifungal

agents, should be used cautiously

Chlodiazepoxide^a

5-10

10-25

Antacids slow absorption; disulfiram inhibits its

hepatic metabolism (hydroxylation and dealkylation);

ketoconazole reduces its clearance

Zolpidem

5-10 (6.25)^b

10-20 (12.5)^b

Potent inducers of CYP 450 3A4 (carbamazepine,

phenytoin, rifampicin) reduce its hypnotic effect;

ketoconazole causes increased plasma concentrations,

SSRIs and zolpidem may lead to delirium

Zaleplon

5-10

10-20

Drugs that are potent CYP 450 3A4 inducers (rifampin,

phenytoin, carbamazepine, phenobarbital) may

cause its ineffectiveness.

Eszopiclone

1-2

Drugs that are potent CYP 450 3A4 inducers (rifampin,

phenytoin, carbamazepine, phenobarbital) may cause

its ineffectiveness

Amitriptyline^c

10-25

Other antidepressants: SSRIs, type 1C antiarrhythmics

Desipramine^c

Anticholinergic and sympathomimetic drugs

Imipramine^c

Anticholinergic drugs (excessive anticholinergic effects);

MAO inhibitors contraindicated

Nortriptyline^c

25-75

Baclofen—short-term memory loss; barbiturates

can increase metabolism of TCAs; TCAs may

inhibit the uptake of bethanidine into NE neuron

and reduce anti-HTN effect; concurrent administration

with drugs capable of prolonging QT interval is

contraindicated; belladonna potentiation of

anticholinergic activity

Doxepin^c

25-50

MAO inhibitors, alcohol, tolazamide (hypoglycemia)

(continued)

164

Chapter 10

n Sleep Disorders

TABLE 10.1

Commonly Used Sleep-Promoting Medications (continued)

Initial

Maintenance

Drug Name

Dose (mg)

Drug Interactions

Chloral hydrate^a

500

500-1000

Increased free levels of phenytoin, initial enhancement

of anticoagulation by coumarins because of increased

free levels; furosemide

Diphenhydramine

25-50

50-100

Enhanced risk for adynamic ileus, urinary retention,

chronic glaucoma with tricyclics and other

antihistamines

CYP, cytochrome P enzyme; SSRI, selective serotonin reuptake inhibitor; MAO, monoamine oxidase; NE, norepinephrine; TCA, tricyclic

antidepressant; HTN, hypertension.

^aAdditive effect of other central nervous system depressants and centrally acting muscle relaxants.

^bExtended release formulation.

^cDrugs that inhibit cytochrome P450 2D6 (quinidine, phenothiazines, and bupropion) may inhibit metabolism of TCAs via inhibition of

CYP 450 2D6.

Other antidepressants: SSRIs, anticholinergic, and sympathomimetic drugs; some TCAs may increase half-life and bioavailability of oral

anticoagulants, with amphetamine-like agents-enhanced amphetamine effects; amprenavir may increase serum concentration of TCAs and lead to

arrhythmias, due to inhibition of CYP 450 3A4 isoenzyme.

or three nights is indicated. Sleep induction is re-

notics in place of benzodiazepines. Only five

lated to the rate of drug absorption. Sleep main-

benzodiazepines are currently marketed for

tenance is related to dosage and half-life. The

hypnotic purposes in the United States: triazo-

timing of the intake of the medications is, there-

lam, temazepam, quazepam, flurazepam, and

fore, important. Hypnotics with longer half-lives

estazolam. Various benzodiazepine anxiolytics

(lasting more than 24 hours) show increased ef-

(e.g., diazepam, alprazolam, lorazepam, or ox-

ficacy with two or three nights of administra-

azepam) also are prescribed for insomnia asso-

tion, but they also show increased residual

ciated with anxiety disorders. Unfortunately,

daytime effects. Some benzodiazepines, such as

there is limited evidence to support their effi-

flurazepam, produce persistent long-acting

cacy for these disorders. The drug of choice

metabolites and cause definite impairment in

for sleep-onset insomnia differs from that for

alertness, motor performance, and cognitive

sleep-maintenance insomnia (i.e., triazolam for

function in the morning. Because of the intrinsic

the former, and temazepam for the latter).

“tapering” effect of compounds with long half-

Onset of action after an oral dose depends on

lives, rebound and/or withdrawal phenomena

rapidity of absorption from the gastrointestinal

appear to be unlikely; when they do occur, such

tract. Duration of action of a single dose of a

effects are delayed in onset and are relatively

benzodiazepine hypnotic depends on its distri-

mild. However, there is a much higher likelihood

bution (e.g., it may concentrate in sites such as

of rebound or withdrawal effect after abrupt dis-

adipose tissue, where it exerts no pharmacologic

continuation of short-half-life hypnotics, for

activity) and on elimination and clearance. With

which dose tapering is appropriate. When the

repeated administration at a fixed dosing rate, a

initial therapy is unsuccessful, changing classes

drug will accumulate in plasma and brain until a

of medications may be useful.

steady state is reached. Time necessary to reach

In the last two decades, sleep medicine has

a steady-state condition depends only on the

seen an almost complete replacement of bar-

drug’s elimination half-life. For a drug such as

biturates by benzodiazepines, followed by

triazolam with a very short elimination half-life,

an introduction of nonbenzodiazepine hyp-

accumulation will be complete within 1 day;

165

Chapter 10

n Sleep Disorders

that is, the mean plasma concentration will be

and no change in REM sleep. In middle-aged pa-

no higher after multiple days of therapy than

tients, there is a reduction of wakefulness after

after the first day. At the other extreme is a drug

sleep onset (WASO) time and increase of N2

such as flurazepam, with its principal active

sleep, without changes in REM sleep.

metabolite desalkylflurazepam. This compound

Zaleplon is a nonbenzodiazepine hypnotic

has a very long elimination half-life; 2 weeks or

from the pyrazolopyrimidine class. It interacts

more of long-term treatment will be necessary

with the GABA-BZ receptor complex, selec-

for a steady state to be attained. The rate of drug

tively on omega-1 receptor on the alpha subunit

disappearance following discontinuation after

of the GABA A receptor complex. In controlled

long-term treatment will mirror the rate of accu-

trials it shortened sleep latency. It is metabo-

mulation (i.e., the longer the elimination half-

lized by aldehyde oxidase and to a lesser degree

life, the more time will be needed for the drug to

by CYP 450 3A4. Inhibitors of these enzymes

disappear). A potential benefit of accumulating

may decrease its clearance and enhance sedative/

a benzodiazepine is that persistence of drug at

hypnotic effect. Due to its short half-life of only

the receptor sites throughout each 24-hour dos-

30 minutes, it may be used for initial as well as

ing interval increases the likelihood of a daytime

maintenance insomnia.

anxiolytic effect, a potential benefit for patients

Eszopiclone is a cyclopyrrolone compound, a

with both anxiety and insomnia. For short half-

nonbenzodiazepine hypnotic that has been ap-

life hypnotics such as triazolam, however, in-

proved by the U.S. Food and Drug Administra-

creased daytime anxiety has been reported in

tion (FDA) for treatment of insomnia. It has an

some studies, possibly attributable to wide fluc-

onset of action of 1 hour and half-life of about

tuations in plasma and receptor-site concentra-

6 hours. Eszopiclone has been shown to decrease

tions between doses. Estazolam, a relatively new

sleep latency and improve measures of sleep con-

benzodiazepine, remains effective as a hypnotic

tinuity. It has not been associated with the devel-

for at least 6 weeks of continuous administra-

opment of tolerance over 6 months of use.

tion at a dosage of 2 mg at bedtime, with no ev-

A structurally new compound with a dis-

idence of clinically significant tolerance. It

tinct mechanism of action was recently intro-

improves sleep latency and total sleep time, re-

duced in treatment of insomnia. Ramelteon is a

duces the number of nocturnal awakenings, and

nonsedating melatonin receptor agonist that is

improves both depth of sleep and sleep quality

rapidly absorbed from the GI tract, gives a

in adults with chronic insomnia.

peak concentration at 0.5 to 1.5 hours and has

the half-life of 1 to 2.5 hours. It then undergoes

n SPECIAL CLINICAL POINT: In the last

extensive liver metabolism, yielding weak, ac-

decade, several nonbenzodiazepine hypnotics

tive metabolites that have an elimination half-

have become the most commonly prescribed

life of 2 to 5 hours. Ramelteon produces modest

medications for insomnia. Their main advantage

shortening of sleep latency.

compared to the benzodiazepines is their

favorable side effect profile, less potential for

residual daytime effects, and less potential for

Precautions

abuse.

Patients who are pregnant, who are alcoholic,

Zolpidem, and its slow-release formulation, is a

or who have sleep apnea should not be given

benzodiazepine receptor ligand structurally un-

hypnotics, except in low doses and only in spe-

related to benzodiazepines (an omega 1-selective

cial circumstances. Preference for nonbenzodi-

nonbenzodiazepine hypnotic). It has an elimina-

azepines over benzodiazepines is based on the

tion half-life of 3.5 to 5.1 hours (mean, 4 hours).

former’s lower toxicity and potential for abuse.

In young adults, zolpidem leads to a marked in-

The prescribing of hypnotics to children is

crease in slow wave sleep, with reduction of N2

not recommended, except for rare use in the

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Chapter 10

n Sleep Disorders

treatment of night terrors or severe somnam-

has been associated with complex behaviors in

bulism. Benzodiazepine metabolism varies and

sleep, including sleep eating. Patients taking es-

is largely age dependent. The elimination half-

zopiclone may report an unpleasant taste in the

life of diazepam in healthy men may increase

mouth.

threefold to fourfold from 20 years of age to

80 years of age. The elimination of hypnotics is

Alternative Therapies

decreased in elderly people who might have a

low renal glomerular filtration rate, a reduced

The most popular and well-studied herbal

hepatic blood flow, and a decreased activity of

treatment of depression is St. John’s wort (Hy-

hepatic drug-metabolizing enzymes. The choice

pericum perforatum), a remedy used for wound

of hypnosedatives for elderly patients with sleep-

healing, sedation, and pain relief. Its use as a

onset delay, especially when they are acutely

hypnotic has not been studied systematically,

hospitalized, is complicated by the risk of a par-

but it may promote “deep sleep” and prolong

adoxical excitation at nighttime (sun-downing),

REM latency.

which may be precipitated or exacerbated by

Valerian root

(Valeriana officinalis) has

medication. Although diphenhydramine has

been used widely for its hypnotic properties. A

been useful in many of these patients, there is a

limited number of human studies suggest that

risk of increasing their confusion because of its

valerian could be used as a mild hypnotic with

anticholinergic effect. These problems can be

minimal side effects. It seems to affect GABA

minimized by adjunctive measures, such as leav-

metabolism and reuptake, mainly GABA A re-

ing a light on in the patient’s room, and by fre-

ceptors, 5HT-1a, and adenosine receptors. Nu-

quently reorienting the patient to the unfamiliar

merous herbs are used in combinations by

surroundings. A family member occasionally

traditional Chinese medicine. However, there

may be required to stay with the patient.

are no well-designed studies to document their

Because of the intrinsic “tapering” effect of

effectiveness and safety.

long-half-life compounds, rebound and with-

Anxiety disorders often are linked to insom-

drawal phenomena appear to be unlikely;

nia. Anxiety may respond to kava kava (Piper

when they do occur, such effects are delayed in

methysticum). Its mechanism of action is

onset and are relatively mild. However, there is

thought to involve GABA A receptors.

a much higher likelihood of rebound or with-

Melatonin is used to reset the circadian

drawal effect after abrupt discontinuation of

clock and help proper positioning of the sleep

short-half-life hypnotics, so dose tapering is

cycle within a 24-hour period, but it also has a

appropriate.

mild direct sedative-hypnotic effect (the most

Although many of these drugs, especially

common doses are 2-10 mg 30 minutes to 2

the benzodiazepines, have been marketed with

hours before bedtime). Caution should be exer-

emphasis on their short duration of action,

cised in patients with known cardiovascular

many have long-acting active metabolites. This

disease because melatonin reportedly causes

is often a problem in the patient who experi-

vasoconstriction in coronary and cerebral ar-

ences a decrement in liver function. Sedative ef-

teries of rats. Other possible side effects are in-

fects are additive and may convert what would

hibition of fertility, increased depression or

have been a mild metabolic encephalopathy into

induced depression, suppression of male libido,

a coma days after the initiation of treatment.

retinal damage, and hypothermia. Melatonin’s

Non-benzodiazepine hypnotics are gener-

interactions with other drugs are not fully un-

ally better tolerated and associated with fewer

derstood, which is of particular concern in the

side effects. Dizziness, hypersomnolence, and

elderly population. As with other dietary sup-

headache are the most common side effects of

plements, there is a concern about purity of the

zolpidem, zaleplon, and eszopiclone. Zolpidem

product. Catnip (Nepeta cataria) is used as a

167

Chapter 10

n Sleep Disorders

“tonic” for sleep, as is chamomile (Marticaria

1. A sensation of an urge to move the limbs

recutita). Several other herbs are used as sleep

(usually legs)

aids because of their reported sedative effects:

2. Motor restlessness to reduce sensations

gotu cola (Centella asiatica), hops (Humulus

3. Onset or worsening of the symptoms when

lupulus), lavender (Lavandula angustifolia and

at rest

others), passionflower (Passiflora incarnata),

4. Marked circadian variation in occurrence

and scullcap (Scutellaria lateriflora). Hepatox-

or severity of symptoms, with worsening or

icity was described for scullcap when used in

sole presence of symptoms in the evening.

combination with valerian root, but this may

have resulted from substitution of a particular

Once asleep, approximately 85% of patients

herb with species of germander (Teucrium).

with RLS experience PLMs causing numerous

The FDA recalled all products of L-trypto-

arousals and poor quality of sleep. Many pa-

phan in the United States, but it still is manu-

tients with RLS experience PLMs while awake

factured worldwide. It has resurfaced in the

(PLMs of wakefulness, PLMW), especially in

form of 5-hydroxytryptamine. It was found

sedentary situations. Although total sleep time

that the new product contains the same impu-

may be markedly reduced and sleep efficiency

rities previously found in L-tryptophan re-

is very low, patients with RLS generally do not

sponsible for eosinophilia-myalgia syndrome.

report sleepiness and/or sleep attacks, but they

L-tryptophan also is found in some protein

usually complain of tiredness and not feeling

supplements.

fully alert.

Prevalence of RLS is 5% to 10% and it in-

creases with age. In the majority of studies,

RESTLESS LEGS SYNDROME

RLS is more prevalent in women. The large

majority of patients afflicted by RLS appear to

Insomnia characterized by marked sleep-onset

represent idiopathic cases, unrelated to any

delay may result from RLS because of increas-

other medical condition as a possible cause.

ing severity of unpleasant sensations in the

Several secondary causes of RLS have been

limbs when at rest at night. The patient experi-

well documented: pregnancy, iron deficiency,

ences disagreeable deep sensations of creeping

and end-stage renal disease. Neuropathies and

inside the calves whenever at rest (sitting or

radiculopathies have been accepted as possible

lying down). These dysesthesias cause an al-

secondary causes of RLS, specifically neuropa-

most irresistible urge to move the limbs and

thy associated with rheumatoid arthritis and

thus interfere with the sleep onset. Movements

diabetes mellitus. Some studies suggest other

bring a relief of the sensation, but it typically

causes of secondary RLS, including peripheral

lasts only an instant. Although majority of pa-

vascular disease, chronic obstructive pul-

tients with RLS also have sleep-related PLMs,

monary disease, asthma, and fibromyalgia.

coincident PLMs are not required for the diag-

The exact pathophysiology of RLS is un-

nosis of RLS.

known. However, several studies suggest sub-

n SPECIAL CLINICAL POINT: The diagnosis

cortical dopamine system’s dysfunction, which

of RLS relies entirely on the patient’s

results in reduction of the spinal and possibly

symptoms, and no laboratory testing is

cortical inhibition that may be state dependent.

necessary to make it.

The positron emission tomography and single-

Revised criteria emphasize the onset of symp-

photon emission computed tomography stud-

toms with rest and a clear circadian pattern to

ies showed small decreases in dopaminergic

the symptoms. The four essential criteria for

function in the striatum of patients with

the diagnosis have been published and widely

RLS compared to control subjects. All the

accepted:

clinical conditions

(end-stage renal disease,

168

Chapter 10

n Sleep Disorders

iron deficiency, pregnancy) associated with

RLS symptoms in the morning, after the effects

iron deficiency also are associated with RLS.

of a dose of levodopa wears off. Carbidopa/

Low brain iron may lead to dopaminergic dys-

levodopa, especially its sublingual formulation

function, as documented by decreased D2R,

(Parcopa), may be still useful in control of

decreased dopamine transporter, and increased

episodic, intermittent RLS symptoms, especially

extracellular dopamine in rats deprived of iron

during long periods of inactivity (air flights etc.).

in early life. In some cases, restless legs and

Bromocriptine is another dopaminergic ago-

PLMs are caused or exacerbated by dietary

nist that has been used successfully, but is no

substances (e.g., caffeine) or medications (e.g.,

longer commonly used, because of common

neuroleptics and tricyclic antidepressants).

side effects, including nasal stuffiness, gas-

trointestinal discomfort, especially hypoten-

sion, and ergot-related fibrosis. Another ergot-

Drug Treatment

based dopamine agonist, pergolide has been

Accepted and fairly successful treatments for

withdrawn from the market.

restless legs and PLMs include dopaminergic

Non-ergot, direct dopamine agonists are very

drugs, opioids, and some miscellaneous drugs.

effective therapeutic agents in the treatment

Treatment choices are the same for primary

of RLS. Pramipexole (Mirapex) and ropinirole

and secondary RLS.

(Requip) are currently used as a treatment of

choice. They are typically introduced at lowest

n SPECIAL CLINICAL POINT: Given the

doses, and titrated up every few days until they

prevalence of iron deficiency in RLS, assessing

iron and ferritin levels is essential. If iron

control evening and nocturnal symptoms. At

deficiency is noted, iron supplementation is

doses used to treat RLS, the side effects of these

usually needed for adequate control of RLS

medications are typically minor, and involve

symptoms, along with an investigation of the

dizziness, lightheadedness, and insomnia. At

reasons of iron deficiency. Typically, achieving

higher doses, the dopamine agonists may pro-

the ferritin level of 50 mg/L or more is the goal.

duce sleep attacks—a sudden sensation of

Oral iron supplementation is more effective if it

overwhelming sleepiness.

is taken on an empty stomach and 60 minutes

Gabapentin is now considered an alternative

before a meal.

treatment of mild RLS, especially if coinciding

Among pharmacological agents used for RLS,

with neuropathy, chronic pain, or neurodegen-

dopaminergic medications are now considered

erative diseases, such as Parkinson disease and

first-line agents (Table 10.2). The dopaminer-

dementia. Typical side effects of gabapentin in-

gic agent carbidopa/levodopa

(Sinemet) im-

clude gait unsteadiness and somnolence.

proves all of the features of both RLS and PLM

Numerous opioids have been used, such as

disorder, including discomfort in the legs, in-

codeine, propoxyphene (Darvon), oxycodone

voluntary movements during the waking state

(Percodan), pentazocine (Talwin), levorphanol

(dyskinesias while awake), PLMs during sleep,

(Levo-Dromoran), and methadone. Their ef-

and sleep fragmentation, but its use has been

fectiveness has been tested formally by only a

decreasing, because of the augmentation that

few studies. Although widely prescribed for the

develops with its continued use. Side effects in-

treatment of PLMs, clonazepam was not shown

clude gastrointestinal discomfort, nausea, and

to reduce symptoms of RLS, and even reduc-

vomiting. Augmentation consists of increasing

tion of PLMs seems to be small.

intensity of the symptoms, earlier onset of the

symptoms in the day, reduced time at rest be-

Alternative Treatments

fore symptoms start, and in some cases, more

widespread dysesthesias and restlessness. Re-

The behavioral manipulations of avoidance of

bound is a phenomenon of reappearance of

smoking, certain drugs, and alcohol are almost

170

Chapter 10

n Sleep Disorders

routinely recommended to patients complain-

In contrast, bipolar depression frequently is

ing of insomnia. Avoidance of over-the-counter

associated with hypersomnia; however, this

stimulants such as decongestants with pseu-

state again is accompanied by a shortened

doephedrine, phenylephrine, and appetite sup-

REM latency and reduced stage N3 sleep. The

pressants such as phenylpropanolamine is

onset of sleep is delayed and sleep is short

advised, especially at bedtime.

in mania and hypomania. Insomnia may pre-

Moderate exercise prior to bedtime, vigor-

cede all other symptoms of depression, and

ous enough to cause release of beta-endorphin,

restoration of sleep may be the first sign of

is suggested, preferably before 7 PM. Light cal-

recovery.

isthenics or stretching for 5 to 10 minutes at

In patients with early morning awakening,

bedtime supplements the exercise regimen.

sedative therapy usually is accompanied by an

Stress reduction (meditation, yoga, and relax-

unacceptable degree of morning sedation. An-

ation response) combined with sleep hygiene

tidepressants appear to offer the best results

complements other behavioral techniques.

and should be the initial form of therapy. Tri-

Distraction or counterstimulation of the legs

cyclic antidepressants with sedative properties,

is another approach. It includes hot foot socks

such as amitriptyline (Elavil) and trimipramine

or ice packs; rubbing feet, pounding thighs, or

(Surmontil), reduce sleep latency and improve

wearing socks to bed. Massage, electrical stim-

sleep continuity. Trazodone, a nontricyclic,

ulation, acupuncture, hypnosis, and cognitive

also is used widely for treatment of insomnia in

therapy add to the repertoire of these ap-

patients who are depressed. Although an im-

proaches. Sclerotherapy, once thought to rep-

provement in sleep often precedes an improve-

resent a promising option in patients with

ment in mood, changes of affect should

varicose veins, is unlikely to alleviate the symp-

determine the endpoint in therapy.

toms. Magnesium is noted to improve PLMs

Drug-induced early morning awakening may

and RLS. In addition to iron, a supplementa-

occur with the use of some short-acting benzo-

tion of vitamin E, B₁₂, folate, and B₆ is useful,

diazepines, such as oxazepam or lorazepam.

especially in cases with documented deficien-

They are almost completely inactivated by a

cies. Valerian root and kava kava may be help-

conjugation in the liver, and they have few

ful as mild hypnotic-sedative agents.

residual morning aftereffects. Patients who

drink alcoholic beverages prior to sleep may

develop early morning awakening, apparently

related to an increase in REM sleep (REM

EARLY MORNING AWAKENING

rebound) after the alcohol is metabolized. An

Early morning awakening can be seen in nu-

underlying psychiatric problem should be

merous clinical settings, including depression,

considered, as in any patient with an alcohol-

use of some drugs, and advanced sleep-phase

related problem. Therapy involves a slow with-

syndrome. Endogenous depression is charac-

drawal of the causative agent.

terized by a typical premature awakening and

Advanced-sleep-phase syndrome may mimic

an inability to fall asleep again, with variable

a pattern of early morning awakening typical

sleep-onset disturbance depending on the in-

of depression. It is seen most frequently in eld-

dividual’s component of agitation. A key

erly people. There are no established treat-

polysomnographic finding is shortened REM

ments for this condition, although reverse

sleep latency, which is considered by some ex-

chronotherapy or exposure to light in the

perts to be a biologic marker of depression, in

evening accompanied by light deprivation in

addition to an increased intensity of REM

the morning may be helpful. Either treatment

sleep. Deep (delta) NREM sleep also is re-

requires the skills of experts in sleep disorders

duced; this is a relatively nonspecific feature.

centers.

171

Chapter 10

n Sleep Disorders

chronic pain, and endocrine diseases such as

SLEEP FRAGMENTATION

hyperthyroidism and Addison disease. In these

patients, treatment of the underlying disorder

A major complaint of frequent awakenings at

can be expected to alleviate the sleep distur-

night often signals the presence of a primary

bance and thus obviate the need for hypnotics.

sleep disorder, specifically sleep apnea or

Of note, hypercortisolism

(especially iatro-

PLMs. Multiple medical conditions also can in-

genic) should be considered if sleep fragmen-

terfere with sleep maintenance, whereas psy-

tation is prominent. Parkinsonian patients

chiatric etiology is a less likely explanation.

receiving therapy with levodopa also are sub-

In sleep apnea, sleep disruption is caused by

ject to this complaint. These patients frequently

cessation of breathing during apneic periods

report daytime napping and their response to

and subsequent short awakenings. While these

hypnosedatives and tricyclics is unpredictable.

events may be very frequent, they are usually

Not taking dopaminergic drugs after eating

not realized by the patient, and only reported

supper is helpful for many patients. Another

by his or her bed partner. Occasionally, pa-

cause of sleep fragmentation is bruxism (teeth

tients with sleep apnea do realize that they

grinding).

wake up frequently at night; this presentation

is more frequent in central rather than obstruc-

tive sleep apnea, and in women.

PLM disorder is a condition in which in-

WHEN TO REFER THE INSOMNIAC

somnia is associated with the occurrence of pe-

TO A SLEEP SPECIALIST

riodic episodes of repetitive and highly

Primary care physicians and other nonspecial-

stereotypical leg jerks during sleep. These are

ists may attempt to treat an acute insomnia, es-

followed consistently by a partial arousal. Pa-

pecially if the trigger or the etiology is easily

tients are often unaware of the movements at

identifiable. The treatments include a short

night; rather, they report frequent nocturnal

course of hypnotics or simple behavioral inter-

awakenings and unrefreshing sleep. A bed

ventions (sleep hygiene). When patients present

partner usually can provide an accurate de-

with chronic (more than 6 months) insomnia,

scription of the movements.

it is advisable to refer the patient to the sleep

Medical conditions that sometimes lead to

specialist for formal evaluation and a trial of

insomnia include alveolar hypoventilation,

behavioral and/or medical therapy.

which in adults could be secondary to massive

obesity; chronic obstructive pulmonary dis-

ease; myopathy; cordotomy; or lesions involv-

SPECIAL CHALLENGES FOR

ing structures that control sleep and breathing,

HOSPITALIZED PATIENTS

including stroke. Primary alveolar hypoventila-

tion (previously termed “Ondine curse”) typi-

Anesthesiologists have to be aware of the reac-

cally presents in infants and is associated with

tions some of the patients with RLS may de-

a further worsening of hypercapnia and hy-

velop if given antidopaminergics. The reaction

poxemia in sleep. Gastroesophageal reflux

can be severe and look as a “forme fruste” neu-

with regurgitation, heartburn, and dyspepsia;

roleptic malignant syndrome (crampy stiffness

nocturnal angina; sleep-related asthma; night-

without fever). This is especially likely to occur

mares; and cluster headaches all may cause a

when patients awaken after they were given

serious insomnia as a result of severe sleep

droperidol (a potent, long-acting dopamine an-

fragmentation. Other medical and neurologic

tagonist) while withdrawing from fentanyl (a

conditions can be associated with this form

potent, short-acting µ-opiate agonist). The tim-

of insomnia, including CNS infections, head

ing of this emergency coincides with circadian

traumas, nocturnal epilepsy, fibromyalgia,

enhancement of RLS (late afternoon). Recom-

172

Chapter 10

n Sleep Disorders

mended substitutes for nausea include on-

Other major causes of excessive daytime

dansetron (5HT-3 blocker) and domperidone

sleepiness include sleep apnea syndrome and

(large molecule dopamine antagonist, which

narcolepsy.

does not penetrate the blood-brain barrier, but

area postrema has none). Domperidone is not

available in the United States.

SLEEP APNEA

Patients with RLS may tolerate the follow-

ing antipsychotic medications: quetiapine and

A potentially lethal condition, sleep apnea is

clozapine. Although many patients have trou-

an abnormal breathing pattern during sleep

ble sleeping in the hospital, during hospitaliza-

defined as a cessation of airflow at the level of

tion special attention must be given to subjects

the nostrils and the mouth, lasting for at least

with RLS.

10 seconds. Depending on the criteria em-

ployed, the estimated prevalence of sleep

apnea syndrome ranges from 2% to 10% of

the adult population. It is the most frequent di-

SLEEP DISORDERS ASSOCIATED

agnosis in sleep disorder centers and the most

WITH HYPERSOMNOLENCE

frequent cause of excessive daytime sleepiness.

Included in this category of sleep disorders as-

Apneas are subdivided by type: obstructive

sociated with hypersomnolence are intrinsic

apnea secondary to a sleep-induced obstruc-

and extrinsic sleep disorders as well as para-

tion of the airway (Fig. 10.3); central apnea

somnias and disorders associated with medical/

secondary to decreased respiratory muscle

psychiatric disorders. The chief symptoms in-

activity; and mixed apnea combining both

clude an inappropriate and undesirable sleepi-

phenomena. Mixed apnea usually starts as a

ness during waking hours, decreased cognitive

central apnea (with no respiratory effort) and

and motor performance, an excessive tendency

develops into an obstruction later. Obstruc-

to sleep, unavoidable napping, an increase in

tive apneas are much more common than

total sleep over 24 hours (“true” hypersom-

central apneas; typically either obstructive or

nia), and a difficulty in achieving full arousal

central apnea predominates in each patient.

on awakening. The term hypersomnolence in a

Obstructive sleep apnea (OSA) is caused by

strict sense should be reserved for patients who

pharyngeal collapse during inspiration and

have a demonstrable tendency to fall asleep in

not by an active musculature contraction.

the waking state when sedentary or who have

Contributing factors may include abnormal

sleep “attacks.” There also may be diminished

anatomic relationships among the muscular or

alertness in the waking state, described by the

bony structures of the nasopharynx, orophar-

term subwakefulness. In all patients presenting

ynx, or hypopharynx (e.g., a short thick neck,

with these symptoms, it is important to sepa-

macroglossia, micrognathia, retrognathia, a rel-

rate excessive daytime somnolence from less

atively small and low-positioned hyoid bone, or

specific symptoms of tiredness, fatigue, malaise,

a narrow pharynx). Alternatively, inappropriate

or depression.

involuntary respiratory control of the pharyn-

geal (genioglossus) and diaphragmatic muscle

n SPECIAL CLINICAL POINT: Insufficient

tone may be responsible. Occasionally patients

sleep time is the most prevalent reason for

demonstrate increased compliance of their pha-

daytime sleepiness; responding to the demands

ryngeal walls, especially when they have fatty or

of everyday life many people wake up to an

redundant pharyngeal and submucosal folds, or,

alarm clock every day, curtailing their natural

sleep. Prolonging sleep time, with an aim of

less frequently, enlarged tonsils. As an end-result,

spontaneous arousals on most days, is

patients with OSA have an imbalance between

frequently the first advice to a sleepy patient.

the forces that tend to collapse the upper airway

173

Chapter 10

n Sleep Disorders

FIGURE 10.3 Obstructive apnea. During the of rapid eye movement (REM) stage, airflow ceases

for 21 seconds while unsuccessful respiratory effort continues, indicating obstruction of the upper

airway. Oxygen saturation falls to 81%. Immediately prior to the resumption of ventilation, the

electrocardiogram (ECG) demonstrates second-degree atrioventricular block. When ventilation occurs,

sinus rhythm appears in the electroencephalogram (EEG) and tachycardia is evident in the ECG.

and forces that keep it open. Although many pa-

sedative drug intake. Important features in the

tients with OSA are moderately overweight,

clinical history are often best confirmed by in-

morbid obesity is present only in a minority.

terviewing the bed partner are loud snoring

and witnessed respiratory pauses, frequently

n SPECIAL CLINICAL POINT: Sleep apnea

alarming to the bed partner. Awakenings due

should be suspected in an individual with

to choking sensation or loud sounds produced

snoring, witnessed pauses in breathing at

by snoring (snort arousals) are sometimes re-

night, and excessive daytime sleepiness.

ported. Sensation of excessive sweating at

Obesity and elevated blood pressure are

night, related to sympathetic activation pro-

frequently present.

duced by apneas, is frequently present. Finally,

Obstructive sleep apneas are more prevalent

patients with OSA frequently report dryness in

with increasing age and worsen after alcohol or

the mouth/throat upon awakening, and, less

174

Chapter 10

n Sleep Disorders

commonly, morning headaches that are present

association of hypertension and OSA, and

upon awakening and disappear quickly during

sleep apnea has been detected in 22% to 30%

the day. Suspicion of OSA is frequently raised

of patients with systemic hypertension. Sleep

by excessive daytime sleepiness, and restless

apnea increases the risk of ischemic heart dis-

sleep with frequent awakenings. On examina-

ease, cardiovascular death, congestive heart

tion, a large neck circumference (≥17 inches in

failure (CHF), and atrial fibrillation. Finally,

males and ≥16 inches in females), micrognathia

recent reports link OSA with the development

and retrognathia and excessive oropharyngeal

or worsening of insulin resistance and type 2

soft tissue should suggest the diagnosis of

diabetes.

OSA. Objective confirmation of the diagnosis

Central sleep apnea is not a single disease

is made with an attended or unattended sleep

entity but results from any one of a number of

study that typically records EEG, electrocardio-

processes that produce instability of respira-

gram, oximetry, breathing effort, and airflow.

tory control. In contrast to patients with OSA,

these patients are older; they complain mainly

n SPECIAL CLINICAL POINT: In sleep apnea,

of sleep fragmentation; they are not over-

the patient is usually unaware of nocturnal

weight; and they have less pronounced oxygen

symptoms and may be resistant to undergoing

desaturation and a more moderate hemody-

an evaluation of sleep; presence of a bed

namic impact. There is no definite sex distribu-

partner during history intake may greatly

tion. Central sleep apnea may be present in a

facilitate the evaluation.

sizeable proportion of patients with CHF. In

Waking respiratory functions are usually within

this group, central apneas are due to increased

normal limits. Hypertension has been reported

sensitivity of the respiratory center to pCO₂,

in >50% of patients with OSA. Alveolar hy-

producing relative hypocapnia, and prolonged

poventilation, associated with an elevated wak-

circulation time; in patients with CHF, central

ing PaCO₂, occasionally accompanies OSA.

apneas frequently alternate with periods of hy-

Increased PaCO₂ of 45 mmHg or higher has

perpnea, to cause periodic breathing pattern.

been reported in 23% of obese patients with

Complex sleep apnea, a recently recognized

OSA, and may be due to hypoventilation, or a

entity, combines the presence of OSA with cen-

coexistence of OSA and chronic obstructive

tral apneas that become apparent when treat-

pulmonary disease, COPD (overlap syndrome).

ment of obstructive events is attempted. These

Sleep apneas substantially affect the cardio-

patients typically present with a phenotype

vascular system, and association between sev-

close to a patient with OSA and their condition

eral cardiovascular diseases and OSA is now

is only revealed during sleep testing and trial of

well documented. Marked cyclic sinus arrhyth-

therapy of OSA.

mia appears during sleep and apnea. This

Upper airway patency does not need to be

rhythm pattern is characterized by progressive

fully compromised for symptoms of daytime

sinus bradycardia during apnea (heart rates of

sleepiness to develop. The upper airway resist-

less than

40 beats/min are not uncommon)

ance syndrome (UARS) is accompanied by sub-

with an abrupt reversal and sinus acceleration

jective and objective evidence of pathologic

at the arousal and onset of ventilation, caused

sleepiness. In some individuals, even a minor

by a sudden sympathetic output. Second-

reduction of airway patency with sleep onset

degree atrioventricular block, prolonged sinus

may lead to a modest increase in upper airway

pauses, nonsustained ventricular tachycardia,

resistance and a slight decrease of tidal volume

and paroxysmal atrial tachycardia episodes also

without hypoxemia. In response to increased

occur. Furthermore, systemic and pulmonary

resistance, inspiratory muscles increase their

artery pressures increase in association with

effort to maintain normal tidal volume. This

obstructive apneas. There is an independent

compensatory increase in respiratory effort

175

Chapter 10

n Sleep Disorders

usually triggers a brief alpha EEG arousal (3 to

consequence, all types of apneas may occur.

14 seconds in duration), interrupting further

These patients are vulnerable to develop respi-

development of obstruction before oxygen de-

ratory failure with acute respiratory infection

saturation occurs. If the alpha EEG arousals

and may require assisted ventilation in inten-

are frequent, clinically significant daytime

sive care units until the infection is controlled.

sleepiness may arise. Snoring is noted in most,

but not all, of these individuals.

EVALUATION OF SUSPECTED

Both central and OSA can be a complication

SLEEP APNEA

of another medical or neurologic disorder, in-

cluding brainstem infarction, lateral medullary

The evaluation of patients suspected of having

syndrome, bulbar poliomyelitis, medullary neo-

sleep apnea syndrome includes a full daytime

plasms, syringomyelia and syringobulbia, olivo-

and sleep history obtained not only from them

pontocerebellar atrophy, Alzheimer disease,

but also (and most importantly) from their bed

encephalitides, Creutzfeldt-Jakob disease, pos-

partner. A physical examination should con-

tencephalitic parkinsonism, cervical cordotomy,

centrate on blood pressure, evidence of right

neuromuscular disorders affecting intercostal

heart failure, and abnormal skeletal and mus-

muscles and the diaphragm (such as myasthenia

cle configurations of the face and neck. The

gravis), higher cervical spinal poliomyelitis,

ear, nose, and throat examination is of primary

Guillain-Barré syndrome, limb-girdle dystro-

importance. Chest radiographs and electrocar-

phies, and especially myotonic dystrophy. Hy-

diograms are useful for evaluating pulmonary

poventilation and daytime drowsiness are

hypertension, determining the status of the

prominent in all of these disorders. Enlarged

right and left ventricles, and establishing possi-

tonsils (an especially important factor in the

ble coexistence of other cardiopulmonary dis-

etiology of sleep apnea and snoring in chil-

orders. A complete blood count may document

dren), myxedema, micrognathia and other fa-

the presence of polycythemia in chronic hypox-

cial and mandibular abnormalities, platybasia,

emia or right-sided heart failure. Pulmonary

neck infiltration secondary to Hodgkin disease,

function studies with arterial blood gas sam-

lymphoma, or radiation therapy to the neck,

pling may be necessary to determine airway

acromegaly, and familial or acquired dysau-

obstruction, or investigate for primary hy-

tonomia (usually mixed central and OSA) may

poventilation during the waking state and doc-

all cause OSA.

ument hypo- and hypercapnia. The primary

Of special interest is the development of

test that establishes the diagnosis of OSA is a

postpolio syndrome years after the acute stage

polysomnographic study (PSMG), which is es-

of poliomyelitis. It starts with fatigue, new

sential in an estimation of the severity of sleep-

muscular weakness, musculoskeletal pain, and

disordered breathing, sleep fragmentation, and

dysphagia. During sleep, patients experience

oxihemoglobin desaturations. The severity of

central and obstructive sleep apnea, which is

sleep apnea, defined by the so-called “apnea-

worse during REM sleep because of the com-

hypopnea index,” AHI (i.e., the number of

bined REM sleep-induced atonia and abnormal

episodes per hour of sleep), the degree of oxy-

motor (phrenic) output caused by medullary

gen desaturation, sleep fragmentation and the

dysfunction. Poliomyelitis also can cause atro-

presence of significant arrhythmias will be de-

phy of respiratory accessory muscles and tho-

rived from sleep study and will guide future

racoabdominal muscles, leading to severe chest

treatment

(Fig.

10.4). Availability of sleep

deformity such as kyphoscoliosis. Furthermore,

centers has been one of the major factors lim-

impairment of cranial motor nerves (hypoglos-

iting the frequency of diagnosis of OSA. Re-

sal, facial, and trigeminal) may adversely affect

cently, the use of home devices that give a

tongue and other upper airway muscles. As a

limited number of physiological variables in

176

Chapter 10

n Sleep Disorders

FIGURE 10.4 The sleep architecture of an adult man with obstructive sleep apnea syndrome. Stages

3 and 4 are lacking; frequent arousals occur, which fragment the sleep cycle; rapid eye movement

(REM) sleep is much reduced as a proportion of the sleep period; and REM periodicity is abolished.

The majority of the sleep period consists of nonrapid eye movement (NREM) stages 1 and 2.

sleep has been approved as a means to diag-

drug, with about 30% to 50% of patients show-

nose OSA.

ing improved oxygenation during sleep. Simi-

lar results have been recently reported with

mirtazapine.

Treatment of Sleep Apnea

A number of studies suggest that the admin-

The treatment of sleep apnea syndromes de-

istration of oxygen may be a useful method of

pends on its cause (Table 10.3). An important

treating central sleep apnea, although the

general treatment is weight loss, provided the

mechanism by which it reduces central apneic

loss of weight is not only achieved but also

events has not been established. It is hypothe-

maintained. Similarly, abstinence from alco-

sized that the potential destabilizing influence

hol and avoidance of hypnosedative drugs are

of the hypoxic ventilatory response on respira-

advocated.

tory control may be counteracted by the ad-

Pharmacologic approaches including aceta-

ministration of oxygen. However, in some

zolamide, theophylline, naloxone, medrox-

cases, hypercapnia and the frequency of OSA

yprogesterone, and clomipramine have not

may increase.

been studied systematically on large numbers

Due to the effect of gravity on the airway,

of subjects. The only widely used drug is pro-

OSA is typically worse in the supine than in

triptyline, which may exert a beneficial effect

nonsupine position of sleep. In some situations,

in an occasional patient with OSA. Its effect

sleep apnea is only present in the supine posi-

may be the result of a reported direct action on

tion, while the lateral sleep is normal. If this is

the muscle tone of the upper airway. A recent

a case, restriction of sleep position may be used

crossover unblinded trial of protriptyline and

to control apnea. Several devices that make

fluoxetine suggests equal effectiveness of either

supine sleep uncomfortable by placing a bulky

177

Chapter 10

n Sleep Disorders

TABLE 10.3

Treatment Options for Sleep Apnea

Behavioral interventions

Weight loss

Avoidance of alcohol and sedatives

Avoidance of supine sleep position

Discontinuation of smoking

Continuous positive airway pressure treatments

Nasal or oral positive airway pressure (NCPAP or OPAP)

Bilevel positive airway pressure (BPAP)

Auto-adjusting positive airway pressure (Auto-PAP)

Oral appliances

Surgical procedures

Bypass surgery

Tracheostomy

Upper airway reconstructions

Soft-tissue modifications (Uvulopalatopharyngoplasty [UPPP], laser-assisted UPPP [LAUP], somnoplasty,

radiofrequency volumetric reduction of the tongue, laser lingual resection—lingualplasty, tongue base

suspension, tonsillectomy)

Skeletal modifications

Mandibular osteotomy with genioglossal advancement and hyoid suspension, maxillomandibular osteotomy and

advancement, hyoid myotomy and suspension to mandible, hyoid myotomy and suspension to thyroid cartilage,

anterior hyoid advancement, transpalatal advancement pharyngoplasty, nasal surgery

Pharmacologic agents

Medroxyprogesterone, decongestants, nasal steroids, antihistamines, protryptiline, and serotonergic agents:

fluoxetine and other selective serotonin reuptake inhibitors, L-tryptophane

object on patient’s back, such as a tennis ball t-

against the incoming air. Early intensive

shirt, are used to this effect.

support with phone calls and follow-up visits

improve long-term compliance with CPAP.

The most widely used treatment of OSA is

nasal continuous positive airway pressure (CPAP),

Newer devices are now equipped with systems

which acts by establishing a “pneumatic splint”

that lower the pressure during an early expira-

to the upper airway. CPAP is produced by a

tion, improving comfort of breathing. Addi-

blower unit, which then pressurizes, via a con-

tionally, some patients do not use their CPAP

ducting hose, a tight fitting nasal, oronasal, or

due to social or cosmetic reasons and due to

oral mask. Pressurized air then causes elevation

nasal obstruction.

of the pressure in the oropharynx, thus reversing

Some patients whose apneas are eliminated

the transmural pressure gradient across the

with CPAP continue to have non-apneic desat-

oropharyngeal airway, which results in airway

urations, especially during REM sleep. These

opening. Poor compliance is a major obstacle

patients may have chronic obstructive pul-

limiting this otherwise successful treatment.

monary disease in addition to sleep apnea

(overlap syndrome). In such situations, supple-

n SPECIAL CLINICAL POINT: Many patients

mental oxygen may be beneficial. The benefits

with sleep apnea resist the use of CPAP. The

main reasons for poor compliance are

derived from oxygen treatment should be veri-

discomfort from the mask, poor mask fit

fied either by a polysomnography or an over-

resulting in air leakage, and trouble breathing

night oximetry.

178

Chapter 10

n Sleep Disorders

Bilevel positive airway pressure in a spon-

the treatment of snoring. A 75% to 100% suc-

taneous mode (BPAP-S) offers an effective

cess rate for the elimination of snoring has

alternative for patients who are uncomfortable

been reported; this is not unexpected as struc-

while expiring against the high pressures deliv-

tures generating the sounds of snoring are sur-

ered by CPAP. This device allows independent

gically removed. This may be misinterpreted as

titration of expiratory (EPAP) and inspiratory

a sign of apnea cure, but the apneas may persist

(IPAP) airway pressure. The difference between

despite the disappearance of snoring. Laser-

the EPAP and IPAP reflects the pressure sup-

assisted uvulopalatoplasty, involving partial re-

port delivered by the device. BPAP is typically

section of the uvula and soft palate using a

used in cases of comorbid obesity, intrinsic

laser, is a simple surgical procedure that can be

lung disease, and chest deformity, conditions

done on an outpatient basis in two to seven

associated with hypoventilation.

sessions without general anesthesia. It seems

A bilevel device can also be used to provide

highly effective in eliminating habitual snoring,

spontaneous ventilation with a pressure support,

with success rates from 70% to 84%. Simi-

with a minimal back-up rate (non-invasive me-

larly, placement of implants within the soft

chanical ventilation, NIMV or bilevel positive

palate reduces snoring but is unlikely to resolve

airway pressure in spontaneous-timed mode,

apnea. Finally, surgical correction of the

BPAP-ST). This mode of therapy is typically

maxillofacial anomalies

(maxillary advance-

used in central sleep apnea and in conditions

ment, mandibular advancement, surgery in-

associated with hypoventilation. A variation

volving the attachment of the genioglossus to

of this treatment modality, an adapt-servo ven-

the mandible, hyoid bone suspension) has been

tilator has been recently introduced to specifi-

used to correct sleep apnea in patients with

cally address central apneas, especially in a

craniofacial abnormalities.

form of periodic breathing pattern. The device

There are at least 35 oral appliances that

detects the patient-generated flow and supple-

have been developed to help with snoring and

ments it, breath by breath, with a variable,

sleep apnea. They all focus on the nasopharyn-

rather than constant pressure support. This

geal inlet and position of the base of the tongue.

modality has been shown to resolve a large

They either attach to the tongue and pull it for-

proportion of idiopathic and opioid-related

ward directly or advance the mandible, and

central sleep apnea, Cheyne-Stokes breathing,

hence, the attachment of the genioglossus mus-

and complex sleep apnea.

cle, thus opening the retrolingual space in the

Several surgical techniques have been used in

throat. Typically the oral appliances are used in

treatment of OSA. Sometimes, correction of

patients with mild to moderate sleep apnea

nasal obstruction can result in significant re-

who prefer oral appliances to CPAP, do not re-

duction of sleep apneas. Similarly, in cases of

spond to CPAP, or are not candidates for CPAP

airway obstruction due to excess lymphoid tis-

therapy. Based on a recent pooled analysis of

sue (most common etiology of OSA in children,

several trials, oral appliances are able to reduce

less common in adults), an adenoidectomy or

the apnea-hypopnea index to <10 in about

tonsillectomy can be curative. Attempts to pro-

50% of treated patients. Use of oral appliances

mote uvulopalatopharyngoplasty (UPPP) as an

has also been associated with improved day-

alternative surgical treatment of sleep apnea

time sleepiness. Compliance of patients with

have not been successful. Multiple studies indi-

oral appliances is comparable to that of CPAP

cate at best a success rate of 33% to 70%. The

and side effects (salivation and teeth discom-

success rate may improve somewhat, provided

fort) are generally mild, though frequent.

selection of patients is based on the determina-

In summary, although significant progress in

tion of the level of obstruction prior to the sur-

evaluation and treatment of sleep-disordered

gery. More encouraging are results of UPPP in

breathing has been made, the exact etiology

179

Chapter 10

n Sleep Disorders

and pathophysiologic mechanism(s) currently

An auxiliary symptom of narcolepsy in-

are unknown. Sleep-disordered breathing has a

cludes sleep paralysis, which occurs while the

profound effect on health. The range of seque-

patient is falling asleep or waking from sleep.

lae varies from sudden death or cor pulmonale

Consciousness is preserved, and it is accompa-

to failure to thrive or to perform at work and

nied by an intense feeling of fear. Hallucina-

school. If unrecognized, lifelong problems may

tions also occur at the onset of sleep or on

arise.

awakening, and they are usually frightening.

Automatic behavior, sometimes reported as a

“blackout,” is a reflection of severe sleepiness.

Nocturnal sleep also is disturbed with frequent

NARCOLEPSY

awakenings, frequent sleep-onset REM peri-

Narcolepsy is a syndrome consisting of exces-

ods, and vivid dreams. The combination of ex-

sive daytime sleepiness and abnormal manifes-

cessive daytime sleepiness and cataplexy is

tations of REM sleep. The latter includes

pathognomonic for narcolepsy.

frequent sleep-onset REM periods, which

The diagnosis of narcolepsy is based on the

may be subjectively appreciated as hypnagogic

presence of excessive daytime sleepiness, sleep

(sleep-onset) or hypnopompic

(sleep-offset)

attacks, cataplexy, and other auxiliary symp-

hallucinations, and dissociated REM sleep-

toms. Typically the diagnosis is made by rul-

inhibitory processes (i.e., cataplexy and sleep

ing out other causes of sleepiness (insufficient

paralysis). The appearance of REM sleep within

sleep time, presence of sleep apnea or PLM

10 minutes of sleep onset is considered evidence

disorder, or use of medications or substances

for narcolepsy. In narcolepsy, the patient falls

of abuse), and confirming the pathologic

asleep in the midst of activities, although most

sleepiness by the Multiple Sleep Latency test

people will stay awake during animated conver-

(MSLT), showing a mean sleep latency of 5

sation, walking, eating, or coitus.

minutes or less, with two or more sleep-onset

The cardinal symptoms of narcolepsy are

REM periods. Presence of shortened noctur-

excessive daytime sleepiness, sleep attacks, and

nal REM latency (<20 minutes) may support

cataplexy. Although sleep attacks are charac-

the diagnosis.

teristic of this disease, excessive sleepiness is

n SPECIAL CLINICAL POINT: It is advised that

equally disturbing

(i.e., a permanent, some-

prior to MSLT testing all medications that might

times profound, impairment of vigilance or

affect the central nervous system (anxiolytics,

wakefulness between attacks). Sleep attacks

sedatives, stimulants, antidepressants) be stopped

usually last about

15 minutes. The patient

for 2-4 weeks. Further, sufficient sleep time

awakens refreshed, and there is a definite re-

2 weeks prior to testing should be documented

with actigraphy or a sleep log. In all instances, a

fractory period of 1 to 5 hours before the next

polysomnogram is recorded on the night prior to

attack. Cataplexy is a sudden decrease in, or

the MSLT.

abrupt loss of, muscle tone that either is gener-

alized or limited to particular muscle groups.

More than 85% of all narcoleptics with defi-

Cataplexy ranges from weakness in the mus-

nite cataplexy share a specific human leuko-

cles supporting the jaw, or a sense of weakness

cyte antigen (HLA) allele, HLA DQB1-0602

in the knees, to a complete muscular weakness

(most often in combination with HLA DR2),

causing the patient to slump to the floor, un-

compared to 12% to 38% of the general pop-

able to move. Cataplectic attacks characteristi-

ulation in various ethnic groups. DQB1-

cally are initiated by laughter, surprise, outbursts

0602 may represent a genetic marker for the

of anger, or a feeling of exaltation. These at-

disorder, indicating the presence of the pos-

tacks generally last for only a few seconds or

sible narcolepsy-susceptibility gene on chro-

for as long as 30 minutes.

mosome 6. A negative test for DQB1-0602

180

Chapter 10

n Sleep Disorders

does not rule out diagnosis of narcolepsy be-

Both discoveries prompted intense research

cause a rare narcoleptic patient with cata-

in humans. Hypocretin-containing neurons are

plexy may be DQB1-0602 negative. Only

localized in the dorsolateral hypothalamus

8% to 10% of narcoleptics are aware of an-

around the perifornical nucleus. In humans,

other member of the family with nar-

the number of hypocretin-containing neurons

colepsy/cataplexy. Prevalence studies have

is estimated to range from 15,000 to 20,000 to

shown that the risk for a first-degree relative

50,000 to 80,000. These cells project widely to

of a patient having narcolepsy with cataplexy

the entire brain: cerebral cortex, basal fore-

1% to 2%. Usually, patients with nar-

brain structures, such as the diagonal band of

colepsy can be reassured that the illness will

Broca; the amygdala; and the brainstem areas

not develop in their relatives. However, a 1%

such as reticular formation, raphe nuclei, and

to 2% risk is 10 to 40 times higher than the

LC. The role of hypocretin transmission in

prevalence observed in the general popula-

human narcolepsy has been confirmed by find-

tion, suggesting the existence of genetic pre-

ing of low hypocretin levels in CSF in narcolep-

disposing factors. Twin studies demonstrated

tics, compared to controls, and absence of

only a 25% to 31% concordance rate for nar-

hypocretic-containing neurons in the brains of

colepsy in monozygotic twins. Genetic fac-

patients with narcolepsy.

tors are defining susceptibility, but other

(environmental) may trigger the onset of the

Treatment of Narcolepsy

disease. Although almost all diseases associ-

ated with the specific HLA allele are autoim-

Treatment of narcolepsy comprises treatment

mune in nature, an extensive search for

of the two most disabling symptoms of nar-

known general markers (cerebrospinal fluid

colepsy: excessive daytime sleepiness/sleep at-

[CSF] oligoclonal bands, serum immunoglob-

tacks and cataplexy (Tables 10.4 and 10.5).

ulin levels, lymphocyte subset ratios) of au-

In the rare patient, successful treatment in-

toimmune activation was negative.

volves only improved sleep hygiene, as previ-

However, as postulated by Mignot in 1995,

ously described. Most patients, however, will

the possibility of autoimmune cell destruction

need stimulants, primarily dextroamphetamine

in a small part of the brain has become more

or methylphenidate. Stimulants enhance the re-

likely in light of the discovery of the hypocretin

lease and inhibit the reuptake of catecholamines

system and its crucial role in the development

and, to a lesser extent, serotonin in the CNS.

of narcolepsy.

Stimulants are likely to reduce but not eliminate

Genetic canine narcolepsy has been shown

excessive daytime sleepiness and performance

to be caused by mutations in the hypocretin-

deficits. Methamphetamine in doses higher than

2 receptor gene. Almost simultaneously an-

those recommended for treatment of obesity

other group reported on the phenotype of

was found to normalize sleepiness and perform-

the preprohypocretin (the precursor to two

ance in eight subjects studied, but it rarely is

peptides: hypocretin-1 and hypocretin-2)

used because of concerns about abuse and re-

knockout mice. The homozygous mice were

lated adverse behaviors.

observed to have numerous periods of “behav-

Side effects often limit the use of stimulants.

ioral arrests.” Twenty-four-hour EEG record-

The dose-related clinically significant side ef-

ings revealed an increased amount of sleep

fects include irritability, agitation, headache,

during the dark period, reduced REM la-

tachycardia, hypertension, and peripheral

tency, and sleep-onset REM periods. Thus, a

sympathetic stimulation. Stimulants may be

mouse model of narcolepsy with cataplexy

associated with dependence. A novel wake-

was discovered.

promoting agent, modafinil usually is grouped

181

Chapter 10

n Sleep Disorders

TABLE 10.4

Wake-Promoting Drugs for Treatment of Excessive Daytime Sleepiness

Initial Dose

Maintenance

Drug Name

(mg)

Dose (mg)

Drug Interactions

Dextroamphetamine

5-60

Because it is an indirect-acting sympathomimetic,

may precipitate HTN crisis if taken with MAOI; with

beta blockers may produce severe HTN,

arrhythmias with tricyclics; may diminish the

effectiveness of the anti-HTN drugs; may delay

absorption of phenobarbital, ethosuximide,

phenytoin

Methylphenidate

5-10

10-60

May decrease hypotensive effect of guamethidine;

may inhibit metabolism of coumarin anticoagulants,

some anticonvulsants, phenylbuthazone, and tricyclic

drugs; safe use with clonidine and other alpha-2-

agonists has not been systematically evaluated

Methamphetamine

10-50

MAOIs contraindicated; may decrease hypotensive

effect of guanethidine; insulin requirement may be

changed; phenothiazines antagonize stimulant effect

of the amphetamines

Modafinil

100-200

200-400

Coadministration of potent CYP 450 3A4 inducers

(carbamazepine, phenobarbital, rifampin) or

inhibitors of CYP 450 3A4 inhibitors (ketoconazole,

itraconazole) could alter modafinil’s levels; it is a

very modest CYP 3A4 inducer (cyclosporine,

steroidal contraceptive clearance may increase).

Because it is reversible inhibitor of CYP 2C19 (used

for alternative metabolism of tricyclics) in patients

deficient in CYP 2D6 the levels may rise

Selegiline

10-40

Stupor, muscle rigidity, hyperpyrexia with meperidine,

and MAOIs (severe agitation, hallucinations, and

death); severe toxicity with tricyclics and SSRIs

Sodium oxybate

3 g in

3-9 g in

Other CNS depressants and centrally acting muscle

two doses

relaxants (benzodiazepines, opioids, barbiturates,

ethanol, etc.)

HTN, hypertension; MAOI, monoamine oxidase inhibitor; CYP, cytochrome P enzyme; SSRIs, selective serotonin reuptake inhibitors.

with stimulants but seems to have a different

side effects, especially less irritability and agita-

mechanism of action that is not fully under-

tion; however, if it is titrated rapidly, headache

stood at present time. Modafinil increases the

may emerge. Selegiline

(monoamine oxidase

levels of dopamine and noradrenaline in several

[MAO] B inhibitor), combined with a low tyra-

parts of the CNS. It activates glutamate-depen-

mine diet, also improves daytime sleepiness.

dent pathways and reduces GABA-ergic trans-

Sodium oxybate was recently approved by the

mission. The advantage of modafinil over other

FDA for treatment of cataplexy and excessive

stimulants is lower frequency and severity of

daytime sleepiness in patients with narcolepsy.

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TABLE 10.5

Anticataplectic Medications

Initial

Maintenance

Drug Name

Dose (mg)

Drug Interactions

Imipramine

10-100

See Table 10.1

Nortriptyline

25-75

See Table 10.1

Protriptyline

5-40

See Table 10.1

Clomipramine

50-150

Interactions same as for other TCAs; combination

with tranylcypromine is particularly hazardous and the

serotonin syndrome developed with concurrent use of

moclobemide

Fluoxetine

20-80

It inhibits CYP 450 2D6 isoenzyme; this may require

reduction of the dose of concomitant medication;

thioridazine is contraindicated because of potential fatal

arrhythmias; elevations of carbamazepine, phenytoin,

tricyclics, clozapine levels were observed; also some

benzodiazepine levels rose; sumatripan—weakness,

incoordination, hyperreflexia; other tightly protein-bound

drugs (warfarin, digitoxin)

Paroxetine

20-60

Weakness and hyperreflexia if used with almotripan;

inhibition of TCA metabolism in some people—it is an

inhibitor of CYP 450 2D6 and may inhibit other

P450 isoenzymes including CYP 3A4; its metabolism can

be inhibited by bupropion; cimetidine may increase

serum concentrations of paroxetine via inhibition of

CYP 450 metabolism of paroxetine; serotonin

syndrome with MAOI—concurrent use

contraindicated; increased serum concentration of

clozapine with SSRIs; cyproheptadine reduces its

effectiveness by antagonizing postsynaptic serotonin

Sertaline

50-100

Combination with other CNS drugs was not studied

systematically; potential interaction with other drugs

tightly bound to proteins (warfarin, digoxin) may result

in increased levels; cimetidine led to significant increases

in AUC and prolonged half-life

Citalopram

20-60

Substrate for CYP 450 3A4 and 2C19, is expected to

interact with potent inhibitors of CYP 450 3A4

(ketoconazole, itraconazole, and macrolide antibiotics),

and potent inhibitors of CYP P450 2C19 (omeprazole),

but no clinically significant interactions observed;

increased metoprolol levels; sumatripan in combination

resulted in weakness, hyperreflexia, and incoordination

Sodium oxybate

3 g in two

3-9 g in two

See Table 10.4

divided

doses

TCA, tricyclic antidepressant; CYP, cytochrome P enzyme; MAOI, monoamine oxidase inhibitor; SSRIs, selective serotonin reuptake inhibitors;

AUC, area under the curve.

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Chapter 10

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Tricyclic antidepressants have been tradi-

Pharmacologic approaches are generally not

tionally used in treatment of narcolepsy (as a

entirely satisfactory, and many patients benefit

REM suppressant) and cataplexy. Cataplec-

from social support provided by Narcolepsy

tic attacks respond to imipramine, nortripty-

Network and other similar organizations.

line, and protriptyline. One of the most

effective drugs for treatment of cataplexy is

Alternative Wake-Promoting Agents

clomipramine, a triglyceric with a potent sero-

tonin-uptake inhibitor. Side effects, mainly

Caffeine is a mild stimulant derived from the

resulting from their anticholinergic proper-

seeds, leaves, or fruits of 60 plant species. These

ties, may limit the use of tricyclics. The most

plants are sources of caffeine for beverages such

frequently reported side effects are dry mouth,

as coffee (Coffea arabica, Coffea canephora) or

increased sweating, sexual dysfunction (impo-

black or green tea (Camellia sinensis). Kola

tence, delayed orgasm, erection, and ejaculation

(Kola acuminata), guarana (Paullinia cupana),

dysfunction) weight gain, tachycardia, constipa-

and mate (Ilex paraguariensis) are sources of

tion, blurred vision, and urinary retention and

caffeine for cola and other citrus beverages.

xerostomia. Sudden discontinuation of tricyclics

Herbal medicinal products containing caf-

is likely to result in severe worsening of cata-

feine include herbal teas, antioxidant green

plexy and even status cataplecticus. Newer anti-

tea preparations, and weight loss formula-

depressants with more exclusive inhibition of

tions. Weight loss preparations often combine

serotonin uptake (e.g., fluoxetine, paroxetine,

caffeine with ephedrine-containing products.

and sertraline) are useful alternatives in the

Caffeine enhances alertness presumably

management of cataplexy, with fewer anti-

via antagonism of the adenosine receptors.

cholinergic side effects. The anticataplectic ef-

Ephedra is the source of ephedrine, an over-

fects of these drugs are most likely related to

the-counter compound used for treatment of

their desmethyl metabolites, which are potent

asthma. Ephedrine also is used and abused for

adrenergic uptake inhibitors.

energy, weight loss, and body building. Lesser

An FDA-approved drug for treatment of cat-

known sources of ephedrine or related com-

aplexy is sodium oxybate. Sodium oxybate is a

pounds are Indian sida (Sida cordifolia) and

salt of a CNS depressant, gamma-hydroxybutyric

bitter orange (Citrus aurantium), sometimes

acid. Published and reported data indicate its

found in energy or weight loss preparations.

powerful effect in control of cataplexy, im-

Ginseng (Panax ginseng—Korean ginseng) is

provement of sleep quality, with increase in

a substance used to counteract fatigue (mild

slow wave sleep, and reduction of daytime

stimulant) or enhance performance. Siberian

sleepiness. Side effects are mild (nausea, vomit-

ginseng (Eleutherococcus senticosus) is used

ing, dizziness, enuresis, dream abnormality,

to enhance physical endurance and work ca-

headache), and the drug is generally well toler-

pacity. There is no known herbal treatment

ated. Given the high potential for misuse, the

for cataplexy.

drug is strictly regulated.

Improvements observed with the use of

L-tyrosine, codeine, or propranolol have not

INSUFFICIENT SLEEP

been documented in controlled trials. When

sleep fragmentation is a major complaint, judi-

Insufficient sleep is the most frequent cause of

cious use of short-acting hypnotics once or

daytime somnolence. The individual is volun-

twice per week may be helpful. Significant im-

tarily, but often unwittingly, chronically sleep

provement of nocturnal sleep with sodium

deprived. Although this relationship may seem

oxybate was reported in double-blind, placebo-

self-evident, most patients are unaware that

controlled trials.

their chronic sleep deprivation is responsible

184

Chapter 10

n Sleep Disorders

for their continuous excessive sleepiness. When

screening is positive, the patient should be re-

these individuals obtain adequate sleep, their

ferred for the evaluation and workup in a sleep

complaint of somnolence during the day disap-

center. Of particular importance is quick and

pears. In the most typical scenario, the sleep

proper diagnosis and treatment of the sleep dis-

debt is built over weekdays and is partially re-

orders accompanied by severe sleepiness (OSA,

lieved by prolonged sleep time on weekends.

narcolepsy) in professional drivers.

Various other medical and medicinal

causes of excessive daytime somnolence de-

Special Challenges for

serve mention. Hypnosedatives, anticonvul-

Hospitalized Patients

sants, antihypertensives, antihistamines, and

antidepressants are common causes. A with-

Of all types of hypersomnolence, sleep apnea

drawal from stimulants also may give rise to

poses prominent challenges to hospital per-

severe sleepiness. Multiple medical and toxic

sonnel who may not be familiar with patients

conditions may be associated with drowsi-

carrying this diagnosis. For a patient with diag-

ness: hyperglycemia (prior to ketoacidosis or

nosed sleep apnea, useful guidelines include

nonketotic coma), hypocortisolism, hypo-

optimizing all associated medical conditions

glycemia, hypothyroidism, panhypopituitarism,

before elective surgery and using local or re-

hepatic encephalopathy, hypercalcemia, renal in-

quired anesthesia without sedation or narcotic

sufficiency, vitamin B₁₂ deficiency, chronic sub-

use whenever possible. Full general anesthesia

dural hematoma, encephalitis, intracranial

with adequate control of the airway is pre-

neoplasm (primary or secondary), meningitis,

ferred to deep sedation. Patients should be ex-

or the aftereffects of trauma. Hypersomno-

tubated only after they fully wake up, and

lence is a misnomer in many of these conditions

preferably in a nonsupine position. CPAP

because more often a state of obtundation oc-

should be used postoperatively as soon as it is

curs. There are also two rare periodic disorders

feasible in all patients who had used CPAP

of excessive sleepiness: (a) Kleine-Levin syn-

prior to surgery. Continuous, rather than inter-

drome, characterized by recurrent periods of

mittent oximetry monitoring is indicated in

extended sleep, megaphagia, sexual disinhibi-

postoperative patients with sleep apnea; it can

tions, and social withdrawal if awake, and

take place in the intensive care unit, stepdown,

(b) menstruation-associated hypersomnia, a pe-

telemetry, or general ward setting. Patients

riod of sleepiness during a patient’s menstrual

with the following are especially at risk and re-

period (without observed changes in behavior).

quire extreme vigilance: heavy narcotic re-

quirement, severe sleep apnea (based on sleep

study/clinical suspicion), and severe systemic

When to Refer the Patient with

manifestations. These patients should be ob-

Hypersomnia to the Sleep Specialist

served in the intensive care unit.

Excessive daytime sleepiness is most frequently

the result of sleep deprivation, poor sleep hy-

giene, prescribed or nonprescribed drugs, or sleep

PARASOMNIAS

apnea. However, it is often a life-threatening

symptom in situations requiring full vigilance

Parasomnias, which include a heterogeneous

(driving, operating machinery, combat, etc.).

group of behavioral disturbances that occur

Primary care physicians are advised to use

only during sleep or are exacerbated by sleep,

short

(one-page) screening questionnaires in

do not have a common pathophysiologic mech-

their outpatient offices because the patients

anism. They represent disorders of arousal,

often do not volunteer the information. If the

partial arousal, and sleep-stage transitions.

185

Chapter 10

n Sleep Disorders

Disorders of arousal

(confusional arousals,

ing locks on windows. If predisposing and

sleep walking, and sleep terrors) all arise from

triggering factors are identified, every effort

NREM sleep, usually delta sleep; can be trig-

should be made to minimize or avoid them.

gered by forced arousal from delta sleep; and

Many patients respond to benzodiazepines:

are prevalent in childhood. Arousals from

triazolam, clonazepam (0.5-2.0 mg), and di-

delta sleep are characterized by confusion,

azepam (5-10 mg) in the usual evening doses.

disorientation in time and space, and slow

Tricyclic drugs, such as imipramine, de-

speech and mentation. These confusional

sipramine, and clomipramine in the doses of

arousals usually occur in children and may

10 to 50 mg, also may be effective.

progress into sleepwalking (somnambulism)

REM sleep behavior disorder, recurrent iso-

or sleep terror

(pavor nocturnus, incubus).

lated sleep paralysis and nightmare disorder

Typically there is very little if any recall for

are all classified as parasomnias usually associ-

the event the following morning and minimal

ated with REM sleep. A nightmare is an

if any recall of dreamlike mentation. Most

arousal from REM sleep with the recall of a

somnambulistic episodes last a few seconds to

disturbing dream, accompanied by anxiety and

a few minutes. A sleep terror is an arousal

much less prominent autonomic arousal. The

from NREM sleep accompanied by a piercing

awakened patient instantly is oriented and

scream or cry and behavioral manifestations

alert. Vocalization, fear, and motor activity are

of intense anxiety indicating autonomic

less intense than in sleep terrors. Nightmares

arousal. Autonomic manifestations include

are more likely to occur in the second half of

mydriasis, perspiration, piloerection, rapid

the night, when more prolonged REM episodes

breathing, and tachycardia. Morning amnesia

are likely to occur. Withdrawal from alcohol,

for the episode is the rule. Several groups of

amphetamines, or hypnotics may lead to REM

factors contribute to the occurrence of disor-

sleep rebound and cause nightmares.

ders of arousal. They include predisposing

REM sleep behavior disorder (RBD) is a

factors

(genetic factors), factors causing in-

parasomnia characterized by vigorous motor

creased amount of delta sleep or difficulty

activity, instead of atonia, in response to dream

awakening (age, recovery from prior sleep dep-

content, often resulting in an injury. Manifesta-

rivation, fever, CNS depressant drugs, etc.),

tions of acting out dreams include laughing,

and factors causing sleep fragmentation (pain,

talking, chanting, singing, yelling, swearing,

environmental stimuli, stimulants, stress, sleep

gesturing, reaching, grabbing, arm flailing,

apnea, PLMs, etc.).

punching, kicking, sitting up, jumping out of

There is often a concurrence of more than

bed, crawling, and running movements.

one of these disorders in the same child, and

a hereditary predisposition to parasomnias

n SPECIAL CLINICAL POINT: A high

percentage of patients with RBD have a

has been noted. Somnambulism in children is

demonstrable underlying neurologic disorder,

not considered to be caused by psychologic

typically a synucleinopathy (Parkinson disease,

factors, although its persistence into adult-

dementia with Lewy bodies, multiple system

hood may represent a serious problem and

atrophy or pure autonomic failure); RBD may

occasionally may be associated with diverse

predate the onset of other neurological

forms of personality disturbance and psy-

symptoms by years.

chopathology. Most children grow out of this

condition between the ages of

7 and 14

A minority of cases are idiopathic and tend to

years. It is important to protect patients

occur in the elderly. Transient RBD has been

against injury by, for example, installing

seen in association with acute drug intoxica-

safety rails at the head of stairways and plac-

tions and withdrawal states.

186

Chapter 10

n Sleep Disorders

Making the bedroom environment safe

cases when a diagnosis of epileptic (as opposed

for the patient by moving the furniture away

to non-epileptic) episodic behavior is needed.

from the bed, placing a mattress on the floor

Sleep-related eating disorder may occur in as-

next to the bed, and keeping any weapons out

sociation with OSA, somnambulism, daytime

of the bedroom are mainstays of management

eating disorders, medication abuse; it may occur

of RBD. Clonazepam (initial dose 0.5-1.0 mg)

in isolation. A sleep-related eating disorder is

is the drug of choice for treatment of RBD.

characterized by almost nightly eating and

Anecdotal reports suggest effectiveness of cloza-

weight gain that patients attribute to the noctur-

pine, quetiapine, and melatonin.

nal eating. Most patients are only partially con-

Sleep-related enuresis is involuntary mic-

scious during the eating episode. Two thirds of

turition beginning usually during deep NREM

patients with this condition are women who

sleep in an individual who has or should have

generally are concerned about the weight gain.

voluntary waking control of the bladder. In

Daytime binge eating or obsessive-compulsive

contrast to this idiopathic nocturnal enuresis,

disorder is absent. Treatments include clon-

symptomatic enuresis is the result of urogenital

azepam, carbidopa/levodopa, and fluoxetine and

or other diseases and is generally less benign.

topiramate. Cases of sleep-related eating disorder

Idiopathic enuresis and somnambulism tend to

due to zolpidem have been described.

disappear by late childhood or adolescence,

Other parasomnias that may occur in child-

probably representing a phenomenon of de-

hood as well as in adulthood include bruxism,

layed maturation. At 5 years of age, 15% of

head banging (jactatio capitis nocturna), abnor-

boys and 10% of girls are still enuretic. Rec-

mal swallowing, and painful penile erections.

ommended treatment includes tricyclic antide-

Whether these conditions require a polysomno-

pressants

(e.g., imipramine,

25-75 mg at

graphic evaluation and treatment depends en-

bedtime [approximately 1.0-1.5 mg/kg/day])

tirely on the persistence of the symptoms and

and daytime bladder exercises aimed at in-

the degree of the patient’s disability. Nocturnal

creasing bladder capacity. Oxybutynin chlo-

groaning (catathrenia) is a parasomnia charac-

ride has been used with variable success.

terized by groaning or monotonous vocaliza-

Intranasal desamino-D-arginine vasopressin

tion and is predominantly seen in REM sleep.

(DDAVP) at low doses has been shown to have

a definite effect, especially in children older

Alternative Treatments

than age 9 years and adults. Conditioning with

a buzzer and pad is the most successful treat-

There are no alternative treatments, other than

ment for enuresis, but success may depend on

anecdotal reports of alarms triggered by as-

continued use of the buzzer.

sumption of an erect posture, presumably ac-

Parasomnias also include a cluster headache

complishing an awakening. If fully awake, the

and the related (but more chronic) condition of

patient is less likely to be exposed to injury,

paroxysmal hemicrania. Cluster headaches

consume undesirable food, or the like.

occur in REM sleep and may be related to an in-

creased cerebral blood flow during REM sleep.

When to Refer the Patient with

About 45% of patients with seizure disorders

Parasomnia to the Sleep Specialist

have seizures mainly during sleep. Generalized

seizures are markedly activated by NREM

Age, frequency, and the type of parasomnia

sleep; specifically, generalized tonic-clonic

should guide the nonspecialist to refer the pa-

seizures are most common during stages 1 and

tient. In childhood usually the parents are initi-

2 NREM sleep. Partial seizures may occur dur-

ating the referral because the events could be

ing NREM and REM sleep. Prolonged EEG

dramatic and the parents are concerned about

monitoring may be necessary in some difficult

the safety of their child.

187

Chapter 10

n Sleep Disorders

hallucinations for the last 4 years. He

Always Remember

states he has never been treated for the

disorder and recognized his problem from

• In a patient with psychophysiological insomnia,

reading about narcolepsy in a magazine.

behavioral therapy typically results in more

The neurologic examination is normal.

sustained benefit than pharmacologic therapy

The physical examination reveals a

alone.

nervous man with a heart rate of

• The diagnosis of restless legs syndrome is

102 beats/min, but otherwise normal vital

made on purely clinical grounds and does not

signs. The remainder of the physical

require any testing in the sleep laboratory

examination is normal. A routine

unless some other sleep pathology is

complete blood count, general chemistry

suspected.

screen, electrocardiogram (ECG), and

• Insufficient sleep time is the most common

chest x-ray film are normal. A thyroid

reason for hypersomnolence. Extending sleep

battery is within normal limits. Which of

time with a goal of spontaneous, rather than

the following is the most appropriate

alarm-triggered awakenings is typically one of

management of this patient?

the first steps in evaluating a person with

A. Prescription of D-amphetamine, 5 mg

hypersomnolence.

three times daily

• Patients with obstructive sleep apnea are

B. Administration of D-amphetamine in

frequently not aware of the severity of their

combination with a tricyclic

nocturnal and diurnal symptoms and may

antidepressant

resist formal evaluation. Involving their bed

C. Routine all-night PSMG

partner in this evaluation during the history

D. Urine screening for amphetamine

taking may facilitate it.

metabolites

• Most problems with continuous positive

E. Scheduling for a series of daytime naps

airway pressure (CPAP) compliance by

in the sleep laboratory

patients with obstructive sleep apnea are due

to mask problems. Early intensive support—

The correct answer is D. The usual practice is

follow-up visits and phone calls improve

to screen the urine for amphetamine metabo-

long-term compliance with CPAP.

lites before doing a more involved study. It is

• In most patients with suspected narcolepsy, all

usually a bad sign to have a patient who

CNS-active medications (anxiolytics,

knows the classic symptoms of narcolepsy and

sedatives, antidepressants, and stimulants)

maintains he has never been diagnosed or

should be stopped 2 to 4 weeks prior to

treated. In most cases of narcolepsy, excessive

sleep evaluation.

daytime sleepiness and sleep attacks are initial

• Appearance of REM behavior disorder with

symptoms of the disease, whereas associated

dream enactment may be an early sign of

symptoms develop later. A patient with all

neurodegenerative disease.

components of the syndrome early in the

course of the disorder is subject to suspicion.

Once urine samples are known to be “clean,”

all-night PSG and MSLT are useful to estab-

lish the diagnosis. If a patient is suspected of

QUESTIONS AND DISCUSSION

covert stimulant use, a prolonged period of

1. A 23-year-old man presents with a chief

abstinence should be documented before as-

complaint of “narcolepsy.” His history

suming that an REM-onset sleep episode is

indicates the presence of sleep attacks,

narcolepsy (because the same pattern may ap-

cataplexy, sleep paralysis, and hypnagogic

pear as part of stimulant withdrawal). Empiric

188

Chapter 10

n Sleep Disorders

therapy with stimulants is a practice that

sedative drug abuse is too frequently a cause

should be avoided.

of this symptom to overlook it as a possibility.

Our usual approach is to screen for sedatives,

2. A 36-year-old schoolteacher is referred for

then to proceed with an all-night PSMG, with

an evaluation of excessive somnolence. The

respiratory and cardiac monitoring. If the re-

patient states that he feels extremely

sults are negative, daytime naps are studied

drowsy unless he is actively involved in a

with an MSLT the following day to exclude

novel behavior. The problem has been

narcolepsy. The studies in answers A, B, and

present for at least 3 years but seems to be

C are rarely of any value in evaluating these

getting worse. He has fallen asleep at the

patients. In this particular case, an all-night

wheel of his car twice in the last 6 months.

PSMG documented the presence of a severe

He denies a significant history of alcohol

OSA with associated cardiac arrhythmias. The

ingestion and is not taking medications.

elevated red blood cell count appeared to be a

The physical examination reveals a large

secondary complication of nocturnal apnea.

(160-cm, 82-kg) individual with normal

vital signs. The physical and neurologic

3. You are consulted by a 23-year-old man

examinations are normal. After leaving the

who described episodes of “amnesia.” On

room to answer a call, you return to find

several occasions, he has found himself at

the patient sleeping. A routine blood count

various locations with no recollection of

reveals hemoglobin of 17 g/dL, with

having traveled to them. He recollects

normal indices and normal white blood cell

being at another location hours before; his

count. Biochemical screening is normal. A

memory for previous events is good, and

routine ECG is normal. Thyroid hormone

he denies any other symptoms preceding

levels and cortisol determinations are

the attack. Observers have seen him

unremarkable. A urine screen for sedatives

during an episode, and he appeared

is unrevealing. Which of the following

distracted but carried on social conversations

studies is most appropriate at this time?

appropriately and on one occasion drove a

A. EEG

car without incident. He appears relatively

B. CT of the head

stable, and attacks occur in situations that

C. MRI of the brain

seem devoid of any emotional importance.

D. All-night PSMG study, with respiratory

The patient does not drink alcohol. The

and cardiac monitoring and if negative,

neurologic examination is normal. A

followed by a series of daytime naps in

sleep-deprived EEG without sedation is

the sleep laboratory

read as normal, although it is noted that

The correct answer is D. This is a fairly typi-

drowsiness is followed quickly by the onset

cal history in a sleep clinic—the diagnostic

of low-voltage fast activity. Biochemical

possibilities include narcolepsy, sleep apnea,

studies including a 6-hour glucose tolerance

and idiopathic hypersomnia. The history

test are all normal. An MRI of the brain is

given, however, lacks the important details

normal. Empiric therapy with phenytoin

that would help clarify these diagnostic possi-

(100 mg three times daily) leads to

bilities such as a history of snoring, cataplectic

worsening of the symptoms. Which of the

episodes or episodes of sleep paralysis,

following disorders is most compatible

episodic amnesia, morning headache, or a

with this history?

family history of a similar problem. Any of

A. Pseudoseizure or hypoglycemia

the possibilities could be entertained from this

B. Narcolepsy-cataplexy syndrome or sleep

history. The patient’s weight and sex make

apnea syndrome

sleep apnea statistically more likely, but

C. Somnambulism

189

Chapter 10

n Sleep Disorders

D. Transient global amnesia or amnestic

or surgical management has been reported to

migraine

alleviate this symptom complex.

E. Complex partial seizure

4. A 43-year-old accountant is referred for

sleep evaluation for snoring and bizarre

The correct answers is B. The episodes de-

nighttime behaviors. For the past several

scribed are typical of “automatic behavior”

years, his sleep has been very active; a bed

syndrome. This behavioral abnormality is as-

partner reports snoring, snorting,

sociated with the appearance of “microsleep”

vocalizations, frequent position changes,

episodes, which electroencephalographically

and repeated leg movements. On several

are stage N1 sleep. Sleep apnea and nar-

occasions he has been noted to wake up

colepsy are associated with this disorder.

and not knowing where he was, he also

Although the diagnosis of complex partial

could not recognize his bed partner for a

seizures is difficult to rule out on the basis of a

brief period of time. There were single

normal EEG, the adverse response to empiric

episodes of sleep paralysis and sleep

anticonvulsants is more typical of an “auto-

hallucinations, but no cataplexy. His

matic behavior” syndrome. Transient global

daytime functioning is impaired by his

amnesia presents a similar clinical picture but

stressful job, his obesity, and significant

is an entity restricted to late middle life; fre-

sleepiness that tend to develop in the

quent recurrences are unusual in this syn-

afternoons. In the evening he tends to fall

drome. Somnambulism is a similar

asleep in front of TV, but denies any leg

phenomenon but is more frequent in child-

discomfort or urge to move the legs. He

hood and arises from a period of normal

moved and changed his job 3 years prior to

sleep; it is usually a stage N3 sleep event.

this evaluation, and gained 50 lbs since. He

Amnestic migraine may produce recurrent

is otherwise healthy, has not had any

amnestic episodes but usually does so in the

neurological problems in the past, and does

presence of more typical migrainous episodes.

not take any medications.

There is some question of whether this is a sui

On examination, he is obese with the

generis disorder or this represents the coexis-

body mass index (BMI) of 44.5 kg/m², has

tence of two phenomena in a single individual.

a large tongue with side indentations, short

Pseudoseizures rarely are characterized by

thick neck, bilaterally decreased breath

amnesia and are usually situationally related.

sounds, and minimal peripheral edema.

Hypoglycemia may present as transient de-

Which of the following diagnoses is the

crease in consciousness, but is usually associ-

most likely?

ated with signs of sympathetic stimulation;

A. Narcolepsy without cataplexy

history of apparent normal behavior during

B. Confusional arousals

the episode makes it less likely.

C. Restless legs syndrome

Appropriate management in this case would

D. Obstructive sleep apnea

include an all-night PSMG and if negative fol-

E. Nocturnal epilepsy

lowed by the Multiple Sleep Latency test the

next day as well as a routine 16-channel EEG.

The correct answer is D. Obstructive sleep

A careful history-taking directed specifically

apnea is the most likely explanation of this

toward cataplexy, daytime napping, nocturnal

variety of symptoms presented by the patient.

apnea, and snoring would help in a differentia-

Obstructive sleep apnea typically presents

tion of the underlying condition. Hypnoseda-

with snoring and excessive daytime sleepiness;

tives, anticonvulsants, and diazepam usually

obesity is a known risk factor. OSA may pro-

cause worsening of the symptoms. In patients

duce, via sleep fragmentation related to

with sleep apnea of any cause, proper medical

apnea-related arousals, whole number of

190

Chapter 10

n Sleep Disorders

nighttime symptoms ranging from frequent

Gay P, Weaver T, Loube D, et al. Evaluation of positive

airway pressure treatment for sleep related breathing

position changes, leg movements, vocaliza-

disorders in adults. Sleep. 2006;29(3):381-401.

tions, confusional arousals, to apparent REM-

Gross JB, Bachenberg KL, Benumof JL, et al. Practice

intrusion phenomena such as sleep paralysis

guidelines for the perioperative management of pa-

and sleep hallucinations.

tients with obstructive sleep apnea: a report by the

Narcolepsy typically presents in adoles-

American Society of Anesthesiologists Task Force on

Perioperative Management of patients with obstruc-

cents and young adults; late presentation in a

tive sleep apnea. Anesthesiology. 2006;104(5):1081-

middle-aged adult is uncommon, but delayed

1093; quiz 1117-1118.

diagnosis is frequent. Also, the sleep of a pa-

Guilleminault C, Chowdhuri S. Upper airway resistance

tient with narcolepsy is highly fragmented,

syndrome is a distinct syndrome. Am J Respir Crit

but typically devoid of parasomnias. The pa-

Care Med. 2000;161(5):1412-1413.

tient does not report daytime symptoms char-

Hauri P, Linde S. No More Sleepless Nights. New York:

acteristic of RLS. Confusional arousals with

Wiley; 1996.

or without more complex behaviors, is a

Kushida CA, Littner MR, Hirshkowitz M, et al. Practice

parameters for the use of continuous and bilevel posi-

parasomnia typical for children; the multitude

tive airway pressure devices to treat adult patients

of other nocturnal symptoms make it unlikely

with sleep-related breathing disorders. Sleep.

in this patient. Nocturnal epilepsy may pres-

2006;29(3):375-380.

ent as bizarre behavior at night, but these are

Lin HC, Friedman M, Chang HW, et al. The efficacy of

usually stereotyped in nature. Presence of

multilevel surgery of the upper airway in adults with

obstructive sleep apnea/hypopnea syndrome. Laryngo-

daytime sleepiness and physical examination

scope. 2008;118(5):902-908.

findings typical of OSA make this diagnosis

Lin L, Faraco J, Li R, et al. The sleep disorder canine nar-

more likely.

colepsy is caused by a mutation in the hypocretin

(orexin) receptor 2 gene. Cell. 1999;98:365-376.

Littner MR, Kushida C, Anderson WM, et al. Practice pa-

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Westchester: American Academy of Sleep Medicine;

Mahowald MW, Schenck CH. Non-rapid eye movement

2005.

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1106, vii.

Ancoli-Israel S, Roth T. Characteristics of insomnia

in the United States: results of the 1991 National

Montplaisir J, Boucher S, Poirier G, et al. Clinical,

Sleep Foundation survey. I. Sleep. 1999;22 (suppl 2):

polysomnographic, and genetic characteristics of

S347-S353.

restless legs syndrome: a study of 133 patients diag-

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1997;12:61-65.

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rameters for the psychological and behavioral treat-

Boeve BF, Silber MH, Saper CB, et al. Pathophysiology of

ment of insomnia: an update. An American Academy

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rodegenerative disease. Brain. 2007;130(pt 11):

1419.

2770-2788.

Morin CM. Insomnia: Psychological Assessment and

Caples SM, Garcia-Touchard A, Somers VK. Sleep-

Management. New York: Guilford Press; 1993.

disordered breathing and cardiovascular risk. Sleep.

2007;30(3):291-303.

Morin CM, Bootzin RR, Buysse DJ, et al. Psychological

and behavioral treatment of insomnia: update of the

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1398-1414.

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Academy of Sleep Medicine review. Sleep. 1999;22:

989-1007; abstract ix.

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Parish JM, Somers VK. Obstructive sleep apnea and car-

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(orexins) in sleep regulation and narcolepsy. Annu Rev

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Powell NB, Riley RW, Robinson A. Surgical management

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392-402.

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Sherin JE, Shiromani PJ, McCarley RW, et al. Activation

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N Engl J Med. 1993;328(17):1230-1235.

Multiple Sclerosis

PETER A. CALABRESI AND SCOTT D. NEWSOME

key points

• Multiple sclerosis (MS) is an immune-mediated,

multiphasic, mutifocal disease of the central nervous

system.

• The primary etiology of MS is unknown; however, the

disease has features of inflammation, demyelination,

axonal injury, and neurodegeneration.

• Visual dysfunction, sensory disturbances, and gait

impairment are very common presenting symptoms.

• MRI is the single most useful test in confirming the

diagnosis of MS.

• Early and accurate diagnosis is paramount.

• Initiating early disease-modifying treatment can

influence the clinical course.

• Symptomatic therapy can greatly improve MS patients’

quality of life.

ultiple sclerosis

a period of unpredictable relapses and remis-

(MS) is a neurodegenerative disease with early

sions, which in the majority is followed by an

intense inflammation of the central nervous

accumulation of neurologic dysfunction and a

system (CNS). The primary etiology of MS re-

chronic progressive course. The life expectancy

mains unknown and is likely multifactorial.

has been shown to be only 6 to 7 years less

The disease is characterized pathologically by

than that for a control population without MS,

inflammatory infiltrates and demyelination,

but the emotional and economic cost to society

followed by varying degrees of secondary ax-

as a result of the disability is enormous.

onal degeneration.

■ SPECIAL CLINICAL POINT: Multiple

HISTORY

sclerosis is the most common nontraumatic

cause of neurologic disability in young adults

The earliest account of a disease that appears

and affects approximately 400,000 people in the

likely to have been MS is found in writings

United States. An estimated 200 people per

from the 14th century, describing the illness of

week are newly diagnosed.

a Dutch nun, “Blessed Lidwina of Schiedam.”

MS affects women two to three times more

The earliest pathologic descriptions by Carswell

commonly than men. Most patients start with

and Cruveilhier date to between

1838 and

192

193

Chapter 11

■ Multiple Sclerosis

1845. Charcot is generally credited with the

country, and the prevalence of African Americans

first comprehensive account of the clinical and

with MS has not been reexamined adequately

pathologic features of MS, which was pub-

in the magnetic resonance imaging (MRI) era

lished in 1868.

of diagnosis.

Migration studies suggest that the risk of ac-

quiring MS is related to the location in which

EPIDEMIOLOGY

one has lived before puberty. Individuals migrat-

ing from high- to low-risk areas decreased their

Epidemiologic studies have shown that MS has

expected risk of developing MS, as determined

an unequal geographic distribution, with large

from their area of birth. Conversely, migration

regional and ethnic variations in the prevalence

from low- to high-risk areas increased the risk of

of disease (Fig. 11.1). MS is rare in the tropics

acquiring MS. The reliability of migration stud-

and increases in frequency at higher latitudes

ies has been questioned, and no definite conclu-

north and south of the equator. The prevalence

sions can be made from these data.

in the United States is reported at 57.8 per

Numerous instances of MS clusters have

100,000 and is almost twice as common in the

been reported. Several clusters have been re-

Northern as compared to the Southern United

lated to exposure to heavy metals and canine

States. The prevalence rate has been increasing,

distemper virus, but no conclusive link has

probably because of better recognition of MS

been established. Genetic studies strongly sug-

and improved treatment of complications with

gest that the disease is polygenic and that ge-

a correspondingly increased longevity of

netic factors may have a stronger influence in

those affected. Prevalence rates of less than

determining susceptibility to MS than environ-

5 per 100,000 are found in Asia, Africa (except

mental factors.

English-speaking whites in South Africa), and

northern South America. MS is also said to be

much less common among Eskimos, Gypsies,

PATHOLOGY OF MULTIPLE SCLEROSIS

and African Americans. However, these pat-

terns may be changing with increased travel;

Classic descriptions of the MS lesion as pre-

cases of MS have been reported in native

dominantly demyelinating with relative spar-

Africans who have not traveled out of the

ing of axons still hold true today. Modern tools

FIGURE 11.1 Map of the world depicting areas of high prevalence (30+/100,000, solid), medium

prevalence (5-29/100,000, dotted), and low prevalence (0-4/100,000, dashed). White areas are

regions without data or people. (From Kurtzke JF, Wallin MT. Epidemiology. In: Burks JS, Johnson KP,

eds. Multiple sclerosis: diagnosis, medical management, and rehabilitation. New York: Demos Medical

Publishing; 2000. Reproduced with permission from Demos Medical Publishing.)

194

Chapter 11

■ Multiple Sclerosis

FIGURE 11.2 Perivenular infiltrate typical of the early acute inflammatory event in an active lesion.

have afforded more detailed descriptions of the

The MS plaque appears to begin with the mi-

immunologic and structural events occurring

gration of lymphocytes and macrophages across

within lesions and have reemphasized the sec-

the blood-brain barrier into the perivenular

ondary axonal degenerative stage of the lesion.

space (Fig. 11.2). This is followed by diffuse

Major advances in the classification of MS

parenchymal infiltration by inflammatory cells,

pathology have been made from biopsy and

edema, and active stripping of myelin from

rapid autopsy material. Clinicopathologic cor-

axons by macrophages, leading to multifocal

relations using MRI and spectroscopy provide

areas of demyelination (Fig. 11.3). Subsequently,

hope that advances in our understanding of the

astrocytic hyperplasia and the accumulation of

pathologic state will allow guided therapeutic

lipid-laden macrophages ensue. As plaques

interventions.

enlarge and coalesce, the initial perivenular

FIGURE 11.3 Luxol fast blue stain revealing loss of myelin in several irregular geographic lesions.

195

Chapter 11

■ Multiple Sclerosis

distribution of the lesions becomes less apparent.

metabolic dysfunction of the nerve axon. Con-

The inflammatory reaction is usually less pro-

duction can recover acutely on resolution of

nounced in grey matter, probably because of the

edema, subacutely with redistribution of sodium

smaller amount of myelin in these areas. The ex-

channels along the internodal membrane, or

tent of axonal loss in the demyelinated areas is

chronically after partial remyelination.

highly variable. The sparing of axons is relative,

and some axonal loss occurs in almost all lesions

Pathologic Correlations with

and can become substantial in severe cases. Ax-

Magnetic Resonance Imaging

onal loss can also occur very early and even be

■ SPECIAL CLINICAL POINT: The profound

present during the first clinical attack.

impact of modern imaging technologies,

Plaquelike areas of pale myelin staining are

particularly MRI, is evident from its expanding

called shadow plaques and are generally re-

role in the diagnosis and prognosis of MS.

garded as evidence of partial remyelination.

Several studies have confirmed a remarkable

High signal (bright) T2-weighted lesions corre-

potential for oligodendrocyte proliferation and

late well with the presence of lesions on gross

partial remyelination, which seems to be im-

pathology. However, T2 lesions lack specificity

peded by as-yet-unknown local factors.

for microscopic tissue pathology and seem to

represent a composite of factors including

edema, demyelination, remyelination, gliosis,

Myelin and Nerve Conduction

and axonal loss. Therefore, the T2-lesion bur-

Proteolipid protein (PLP), myelin basic protein

den does not correlate strongly with clinical dis-

(MBP), and their isoforms make up 80% to

ability even in clinically eloquent areas of the

90% of the myelin sheath with 2′,3′-cyclic nu-

CNS (brainstem and spinal cord) because not

cleotide 3′-phosphohydrolase (CNPase), myelin-

all T2 lesions purport the destructive axonal

associated glycoprotein (MAG), myelin oligo-

pathology. Indeed, this is exactly what the

dendrocyte protein (MOG), and other minor

T2-weighted lesion volume studies show—a

proteins making up the rest. Both PLP and CN-

weak but significant correlation with clinical

Pase are restricted to CNS myelin, whereas

disability (Expanded Disability Status Scale, or

MBP constitutes about 10% of the protein in

EDSS, and cognitive impairment). Because of

PNS myelin. Lipids constitute 80% of the dry

the imprecise specificity of T2 images, more

weight of myelin. Cultured oligodendroglial

emphasis is being placed on T1-weighted im-

cells contain a family of gangliosides of which

ages in which persistent low signal (black holes)

GM₃ and GM₁ are the principal components.

seems to correlate better with axonal dropout

One oligodendrocyte usually forms intern-

and clinical disability. However, one must be

odal segments of myelin on several different

cautious because during the acute enhancing

nerve fibers. This differs from the peripheral

phase of a lesion, and perhaps for several

nervous system, where one Schwann cell con-

months thereafter, low signal T1 lesions may

tributes myelin to only one internodal segment.

represent extracellular edema that can resolve.

This difference may account, in part, for the

Another misunderstood aspect of imaging

much greater efficiency of regeneration in pe-

is that there is a temporal sequence of lesion

ripheral myelin. The nodes of Ranvier have a

pathology such that acute contrast-enhanced le-

high concentration of sodium channels concen-

sions correlate well with the perivenular infil-

trated in the nodal membrane, which are re-

trate and the likelihood of a clinical exacerbation

quired for saltatory conduction. During an

but also predict future formation of black holes

episode of inflammatory demyelination, conduc-

and brain atrophy. Indeed in a clinical trial of

tion may be transiently impaired as a result of

interferon beta

(IFNβ), the drug suppressed

edema, loss of myelin, and some degree of

inflammation on the MRI in the first year of

196

Chapter 11

■ Multiple Sclerosis

treatment but did not slow brain atrophy until

observations made regarding latitudinal gradient,

the second year. This suggests that those axons

migration, and disease clustering have strongly

that were already demyelinated prior to treat-

suggested an environmental role in the disease.

ment may follow an inexorable course of de-

Although no specific microbial agent has stood

generation during the first year of treatment,

the test of time, modern molecular immunology

but the axons that were salvaged from demyeli-

has provided numerous potential mechanisms

nation by suppression of the inflammatory

through which numerous infections could medi-

attack in the first year are spared degeneration

ate autoimmunity.

in the second year. This also would explain why

in two recent short-term trials of potent im-

Genetics

munosuppressive drugs used for 12 months or

one dose, contrast-enhancing lesions were re-

Genetic susceptibility to MS has long been sus-

duced, but there was no effect on progression of

pected, based on widely differing prevalence in

disability or brain atrophy. Newer methods such

different ethnic populations. Family studies have

as magnetization transfer imaging, diffusion

found that first-degree relatives of patients are at

tensor imaging, and proton magnetic resonance

20-fold increased risk of developing MS. Fur-

spectroscopy (¹H-MRS) may be more sensitive

thermore, monozygotic twins are more likely to

measures of underlying structural pathology.

be concordant for MS (20% to 40%) than dizy-

gotic twins

(3% to 4%). Nonbiologic first-

degree (adopted) relatives are no more likely to

ETIOLOGY AND

develop MS than the population at large, which

IMMUNOPATHOGENESIS

further supports the notion that familial cluster-

ing for MS is largely genetic in origin. However,

Although the cause of MS remains uncertain,

unless one invokes incomplete penetrance of

our understanding of the underlying mecha-

genes, the twin studies also suggest a strong envi-

nisms and pathology has grown enormously.

ronmental component because no more than

■ SPECIAL CLINICAL POINT: The best

40% of monozygotic twins are concordant for

formulation of the pathogenesis of MS is that

MS. Widely different MS prevalence among

the disease is an autoimmune process that

similar high-susceptibility genetic groups that

occurs in a genetically susceptible individual

inhabit different environments (such as Anglo-

after an environmental exposure.

Saxons in England versus in South Africa)

This hypothesis is supported by an extensive and

presumably must be tied to this second, environ-

diverse literature but is based on three seminal

mental element of disease etiology. Studies of

discoveries. The recognition by Rivers that the

candidate genes and whole-genome screens sug-

acute paralytic encephalitis that occasionally fol-

gest that multiple weakly acting genes interact

lowed rabies and small pox vaccination was an

epistatically to determine risk toward MS, as

autoimmune reaction to contaminating self-

suspected from epidemiologic studies. Recently,

proteins led him to the discovery of experimental

various single-nucleotide polymorphisms (SNPs)

allergic encephalomyelitis (EAE), which has since

associated with a higher risk of developing MS

been studied extensively as an animal model for

were identified on the interleukin-2 receptor

MS. The discoveries that genes influence disease

α gene, interleukin-7 receptor α gene, and con-

susceptibility and specifically that the human

firmed in the HLA-DRA locus.

leukocyte antigen class II region on the short arm

of chromosome 6 is associated with the risk of

Immunology of Multiple Sclerosis

developing MS have led to a multitude of studies

suggesting that polygenetic influences predispose

The inflammatory reaction in MS is of un-

certain individuals to acquiring MS. Finally, the

known origin. Although no infectious agent has

197

Chapter 11

■ Multiple Sclerosis

been proved to be the cause of MS, it is hypoth-

to excitotoxic injury of oligodendrocytes or

esized that many common viruses can trigger

neurons. There has been more emphasis recently

autoimmune-mediated demyelination in suscep-

on the role of innate immune cells in MS, specif-

tible individuals through molecular mimicry

ically, dendritic cells and microglia. These cells

(cross-reactivity between microbial proteins and

seem to help facilitate the proinflammatory im-

myelin). In addition, there is evidence that quies-

mune response in MS and direct autoreactive

cent autoreactive T cells that are present in

T-cell function within the CNS through antigen

healthy individuals may be activated through

presentation. Therapies directed toward these

bystander activation by cytokine or polyclonal

cells could prove to be very beneficial.

T-cell activation mediated by bacteria or viruses.

■ SPECIAL CLINICAL POINT: It remains

DISEASE COURSE AND

uncertain how tissue injury (to myelin,

CLINICAL PATTERNS

oligodendroglia, axons, and neurons) occurs in

MS, but the inflammatory events surrounding

The clinical course of MS is divided into cate-

the vast majority of acute MS lesions seem to

gories according to neurologic symptoms as

suggest a direct immune-mediated pathology.

they develop over time. A new classification for

MS categories was developed by consensus

The MS lesion resembles a delayed-type hyper-

among MS experts (Table 11.1).

sensitivity (DTH) reaction, containing activated

T cells, B cells, numerous mononuclear phago-

Relapsing-Remitting Multiple Sclerosis

cytes, inflammatory cytokines, and adhesion

molecules. Electron microscopy studies suggest

Relapsing-remitting MS (RR-MS) is the most

the macrophage may play a major role in the di-

common form in patients younger than age

rect stripping of myelin from axons, although

40 years. Patients may develop focal neurologic

this could be a secondary phagocytic response

symptoms and signs acutely or over a few days.

TABLE 11.1

Multiple Sclerosis Clinical Categories

Multiple Sclerosis Clinical Categories and Disease Explanation

Relapsing-

Secondary

Primary

Progressive-

remitting

progressive

relapsing

(RR-MS)

(SP-MS)

(PP-MS)

(PR-MS)

Episodes of acute

Gradual neurologic

Gradual, nearly

Gradual neurologic

worsening with

deterioration with or

continuous neurologic

deterioration from

recovery and stable

without superimposed

deterioration from

onset of symptoms

course between

relapses in a previous

onset of symptoms

with subsequent

relapses

RR-MS patient

superimposed relapses

Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology. 1996;46:907-911.

198

Chapter 11

■ Multiple Sclerosis

These exacerbations or attacks are remarkably

patients with SP-MS spontaneously stabilize for

unpredictable and heterogeneous in character,

considerable periods, although they only rarely

probably because they result from varying de-

recover after deficits have persisted for 6 months.

grees of inflammation that can occur in any

The pathogenic mechanisms underlying conver-

part of the brain or spinal cord.

sion from RR-MS to SP-MS may relate to failure

of remyelination and progressive axonal injury.

■ SPECIAL CLINICAL POINT: Common

presentations of multiple sclerosis include

blurred or double vision, sensory symptoms

Primary Progressive Multiple Sclerosis

(numbness, tingling, or pain), weakness, vertigo,

Primary progressive MS (PP-MS) accounts for

or impaired balance.

approximately 10% to 15% of patients and is

A new symptom will commonly present over 24

characterized by progressive worsening from

to 72 hours, stabilize for a few days or weeks,

the onset of symptoms without interposed re-

and then improve spontaneously over 4 to 12

lapses. Patients with PP-MS are more likely to

weeks. Subsequent new focal symptoms or

be men and older than 40 years of age at symp-

signs typically follow the initial attack months

tom onset. This form of the disease often pres-

or years later and again remit partially or com-

ents with progressive gait disorder as a result of

pletely. It is very common for old symptoms to

leg weakness, spasticity, and impaired coordi-

persist or reoccur, especially in response to peri-

nation. In cases of progressive neurologic dys-

ods of stress such as infections or prolonged el-

function, it is extremely important to rule out

evations of core body temperature. Over time,

structural pathology, infections, and hereditary

it becomes difficult to determine whether the

and other neurodegenerative diseases. Patients

symptom flare represents a new exacerbation

with PP-MS have fewer gadolinium-enhancing

or worsening symptoms referable to past dis-

brain lesions on MRI, less tissue inflammation

ease. Recovery from relapses is often incom-

on histopathologic assessment, and less cere-

plete, and permanent disability can accumulate

brospinal fluid (CSF) inflammation than typical

in a stepwise fashion at this stage of the disease.

for SP-MS; pathologic studies have suggested

this form of the disease may represent a pri-

mary problem with the oligodendrocyte.

Secondary Progressive Multiple Sclerosis

Secondary progressive MS (SP-MS) refers to the

Progressive-Relapsing Multiple Sclerosis

patient with an initial RR-MS course who then

progressively worsens over months (at least 6)

According to the new classification, progres-

to years. Natural history studies have shown

sive-relapsing MS (PR-MS) refers to the rare

that with time most patients with RR-MS con-

patient with progressive disease from symptom

vert to SP-MS. This usually occurs after 10 to

onset, who subsequently experiences one or

20 years from onset or after the age of 40. A

more relapses. In all likelihood, this is another

patient with SP-MS may still experience re-

form of SP-MS without clinically apparent re-

lapses but does not stabilize between relapses.

lapses in the early stages of disease, and if con-

The predominant clinical pattern is one of con-

sidered separately, this group comprises only

tinued clinical worsening. As time passes, re-

6% or fewer of all patients with MS.

lapses become less discrete, and the pattern

Disease patterns change over time, and it

becomes one of continued worsening without

may be difficult at a given time to clearly catego-

relapses. Conversion to SP-MS is considered a

rize a patient’s disease. The problem is particu-

poor prognostic sign because this stage of the

larly difficult when a patient is converting from

disease is much more refractory to the presently

a purely relapsing-remitting disease course to a

available immunomodulatory therapies. Some

purely progressive disease course. This has been

199

Chapter 11

■ Multiple Sclerosis

termed “relapsing progressive MS” by some

Marburg Disease

and “transitional MS” by others, but these dis-

An acute rapidly progressive form of MS, often

ease categories cannot be defined precisely by

called Marburg disease, is characterized by a

current methods. Observation for as long as

person who develops acute or subacute pro-

1 year may be required to categorize such a pa-

gressive neurologic deterioration, leading to

tient with confidence.

severe disability within days to months. The

disease may progress steadily to a quadriplegic

Clinically Isolated Syndromes

obtunded state with death as a result of inter-

and Prognosis

current infection, aspiration, or respiratory

failure from brainstem involvement. Post-

■ SPECIAL CLINICAL POINT: In the era of

mortem studies have documented inflamma-

partially effective prophylactic MS therapies,

tion in the optic nerves, optic chiasm, cerebral

there has been increased emphasis on making a

hemispheres, and spinal cord. The pathology

diagnosis early in the course of the disease to

reveals a pronounced mononuclear cell infil-

initiate appropriate preventative treatment.

trate with severe axonal damage and tissue

The use of MRI as a diagnostic tool is dis-

necrosis.

cussed later. T2-lesion burden at the time of

first MS symptoms (optic neuritis, transverse

myelitis, etc.) not only determines the likeli-

Neuromyelitis Optica

hood of converting to clinically definite MS

Neuromyelitis optica (NMO) or Devic disease

but is also predictive of future disability.

refers to the patient who presents with both

For example, a patient with a single episode

optic neuritis and transverse myelitis, occur-

of optic neuritis and an abnormal brain MRI

ring either simultaneously or separated by a

has a 50% to 80% risk of subsequently being

few months to years. Several features differen-

diagnosed with MS in 5 to 10 years. The fre-

tiate this disease from classical MS, including

quency of gadolinium-enhancing lesions cor-

older age of onset, higher female to male inci-

relates with the likelihood of having a clinical

dence (9:1), limited white matter lesions on a

exacerbation and predicts future brain atrophy.

brain MRI, multilevel contiguous typically cen-

However, because T2-weighted lesions lack

tral spinal cord lesions (three or more vertebral

specificity for tissue pathology and gadolinium

levels), and severe disability and death as a re-

enhancement is transient (2 to 8 weeks), T1

sult of respiratory failure in one third of all pa-

hypointense lesions (black holes) and brain

tients. NMO also seems to be more common

atrophy may be a better measure of axonal

than MS in non-Caucasians. Pathologically,

loss and have been shown to correlate more

the syndrome is variable with some lesions

strongly with both present and future disabil-

characterized by inflammation and demyelina-

ity. The presence of mild atrophy or persistent

tion, but it is invariable with severe necrosis

T1 black holes early in the course of MS should

and many patients having cavitary lesions in

alert the physician to a potentially aggressive

the spinal cord. Those patients who survive the

form of the disease.

acute attack commonly follow a course with

features indistinguishable from RR-MS but

have a worse prognosis. An NMO serum bio-

OTHER VARIANTS OF

marker (NMO-IgG) has recently become com-

MULTIPLE SCLEROSIS AND

mercially available, which can help differentiate

IMPORTANT MIMICKERS

this disease from MS. This distinction is of

Several other variants of MS have been de-

utmost importance since the therapeutic inter-

scribed and are important to recognize.

ventions are different for NMO and MS. While

200

Chapter 11

■ Multiple Sclerosis

the NMO-IgG blood test is highly specific and

immune regulation. The anti-inflammatory cy-

the majority of clinically diagnosed NMO

tokine, transforming growth factor-β₁ (TGF-

patients will be NMO-IgG positive, a negative

β₁), is typically decreased in MS and increases

blood test does not exclude the diagnosis.

upon vitamin D supplementation. This associa-

tion further supports the contributions of envi-

Acute Disseminated Encephalomyelitis

ronmental factors, especially since sunlight

exposure provides a major source for vitamin

Acute disseminated encephalomyelitis (ADEM)

D. This could also explain the unusual geo-

and its hyperacute form, acute necrotizing hem-

graphical distribution of MS.

orrhagic encephalopathy (ANHE), are thought

to be forms of immune-mediated inflammatory

demyelination. They differ from MS in that they

SYMPTOMS AND SIGNS

are typically monophasic, whereas MS is by def-

See Tables 11.2 and 11.3.

inition multiphasic or chronically progressive.

Patients with ADEM or ANHE usually present

with fever, headache, meningeal signs, and al-

Optic Neuritis

tered consciousness, which are exceedingly rare

Multiple sclerosis commonly affects the optic

in MS. Multiple reports of clinical and patho-

nerves and chiasm, and approximately 30% of

logic overlap have been published. Some authors

patients present with visual symptoms. In acute

have suggested that the MRI can be used to dif-

optic neuritis, the patient experiences monocu-

ferentiate MS from ADEM, but no reliable clini-

lar loss of central vision and often has eye or

cal criteria to differentiate the two processes

brow pain, which worsens on lateral eye move-

exist.

ment. The symptoms may present over a few

hours to 7 days, with a few cases progressing

over several weeks. Loss of visual acuity and

PRECIPITATING FACTORS

color perception are often considerable. Most

Exposure to viruses and bacteria has been asso-

patients will recover significantly after

2 to

ciated with precipitating disease exacerbations.

3 months, although continued improvement

The risk of an exacerbation decreases during

pregnancy, with the rate being decreased by ap-

TABLE 11.2

proximately two thirds in the third trimester.

Initial Symptoms in Patients with

The risk of an acute attack in the first 3 months

Multiple Sclerosis

postpartum is increased and has been estimated

that 20% to 40% of postpartum patients with

Symptom

Percentage

MS will have an exacerbation. The decreased

Sensory disturbance in one or

relapse rate during pregnancy is probably re-

more limbs

lated to a family of immunosuppressive hor-

Disturbance of balance and gait

mones and Th2. Overall, pregnancy probably

Vision loss in one eye

has little overall effect on the course of the dis-

Diplopia

ease, and therefore remains a realistic possibil-

Progressive weakness

ity for woman with MS. There is increasing

Acute myelitis

evidence that vitamin D deficiency may play an

Lhermitte’s symptom

important role in MS. Recent studies have sug-

Sensory disturbance in face

gested that higher serum vitamin D levels corre-

Pain

spond to a decreased risk of developing MS. It

Paty DW, Poser CM. Clinical symptoms and signs of multiple

is well established that vitamin D receptors are

sclerosis. In: Poser CM, ed. The Diagnosis of Multiple Sclerosis.

New York: Thieme & Stratton; 1984:27.

present within immune cells and may promote

201

Chapter 11

■ Multiple Sclerosis

TABLE 11.3

Common Symptoms and Signs in Patients with Multiple Sclerosis

Symptom

Sign

Comment

Visual blurring (central)

Diminished acuity (central)

Syndrome of optic neuritis seen

usually early in disease

Vision loss/eye pain

Scotoma/deafferented pupil

Diplopia

Internuclear ophthalmoplegia

May be associated with nausea,

vertigo, or other brainstem signs

Oscillopsia

Rarely other oculomotor weakness,

flutter, or dysmetria

Loss of dexterity

Upper motor neuron signs often

Develops in many MS patients

affecting legs early and arms later

over time

Weakness

Tightness and pain

Shaking

Intention tremor, dysmetria, dysarthria,

Occurs in 30% of patients; may

truncal or head titubation

be the predominant

manifestations in some patients

Imbalance

Paresthesias

Decreased vibration and position

Sensory symptoms are often

sense in legs > hands

painful and distressing

Loss of sensation

Decreased fine sensation in hands

Bandlike disturbance

Sensory level

Falls

Wide-based gait

Gait disturbances are common in

MS and can cause severe disability

Lack of coordination

Ataxic and unsteady gait

Inability to concentrate

Diminished concentration, processing

May be subtle or have severe impact

or learn

speed, or verbal learning on

on patient and family; severe

neuropsychologic testing

dementia in <10% of patients

Easily distractible

Emotional lability

Episodic crying or laughing

Distressing to patient; generally not

related to patients’ actual emotions

Depression

—

Commonly underrecognized or

underestimated

Fatigue

—

Disabling in many patients with MS;

does not correlate with severity of

motor signs

Pain

—

Numerous etiologies (see text)

Urinary urgency,

Requires urodynamic testing to

Often complicated by intercurrent

hesitancy, frequency,

fully characterize type of bladder

UTI

and incontinence

dysfunction

MS, multiple sclerosis; UTI, urinary tract infection.

202

Chapter 11

■ Multiple Sclerosis

can occur as long as a year later; however, some

muscle palsies, and the classical internuclear

patients sustain permanent damage and can be-

ophthalmoplegia (INO).

come blind. Acuity is variably diminished in the

■ SPECIAL CLINICAL POINT: An INO results

affected eye. A central or centrocecal scotoma

from damage to the medial longitudinal

(marked enlargement of the blind spot to in-

fasciculus, and its presence in a young adult,

volve central vision) can be documented at the

particularly when bilateral, is highly suggestive

bedside with an Amsler grid, and red desatura-

of MS.

tion can be demonstrated with color plates or

with a red-tipped hat pin. Using the swinging

In its complete form, one eye is unable to

flashlight test in a darkened room, one can

adduct and the other has abducting nystagmus.

demonstrate a defect in the afferent pathway

More commonly one observes varying degrees

such that pupillary constriction in the affected

of adduction lag with dysconjugate nystagmus.

eye is greater with contralateral than with

The patient is asked to make a rapid saccade

direct light stimulus. A positive test reveals a

from midline to a laterally situated target, and

relative afferent pupillary defect, sometimes

the examiner focuses on whether the eyes move

called a Marcus Gunn pupil. Funduscopic

in a conjugate manner. The condition is fre-

examination is usually normal in acute retrob-

quently bilateral, with one eye being more in-

ulbar neuritis. When the optic nerve is affected

volved than the other. Quantitative infrared

anteriorly, the disc may be congested and

oculography has demonstrated that the fre-

swollen, thus resembling papilledema. Several

quency of subtle INOs is probably much

months after an optic neuritis, the disc often ap-

greater than can be clinically appreciated.

pears pale, especially at the temporal border,

and this can provide evidence of a previous at-

Motor Dysfunction

tack. Occasionally, optic nerve demyelination

and axonal damage can manifest silently and is

Weakness, spasticity, hyperreflexia, and Babinski’s

noticed only in the setting of other symptoms

sign (upgoing toe) are common manifestations

suggestive of MS.

of damage to the pyramidal tracts

(corti-

A novel noninvasive eye scan called optical

cospinal tracts) in patients with MS. This most

coherence tomography (OCT) is now being

commonly presents in the legs (spastic para-

used to assess MS patients. The scan provides

paresis) because of the relative length that these

high-resolution quantifiable images of the reti-

fibers have to travel, which makes them more

nal nerve fiber layer that have been shown in

susceptible to numerous areas of demyelina-

recent studies to reflect optic nerve damage

tion and noticeable conduction delays. It is not

even in asymptomatic eyes. OCT scans may

uncommon for cervical lesions to manifest first

prove to be a very important biomarker for dis-

in the lower extremities. Concomitant symp-

ease monitoring and therapeutic effectiveness;

toms include stiffness, spasms, and pain. Ex-

however, since OCT scans are not specific for

treme hyperreflexia causes clonus, which is

MS/optic nerve pathology, they are not consid-

usually described by the patient as a shaking or

ered a diagnostic test to the exclusion of a thor-

tremor.

ough eye exam.

Cerebellar Signs

Oculomotor Syndromes

End-point tremor

(dysmetria) on finger to

Eye movement abnormalities are also extremely

nose testing is most noticeable in the upper ex-

common in MS and include broken (saccadic)

tremities, probably because of their important

smooth pursuits, nystagmus, ocular dysmetria

role in fine movement tasks. Lower extrem-

(overshooting target), isolated extraocular

ity and midline truncal ataxia result in gait

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Chapter 11

■ Multiple Sclerosis

Cognitive and Memory Symptoms

impairment, and some patients with MS are

mistaken for being intoxicated. Head or trun-

■ SPECIAL CLINICAL POINT: Approximately

cal titubation or scanning dysarthria (impaired

50% of patients with MS exhibit significant

prosody) can become disabling aspects of the

short-term memory loss or difficulty with

disease.

concentration, attention, and processing speed.

Cortical deficits relating to language and visual

Sensory Symptoms

spatial function are much less common. In only

a minority of patients is dementia an incapaci-

Approximately one third of patients with MS

tating aspect of the disease. Correlations be-

present initially with sensory disturbance in-

tween the severity of cognitive impairment and

volving the limbs, and the majority of patients

the extent of MRI changes have been found.

will have paresthesias as the disease progresses.

Symptoms are usually described as “pins and

Psychiatric Manifestations

needles” and less commonly as a loss of sensa-

tion. Paresthesias can be painful burning or

Inappropriate laughing and weeping, often in

electrical sensations. The sensory symptoms

response to minor provocation, occurs in more

follow a spinal cord pattern, often with an in-

than 10% of patients with MS. Approximately

complete loss of sensation to either vibration

50% of patients with MS will have an episode

(posterior columns) or pinprick (spinothalamic)

of major depression during the course of their

pathways. It is important to distinguish the

illness, and many patients will have chronic

spinal pattern from peripheral or root lesions,

low-level depressive symptoms. MRI studies

which follow cutaneous or dermatomal pat-

have confirmed an association with lesion load

terns of sensory loss. Occasionally, patients will

or atrophy, especially in the frontal and tem-

describe patches of numbness or symptoms in

poral lobes, and depression in MS. The health

an apparently nonanatomic distribution, which

care provider should have a heightened aware-

presumably could relate to multifocal areas of

ness of the risk of suicide in patients with MS.

demyelination or may be a manifestation of

Depression may also be part of a bipolar ill-

psychiatric disease.

ness, which is more common in patients with

Lhermitte’s phenomenon refers to an elec-

MS than in control populations.

tric tingling sensation that is precipitated by

Fatigue

neck flexion, usually into the arms or down the

back. Lhermitte’s phenomenon suggests cervi-

Fatigue may be the most common single com-

cal spinal cord disease. It is very common in

plaint of patients with MS and can be dis-

patients with MS with cervical spinal cord in-

abling. Fatigue usually comes on late in the

volvement but is not specific for MS.

afternoon or may occur with strenuous activity

or with exposure to heat. Short rest periods

usually restore function. A less specific and

Pain

more generalized fatigue is also seen and may

Pain is very common in MS and may be caused

take the form of overwhelming lassitude, which

directly by abnormal firing of sensory nerves,

can be disabling. Episodic fatigue may herald

as a result of severe spasticity, or because of

clinical disease exacerbation. The mechanisms

secondary orthopedic injuries. Trigeminal neu-

underlying MS fatigue are unknown.

ralgia (TN) or atypical facial pain are common

causes of severe pain in MS. Younger patients

Bladder, Bowel, and Sexual Dysfunction

who present with TN should be evaluated for

MS as this pain syndrome is more common

Bladder dysfunction is common and can be di-

above the age of 50.

vided into two categories. Patients may fail to

204

Chapter 11

■ Multiple Sclerosis

empty urine adequately, causing urinary hesi-

diagnostic criteria based on clinical features

tancy, postvoid fullness or dribbling, or frank

supplemented by laboratory tests have been

inability to initiate urination despite a feeling

used. The original and recently revised Mc-

of fullness. Alternatively, patients may fail to

Donald criteria were developed by a panel of

properly store urine, causing urgency, urge in-

MS experts and were based on review of ex-

continence, dysuria, frequency, and nocturia.

tensive supportive scientific studies focusing

The correlation between bladder symptoms

on the sensitivity and specificity of MRI diag-

and the underlying pathophysiology is often

nostic criteria (Table 11.4). The major change

imperfect; therefore, objective testing by cys-

associated with the latest criteria is that a di-

tometrogram is often necessary to characterize

agnosis of MS can be made early after a clini-

the problem and to guide management.

cally isolated syndrome if a follow-up MRI

Constipation is also common in MS and

performed 1 month later demonstrates the

should be managed aggressively to prevent

formation of a new T2 lesion that is of suffi-

complications. Fortunately, fecal incontinence

cient size and location (Tables 11.5 and 11.6).

is relatively rare but when present is socially

These criteria also define MRI lesion charac-

devastating.

teristics that increase the likelihood of MS:

Sexual dysfunction is reported by 50% to

number (>9), abutting the ventricles, juxtacor-

75% of patients with MS and is exacerbated by

tical, infratentorial, spinal, and contrast en-

a variety of problems, including fatigue, de-

hancing. As with all the criteria, the clause

creased sensation, decreased libido, erectile

that “there must be no better explanation” re-

dysfunction, spasticity, impaired lubrication,

mains a critical part of the definition of MS.

body image disorder, and depression.

Critics of these criteria have complained they

are too restrictive, whereas purists remain un-

Other Manifestations

convinced of the utility of MRI for diagnosis.

The lack of specificity for MS of white matter

Paroxysmal disorders in MS include dystonic

lesions seen on MRI must also be remem-

spasms, tic douloureux, episodic paresthesias,

bered, and overreliance on imaging to the ex-

seizures, ataxia, and dysarthria. Sleep disorders

clusion of the clinical picture can lead to

and sleep-related movement disorders (restless

diagnostic errors. Ultimately, how one defines

leg syndrome) are common in MS and can con-

the clinical syndrome of MS, within the recog-

tribute to daytime fatigue. Various other disease

nized spectrum of multifocal demyelination

manifestations occur more rarely, including

discovered at autopsy to hyperacute demyeli-

hearing loss, spasms, aphasia, homonymous

nating syndromes, remains an ongoing de-

hemianopsia, gait apraxia, movement disorders

bate. The revised McDonald criteria provide

(myoclonus and chorea), and autonomic dys-

an important update and have been adopted

function (sweating, feeling hot and cold, edema,

for the incorporation of patients in research

and postural hypotension).

studies.

Important Radiologic and

DIAGNOSIS OF MULTIPLE SCLEROSIS

Laboratory Features

■ SPECIAL CLINICAL POINT: MS is

Magnetic Resonance Imaging

diagnosed clinically through the demonstration

of CNS lesions disseminated in time and space

■ SPECIAL CLINICAL POINT: MRI is the

and with no better explanation for the disease

single most useful test in confirming the

process.

diagnosis of MS.

There is no single diagnostic test, and several

A brain MRI performed on a high field (>1.5

other diseases can mimic MS. Therefore,

Tesla) magnet is abnormal in 95% of patients

205

Chapter 11

■ Multiple Sclerosis

TABLE 11.4

McDonald Diagnostic Criteria

Paraclinical Tests Needed

Clinical Presentation

Space

Time

Two attacks; two locations

Two attacks; one location

MRI abnormal or

two MRI lesions + CSF

One attack; two locations

MRI criteria or

One attack; one location (CIS)

MRI abnormal or

second attack

two MRI lesions + CSF

MRI criteria or

second attack

PP-MS (progression for 1 year)

Need two of the following:

Nine MRI brain lesions or four

to eight brain lesions + VEP

Two MRI cord lesions

Positive CSF^a

CSF, cerebrospinal fluid; CIS, clinically isolated syndromes; PP-MS, primary progressive multiple sclerosis; VEP, visual-evoked potential.

^aEvidence of oligoclonal bands or increased IgG index or both.

Modified from Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.” Ann

Neurol. 2005;58:840-846.

with clinically definite MS, and the absence of

best on sagittal imaging

(Dawson’s fingers).

high signal abnormalities in either the brain or

Typical locations include the corpus callosum,

spinal cord is strong evidence against the diag-

abutting the walls of the ventricles, in the juxta-

nosis of MS. MS lesions appear as areas of high

cortical lesions

(grey-white junction), in the

signal usually in the cerebral white matter on

posterior fossa (pons and cerebellar peduncles),

T2-weighted images (Figs. 11.4 and 11.5). They

and in the spinal cord (cervical twice as com-

are typically round or ovoid but may appear as

monly as thoracic). Fluid-attenuated inversion

fingerlike projections extending perpendicu-

recovery (FLAIR) is more sensitive than con-

larly from the ventricular wall that is visualized

ventional T2-weighted imaging for cerebral

lesions but is less useful in the posterior fossa or

spinal cord. Short tau inversion recovery (STIR)

TABLE 11.5

images have the highest sensitivity for detecting

MRI Criteria for Brain Abnormality

Three of the following^a:

TABLE 11.6

One Gd-enhancing lesion or nine T2-hyperintense

Dissemination in Time

lesions if there is no Gd-enhancing lesion

At least one infratentorial lesion

Two possible ways to demonstrate imaging

At least one juxtacortical lesion

dissemination in time:

At least three periventricular lesions

(1) Scan 3 months after clinical event showing a Gd-

positive lesion not at same site of original event

Gd, gadolinium.

(2) New T2W lesion at least 30 days after initial

^aOne spinal cord lesion can be substituted for one infratentorial

brain lesion. An enhancing cord lesion can substitute for an

clinical event scan

enhancing brain lesion and count twice in the MRI criteria for

diagnosis (one enhancing lesion and one infratentorial lesion).

Gd, gadolinium; T2W, T2-weighted.

Polman CH, Reingold SC, Edan G, et al. Ann Neurol. 2005;58:840-846.

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Chapter 11

■ Multiple Sclerosis

FIGURE 11.4 Magnetic resonance imaging scans of the brain of a patient with multiple sclerosis.

A: Fluid-attenuated inversion recovery (FLAIR) sequence demonstrating typical periventricular white

matter lesions. B: On T1-weighted image with contrast only two of these lesions appear active. C: In a

separate patient, T2-weighted scan demonstrating two demyelinating lesions of apparent equal intensity.

D: The T1-weighted images with contrast reveal one lesion is active and the other is hypointense,

suggesting formation of a T1 black hole. Persistence of T1 holes correlates with axonal dropout.

demyelination in the spinal cord. All MRIs per-

structural lesions such as spinal tumors, sy-

formed in suspected or definite patients with

rinxes, Chiari malformations, and herniated

MS should be done before and after intra-

disc material.

venous (IV) administration of the paramagnetic

agent gadolinium diethylenetriaminepentaacetic

CSF Analysis

acid

(GdDTPA). Lesions that enhance after

GdDTPA have been shown to represent acute

CSF studies to rule out infectious and neoplas-

inflammatory lesions and as such increase the

tic etiologies and to look for the presence of in-

likelihood that a lesion is related to MS as op-

trathecal immunoglobulin (Ig) synthesis are an

posed to a nonspecific small-vessel disease

important part of laboratory testing in cases in

process. Enhancing lesions are also used as a

which the clinical picture and MRI are not di-

measure of disease activity in clinical trials. En-

agnostic. The presence of more than 50 mononu-

hancing lesions last only for 2 to 8 weeks and

clear cells/mm3, any neutrophils, or a CSF

therefore can be missed easily, so FLAIR is a

protein of greater than 100 mg/dL should raise

more reliable measure of the total burden of

concern about a diagnosis of MS. Depending on

disease or for infrequent serial scanning. MRI

the laboratory and technique, approximately

is also useful for ruling out non-MS-related

80% to 90% of patients with clinically definite

208

Chapter 11

■ Multiple Sclerosis

system and in about 15% of patients with non-

Serologic Testing

inflammatory diseases such as tumors and in-

As part of excluding other disease processes, it

farctions. MBP is released after CNS tissue

is often prudent to obtain peripheral blood to

injury from many processes, and other than

test: vitamin B₁₂, methylmalonic acid, 25-OH

documenting an organic etiology to the clinical

vitamin D, thyroid-stimulating hormone, ery-

presentation, the test is not helpful.

throcyte sedimentation rate, antinuclear anti-

bodies, Lyme titer, and rapid plasma reagin. In

Evoked Potentials

unusual cases, more extensive testing may in-

clude antineutrophil cytoplasmic antibodies,

Sensory evoked potentials are used in MS to

antiphospholipid antibodies, anti-dsDNA anti-

provide objective evidence to supplement sub-

bodies, anti-Smith antibodies, Sjögren syn-

jective sensory symptoms or occasionally to re-

drome A and B antibodies, hepatitis profile,

veal clinically silent lesions. This can be

copper levels, ceruloplasmin, NMO-IgG, and

particularly valuable if a psychiatric basis for

angiotensin-converting enzyme. Rarely, human

the symptoms is being considered or in early

immunodeficiency virus and opportunistic in-

cases in which MRIs are inconclusive. Of the

fection can mimic MS. Some risk exists of ob-

three types of evoked potentials, brainstem au-

taining false-positive tests, and some experts

ditory evoked response (BAER), somatosen-

have questioned the cost-effectiveness of exten-

sory evoked potential

(SSEP), and visual

sive serologic testing.

evoked potential (VEP), the latter is the most

useful because remote optic nerve disease is

Errors in Diagnosing Multiple Sclerosis

common and not well visualized on MRI. VEPs

can also be helpful in supporting a diagnosis of

Conditions commonly misdiagnosed for MS are

PP-MS based on the McDonald criteria.

listed in Tables 11.7 and 11.8.

TABLE 11.7

Conditions Commonly Mistaken for Multiple Sclerosis

Vascular

Structural

Degenerative

Other

Infections

Diseases

Lesions

Diseases

Conditions

Small-vessel

Cervical

Motor system disease

HIV myelopathy

Neuromyelitis Optica

disease

spondylosis

Spinocerebellar deg.

HIV cerebritis

Sarcoidosis

AVM

Skull-base anomaly

HSP

HTLV-1

Sjögren syndrome

Vasculitis

Infratentorial tumors

Lyme disease

Cobalamin deficiency

Spinal cord tumors

AVM, arteriovenous malformation; Deg., degeneration; HSP, hereditary spastic paraparesis; HIV, human immunodeficiency virus; HTLV-1, human

T-cell lymphotrophic virus type-1.

209

Chapter 11

■ Multiple Sclerosis

TABLE 11.8

may be lacking and comorbid psychiatric dis-

Diseases That Mimic Multiple

ease can be the primary symptom. The level of

Sclerosis on MRI

confidence in the diagnosis of MS increases

with time, and the physician should always

ADEM

Histiocytosis

be alert to alternative or coexistent disease

HTN/small-vessel disease

HTLV-1

processes even in patients who carry a diagno-

CADASIL

Lyme disease

sis of MS.

Sarcoidosis

Leukodystrophies

Vasculitis

Mitochondrial disease

When to Refer a Patient to a Neurologist

Migraine

Lupus

Aging-related changes

Behçet disease

MS is a complicated neurologic disease, and

Organic aciduria

HIV

the approaches to diagnosis and treatment are

ADEM, acute disseminated encephalomyelitis; HTN, hypertension;

changing rapidly.

HTLV-1, human T-cell lymphotrophic virus type-1; CADASIL, cerebral

autosomal dominant arteriopathy with subcortical infarcts and

■ SPECIAL CLINICAL POINT: It is

leukoencephalopathy.

appropriate to refer any patient suspected of

having MS to a neurologist with MS experience,

even if the patient has had only a single clinical

■ SPECIAL CLINICAL POINT: The rules of

event.

dissemination in time and space are critical to

Symptoms that are suspicious for MS include

making an accurate diagnosis of MS.

unexplained numbness/tingling, fatigue, uri-

ADEM can appear clinically and radiographi-

nary urgency, loss of vision in one eye, or im-

cally like MS but is usually a monophasic dis-

paired coordination. Although many of these

ease process. Similarly, the presence of a

symptoms occur commonly in healthy people,

cervicomedullary lesion such as with a Chiari

it is the persistence of a symptom or multiple

malformation can cause multiple symptoms

symptoms that should provoke further evalua-

emanating from one location in the nervous

tion. The non-neurologist should not be dis-

system, so careful attention to documenting a

suaded by concomitant emotionality or

clear second location is critical. In both situa-

psychiatric disease because this can be part of

tions, MRI has proved extremely useful; how-

the presentation of MS. A brain MRI is a good

ever, T2-weighted lesions are not specific for

first step in screening for MS. The presence of

MS, and therefore vascular, infectious, and neo-

any high signal lesions in a young person war-

plastic etiologies of multifocal disease must be

rants neurologic consultation.

considered. The extent of exclusionary testing

is usually dictated by the clinical presentation.

In a case of RR-MS with typical findings and

THERAPY OF MULTIPLE SCLEROSIS

confirmatory brain MRI, little other testing is

Disease-Modifying Therapies

necessary. In atypical presentations with un-

usual historical features (fever, altered level of

Four partially effective disease-modifying thera-

consciousness, exposures, no relapses), strong

pies (DMT) for the initial management of MS

family history, no eye findings, purely progres-

are available in the United States: IFNb-1a

sive disease, or very aggressive disease from

(Avonex), IFNb-1a

(Rebif), IFNb-1b

(Be-

onset (NMO), more extensive testing is manda-

taseron), and glatiramer acetate

(Copaxone).

tory. Finally, psychiatric disease must be consid-

Mitoxantrone (Novantrone) was approved in

ered in the patient with numerous symptoms

the United States for the treatment of worsening

and little objective evidence for disease. The ex-

forms of RR-MS, PR-MS, and SP-MS. A sixth

perienced clinician, however, recognizes that

novel agent, Natalizumab (Tysabri), was reap-

early in the course of MS, objective evidence

proved for use in the United States for patients

210

Chapter 11

■ Multiple Sclerosis

TABLE 11.9

Pharmacologic Treatments: Immunomodulating and Acute Relapses

Drug Name

Indication

Starting Dose

Stable Dose

Comments

Avonex

Relapsing MS

30 mcg IM q.d.

Flulike side effects

(Interferon beta-1a)

CIS

Rebif

Relapsing MS

22 mcg SC t.i.w.

44 mcg t.i.w.

Flulike side effects

(Interferon beta-1a)

CIS

Betaseron

Relapsing MS

0.0625 mg SC

0.25 mg SC q.o.d.

Flulike side effects

(Interferon beta-1b)

CIS

q.o.d.

Copaxone

Relapsing MS

20 mg SC q.d.

Idiosyncratic chest

(Glatiramer acetate)

CIS

pain/palpitations

Tysabri

Relapsing MS

300 mg IV q4

PML and other

(Natalizumab)

weeks

infections reported

Mitoxantrone

Worsening forms

5-12 mg/m² IV

Maximum lifetime dose

(Novantrone)

of relapsing MS

q3 months for

140 mg/m²

and SPMS

2-3 years

Cardiotoxicity and

leukemia reported

Contraindicated in

Methylprednisolone Acute relapses

1,000 mg IV q.a.m.

1,000 mg IV

avascular necrosis

× 3-5 days

q.a.m. × 3-5 days

MS, multiple sclerosis; CIS, clinically isolated syndrome; IM, intramuscularly; SC, subcutaneous; IV, intravenous; SPMS, secondary progressive multiple

sclerosis.

with RR-MS who have either inadequate re-

that these drugs improve quality of life and

sponse to first-line therapies or are intolerant

cognitive function.

to them. Table 11.9 lists these immunomodu-

The major difference between the IFNβ

lating pharmacologic treatments.

drugs is that Avonex is given weekly intramus-

cularly (IM), Rebif is given three times a week

Beta Interferons Beta interferons

(IFNα) are

subcutaneously (SC), and Betaseron is given

naturally occurring cytokines with a variety

every other day SC. The adequacy of IFNβ-1a

of immunomodulating and antiviral activities

weekly dosing has been questioned. Studies ap-

that may account for their therapeutic utility.

pear to support a modest dose-response effect

IFNα may act through several mechanisms

for IFNβ; however, one study of double dose

including modulation of major histocompati-

(60 mg IM) Avonex, once a week, found no

bility complex (MHC) expression, suppressor

benefit over the single-dose regimen. Whether

T-cell function, adhesion molecules, and ma-

the benefit of more frequent dosing is sustained

trix metalloproteinases. All three IFNα drugs

for periods longer than 2 years remains un-

have been shown to reduce relapses by about

clear, and the increased incidence of neutraliz-

one third in double-blind placebo-controlled

ing antibodies (NAbs) with the more frequent

trials and are recommended either as first-

SC dosing must also be considered.

line therapies or for glatiramer acetate intol-

Flulike symptoms, including fever, chills,

erant patients with RR-MS. In addition, in

malaise, muscle aches, and fatigue, occur in ap-

each of these trials, IFNβ resulted in a 50%

proximately 60% of patients treated with ei-

to 80% reduction of the inflammatory lesions

ther IFNβ-1a or IFNβ-1b and usually dissipate

visualized on brain MRI. Evidence also exists

with continued use and premedication with

211

Chapter 11

■ Multiple Sclerosis

nonsteroidal anti-inflammatory drugs (NSAIDs).

placebo-controlled, multicenter trial to reduce

Other side effects include injection-site reactions,

the number of treated relapses by 67% and

worsening of preexisting spasticity, depression,

slowed progression on EDSS, ambulation

mild anemia, thrombocytopenia, and elevations

index, and MRI measures of disease activity. It

in transaminases, which are usually not severe

is therefore recommended for worsening forms

and rarely lead to treatment discontinuation.

of MS. Acute side effects of mitoxantrone in-

Development of NAbs can occur with any

clude nausea and alopecia. The lifetime use of

of the IFNβ products. Although the results are

this drug is limited to 2 to 3 years (or a cumu-

variable, IFNβ-1a weekly IM (Avonex) is re-

lative dose of 120 to 140 mg/m²) because of its

ported to have the lowest incidence. The effect

cumulative cardiotoxicity. Since a more rapid

of NAbs on long-term efficacy remains to be

cardiotoxicity can occur, a new black box

fully defined. Some experts recommend that

warning was added recommending patients to

the results of an NAb assay in patients who ex-

have their baseline left ventricular ejection

hibit insufficient treatment response may guide

fraction checked prior to the start of therapy

decisions for alternative therapy.

and retested before each subsequent dose.

There is also increasing awareness and concern

Glatiramer Acetate Glatiramer acetate (Copax-

about treatment-related leukemias with this

one) is a polypeptide mixture that was origi-

drug. More cases have been identified over the

nally designed to mimic MBP. The mechanism

last year suggesting that the risk is higher than

of action of glatiramer acetate is distinct from

once suspected. Mitoxantrone is a chemother-

that of IFNβ; therefore, patients may respond

apeutic agent that should be prescribed and ad-

differently to this drug. Glatiramer acetate

ministered only by experienced physicians.

(20 mg SC q.d.) has also been shown to re-

duce the frequency of relapses by approxi-

Natalizumab Natalizumab (Tysabri) is a novel

mately one third and therefore is also

monoclonal antibody (mAb) directed against

recommended as a first-line treatment for RR-

the adhesion molecule very late antigen-4

MS or for patients who are IFNβ intolerant.

(VLA-4) that is expressed on leukocytes (ex-

Glatiramer acetate results in a one-third reduc-

cept neutrophils). This agent is the first and

tion in the inflammatory activity seen on MRI.

currently the only mAb approved for use in

Glatiramer acetate is generally well toler-

MS. Natalizumab prevents leukocytes from

ated and unassociated with flulike symptoms.

binding to the vascular endothelium, especially

Immediate postinjection reactions associated

during inflammation and ultimately prevents

with administration of glatiramer acetate in-

their transmigration into the CNS. Natal-

clude a local inflammatory reaction and an un-

izumab had promising results in a phase II trial

common idiosyncratic reaction consisting of

and two phase III clinical trials. In the phase III

flushing, chest tightness with palpitations,

trial, AFFIRM, sustained progression of dis-

anxiety, or dyspnea, which resolves sponta-

ability was reduced by 42%, clinical relapse

neously without sequelae. Routine laboratory

rate was reduced by 68%, and MRI activity

monitoring is not considered necessary in pa-

(enhancing lesions) was reduced by 92% in the

tients treated with glatiramer acetate, and the

natalizumab-treated group compared to

development of binding antibodies does not

placebo. Natalizumab was removed from the

interfere with the therapeutic efficacy of glati-

market in early 2005 after two MS patients

ramer acetate.

from the second phase III trial (SENTINEL)

developed a rare, deadly viral infection of the

Mitoxantrone Mitoxantrone

(Novantrone) is

brain called progressive multifocal leukoen-

an anthracenedione antineoplastic agent that

cephalopathy (PML). Both patients were on

was shown in a phase III, randomized,

combination therapy, Avonex plus natalizumab.

212

Chapter 11

■ Multiple Sclerosis

One patient eventually died and the other suf-

the modest effect of intravenous immunoglob-

fered major sustained disability. Natalizumab

ulin G (IVIg), azathioprine, methotrexate, my-

was subsequently reintroduced to the market

cophenolate mofetil, and cyclophosphamide.

in 2006 with a restricted indication for use as a

second-line monotherapy treatment in RR-MS.

Initiation of Early Therapy

It was initially thought that PML might occur

■ SPECIAL CLINICAL POINT: Evidence is

only in the setting of combination therapy;

accumulating that the best time to initiate

however, since reapproval, at least four more

disease-modifying treatment is early in the

cases of PML have been confirmed. There are

course of the disease.

now a total of seven known cases of PML as of

December 2008 (one case was identified post-

Data indicate that irreversible axon damage may

mortem in a Crohn disease clinical trial after

occur early in the course of RR-MS and that

natalizumab treatment). The absolute risk of

available therapies appear to be most effective

PML associated with natalizumab use is un-

at preventing new lesion formation but do not

known, but an estimated risk of

0.1% is

repair old lesions. With disease progression,

quoted and based on the previous clinical trial

the autoimmune response of MS may become

data. Natalizumab is only available in the

more difficult to suppress. Weekly IM IFNβ-1a

United States through the TOUCH program,

(Avonex) has been proved to reduce the cumula-

which was implemented for careful monitoring

tive probability of developing clinically definite

of potential drug-related side effects (specifi-

MS in patients who present with a first clinical

cally PML). TYGRIS is a worldwide phase IV

demyelinating episode and have two or more

safety study that is monitoring the use of natal-

brain lesions on MRI (CHAMPS trial). High-

izumab abroad. Natalizumab is given intra-

dose interferon and glatiramer acetate therapy

venously every 4 weeks under the care and

have further supported earlier treatment in clini-

supervision of an experienced infusion center

cal trials (ETOMS, BENEFIT, and PRECISE).

staff. Serious allergic reactions can occur and

Based on these data, the National Multiple Scle-

typically happen within 2 hours from the start

rosis Society (NMSS) recommends initiation of

of infusion. Other more common side effects

immunomodulating treatment at the time of di-

include infusion-related reactions, rashes, ele-

agnosis. The clinician must weigh these consider-

vated transaminases, leucopenia, reactivation

ations against the practical concerns of young

of various herpetic infections, sinusitis, and

patients, for whom the prospect of starting a

bladder/bowel infections. Two cases of

therapy that requires self-injection may be fright-

melanoma were recently reported after natal-

ening and burdensome. There are also few long-

izumab use; however, it is unclear whether a

term (more than 10 years) data regarding the

true association exists. Close neurologic moni-

safety and sustained efficacy of disease-modify-

toring is required during natalizumab use

ing drugs. Some patients will opt to defer ther-

along with frequent blood work monitoring.

apy, hoping to be among the minority of patients

Natalizumab is a potent monoclonal antibody

with benign MS, but certain MRI and clinical

that should be prescribed and administered

features should prompt the physician and pa-

only by experienced physicians.

tient to reconsider this approach. An MRI with

contrast-enhancing lesions, large burden of

Other Drugs Used in Multiple Sclerosis Several

white matter disease, or presence of any T1 low

other drugs are commonly used in MS despite

signal lesions (black holes) suggests a relatively

the lack of U.S. Food and Drug Administra-

poor prognosis. It may be useful to repeat the

tion approval and definitive evidence of effi-

brain MRI in 6 months or 1 year to determine

cacy. Numerous small clinical trials support

how quickly the disease process is evolving. The

213

Chapter 11

■ Multiple Sclerosis

FIGURE 11.6 T1-weighted magnetic resonance imaging scans of the brain of a patient with multiple

sclerosis demonstrating atrophy. A: Sagittal image revealing thinned corpus callosum and ventriculomegaly.

B: Axial image with extensive ventriculomegaly and T1 black hole formation.

presence of spinal cord lesions or atrophy also

other diseases, but further testing is required

suggests a poor prognosis (Figs. 11.6 and 11.7).

both to ensure its safety and to ensure that the

Clinical features may be less useful for assessing

mechanism of action of one drug does not inter-

prognosis, and once definite disability develops,

fere with that of the other drug. Recently, a lack

it may be too late to treat that component of the

of clinical efficacy was observed in the Avonex

disease.

Combination Trial (Avonex and oral methotrex-

ate) despite being well tolerated. Combination

therapies may increase the risk of serious com-

Combination Therapy

plications due to excessive immunosuppression

Several trials are studying the addition of oral

or decreased immune surveillance, so caution

immunosuppressive drugs, IVIg, glatiramer ac-

is advised when considering this treatment

etate to IFNβ, and other agents in patients who

paradigm.

continue to have disease activity. The rationale

for this approach is based on experience with

Symptomatic Therapy

■ SPECIAL CLINICAL POINT: Appropriate

recognition and treatment of ongoing

symptoms can greatly improve quality of life

in patients with MS (Table 11.10).

Despite the recent advances in immunomodu-

lating therapies to decrease new disease activity,

many patients continue to suffer from ongoing

symptoms related to preestablished lesions.

■ SPECIAL CLINICAL POINT:

Corticosteroids are the mainstay of acute

relapse treatment and are discussed as a

FIGURE 11.7 Magnetic resonance imaging scans of

symptomatic therapy because at this time no

the spinal cord of a patient with multiple sclerosis

conclusive evidence exists that they have any

revealing multiple high signal lesions best seen using the

effect on the natural history or long-term

short tau inversion recovery (STIR) sequence.

outcome of a disease exacerbation.

214

Chapter 11

■

Multiple Sclerosis

TABLE 11.10

Pharmacologic Treatments: Symptomatic

Drug

Indication

Starting Dose

Stable Dose

Comments

Baclofen

Spasticity

5 mg t.i.d.

10-40 mg

Severe withdrawal

t.i.d./q.i.d.

reaction

Tizanidine

Spasticity

2 mg q.h.s.

4-8 mg t.i.d.

—

Diazepam

Spasticity, anxiety,

2-5 mg q.h.s.

5-10 mg t.i.d.

—

insomnia, vertigo

Meclizine

Vertigo

12.5 mg t.i.d.

25 mg t.i.d.

—

Oxybutynin

Urinary urgency

5 mg q.d.

5-10 mg b.i.d.

Anticholinergic effects

may be contraindicated

with glaucoma

Tolterodine

Urinary urgency

1 mg q.d.

1-2 mg b.i.d.

Anticholinergic effects

may be contraindicated

with glaucoma

Sildenafil

Erectile

50 mg 0.5-4 hours

25-100 mg

Contraindicated in

dysfunction

prior to intercourse

macular degeneration

and with nitrates

Modafinil

Fatigue

200 mg q.a.m.

100-200 mg

Contraindicated with

q.d./b.i.d.

certain heart conditions

Amantadine

Fatigue

100 mg b.i.d.

—

Gabapentin

Pain, dystonic

300 mg q.h.s.

300-900 mg

—

spasms

t.i.d./q.i.d.

Carbamazepine

Pain, dystonic

100 mg q.d.

100-600 mg

Contraindicated in patients

spasms

t.i.d./q.i.d.

with preexisting

cytopenias

Corticosteroids There is evidence that corticos-

this appears to be a wise approach. Patients who

teroids shorten the duration and severity of an

become refractory to a short course of IVMP

exacerbation. Intravenous methylprednisolone

may respond to higher doses (2 g/day), longer

(IVMP), 1,000 mg, is administered daily for 3 to

courses (10 days), or plasma exchange.

5 days in the office or at home by a visiting

The most common side effects of treatment

nurse. On completion of the IVMP, prednisone

are irritability, difficulty sleeping, and fluid re-

may be started, 60 mg orally in the morning and

tention. Additional well-recognized risks in-

reduced by 10 mg every other day until tapered

clude hypokalemia, gastrointestinal side effects,

off. The prednisone taper is not necessary but

and osteoporosis. Fluid retention can be mini-

helps reduce withdrawal symptoms in some pa-

mized by salt restriction during the therapy, and

tients. An H2 blocker or proton pump inhibitor

diuretic use is discouraged because of the exag-

may be coadministered in patients with a his-

gerated risk of hypokalemia. Ankle edema can

tory of ulcer or heartburn. Metoclopramide

be minimized by wearing elastic stockings and

may be useful in patients who develop singultus

elevating the leg. Hypokalemia is usually not a

(hiccups). The effects of steroids appear to di-

problem in the absence of concurrent potas-

minish with repeated usage, and many patients

sium wasting, such as with diuretic therapy, but

reach a stage of unresponsiveness to steroids. It

in the presence of heart disease or with concur-

is unclear whether that stage can be delayed or

rent diuretic therapy, oral potassium replace-

prevented by restricting the use of steroids, but

ment should be administered and electrolyte

215

Chapter 11

■ Multiple Sclerosis

levels should be monitored during therapy.

agonist that exerts an antispastic effect by stim-

Anxiety and difficulty sleeping are usually

ulating central pathways that provide descend-

minor problems. Patients may on rare occa-

ing inhibitory input to the spinal cord.

sions develop significant depression or mania

Tizanidine is best initiated very slowly, starting

during corticosteroid therapy.

with 2 mg at bedtime, with gradual dosage ad-

In the Optic Neuritis Treatment Trial

justment by 2- to 4-mg increments to a maxi-

(ONTT), the rate of visual recovery was signif-

mum of 12 mg three times a day. The principal

icantly faster in the IVMP group than in pa-

side effects are sleepiness, orthostatic hypoten-

tients treated with placebo or oral prednisone,

sion, and dry mouth. Tizanidine is said to

but no significant differences in visual out-

be less likely to cause motor weakness than

come were found between groups at 6 months.

baclofen, but its efficacy is often limited by

Prednisone therapy alone increased the risk of

somnolence. It can be used alone but is often

new episodes of optic neuritis in either eye;

successful in low doses combined with ba-

however, the oral dose used was not equivalent

clofen. Gabapentin and benzodiazepines also

to the IV dose. The ONTT results have led to

have muscle-relaxant properties. In cases of ex-

widespread use of IVMP for patients with

treme spasticity, continuous intrathecal ba-

optic neuritis and an abnormal brain MRI, al-

clofen can be delivered through an implantable

though equivalent doses of oral prednisone

infusion pump placed in an abdominal subcu-

may be just as efficacious. Hints of a neuro-

taneous pocket and connected to a plastic

protective effect of steroids in other studies

catheter that is tethered in the lumbar sub-

await confirmation.

arachnoid space. Occasionally, botulinum

toxin injections can be used for spasticity;

Spasticity Mild spasticity may be managed by

however, it is less effective for larger muscle

stretching and exercise programs such as aqua

groups (hamstrings) and can be technically dif-

therapy and yoga. Drug therapy is indicated

ficult with varying success.

when stiffness, spasms, or clonus interfere with

function or sleep. Baclofen is a good first

Pain and Spasms Patients with disagreeable

choice for monotherapy. It exerts an antispas-

paresthesias, atypical facial pain, or tic

tic effect by stimulating receptors for the in-

douloureux often respond to antiepileptic drugs

hibitory neurotransmitter, GABA. The initial

such as carbamazepine, oxcarbamazepine,

dosage is 5 to 10 mg three times a day with in-

phenytoin, gabapentin, or pregabalin. Occa-

termittent upward dosage adjustments to

sionally, amitriptyline can be helpful. Narcotic

achieve a therapeutic response or maximum

analgesics are rarely the solution for chronic

tolerated dose, which may exceed 100 mg in

pain in MS. For refractory TN, IV phenytoin

some patients. Some patients may only require

may provide rapid relief. Baclofen, mexiletine,

bedtime dosing to control nocturnal spasms.

misoprostol, valproic acid, topiramate, and

The principal limiting side effects of baclofen

lidocaine have also been suggested but have

are confusion, sedation, or increased muscle

shown variable success. Surgical procedures to

weakness, and careful attention must be given

relieve medically intractable pain include rhizo-

to not overmedicate patients who are depend-

tomy, injection of anesthetics, and gamma

ent on their muscle tone to ambulate. Baclofen

knife. Paroxysmal dystonic spasms can be seen

may also unpredictably improve or worsen

in MS and respond well in most instances to

bladder function. Patients should never

low doses of some antiepileptic drugs.

abruptly discontinue baclofen from doses

greater than 30 mg/day because a withdrawal

Bladder, Bowel, and Sexual Dysfunction The first

syndrome can occur consisting of confusion,

step in managing a neurogenic bladder is to de-

seizures, or both. Tizanidine is an α-adrenergic

termine whether the problem is one of failure to

216

Chapter 11

■ Multiple Sclerosis

empty, failure to store, or a combination of both

incontinence by temporarily suppressing urine

called detrusor external sphincter dyssynergia. A

production. This approach should be used

thorough history and urinalysis to rule out infec-

with caution in patients with hypertension or

tion is appropriate. Immediate treatment of bac-

hyponatremia.

teriuria with antibiotics, even in the absence of

Constipation is very common in MS and

typical dysuria, is necessary in MS because of the

should be managed aggressively to avoid

known propensity for infection to cause disease

long-term complications. Eating foods rich in

exacerbation. A postvoid residual urinary vol-

fiber may help with mild constipation. Stool

ume is the best means to determine if there is re-

softeners and/or laxatives can be used for

tention. Anticholinergic drugs are the initial

moderate constipation. For fecal inconti-

drugs of choice for irritative bladder symptoms

nence, the addition of fiber in the form of a

in the absence of infection. Oxybutynin, 5 mg, is

bulk fiber laxative

(e.g., Metamucil) twice

increased gradually until symptom relief or dis-

a day can provide enough bulk to the stool

tressing side effects, such as dry mouth, blurred

to allow a partially incompetent sphincter to

vision, or worsening constipation, occur. Oxy-

hold in the bowel movement long enough to

butynin is also available in a long-acting formu-

allow the patient to reach a bathroom. The

lation with reduced peak side effects and

use of anticholinergics or antidiarrheal agents

enhanced efficacy compared with other agents.

may be effective for short periods to combat

Tolterodine, 1 to 2 mg twice a day, is a useful al-

incontinence associated with diarrhea.

ternative with fewer anticholinergic side effects.

A careful sexual history to determine the

Solifenacin, 5 to 10 mg daily, and Trospium, 20

problem(s) is a good first step in treating sexual

mg two times a day, are newer overactive blad-

dysfunction. Counseling the patient regarding

der agents. Propantheline bromide and

avoiding the ill effects of elevated body temper-

hyoscyamine sulfate are older alternative anti-

ature can be critical in managing problems that

cholinergic agents. Anticholinergic drugs can be

worsen with sexual intimacy. Erectile dysfunc-

used intermittently if bladder symptoms are dis-

tion (ED) in MS can be managed with sildenafil

tressing at particular times, such as at bedtime or

effectively initiated at 50 mg 60 minutes before

before a long automobile ride. The patient

intercourse

(higher doses may be necessary).

should be made aware of possible urinary reten-

Sildenafil should be used with caution in older

tion with anticholinergics. Urinary residual vol-

patients or in those with a history of heart dis-

ume should be checked after initiating therapy or

ease. This agent is contraindicated in patients

should concerns arise about retention.

taking medications with nitrates in them and in

In cases of concomitant retention and urgency,

patients with macular degeneration. Newer

anticholinergics can be used in combination

agents including vardenafil and tadalafil can

with intermittent bladder self-catheterization.

also help with ED. Discontinuation of medica-

Patients failing to achieve urinary continence

tions known to decrease libido (selective sero-

with anticholinergic pharmacotherapy, with or

tonin reuptake inhibitors [SSRIs]) or impotence

without self-catheterization, need formal uro-

(β-blockers) should be considered if possible.

logic evaluation for consideration of diversion

procedures.

Neurobehavioral Manifestations The most com-

Drug treatment of urinary retention is usu-

mon neurobehavioral manifestation amenable

ally ineffective, but some patients may benefit

to drug therapy is depression, which occurs in

from attempts at decreasing bladder neck tone

more than 50% of patients with MS. Moderate

using α₁-adrenergic receptor antagonists such

or severe depression should be treated with one

as terazosin, doxazosin, prazosin, and tamsu-

of the SSRIs. For patients with psychomotor

losin. Desmopressin, a vasopressin analogue,

retardation and depression, fluoxetine, 20 to

can be used at a dose of 20 mg by intranasal

80 mg daily, or sertraline, 50 to 200 mg daily,

administration nightly to treat nocturnal

may be particularly effective. Paroxetine, 100 to

217

Chapter 11

■ Multiple Sclerosis

200 mg daily, is often useful for patients who

MS at a dose of 200 mg in the morning. Occa-

are anxious and depressed. These drugs in-

sionally, treatment with an SSRI (fluoxetine

crease the levels of tricyclic antidepressants

and sertraline) can have a positive effect on

(TCAs), so care should be exercised in com-

fatigue even in the absence of overt depression.

bining SSRIs with TCAs. Amitriptyline, 50 to

4-Aminopyridine (Fampridine or 4-AP) is an

200 mg at bedtime, can be useful in depressed

investigational voltage-gated potassium chan-

patients who are also having difficulty sleeping,

nel (Kv1.4) blocker, that may help with fatigue,

headaches, or other pain. Treatment should be

endurance, and ambulation in MS by prolong-

instituted gradually to minimize anticholinergic

ing action potentials. In higher doses, this

or CNS side effects. The patient and family

agent has been associated with seizures and

should be warned of the delay between initiat-

confusion limiting its use. A newer sustained-

ing therapy and observing a benefit. The

release formulation of 4-AP is under intense in-

pseudobulbar syndrome of pathologic laughing

vestigation. A recent dose comparison study

or weeping may respond to amitriptyline in low

suggested that walking speed in some patients

doses. Several newer antidepressants may be

may improve with the sustained-release form;

useful when the anticholinergic side effects of

however, two people experienced de novo

TCAs or the sexual side effects of SSRIs (de-

seizures at the higher dose. Future studies are

creased libido and orgasm) become intolerable.

planned to further assess the risk-benefit pro-

Bupropion, citalopram, escitalopram, and ven-

file of this newer formulation.

lafaxine all may be better tolerated. Bipolar dis-

order is also increased in MS and commonly

Special Challenges for Hospitalized Patients

treated with valproic acid or lithium. SSRIs can

Patients with MS may be hospitalized either dur-

aggravate mania complicating treatment of

ing severe exacerbations or for other medical

bipolar disorder, which may warrant psychi-

problems. In the case of an MS exacerbation,

atric consultation.

the patient should be screened for sources of in-

Alprazolam, a benzodiazepine analogue,

fection and treated with antibiotics as appropri-

has been useful for anxiety in some patients. A

ate. Rapid control of fever is also important to

dose of 0.25 to 0.50 mg two or three times a

prevent worsening of symptoms. Exacerbations

day is usually sufficient. Diazepam can be used

that warrant hospitalization are usually related

as an alternative drug. Infrequently, antipsy-

to acute inability to ambulate or loss of self-

chotic medications are needed in MS. Atypical

care in the more advanced patient, and IV cor-

antipsychotic agents (risperidone, olanzapine,

ticosteroids are usually instituted. Plasma

quetiapine) are preferred over typical agents

exchange may be useful in steroid-unresponsive

(Haldol, Thorazine) to minimize the potential

cases and requires hospitalization. Physical and

for extrapyramidal and anticholinergic side

occupational therapy should be initiated imme-

effects. As with other symptomatic therapies,

diately, and a rehabilitation plan should be put

the need for pharmacotherapy over time should

in place with attention to adaptive devices for

be assessed intermittently, and the drug should

the home and orthotics or ambulation aids. For

be tapered if appropriate.

non-MS-related hospitalization, it is equally

important to be vigilant about infections to pre-

Fatigue Some types of MS fatigue may respond

vent exacerbation. MS rarely causes respiratory

to short periods of rest, but if this is not possi-

compromise, and there are no absolute con-

ble, or in cases of severe fatigue, medication

traindications to anesthesia. Cosmetic surgery

should be considered. Amantadine, 100 mg

is discouraged, but necessary operations are

twice a day, may be effective in treating about

usually well tolerated. Patients with MS do not

one third of the cases of fatigue. Modafinil, a

have any impairment in wound healing. Post-

newer narcolepsy drug that acts as a CNS stim-

partum exacerbations usually do not occur for

ulant, was found to be effective in patients with

several weeks after delivery and thus are not

218

Chapter 11

■ Multiple Sclerosis

a major obstetric complication. Counseling,

shown to improve disability from MS inde-

social work, and attention to severe depression

pendent of drug interventions and should be

should be considered during periods of stress

continued on a regular basis as part of a main-

such as may occur during hospitalization.

tenance regimen.

Alternative Therapies Used by Patients with Multiple

Novel Experimental Immunomodulatory

Sclerosis Numerous alternative therapies have

Approaches

been advocated for MS but they are rarely tested

in a placebo-controlled manner and, therefore,

Several treatments are being tested in prelimi-

they cannot be recommended. Because MS is an

nary trials, including antibodies to various crit-

unpredictable disease characterized early by re-

ical immune molecules (CD25 IL-2α receptor,

lapses and spontaneous recovery, patients are

CD20 B-cell marker, and the CD52 leukocyte

very susceptible to placebo effects and misguided

marker), phosphodiesterase inhibitors, novel

judgments about the efficacy of alternative ther-

NSAIDs, β-adrenergic agonists, and immuno-

apies. Bee stings have been used for many years,

suppressive regimens used during organ trans-

and for those who are not allergic about half of

plantation and malignancies. Of these

patients report a temporary boost in energy per-

therapies, the monoclonal antibodies

(alem-

haps related to endogenous corticosteroid re-

tuzumab, daclizumab, rituximab) and novel

lease in response to cutaneous inflammation.

oral agents (fingolimod, cladribine) seem to

Procarin is a patch used by some patients with

have the most promise in MS, as shown in re-

MS and contains vitamin B₁₂, histamine, caf-

cent clinical trials. Despite the encouraging

feine, and a proprietary substance. Several diets

trial data, there have been several serious com-

for MS, such as the Swank diet, have been popu-

plications associated with many of these

lar. Acupuncture is used to relieve pain and

agents, which will potentially limit their future

sometimes boost energy. Low-dose naltrexone

widespread use. Immunoablative protocols

(LDN) has been used off-label for MS and other

using extremely high doses of chemotherapies,

diseases. Naltrexone is an opioid receptor antag-

followed by autologous stem-cell rescue, have

onist approved for the treatment of alcohol and

been used in particularly aggressive forms of

opioid dependence. Its use in MS is controversial

MS. This approach has afforded disease stabi-

and there have been no randomized, double-

lization, both clinically and by MRI, but has an

blinded, placebo-controlled trials to assess LDN

unacceptably high morbidity and mortality at

tolerability or efficacy. A small, open-label pilot

present.

study was done suggesting improvements in fa-

tigue; however, the NMSS currently does not

Remyelination and Neuroprotection

support the use of this agent until further testing

is done. None of the above approaches has been

Theoretical approaches to remyelination in-

tested adequately. Complementary medicine ad-

clude enhancing existing oligodendrocyte pre-

vocates recommend yoga, meditation, aqua ther-

cursors or neural stem cells by using growth

apy, body-cooling devices, and stress reduction,

factors or direct transplantation of oligodendro-

all of which are reasonable and safe approaches

cytes or autologous stem cells. Growth factors

to dealing with MS.

such as insulinlike growth factor carry the inher-

ent risk of nonspecifically activating the im-

Physical Therapy Physical therapy has an im-

mune system. Anti-LINGO antibodies appear to

portant role in managing MS. Regular exer-

be a promising means of inducing endogenous

cise and stretching decrease MS symptoms of

remyelination by enhancing oligodendrocyte

stiffness, weakness, and pain and improve

progenitor cell differentiation into myelin-form-

overall well-being. Physical therapy has been

ing cells in vitro and in animal models.

219

Chapter 11

■ Multiple Sclerosis

D. Treat her for depression and reevaluate

Always Remember

in 3 to 6 months for improvement.

• Multiple sclerosis (MS) has features of

The correct answer is C. This woman could

inflammation, demyelination, axonal injury,

have early signs of MS, and because there is

and neurodegeneration.

strong evidence to support early initiation of

• Visual dysfunction, sensory disturbances, and

therapy, it is important to make a diagnosis.

gait impairment are very common presenting

Blood testing is indicated to exclude thyroid

symptoms.

disease, vitamin B₁₂ deficiency, other inflam-

• MS is diagnosed clinically through the

matory neurologic disorders, and infections. A

demonstration of CNS lesions disseminated

brain MRI is the single best screening tool for

in time and space and with no better

MS. Depression may be a symptom of MS and

explanation for the disease process.

should not be considered an adequate expla-

• MRI is the single most useful test in

nation for ill-defined somatic symptoms.

confirming the diagnosis of MS.

Carpal tunnel syndrome is a common cause

• Initiating early disease-modifying treatment

of hand numbness but is usually unilateral

can influence the clinical course.

and would not explain the other reported

• Symptomatic therapy can greatly improve MS

symptoms.

patients’ quality of life.

2. A 36-year old woman is diagnosed with

• MS is a complicated neurologic disease, and

optic neuritis. Her initial brain MRI reveals

the approaches to diagnosis and treatment

several demyelinating lesions. She is

are changing rapidly, therefore, it is

referred to a neurologist, but she declines

appropriate to refer any patient suspected of

immunomodulating therapy and prefers to

having MS to a neurologist with MS

“wait and see.” Three months later, a

experience.

repeat MRI is obtained and reveals a new

gadolinium-enhancing lesion. At this time:

A. She has clinically definite MS according

to McDonald criteria but treatment is

QUESTIONS AND DISCUSSION

not indicated because this is probably a

benign case.

1. A 24-year-old nursing school student

B. She has clinically definite MS according

presents to her primary care physician

to McDonald criteria and treatment with

(PCP) with complaints of numbness and

either IFNβ or glatiramer acetate would

tingling in her hands for 1 month. On

be appropriate.

questioning, she responds that she has had

C. She has PP-MS for which unfortunately

recent fatigue and mild depression, which

there is no treatment.

she attributed to stress. She denies any

D. In the absence of a second clinical event,

other past medical history and is only

she cannot be diagnosed with multiple

taking birth control pills. Her entire

sclerosis.

physical examination is normal. The next

appropriate step is to:

The correct answer is B. The demonstration

A. Recommend EMG/NCS to rule out

of a new lesion on MRI more than 3 months

carpal tunnel syndrome.

later provides evidence for dissemination in

B. Reassure her that she has no abnormal

time and now fulfills criteria for a definite

signs on examination and therefore

diagnosis of MS. The National Multiple Scle-

cannot be diagnosed with multiple

rosis Society and many MS experts now favor

sclerosis at this time.

early initiation of therapy. Benign MS is de-

C. Order blood tests and a brain MRI.

fined as no disability after at least 10 years

220

Chapter 11

■ Multiple Sclerosis

and can only be diagnosed retrospectively.

finger to nose dysmetria, severe gait ataxia,

Progressive MS is defined as 6 months of un-

and facial asymmetry. You recommend the

abated worsening without exacerbations, and

following:

1 year of disease progression is required to

A. Treatment with 2 weeks of prednisone

make a diagnosis of PP-MS.

(approximately 1 mg/kg).

B. Strict bedrest until the symptoms resolve.

3. A 40-year-old woman with RR-MS

C. A brain MRI as soon as possible to

presents for routine follow-up. She is being

confirm an MS exacerbation.

treated with IFNβ injections, and although

D. Treatment with 3 to 5 days of IV

she has had no exacerbations since being

methylprednisolone (1 g/day).

on treatment, she complains of increased

stiffness in her legs, and on questioning she

The correct answer is D. The patient is

also admits to urinary urgency with

having an acute disabling exacerbation and

occasional episodes of incontinence. On

should be treated with IV methylpred-

examination, she is more spastic and

nisolone. A brain MRI is a useful means of

hyperreflexic in her legs than 6 months

assessing disease activity (gadolinium-en-

ago, but there is no clear sensory level over

hancing lesions and new T2 lesions) and

her spine or weakness. At this point:

determining the extent of breakthrough dis-

A. She should stop taking the medication as

ease activity but is not obligatory if the

she now has secondary progressive

clinical picture is clear.

disease.

B. She should switch to another

immunomodulating drug as she has

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D. She should stop taking the medication

Brex PA, Miszkiel KA, O’Riordan JI, et al. Assessing

as these are likely side effects of the IFNβ.

the risk of early multiple sclerosis in patients with

clinically isolated syndromes: the role of a follow

The correct answer is C. Minor changes

up MRI. J Neurol Neurosurg Psychiatry. 2001;70:

in neurologic function do not constitute

390-393.

progressive disease, and it is likely that the

Brex PA, Ciccarelli O, O’Riordan JI, et al. A longitudinal

reduction in relapses suggests that the IFNβ

study of abnormalities on MRI and disability from

is effective. Although exacerbation of spas-

multiple sclerosis. N Engl J Med. 2002;346:158-164.

ticity can be a side effect of IFNβ, bladder

Comi G. Why treat early multiple sclerosis patients? Curr

frequency is part of underlying MS and is

Opin Neurol. 2000;13:235-240.

often a sign of urinary tract infection. An-

Dhib-Jalbut S. Mechanisms of action of interferons and

tibiotic treatment of bacteriuria often allevi-

glatiramer acetate in multiple sclerosis. Neurology.

2002;58:S3-S9.

ates the bladder symptoms and sometimes

other new symptoms as well.

Frohman EM, Zhang H, Kramer PD, et al. MRI charac-

teristics of the MLF in MS patients with chronic

4. A patient with MS presents to the office

internuclear ophthalmoparesis. Neurology.

2001;57:762-768.

with several days of dizziness, diplopia, and

trouble walking straight. There has been no

Frohman EM, Racke MK, Raine CS. Multiple sclerosis—

the plaque and its pathogenesis. N Engl J Med.

obvious precipitating factor (infection,

2006;354:942-955.

heat, stress), and she has been taking her

Grudzinski AN, Hakim Z, Cox ER, et al. The economics

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1999;15:229-240.

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Hafler DA, Compston A, Sawcer S, et al. Risk alleles for

Lutterotti A, Martin R. Getting specific: monoclonal

multiple sclerosis identified by a genomewide study.

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N Engl J Med. 2007;357:851-862.

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Hemmer B, Archelos JJ, Hartung HP. New concepts in the

Polman CH, Reingold SC, Edan G, et al. Diagnostic

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“McDonald Criteria.” Ann Neurol. 2005;58:840-846.

Krupp LB, Rizvi SA. Symptomatic therapy for underrec-

Trapp BD, Peterson J, Ransohoff RM, et al. Axonal tran-

ognized manifestations of multiple sclerosis. Neurol-

section in the lesions of multiple sclerosis. N Engl J

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Med. 1998;338:278-285.

Lucchinetti C, Bruck W, Parisi J, et al. Heterogeneity of

Wingerchuk DM, Lennon VA, Lucchinetti CF, et al. The

multiple sclerosis lesions: implications for the pathogen-

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esis of demyelination. Ann Neurol. 2000;47:707-717.

2007;6:805-815.

Parkinson

Disease

BRADLEY J. ROBOTTOM, LISA M. SHULMAN,

AND WILLIAM J. WEINER

key points

• Parkinson disease is the second most common

neurodegenerative disease worldwide.

• Parkinson disease has four major cardinal signs: resting

tremor, cogwheel rigidity, bradykinesia, and postural

instability.

• Resting tremor is the most common presenting

symptom.

• Nonmotor symptoms such as depression, apathy, and

anxiety are common and have a negative impact on

quality of life.

• A variety of effective, symptomatic treatments are

available.

• Antipsychotics and other dopamine blocking agents

should be avoided in Parkinson disease patients.

• A careful medication history asking about exposure to

dopamine blocking agents is important in making a

diagnosis of Parkinson disease.

arkinson disease is

only because of the prevalence of the disorder

the most common akinetic rigid syndrome and

but also because the pharmacology of Parkinson

the most frequently encountered extrapyramidal

disease has led to fundamental changes in the

movement disorder. It is a neurodegenerative dis-

way investigators and physicians view central

ease of unknown etiology that most often begins

nervous system neurotransmitter function.

at 58 to 60 years of age. Approximately 10% to

15% of patients will have disease onset before

CLINICAL FEATURES

age 50. As the population of the United States

ages, the number of people at risk for the devel-

Parkinson disease is characterized by a typical

opment of Parkinson disease increases. Diagnos-

history of progressive neurologic disability and

tic and therapeutic knowledge is important not

the following four major neurologic signs: resting

222

223

Chapter 12

■ Parkinson Disease

FIGURE 12.1 A: This handwriting sample from a 55-year-old patient with untreated Parkinson

disease is a good example of the typical micrographic handwriting that is often characteristic of this

condition. The handwriting samples shown in (B) and (C) are from a patient with essential tremor.

B: Prior to treatment, the sample shows the typical large, sloppy script. C: This sample, taken from the

same patient with essential tremor while being treated with propranolol (160 mg/day), shows obvious

improvement. Changes in written script can provide excellent clues to the type of movement

disorder that is present (see Chapter 13).

tremor, cogwheel rigidity, bradykinesia, and

occasionally notice an inability to stop walking

impaired postural reflexes. It is often observed

forward (propulsion) or backward (retropul-

that when a patient first presents to a physician

sion). Family members may also report that the

for the evaluation of symptoms, the syndrome

patient’s facial expression has changed and

has been present for 1 to 2 years. Unilateral

that he or she does not smile as much (masked

tremor involving a single limb is the most com-

faces; Fig. 12.2), that he or she seems to stare

mon presenting symptom and sign. However,

all the time (reptilian stare), that her or his pos-

careful history taking often reveals that diffi-

ture has become stooped and flexed (simian

culty buttoning shirts or blouses, fastening

posture; Fig.

12.3), and that he or she has

snaps, cutting food; alterations in handwriting

become exasperatingly slow. It may take 30 to

(Fig. 12.1); a feeling of stiffness; or a feeling

90 minutes to dress in the morning and even

of overall slowness may have been noted up to

longer to disrobe in the evening.

12 to 24 months earlier and that these symp-

The elucidation of this history may make

toms have gradually become worse. In addi-

the diagnosis of parkinsonism evident. Not

tion, a patient may note voice fluctuations and

all patients will present with all of these symp-

intermittent loss of volume. Inquiring whether

toms, and a patient will occasionally present

the patient has difficulty rising from low, soft

with only a single symptom and will yet have

chairs or sofas; difficulty entering and leaving

parkinsonism. Inquiring whether the onset of

an automobile, difficulty turning in bed; or

symptoms was abrupt or insidious; whether

difficulty walking and maintaining balance

there has been a gradual progression of symp-

in a crowd highlight the functional impact

toms; whether there is a family history of

of bradykinesia, rigidity, gait impairment, and

neurologic syndromes; and whether there is

impaired postural reflexes. The patient may

concurrent drug use, past history of encephalitis,

224

Chapter 12

■ Parkinson Disease

FIGURE 12.2 Typical masked faces in a patient with Parkinson disease.

or exposure to various toxins, including the

bilateral. Tremor is the initial presenting symp-

use of street drugs, may help determine the

tom in 75% of patients. With the exception of

etiology of the syndrome.

impaired postural reflexes, the major signs of

Resting tremor is the most frequent present-

parkinsonism usually appear unilaterally.

ing sign in these patients. The appearance of

Careful observation of the tremor will reveal

this tremor often precipitates the patient’s visit

that it is a resting tremor that is ameliorated

to the doctor. Parkinsonian tremor is highly

with purposeful movement. A simple way of

characteristic and consists of a low-to-medium

assessing whether a tremor is primarily resting,

amplitude, with four to five cycles per second

postural, or kinetic is to have the patient per-

alternating movement. Tremor is defined as the

form the finger-to-finger and finger-to-nose

involuntary rhythmic oscillatory sinusoidal

maneuver and to observe the affected limb at

movement that results from the alternating or

rest, with outstretched posture and with move-

synchronous contractions of reciprocally inner-

ment. The patient with a resting tremor will

vated antagonistic muscles. Resting tremor has

have a marked amelioration of tremor when

been described as “pill rolling” because of the

the arm springs into action. The patient with

movement of the fingers and thumb. Its ap-

kinetic tremor will have no tremor at rest but

pearance resembles the activity of an

“old

will typically develop increased tremor as the

time” pharmacist preparing a pill. The tremor,

hand approaches the target. When the resting

however, may begin in the hands, legs, or face

limb is raised to an outstretched position, the

and most often appears unilaterally in a single

tremor of Parkinson disease will diminish, al-

limb. It will often progress to involve the sec-

though with maintained posture, the tremor may

ond limb of the same side before becoming

reappear until movement is initiated again.

225

Chapter 12

■ Parkinson Disease

ratchetlike sensation is appreciated by the

examiner with passive movement. There are

some patients in whom the initial symptoma-

tology is cervical or low back discomfort, and

the question of whether increased muscle tone

is responsible for this symptom has been

raised.

Bradykinesia is responsible for much of the

disability associated with parkinsonism. Slow-

ness of voluntary movement contributes to in-

creasing difficulty with the activities of daily

living such as getting in and out of a car, rising

from chairs, cutting meat, preparing food,

dressing, and walking. Some of these difficul-

ties can be easily observed during an examina-

tion by watching the patient rise from a chair,

walk to the examining room, and undress. Gait

impairment accounts for the greatest propor-

tion of the emerging disability, as severe gait

impairment results in a loss of independence in

many of these activities of daily living.

Postural reflexes refer to the ability of the pa-

tient to right himself and to keep from losing bal-

ance when sustaining postural perturbations

(e.g., being jostled in a crowd). In addition, these

reflexes are also important when turning around

and changing direction while walking without

FIGURE 12.3 Moderate simian posture in a patient

losing balance. These reflexes can be evaluated

with Parkinson disease. Note the flexion of the upper

simply and effectively by observing the patient

extremities, upper trunk, and head. Facial masking is also

walk 10 to 15 steps and turn around. A patient

apparent.

with normal postural reflexes should be able to

pivot and turn without taking extra steps. In

When the limb is totally supported and at rest,

parkinsonism, one will often observe that the pa-

the patient with resting tremor will be seen to

tient takes three to five steps to change direction.

have the tremor, whereas those patients with

Another test of postural reflexes during the of-

kinetic tremor will not. Although resting tremor

fice visit is a firm backward pull on the shoulders

is a common early sign, tremor is rarely a

or chest with the admonition to the patient that

source of disability.

he should attempt to stop his backward motion

Cogwheel rigidity is a sign that can be pres-

in one to two steps. The examiner must be posi-

ent either unilaterally or bilaterally, depend-

tioned behind the patient during this maneuver

ing on the stage of illness. The patient does

and prepared to stop the retropulsive movement

not complain of “cogwheeling.” This sign is

or prevent a fall if necessary (Fig. 12.4). Impaired

elicited by passive movement of the limb or

postural reflexes with frequent falls are a source

neck through a full range of motion. When

of severe disability and injury in advanced

present, this sign is best elicited by slow flex-

parkinsonism (e.g., subdural hematoma, frac-

ion and extension of the wrist or neck. In

tures of the hip or wrist). It should be noted that

addition to increased tone, a characteristic

when postural reflex impairment is a prominent

226

Chapter 12

■

Parkinson Disease

There is also no known biologic marker of

Parkinson disease, and there is no definitive

laboratory or imaging study to confirm the di-

agnosis. Furthermore, identifying parkinson-

ism by history and clinical examination does

not imply that the diagnosis is Parkinson dis-

ease, which is characterized by a specific neu-

ropathology. Patients with a minimum of two

of the four cardinal symptoms (tremor, rigidity,

bradykinesia, and impaired postural reflexes)

in the absence of this specific neuropathology

are diagnosed as having an akinetic rigid syn-

drome or parkinsonism, the most common

cause of which is Parkinson disease. Clinical

features that help distinguish Parkinson disease

from other forms of parkinsonism include uni-

lateral presentation of symptoms and signs,

slow progression, resting tremor, and respon-

siveness to dopaminergic agents.

MECHANISMS OF DISEASE

Parkinson disease is defined pathologically by

the loss of dopaminergic neurons in the substan-

tia nigra pars compacta and the presence of in-

tracytoplasmic Lewy bodies, which stain for

α-synuclein. The idiopathic degeneration of

FIGURE 12.4 A loss of postural reflexes is often seen

these neurons leads to loss of dopaminergic

in patients with Parkinson disease. After instructing the

input to the corpus striatum. The progressive

patient to maintain his or her posture, the examiner has

failure of the nigrostriatal pathway results in the

administered a backward thrust to the patient’s chest. The

symptoms of Parkinson disease. Neuropatho-

postural response is quite poor: rather than maintaining a

fixed postural response to the thrust or taking one or

logic examination of the brain of a patient with

two steps backward, the patient has lost balance entirely

a history of Parkinson disease reveals loss of the

and requires the assistance of the examiner to prevent

pigmented neurons in the substantia nigra and

him or her from falling to the ground.

loss of dopamine in the striatum where the ni-

grostriatal fibers project. Olfactory dysfunction,

constipation, and rapid eye movement (REM)

early sign of parkinsonism, the diagnosis more

sleep disorder may represent early nonmotor

often than not is not true Parkinson disease but

manifestations of Parkinson disease, but this re-

instead one of the other neurodegenerative disor-

mains more speculation than fact.

ders that produces parkinsonism, such as pro-

The etiology of Parkinson disease remains

gressive supranuclear palsy (PSP) or multiple

elusive. Although numerous epidemiologic stud-

system atrophy (MSA).

ies have investigated Parkinson disease, definitive

There is no single pathognomonic sign of

environmental factors have not been identified.

Parkinson disease; instead, the informed and

Nevertheless, there are many leads, and the pres-

experienced clinician uses a constellation of

ence of significant environmental toxin exposure

symptoms and signs to make the diagnosis.

in genetically predisposed individuals remains a

227

Chapter 12

■ Parkinson Disease

strong possibility. Inherited forms of Parkinson

(carbidopa) with levodopa results in a marked

disease have been identified, the most common

reduction in the dose of levodopa necessary to

of which is leucine-rich repeat kinase (LRRK2)

achieve a central effect.

autosomal dominant Parkinson disease. LRRK2

Another enzyme that plays a role in deter-

mutations account for 10% to 40% of spo-

mining how much levodopa circulating in

radic and inherited Parkinson disease in the

the blood reaches the brain is catechol-O-

Ashkenazi Jewish and North African Arab

methyltransferase (COMT). COMT methylates

populations and lead to a typical, adult-onset

levodopa and also reduces the concentration of

Parkinson disease phenotype. Other autosomal

levodopa that is available for transport across

dominant (α-synuclein) and autosomal reces-

the blood-brain barrier. Peripheral COMT

sive (parkin, PINK1, DJ-1) forms of Parkinson

inhibition is another therapeutic maneuver to

disease lead to young-onset Parkinson disease.

enhance levodopa bioavailability in the brain

However, surveys of large numbers of patients

to increase central dopamine activity.

seen in movement disorder centers do not

An additional enzyme that affects central

reveal a family history of Parkinson disease in

levodopa availability is monoamine oxidase

the majority of patients with Parkinson dis-

B (MAO-B). MAO-B acts by deaminating

ease. Nonetheless, identifying the α-synuclein

dopamine, leading to reduced availability in

and Parkin mutations has led to the discovery

the synaptic vesicles. Central MAO-B inhibi-

that the Lewy body is partly composed of

tion is yet another therapeutic target to amelio-

α-synuclein and to the potential role of the pro-

rate symptoms of Parkinson disease by increasing

teosome in the pathogenesis of Parkinson dis-

levodopa bioavailability.

ease. These recent genetic discoveries are very

Because increasing the concentration of

important and have opened the door to the

dopamine in the striatum results in dramatic

concept that Parkinson disease may be a com-

clinical improvement in patients with Parkin-

plex genetic disease.

son disease, the neural substrate that dopamine

The demonstration in 1967 that orally ad-

acts on (the striatal dopamine receptors) is

ministered levodopa could produce dramatic

obviously relatively intact. The dopamine

improvement in the symptoms of Parkinson

receptor sites are divided into five different

disease was a remarkable therapeutic ad-

subtypes, but there are two main families: the

vance. For levodopa to have a therapeutic ef-

D₁ and D₅ group and the D₂, D₃, and D₄

fect, it must cross the blood-brain barrier and

group. Drugs acting as dopamine receptor

be decarboxylated to dopamine. The enzyme

agonists must have D₂ activity to be effective

that decarboxylates dopa to dopamine is

in the treatment of Parkinson disease. The

ubiquitous and also decarboxylates several

dopamine receptor agonists that are available

other aromatic amino acids. This enzyme,

to treat Parkinson disease include ergot-

termed “aromatic amino acid decarboxylase”

derived

(bromocriptine and pergolide) and

or “dopa decarboxylase,” is found in several

non-ergot-derived

(pramipexole, ropinirole,

extracerebral locations, including the gastroin-

and rotigotine) compounds. Although all of

testinal tract, liver, and kidney. When orally

the dopamine receptor agonists have D₂ activ-

administered, levodopa is absorbed; acted on

ity, they have somewhat different profiles of

by the extracerebral decarboxylase; and con-

activation for the various dopamine receptors.

verted to dopamine, which cannot cross the

Although all agonists have similar efficacy

blood-brain barrier. If levodopa is adminis-

and adverse event profiles, there are varia-

tered alone, enormous quantities are required

tions among individual patients in regard to

to overcome the peripheral decarboxylase sys-

which agonist is the most efficacious. Al-

tems and achieve a therapeutic benefit. The

though the number of antiparkinsonian med-

use of a peripheral decarboxylase inhibitor

ications grows steadily, levodopa remains the

228

Chapter 12

■ Parkinson Disease

gold standard of therapy, the most potent

deficiency state in the striatum of patients with

drug for the symptomatic treatment of Parkin-

Parkinson disease results in a relatively elevated

son disease.

cholinergic tone. Anticholinergics exert their

beneficial effect by partially correcting this rela-

tive cholinergic excess. Anticholinergics must be

TREATMENT

used with caution in older patients because they

All medications currently used to treat Parkin-

can induce memory dysfunction and confusion.

son disease only provide symptomatic relief

In older men, anticholinergics can also lead to

and do not alter the underlying pathogenesis of

urinary hesitancy and retention.

the disorder (Table 12.1).

Amantadine is also useful in the treatment

In other words, the natural progression of

of early Parkinson disease and can be helpful for

Parkinson disease continues despite current

early bradykinesia. Amantadine has anticholin-

treatment. The treatment of each patient with

ergic activity, mild dopaminergic activity, and

Parkinson disease should be highly individual-

antiglutaminergic activity. Amantadine is also

ized to provide functional improvement. If a pa-

useful in treatment of drug-related dyskinesia in

tient’s symptoms are very mild and causing no

more advanced Parkinson disease. Other op-

impairment in the activities of daily living, delay

tions for patients with early troublesome symp-

of treatment may be the appropriate choice. If

toms include monotherapy with the dopamine

a patient’s symptoms are mildly troublesome,

receptor agonists (pramipexole, ropinirole, or

with tremor as the predominant feature, low-

rotigotine), or low-dose carbidopa-levodopa

dose anticholinergics (e.g., trihexyphenidyl, ben-

with or without a COMT inhibitor (tolcapone

ztropine) may be all that is required. The

or entacapone). The progression of the disease

anticholinergics, the oldest drugs available to

process will eventually result in the need for

treat Parkinson disease, remain useful because

more powerful dopaminergic stimulation.

the striatum contains high levels of both

The use of levodopa as a precursor loading

dopamine and acetylcholine, and the dopamine

strategy to increase central dopamine and to

ameliorate Parkinson disease has been one of

the major therapeutic advances in neurology.

However, high-dose levodopa administration

TABLE 12.1

Medications Used in the Treatment of

without the addition of a peripheral dopa de-

Parkinson Disease

carboxylase inhibitor, such as carbidopa, pro-

duces anorexia, nausea, and vomiting. These

Dopamine Replacement

MAO-B Inhibitors

symptoms occur because of the high levels of

Carbidopa/levodopa

Rasagiline (Azilect)

(Sinemet)

circulating peripheral dopamine that are present

Carbidopa/levodopa/

Selegiline (Eldepryl,

as a result of extensive extracerebral decarboxy-

entacapone (Stalevo)

Zelapar)

lation and result in the stimulation of the area

postrema (emesis center) of the brain. The de-

Dopamine Agonist

COMT Inhibitors

velopment of peripheral dopa decarboxylase

Pramipexole (Mirapex)

Entacapone (Comtan)

inhibitors in large part ameliorated these prob-

Ropinirole (Requip,

Tolcapone (Tasmar)

Requip XL)

lems and led to the development of combina-

Rotigotine (Neupro)

tion therapy with carbidopa and levodopa.

Apomorphine (Apokyn)

Anticholinergics

This drug is available in fixed ratios of 10/100,

Benztropine

25/100, and 25/250, with the numerator indi-

(Cogentin)

cating the milligram dose of carbidopa and the

denominator indicating the milligram dose of

NMDA Antagonist

Trihexyphenidyl

Amantadine

(Artane)

levodopa. The most important advantage of

this drug is the ability to administer less

229

Chapter 12

■ Parkinson Disease

levodopa to obtain the same central effect with

ergot-derived preparations) and withdrawn

a marked reduction in nausea and vomiting. In

from the United States market. Pramipexole,

fact, the ease of administration of carbidopa-

ropinirole, and rotigotine have been approved

levodopa therapy both for patient and the

for use in both early and late (pramipexole and

treating physician has resulted in it being used

ropinirole) Parkinson disease. These non-ergot

almost exclusively in the treatment of patients

dopamine agonists are effective and well toler-

with Parkinson disease who require levodopa.

ated in early Parkinson disease. Rotigotine is

Carbidopa-levodopa in a controlled-release

marketed as a transdermal patch, which is

(CR) formulation (CR 25/100, CR 50/200)

unique among the dopamine agonists. How-

provides a slower and longer-lasting effect of

ever, problems with the patch’s medication de-

levodopa. CR preparations may be useful to

livery system led to its being withdrawn from

treat motor fluctuations, nighttime bradykine-

the market. It is expected that rotigotine will be

sia resulting in sleep disruption, early morning

reintroduced at a future date. The use of these

painful dystonic cramps, and early morning se-

drugs instead of levodopa as initial therapy has

vere bradykinesia. There is also a triple combi-

been shown to delay the onset of drug-induced

nation (levodopa/carbidopa/entacapone) tablet

dyskinesia. They are also very helpful in man-

to treat Parkinson disease, which will allow

aging motor fluctuations and dyskinesias in

some patients to take fewer pills daily. Lev-

more advanced Parkinson disease.

odopa remains the most potent drug for

Because there are no known neuroprotective

the treatment of bradykinesia and rigidity in

agents that modify disease progression in

Parkinson disease.

Parkinson disease, treatment is directed at

The direct-acting dopamine receptor ago-

symptomatic improvement. If the diagnosis of

nists approved in the United States for the treat-

Parkinson disease is made, there is no need to

ment of Parkinson disease include pramipexole,

start treatment with any anti-Parkinsonian

ropinirole, and rotigotine. Previous-generation

medications unless the patient is experiencing

dopamine agonists that are no longer used for

functional disability in activities of daily living,

Parkinson disease include bromocriptine and

on the job, or in recreational activities.

pergolide. Because dopamine receptor agonists

There is continuing controversy about

exert their effect on the striatal dopamine re-

whether to start treatment with levodopa or a

ceptors (which presumably are not involved in

dopamine agonist when functional impairment

the substantia nigra degenerative process), it

begins. A number of clinical trials of pramipex-

was felt that they might be an effective substi-

ole, ropinirole, and levodopa in early untreated

tute for levodopa. Although dopamine agonists

patients with Parkinson disease have demon-

have assumed an important role in Parkinson’s

strated that levodopa is more effective than the

therapy, none of the agonists are as potent

dopamine agonists in relieving motor symptoms

as levodopa for relief of symptoms of Parkinson

and that dopamine agonists induce less motor

disease. Clinical experience with the dopamine

fluctuations and dyskinesias in the early years

agonists has shown that they are effective not

(2 to 5) of Parkinson disease. The American

only in the treatment of Parkinson disease but

Academy of Neurology issued a practice param-

also in ameliorating motor fluctuations in

eter examining this issue and concluded that ini-

patients treated with carbidopa-levodopa.

tial symptomatic treatment of Parkinson disease

Bromocriptine, the first dopamine agonist in-

could begin with either levodopa or a dopamine

troduced, is rarely used today both because

agonist. When choosing initial treatment, many

of its cost and because the new agonists are

factors including age, degree of disability, cogni-

generally more potent and effective. Pergolide,

tive status, and cost all need to be considered.

although effective, has been linked to valvular

Selegiline, an MAO-B inhibitor, also known

heart disease (fibrotic changes associated with

as l-deprenyl, inhibits the catabolism of

230

Chapter 12

■ Parkinson Disease

dopamine and promotes dopaminergic activity.

COMPLICATIONS

Selegiline has been used in early Parkinson dis-

ease and has been shown to delay the need for

Although there is no question that carbidopa-

levodopa. There has been considerable discus-

levodopa is the mainstay of therapy in this dis-

sion as to whether this effect in early Parkinson

order, numerous problems are associated with

disease is “neuroprotective” or simply sympto-

its use (Table 12.2). However, it should be rec-

matic. The evidence strongly suggests that the

ognized that several long-term follow-up stud-

effect of selegiline is symptomatic.

ies of patients with Parkinson disease who

Rasagiline, another MAO-B inhibitor that

were treated with levodopa demonstrated that

is not metabolized to amphetamine byprod-

at the end of 5 years of treatment, most pa-

ucts, has been demonstrated to be effective in

tients’ motor function was no worse than prior

early Parkinson disease and in managing

to treatment or, in many cases, still better than

motor fluctuations in advanced Parkinson

before they were treated. This finding is ex-

disease. Like selegiline, rasagiline has been

traordinary because prior to levodopa therapy,

proposed to have neuroprotective effects. A

the prognosis in Parkinson disease was dismal.

recently completed delayed-start trial of rasag-

Several major side effects are associated with

iline suggested a disease-modifying effect.

the use of carbidopa-levodopa, including drug-

However, the full study results have elicited

induced dyskinesias, drug-induced psychiatric

considerable controversy regarding the results.

problems, and motor fluctuations. Levodopa-

The research question is not whether the small

induced dyskinesias are a striking long-term

effect size achieved is statistically significant,

complication of this therapy. The dyskinesias

but is it clinically meaningful.

are most often choreic. Chorea consists of irreg-

Entacapone and tolcapone are COMT

ular, unpredictable, brief, jerky movements that

inhibitors approved for the treatment of

flit from one body part to another in a continu-

Parkinson disease. COMT inhibitors must be

ous random sequence. Occasionally, levodopa-

administered in combination with levodopa,

induced dyskinesias are dystonic. Dystonia

resulting in increased bioavailability of lev-

describes movements that are dominated by

odopa to the brain. COMT inhibitors may en-

sustained muscle contraction, frequently result-

hance dopaminergic side effects; therefore,

ing in twisting repetitive movements and abnor-

downward titration of carbidopa-levodopa

mal postures. The dyskinesia may involve the

may be required, particularly in patients who

lingual, facial, and buccal regions; the limbs;

already have dyskinesia. Tolcapone and enta-

and the axial musculature. It is particularly

capone have been shown to be effective in pa-

striking to see patients with this drug-related

tients experiencing motor fluctuations. Both

drugs are easy to administer, and their thera-

peutic efficacy can be ascertained quickly. The

TABLE 12.2

Toxicity Associated with Chronic

FDA determined that hepatotoxicity associated

Levodopa Therapy

with tolcapone necessitates stringent liver func-

tion monitoring and informed consent when

Central toxicity

Dyskinesias

prescribing this drug. Entacapone is not associ-

Motor fluctuations

“On-Off ” phenomenon

ated with liver toxicity. Entacapone has been

Sleep disturbances

combined with levodopa and carbidopa in one

Psychiatric disturbances

tablet.

Peripheral toxicity

Nausea and vomiting

It should be noted that all of the anti-

Mixed central and

Orthostatic hypotension

Parkinson medications may be used in combi-

questionable

nation, particularly in the advanced patient

peripheral toxicity

with complex symptoms.

231

Chapter 12

■ Parkinson Disease

movement disorder because patients with

particularly to reduce the administration of

Parkinson disease were previously character-

other medications that depress the nervous

ized by slowness and poverty of movement. The

system, including sedatives, hypnotics, anxi-

chorea seen in this setting may resemble the

olytics, anticholinergics, opiates, and muscle

chorea seen in Huntington disease or tardive

relaxants. When this is not sufficient to relieve

dyskinesia.

hallucinations and delusions, the use of an-

Levodopa-induced dyskinesias are common

tipsychotic medications is indicated to be able

and may be seen in more than half the patients

to continue dopaminergic medications at a

at the end of 5 years of carbidopa-levodopa

level to maintain the patient’s motor function.

treatment. However, patients with onset of

There are several atypical neuroleptic drugs

dyskinesias during the first 5 years of levodopa

available that can reduce or abolish psychosis

treatment experience very mild abnormal

with less potential for extrapyramidal side

movements that do not usually interfere with

effects. Clozapine is the only neuroleptic med-

function. The severity of the chorea may in-

ication proven to be effective in Parkinson dis-

crease with continued treatment, and the dose

ease psychosis that does not produce adverse

of levodopa required to elicit chorea may de-

motor effects. Quetiapine is often used as a

crease with time. The relationship between du-

first-line treatment. Although quetiapine does

ration of disease, levodopa treatment, and

not have the proven efficacy of clozapine, que-

onset of dyskinesias is unclear. A reduction in

tiapine also does not carry the same risk of se-

levodopa dosage invariably will ameliorate this

rious adverse hematologic events. Traditional

drug-induced movement disorder. Although

neuroleptics should not be used for psychosis

the chorea may be severe, the parkinsonian pa-

in Parkinson disease patients because of the

tient often does not find the movement trou-

adverse effect on motor function. All of the

bling; it is usually the family or the physician

atypical neuroleptics are used in much lower

who first notices the chorea. This is probably

dosage in Parkinson disease then when indi-

best explained by the fact that while a patient

cated for schizophrenia.

is choreic, they are still able to move voluntar-

Fluctuation in motor performance is an ad-

ily with relative ease. Given a choice, most

ditional complication associated with both

parkinsonian patients prefer excess movement

chronic dopaminergic therapy and duration of

to bradykinesia. However, severe levodopa-

disease. After a variable period of treatment,

induced dyskinesia can be as disabling as

patients note that the beneficial effects of the

bradykinesia.

drug begin to wear off before they are due

The psychiatric side effects of long-term

to take their next dose (“wearing off” or end-

dopaminergic therapy include altered sleep

of-dose akinesia) and that they may be very

patterns, vivid nightmares, auditory and vi-

akinetic in the morning before the first dose of

sual hallucinations, paranoia, and psychosis.

medication (morning akinesia). One or more

Although there may be a continuum of in-

doses often do not seem to work. Later, partic-

creasing severity of psychiatric symptomatology

ularly in patients on multiple overlapping

with increasing dopaminergic medication

doses of carbidopa-levodopa, the fluctuations

dose and duration, the symptoms may de-

from a mobile state or “on” to “off” with ob-

velop insidiously in some patients and acutely

vious parkinsonism may appear random with

in others. These drug-related complications

no obvious relation to dosage timing. The

can be ameliorated by reduction of dopamin-

transition between relatively normal functions

ergic medications.

to complete reemergence of the parkinsonian

The simplest approach to drug-induced psy-

state can occur in several minutes, and it can

chosis in Parkinson disease is to reduce the

persist for up to 3 to 4 hours. Sudden, rapid,

dosage of antiparkinsonian medications and

unpredictable fluctuations between these two

232

Chapter 12

■ Parkinson Disease

extremes can also occur. Clinically, these fluc-

testinal transport system with other aromatic

tuations can be striking, and the dramatic na-

amino acids, and high-protein meals result in

ture of these transitions occasionally can be

greater competition for the uptake system, re-

observed during an office evaluation. A pa-

ducing the amount of levodopa available to

tient may be seen in a severely parkinsonian

the brain. In patients who note loss of efficacy

state (“off”) with marked cogwheel rigidity,

of carbidopa-levodopa when it is adminis-

resting tremor, and severe akinesia to the de-

tered with a protein meal, the restricted-pro-

gree that the patient is unable to rise from a

tein diet may provide smoother motor

chair and have impaired postural reflexes to

response throughout the day. This is not a

the point of falling or being unable to stand.

low-protein diet; it restricts daytime protein

During 5 to 6 minutes, the same patient may

intake to enhance motor performance during

turn “on” and be observed to be able to stand

the day and shifts a greater proportion of the

and sit without difficulty, to have no tremor,

daily protein to the evening meal.

and to be able to walk relatively normally and

The symptoms of Parkinson disease remain

not look at all parkinsonian. The observer

responsive to the effects of levodopa throughout

who is unfamiliar with these rapid transitions

the duration of the illness; however, as the dis-

is astounded by these fluctuations, and the un-

ease advances, the degree of symptom relief is

informed observer may even believe that the

less dramatic as the complications of motor fluc-

severe parkinsonian state, or “off,” may re-

tuations, dyskinesia, and hallucinosis emerge.

flect a functional or nonorganic problem.

The administration of levodopa or a dopamine

This perplexing problem seems to be re-

agonist should begin when the patient’s ability to

lated to alterations in central dopamine recep-

carry out daily functions is impaired. All of these

tor-site responsiveness and to fluctuating

medications are symptomatic and not disease

levels of available dopamine. It is a problem

modifying; therefore, it is important to treat a

typically encountered only in patients with

“symptom.” The precise timing is individualized

advanced Parkinson disease. There are many

based on many issues including lifestyle and indi-

therapeutic maneuvers to try in a patient with

vidual response to symptomatology. There is no

motor fluctuations, including increasing the

benefit to withholding treatment until advanced

antiparkinsonian medication dose or dosing

disability ensues.

frequency, adding the controlled-release for-

Management of advanced Parkinson disease

mulation of carbidopa-levodopa, adding a

is challenging because the clinician often con-

dopamine receptor agonist, adding a COMT

fronts a double bind; the patient requires

inhibitor, adding a MAO-B inhibitor, or im-

increased levodopa to improve his or her

plementing a restricted-protein diet. New

parkinsonism but needs decreased levodopa to

medications should be added one at a time.

reduce dopaminergic adverse events. The intro-

Both levodopa and the dopamine receptor

duction of dopamine receptor agonists, MAO-B

agonists

(pramipexole and ropinirole) must

inhibitors, or COMT inhibitors can be useful

be initiated at a low dose and gradually

for problems with motor fluctuations and drug-

titrated upward to the therapeutic range,

related dyskinesia. Dopamine receptor agonist

whereas the COMT inhibitors (tolcapone or

administration provides dopaminergic stimula-

entacapone) and MAO-B inhibitors (selegiline

tion of the postsynaptic striatal dopamine

and rasagiline) are initiated at an effective

receptors and also often allows a reduction

dose. The restricted-protein diet is mainly

in carbidopa-levodopa dose. In some patients,

helpful in patients who report a significant

the combination of dopamine agonist with

effect of diet on their response to carbidopa-

levodopa will result in more consistent motor

levodopa. Levodopa shares the same gastroin-

improvement with less dyskinesia.

233

Chapter 12

■ Parkinson Disease

of balance) are not relieved by this procedure.

SURGERY

When the target is the globus pallidus or the

subthalamic nucleus, more pervasive sympto-

The history of surgical treatment of Parkinson

matic relief including tremor, rigidity, bradyki-

disease begins more than 60 years ago. In 1968

nesia, and dyskinesia may be achieved.

1969 when levodopa treatment became

Currently, the most common target for DBS is

widely available, surgical procedures for

the subthalamic nucleus. DBS targeting the

Parkinson disease dropped precipitously and al-

subthalamic nucleus provides the most robust

most disappeared. However, in the last 15 years

relief of motor symptoms, but it carries a risk

there has been a resurgence of interest in surgi-

of cognitive or behavioral problems developing

cal treatment. This has developed because phar-

after surgery. Formal trials comparing pallido-

macologic treatment has limitations, greater

tomy to DBS procedures for Parkinson disease

insight into basal ganglia function was

have not yet been reported.

achieved, and improved surgical techniques and

There has been considerable interest in

technologies became available. Pallidotomy uti-

the role of fetal tissue

(mesencephalon) im-

lizing updated stereotactic techniques has been

plants in the treatment of Parkinson disease.

reintroduced to treat advanced Parkinson dis-

This concept involves the transplantation of

ease. In this procedure, a small lesion is made

the dopamine-producing mesencephalon cells

by the neurosurgeon in the globus pallidus in an

from an aborted fetal brain into the brain of

attempt to disrupt the physiologic outflow of

the patient with Parkinson disease. Unfortu-

the basal ganglia and relieve the symptoms of

nately, two well-controlled, blinded trials of

Parkinson disease. Some centers report a 20%

human fetal tissue transplants in Parkinson dis-

to 30% improvement in the motor symptoms

ease failed to demonstrate therapeutic benefit

of Parkinson disease and resolution of dyskine-

and provoked uncontrollable dyskinesias in a

sia in selected patients. Neurosurgical compli-

number of study subjects.

cations include intraparenchymal hemorrhage,

Whether or not the implantation of stem

cerebral vascular accident, and altered mental

cells into the basal ganglia will be beneficial to

status. Patients with severe intractable drug-

patients remains to be determined. Currently,

related dyskinesia are generally the best candi-

there are many technologic problems related to

dates for this procedure.

the stem cells that need to be solved before clin-

Another surgical procedure that has largely

ical trials can begin.

replaced pallidotomy is deep brain stimulation

(DBS). DBS is a neurosurgical stereotactic pro-

cedure in which a stimulating electrode is

DRUG-INDUCED PARKINSONISM

placed in a selected brain region (target) and

wires are subcutaneously passed from the tar-

Drug-induced parkinsonism can be precipitated

get to an electronic stimulator that is implanted

by any drug that reduces central dopaminergic

in the chest wall (analogous to a cardiac pace-

activity

(Table

12.3). Drugs that block the

maker). The stimulator can be turned off and

dopamine receptor (e.g., neuroleptics, metoclo-

on by the patient with the use of a magnetic

pramide) or deplete central dopamine

(e.g.,

“wand.” DBS for Parkinson’s symptoms has

reserpine, tetrabenazine) often result in parkin-

been targeted at the Vim nucleus of the thala-

sonian symptomatology. Parkinsonism induced

mus, the globus pallidus, or the subthalamic

by drugs can mimic all of the features seen

nucleus. When the target is the Vim nucleus of

in Parkinson disease. Akinesia and rigidity are

the thalamus, relief of tremor is most likely to

the most common signs, and resting tremor is

be achieved; however, the other symptoms of

seen less often. Other features that may help

Parkinson disease (bradykinesia, rigidity, loss

distinguish drug-induced parkinsonism from

234

Chapter 12

■ Parkinson Disease

TABLE 12.3

sonism does not resolve, Parkinson disease may

Medications Causing Parkinsonism

have been unmasked.

Typical Antipsychotics

Antiemetics

Amoxapine

Chlorpromazine

FURTHER CONSIDERATIONS

Molindone

Metoclopramide

Thioridazine

Promethazine

Although the etiology of Parkinson disease re-

Fluphenazine

Prochlorperazine

mains unknown, there have been recent at-

Loxapine

Thiethylperazine

tempts to modify the natural history of this

Mesorizadine

Neurotransmitter

disorder and delay progression. This approach

Trifluoperazine

Depletors

to treatment, sometimes referred to as “neuro-

Perphenazine

Reserpine

protective” or “disease-modifying therapy,” has

Haloperidal

Tetrabenazine

been based on a wide variety of theoretic and

Thiothixene

Calcium Channel

preclinical models. Attempts to modify disease

Pimozide

Blockers

progression using vitamin E (2,000 units/day)

Zuclopenthixol

Flunarizine

and selegiline (5 mg b.i.d.) failed. Vitamin C

Atypical

Amlodipine

Antipsychotics

Cinnarizine

in doses of 1,500 to 3,000 mg/day has been

Olanzapine

Miscellaneous

proposed as an additional antioxidant treat-

Quetiapine

Lithium

ment, but vitamin C has never been tested ad-

Clozapine

Valproic acid

equately. The results from a trial of rasagiline,

Risperdal

Fluoxetine

which purports to show disease modification,

Aripiprazole

have not yet been published. At present, there

Ziprasidone

is no “neuroprotective” therapy for Parkinson

Paliperidone

disease; however, there is continued interest in

disease-modifying therapies and a number of

trials are in progress.

The levodopa treatment era in Parkinson

Parkinson disease include a clear history of ex-

disease with improved function and life ex-

posure to a compound known to interfere with

pectancy led to broadening the scope of what is

central dopamine activity, a relatively short

considered to be the central nervous system

time from onset of parkinsonian symptoms to

dysfunction seen in this disorder. Although

functional impairment (about 1 to 2 months as

James Parkinson did not originally describe

opposed to 12 to 24 months), bilateral presen-

cognitive dysfunction as part of the illness, it is

tation instead of unilateral presentation of

apparent that cognitive impairment and demen-

symptoms and signs, and the presence of other

tia are often associated with Parkinson disease.

drug-related motor abnormalities (e.g., tardive

There is evidence from the pre-levodopa era to

dyskinesia; see Chapter 13).

suggest that

25% to 30% of patients with

The diagnosis of drug-induced parkinsonism

Parkinson disease eventually were institutional-

requires a high index of suspicion. Once the di-

ized because of dementia and not because of in-

agnosis is made, treatment should be directed at

capacitating motor performance. However, the

stopping the offending drug. In almost all pa-

increased longevity and maintenance of com-

tients with this syndrome, the parkinsonism will

municative abilities in patients with Parkinson

resolve over time. Resolution of drug-induced

disease led to further understanding of cogni-

parkinsonism may take weeks to months. If

tive dysfunction in Parkinson disease. Studies

active treatment is required, anticholinergics,

confirm earlier observations that as many as

amantadine, and levodopa-carbidopa have been

25% to 50% of patients with Parkinson disease

used successfully. When drug-induced parkin-

may develop dementia. Parkinson disease

235

Chapter 12

■ Parkinson Disease

dementia is characterized primarily by execu-

WHEN TO REFER TO A NEUROLOGIST

tive dysfunction, rather than an amnestic de-

mentia, as seen in Alzheimer disease. Trials of

Parkinson disease is a common disorder, and it is

the acetylcholinesterase inhibitors, donepezil

believed that there may be 1 million people in the

and rivastigmine, have both shown modest ben-

United States with this illness. Because there is no

efits on cognition in Parkinson disease demen-

specific imaging study or biomarkers to confirm

tia and may be considered for treatment.

the diagnosis, Parkinson disease is a clinical di-

There is considerable interest in other non-

agnosis. Physicians making this diagnosis should

motor symptoms of Parkinson disease includ-

be comfortable in determining that a patient has

ing depression, apathy, fatigue, anxiety, and

Parkinson disease based on the patient’s history

sleep disruption. Studies indicate that all of

and examination. Parkinson disease is a chronic

these nonmotor symptoms are much more fre-

progressive illness that ultimately results in sig-

quent than previously understood, and con-

nificant disability; the diagnosis is a serious one.

tribute significantly to quality of life and

Although the diagnosis of Parkinson disease

disability in Parkinson disease.

certainly can be made by a non-neurologist,

Any drug or degenerative process that in-

many patients and families will ask for referral

terferes with central dopaminergic activity

for confirmation. There is great interest in clinical

can lead to parkinsonism. The dysfunction of

research trials for neuroprotective agents for

the dopamine system may involve the nigral

Parkinson disease, and most of these trials seek to

(presynaptic) neuron or the striatal dopamine

enroll early patients. Referral of patients for pos-

receptor (postsynaptic). Drugs or degenera-

sible participation in studies can be of great value

tive processes that affect not the presynaptic

for the patient because there currently are no

nigrostriatal dopaminergic pathway but the

drugs that slow the progression of Parkinson dis-

striatal dopamine receptors may result in

ease and it may give the patient a sense of being

the same clinical signs. The latter situation is

more proactive about dealing with this diagnosis.

sometimes referred to as postsynaptic parkin-

The early years of symptomatic treatment are

sonism. Examples of postsynaptic parkinson-

often uneventful and the patient can be cared

ism include some drug-induced states and

for by the non-neurologist. If patients develop

metabolic disturbances that result in calcifi-

motor fluctuations, dyskinesias, or hallucina-

cation of the basal ganglia and familial stria-

tions and psychosis, referral to a neurologist is

tonigral degeneration. Because the pathology

indicated for further treatment.

in these syndromes is located primarily

within the striatum and involves the

dopamine receptors, it should not be surpris-

COMPLEMENTARY THERAPIES

ing that carbidopa-levodopa therapy is less

effective in these disorders. Other neurode-

Some people say that there are no alternative

generative disorders have elements of both

therapies in medicine—only therapies that

presynaptic and postsynaptic dopaminergic

work and those that do not. This applies to

dysfunction including the spinocerebellar

Parkinson disease. Few alternative therapies in

ataxias (SCA), PSP, and MSA. Clinical clues

Parkinson disease have been tested. High-dose

to identify these syndromes include variable

vitamin E (2,000 units/day) was demonstrated

response to levodopa, the presence of a ki-

to have no effect in modifying disease progres-

netic tremor (SCA), the failure of voluntary

sion. Early studies of coenzyme Q10 were

conjugate gaze

(PSP), and the presence of

promising, but it is premature to conclude that

severe orthostatic hypotension and other au-

it is

“neuroprotective.” Studies of coenzyme

tonomic signs (MSA).

Q10 are still ongoing.

236

Chapter 12

■ Parkinson Disease

A small study of acupuncture was con-

remain fully informed about the medications

ducted in Parkinson disease. Acupuncture was

being administered.

ineffective for all motor and nonmotor symp-

If hospitalized patients with Parkinson dis-

toms with the exception of some benefit for

ease become agitated, with delirium or psy-

sleep and rest.

chotic ideation, care must be taken to avoid

Physical therapy is helpful for alleviating

agents that interfere with the efficacy of

rigidity and bradykinesia in Parkinson disease.

Parkinson disease medications. The use of tra-

There is currently great interest on the possible

ditional neuroleptics, and certain antiemetics,

interactions between exercise and cognition.

or gastrointestinal agents

(metoclopramide)

Physical therapy and regular exercise may have

can interfere with dopamine neurotransmis-

benefits on cognition in addition to purely

sion and result in motor worsening.

physical benefits. Speech therapy may also be

The dramatic changes in motor function of

helpful to patients with Parkinson disease. One

the patient with Parkinson disease with motor

therapy in particular

(Lee Silverman Voice

fluctuations may result in confusion on the part

Treatment) is effective for hypophonia in

of the hospital staff. Staff may observe a patient

Parkinson disease patients.

“on” who is able to perform all activities of

There is no special diet for most patients with

daily living without assistance and later observe

Parkinson disease. In some patients with motor

the same patient “off” and immobile. During

fluctuations that are sensitive to protein intake

“off” periods, the patient may require assis-

(after a protein meal medications may not work

tance and the staff may mistakenly believe the

as well), a protein redistribution diet may be of

patient’s request for assistance is not necessary.

value. A wide variety of additional treatments

Staff education about the changeable nature of

are marketed as possible therapeutic agents for

symptoms in fluctuating patients is important.

Parkinson disease. These include over-the-

All medical and surgical services caring for

counter antioxidants, food supplements, ginkgo

patients with Parkinson disease should be

biloba, ginseng, herbal preparations, massive

proactive in instituting preventative measures

doses of vitamins, spa treatments, NADH (re-

to avoid deep-vein thrombosis and aspiration

duced form of nicotinamide adenine dinu-

pneumonia in patients with Parkinson-related

cleotide) preparations, and chelation therapy.

immobility. Fall precautions should also be

None of these have been shown to be effective.

taken for Parkinson disease patients with gait

disturbances or impaired postural reflexes.

SPECIAL CHALLENGES FOR

Always Remember

HOSPITALIZED PATIENTS

• Parkinson disease has four major cardinal

When patients with Parkinson disease enter the

signs: resting tremor, cogwheel rigidity,

hospital for medical or surgical conditions unre-

bradykinesia, and postural instability.

lated to Parkinson disease, special precautions

• Levodopa is the most effective medication for

are indicated. Most patients with moderate

symptomatic treatment of Parkinson disease.

Parkinson disease have specific requirements for

• Parkinson disease has motor, cognitive, and

the timing of their medications to maintain opti-

emotional/behavioral consequences.

mum motor function. Hospital routines often

• A careful history regarding exposure to

do not accommodate well to complicated time-

dopamine blocking agents should be taken,

specific oral medication schedules. One way to

and typical antipsychotics and

address this problem is to have patients and

metoclopramide should be avoided in

families remain in control of administering the

Parkinson disease patients.

antiparkinsonian medications. The staff must

237

Chapter 12

■ Parkinson Disease

the presentation, the diagnosis of Parkinson

QUESTIONS AND DISCUSSION

disease is questionable. However, postural re-

flex impairment is a common sign in advanced

1. A 62-year-old right-handed man presented

Parkinson disease.

to his physician with the following

problems. He has noticed for the last

2. A 59-year-old right-handed woman has an

6 months that his handwriting has changed

8-year history of left upper extremity

and that it appears small and cramped. In

resting tremor. She has been treated with

addition, he has the feeling that his right

carbidopa-levodopa for the last 7 years.

hand is not as strong as it used to be, and

Although she states that originally her

he often has to struggle to button his shirt.

tremor was much improved, she has been

The week prior to his visit, his wife noticed

having difficulty with increasing

that his right hand appeared to be shaking

involuntary “dancelike” gyrating,

when he was resting quietly in an easy chair.

nonpurposeful movements of the left upper

The most likely diagnosis in this patient

and lower extremities. In addition, her

based on history alone is:

husband reports that occasionally his wife

A. Parkinson disease

sees visitors in the house when they are

B. Wilson disease

alone. Questioning the patient reveals that

C. Huntington disease

she often sees people who are not really

D. Dystonia

there. She speaks lucidly about this and

recognizes that they are not real. The

Neurologic signs present on examination

correct diagnosis in this patient would be:

might include which of the following?

A. Dystonic posturing of the left upper

A. Bilateral limb chorea, linguofaciobuccal

extremities

dyskinesias

B. Tardive dyskinesia

B. Resting tremor of the right hand,

C. Parkinson disease with dopaminergic

cogwheel rigidity of the right upper

adverse events

extremity

D. Wilson disease and dopaminergic

C. Fixed dystonic posturing of the right

adverse events

hand

The correct answer is C. The patient’s initial

D. Kinetic tremor of the right hand

presenting complaint is the spontaneous ap-

E. Three-step retropulsion, two to three

pearance of a unilateral resting tremor that is

extra steps in turning maneuvers

relieved by dopaminergic agents. This is a

The answer to the first part of the question is

characteristic early presentation of unilateral

A and the answer to the second part is B. This

Parkinson disease, and the additional informa-

is a typical history of Parkinson disease char-

tion that dopaminergic therapy ameliorated

acterized by slow progression and a predomi-

the symptoms suggests the diagnosis of

nantly unilateral presentation of the

Parkinson disease. The patient’s present com-

symptoms and signs. In addition, the hand-

plaints are adverse events associated with

writing is described as cramped and small (mi-

chronic dopaminergic therapy, specifically

crographic). The feeling of weakness in an

levodopa-induced dyskinesias and hallucina-

involved extremity is a common complaint, al-

tions. Levodopa-induced dyskinesias in Parkin-

though there is usually no objective sign of

son disease are often choreiform and are not

weakness. The presence of unilateral signs of

phenomenologically distinguishable from the

tremor and cogwheel rigidity is typical. If pos-

chorea seen in many other choreatic states.

tural reflexes are impaired (retropulsion and

The hallucinations reported by this patient are

increased steps on turning maneuvers) early in

typical, nonthreatening visual hallucinations.

238

Chapter 12

■ Parkinson Disease

Answer A is incorrect because dystonic pos-

Answer A is incorrect because this is a

tures and movements are not “dancelike” and

drug-induced syndrome and raising the dose

gyrating. Answer B is incorrect because there is

of the drug will not ameliorate the problem—

no drug history of neuroleptic medication and

it will exacerbate it. Answer B is incorrect be-

tardive dyskinesia is by definition secondary to

cause anticholinergics will not improve chorea

chronic dopamine receptor blockade. Answer

and are likely to increase the psychotic symp-

D is incorrect because Wilson disease does not

toms. Answer D is incorrect because typical

present so late in life. The average age of onset

neuroleptics lead to unacceptable motor dete-

of Wilson disease presenting with neurologic

rioration in patients with PD.

symptomatology is 19 years.

3. A 65-year-old right-handed man presents

The most appropriate therapy in this pa-

with generalized slowing of mobility and

tient would be:

difficulty seeing the food on his plate. His

A. Raising the dose of carbidopa-levodopa

family says that his problem has been

B. Adding an anticholinergic

getting worse for the last 12 months and

C. Reducing the dose of carbidopa-

that the patient also has difficulty walking

levodopa

up stairs. In addition, he describes that he

D. Administering a typical neuroleptic

is having difficulty buttoning his shirt,

rising from a chair, and turning over in bed.

The correct answer is C. The patient’s current

The family also reports that his facial

problems of dyskinesias and hallucinations are

expression has changed (he does not smile

secondary to chronic dopaminergic stimula-

as much) and that a tremor of his left hand

tion, and the appropriate therapy is to reduce

is occasionally noted. Examination reveals

the dose of dopaminergic therapy if possible.

that there is a resting tremor of the left

These drug-induced effects will be ameliorated

hand, cogwheel rigidity in the left upper

when dopaminergic agents are reduced. When

extremity is present, and postural reflexes

the dose of the dopaminergic is reduced or

are mildly impaired. Additional findings

discontinued, the patient’s parkinsonian

include increased extensor tone in the neck

symptoms will become worse.

and marked impairment of voluntary

Typical neuroleptics should be avoided be-

conjugate gaze. The patient is unable to

cause of their high predilection for worsening

look down voluntarily, and there is also

motor function in patients with PD. However,

moderate impairment of upward gaze. In

if reduction in levodopa dosage results in ex-

addition, right and left lateral gaze are not

cessive motor dysfunction with functional im-

normal. The correct diagnosis in this

pairment, the addition of an atypical

patient would be:

neuroleptic may be necessary. First, confirm

A. Wilson disease

that the patient is not taking other types of

B. Huntington disease

medications that may significantly contribute

C. Parkinson disease

to confusion and psychotic ideation, such as

D. Progressive supranuclear palsy

sedatives, tranquilizers, and anticholinergics. If

E. Multiple system atrophy

the drug regimen is simplified but the psychotic

symptoms persist, choose either clozapine or

The correct answer is D. PSP is an idiopathic

quetiapine for their antipsychotic effects. Use

midbrain and brainstem degenerative disorder

the lowest effective dosage to avoid adverse ef-

that is characterized by parkinsonian features

fects. If drug-induced dyskinesia persists and is

and progressively impaired voluntary conju-

very troublesome despite maximal reduction of

gate gaze. This patient is described as having

antiparkinsonian medications, surgical inter-

parkinsonian features (resting tremor, cog-

vention may be considered.

wheel rigidity, impaired postural reflexes, and

239

Chapter 12

■ Parkinson Disease

mild bradykinesia) and has markedly impaired

the striatum. Dopamine is the neurotransmit-

conjugate gaze. A useful office maneuver to

ter used by this system, and the dopamine

determine whether the gaze dysfunction is

within the striatum is contained primarily

supranuclear or nuclear is the doll’s head pro-

within the axonal terminations of the nigral

cedure. In this maneuver, the head is passively

neurons.

flexed and extended, and in a separate maneu-

5. A 65-year-old woman was diagnosed with

ver, it is rotated to the right and to the left

Parkinson disease 9 years ago when she

while the passive motion of the eyes is ob-

developed a resting tremor of the left hand.

served. In a patient with supranuclear gaze

When levodopa-carbidopa treatment was

dysfunction, the eyes will move reflexly and

started, she had a positive response and her

conjugately in an appropriate direction. This

tremor, clumsiness of the left hand, and gait

maneuver and its physiology are discussed in

improved. She is now taking levodopa-

greater detail in Chapter 20.

carbidopa 25/100 mg 2 tablets q.i.d.,

Answer A is incorrect because of the late

pramipexole 1 mg t.i.d., and entacapone

onset of neurologic symptoms and the type of

200 mg q.i.d. On this schedule, she

eye movements observed. Answer B is incor-

experiences end-of-dose wearing off and

rect because of the late onset of neurologic

moderate dyskinesias. She has no

symptoms and because the movement disorder

hallucinations or delusions, is not

is not that seen in adult-onset Huntington dis-

depressed, and is otherwise in good health.

ease. Although definite parkinsonian features

The motor fluctuations and dyskinesias

are present, Answer C is incorrect because of

have become troublesome to her.

the additional findings of disturbed volitional

Management of her motor fluctuations

gaze. Answer E is incorrect because of the

and dyskinesia may include:

pronounced oculomotor dysfunction.

A. Increasing levodopa-carbidopa dosage

4. The degenerative cellular pathology seen in

and frequency

Parkinson disease is localized primarily in

B. Increasing pramipexole dosage

the:

C. Adding an additional dopamine agonist

A. Cerebral cortex

D. Perform surgical procedure (DBS)

B. Thalamus

The correct answer is D. This patient has a

C. Cerebellum

complex problem that reflects advancing

D. Substantia nigra

parkinsonism and drug-associated problems.

E. Corpus striatum

Decreasing the dosage of pramipexole, enta-

The loss of cell bodies and their projection sys-

capone, or levodopa will ameliorate her dyski-

tems in the correct answer to the first part of

nesia. However, her parkinsonism may worsen

this question results in what biochemical lesion?

to an unacceptable degree. Another option

A. Loss of acetylcholine in the striatum

would be to start amantadine 100 mg b.i.d. in

B. Loss of dopamine in the striatum

order to reduce dyskinesia. DBS is a good

C. Loss of dopamine in the cerebral cortex

therapeutic choice when medical options have

D. Loss of acetylcholine in the cerebellum

been exhausted because it can alleviate both

The answer to the first part of the question is

motor fluctuations and dyskinesias.

D, and the answer to the second part of the

The following conditions exclude a patient

question is B. Parkinson disease is pathologi-

from DBS surgery for Parkinson disease: unsta-

cally characterized by depigmentation, Lewy

ble medical conditions, cognitive impairment,

bodies, and cell loss in the substantia nigra.

poor response to levodopa, neurobehavioral

The destruction of the nigral striatal projec-

problems, and atypical parkinsonism. The DBS

tion system results in the loss of dopamine in

candidates with the best chance of a successful

240

Chapter 12

■ Parkinson Disease

outcome are relatively healthy, have no cogni-

Standards Subcommittee of the American Academy of

Neurology. Neurology. 2002;58:11-17.

tive impairment or significant behavioral prob-

lems

(depression, anxiety), still have some

Miyasaki JM, Shannon K, Voon V, et al. Practice parame-

ter: evaluation and treatment of depression, psychosis,

good response to levodopa administration,

and dementia in Parkinson disease (an evidence-based

have Parkinson disease, and understand that

review): report of the Quality Standards Subcommittee

DBS for Parkinson disease is not a cure.

of the American Academy of Neurology. Neurology.

2006;66:996-1002.

Pahwa R, Factor SA, Lyons KE, et al. Practice parameter:

treatment of Parkinson disease with motor fluctuations

SUGGESTED READING

and dyskinesia (an evidence-based review): report of

Cotzias GC, Van Woert MH, Schiffer LM. Aromatic

the Quality Standards Subcommittee of the American

amino acids and modifications of Parkinsonism. N

Academy of Neurology. Neurology. 2006;66:983-995.

Engl J Med. 1967;276:374.

Shulman LM, Gruber-Baldini AL, Anderson KE, et al.

Factor SA, Weiner WJ, eds. Parkinson’s Disease: Diagno-

The evolution of disability in Parkinson disease. Mov

sis and Clinical Management. 2nd ed. New York:

Disord. 2008;23:790-796.

Demos Press; 2008.

Suchowersky O, Reich SG, Perlmutter J, et al. Practice pa-

Havemann J. A Life Shaken—My Encounter with Parkin-

rameter: diagnosis and prognosis of new onset Parkin-

son’s Disease. Baltimore: Johns Hopkins University

son disease (an evidence-based review): report of the

Press; 2002.

Quality Standards Subcommittee of the American

Academy of Neurology. Neurology. 2006;66:968-975.

Jankovic J, Marsden CD. Therapeutic strategies in

Parkinson’s disease. In: Jankovic J, Tolosa E, eds.

The Parkinson Study Group. Effect of deprenyl on the

Parkinson’s Disease and Movement Disorders. 3rd ed.

progression of disability in early Parkinson’s disease.

Baltimore: Williams & Wilkins; 1998:191.

N Engl J Med. 1989;321:1364.

Miyasaki JM, Martin W, Suchowersky O, et al. Practice

Weiner WJ, Shulman LM, Lang AE. Parkinson’s Disease:

parameter: initiation of treatment for Parkinson’s dis-

A Complete Guide for Patients and Families. 2nd ed.

ease: an evidence-based review: report of the Quality

Baltimore: Johns Hopkins University Press; 2006.

Hyperkinetic

Movement

Disorders

GONZALO J. REVUELTA, WILLIAM J.

WEINER, AND STEWART A. FACTOR

key points

• Dystonia is a movement disorder seen in a variety of

genetic, sporadic, and acquired conditions, for which

multiple medical therapies and surgical interventions

are available.

• Essential tremor (ET) is primarily a postural and kinetic

tremor that often responds to medical therapy, but if

severe it can be treated effectively with deep brain

stimulation (DBS).

• Huntington disease (HD) is a progressive inherited

neuropsychiatric disorder for which a definitive genetic

diagnosis is available; however, this information is very

sensitive and should be handled by multidisciplinary

centers experienced with this process.

• Wilson disease (WD) is a hereditary, potentially

reversible condition that can be associated with myriad

movement disorders, and, if not diagnosed and treated

appropriately, is fatal.

• Gilles de la Tourette syndrome (GTS) is a tic disorder

associated with a variety of behavioral disorders often

necessitating a multidisciplinary treatment approach.

• Tardive dyskinesia (TD) is a choreo-dystonic, persistent

movement disorder that occurs as an adverse effect of

neuroleptic and antiemetic therapy.

241

242

Chapter 13

■ Hyperkinetic Movement Disorders

randomly distributed, and often have a flowing

“dancelike” quality that involves multiple

body parts.

Tics: Repetitive, brief, rapid, purposeless,

stereotyped movements that involve single or

multiple muscle groups. The tics can be a pat-

trange, abnormal involuntary

terned sequence of coordinated movements

movements are the hallmarks of a number of

that may be complex or simple, associated with

neurologic diseases; they are collectively termed

a premonitory urge, and are suppressible.

“hyperkinetic movement disorders” (also re-

Myoclonus: Rapid, shock-like, arrhythmic

ferred to as dyskinesias). In such conditions, the

(usually), and often repetitive involuntary move-

movements are easily visible, and observation

ments. Myoclonus can be classified by location

allows the clinician, in most instances, to sug-

(focal, multifocal, or generalized) and by etiology.

gest the proper diagnosis or class of disorders.

Stereotypy: Patterned, repetitive, and pur-

The characteristic tremor of Parkinson disease,

poseless movements that are performed exactly

which is present at rest but markedly diminished

the same way each time.

during volitional movements, is an example

(Chapter 10). In this chapter, six hyperkinetic

DYSTONIA

movement disorders are described. All are dra-

matic visually because bizarre and abnormal

Dystonia is divided into primary (idiopathic)

involuntary movements are their major fea-

and secondary forms. Several primary dystonic

tures. The non-neurologist encounters patients

conditions have been identified which are char-

with these disorders in an office practice and

acterized by dystonia as the sole clinical fea-

also identifies them in public (e.g., in parks,

ture. The prevalence of primary dystonia is

trains, and shopping centers).

estimated to be 33 per 100,000. Dystonia of

The disorders discussed in this chapter are

primary origin has a number of unusual but

dystonia, essential tremor (ET), Huntington

characteristic features. At onset, the movements

disease (HD), Wilson disease (WD), Gilles de

may occur in relation to specific voluntary ac-

la Tourette syndrome (GTS), and tardive dysk-

tions (such as in writer’s cramp) or with varied

inesia (TD).

movements, so-called “action-induced dysto-

nia.” It may occur in one body part with move-

ment of another (overflow dystonia). Later,

Definitions

with progression of disease, dystonia becomes

Dystonia: Involuntary sustained muscle con-

present at rest. Dystonic movements typically

tractions producing twisting or squeezing

worsen with anxiety, heightened emotions, and

movements and abnormal postures. Dystonia

fatigue, whereas they decrease with relaxation

can have stereotyped, repetitive movements

and disappear during sleep. There may be diur-

that vary in speed from rapid to slow and that

nal fluctuations in dystonia, which manifest as

may result in fixed postures from the sustained

little or no involuntary movements in the morn-

muscle contractions.

ing (morning honeymoon) followed by severe

Tremor: Involuntary rhythmic oscillating

disabling dystonia in the afternoon and evening.

movement that results from the alternating or

Whereas morning improvement is seen with

synchronous contraction of reciprocally inner-

several types of dystonia, one particular form of

vated antagonist muscles. Tremor may be clas-

childhood-onset dystonia is characterized by

sified according to its prominence during

this feature (dopa-responsive dystonia [DRD]

activity or at rest.

or Segawa dystonia).

Chorea: Excessive, spontaneous movements

Dystonia may occur in nearly any muscle

that are irregularly timed, nonrepetitive,

group. The following terms are used to describe

243

Chapter 13

■ Hyperkinetic Movement Disorders

dystonia in varied distributions. When the

opisthotonus. Dystonic movements of the

upper face and eyelids are involved and the

legs (crural dystonia) may occur with action

eyes are involuntarily closed the clinical

or at rest and present most commonly with

symptom is blepharospasm. When the lower

equinovarus posturing of the foot while

face, lips, and jaw are involved and the pa-

walking, twisting of the foot, or increased el-

tient presents with involuntary opening or

evation of the leg when walking. The knee

closing of the jaw, retraction or puckering of

usually maintains a hyperextended position

the lips, and repetitive contractions of the

with crural dystonia. Some patients walk

platysma, the term is “oromandibular dysto-

backward, run, or even dance without inci-

nia.” Pharyngeal dystonia is associated with

dent, but when they attempt to walk nor-

dysphagia, dysphonia, or dysarthria and is

mally, dystonia recurs. Patients with dystonic

typically action induced. Lingual dystonia

disorders often discover ways to suppress or

may occur at rest, presenting as sustained or

hide the movements using an array of

repetitive protrusion of the tongue or upward

“tricks.” These often consist of postural al-

deflection of the tongue against the hard

terations or counterpressure maneuvers that

palate, or it may be action induced via speak-

are primarily sensory in nature. Examples in-

ing or eating. Laryngeal dystonia (involving

clude touching an eyebrow in blepharospasm,

the vocal cords) causes spasmodic dysphonia

which leads to eye opening, or the classical

in which the speech is tight, constricted, and

geste antagonistique, where a finger placed

forced, or it may be whispery, depending on

lightly on the chin will neutralize neck-turning

whether the adductor or abductor muscle

in cervical dystonia. There are also motor

groups are involved. The smooth flow of

tasks that may deactivate dystonia, including

speech is lost, and certain sounds are held

singing or whistling in blepharospasm or oro-

longer and overemphasized. Spasmodic dys-

mandibular dystonia and dancing in cervical

phonia is typically action induced by speech,

or truncal dystonia. Typically, these tricks lose

and it most commonly involves the adductor

their effectiveness with time.

muscles of the larynx. Abductor dysphonia

The pathophysiology of dystonic move-

resulting in a soft whispery voice is less

ments and tricks remain a mystery. However,

common.

some clues have emerged. Briefly, it is believed

Dystonic contractions of the neck muscles,

that dystonia is the result of basal ganglia dys-

referred to as spasmodic torticollis or cervical

function. This is primarily based on work in-

dystonia, result in torticollis, retrocollis, an-

volving cases of secondary dystonia and

terocollis, or laterocollis. In spasmodic torti-

neuroimaging studies in idiopathic cases. There

collis, rapid jerking and twisting neck

appears to be decreased output from the pri-

movements may accompany sustained pos-

mary output nucleus of the basal ganglia, the

turing of the neck. Some patients have head

medial globus pallidus. Microelectrode record-

tremor and others have a fixed abnormal

ings from the globus pallidus in patients under-

neck posture without spasmodic movements

going surgery have demonstrated irregular,

or tremor. The shoulder on the side of the

intermittent group discharges leading to irregu-

head tilt typically is elevated. Dystonic move-

lar output from that region to the thalamus

ments of the arms (brachial dystonia) com-

and cortex. This supports the notion that the

monly present as pronation of the arm, often

basal ganglia are the source of the problem.

behind the back. The movements are often

There also appears to be sensory and motor

action induced as in writing (writer’s cramp),

cortical involvement in the physiology of dys-

manipulating a musical instrument

(musi-

tonia. Sensory involvement is suggested by the

cian’s cramp), and other occupational ma-

usefulness of sensory tricks. Physiologic studies

neuvers. Truncal or axial dystonia manifests

also have demonstrated that motor cortex is

as lordosis, scoliosis, kyphosis, tortipelvis, or

hyperexcitable and that there is decreased

244

Chapter 13

■ Hyperkinetic Movement Disorders

activation of these regions. It is possible that

is important in formulating a proper diagnosis.

certain patterned or learned tasks (tricks), both

For example, hemidystonia is usually the result

sensory and motor, interrupt the production of

of a basal ganglia infarction or space-occupying

dystonia through alterations in cortical activity.

lesion, whereas generalized dystonia is most

Dystonia often is misdiagnosed as hysterical

likely a primary early-onset disease and has a

or psychiatric in origin. The basis for this arises

worse prognosis than focal dystonia or hemidys-

from its typical features, including the varied,

tonia. Early-onset and generalized dystonia

often bizarre, movements and postures, the fact

appear to be most responsive to deep brain stim-

that they are often action induced, the worsen-

ulation (DBS) surgery.

ing of dystonia with stress and improvement

Classification by etiology has undergone

with relaxation, the diurnal fluctuations, and

substantial change in the last decade, prima-

the effectiveness of various tricks. Knowledge

rily because of the linkage (or nonlinkage) of

of the unusual characteristics of dystonic disor-

many types of dystonia to a variety of genes

ders will be helpful in avoiding a misdiagnosis.

(Table

13.1). The primary dystonias

(also

known as idiopathic torsion dystonias) are

Classification

TABLE 13.1

Classification of dystonia has been based on

Classification of Dystonia

(a) age of onset,

(b) distribution of move-

Primary dystonia

ments, and (c) etiology. Clinical and genetic

Early-onset dystonia (Oppenheim dystonia):

studies have demonstrated that they are all

chromosome 9q (DYT1)

connected. Use of the first two items in the pa-

Non DYT1 autosomal dominant early-onset

tient’s initial assessment can lead to etiology.

dystonia with whispering dysphonia (DYT4)

The age-of-onset classification separates pa-

Autosomal recessive dystonia: DYT2 and DYT16

tients into early onset (younger than age 26

Adult-onset familial torticollis

years) and late onset (older than age 26 years).

Adult-onset familial cervicocranial dystonia:

chromosome 18p (DYT7)

Early onset typically begins with limb involve-

Mixed adult- and childhood-onset dystonia:

ment and carries a worse prognosis than older

chromosome 8p (DYT6)

onset because generalization of the movement

Mixed but predominantly adult-onset segmental

disorder is more likely. Early-onset patients

dystonia (occasionally childhood onset and

more often have hereditary disease, most com-

generalized): chromosome 1p36 (DYT13)

monly DYT1. Late-onset patients have focal or

Adult-onset sporadic focal dystonia

segmental dystonia that primarily involves the

“Dystonia plus” syndromes

craniocervical region and does not generalize.

Dopa-responsive (Segawa) dystonia: chromosomes

The distribution of dystonia is focal, multifo-

14q22 and 11p (DYT5)

cal, hemidystonia, or generalized. Focal dystonia

Myoclonus dystonia: chromosome 7q21 (DYT11)

is dystonia in a single body part. Multifocal dys-

or chromosome 18p11 (DYT 15)

tonia includes dystonic movements in more than

Rapid-onset dystonia, parkinsonism: chromosome

one body part yet not fulfilling the criteria for

19q (DYT12)

generalized dystonia; segmental dystonia is a

Secondary dystonia related to exogenous causes

form of multifocal dystonia in which contiguous

(see Table 13.2)

body parts are affected. In hemidystonia, an arm

Hereditary and degenerative diseases associated

and a leg on the same side are involved. Finally,

with dystonia

Degenerative disorders

generalized dystonia refers to the presence of

Parkinsonian syndromes including PSP, CBD, MSA,

dystonia in at least one leg, the trunk, and an ad-

IPD, and juvenile PD

ditional body part (cranial, cervical, or brachial)

Huntington disease

or in both legs and the trunk. This classification

245

Chapter 13

■ Hyperkinetic Movement Disorders

TABLE 13.1

mary dystonias are genetically and clinically

Classification of Dystonia (continued)

heterogeneous. Dystonia genes are depicted by

the symbol DYT (followed by a number) by

SCAs such as types 2, 3, 6, 17

Autosomal recessive ataxias:

the Human Genome Organization/Genome

Database. DYT designations have been as-

AVED

signed to a variety of clinically defined dys-

AOA

tonic syndromes and unmapped, genetically

Hallervorden-Spatz disease (NBIA/PKAN)

linked primary dystonias. Dystonia syndromes

Lubag (Filipino X-linked dystonia parkinsonism):

not classified as primary but with dystonia as

Chromosome Xq13 (DYT3)

a predominating feature are also designated

Fahr

(Table 13.1). Fifteen genetic causes of dystonia

DRPLA

have been identified; four are primary dysto-

Neuroferritinopathy

nias, which are discussed in this chapter.

Hereditary metabolic disorders

A second etiological category comprises the

Wilson disease

Hexosaminidase deficiency

dystonia-plus syndromes. These are also con-

Glutaric acidemia

sidered to be neurochemical in origin, but also

Gangliosidoses (GM1, GM2)

have features other than dystonia (e.g., patients

Metachromatic leudodystrophy

with DRD have parkinsonian features). The

Homocesteinuria

third category is secondary dystonia, which de-

Propionic academia

velops as the result of a wide variety of known

Methylmalonic aciduria

etiologies (Table 13.2). The fourth category in-

Niemann-Pick type C

cludes hereditary-degenerative syndromes that

Ceroid lipofuscinosis

have dystonia as part of the clinical spectrum.

Lesch-Nyhan syndrome

Examples include Parkinson disease, WD, HD,

Neuroacanthocytosis

and X-linked dystonia parkinsonism (Lubag).

Hereditary Mitochondrial disorders

Leber optic neuropathy with dystonia

Leigh disease

Primary Inherited Dystonias Dystonia is the

MERRF

only neurologic abnormality in patients with

MELAS

primary dystonia (although many may have

Dystonia related to hereditary dyskinetic

tremor), and any distribution of abnormal in-

disorders

voluntary movements may be observed. The

Dystonic tics

primary dystonias have an insidious onset and

Paroxysmal kinesiogenic dyskinesia (DYT10)

are progressive. Initially, the movements may

Paroxysmal non-kinesiogenic dyskinesia (DYT8)

be only action induced, but with disease pro-

Paroxysmal dyskinesia with spasticity (DYT9)

gression they occur at rest and produce fixed

AT, ataxia telangiectasia; AVED, ataxia with vitamin E deficiency;

and sustained postures. The disorder ulti-

AOA, ataxia with oculomotor apraxia; PSP, progressive

supranuclear palsy; CBD, corticobasal degeneration; MSA, multiple

mately plateaus in severity. Five criteria for

system atrophy; IPD, idiopathic Parkinson disease; juvenile PD,

the diagnosis of primary dystonia are estab-

juvenile Parkinson disease; SCA, spinocerebellar ataxia; DRPLA,

dentatorubral-pallidoluysian atrophy; MERRF, myoclonic epilepsy

lished. These include (a) the development of

with ragged red fibers; MELAS, mitochondrial encephalopathy,lactic

dystonic movements or postures, (b) a normal

acidosis, and stroke-like episodes.

perinatal and developmental history, (c) no

precipitating illnesses or exposure to drugs

defined as syndromes in which the sole mani-

known to cause dystonia, (d) no evidence of

festation is dystonia, with the exception that

intellectual, pyramidal, cerebellar, or sensory

tremor may be present. It is unclear if this dis-

deficits, and (e) negative results of investiga-

order is purely neurochemical in origin or if

tion for secondary causes of dystonia (partic-

some degree of neurodegeneration exists. Pri-

ularly WD). Two factors are indicators of a

246

Chapter 13

■ Hyperkinetic Movement Disorders

TABLE 13.2

order dystonia musculorum deformans and it

Secondary Forms of Dystonia

has since been renamed primary torsion dysto-

nia or Oppenheim dystonia. DYT1 dystonia is

Drugs

Dopamine antagonists (i.e., haloperidol, thoridizine,

inherited in an autosomal dominant pattern,

compazine, metoclopramide)

with a 30% to 40% penetrance. The gene is lo-

Dopamine agonists (i.e., levodopa, bromocriptine)

cated at chromosome 9q34. The gene abnormal-

Antidepressants (tricyclics, SSRIs, lithium)

ity is a unique three-base pair GAG deletion.

Antihistamines

The resulting protein, torsin A, is characterized

Calcium channel blockers

by the loss of one of a pair of glutamic acid

Stimulants (cocaine)

residues. The function of this protein and its role

Buspirone

in altering basal ganglia function to cause dysto-

Vascular disease

nia remain unknown. The mutant protein is dis-

Basal ganglia infarction

torted leading to the formation of cytoplasmic

Basal ganglia hemorrhage

inclusions. There is a high prevalence of early-

Arteriovenous malformation

onset dystonia in Ashkenazi Jewish families,

Neoplasms

with more than 90% resulting from a single

Astrocytoma or glioma of the basal ganglia

founder mutation in the DYT1 gene. This muta-

Metastatic neoplasm

tion has been traced back more than 350 years

Cervical spinal cord tumor

to Lithuania, and the current gene frequency is

Others

approximately 1 in 2000. In 50% to 60% of

Head trauma

non-Jewish ethnically diverse families with early-

Thalamotomy

onset dystonia, the disease results from the same

Anoxia (in adulthood or perinatal)

DYT1 mutation that has arisen independently in

Meningitis (fungal or tuberculosis)

Syringomyelia

varied populations. Apparently, only one varia-

Colloid cyst of the third ventricle

tion in the encoded protein can give rise to the

Munchausen syndrome

DYT1 phenotype.

AIDS (toxoplasmosis abscess of basal ganglia, PML)

The clinical spectrum of early-onset DYT1

SSRIs, PML

dystonia is similar in all ethnic populations.

Paraneoplastic

Onset of symptoms occurs at an average age of

Central pontine myelinolysis

12 years, but most patients have onset before

Primary antiphospholipid syndrome

age 26. The initial presentation is with limb

Multiple sclerosis

onset, usually leg (crural dystonia). The pres-

Peripheral injury: complex regional pain syndrome

ence of leg or foot dystonia is the best predictor

of a DYT1 mutation. The foot often is twisted

AIDS, acquired immunodeficiency syndrome; PML, progressive

multifocal leukoencephalopathy; SSRIs, selective serotonin

and plantar flexed while ambulating, and the

reuptake inhibitors.

patient usually toe-walks. All patients ulti-

mately have leg involvement. The disorder may

poor prognosis: onset in childhood and in a

start in the arm (possibly as writer’s cramp), al-

crural distribution. Poor prognosis in dystonia

though less frequently. In these cases, the age of

refers to increased disability. Most patients

onset is a little older than crural onset and the

with crural dystonia have onset of disease in

patients are less likely to end up with general-

childhood or early adulthood. The clinical

ized dystonia. Early-onset dystonia progresses

presentation is heterogeneous.

by spreading across or down/up over a period

The classical early-onset primary dystonia is

of approximately 5 years; 50% of patients be-

DYT1 dystonia. It is the most severe and the

come either bedridden or wheelchair bound.

most common form of hereditary early-onset

No cognitive problems or other neurologic ab-

dystonia. Oppenheim, who first used the term

normalities are seen. Spasmodic dysphonia

“dystonia” in 1911, called this particular dis-

occurs in about 5%; cervical involvement is

247

Chapter 13

■ Hyperkinetic Movement Disorders

rare; and cranial involvement is generally not

Adult-Onset Primary Dystonia Adult-onset pri-

seen. Onset in the neck or vocal cords in early-

mary dystonia is the most common type of

onset patients, even if they are of Ashkenazi

dystonia. It presents with brachial and cranio-

Jewish descent, rarely is caused by the DYT1

cervical dystonia and only rarely as truncal or

gene. These patients rarely generalize. Late-

crural dystonia. Only 18% of these patients de-

onset (older than age 26) craniocervical dysto-

velop generalized dystonia, with even a smaller

nia indicates that the patient does not have

percentage ever becoming wheelchair bound or

DYT1 dystonia. The DYT1 patient often stabi-

bedridden. The dystonia usually remains as a

lizes and may even improve to some degree,

focal dystonia, but it may spread to a contigu-

but the disorder does not spontaneously remit.

ous body region in some cases, becoming seg-

Genetic testing is available for DYT1 dystonia

mental in distribution. The course is usually

and should be considered in early-onset pri-

benign (meaning not life threatening but it can

mary dystonias and in late-onset patients with

be disabling), and remissions occur in approxi-

a family history. The specificity of using age 26

mately 10% of patients.

as a cutoff age is 63% for Ashkenazi Jews and

43% for non-Jews.

Cranial Dystonia Blepharospasm-oromandibular

Linkage studies involving several large fami-

dystonia (Meige syndrome) was first described

lies with adult- or mixed-onset dystonia of a va-

by the French neurologist Henry Meige in

riety of distributions have excluded the DYT1

1910. Blepharospasm and oromandibular

locus. However, dystonia families have been

dystonia may occur independently, but the

linked to other possible genes. DYT6 has been

combination is more frequent (in more than

linked to chromosome 8p in two Mennonite

50% of the patients). Pharyngeal, laryngeal,

families from the midwestern United States

lingual, or cervical dystonia may occur.

with an autosomal dominant form of dystonia

Blepharospasm in isolation (referred to as be-

with incomplete penetrance. The phenotype of

nign essential blepharospasm [BEB]) is more

these families includes a broader age of onset (5

common than oromandibular dystonia. Ble-

to 38 years; mean, 19) and an onset distribution

pharospasm is often preceded by eye irritation,

that includes limbs and cervical or cranial

photophobia, and increased blinking. It may

areas. There are also differences from typical

start in one eye and spread to the other, or it

adult-onset craniocervical dystonia because

may start in both. It results in involuntary

DYT6 dystonia commonly spreads to the limbs,

blinking, repetitive contractions

(blepharo-

but the former syndrome does not.

clonus), squinting, or sustained closing of the

The DYT7 gene is linked to chromosome

eyes. Approximately 12% of these patients are

18p in a family from northwest Germany. This

functionally blind because of their inability to

family has an autosomal dominant form of

voluntarily open their eyes. Features that ag-

adult-onset craniocervical dystonia with in-

gravate blepharospasm include sunlight (many

complete penetrance. The average age of onset

wear wrap-around dark sunglasses, even in-

was 41 years (range 28 to 70 years), and most

doors), looking upward, feeling stress, fatigue,

patients had focal cervical dystonia. Some fam-

watching television, walking, driving, talking,

ily members had cranial or laryngeal involve-

and even yawning. Sensory tricks used by pa-

ment, and postural hand tremor. Another

tients to open their eyes include forced raising

family was designated DYT13 and linked to

of the eyelids, applying pressure on the supe-

chromosome 1p36. This was an Italian family

rior orbital ridges with a finger, and rubbing

with focal and segmental dystonia usually af-

the eyelids. In addition, some find that forced

fecting the craniocervical region. Some had

jaw opening, neck movements, whistling, and

early-onset disease and generalized, indicating

wearing dark glasses are helpful. Some pa-

a mixed presentation. Other inherited forms of

tients use eyeglasses with eyelid crutches to

dystonia are listed in Table 13.1.

hold the lids open.

248

Chapter 13

■ Hyperkinetic Movement Disorders

Oromandibular dystonia, jaw opening or

neck and shoulders that are often painful, and

closing dystonia, is frequently accompanied by

hypertrophy of involved neck muscles. Pain is

lingual protrusion dystonia. It may be aggra-

present in about 80% of patients, and hypertro-

vated by talking, chewing, or swallowing. Sen-

phy is seen in all. Initially, some patients do not

sory tricks include pressing on the lips or teeth

perceive their dystonia, and it is brought to

with fingers, pressing on the hard palate with

their attention by others. This suggests that a

the tongue, or putting a finger in the mouth.

problem with perception of head position

About 20% of patients have their ability to eat

exists. The movements may be intermittent at

severely compromised.

first and associated with specific actions. Most

Meige syndrome affects women more com-

patients deteriorate during the initial 5 years

monly than men and presents in the sixth

and then stabilize. The condition may be char-

decade of life. It often begins with ble-

acterized ultimately by dystonic postures that

pharospasm, followed by oromandibular, lin-

are present at rest, worsen with action, and im-

gual, and pharyngeal dystonia. Other dystonic

prove in sleep. Spontaneous remissions occur in

movements may occur in some patients, and

10% to 30%, most commonly in the first year.

hand tremor similar to ET may be an associ-

All patients relapse eventually but few have a

ated problem. The severity of dystonia fluctu-

second remission. Rotation of the neck (torti-

ates from day to day and disappears with sleep.

collis) is the most common posture seen, with

Spontaneous remissions are rare.

lateral flexion (laterocollis), flexion (anterocol-

lis), and extension

(retrocollis) occurring in

Cervical Dystonia (Spasmodic Torticollis) Cervi-

various combinations. Spasmodic

(dynamic)

cal dystonia is the most common adult-

movements are not present in all patients de-

onset focal dystonia, making up about 40%

spite the commonly used term “spasmodic tor-

(Fig. 13.1). The age of onset is in the fourth or

ticollis.” In fact, they occur in only 10% to

fifth decade (mean age, 41 years) and women

15% of patients. Factors that may exacerbate

are affected more frequently than men (3 to 1).

cervical dystonia include emotional stress, fa-

The disorder is characterized by involuntary

tigue, walking, working with the hands, and

neck movements, abnormal postures of the

attempting to look in the opposite direction of

FIGURE 13.1 Cervical dystonia resulting in rotation of the neck to the left.

249

Chapter 13

■ Hyperkinetic Movement Disorders

the dystonic contractions. When the patient tries

tremor and relaxes the muscles for variable

to overcome the movements and look in the op-

durations of time. Tricks usually lose their

posite direction, he or she may experience a

effectiveness. Cervical dystonia may be associ-

high-amplitude, jerky tremor referred to as dys-

ated with Meige syndrome, writer’s cramp, and

tonic tremor. Some patients present with bidirec-

ET. Complications of prolonged cervical dysto-

tional torticollis because at varying times the

nia occur in many patients including those with

head may turn in different directions and mus-

degenerative osteoarthritis of the cervical spine

cles of both sides of the neck may be involved.

with the expected sequelae of radiculopathy

and myelopathy. These complications could

■ SPECIAL CLINICAL POINT: Many patients

lead to permanent neurologic deficits.

with cervical dystonia (spasmodic torticollis)

present with head tremor (40%). The tremor

varies in amplitude and, if there is little

Writer’s Cramp Writer’s cramp (Fig. 13.3) is

directional change, the patients frequently are

a dystonic spasm induced by a specific task

misdiagnosed as having essential tremor (ET).

(action-induced or task-specific dystonia). When

The distinction is important because dystonia

these cramps occur with a single type of action

does not respond to tremor medications but

(such as writing), they are referred to as simple

does respond to botulinum toxin.

writer’s cramp, but when the spasms occur

This tremor can be distinguished from essential

with a variety of activities, they are referred to

head tremor by the presence of subtle changes

as dystonic cramps. Writer’s cramp occurs in

in posture, a jerky nonrhythmic quality, and

both men and women, and the age of onset

muscle hypertrophy along with improvement

ranges from 20 to 70 years. These patients pres-

with sensory tricks. Sensory tricks usually

ent with a change in handwriting that becomes

involve the use of a light touch or pressure to

sloppy and illegible. Some patients squeeze the

the chin or cheek with fingers (geste antagonis-

pen tightly and press down hard on the writing

tique) (Fig. 13.2) or other objects such as a pen

surface, which results in a jerky writing motion

or eye glasses and holding the back of the head

and tearing of the paper. In others, the fingers

with the hand or leaning the head against a wall

splay and pull away from the pen. Writing is

or a headrest. This lessens the head tilt and

painful in most patients. Initially, the dystonic

FIGURE 13.2 Cervical dystonia improved with a trick, touching the back of the head.

250

Chapter 13

■ Hyperkinetic Movement Disorders

FIGURE 13.3 Writer’s cramp is an action-induced dystonic spasm, resulting, in this patient, in wrist

flexion, metacarpophalangeal joint extension, extension of the thumb, and flexion of the distal

interphalangeal joints, leaving the patient with an inability to continue writing.

contraction occurs with persistence of task, but

neuroplasticity as the etiology of task-specific

as the disorder progresses, it occurs with initia-

dystonias in genetically susceptible individuals.

tion of the task. Initially, other tasks performed

Dopa-Responsive Dystonia One “dystonia plus”

with the same hand are normal, but later these

syndrome that warrants discussion is DRD

too may become involved. The disorder is usu-

(DYT5). DRD is characterized by childhood

ally asymmetric, but those patients who learn

(mean age, 6 years) or adolescent onset, female

to write with the opposite hand, the disorder

predominance (four times that of males), foot

may become bilateral (about 25% of patients).

dystonia in childhood, parkinsonism in adults,

When some patients write with the unaffected

and diurnal fluctuation. Patients function well

hand, the affected hand exhibits involuntary

in the morning and deteriorate as the day

spasms—so-called “mirror dystonia.” Writer’s

wears on. They improve with sleep. Purely dys-

cramp may be associated with ET and may be

tonic limb presentations are most common.

related to the syndrome of primary writing

Some patients have mixed dystonia and parkin-

tremor, which is thought by some to be a vari-

sonism, and the parkinsonism becomes more

ant of ET. Other occupational cramps that have

prominent with age. The clinical spectrum in-

been reported include pianist’s and violinist’s

cludes developmental delay and spasticity mim-

palsy, golfer’s palsy, and dart-thrower’s palsy.

icking cerebral palsy. The most characteristic

The common factor of these disorders is the oc-

feature is profound and sustained response to

currence during the performance of a well-

levodopa

300 mg/day.

learned motor (manual) task and perhaps the

overuse of the hand with that particular task. In

■ SPECIAL CLINICAL POINT: So profound

writer’s cramp, there appears to be co-contrac-

and sustained is the treatment response in

tion of agonist and antagonist muscles, perhaps

dopa-responsive dystonia (DRD) that all

related to loss of reciprocal inhibition. Evidence

individuals presenting with dystonia should be

has been mounting to support abnormalities in

given a trial of levodopa.

251

Chapter 13

■ Hyperkinetic Movement Disorders

DRD has been linked to two chromosomes.

may mimic idiopathic dystonia. For instance,

The most common is chromosome 14q11-

stroke in the basal ganglia may cause typical-

24.3—the gene codes for an enzyme in the

looking cervical dystonia and neuroleptic-

rate-limiting step in the biosynthesis of tetrahy-

induced (tardive) dystonia in adult patients may

drobiopterin (GTP cyclohydrolase I), a cofac-

be symptomatically identical to adult-onset pri-

tor in dopamine synthesis, and is dominantly

mary dystonia. Clues that tardive dystonia is

inherited. The other link is to a rare defect seen

more likely include retrocollis, a more phasic

on chromosome 11p15.5—the gene codes for

or dynamic form of torticollis, and the co-

tyrosine hydroxylase, the rate-limiting step in

occurrence of choreiform movements. These

catecholamine metabolism—and is recessively

patients also report less effectiveness of tricks

inherited. The resulting deficiency of biopterin,

and do not often have head tremor. A lack of

a cofactor in catecholamine synthesis, leads to

muscle hypertrophy also suggests drug-induced

decreased levels of dopamine, which explains

dystonia.

the long-term responsiveness of patients to lev-

An important feature of secondary dystonia

odopa. Dopamine transporter single-photon

is that dystonia may have a delayed onset after

emission computed tomography (SPECT) scan-

a cerebral insult. In adults, the most frequent

ning is normal in patients with DRD, and this

cause of delayed-onset dystonia is cerebral in-

helps differentiate these patients from those

farction. The duration of the delay can vary

with early-onset Parkinson disease. Diagnosis

from weeks to years and is often associated

of DRD is based on clinical profile and re-

with an improvement of the original neurologic

sponse to levodopa.

deficit. In children, the most frequent cause of

delayed-onset dystonia is perinatal trauma or

Secondary Dystonia To make a diagnosis of

hypoxia. The reason for the delay is unclear,

primary dystonia, known causes of dystonia

but it has been postulated that dystonia in these

(i.e., secondary or symptomatic dystonias

circumstances is a result of neuronal sprouting

[Table 13.2] and hereditary degenerative dis-

stimulated by the original injury. A history of

eases [Table 13.1]) must be excluded. Clues to

perinatal difficulties must be ruled out if a diag-

the diagnosis of a secondary dystonia can be

nosis of primary dystonia is made.

uncovered with a thorough history and physi-

■ SPECIAL CLINICAL POINT: The most

cal examination, and radiologic and laboratory

important disorder to exclude in a new-onset

testing. Usually, examination findings in addi-

young dystonia patient is Wilson disease (WD).

tion to dystonia are suggestive of dysfunction

Screening for WD and an imaging study of the

of other parts of the central nervous system

brain should be performed on all young dystonia

(CNS), including the cranial nerves, pyramidal

patients. The rest of the diagnostic evaluation

system, cerebellar system, and higher cortical

should be tailored to the individual patient.

function. There is often an abrupt onset to dys-

It had been suggested that secondary dystonia

tonia, and dystonia is present at rest from the

occurs in genetically susceptible individuals.

start in secondary cases.

However, it has been demonstrated that these

patients are not genetically susceptible.

■ SPECIAL CLINICAL POINT: The presence

of hemidystonia suggests a focal lesion such as a

tumor, infarction, abscess, or arteriovenous

Pathology and Neurochemistry

malformation in the basal ganglia.

Dystonia is related to basal ganglia dysfunction.

In patients with a single nonprogressive event

Because there have been few neuropathologic ex-

such as an infarction or trauma, dystonia will

aminations of patients with dystonia (most were

stabilize and not be progressive. The examiner

without abnormality), the pathologic-anatomic

should be cautious because secondary dystonia

basis of this movement disorder has been based

252

Chapter 13

■ Hyperkinetic Movement Disorders

TABLE 13.3

Medical Treatment of Dystonia

Drug Name

Initial Daily Dose (mg)

Usual Daily Dose Range (mg)

Levodopa

100

300-600

Trihexyphenidyl

12-24

Baclofen

60-120

Clonazepam

0.5

3-6

Reserpine

0.1

1-3

Tetrabenazine

100-200

almost exclusively on cases of symptomatic dys-

Table 13.3). The approach is to treat patients

tonia. Abnormalities were seen in the putamen

empirically with one agent at a time. Ulti-

and, to a lesser extent, the caudate nucleus and

mately various combinations may be tried. Un-

the thalamus. These findings have been sup-

fortunately, less than 50% of dystonic patients

ported by imaging studies. Interestingly, in those

respond to medical therapy.

rare cases of dystonia with pathologic abnormal-

Because of the dramatic effect levodopa has

ities, the microscopic changes were observed in

on DRD, it is recommended that every patient

the brainstem. The neurochemical basis of dys-

with dystonia be tried on levodopa. Patients

tonia is also unclear. It has been suggested that

with DRD usually respond rapidly to low

the abnormality in this disorder is in the

doses (<300 mg/day), but in some cases higher

dopamine or acetylcholine systems. Clinical evi-

doses are needed. If there is no benefit, the dose

dence to suggest these hypotheses include the

is pushed to 600 mg/day over 2 to 3 weeks.

onset of dystonia after treatment with dopamine

Anticholinergics are the most frequently used

receptor antagonists and the response of dysto-

agents to treat primary dystonia. In an open-

nia to anticholinergic medications. In addition,

label trial, improvement was seen in 61% of chil-

the discovery that DRD is acutely responsive to

dren and 38% of adults. The average daily dose

small doses of levodopa and that it is caused by

of trihexyphenidyl in children and adults was

two genes involved in the biosynthesis of

41 mg and 24 mg, respectively. Adverse effects

dopamine support a dopaminergic hypothesis.

include blurred vision, dry mouth, urinary diffi-

Finally, the expression of torsin A in the substan-

culties, constipation, sleep pattern alteration,

tia nigra pars compacta also implicates the

forgetfulness, weight loss, personality changes,

dopamine system. Norepinephrine is a neuro-

and psychosis. The earlier in the course of dis-

transmitter that, among other actions, inhibits

ease patients were treated, the better they did.

cholinergic neurons. A deficiency of norepineph-

Tetrabenazine, a dopamine-depleting agent,

rine might explain the response of dystonia to

is effective in patients with Meige syndrome and

anticholinergic medications. Other theories in-

other types of dystonia. Reserpine, another

clude alterations in γ-aminobutyric acid (GABA)

dopamine-depleting drug, is effective in approx-

or cerebral somatostatin.

imately 30% of patients. The adverse effects of

most concern with dopamine-depleting agents

include depression (which can be severe, come

Treatment

on suddenly, and have a protracted course),

Because the etiology and neurochemistry of

parkinsonism, orthostatic hypotension, and gas-

dystonia is unclear, medical treatment has been

trointestinal problems.

less than satisfactory. A number of therapeutic

Dopamine antagonists should be avoided.

modalities have been tested

(for review see

Mixed results with baclofen, carbamazepine,

253

Chapter 13

■ Hyperkinetic Movement Disorders

benzodiazepines (particularly clonazepam and

BoNT is one of the most lethal toxins known to

diazepam), mexiletine, and clozapine have

man. Of eight subtypes produced by the anaer-

been observed.

obic organism Clostridium botulinum, three

In patients failing medical and botulinum

have been linked to human botulism: types A,

toxin (BoNT) therapy, surgical techniques, in-

B, E. BoNT A (Botox) has been used therapeu-

cluding both central and peripheral proce-

tically since the mid-1980s for treatment of

dures, have been used. Central procedures are

strabismus. In 1990, BoNT A was approved by

used primarily for generalized dystonia. Modern

the U.S. Food and Drug Administration (FDA)

techniques include the use of DBS with electro-

for treatment of blepharospasm, strabismus,

physiologic microelectrode cellular recording

and hemifacial spasm. In 2000, it was approved

and mapping to improve localization. Two

for cervical dystonia as was BoNT B. The use of

well-designed, double-blind, controlled trials

these toxins is more widespread than these indi-

(22 and 40 patients) demonstrated significant

cations because they are used to treat all types

improvement (54% and 39.9% in movement,

of focal dystonia, including blepharospasm,

and 44% and 38% in disability scores) in pa-

oromandibular dystonia, spasmodic dysphonia,

tients with primary generalized dystonia after

and limb dystonias. BoNTs act presynaptically

DBS using bilateral globus pallidus pars in-

at the cholinergic neuromuscular junction. The

terna as targets. Both studies showed contin-

toxin attaches to an acceptor protein that is

ued improvement up to a year, and a third

specific for each type of BoNT, is endocytosed

study of 31 patients showed 79% improve-

into the nerve terminal and blocks the release of

ment in movement scores up to 2 years follow-

acetylcholine. The blockade of the neuromus-

ing surgery. Serious complications are rare

cular junction results in weakness and atrophy

with DBS, and failures or loss of benefit have

of the muscle and a decrease in muscle spasms,

rarely been reported. The most important fac-

but the effect is transient, lasting 3 to 6 months.

tors for successful treatment with DBS are pa-

If a desirable clinical result is achieved, re-

tient selection, lead placement, and optimal

peated injections are necessary. BoNT is admin-

postsurgical programming of the stimulator.

istered by direct intramuscular injection and all

Surgical candidates suffer from medically re-

adverse effects are local. In blepharospasm im-

fractory, unequivocal dystonia (diagnosed by a

provement is seen after 3 to 14 days. The re-

movement disorder specialist), and significant

sponse lasts 2 to 4 months and treatment is

disability.

needed three or four times per year. Adverse ef-

Peripheral surgical procedures include myec-

fects include ptosis, diplopia, and increased

tomy of the orbicularis oculi for blepharospasm

tearing, all of which are transient. Cervical

and selective peripheral denervation for cervical

dystonia is the most common disorder treated

dystonia. Another technique used to treat gen-

with BoNT. Multiple studies with both toxins

eralized dystonia is intrathecal baclofen. Ba-

have shown significant improvement in a ma-

clofen is delivered to the intrathecal space

jority of patients. As with blepharospasm, re-

through an inserted catheter with a continuous

sponse occurs in 3 to 14 days and lasts 3 to 6

pump. This has been highly effective in treating

months. Neck muscles injected are chosen based

spasticity of spinal and cortical origin. In the

on the presence of pain and hypertrophy and

few patients with dystonia treated, results have

spasm and in relation to the abnormal posture.

been modest. Possible adverse effects include

Ninety percent of cervical dystonia patients re-

respiratory depression from baclofen overdose,

spond. Side effects include transient neck weak-

catheter malfunction, and pump infection.

ness, dysphagia, dry mouth, and a “flu-like”

Intramuscular injection of BoNT remains

syndrome.

the treatment of choice for focal dystonias,

Spasmodic dysphonia of the adductor type,

particularly in the craniocervical distribution.

previously poorly responsive to any therapy,

254

Chapter 13

■ Hyperkinetic Movement Disorders

responds dramatically to BoNT. The thyroary-

Special Challenges for

tenoid muscles are approached through the

Hospitalized Patients

neck with electromyogram (EMG) guidance.

Most hospital staff are unfamiliar with dysto-

The only adverse effects are a breathy, whis-

nia, and because of the bizarre movements,

pery voice and dysphagia, which improves over

cessation with sleep, and exacerbation with

days to weeks. Treatment of oromandibular

anxiety they are likely to assume or suspect

dystonia is also frequently successful. Injec-

that the movements are psychogenic in origin.

tions can be made into the pterygoid muscles

This can lead to frustration and anger on the

(medial or lateral) with EMG guidance, and

part of the patient. Staff education is required.

into the masseters, temporalis, and digastric

Patients may be unable to stay still for testing

muscles in varied combinations depending on

and procedures, and mild sedation may be

whether the patient has jaw opening, closing,

necessary.

or lateral deviation as the main manifestation.

Side effects include dysphagia and weakness of

the soft palate that allows fluid regurgitation

ESSENTIAL TREMOR

through the nose. Limb dystonias

(writer’s

cramp) respond with less consistency because

Essential tremor is a monosymptomatic (kinetic

the resulting weakness of the hand muscles

tremor) syndrome. Tremor is generally classi-

may be more troublesome than the cramps

fied by its anatomic location, frequency, etiol-

themselves. BoNT is the treatment of choice

ogy, or in relation to rest, posture, and action.

for most focal dystonias because of greater ef-

Resting tremor refers to tremor while the body

ficacy and fewer side effects than standard

part is at rest. Resting tremor is seen in Parkin-

medical therapies.

son disease. Postural tremor is seen when the

Physicians administering BoNT should be

body part maintains posture against gravity,

familiar with the disorders treated, mecha-

and is frequently seen in ET. Kinetic tremor

nisms of action, effective doses in each disor-

refers to tremor during goal-directed move-

der, and the anatomy of the area injected. The

ments, as typically seen in cerebellar disease.

disorders treated with BoNT have expanded

This simple classification can be very useful in

beyond dystonia and include spasticity, achala-

developing a differential diagnosis (Table 13.4).

sia, anal and urethral sphincter disorders, hy-

ET is the most common tremor disorder and is

perhydrosis, sialorrhea, and others. BoNT A

the subject of discussion in this section.

also has been approved for cosmetic use for fa-

cial wrinkles.

Clinical Features

There are no alternative medical therapies

with proven effect in dystonia. Physical ther-

ET is a nervous system disorder that occurs in

apy can be a useful adjunct for maintaining

a sporadic or familial form. The familial form

mobility and preventing contractures.

is often autosomal dominant with high but not

full penetrance. ET is the most common move-

ment disorder, occurring in up to 6% of the

When to Refer to a Neurologist

population and 13% of people over age 65. It

Dystonia is a complicated disorder. Neurolo-

occurs equally in men and women and is char-

gists, especially movement disorder specialists,

acterized by a postural tremor, with or without

are most qualified for addressing diagnosis, ge-

a kinetic component, which is most evident in

netic testing, and therapy. In particular, referral

the upper extremities. The kinetic component

should be made to neurologist well versed in

is seen in finger-to-nose testing, although it is

the use of BoNT.

often not as dramatic as in cerebellar disorders,

255

Chapter 13

■ Hyperkinetic Movement Disorders

TABLE 13.4

(age 51). ET usually affects the fingers and

Differential Diagnosis of Tremor

hands first and then moves proximally. Tremor

onset may occur bilaterally in the hands or in

Rest tremors

Parkinson disease

one hand at a time. When bilateral, it may be

Secondary parkinsonism

symmetric or asymmetric.

Hereditary chin quivering

Tremor may spread to the head and neck.

Severe essential tremor

Approximately 50% to 60% of patients with

Drug-induced (neuroleptics)

ET have head involvement, and in some in-

Postural tremors

stances head tremor is the sole manifestation.

Physiologic tremor

Head tremor may present as a vertical nod

Essential tremor

(yes-yes) or as a horizontal nod

(no-no).

Neuropathic tremor (Roussy-Livy syndrome)

Voice tremor occurs in approximately 25%

Cerebellar head tremor (titubation)

to 30% of patients with ET. The voice is char-

Dystonic tremor

acterized by rhythmic alteration in intensity

Drug-induced tremor (lithium, valproate,

at the same frequency as the hand tremor.

neuroleptics, caffeine, theophylline, tricyclic

Head and voice tremor tend to be more fre-

antidepressants, amphetamines)

quent and severe in women. Tremor of the

Action tremors

head or voice should strongly suggest a diag-

Classical cerebellar tremor (multiple sclerosis,

nosis of ET and not Parkinson disease be-

infarction)

cause both are very uncommon in the latter.

Primary writing tremor

Less frequently, tremor occurs in the jaw, face

Mixed tremors

(lips, tongue), trunk, and legs (15%). There

Wilson disease

are also a variety of task-specific tremors

Rubral tremor

Psychogenic tremors

(i.e., primary writing tremor), which are vari-

ants of ET. ET is a slowly progressive disor-

der that can remain stable in some patients

for decades. It is not unusual for patients to

and tremor at rest occurs rarely (in 5% to 10%

seek medical advice after having the tremor

of patients) in the most severe cases when the

for one or two decades. At first tremor may

patient has a long-standing disease. Tremor

occur when the limb is placed in a specific

frequency ranges from 4 to 12 Hz.

posture but later it is aggravated by many dif-

A maneuver to potentiate tremor during

ferent movements or postures. The tremor

physical examination is to have patients hold

disappears during sleep and worsens with

the fingertips of their two open hands close to-

anxiety, fatigue, temperature changes, local

gether under the chin without touching while

pain, caffeine ingestion, aminophylline inges-

holding their elbows out like wings. This ma-

tion, and possibly hunger.

neuver can also bring out a more proximal

■ SPECIAL CLINICAL POINT: Alcohol

tremor distribution. Another examination

characteristically improves essential tremor for

technique is the cup test: the patient holds a full

30 to 60 minutes, which may be a helpful

cup of water and pours it into another cup or

diagnostic clue.

takes a drink. The tremor is often worse as the

hand approaches the face. The onset of ET can

A substantial proportion of patients are func-

be at any age from early childhood to age 90,

tionally disabled, with ~20% having impaired

with a mean of 45 years. The patients with a

job performance and requiring early retire-

family history appear to have an earlier age of

ment. This is the reason the term benign has

onset (age 40) compared with sporadic cases

been eliminated from the name. Other patients

256

Chapter 13

■ Hyperkinetic Movement Disorders

are embarrassed by the tremor and impose so-

Differential Diagnosis

cial isolation on themselves.

The diagnosis of ET is clinical (Table 13.4).

■ SPECIAL CLINICAL POINT: Essential

The most common misdiagnosis in ET pa-

tremor is a clinically heterogeneous disorder

tients is Parkinson disease. The two disorders

that may go unnoticed by the patient, may

can be differentiated by careful history and

simply represent an embarrassment, or actually

physical examination. The tremor of Parkin-

be disabling, leading to difficulties with writing,

son disease occurs at rest, whereas the ET is

drinking, or using kitchen utensils.

postural and kinetic. Patients with parkinson-

Approximately 5 million people in the United

ism have rigidity, bradykinesia, micrographia,

States have this disorder. There are many people

and postural and gait difficulties, and ET is

with this problem who have not bothered to seek

associated with none of these. The handwrit-

medical advice and therefore are not diagnosed.

ing in ET is usually big and shaky but not

small (see Fig. 12.1).

Genetics

■ SPECIAL CLINICAL POINT: Sometimes a

handwriting sample alone can lead to the

At least 60% of ET cases have a clear genetic

correct diagnosis of essential tremor (ET).

component with an autosomal dominant mode

Postural tremor is frequently present in pa-

of inheritance. This may be an underestimate

tients with primary dystonia. This tremor can

because some sporadic cases may represent

be indistinguishable from ET. A family history

nonrecognition in family members. Genetic

of ET is not uncommon in both of these disor-

mapping has resulted in the linking of ET to

ders. Some investigators have indicated that this

genes on four different chromosomes.

frequent association between postural tremor

and dystonia is indicative of a link between ET

Pathology and Pathophysiology

and primary dystonia, but linkage of ET to the

DYT1 gene has been ruled out. Tremor is par-

Because ET is neither life threatening nor life

ticularly frequent in patients with cervical dys-

shortening, the opportunity for a postmortem

tonia and Meige syndrome.

examination of the CNS is not frequent. In

those patients who have been examined patho-

■ SPECIAL CLINICAL POINT: In cervical

logically, there is no distinctive CNS pathology

dystonia (torticollis), a head tremor is present

although Lewy bodies (the hallmark of Parkin-

in approximately 40% of patients and a hand

tremor similar to that seen with ET is found in

son disease) have been reported in brainstem

approximately 20% of patients. It is important

nuclei. The significance of this finding remains

to differentiate between these disorders

to be deciphered. Positron emission tomogra-

because treatments differ.

phy (PET) studies have demonstrated an in-

crease in regional cerebral blood flow in the

Postural and kinetic tremor secondary to cere-

cerebellum and red nucleus, indicating that the

bellar lesions can be differentiated from ET be-

neuronal circuitry involving these regions may

cause of the presence of other signs of cerebellar

be the location of the abnormality. One study

dysfunction and the difference in severity (cere-

also demonstrated increased glucose metabo-

bellar tremor is generally much more disabling

lism in the inferior olivary nucleus of the

with higher amplitude and lower frequency).

medulla. This structure may be the source of

There are three types of cerebellar tremor:

the rhythmic discharge causing the tremors.

(a) cerebellar kinetic tremor, (b) cerebellar out-

This notion is supported by the fact that lesions

flow rubral tremor, and (c) head titubation. The

in the cerebellum and thalamus may stop

cerebellar kinetic tremor appears with goal-

tremor.

related movements most evident at the beginning

257

Chapter 13

■ Hyperkinetic Movement Disorders

and end of the movement. It is much slower

patients under the age of 50 years with atypi-

than ET, 2 to 5 Hz, and of wider amplitude.

cal ET presentation should have an evaluation

The lesion usually includes the dentate nucleus

for WD.

(most common in stroke patients). Outflow

tremor is present at rest, when maintaining pos-

Treatment

ture, and with action. Amplitude and frequency

are similar to the kinetic tremor, and the lesion

Medical treatment of ET can improve function

includes the outflow pathway from dentate nu-

and relieve embarrassment in a substantial por-

cleus to the thalamus, with the most common

tion of patients. However, effectiveness often is

location of the lesion being the midbrain in-

limited (for review of medical therapy of ET see

volving the red nucleus. This type of tremor is

Table 13.5). The two agents considered first-line

most commonly seen in young patients as a

treatment for ET are propranolol and primi-

manifestation of multiple sclerosis and in the

done. Propranolol (standard and long-acting

elderly as the result of a stroke. Finally, tituba-

formulations) is a beta-blocker that has been

tion is a head tremor similar to the head tremor

known to be effective for more than 20 years. It

of ET. It is generally the result of bilateral cere-

is particularly useful in controlling postural and

bellar lesions.

kinetic tremor in the upper extremities and may

Kinetic tremor, similar to ET, is also seen in

make a significant difference to the patient in

the late—adult-onset neurodegenerative disease

terms of being able to feed themselves or write

which affects male carriers of a premutation ex-

legibly. This may be true even though propra-

pansion of the fragile X mental retardation

nolol usually does not abolish the tremor but

gene (FMR-1). This disorder is called fragile X

only decreases its amplitude, having little or no

tremor ataxia syndrome (FXTAS). These pa-

effect on frequency. Approximately

40% to

tients often present with a kinetic tremor that

70% of patients show a decrease in amplitude

interferes with handwriting and can be quite

of 50% to 60%. There does not appear to be a

disabling. This is followed by the development

correlation between plasma concentration of

of progressive ataxia, neuropathy, and psychi-

propranolol or its metabolites and reduction in

atric manifestations.

tremor. There are no apparent features that

separate responders and nonresponders. The

dose of propranolol may range from 60 to

Evaluation

320 mg/day but usually is less than 120 mg/day.

The diagnosis of ET is based on the history and

It exerts its effect in 2 to 6 hours after a single

examination. If the patient presents with the

dose, and the effects may last as long as 8 hours.

typical history and findings, no laboratory or

Withdrawal from propranolol may result in a

imaging studies are necessary except for thy-

rebound increase in amplitude of the tremor,

roid function studies.

which may last longer than a week. The site of

action of propranolol, whether central or pe-

■ SPECIAL CLINICAL POINT: Hyperthyroidism

ripheral, has not been fully established. There

can worsen an already-existing tremor or cause

are certain groups of patients with ET in whom

an enhanced physiologic tremor that may

the use of propranolol is relatively contraindi-

appear similar to ET.

cated. They include patients with diabetes melli-

Any patient with a sudden-onset tremor, unilat-

tus, chronic obstructive lung disease, and

eral tremor, or other complex features that do

asthma; propranolol can cause dyspnea and

not fit with ET or Parkinson disease should be

wheezing in these patients. In these instances the

studied further with imaging studies and screen-

substitution of a different beta antagonist, meto-

ing for WD. The diagnosis of WD is extremely

prolol, may result in amelioration of the tremor

important because it is fatal if undiagnosed. All

and no bronchospastic symptoms. Metoprolol

258

Chapter 13

■ Hyperkinetic Movement Disorders

TABLE 13.5

Medical Therapy for Essential Tremor

Drug Name

Initial Daily Dose (mg)

Usual Daily Dose Range (mg)

First-line agents

Propranolol

60-320

Primidone

50-750

Benzodiazepines

Alprazolam

0.25

0.75-3

Clonazepam

0.5

1.5-6

Carbonic anhydrase inhibitors

Acetazolamide

125

250-750

Methazolamide

100-200

Anticonvulsants

Gabapentin

300

900-3600

Topiramate

100-400

Phenobarbital

60-120

is a beta receptor antagonist that is relatively se-

metabolites do not correlate with responsive-

lective in its action; however, patients who do

ness. It is likely that a combination of primi-

not respond to propranolol also do not respond

done and propranolol will be more effective

to metoprolol, and propranolol is superior. It has

than each drug used alone.

been suggested that the selectivity of metoprolol

is lost when higher doses are used, and at higher

■ SPECIAL CLINICAL POINT: A majority of

patients respond to either propranolol or

doses bronchospastic symptoms may re-emerge.

primidone. However, patients who do not

Acute side effects of beta-blockers include brady-

respond or who are unable to tolerate these

cardia and syncope; chronic problems include

agents face more difficult therapeutic choices.

dizziness, fatigue, impotence, and depression.

Propranolol also rarely causes hallucinations.

Several other drugs have been used in the

Primidone, an anticonvulsant, may be as ef-

treatment of ET. One feature in the clinical his-

fective as propranolol in the treatment of ET.

tory that an adult with ET will volunteer is the

The major problem has been acute adverse ef-

salutary effect of alcohol on the tremor. In

fects that are frequent (30%) and include ver-

fact, alcohol may be the most effective agent;

tigo, a general ill feeling, unsteadiness, nausea,

75% of patients respond quickly and dramati-

ataxia, and confusion. These side effects clear

cally. The occasional use of alcohol in patients

spontaneously after 1 to 7 days, so patients can

with ET is a reasonable recommendation. Ben-

be encouraged to stick with the drug during

zodiazepines, particularly alprazolam and

this time. It has been observed that lower doses

clonazepam, also have been demonstrated to

(50 to 250 mg/day) are as effective as higher

be successful in treating ET. Alprazolam is the

doses and are better tolerated. As with propra-

only one shown to be effective in a small con-

nolol, response has varied from patient to pa-

trolled trial and it induced significant reduc-

tient; the reason for this is unknown. However,

tion in tremor. Some literature suggests

many patients prefer primidone to propra-

clonazepam is particularly useful in kinetic

nolol. Plasma levels of primidone and its

predominant tremor. A major adverse effect of

259

Chapter 13

■ Hyperkinetic Movement Disorders

this class of medications is sedation. Alprazo-

the ventral intermediate nucleus nucleus of the

lam is less sedating than clonazepam.

thalamus has become the surgery of choice.

Other agents useful in some patients with

Chronic stimulating electrodes are implanted

ET include methazolamide and acetazolamide,

through a burr hole in the skull and placed in

gabapentin, phenobarbital, clozapine, and top-

the thalamus using stereotactic techniques and

iramate. Clozapine seems to have a general

magnetic resonance imaging (MRI) or computed

tremorolytic action, improving tremors in ET,

tomography (CT) imaging. The stimulator is ad-

Parkinson disease, and multiple sclerosis. At

justable and reprogrammable depending on pa-

low doses (<50 mg/day) there was reduction in

tient needs. Significant improvement has been

tremor amplitude and frequency. The major dis-

observed in blinded evaluations and maintained

advantage of using this drug is the need to mon-

for 1 year. In one study efficacy was seen up to 8

itor white blood counts because 1% of patients

years. More than 30% of patients with ET expe-

develop agranulocytosis. It is also very sedating.

rience complete resolution, and 90% demon-

Topiramate and gabapentin are both antiepilep-

strate moderate to marked improvement. This

tic agents reported to be helpful in ET. The dose

magnitude of response is not seen with any med-

of gabapentin was up to 3600 mg/day, but typi-

ication. It improves writing, pouring, drinking,

cal dosing schedules range from 300 to 600 mg

and other activities. Surgical complications in-

t.i.d. It can cause sedation, dizziness, slurred

clude low-frequency occurrence of intracerebral

speech, and gait imbalance. Topiramate is an an-

hemorrhage, subdural hematoma, and postoper-

ticonvulsant that enhances GABA activity. It is a

ative seizure. Stimulation-related complications

carbonic anhydrase inhibitor that has been re-

include transient paresthesias, which occur in

ported to be effective in the treatment of moder-

most patients at the time the stimulator is turned

ate to severe ET. Adverse effects include ataxia,

on, headache, gait disequilibrium, limb paresis,

fatigue, dizziness, poor concentration, slowing

dystonia, and dysarthria. These problems may

down, weight loss, paresthesias, nausea, and

disappear with time. Drawbacks of the proce-

renal stones. The data on carbonic anhydrase in-

dure include the cost of the stimulators, implan-

hibitors methazolamide and acetazolamide have

tation of a foreign object and the risk of infection,

been conflicting. In our experience these drugs

need to replace battery (every 3 to 5 years de-

provide no useful effect. Mirtazapine was sug-

pending on the parameters), possibility of break-

gested as an alternative treatment for ET in open

age, and malfunction. There are no alternative

experiences; however, a small randomized, dou-

therapies that are useful for ET. Occupational

ble-blind trial was negative.

therapy suggestions include using either wrist

Several studies indicated that BoNT A

weights to decrease the amplitude of tremor or

(Botox) injection directly into contracting mus-

weighted cups and utensils.

cles may be useful in dampening tremor. Pilot

studies in patients with head, hand, and voice

When to Refer to a Neurologist

tremors with moderate to marked functional im-

provement have shown tremor reduction in ap-

Most patients are well controlled with propra-

proximately 70% of patients. It is not used often

nolol or primidone. However, if tremor is severe

for hand or arm tremor because of the trade-off

and unresponsive to these agents, referral to a

related to weakness. However, it is very useful

neurologist is necessary. This is particularly true

for the treatment of head and voice tremor.

if surgery is considered. The referral should be

Thirty percent to 60% of patients do not re-

to a specialty center performing DBS. If BoNT

spond to medication, and the rest have only a

injection is considered, then referral should be

partial response. Those who have severe

made to a neurologist with experience with this

tremor are possible surgical candidates. DBS of

modality of therapy. Finally, if tremor is complex

260

Chapter 13

■ Hyperkinetic Movement Disorders

and diagnosis is unsure, referral to a movement

Family members notice a peculiar gait associated

disorders center is suggested.

with irregular involuntary hand movements.

The patient may try to mask the involuntary

facial movements by chewing gum and the

Special Challenges for

limb movements by sitting on their hands.

Hospitalized Patients

Carrying out of a continuous movement fre-

Education of hospital staff should be directed

quently is impeded by the superimposition of

at possible functional impairment. Assistance

chorea. Reflexes are frequently brisk, but pa-

in feeding and other activities of daily living

tients rarely have a Babinski sign until the final

may be required.

stages of the disease. Voice often affected is by

this condition, and abnormalities of respira-

tory and articulatory muscles may lead to se-

vere dysarthria and erratic, explosive, speech.

HUNTINGTON DISEASE

As the disorder progresses, the chorea may di-

Huntington disease is a progressive degenera-

minish and rigidity and dystonia emerge.

tive disorder of the CNS characterized by invol-

Other movements, including dystonia, parkin-

untary movements (mostly chorea), psychiatric

sonism, and myoclonus, may predominate in-

symptoms, and progressive dementia. Preva-

stead of chorea.

lence in the United States is approximately 12

Approximately 5% of patients have onset

per 100,000 population. HD is an autosomal

in childhood. Of these patients,

60% have

dominant disorder and commonly presents in

parkinsonian features, not chorea. This is

mid adult life. It is named after George Hunt-

known as the Westphal variant. There is an in-

ington, who initially described this disease in

creased incidence of seizures in children with

1872. The word chorea is derived from the

HD (30% to 60%). Children progress more

Greek word for dance (choreia) and originally

rapidly than adults and die in an average of

was used to describe the dancelike gait and

9 years. Childhood-onset cases more frequently

continual limb movements of parainfectious

inherit the disease from their fathers.

forms of chorea (Sydenham chorea). Chor-

Progressive intellectual and psychiatric dete-

eiform movements disappear during sleep and

rioration can manifest as personality change,

are exacerbated by nervousness and emotional

depression, or dementia. Some patients show

distress.

more personality changes than intellectual de-

cline, becoming irritable, agitated, excitable, or

apathetic. Inattention, poor concentration and

Clinical Features

judgment, and eventual memory loss progress

■ SPECIAL CLINICAL POINT: A patient with

until the patient is demented. Other psychiatric

HD may manifest disease initially with chorea,

features include psychosis and obsessive-

psychiatric features, or dementia, although

compulsive disorder (OCD).

eventually all of these abnormalities are seen.

Difficulties include abnormal ocular motor

HD may begin any time from the first to the

function, gait, and loss of finger and hand dex-

eighth decade of life, but it most commonly

terity. The ocular motor difficulties include im-

presents between 35 and 42 years. The onset

pairment of fixation, increased ocular reaction

of chorea is insidious with a few irregular

time with an obvious latency before move-

movements of the face and limbs. Patients find

ment is initiated, loss of smooth pursuit move-

themselves to be fidgety and clumsy. The typi-

ments, and an inability to look toward an

cal history includes slight clumsiness or rest-

object without accompanying head movements

lessness that progresses to

“piano playing”

and blinking (impaired saccades). These find-

movements of the fingers and facial grimacing.

ings are frequently observed early in the course

261

Chapter 13

■ Hyperkinetic Movement Disorders

of the disease. Gait is characterized by a stut-

history revealed that 75% have the disease.

tering and dancing character with a wide-based

Dementia and emotional symptoms are not es-

stance, swaying motions, decreased arm swing,

sential for the diagnosis and are not consid-

spontaneous knee flexion, and variable ca-

ered sufficient evidence of HD in a family, but

dence. The inability to maintain tongue protru-

a history of family members hospitalized for

sion is a sign of motor impersistence.

these reasons in middle age or because of neu-

rologic problems helps to raise the index of

■ SPECIAL CLINICAL POINT: Weight loss

suspicion in patients with choreiform move-

can be a serious issue for patients with

ments. There are a number of disorders that

Huntington disease.

present with chorea (Table 13.6).

Patients with HD live 10 to 30 years (average,

17 years) and usually die from pulmonary

Genetics

causes (aspiration pneumonia), sepsis secondary

■ SPECIAL CLINICAL POINT: Huntington

to urinary tract infections, cardiac disease (is-

disease is an autosomal dominant disorder with

chemic heart disease), trauma-related injuries

100% penetrance. Children of an affected

(subdural hematoma) from multiple falls, or nu-

parent have a 50% risk of developing the

tritional deficiencies. Slower progression of dis-

disease.

ease is associated with older age of onset and

heavier body weight. Since the discovery of the

The emotional impact of the disease on children

gene, it has become obvious that HD is clinically

of an HD patient is profound. They must watch

heterogeneous. For instance, patients with late-

as a parent deteriorates slowly, inexorably,

onset chorea and no dementia have been shown

while facing the prospect of inheriting the same

to have the HD gene. End-stage disease includes

disorder. Enormous advances have been made in

loss of ambulatory function, severe dysarthria,

the last decade regarding the genetics of HD. In

dysphagia with aspiration, and dementia.

1993, the HD gene was discovered, and genetic

testing became available. The availability of this

■ SPECIAL CLINICAL POINT: The clinical

test has raised a number of ethical questions,

spectrum of Huntington disease is variable, and

most fundamental of which is the following:

some patients have more chorea than mental

Why should predictive testing be performed for

changes, but the reverse is also possible.

an illness that has no effective therapy? The im-

This can lead to difficulties with diagnosis.

pact of revealing to a young healthy person the

Because HD is an inherited, progressive, debil-

rather bleak future of HD may be devastating.

itating disorder with no cure, accurate diagno-

The results could be marital difficulties leading

sis is of utmost importance. In the patient with

to disruption of the family and divorce, loss of

adult-onset chorea, dementia, and a positive

employment, and psychiatric problems includ-

family history, the diagnosis can be made eas-

ing suicide. However, positive reasons for ge-

ily. However, in patients with chorea and even

netic testing are numerous and include family

dementia who have no family history, the di-

and financial planning. In at-risk symptomatic

agnosis of HD requires a diagnostic gene test.

patients, genetic testing is the gold standard for

If a patient has chorea but a definite lack of

diagnosis. Its use will avoid a costly workup for

family history, the chorea may result from

other causes of chorea. In asymptomatic indi-

some other etiology. However, studies of pa-

viduals, genetic testing allows for personal and

tients with a sporadic form of chorea resem-

family planning and relieves uncertainty, and in

bling HD have shown that a majority of these

both groups it will prepare patient and physi-

patients do indeed have the HD gene. A fol-

cian for treatment possibilities

(e.g., clinical

low-up study of 49 patients suspected to have

trials or new treatment). There are realistic

HD on clinical grounds but without family

hopes that research in genetics and pathogenesis

262

Chapter 13

■ Hyperkinetic Movement Disorders

TABLE 13.6

Differential Diagnosis of Huntington Disease

Acquired

Inherited

Senile chorea

Benign hereditary chorea

SLE

Familial Alzheimer disease with myoclonus

Antiphospholipid syndrome

Inherited prion disease (including HDL1)

AIDS

Wilson disease

CJD

Neuroacanthocytosis

Tardive dyskinesia in a psychiatric patient

DRPLA (chromosome 11)

Basal ganglia or subthalamic infarction or

Spinocerebellar ataxias 1, 3, and 17

structural lesion

Patients with Parkinson disease treated

Brain iron accumulation disorders (including PKAN

with levodopa

and neuroferritinopathies)

Polycythaemia rubra vera

Friedreich ataxia

Choreoathetotic cerebral palsy

Mitochondrial disease

Chorea gravidarum

MacLeod syndrome

Postinfective (following Sydenham chorea,

HDL2 (caused by junctophilin mutations)

PANDAS, or herpes simplex encephalitis)

Other drug-induced choreas (oral contraceptives,

HDL3 (mutation unknown—extremely rare)

anticonvulsants, stimulants, antidepressants,

anticholinergics, calcium channel blockers, buspirone)

Hyperthyroid chorea

Lysosomal storage disorders

Tuberous sclerosis

Amino acid disorders

Ataxia telangiectasia

SLE, Systemic lupus erythematosus; AIDS, Acquired immunodeficiency syndrome; CJD, Creutzfeldt-Jakob disease; DRPLA, dentatorubral-

pallidoluysian atrophy; PANDAS, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection; PKAN, pantothenate

kinase-associated neurodegeneration.

will lead to disease-modifying therapies. There

they will develop HD. When it is discovered

are also legal and social issues related to predic-

they do not carry the gene, they experience re-

tive testing that need to be addressed. Early

grets, and this can have a significant impact on

studies showed that approximately 75% of at-

family relationships. In addition, there is guilt

risk patients would be interested in participating

for being gene negative while other family

in predictive testing, but with the advent of such

members suffer with the disease. This may

testing this was found to be a gross overestima-

cause the gene-negative persons to either spend

tion. Experience has demonstrated that less than

inordinate amounts of time helping the af-

5% of at-risk individuals actually request the

fected siblings or distance themselves.

predictive test.

Huntington disease genetic testing is ex-

■ SPECIAL CLINICAL POINT: The HD

testing process should be performed at a center

tremely serious. One can imagine the devastat-

staffed with the appropriate team of personnel

ing effect of a positive result on a young

in genetics, neurology, psychiatry, psychology,

asymptomatic person and his or her family,

social work, speech therapy, and nutrition.

but, surprisingly, a negative result also can

cause havoc. Some people live their lives and

The goals of such a program are to ensure that

make decisions based on the probability that

an informed decision is made, to prepare the

263

Chapter 13

■ Hyperkinetic Movement Disorders

subject for the result, and to ensure that an ad-

located on exon 1 of 67. The instability leads to

equate support system is in place. The program

variations (expansion) in length between gener-

must have maximal control over whether the

ations, especially if the father carries the gene.

patient and his or her family receive this irrev-

In normal individuals, this sequence repeats up

ocable information (because of its profound

to 29 times. Repeat lengths of 30 to 34 could

impact); it must provide the opportunity for

lead to paternal transmission if expansion oc-

the patient to withdraw; and it must be able to

curs, and lengths of 35 to 39 represent an inter-

ensure confidentiality. In most centers, the

mediate or a reduced penetrance as well as

process of genetic testing for at-risk asympto-

expansion in offspring. In HD, there are 40 or

matic patients begins with an initial visit to a

more copies and every person with this se-

genetics counselor or psychologist followed by

quence ultimately is affected. Longer segments

evaluations from neurology and psychiatry.

(55 or greater) are found in juvenile cases, sug-

Occasionally, a second genetic visit is required.

gesting there is an inverse correlation between

Once all evaluations are complete, the team

repeat length and age of onset of symptoms.

meets and addresses whether the patient is al-

This is a statistical correlation, but any given

ready symptomatic, and decides if testing can

expansion may be associated with a broad

be performed safely or if it needs to be delayed.

range of onset ages and thus is not predictive.

The patient then comes in for blood to be

The repeat length may expand with each gener-

drawn and returns for results. Results are never

ation if the affected parent is the father and this

given on phone or by mail. In early sympto-

could lead to the phenomenon of anticipation,

matic patients, the process is the same, but in

when the disease occurs at younger ages with

advanced cases, and where a diagnosis is not

each new generation. There is also a correlation

clear, many of the steps are skipped depending

between repeat length and severity of disease

on decisions made by the testing team. In some

and pathology. There are no differences in re-

centers prenatal testing is performed, but this

peat length in those patients presenting with

leads to new issues. For instance, a positive test

neurologic or psychiatric symptoms.

may reveal simultaneously the carrier status in

the parent and child (if the parents’ status is

Pathology, Neurochemistry,

not known) and counseling regarding the op-

and Pathogenesis

tion of terminating the pregnancy. Testing

should be avoided under the following circum-

Postmortem examination of brain tissue from

stances: when not requested by the patient but

patients with HD reveals characteristic

requested by an employer, insurance company,

pathologic abnormalities. Grossly, the cau-

prison, court, or the military; if the subject is

date nucleus, putamen, and cerebral cortex

younger than 18 years (debatable); if there

are atrophied. In advanced cases brain weight

is no informed consent; and if the subject has a

may decrease up to 30%. On microscopic exam-

poor support system. Most clinical geneticists

ination, severe neuronal loss and gliosis in the

advise against presymptomatic testing of un-

striatum are detected, with the caudate nu-

derage patients for adult-onset diseases for

cleus being more affected than the putamen.

which testing provides little or no medical

Neuronal intranuclear inclusions are seen.

benefit.

Although it has been suggested that early

The HD gene is on chromosome 4p16.3 and

features of disease are related to striatal

is referred to as IT15 (IT, interesting transcrip-

degeneration, it has been demonstrated that

tion). The gene product is a protein designated

widespread neuronal degeneration occurs early.

as huntingtin. The abnormality within the gene

Occasionally, patients come to postmortem

is a polymorphic trinucleotide repeat sequence

examination with well-documented chorea

[(CAG)_n] that is expanded and unstable and

and no pathologic changes.

264

Chapter 13

■ Hyperkinetic Movement Disorders

Postmortem studies have revealed that levels

hancement of the transcription of brain-derived

of many neurotransmitters, biosynthetic en-

neurotrophic factor stimulation. It has been

zymes, and receptor-binding sites are abnormal.

suggested that the mutant gene is less efficient

These studies also indicate that there is selective

at this task, leading to decreased levels of the

death of neurons depending on their predomi-

nerve growth factor and the development of

nant transmitter type. GABA and glutamic acid

apoptosis. Huntingtin, in the wild-type form, is

decarboxylase (GAD) levels are diminished in

ubiquitous, being expressed in the cytoplasm of

the striatum and globus pallidus. A threefold to

most cells in the body. In the brain, it primarily

fivefold relative increase in somatostatin has

is seen in neurons and is associated with several

been discovered in the caudate, putamen, and

organelles including endoplasmic reticulum,

globus pallidus in patients with HD compared

microtubules, vesicles, and mitochondria. The

with controls, indicating that the neurons con-

widespread location of the protein begs the

taining it are spared. This indicates that cell

question of how selective neuronal degenera-

death is selective in terms of both regions and

tion occurs in disease. The mutant protein is

cell type. Striatal cholinergic interneurons also

found in cytoplasm and the nucleus where it

appear to be spared. Other neurochemical ab-

forms aggregates. When the mutant enters the

normalities include diminished levels of sub-

nucleus it is cleaved by caspases, making the

stance P, cholecystokinin, met-enkephalin, and

protein more susceptible to aggregate forma-

angiotensin-converting enzyme, plus an increase

tion. The interaction between huntingtin and

in neuropeptide Y. All these abnormalities are

caspases is an important step in neuronal toxic-

seen in the basal ganglia. The pathogenesis of

ity. It appears that nuclear aggregates are toxic

the selective neuronal degeneration in the stria-

to cells; in fact, it is suggested that penetration

tum remains unknown.

of huntingtin into the nucleus is a necessary

The study of the pathophysiology of HD has

step for toxicity. The presence of aggregates dis-

made great progress since the development of

turbs proteolysis within cells. An increased

transgenic animals. The normal function of

number of polyQ repeats correlates with the

huntingtin and the effect of the mutation on

number of aggregates. Some additional roles

that function remain unknown. There are now

of huntingtin include iron homeostasis, main-

several transgenic animals including mice, fruit

tenance of perinuclear organelle structure,

flies, and worms. The key finding in these mice

trafficking of secretory membranes, and gene

is that they parallel the human disease closely.

expression.

Clinically they develop a progressive disease

Mutant huntingtin potentially affects sev-

with weight loss and a movement disorder, and

eral pathways to cell death. These include alter-

the pathology is characterized by neuronal loss,

ation of brain-derived neurotrophic factor

gliosis, and neuronal intranuclear inclusions in

activity, excitotoxicity, free radical formation,

the striatum. In addition, there is increasing ev-

reduction of energy production, activation of

idence that excitotoxicity, mitochondrial dys-

apoptosis, and disruption of gene transcription

function, and free radical formation play a role

through varied protein interactions. Entrance

in the pathophysiology of cell death in the

of the protein into the nucleus and caspase-

animal model. The CAG trinucleotide repeat

induced cleavage and aggregation seem to be

expansion in the gene results in a polyglutamine

important steps in cellular toxicity. All of these

(polyQ) stretch within the huntingtin protein

mechanisms relate to progression and are being

near the N-terminus. The protein is necessary

explained as possible disease-altering agents in

for normal growth and development as demon-

transgenic animals. Free radical scavengers,

strated by the fact that knockout animals (not

glutamate antagonists, creatine, and caspase

expressing the gene) do not survive. Its role in

inhibitors

(including minocycline) prolonged

cell survival may be the result, in part, of en-

life by 20% in mice.

265

Chapter 13

■ Hyperkinetic Movement Disorders

Treatment

■ SPECIAL CLINICAL POINT: In Huntington

disease, improvement in chorea may not

Disease-Modifying Agents The goal of therapy is

improve functional ability or quality of life.

to find an agent (or agents) that will stop or

Frequently a patient with gait disorder and

slow the disease process. Glutamate antagonists

chorea is treated with neuroleptics, but often

have been examined most frequently as disease-

the gait worsens because of the development of

modifying therapy. Baclofen, remacemide, rilu-

parkinsonism.

zole, and lamotrigine all failed. However,

The treatment of chorea should be limited to

remacemide, riluzole, and amantadine have an-

those in whom it is severe and troublesome.

tichoreic effects. Amantadine is readily avail-

Atypical antipsychotics may have a role be-

able, and at 200 to 400 mg/day improvement in

cause of their potential for fewer extrapyra-

chorea can be seen. This drug is better tolerated

midal effects. Clozapine (25 to 500 mg/day)

than neuroleptics in most patients. Free radical

yields some improvement in chorea, but is

scavengers and energy boosters also have been

often associated with sedation and little or no

examined in HD. Vitamin E, OPC-14117, and

improvement in quality of life. Experience

idebenone all failed. However, one study

with risperidone for symptomatic treatment

demonstrated possible effects of the supplemen-

of chorea is even more limited. It appears to

tal coenzyme Q10. This compound occurs natu-

have an effect similar to haloperidol when

rally in mitochondria and shuttles electrons

used at doses between 1 and 6 mg/day. There

between complexes I, II, and III, and it functions

is no significant literature regarding the use

as an antioxidant and a respiratory chain activa-

of other atypical agents in HD. Experience

tor. Coenzyme Q10 was used in a 30-month,

from practice has demonstrated that risperi-

double-blind trial in 360 patients to examine its

done and olanzapine can be used in a manner

potential disease-modifying effects. Patients on

similar to standard neuroleptics for the treat-

coenzyme Q10 demonstrated a 13% slowing

ment of chorea. Quetiapine has even less ef-

in total functional capacity decline, which was

fect, but atypical agents should be used prior

not significantly different from other groups.

to standard neuroleptics in the treatment of

Coenzyme Q10 (600 mg/day) was safe and well

chorea. Other agents that decrease striatal

tolerated. A large scale double-blind, placebo-

dopaminergic activity and should reduce chorea

controlled study of 2400 mg of co-enzyme Q10

include reserpine, alpha-methylparatyrosine,

is underway (the 2CARE study) and a clinical

and tetrabenazine. Historically, reserpine was

trial using high-dose creatine has also just begun.

the first agent reported to be of use in the

treatment of chorea. Reserpine acts to block

Symptomatic Therapy The management of HD

intravesicular neurotransmitter reuptake and

involves a multidisciplinary approach. HD

depletes the brain of dopamine. It also de-

clinics usually include neurologists, genetic

pletes central norepinephrine and serotonin,

counselors, psychologists, psychiatrists, speech

and is used in the treatment of HD at doses of

therapists, physiotherapists, nutritionists, and

0.5 to 3 mg/day because it has a less severe

social workers. From the neurologic stand-

side-effect profile than dopamine antagonists.

point the only feature amenable to sympto-

Tetrabenazine, a dopamine depletor with minor

matic therapy is the movement disorder.

dopamine receptor-blocking effects, is a re-

Historically, the mainstay of therapy for

versible vesicle uptake inhibitor and is useful

chorea has been dopamine receptor antago-

in HD. Tetrabenazine adverse events (hypoten-

nists. Phenothiazines

(e.g., chlorpromazine)

sion and depression) are less severe than those of

and butyrophenones (e.g., haloperidol) share

reserpine. The typical dose is 50 to 200 mg/day.

the property of dopaminergic receptor block-

Tetrabenazine is the first drug approved by the

ade and may be required for relief of chorea.

FDA for its use in the symptomatic treatment

266

Chapter 13

■ Hyperkinetic Movement Disorders

of chorea in patients with HD at doses of up

frequent in these patients, and staff should be

to 100 mg/day.

aware of them.

■ SPECIAL CLINICAL POINT: Psychiatric

symptoms need to be treated aggressively in HD,

WILSON DISEASE

and pharmacologic therapy may be very helpful.

Wilson disease, or hepatolenticular degenera-

Atypical antipsychotics should be the first

tion, is a rare neurologic disorder of copper

agents used in treating psychosis. Quetiapine,

metabolism with a prevalence of approxi-

olanzapine, risperidone, and clozapine all have

mately 5 to 20 per million; its prevalence is

been shown to be effective in treating HD-

higher in countries with increased consanguin-

related psychosis. These agents also may be

ity, but it is present worldwide. Copper accu-

of benefit in agitation and irritability. For de-

mulation becomes toxic and causes signs and

pression, anxiety, and obsessive-compulsive

symptoms that are neurologic (most notably

symptoms serotonin reuptake inhibitors are ef-

movement disorders), psychiatric, hepatic, or

fective and well tolerated. In the case of depres-

ocular, but they may occur in variable combi-

sion, particular care should be taken in assessing

nations, making WD a difficult disorder to

whether the patient is at risk for suicide. In ad-

recognize.

dition to pharmacotherapy, many of these issues

■ SPECIAL CLINICAL POINT: The

can be addressed with psychologic approaches.

importance of recognizing Wilson disease

There are several other issues that are ad-

cannot be overstated because it is a treatable

dressed routinely at HD clinic visits. These in-

and often reversible disorder that otherwise

clude disability, speech disorders and dysphagia,

inevitably results in death. The only way to

nutritional status, weight loss, and home safety.

make the diagnosis is to always keep it in mind.

These problems require the assessment of physi-

Approximately 75% of deaths from WD result

cal and speech therapists, nutritionists, and social

from a failure to make the diagnosis.

workers. The goals are improved quality of life

Clinical Manifestations

and a safe environment at home. There are some

nursing homes that specialize in HD care.

Approximately 40% of patients with WD pres-

ent with neurologic signs and symptoms. The

■ SPECIAL CLINICAL POINT: The most

most common are speech and extrapyramidal

difficult decisions surround the need for feeding

tubes and nursing home placement.

disorders beginning at 18 to 20 years of age.

WD has a slowly progressive course, often with

When to Refer to a Neurologist

a single symptom predominating for months or

or Other Specialist

even years before other manifestations appear.

However, there may be a sudden dramatic

All patients with HD should be referred to a neu-

worsening of what appears to be a stable neu-

rologist or psychiatrist involved in a multidisci-

rologic deficit.

plinary clinic to provide comprehensive care.

Incoordination involving fine finger move-

This is particularly true for those with more ad-

ments such as in handwriting and typing is

vanced disease. At-risk patients (affected parent

frequently an early manifestation. It may be

or sibling) who request presymptomatic testing

subtle at first but worsens as the disorder

should be referred to a testing center.

progresses.

Resting tremor is a common early manifes-

Special Challenges for Hospitalized Patients

tation, and when associated with rigidity,

Hospital staff should be educated regarding vari-

bradykinesia, and/or gait difficulty, WD may

ability of chorea and the relationship of severity

mimic Parkinson disease. The tremor may be

of chorea to stress. Behavioral abnormalities are

postural or kinetic. When severe, it takes on a

267

Chapter 13

■ Hyperkinetic Movement Disorders

flapping quality at the wrist with high-amplitude

without neurologic deficits, making differen-

oscillations and a “wing beating” appearance at

tiation from the primary psychiatric disorders

the shoulder, often resulting in significant dis-

quite difficult. However, there frequently are

ability. Some patients present with bradykine-

neurologic findings in association with the

sia and rigidity without tremor.

psychiatric symptoms, and this clinical situa-

Focal or generalized dystonia is also a com-

tion should raise the index of suspicion that

mon and predominant symptom of WD.

WD may be the cause of the patients’ prob-

Chorea is rare but may result in movements

lem. In fact, psychiatric symptoms are more

and a gait disorder that resemble HD. Spastic-

closely related to the presence of neurologic

ity and ataxia are rare.

features than hepatic features. Some patients

Dysarthria is a consistent feature of WD. It

with psychiatric manifestations treated with

sometimes is associated with dysphagia, and

neuroleptics, who later develop movement

frequently patients show frustration because of

disorders, are misdiagnosed as having a pri-

their difficulty communicating. Often patients

mary psychiatric disorder and TD.

develop a characteristic facial expression with

■ SPECIAL CLINICAL POINT: Some have

retraction of the upper lip, the mouth con-

advocated that all patients admitted to

stantly agape, and upper teeth protruding. This

psychiatric wards under the age of 30 years

gives the patient the appearance of grinning, or

should be screened for Wilson disease.

a “vacuous smile.”

Hepatic disease may be superimposed on neu-

Approximately 6% of patients have general-

rologic manifestations or may be the present-

ized seizures. A majority of the symptoms are

ing problem in

30% to 50% of patients.

exacerbated by emotional stress and amelio-

Hepatic disease usually presents at an earlier

rated by calm and sleep. There is also an acute

age (approximately age 10) than the neurologic

dystonic form of WD. These patients appear

symptomatology of WD, and hepatic patients

ill, and they have a high fever, significant mus-

with WD may be psychologically and neuro-

cle rigidity, rapid emaciation, and confusion, a

logically normal.

picture that can be confused with a neuroleptic

There are four different presentations for

malignant syndrome. This acute presentation

hepatic WD. First, there may be a transient

could be a preterminal event, so diagnosis is of

acute hepatitis that resolves spontaneously.

utmost importance. Because of the protean na-

This is often misdiagnosed as infectious

ture of WD, it is very important to consider

mononucleosis or viral hepatitis because pa-

this diagnosis in all patients under the age of

tients present with the typical hepatic symp-

40 years presenting with movement disorders.

toms and signs such as jaundice, malaise, and

Approximately 25% of patients with WD

anorexia. The second presentation is fulminant

are seen first by psychiatrists for a wide range

hepatitis, which is seen in adolescents and

of emotional difficulties. At least 50% of pa-

which presents with sudden onset of jaundice

tients have early psychiatric manifestations.

and ascites progressing relentlessly to hepatic

There are no psychiatric manifestations that

failure and death. Third, and most common, is

are specific for WD, and diagnoses may range

chronic active hepatitis that presents with

from adolescent adjustment reactions to de-

weakness, anorexia, jaundice, malaise, and ab-

pression and schizophrenia. The most com-

normal liver function tests. Finally, patients

mon features include abnormal behavior,

may present with cirrhosis, and nearly all pa-

such as irritability, incongruous behavior,

tients have some residual cirrhosis.

aggression, and personality change. Depres-

sion and cognitive impairment are also com-

■ SPECIAL CLINICAL POINT: All patients with

mon, but schizophreniform psychosis is rare.

Wilson disease and neurologic symptoms exhibit

Isolated psychiatric problems may be seen

a Kayser-Fleischer (KF) ring in the cornea.

268

Chapter 13

■ Hyperkinetic Movement Disorders

FIGURE 13.4 Kaiser-Fleischer ring in a patient with Wilson disease.

This is a golden or greenish-brown ring that

softening and discoloration to frank cavita-

represents copper deposition in Descemet’s

tion. Other areas less significantly involved

membrane (Fig. 13.4). The ring is seen easily

include the subcortical white matter, cerebel-

around the limbus in patients with light-

lum (most commonly the dentate nucleus),

colored or blue eyes but may be quite difficult

and other nuclei that make up the basal gan-

to see in those with brown eyes. A slit lamp ex-

glia. Excess copper is distributed throughout

amination should be performed by an experi-

the CNS. Neuronal loss is observed in the

enced ophthalmologist to accurately diagnose

basal ganglia and, to a lesser extent, in the

a KF ring in all those suspected of WD. Al-

cerebral cortex.

though a KF ring is not pathognomonic for

WD, its presence is important in the diagnosis.

Pathogenesis and Genetics

It fades with adequate chelation therapy.

Another unusual ocular manifestation of WD

Excessive accumulation of copper as a result

is the sunflower cataract. This is a disc-shaped

of poor copper excretion leads to organ sys-

opacity with frond-like radiations that often are

tem dysfunction and clinical stigmata of WD.

described as a “cataract like the rays of the Sun.”

Ceruloplasmin, a copper-containing polypep-

Other possible manifestations of WD in-

tide, is deficient in 95% of patients with WD.

clude Coomb negative hemolytic anemia,

Biliary excretion of copper in WD is impaired

skeletal changes including pathologic fractures

and copper accumulates in the liver, binding

from metabolic bone disease and hypertrophic

to thiol and carboxyl groups on copper-storage

osteoarthropathy, renal disease including gross

proteins. The copper binding alters both

hematuria, stones, tubular and glomerular

structure and function of storage proteins,

disease, and the Fanconi syndrome, and car-

disrupting normal cellular activity in a variety

diac symptoms including arrhythmia and

of ways. When storage reaches capacity, ex-

cardiomyopathy.

cess copper begins to move into extrahepatic

storage sites, particularly the eye and brain.

This explains why KF rings are not seen in

Neuropathology

50% of patients with hepatic WD.

The lenticular nuclei are involved bilaterally

Wilson disease is an autosomal recessive disor-

and symmetrically. The lesions vary from

der with the gene locus located on chromosome

269

Chapter 13

■ Hyperkinetic Movement Disorders

13q14-21. In 1993 the WD gene was cloned,

concentrations with immunologic (as opposed

and the gene frequency is 0.6% with a carrier

to enzymatic) assays, as well as due to false el-

frequency of 1 in 90. The gene codes for a

evation of ceruloplasmin in acute inflamma-

copper-transporting p-type ATPase called

tion, pregnancy, estrogen supplementation,

ATP7B. ATP7B functions in copper transport

and use of oral contraceptives. Low ceruloplas-

coupled with the synthesis of ceruloplasmin in

min levels are not diagnostic of WD, especially

the Golgi apparatus. The abnormal protein

if the clinical presentation is not consistent.

from the mutated gene leads to decreased func-

Other conditions where there is marked pro-

tion, which causes failure of the liver to excrete

tein loss, copper deficiency, or rarely Menkes

copper into the bile. Since more than 300 gene

disease and aceruloplasminemia will also ex-

mutations have been identified, genetic testing

hibit low ceruloplasmin levels.

is not available.

If ceruloplasmin level is low, examination

for KF ring and 24-hour urine copper excretion

must be performed. If ceruloplasmin is normal

Diagnosis

and KF ring is present, a liver biopsy should be

■ SPECIAL CLINICAL POINT: It can never be

performed to make the diagnosis. Hepatic WD

said enough that a high index of suspicion is

is the most difficult presentation to diagnose

very important in making the diagnosis of WD.

because ceruloplasmin may be falsely elevated

This is especially true when evaluating patients

or normal in WD hepatitis and a KF ring may

40 years or younger who present with

be absent.

extrapyramidal disorders, psychiatric disorders

(especially when associated with neurologic

■ SPECIAL CLINICAL POINT: If confusion

signs and symptoms), and hepatic disease.

remains after serum ceruloplasmin levels, slit

lamp examination, and 24-hour urinary copper

In addition, a family history of WD (particu-

concentration, liver biopsy is required.

larly a sibling) or hepatic disease at a young age

should alert the physician to a possible diagno-

Wilson disease is inherited as an autosomal re-

sis of WD. Once suspected, the diagnosis of

cessive disorder, so each sibling of a patient with

WD can be confirmed using four tests: (a) a slit

WD has a 25% chance of having the disease.

lamp examination for KF rings (the specificity

of KF rings for patients with neuropsychiatric

■ SPECIAL CLINICAL POINT: All siblings of

patients with Wilson disease should be

WD is nearly 100%), (b) a serum ceruloplas-

screened. If they have WD, treatment will

min level (usually low in 80% of patients with

prevent onset of clinical stigmata.

WD), (c) 24-hour urinary copper excretion (el-

evated in WD to more than 100 µg), and (d) a

At-risk siblings should have slit lamp examina-

liver biopsy with quantitation of copper con-

tion and 24-hour urinary copper and cerulo-

centration—the most definitive of all tests

plasmin determination, along with physical

(copper levels higher than 250 mg/g of dry tis-

and neurologic examinations at regular inter-

sue are considered diagnostic).

vals. If a KF ring is present, ceruloplasmin level

Clinical evaluation and the first three tests

is low, and urinary excretion of copper is ele-

are usually sufficient to make the diagnosis of

vated, the diagnosis of WD is clear and liver

WD in symptomatic patients, and liver biopsy

biopsy is not required. However, if the serum

is not required. A normal serum ceruloplasmin

ceruloplasmin level is low but KF ring is ab-

level (often used to screen for WD) by itself

sent, the patient may be a heterozygote for WD

should not convince the treating physician that

and liver biopsy will be necessary to make a de-

WD is ruled out because 5% to 20% of pa-

finitive diagnosis. Ten percent to 20% of het-

tients with WD have normal levels. This is due,

erozygotes have low serum ceruloplasmin levels,

in part, to overestimation of ceruloplasmin

but these patients do not require treatment.

270

Chapter 13

■ Hyperkinetic Movement Disorders

Following the discovery of multiple polymor-

(TTM). D-penicillamine, a potent chelating

phic DNA markers close to the gene on chro-

agent with thiol groups to bind copper and re-

mosome 13, multilocus linkage analysis makes

move it from organ systems via urinary excre-

possible accurate and informative testing of

tion, had been the treatment of choice for

potential carriers in families with WD in whom

decades. Penicillamine has a rapid action in mo-

the mutation has been found. Such testing is

bilizing and clearing copper through the urine.

now commercially available from certain clinical

Four divided doses of 1 to 2 g should be given 30

laboratories. With these techniques, one could

minutes before or 2 hours after meals to ensure

discriminate between carriers and presympto-

maximal absorption. Pyridoxine,

25 mg/day,

matic patients. Advantages of this technique

should be added because of an antipyridoxine ef-

include its noninvasive nature and early (possi-

fect of penicillamine. Improvement begins

bly prenatal) diagnosis. Direct mutation analy-

weeks to 1 year after the institution of therapy.

sis by whole-genome sequencing is also feasible

Of patients with WD, 75% to 80% respond suc-

and can be integral to the diagnosis in patients

cessfully to penicillamine. In the first 2 months of

where clinical and biochemical investigations

therapy, complete blood count, urinalysis, and

have been unrevealing.

liver enzyme levels should be examined fre-

Neuroimaging techniques are not diagnostic

quently. Some patients initially worsen with

in WD, but typical lesions can be observed. On

penicillamine therapy.

CT scanning, cortical and brainstem atrophy

Adverse effects of penicillamine are many and

are seen in nearly all patients. Hypodensity of

occur early and late. Early adverse effects include

the head of the caudate and putamen is seen

hypersensitivity reactions, fever, rash, adenopa-

early, and cavitation of the putamen is seen late.

thy, leukopenia, thrombocytopenia, collagen

Sometimes, hypodensities are seen in other

vascular disorders, and bone marrow suppres-

areas including cerebellum, brainstem, thala-

sion. Late adverse effects occurring after a year

mus, and cerebral cortex. These lesions do not

of therapy include nephrotic syndrome, agranu-

enhance with contrast. On MRI scanning, hy-

locytosis, thrombocytopenia, Goodpasture syn-

pointense lesions are observed in the lenticular

drome, pemphigus, myasthenia gravis, elastosis

nucleus, thalamus, caudate nucleus, cerebellum,

perforans serpiginosa, and dermopathy. Serious

brainstem, and subcortical white matter on T1-

intolerance to penicillamine occurs in only 3%

weighted images whereas hyperintense lesions

to 5% of patients, and these patients require al-

are observed on T2-weighted images (Fig. 13.5).

ternative therapy.

The accumulation of copper leads to areas of

Trientine, like penicillamine, is a copper-

hypointensity adjacent to the hyperintense re-

chelating agent and is the alternative chelation

gions (Fig. 13.5B). These changes are seen in all

therapy of choice. The dose is 1 to 1.5 g/day

patients with neurologic symptoms and repre-

30 minutes before or 2 hours after meals. Trien-

sent edema, gliosis, or cystic lesions.

tine is effective for the treatment of WD, appar-

ently has fewer side effects than penicillamine,

and only rarely causes acute worsening. Adverse

Treatment

effects include collagen vascular disorders and

Once the diagnosis of WD is confirmed, treat-

iron-deficiency anemia.

ment should be instituted without delay. There

Two newer therapies have changed the ap-

is now a choice of agents including chelating

proach to these patients. Zinc acetate, approved

agents such as D-penicillamine, trientine, or zinc

by the FDA in 1997, induces excretion of cop-

acetate, all of which are now FDA approved

per via the gastrointestinal tract by increasing

(Table 13.7). There is also an experimental agent

the concentration of metallothionein in the

that shows great promise, tetrathiomolybdate

bowel mucosa by 25-fold. As the tissue content

271

Chapter 13

■ Hyperkinetic Movement Disorders

FIGURE 13.5 A: T2-weighted magnetic resonance imaging (MRI) scan of a patient with early

symptomatic Wilson disease, demonstrating hyperintensity in the caudate nucleus and putamen.

B: T2-weighted MRI scan of a more advanced patient with hypointensity in the striatum. The same scan

as seen in (B), showing hyperintensity in the dentate nucleus of the cerebellum (C) and the pons (D).

of this protein increases, the proportion of cop-

after or before food or beverage in adults and

per in the cells increases. Then, as the mucosal

50 mg twice a day in children, and the ultimate

cells are sloughed and lost in the stool, copper is

daily dose ranges from 300 to 1200 mg/day. Pa-

excreted. Metallothionein levels also increase in

tients are monitored by following urinary cop-

the liver; this increases liver copper levels, but

per levels. Monitoring should be performed

the copper is stored in a nontoxic form. Ini-

within the first 2 weeks, and if no change is seen

tially, zinc has a slower effect on copper excre-

the dose is increased. The final dose is individu-

tion than the chelating agents. The dose is

alized. Zinc is less toxic than penicillamine

started at 50 to 100 mg three times a day 1 hour

and does not cause paradoxical worsening of

272

Chapter 13

■ Hyperkinetic Movement Disorders

TABLE 13.7

used concurrently. Some suggest trientine be-

Medical Treatment of Wilson Disease

cause it is less toxic than penicillamine. For

neuropsychiatric presentations, zinc and a

Initial Daily

Usual Daily

chelating agent should be initiated unless

Drug Name

Dose

TTM is available. For maintenance, zinc is the

treatment of choice. No formal controlled

Penicillamine

125 mg q.i.d.

250 mg q.i.d.

trials were conducted to examine this issue.

Trientine

250 mg q.i.d.

Zinc acetate

50 mg t.i.d.

Zinc has become the treatment of choice in

Tetrathiomolybdate^a

20 mg 6

presymptomatic and pregnant patients. Copper-

times

rich foods particularly shellfish and liver

should be avoided.

^aCurrently experimental.

Frequently, patients whose neurologic symp-

toms have resolved are tempted to stop their

chronic medication. It may become difficult for

symptoms as penicillamine can. The side effects

asymptomatic patients to connect their good

include gastrointestinal irritation, elevation of

health to their chronic medication. Discontinu-

serum amylase, and decreased high-density

ing chelation therapy invariably results in dis-

lipoprotein. Rarely, copper deficiency can occur,

aster for these patients, many of whom die of

leading to leukopenia and anemia. It has been

fulminant hepatitis within 3 years. It is the

used successfully as both initial treatment and

physician’s job to reinforce the need for med-

maintenance.

ication and to inform these patients of the dis-

The newest treatment is tetrathiomolyb-

astrous results that lie ahead should the

date (TTM). When given with meals it pre-

medication be stopped. Response to medica-

vents absorption of copper, and when given

tion should be monitored using 24-hour uri-

between meals it is absorbed into the blood

nary copper levels. Chelating agents will cause

and forms complexes with copper and albu-

an increase in urinary copper output before a

min, rendering the copper nontoxic. It has a

decrease.

rapid action in relation to copper metabolism

For patients with liver failure the standard

and does not cause worsening of symptoms. It

measures taken should include lactulose,

has been studied for initial therapy but not for

neomycin, and protein restriction. Liver trans-

maintenance. The daily maintenance dose is

plant is sometimes the only treatment alterna-

20 mg six times a day, three doses with and

tive in patients with fulminant hepatitis and

three without meals. One side effect is a re-

cirrhosis with liver failure. The 1-year survival

versible anemia. The drug is experimental and

rate is about 80% and the 5-year survival rate

has limited availability.

is 40% to 70%. These numbers are quite re-

Initial treatment of WD has become con-

spectable, especially in this situation in which

troversial. Currently, most recommend that a

all patients will otherwise die.

chelating agent should be included in initial

There is no role for alternative therapies in

treatment. Some argue that the old reliable

WD. Physical, occupational, and speech ther-

treatment of penicillamine chelation therapy,

apy may play a role. Speech therapy and assis-

based on decades of experience

(since the

tive devices can be helpful for the dysarthria

1950s), should not be abandoned. Others

that characterizes WD. Physical therapy may

argue that zinc is the appropriate choice be-

be useful for treating dystonia and gait disor-

cause it is equally effective, is much better tol-

ders, perhaps with the addition of assistive de-

erated, and does not cause paradoxical

vices such as walkers. Occupational therapy

worsening. For hepatic presentations, it is

can help patients who have dystonia and

suggested that zinc and a chelating agent be

tremor to continue to function.

273

Chapter 13

■ Hyperkinetic Movement Disorders

When to Refer to a Neurologist

behavior such as cervical injury with neck tics

or Other Specialist

or lip biting. Simple vocal tics are a variety of

inarticulate noises and sounds. Examples in-

Wilson disease is a complex disorder with re-

clude sniffing, snorting, barking, throat clear-

gard to diagnosis and assessment of siblings.

ing, and grunting. Complex vocal tics are

Any patient with neuropsychiatric symptoms

linguistically meaningful utterances. They can

should be referred to a neurologist. Treat-

include the utilization of words

(no-no),

ment is also a complicated matter best han-

phrases (oh boy), or even sentences. Classical

dled by a neurologist with experience. When

forms of complex vocal tics include palilalia

the diagnosis is suspected and an evaluation

(involuntary repetition of words or sen-

for a KF ring is sought, it should be per-

tences), echolalia

(involuntary repetition of

formed by an experienced ophthalmologist.

words or sentences just spoken by another

Finally, all patients should have an evaluation

person), and coprolalia

(involuntary utter-

by a gastroenterologist.

ances of curse words). This latter phenome-

non is perhaps the best known feature in GTS,

but it occurs in less than 10% of patients. Co-

GILLES DE LA TOURETTE SYNDROME

prolalia is distinguished from emotion-driven

Gilles de la Tourette syndrome is a movement

swearing by its cadence, volume, and context.

disorder dominated by tics and various behav-

Vocal tics tend to occur at phrase junctions in

ioral abnormalities. It is seen in approximately

speech and can cause blockage or hesitation

1% to 3% of school children and is three times

of speech patterns.

more common in males than females.

Although motor tics are commonly clonic or

Tics are sudden, brief, intermittent, stereo-

rapid in nature, when they are slow, twisting,

typed involuntary movements or sounds. They

and result in brief sustained postures (resembling

are classified according to whether they are

dystonia), they are referred to as dystonic tics. A

motor or vocal (phonic), simple or complex.

common type involves slow shoulder shrugging

Simple motor tics are abrupt, brief, purpose-

with rotational scapular movements. Others in-

less, isolated (single muscle or muscle group)

clude blepharospasm, ocular deviations, and tor-

movements that are jerky or clonic emerging

ticollis. Sensory tics (premonitory sensations) are

out of a background of normal activity. Exam-

patterns of somatic sensations that have been

ples of simple motor tics are eye blinks, head or

variously described as a pressure, a tickle, a tem-

limb jerks, and shoulder shrugs. Complex

perature change, paresthesias, or an uncomfort-

motor tics are more coordinated, sequential,

able feeling, localized to specific body regions,

and complicated movements or gestures that

and resulting in dysphoric feelings. These un-

almost may appear purposeful but are inappro-

comfortable sensations may provoke a motor

priately intense and timed. Examples of com-

or a vocal tic such as limb stretching, ble-

plex motor tics include eye deviation, facial

pharospasm, and throat clearing. This indicates

grimacing, hand shaking, waving arm move-

that the tic itself actually may be a voluntary

ments, muscle flexing and posing with isomet-

movement under conscious control (sometimes

ric or tonic movements, touching, jumping,

referred to as “unvoluntary”). The uncomfort-

hitting, kicking, squatting, truncal bending or

able sensation is usually relieved by this move-

gyrating, copropraxia

(making obscene ges-

ment, but relief is only temporary, leading to

tures), and echopraxia (mimicking the move-

repeated movements.

ments of others).

Tics have a number of characteristic fea-

Sometimes, a cluster of simple tics will

tures that help to differentiate them from other

appear to be complex. In extreme cases tics

movement disorders. They are suppressible to

may be so forceful as to cause self-injurious

some extent. Often, when patients with GTS

274

Chapter 13

■ Hyperkinetic Movement Disorders

come into the physician’s office, their history

Clinical Spectrum of Tic Disorders

of tics is a better indication than just observa-

■ SPECIAL CLINICAL POINT: Tic disorders

tion because patients can suppress their tics

represent a continuum from a mild transient

(and often do) in the office. In addition, tics

form to a potentially devastating

tend to wax and wane, so they can vary in in-

neurobehavioral disorder.

tensity over time and occur in bouts. This can

Transient tic disorder is probably the most

have a significant bearing on clinical trials.

common and mildest form of the disorder. It is

They also tend to change location over time.

defined as the duration of the tic disorder of

More frequently, tics begin in the eyes with eye

less than 12 months. As such, the diagnosis is

blinking and then move so that there are neck

often retrospective. In these patients, tics are

movements or shoulder shrugs or other types

usually the simple motor type. Chronic multi-

of movements. Patients often will describe an

ple tic disorder is a more severe form than

inner tension or urge that is transiently re-

transient tic disorder. Patients have multiple

lieved by the tic itself. When patients suppress

motor or vocal tics but not both. Multiple

the tics, the inner tension grows and there

motor tics are much more common. The dura-

often will be a flurry of tics once the suppres-

tion of this syndrome is longer than 1 year.

sion is released. Patients often will give a his-

GTS represents the full expression of the tic

tory of having few tics during work but a

disorder. Estimates of the prevalence of GTS

flurry of them once they return home at the

are probably significantly lower than actual

end of the day. Tics, in general, increase with

prevalence because, in milder cases, a large

stress, anger, and excitement and decrease

percentage of patients are unaware that they

with relaxation, concentration, distraction,

have a tic disorder and in many the tics are

and sleep. The urges or sensations may be dis-

not bothersome so they do not seek medical

abling by themselves.

assistance.

Tics usually begin between the ages of 3 and

8 years, although GTS is defined by onset

prior to age 21. They start as facial move-

Associated Behavioral Disturbances

ments, especially blinking, and then move to

■ SPECIAL CLINICAL POINT: Obsessive-

other regions including neck and shoulders.

compulsive disorder is present in 20% to 60% of

Vocal tics typically occur after the motor tics.

patients with Gilles de la Tourette syndrome.

Tics reach peak severity in the early to mid sec-

ond decade and then diminish by the begin-

This behavioral disorder appears to be linked

ning of the third decade. By 18 years, up to

genetically to GTS and may represent an alter-

50% of patients may be tic-free. In the rest the

nate expression of this disorder. Symptoms can

movement disorder persists into adulthood

result in significant stress and disability. Exam-

but with diminished severity. There are occa-

ples of compulsive symptoms include ordered

sional cases with adult-onset tics. The severity

arranging habits, rituals of decontamination,

of tics in childhood has no bearing on severity

including repeated hand washing, checking rit-

in adulthood because even the most severe

uals

(locks on doors or cars and stove

cases can improve or even disappear. Moder-

switches), and ritualistic counting. Obsessive

ate to severe tics in late adolescence, however,

thoughts often intrude on conscious thoughts

can be an indication that patients will have

and interrupt daily routines. Compulsions re-

more severe tics in adulthood. Despite difficul-

lieve the obsessions. Examples of obsessions in-

ties in school at younger ages, most people

clude fears and images of injuries to loved

with tics are employed or complete their edu-

ones, fear of contamination with germs, dirt,

cation as young adults and become very well

or disease, feelings of responsibility for misfor-

adjusted. The need for treatment diminishes in

tune of others, feelings of doubt that one has

adulthood.

performed tasks that are already completed,

275

Chapter 13

■ Hyperkinetic Movement Disorders

and need for exactness and symmetry. Com-

Diagnosis and Differential Diagnosis

pulsive behavior and tics, particularly complex

The diagnosis of GTS is based on clinical symp-

ones, can overlap and they may be difficult to

toms; there are no diagnostic laboratory tests.

differentiate. OCD symptoms, like tics, wax

Because the features can be so varied, there is

and wane and increase with stress.

often a delay in diagnosis. Many patients diag-

Another common behavioral disturbance

nose themselves based on what they see on tele-

associated with GTS is attention deficit hyper-

vision or read on the Internet. Often when

activity disorder

(ADHD). In these patients,

patients recognize their own symptoms they

the disorder can result in a short attention

seek a medical opinion. The Tourette Syndrome

span, restlessness, poor concentration, dimin-

Classification Study Group formulated diagnos-

ished impulse control, and hyperactivity.

tic criteria for GTS, which include the following:

(a) both multiple motor and one or more phonic

■ SPECIAL CLINICAL POINT: Attention

tics must be present sometime during the illness,

deficit hyperactivity disorder (ADHD) may be

present in 40% to 70% of children with Gilles

not necessarily concurrently; (b) tics must occur

de la Tourette syndrome, and it is not

many times per day, nearly every day, for a pe-

uncommon for ADHD to precede the

riod of more than a year; (c) the anatomic loca-

onset of tics.

tion, number, frequency, type, complexity, or

severity of tics must change over time; (d) the

Attention deficit hyperactivity disorder seems

onset is earlier than the age of 21 years; (e) the

to be more common in patients with severe tic

symptoms must not be explainable by other

disorder. Increased irritability, rage attacks,

medical conditions; and (f) the tics should be

vulnerability to drug abuse, depression, and

witnessed by a reliable examiner at some point.

antisocial behavior are common in patients

Tics may be secondary to other etiologies.

with ADHD. Stimulant medications used for

Tics have been seen in patients after stroke,

primary ADHD were believed to provoke or

tumor, head trauma, peripheral trauma (neck or

exacerbate tics. A study by the Tourette Study

face), encephalitis

(and postencephalitic syn-

Group using methylphenidate

(MPH) dis-

drome of encephalitis lethargica), and carbon

pelled that myth and demonstrated that MPH

monoxide poisoning. Lesions in these disorders

can be used in this population with no risk of

include frontal and temporal lobe and basal gan-

inducing tics.

glia. The most common cause of secondary tics

Other behavioral abnormalities include learn-

is chronic use of neuroleptic medications (tardive

ing disabilities, oppositional defiant disorder,

tics). These patients usually have onset in adult-

anxiety (separation anxiety), depression, mania,

hood and a clear history of neuroleptic exposure

conduct disorders, self-injurious behavior, pho-

prior to the onset of the disorder. Other drugs

bias (simple, social, agoraphobia), dyslexia, and

that cause tics include anticonvulsants (pheny-

stuttering.

toin, carbamazepine), stimulants (including co-

caine), and antihistamines. Finally, tics can be a

■ SPECIAL CLINICAL POINT: Behavioral

disorders occur 5 to 20 times more commonly

manifestation of chronic neurodegenerative dis-

in patients with Gilles de la Tourette syndrome

orders; examples include HD and neuro-

than in the general population.

acanthocytosis. They also can be a manifestation

of developmental diseases or chromosomal dis-

It is difficult to know whether these disorders

orders; examples include Klinefelter syndrome,

are secondary to the primary aspects of the dis-

Down syndrome, and fragile X disease.

ease (tics, OCD, ADHD) or they are neurobio-

logically linked. Sleep disorders including

Genetics and Pathophysiology

somnambulism, night terrors, nightmares, dis-

turbances in sleep initiation, and maintenance

Evidence from the study of multiple large fam-

are present in about 50% of the patients.

ilies and twins has suggested that GTS is an

276

Chapter 13

■ Hyperkinetic Movement Disorders

autosomal dominant disorder. It has variable

in a subgroup of patients much the way chorea

expressivity, including transient tic disorder,

does (Sydenham chorea), it seems unlikely that

chronic multiple tic disorder, GTS, and OCD,

this is the cause of GTS.

and is sex influenced because males are af-

The neuroanatomic location of the abnor-

fected more than females. Several methods

mality resulting in GTS is unknown. It is sus-

have been used to isolate genes linked to GTS.

pected from cases of secondary tic disorders and

The nature of GTS genes that lead to the devel-

imaging with PET, SPECT, and MRI that the

opment of the disorder remains elusive. Other

basal ganglia (particularly striatum), midbrain,

disease aspects suggest a genetic pattern differ-

frontal and medial temporal lobes, and limbic

ent from a major dominant gene and that it is

structures may be involved. The biochemical

more likely to be a complex polygenetic pat-

basis of GTS is also not clearly understood.

tern. It has also been suggested that genomic

However, there is evidence to suggest that in-

imprinting, in which gene expression is altered

crease in activity of the dopamine systems is in-

by whether the gene is inherited from the father

volved. This evidence includes (a) response to

or mother, may play a role in GTS. GTS ap-

dopamine antagonist medications, (b) response

pears to be genetically heterogeneous, relating

to dopamine-depleting medications (reserpine,

to the interaction of several genes and influ-

tetrabenazine),

enced, to some extent, by nongenetic factors.

(d) presence of alterations in dopamine metabo-

Despite clear genetic influences, there appear

lites in the cerebrospinal fluid of patients with

to be nongenetic developmental factors that

GTS, and (e) possible increase in density of

influence the form and severity of the disorder.

presynaptic dopamine transporters and postsy-

Such factors include maternal life stresses dur-

naptic D₂ receptors. Two hypotheses related to

ing pregnancy, smoking during pregnancy, gen-

this increase in dopamine stimulation have been

der of the child, severe nausea and/or vomiting

suggested. The more prominent one is that there

in the first trimester, and birth weight.

is dopamine receptor supersensitivity in the

One possible environmental cause of GTS

basal ganglia, similar to that described in TD.

that is currently a matter of debate involves its

There is also the possibility that there is an in-

relationship with streptococcal infection. It is

crease in dopamine input into the striatum.

proposed that an antibody response results in

However, the recent discovery that dopamine

the development of cross-reactive antibodies

agonist medications actually may alleviate tics

against neuronal substrates, so-called

“anti-

has placed the hyperdopaminergic hypothesis in

neuronal antibodies.” Some have argued that

question. Pathologic studies, which are few,

the development of tics or OCD falls into the

have demonstrated various neurochemical alter-

spectrum of childhood-onset disorders called

ations in the brain. Dynorphin levels (from the

PANDAS (pediatric autoimmune neuropsychi-

opiate system) have been found to be reduced in

atric disorders associated with streptococcal

the lateral globus pallidus; serotonin levels are

infection). Although some patients with GTS

low in the brainstem; and glutamate was found

have been found to have antistreptococcal an-

to be diminished in the globus pallidus.

tibodies and antineuronal antibodies in the

sera, the connection between the two remains

Treatment

to be proven. There is no association between

antibody titer and severity of tics, no clear tem-

Effective pharmacologic treatment is available

poral association between infection and exac-

for GTS and its many behavioral manifesta-

erbation of symptoms, and no occurrence of

tions. Multidisciplinary treatment involving a

inflammatory symptoms such as polyarthritis

neurologist, psychiatrist, and social worker is

or mitral valve disease. Although it is possible

the best approach, with patient education as a

that tics may result from a postinfectious process

key component. It may be that many patients

277

Chapter 13

■ Hyperkinetic Movement Disorders

with this disorder do not need treatment be-

effects can be limiting and include sedation,

cause their symptoms are mild. If symptoms

dysphoria, weight gain, TD, acute movement

are not disruptive or disabling, patients should

disorders (akathisia, acute dystonia, parkinson-

be treated supportively. Some patients may do

ism), depression, poor school performance, and

well with behavioral therapy, such as relax-

school phobias.

ation training and self-monitoring. However,

Other neuroleptic medications with fewer

benefits of such therapies are usually tempo-

side effects include pimozide (1.5 to 10 mg/day).

rary. Nevertheless, they may be useful when

This drug can cause prolongation of the QT in-

used in conjunction with pharmacotherapy.

terval, which could lead to cardiac dysrhyth-

Pharmacologic treatment should be used only

mias. An electrocardiogram is required at

in those patients who are severely troubled by

baseline and should be repeated periodically.

their symptomatology.

Atypical neuroleptics including clozapine have

been used in a limited number of patients with

■ SPECIAL CLINICAL POINT: A team

GTS with mixed results. Risperidone demon-

approach to evaluating patients with Gilles de la

strated efficacy in several case reports, short-

Tourette syndrome can dictate which group of

term open trials, and placebo-controlled trials

symptoms require treatment (i.e., tics or

in treating motor tics and perhaps OCD. Ap-

behavioral disorder). Treatment should be

proximately 30% to 60% of patients had tic

individualized and directed toward those

improvement. A 12-week, double-blind, ran-

specific symptoms that are most troublesome

domized comparison with pimozide was re-

(Table 13.8).

ported in 50 patients with GTS. The final mean

With regard to tic control, dopamine receptor

doses were 3.8 mg/day for risperidone and

antagonists (neuroleptics) historically have been

2.9 mg/day for pimozide. Both treatments re-

the most frequently used and effective drugs.

sulted in a significant improvement in tic mea-

Haloperidol (0.25 to 2.5 mg/day) at bedtime can

sures with no difference between groups.

be effective in up to 80% of patients. Adverse

Results were similar for children and adults.

TABLE 13.8

Medical Therapy for Tics

Drug Name

Initial Daily Dose (mg)

Usual Daily Dose Range (mg)

Neuroleptics

Haloperidol

0.25

0.25-20

Pimozide

1.5-10

Atypical antipsychotics

Risperidone

0.5

0.5-4

Olanzapine

2.5

2.5-10

Ziprasidone

20-80

Aripiprazole

5-30

Others

Clonidine

0.1

0.1.3

Guanfacine

1-4

Clonazepam

0.25

0.5-3

Topiramate

25-100

Donepezil

278

Chapter 13

■ Hyperkinetic Movement Disorders

Extrapyramidal symptomatology (EPS) was re-

eliminate the associated urge to perform the

ported in 15% of patients treated with risperi-

tic, and decrease the pain associated with tics.

done and 33% of patients in the pimozide

When treating OCD, cognitive behavioral

group. Somnolence, fatigue, weight gain, and

techniques can be useful; however, pharmaco-

depression were seen with both therapies.

logic intervention is often necessary. Selective

These results indicate that risperidone im-

serotonin reuptake inhibitors are the treatment

proves tics as well as OCD to an equal or better

of choice for this behavioral disorder. Fluoxe-

level than pimozide and causes fewer EPSs.

tine (20 to 60 mg/day), a bicyclic antidepres-

sant, can be useful. Clomipramine, sertraline,

■ SPECIAL CLINICAL POINT: Neuroleptics

paroxetine, venlafaxine, citalopram, escitalo-

should be used in children only when tics are

pram, and fluvoxamine are other selective

severe, and should be avoided if possible in

serotonin reuptake inhibitors that have been

adults, particularly women, who are at greatest

used in primary OCD with favorable results

risk for tardive dyskinesia and other

and may be useful in GTS. These drugs also

extrapyramidal effects.

may be effective in treating associated anxiety,

Olanzapine, ziprasidone, quetiapine, and arip-

depression, and social phobias.

iprazole all have been reported to suppress tics

Attention deficit hyperactivity disorder can

but to a lesser extent. Further studies are

be disabling in GTS. Primary ADHD is often

needed with all three of these drugs. These

treated with stimulant medications, such as

agents can be associated with weight gain, dia-

MPH, dextroamphetamine, and pemoline. A

betes, hypertension, and dyslipidemia as well

multicenter, double-blind trial randomized 37

as sedation.

children to MPH, 34 to clonidine, 33 to cloni-

Neuroleptics are the most potent treatment

dine and MPH, and 32 to placebo. ADHD sig-

for tics; however, the adverse event profile sug-

nificantly improved in all three active groups,

gests they should be used with caution. Cloni-

with the most significant change in the combi-

dine is a useful alternative for GTS. This drug is

nation group. Clonidine was most useful for

an alpha2-adrenergic agonist that inhibits

impulsivity and hyperactivity; MPH was most

presynaptic norepinephrine release. It can be

useful for inattention. A similar degree of tic

useful for tics, and also for behavioral aspects

worsening was seen with MPH and placebo,

of the disorder, particularly ADHD. Daily doses

and tic severity actually lessened in all active

range from 0.15 to 0.5 mg. It is available as oral

groups. In patients with GTS with ADHD and

medication or transdermal patches. Guanfacine

tics, the treatment of choice is MPH (long act-

is a similar class agent but has less sedation. Ad-

ing or short acting, the former is preferred)

verse events include sedation, dry mouth and

plus clonidine. Selegiline, a monoamine oxi-

eyes, headaches, and postural hypotension.

dase B inhibitor that is metabolized to

Alpha2-adrenergic agonists are good first-line

methamphetamine, tricyclic antidepressants,

drugs because of their better side-effect profile.

and norepinephrine reuptake inhibitors, is use-

Other agents used with some success, which

ful in treating ADHD and tics.

have not been studied in controlled trials, in-

The role of DBS for GTS is unknown. Data

clude clonazepam, reserpine, tetrabenazine, se-

have been accumulated for 10 years regarding

legiline, baclofen, donepezil, topiramate,

this therapeutic option for adults with severe

nicotine patches, calcium channel blockers,

and medically refractory disease. Several stud-

and opiate.

ies using different targets have reported benefit

Facial and neck tics, especially dystonic tics,

in both tics and behavioral symptoms with

can be treated with carefully placed intramus-

DBS. Targets have included centromedian

cular BoNT injections. In some patients the in-

parafascicular, ventralis oralis complex of the

jections decrease the tic number and severity,

thalamus, globus pallidus interna, and nucleus

279

Chapter 13

■ Hyperkinetic Movement Disorders

accumbens, but which is a preferable target re-

choreiform movements of the orofacial muscu-

mains to be seen. Sustained benefit has been re-

lature, which constitutes at least half of all tar-

ported for up to 17 months. GTS patients

dive syndromes. Others are classified by the

represent a particular challenge with this pro-

movement disorder that dominates the clinical

cedure because of behavior issues and the na-

picture—tardive dystonia, tardive akathisia,

ture of the tics. There are no data to support

tardive tics, and tardive myoclonus. Although

the use of alternative medications or physical

all these variants occur and can be present at

therapy for GTS.

the same time, there are differences beyond

clinical phenomenology (including natural his-

When to Refer to a Neurologist

tory and pharmacology) and separation of

these syndromes is important from a practical

Tic disorders are often complex, especially

standpoint.

with the associated behavioral disorders, and

may represent diagnostic and therapeutic

Clinical Features

dilemmas. Simple tics are quite common, often

do not require treatment, and need not be re-

■ SPECIAL CLINICAL POINT: Tardive

ferred to a neurologist. If the movements are

dyskinesia occurs in approximately 20%

(0.5%-65%) of patients treated with first-

more severe and associated with behavioral

generation antipsychotic medications.

problems, patients should be referred to a neu-

rologist or psychiatrist for diagnostic clarifica-

The incidence of new cases of TD associated

tion and treatment.

with first-generation antipsychotics increases

5% per year. Approximately 10% to 20% of

Special Challenges for

patients can be severely disabled. Incidence

Hospitalized Patients

with the newer atypical (second-generation)

The hospital is a stressful place for patients.

antipsychotics is reported to be lower than

Stress can make tics worse, so physicians

with first-generation medications. Despite a

should anticipate an escalation. This is particu-

lower incidence, the prevalence of TD re-

larly pertinent to those who have had surgery.

mains the same or higher with atypical an-

Wound infection and tearing of sutures are not

tipsychotics. There are several factors that

unusual. Proper arrangements should be made

may explain this, such as the perceived safety

to avoid these problems.

of atypical antipsychotics that leads to in-

creased use in higher risk patients and off-

label use. All atypical antipsychotics with the

exception of clozapine have been implicated

TARDIVE DYSKINESIA

in causing TD.

Tardive Dyskinesia is an iatrogenic movement

TD is characterized by patterned, stereo-

disorder related to treatment with dopamine re-

typic orobuccolingual

(OBL) chewing-type

ceptor antagonists (neuroleptics and antiemet-

movements or dyskinesias. The tongue often

ics). The term “tardive” was coined to describe

has a writhing-type movement that can result

two features of the illness: (a) that it occurs after

in pushing out the cheeks (bonbon sign), but

chronic therapy with these drugs (arbitrarily

there also may be stereotypic repetitive pro-

3 months for patients younger than age 60 and

trusions

(flycatcher’s tongue). The move-

1 month for those older than 60) and (b) that

ments range in severity from extremely mild

the disorder is persistent. Relative persistence of

(the movements simply look like an exagger-

the dyskinesia is a characteristic feature.

ation of normal movements such as lip wet-

A number of clinical variants of TD exist. The

ting), in which the patients may be unaware

most common is characterized by stereotypic or

of the movements, to severe enough to cause

280

Chapter 13

■ Hyperkinetic Movement Disorders

dysarthria and dysphagia to the point of re-

treat TD is inappropriate and unwarranted.

quiring a feeding tube. On examination, the

The fact that many patients who develop this

tongue movements tend to decrease with pro-

syndrome have an irreversible problem is an in-

trusion. In addition, patients can have jaw

dication of the serious nature of this disorder.

dystonia or stereotypies

(opening, closing,

TD can occur in any patient chronically ex-

deviations), facial grimacing, blepharospasm,

posed to dopamine-blocking agents, including

cheek retraction and puffing, pouting, puck-

those who are neurologically and psychiatri-

ering, and lip smacking.

cally normal. Nevertheless, there are factors

Choreiform movements also may be present

that seem to increase a patient’s risk for the de-

in limbs

(piano playing movements of the

velopment of this disorder.

fingers) and in the axial regions

(dancelike

■ SPECIAL CLINICAL POINT: Age is the most

movements). Involvement of intercostal and

consistent risk factor for tardive dyskinesia.

diaphragm musculature results in respiratory

dyskinesia. These patients have grunting, sigh-

After age 40, there is a dramatic rise in relative

ing, air gasping, and belching sounds, and they

risk. There appears to be a direct relationship

may become short of breath because of irregular

between age and severity, and an inverse corre-

breathing patterns. Respiratory dyskinesias usu-

lation between age and remission rate. Other

ally occur in conjunction with OBL and affect

possible patient-related risk factors include fe-

about 15% of patients with TD. Choreic move-

male gender, diagnosis of affective disorders,

ments can also include pelvic thrusting and

history of drug-induced parkinsonism, con-

twisting movements

(copulatory dyskinesia).

comitant use of anticholinergics, and presence

TD movements may be exacerbated by activat-

of diabetes mellitus. There are also a number of

ing tasks such as testing dexterity maneuvers

treatment-related risk factors, including the use

(finger or toe tapping, rapid alternating move-

of depot formulations of neuroleptics and

ments) and having patients walk and perform

duration of exposure to these drugs. Genetic

cognitive tasks. Anxiety and fatigue also increase

risk factors also have been the subject of study;

the movements.

TD is associated with mutations in the cy-

TD reaches maximal intensity fairly

tochrome P450 2D6 (CYP2D6) gene, a major

quickly, and in 50% of patients, the move-

drug-metabolizing enzyme.

ment disorder is persistent. The intensity of

TD varies depending on a number of factors

Pathophysiology

such as the age of the patient, the drug ad-

ministered, and the duration of exposure. In

Investigations have focused on alterations in

patients in whom the inciting agent is discon-

dopaminergic function as a possible mecha-

tinued, TD may disappear gradually, but this

nism for TD. It has been proposed that the

may take years (as long as 5 years).

chronic administration of neuroleptics results

in a chronic blockade of striatal dopamine re-

■ SPECIAL CLINICAL POINT: In some

ceptor sites and that this chronic blockade ulti-

patients with choreiform movements, the

mately induces alterations in the sensitivity and

continued administration of neuroleptics will

number of dopamine receptors. This hypothe-

result in progression.

sis is supported by the exacerbation of TD with

In these patients, isolated OBL dyskinesias may

dopaminergic medications, suppression of TD

spread to involve the axial, limb, or diaphrag-

with dopamine antagonists, and enhancement

matic musculature. Another example of pro-

of the movements with anticholinergics. In ad-

gression might be an increase in the severity

dition, a study of atypical antipsychotics has

and amplitude of the choreiform movements.

demonstrated that those with the lowest risk

For these reasons, the use of a neuroleptic to

for extrapyramidal side effects are atypical

281

Chapter 13

■ Hyperkinetic Movement Disorders

antipsychotics that do not chronically bind to

TD in which the symptoms and signs may be ir-

dopamine receptors. Clozapine and quetiapine

reversible. There are a series of simple steps

bind loosely to these receptors and are easily

that may help to limit the development of TD

dissociated by the presence of endogenous

in the general population.

dopamine. This phenomenon is referred to

First, the number of patients at risk should

as “loose binding” or “fast dissociation” and

be limited. This implies that standard neu-

equates to lower binding affinity. In the sim-

roleptics should be used to treat only appropri-

plest conceptual terms, TD has been proposed

ate illnesses such as schizophrenia, other forms

to be the result of chemical denervation super-

of psychosis, and GTS syndrome. These agents

sensitivity.

should not be used for minor episodes of anxi-

Although choreiform movements may begin

ety, restlessness, insomnia, minor psychiatric

when the neuroleptic is chronically adminis-

disturbances, or other off-label problems. With

tered without a change in dose, the most com-

antiemetics they should only be used for in-

mon clinical setting in which the movement

tractable nausea and for short durations of

disorder emerges is after the dose is lowered or

time. Metoclopramide is approved for gastro-

discontinued. This latter setting is in keeping

paresis and should not be used for nausea or

with the postulate of lowering the pharmaco-

acid reflux. The development of TD does not

logic blockade of the dopamine receptor and al-

depend on any preexistent brain damage or

lowing normal dopaminergic mechanisms to

psychiatric history, and patients who are nor-

resume their interaction with the already hyper-

mal psychiatrically can develop TD if exposed

sensitized receptor. Although there is much evi-

to neuroleptic agents.

dence in animal models to support this notion,

Other methods of decreasing the incidence

there have been inconsistencies. For this reason,

of TD would be to limit the dose and duration

examination of other neurotransmitter abnor-

of treatment with neuroleptics.

malities and mechanisms related to TD have

Finally, if an antipsychotic agent is needed,

been recommended, such as a decrease in GABA

the choice should be one with less risk of ex-

activity in the basal ganglia. Some studies have

trapyramidal side effects—atypical agents.

indicated that an overactivity of norepinephrine

These include olanzapine, quetiapine, aripipra-

is present and that decreased activity of

zole, and clozapine. Although data suggest a

serotonin (both of which modulate dopamine

lower incidence of extrapyramidal side effects

transmission) and increased glutamatergic

with these drugs, it should be remembered that

transmission also may occur. Finally, there has

it is not zero.

been some suggestion that a decrease in acetyl-

All of these recommendations are common-

choline activity in the striatum might play a role.

sense approaches and seem realistic, although

Another possible pathophysiologic mecha-

there is little information in the literature to

nism for TD is direct neurotoxicity of neuroleptic

confirm these concepts. It is always wise to

medications. It has been theorized that the block-

limit the dose of a pharmacologic agent to the

ade of dopamine receptors results in an increase

symptoms being treated or controlled. Neu-

in dopamine turnover. This, in turn, results in the

roleptic administration is no exception, and the

formation of increased free oxyradicals that ulti-

dose of neuroleptic administered should be tai-

mately damage striatal neurons. Neuroleptics

lored to each patient. This is also true for the

also may be toxic to mitochondrial complex I.

atypical agents.

When neuroleptics are withdrawn from pa-

tients with relapsing psychosis, the relapse rate

Prevention

is significant. However, an initial episode of

As in all iatrogenic disorders, prevention is bet-

psychotic behavior does not necessitate chronic

ter than treatment. This is especially true for

lifelong administration of neuroleptics.

282

Chapter 13

■ Hyperkinetic Movement Disorders

■ SPECIAL CLINICAL POINT: Avoid the

are contraindicated. Serious adverse effects are

concomitant administration of anticholinergic

associated with this medication. The most im-

and neuroleptic medication, particularly on a

portant is agranulocytosis. For this reason, a

chronic basis.

weekly white blood count is required for pa-

tients taking this drug for the first 6 months,

The problem of chronic administration of

and then blood counts are required every other

neuroleptics and anticholinergics concomi-

week.

tantly is that there is some retrospective clini-

Other atypical antipsychotics used to treat

cal evidence that patients who take both have

psychosis include risperidone, olanzapine, que-

a slightly greater risk for the development of

tiapine, ziprasidone, and aripiprazole. All have

TD than those taking neuroleptics alone. The

a higher risk for TD than clozapine.

only reason for the concomitant use of

anticholinergics and neuroleptics is to treat or

prevent drug-induced parkinsonism. The

Treatment

drugs should be used symptomatically, not

preventatively and prudently. If drug-induced

The management of the patient with TD is

parkinsonism has resolved, there is no point

difficult. Medical therapies are frequently

in administering a pharmacologic agent that is

inadequate. In particular, the longer TD is

no longer indicated.

present, the less likely it is to respond. The first

Another step to limit the development of

approach to these patients should be careful re-

TD is early recognition of the syndrome and

view of whether the neuroleptics (or antiemet-

discontinuation of neuroleptics, if psychiatri-

ics) that have been or are being administered

cally possible. The continued administration of

are psychiatrically (or otherwise) indicated. In

neuroleptics in the face of developing TD may

many instances, there is no indication for the

result in progression and permanence of the

use of these drugs. If this is true, these

syndrome.

dopamine receptor-blocking agents should be

tapered.

■ SPECIAL CLINICAL POINT: The best

In many patients, the movement disorder

chance of halting progression and reversing TD

initially becomes worse when the drugs are

resides in early detection of abnormal

discontinued. This should not be surprising

movements.

because if TD is related to increased dopamine

Patients should be routinely monitored for

receptor site sensitivity secondary to chronic

emergence of abnormal movements. A final ap-

dopamine antagonist blockade, and if the pa-

proach to prevention relates to the use of an-

tient is already having involuntary movements

tipsychotic agents that are associated with a

(indicating dopamine receptor site sensitivity

lower risk of TD—atypical antipsychotics.

alteration is present) while on the neuro-

Clozapine does not appear to cause D₂

leptics, and the drug is discontinued with

dopamine receptor supersensitivity and causes

abolition of the blockade, the abnormally hy-

significantly fewer chewing-type movements

persensitive dopamine receptor would be ex-

than standard neuroleptics in animal models.

posed to normal dopaminergic physiology.

Clinical trials demonstrated that this drug is

This is expected to result in increased involun-

much less likely to cause TD. There has not

tary movements. This time period is often dif-

been a case of de novo TD in a patient treated

ficult to manage.

with clozapine. Clozapine is not used as first-

line therapy despite its unique and potent an-

■ SPECIAL CLINICAL POINT: Worsening of

tipsychotic properties. It has been approved for

symptoms with discontinuation of neuroleptic

use in patients who have unresponsive psy-

medication should not be confused with

chosis and in cases where typical neuroleptics

worsening of the disease process itself. This

283

Chapter 13

■ Hyperkinetic Movement Disorders

rebound of tardive dyskinesia on withdrawal of

effect. Variability of response may relate to the

neuroleptic medication may persist for only 2

heterogeneity of TD. However, considerable

to 6 weeks.

caution must be taken when interpreting

At the end of this period, assessment of the

results of the literature because of method-

extent of the baseline disorder is possible. TD

ologic limitations. Studies were open-label

has been reported to be irreversible in 30% to

treatment protocols with inadequate controls.

50% of cases, depending on the age of the pa-

Properly controlled double-blind studies will

tient and other factors. Pharmacologic inter-

be necessary before definitive conclusions can

vention in this choreiform movement disorder

be made. Still, the use of clozapine is strongly

is based on pathophysiologic mechanisms that

recommended as treatment of choice in psy-

indicate that agents that decrease dopaminer-

chotic patients with TD, with discontinuation

gic activity within the brain will decrease

of all standard neuroleptics. The recommended

chorea. Consequently, agents such as reser-

dose ranges from 100 to 900 mg/day, and the

pine or tetrabenazine, which deplete the brain

side effects most commonly seen include sialor-

of dopamine, will ameliorate this movement

rhea, orthostatic hypotension, weight gain, and

disorder. Doses of reserpine (1 to 5 mg/day)

seizures.

and tetrabenazine

(25 to

200 mg/day) are

Dopamine agonists, such as levodopa or

reached with a gradually increasing dose

bromocriptine, have been tried based on the

schedule.

hypothesis that they would “downregulate”

Side effects of these agents include orthosta-

dopaminergic hypersensitivity. Studies have

tic hypotension, parkinsonism, depression,

shown variable results with these agents, and

and gastrointestinal problems. Tetrabenazine

they should not be used. Other pharmaco-

differs from reserpine because it is shorter act-

logic approaches to the treatment of TD are

ing and causes fewer side effects, particularly

based on manipulation of other neurotrans-

orthostatic hypotension and depression.

mitter systems that may be abnormal in TD.

Other drugs that interfere with dopamin-

Increasing cholinergic activity may decrease

ergic activity include neuroleptics. Despite

chorea. The use of a variety of GABA-agonist

the fact that if the neuroleptic dose is raised

medications including valproate, diazepam,

the chorea of TD can be ameliorated, this is

clonazepam, and baclofen has been disap-

an incorrect approach because it will place

pointing, but some patients respond. Nora-

the treating physician in a position of using

drenergic antagonists such as propranolol

the etiologic agent to treat the disorder. The

and clonidine have also been occasionally

movements are simply masked. The only

successful. These drugs are safe and reason-

time that neuroleptics would be appropriate

able choices in the treatment of TD. Gluta-

to treat TD is if it is life threatening, and this

matergic agents such as amantadine may be

is very rare.

helpful in controlling movements. Facial and

Atypical antipsychotics may also have a

neck tardive dystonia may be amenable to in-

therapeutic benefit. Clinical trials evaluating

tramuscular BoNT injections.

the effectiveness of clozapine in psychosis not

Vitamin E, an antioxidant, has a very

only suggested that the drug is less likely to

mixed record in improving TD symptoms. In

cause TD, but also indicated that there may be

addition, retrospective epidemiological study

a therapeutic potential in treating TD. Numer-

suggested that Vitamin E (over 400 IU/day)

ous single case reports and larger studies have

may result in increased mortality. This has

addressed the therapeutic usefulness of clozap-

led to limited use. The roles of physical, oc-

ine in TD.

cupational, and speech therapy are varied de-

Some patients appear to have improvement

pending on patient needs, but they can be

of TD with clozapine, indicating a therapeutic

helpful.

284

Chapter 13

■ Hyperkinetic Movement Disorders

When to Refer to a Neurologist

QUESTIONS AND DISCUSSION

TD is often complex clinically and may present

diagnostic and therapeutic dilemmas. Patients

1. Match the neurologic term with the

with TD should be referred to a movement

appropriate description:

disorder specialist for diagnostic clarification

A. Tremor

1. Excessive, spontaneous

and treatment. In mild cases medication can be

movements irregularly

withdrawn and the patient observed, but in

timed, nonrepetitive,

those in whom the symptoms are troublesome,

randomly distributed, and

referral is recommended.

“dancelike”

B. Chorea

2. An abnormal sustained

posture

Special Challenges for

C. Dystonia 3. Involuntary, rhythmic,

Hospitalized Patients

oscillating movement

Because the movements can be bizarre in ap-

resulting from alternating

pearance and influenced by stress and anxiety,

or synchronous contraction

staff education is required so that they under-

of reciprocally innervated

stand that this is a neurologic disorder.

antagonist muscles

D. Tic

4. Patterned sequence of

coordinated movements

that may be simple or

complex

Always Remember

The correct matches are A and 3, B and 1,

C and 2, D and 4.

• In patients with young-onset dystonia, rule

out Wilson disease and consider a trial of

2. A patient presents with sustained

levodopa.

involuntary eye closure and forced

• When evaluating patients with possible

involuntary mouth opening. Which

essential tremor, it is crucial to differentiate

diagnosis is correct?

alternate etiologies, since this may change

A. Meige syndrome

your treatment approach.

B. Parkinson disease

• Treatment of chorea in patients with

C. Gilles de la Tourette syndrome

Huntington disease does not always result in

D. Essential tremor

functional improvement and should be

The correct answer is A. The description is

reserved for selected patients.

that of Meige syndrome. Parkinson disease,

• A high index of suspicion for Wilson disease

ET, and GTS do not present with dystonic

should be present when evaluating patients

facial movements.

under the age of 40 with a neuropsychiatric

3. A 19-year-old patient complains of the

presentation.

recent onset of shaking, which occurs when

• Treatment in Gilles de la Tourette syndrome

he lifts a cup to drink or tries to retrieve

should be individualized to target only the

food with a fork. When his index fingers

most disabling symptoms, which may or may

are approximated, the tremor worsens. His

not be the tics themselves.

mother has a similar problem. This

• Limit the dose, duration, and overall use of

description suggests

neuroleptics in order to avoid potentially

A. Essential tremor

irreversible side effects.

B. Huntington disease

285

Chapter 13

■ Hyperkinetic Movement Disorders

C. Wilson disease

6. Which of the following is not inherited in

D. Parkinson disease

an autosomal dominant fashion?

A. Primary childhood-onset (Oppenheim)

The correct answer is A. The description is of a

dystonia

postural and kinetic tremor. This is the most

B. Huntington disease

common presentation of ET. ET can be familial

C. Essential tremor

or sporadic and frequently occurs in adolescence

D. Wilson disease

or early adult life. The fact that her mother has

a similar tremor suggests the diagnosis.

The correct answer is D. Wilson disease is in-

herited as an autosomal recessive disorder.

4. Which drug is most effective in reducing

essential tremor?

7. Botulinum toxin is used in therapy for

A. Levadopa

which of the following?

B. Ropinirole

A. Spasmodic torticollis

C. Amphetamine

B. Muscle weakness

D. Propranolol

C. Paresthesias

E. Rasagiline

D. Myoclonus

The correct answer is D. Amphetamines may

The correct answer is A. Botulinum toxin

induce a postural kinetic tremor. Levodopa,

therapy is accepted as safe and effective for

ropinirole, and rasagiline all affect the

the treatment of spasmodic torticollis.

dopaminergic system and are used to treat PD.

Propranolol, a beta-blocker, is very useful in

SUGGESTED READING

treating ET.

Bressman SB. Genetics of dystonia: an overview. Parkin-

5. A patient presents with a generalized

sonism Relat Disord. 2007;13:S347-S355.

choreiform disorder that began at the age

Factor SA, Lang AE, Weiner WJ. Drug-Induced Move-

of 45 years. He denies any neurologic or

ment Disorders. 2nd ed. New York, NY: Blackwell

Futura; 2005.

psychiatric problems before the onset of his

current problem and never received

Gasser T, Bressman S, Durr A, et al. Molecular diagnosis

of inherited movement disorders: Movement Disor-

neuroleptic medications. He denies a family

ders Society Task Force on Molecular Diagnosis. Mov

history of any similar movement disorder,

Disord. 2003;18:3-18.

but his mother was institutionalized at the

Louis ED. Essential tremor. N Engl J Med. 2001;345:

age of 55 for psychiatric reasons. What is

887-891.

this patient’s probable diagnosis?

Lyons KE, Pahwa R. Deep brain stimulation and tremor.

A. Huntington disease

Neurotherapeutics. 2008;5:331-338.

B. Parkinson disease

Ondo WD, Jankovic J, Connor GS, et al. Topiramate in

C. Essential tremor

essential tremor, a double-blind, placebo-controlled

D. Primary dystonia

trial. Neurology. 2006;66:672-677.

Ostrem JL, Starr PA. Treatment of dystonia with deep

The correct answer is A. Huntington disease is

brain stimulation. NeuroRx. 2008;5:320-330.

an autosomal dominant disorder with onset

Pffeifer RF. Wilson’s disease. Semin Neurol. 2007;27:

typically in the middle age. Although psychi-

123-132.

atric symptoms are insufficient for making a

Quartarone A, Rizzo V, Morgante F. Clinical features of

diagnosis of Huntington disease, a family his-

dystonia: a pathophysiological revisitation. Current

tory of a parent with psychiatric disease in a

Opinion in Neurology. 2008;21:484-490.

patient with a choreiform disorder may be

Rezai AR, Machado AG, Deogaonkar M, et al. Surgery for

very suggestive. The diagnosis can be con-

movement disorders. Neurosurgery. 2008;62(suppl 2):

firmed with genetic testing.

809-838.

Alzheimer

Disease and

Other Dementias

NEELUM T. AGGARWAL AND RAJ C. SHAH

key points

• Dementia is a common age-related condition with a

prevalence of about 5% in persons over age 65 years

and up to 50% in persons over the age of 85 years.

• Alzheimer disease is the most frequent type of

dementia in the United States and Europe, comprising

approximately 60 to 80 percent of persons who

present with dementing disorders. Other forms of

dementia, such as Lewy Body disease, frontotemporal

dementia, and vascular dementia, also are increasingly

being recognized.

• Facing increasing numbers of older patients with

cognitive symptoms, primary care physicians need to

have a practical approach for recognizing and managing

Alzheimer’s disease and other dementias.

• The goal of this chapter is to present a framework

diagnosing individuals with cognitive concerns and

developing a tailored care plan.

progressive dementia that he ascribed to the ac-

OVERVIEW

cumulation of senile plaques and tangles found

Dementia (or chronic loss of cognitive func-

on postmortem examination. Based on his case

tion) associated with old age was recognized in

study, the term “Alzheimer disease” (AD) re-

antiquity. For most of history, dementia of

ferred to a relatively uncommon progressive

older persons was attributed to the effects of

dementia in middle-aged persons. However,

aging or to the effects of cerebral artherosclero-

over the past 30 years, it has become apparent

sis (hardening of the arteries). In the early 20th

that most of the older people with dementia

century, Dr Alois Alzheimer presented the

have the same condition described by Alzheimer

clinical history of a 54-year-old woman with a

almost 100 years ago.

287

288

Chapter 14

n Alzheimer Disease and Other Dementias

Only a small proportion of people with de-

n SPECIAL CLINICAL POINT: In persons with

mentia are managed in specialized dementia cen-

MCI, the mini-mental status examination

(MMSE) scores often will appear normal (scores

ters. Because physicians often do not look for or

of 26 to 28). Yet, on neuropsychological

recognize the signs of dementia, many people

examination, persons will show impairment on

with dementia remain undiagnosed. Timely di-

tests of verbal and nonverbal delayed recall, a

agnosis allows for the person with dementia to

finding that is often seen in early AD.

be a part of important care decision-making

processes. It also permits early pharmacologic

As characterization of MCI continues, research

and nonpharmacologic intervention. Finally, it

now has focused on identifying potential risk

can prevent medical emergencies resulting from

factors for the development of dementia and

behavioral disturbances and other superimposed

AD in those with MCI. Recent data suggest

medical problems. Therefore, increased aware-

that persons who have been diagnosed with

ness of dementia offers neurologists and nonneu-

MCI are likely to be at an increased risk of de-

rologists an opportunity to improve the lives of

veloping AD and of cognitive decline. Further,

patients with dementia and their caregivers.

they frequently have the pathology of AD, sug-

gesting that MCI represents preclinical AD in

n SPECIAL CLINICAL POINT: Up to two

many cases. The apolipoprotein e4 allele has

thirds of older people with dementia are not

been associated with the development of AD

detected.

among persons with MCI in multiple studies,

and some small samples have shown that ele-

vated levels of tau in the cerebrospinal fluid

NORMAL AGING AND MILD

may have the potential to predict the develop-

COGNITIVE IMPAIRMENT

ment of AD in MCI patients.

Physicians often are faced with the dilemma of

n SPECIAL CLINICAL POINT: The rates of

trying to determine the importance of com-

progression of MCI to AD are highly variable

plaints such as “senior moments” or “forgetful-

depending on the study; however, it is in the

ness” voiced by their patients. In individuals

10% to 15% per year range.

who ultimately develop dementia and AD, one

can presume that there is a gradual progression

of an underlying process, which begins with

DEMENTIA

“normal aging,” that can culminate into patho-

logically proven AD. Between the state of nor-

Dementia refers to acquired intellectual dete-

mal cognition and mild dementia is a zone

rioration in an adult. Evaluating a person for

often referred to as “mild cognitive impairment”

dementia involves determining whether there

(MCI). In the past, this zone has been referred

has been a loss of cognition relative to a pre-

to as “benign senescent forgetfulness,” “age-

vious level of performance. The clinical eval-

associated memory impairment,” or “cognitive

uation for assessing memory complaints has

impairment no dementia.” In recent years, MCI

four objectives: (a) to determine if the person

has been increasingly used to describe individu-

has dementia; (b) if dementia is present, to

als who typically have mild memory impair-

determine whether its presentation and

ment noted on neuropsychological testing, with

course are consistent with AD; (c) to assess

general cognitive functioning that is otherwise

evidence for any alternate diagnoses, espe-

normal for age and normal activities of daily

cially if the presentation and course are atyp-

living. The clinical evaluation for subjects with

ical for AD; and (d) to evaluate evidence of

suspected MCI is virtually identical to that for

other, coexisting, diseases that may con-

clinical AD, but may involve more detailed neu-

tribute to the dementia, especially conditions

ropsychological testing.

that might respond to treatment. The section

289

Chapter 14

n Alzheimer Disease and Other Dementias

titled

“Differential Diagnosis of Primary

interfere with an individual’s usual occupa-

Neurodegenerative Dementias” will provide

tional or social activities and the cognitive

details on important features in the patient’s

deficit cannot be present in the setting of an

history, key physical examination findings,

altered sensorium such as in delirium or an

and ancillary tests to conduct on an individ-

acute confusional state.

ual with memory concerns. An algorithm

highlighting three decision point questions

Differential Diagnosis for Conditions

for clinically triaging a person with memory

Presenting with Cognitive Impairment

concerns is shown in Figure 14.1.

Typically, evidence is obtained through the

The differential diagnosis of dementia should

clinical history from a knowledgeable in-

emphasize common potentially treatable dis-

formant (a family member or close friend)

orders that may cause or exacerbate cognitive

and should be documented by mental status

impairment, which occur in the elderly. Re-

testing. When the clinical history is not avail-

versible conditions including delirium, depres-

able, test results from a single evaluation can

sion, structural conditions, and toxic or

be contrasted with the estimated premorbid

metabolic disorders, often are cited as potential

level of ability based on the patient’s educa-

causes of cognitive impairment. A thorough

tion and occupation. In some cases, formal

evaluation of each condition is justified for per-

neuropsychologic performance testing on

sons suspected of having dementia. If one of

two or more occasions over a period of 12 or

the conditions described below is identified as

more months may be necessary to document

a potential cause of the cognitive impairment,

cognitive decline. For clinical purposes, loss

appropriate treatment should be started. How-

of cognition should be sufficiently severe to

ever, it is important to re-evaluate an individual

An Approach to the Individual with Memory Concerns

I have a chronic cognition problem?

Yes

“Normal” Cognition

Does this individual

vs. Acute Conditions

have a dementia?

Yes

Does this individual

MCI

have AD?

Yes

Other Dementias

FIGURE 14.1 An algorithm for clinically triaging a person with memory concerns. MCI, mild

cognitive impairment. AD, Alzheimer disease.

290

Chapter 14

n Alzheimer Disease and Other Dementias

after treatment is completed to determine if

a personality change and/or intellectual de-

cognitive difficulties have resolved. If resolu-

cline. Subtle focal findings usually can be

tion is not achieved fully, an underlying pri-

demonstrated on the neurologic examination,

mary neurodegenerative cause for cognitive

but they occasionally are lacking. Similar com-

decline may also be present.

ments may be applied to subdural hematomas,

especially in the geriatric age group. Thus,

Delirium Delirium differs from dementia by

some type of neuroimaging procedure remains

the onset and duration of cognitive impairment

warranted for all patients being evaluated for

and by the level of consciousness. The onset of

dementia.

cognitive impairment in delirium typically is

No other syndrome causing dementia has

hours to days, and it lasts days to weeks. In ad-

generated such intense interest (and frustration)

dition, individuals often are either hyperalert

among neurologists as normal pressure hydro-

or hypo-alert. However, in older persons, al-

cephalus (NPH). The classic syndrome consists

tered consciousness may be less evident. A

of gait disturbance, dementia, and inconti-

delirium may be the initial manifestation of an

nence. However, this triad is also seen com-

underlying, unrecognized dementia. Thus, data

monly in AD and other degenerative dementias.

suggest that delirium in the elderly may take

many months to resolve or may not resolve at

n SPECIAL CLINICAL POINT: NPH typically

presents first as a gait disorder, and over time

all. The occurrence of delirium in the hospital-

cognitive impairment and urinary incontinence

ized elderly has been associated with excess

can occur.

mortality.

The onset can progress over months or years.

Depression Loss of interest in hobbies and

The dementia is mild, often

“subcortical”

community activities, apathy, weight loss, and

with slowing of thought and relative preser-

sleep disorders may be interpreted by the fam-

vation of “cortical” features such as naming

ily as depression, although they actually may

and language skills. Often there is no pro-

be the result of the dementia itself. Among the

found short-term

(or episodic) memory

elderly, depression and dementia coexist and

deficit that distinguishes this dementia from

do not always present as two distinct entities.

AD. Brain scans typically demonstrate hydro-

Although it is useful to ask the caregiver

cephalus with enlargement of ventricles out of

about symptoms suggesting dysphoric mood

proportion to sulci enlargement. Numerous

such as crying, complaining, and depression

studies have attempted to determine predictors

in the elderly may present with agitation or

of improvement following ventricular shunt-

increased irritability. Depression may con-

ing, without much success. Perhaps the most

tribute to impairment of activities of daily liv-

useful piece of clinical information is the his-

ing and rarely to the cognitive deficits. If

tory of a reason for hydrocephalus (such as

impairment in activities of daily living exceeds

meningitis or subarachnoid hemorrhage from

what is expected for the severity of cognitive

either a ruptured aneurysm or, more com-

dysfunction, the possibility of a coexisting de-

monly, a previous traumatic head injury).

pression should be considered.

Some patients with gait problems or dementia

improve with cerebrospinal fluid shunting pro-

Structural Conditions Brain tumors rarely

cedures; however, the insertion of a shunt is not

present with a degenerative dementia. When

a benign procedure, especially in geriatric pa-

they do, there usually are other major focal

tients. Although the diagnosis of NPH rarely, if

findings and signs of increased intracranial

ever, can be made with complete confidence, an

pressure. Although rare, brain tumors in the

etiology for the hydrocephalus should be

“silent” areas of the brain may present only as

sought prior to recommending shunting.

291

Chapter 14

n Alzheimer Disease and Other Dementias

Toxic or Metabolic Disorders Drug toxicity is a

precipitated by administration of carbohydrates

common reversible cause of delirium in the eld-

to patients with marginal thiamine stores.

erly. Older persons may be more susceptible

Cognitive impairment is among the most

than younger persons to drug side effects on

common neurologic manifestations of acquired

cognition. This is the result of many factors, in-

immunodeficiency syndrome (AIDS) and may

cluding altered drug kinetics and use of multi-

precede the development of other signs of in-

ple medications in older persons with several

fection with the human immunodeficiency

illnesses or complaints (polypharmacy). Clini-

virus (HIV). Persons with AIDS dementia com-

cians also should be alert to the possibility of

plex present with forgetfulness and poor atten-

drug side effects further impairing cognition in

tion, generally over several months with the

persons with preexisting cognitive impairment.

memory impairment significantly less striking

A typical presentation is the rapid worsening of

than that seen in AD. Chronic meningitis, espe-

dementia following the administration of a

cially cryptococcal meningitis, also can present

new drug (or following the reinstitution of a

as dementia, although there are almost always

previous medication that the patient has not

other associated signs and symptoms. The

taken for some time), with or without altered

same can be said for neurosyphilis. Brain ab-

level of consciousness.

scesses, like brain tumors, can present solely

with dementia, although focal findings are usu-

n SPECIAL CLINICAL POINT: Psychotropic

ally present.

(including neuroleptic), sedative-hypnotic,

anticholinergic, and antihistaminic medications

are common agents associated with cognitive

Differential Diagnosis of Primary

impairment.

Neurodegenerative Dementias

Hypothyroidism has been recognized for

Once the conditions presenting with cognitive

many years as being associated with altered

impairment have been ruled out, the clinician

mental state, although it is currently quite rare

then must determine the underlying nature of

in the United States. Similar cases are seen with

the dementia. It is at this time, referrals some-

disorders of calcium metabolism, especially

times are made to a neurologist, as diagnosing

hypercalcemia, and also with an electrolyte im-

of the exact neurodegenerative cause of a de-

balance. Chronic liver and renal diseases fre-

mentia may be problematic.

quently are associated with an altered mental

Generally speaking, if an elderly person

state; however, it is unusual for these diseases

presents with a gradual progression of a mem-

to be present without prominent manifestations

ory disorder, which is now advanced to involve

of the primary illnesses. Finally, Korsakoff syn-

other nonmemory cognitive domains and these

drome, a result of thiamine deficiency, also can

changes have affected daily functioning, AD is

present with an amnestic syndrome mimicking

the most likely diagnosis. Vascular dementia

a dementia. It classically develops in the wake

(VaD) can involve abrupt changes in cognition

of an acute Wernicke encephalopathy with

if large vessels are affected, or can be present

confusion, ophthalmoplegia, and ataxia. How-

insidiously if subcortical ischemia is responsi-

ever, many patients with Korsakoff syndrome

ble for the change in function. In subjects with

do not present with a Wernicke encephalopa-

parkinsonism, hallucinations, and wide fluctu-

thy. Although alcoholism is the most frequent

ations in behavior, dementia with Lewy bodies

setting for this syndrome in developed coun-

(DLB) might be more likely than AD. Alterna-

tries, it also may be associated with other

tively, if the initial presentation is one of the

conditions leading to nutritional deficiency, in-

changes in personality or behavior instead of

cluding starvation, malnutrition, protracted

memory, a frontotemporal dementia

(FTD)

vomiting, and gastric resection. It also can be

should be considered. Finally, if the time course

292

Chapter 14

n Alzheimer Disease and Other Dementias

of the dementia is relatively rapid over months

risk of developing AD, and the risk is even

and the clinical features include psychiatric

higher among those homozygous for the allele.

symptoms and motor function abnormalities, a

By contrast, the apolipoprotein E e2 allele ap-

prion disorder such as Creutzfeld-Jakob dis-

pears to lower risk of the disease. The mecha-

ease (CJD) should be considered.

nism whereby this allele causes the disease is

unknown, but recent data suggest that it in-

Alzheimer Disease In 2000, it was estimated

creases the deposition of AD pathology.

that there were approximately 4.5 million indi-

n SPECIAL CLINICAL POINT: Familial

viduals with AD in the United States and this

autosomal dominant cases comprise 5% to

number has been projected to increase to

10% of all the cases with AD.

14 million by 2050. Prevalence estimates sug-

gest that AD affects about 10% of persons over

Clinical Symptoms

the age of 65, making it one of the most com-

mon chronic diseases of the elderly. The occur-

n SPECIAL CLINICAL POINT: The most

rence of AD is strongly related to age, with the

common initial sign of AD is difficulty with

incidence doubling every 5 years after the age

episodic memory (the ability to learn new

information). Old memories are often accurate

of 65.

and intact until the mid to later stages of

n SPECIAL CLINICAL POINT: From the

the disease.

ages 65 to 85, the prevalence of AD doubles

The clinical history should focus on the tempo-

approximately every 5 years.

ral relationship between the loss of different

Other than age, there are few well-documented

cognitive abilities and the development of be-

risk factors for AD. There is some evidence

havioral disturbances and impairment of motor

that women may be more likely to develop the

abilities. At the onset, this disease may be almost

disease than men. However, this observation

imperceptible, but it typically will progress to

appears to be attributed, in large part, to the

become a more serious problem in a few years’

fact that women live longer than men. Years of

time. The family will report that the patient fre-

formal education have been associated with a

quently repeats himself or herself. He or she

reduced risk of disease in many, although not

leaves important tasks undone, such as bills un-

all studies. The mechanism linking education

paid and appointments not kept. After the mem-

to risk of disease is unclear, but recent evidence

ory disorder becomes apparent, the family will

suggests that participation in cognitively stimu-

notice other disorders of cognition. Confusion

lating activities also reduces the risk of disease.

in following directions also can be a common

The first-degree relative appears to have a

earlier symptom. If the person is driving a car, he

slightly greater risk of inheriting disease. In

or she may get lost or “turned around” (an

rare families, however, AD is inherited as an

event that frequently precipitates the first evalu-

autosomal dominant disease in which half of

ation by a physician), have an increase in minor

the family members are affected. In these fami-

“fender benders,” or use poor judgment while

lies, the disease has been linked to mutations

driving. Frightening lapses of memory, such as

on one of three different chromosomes: 21, 14,

leaving on a gas stove, also may occur.

and 1 and often age of onset is very young

As the disease progresses, the person may have

(<65 years). The majority of cases of AD are

difficulty in remembering simple words or names

“late onset” and in some of these cases, chro-

and may be unable to participate in normal con-

mosome 19 has been implicated. Chromosome

versation. Often family members comment that

19 is thought to code for the apolipoprotein E

the individual has become a “listener” instead of

alleles. The presence of one apolipoprotein E e4

actively participating in conversations. Read-

allele approximately doubles an individual’s

ing and writing also will be impaired, as will

293

Chapter 14

n Alzheimer Disease and Other Dementias

simple activities of daily living, such as bathing

ranges of measures are available for this pur-

and dressing.

pose. Several brief measures (e.g., the MMSE

Agitation, hallucination, delusions, and

and the blessed orientation, memory concen-

even violent outbursts may be seen at any time

tration test) are suitable for use at the bedside

during the course of the illness. Previous per-

or in the physician’s office. Although they may

sonality traits may be exaggerated or may be

help distinguish persons with dementia from

obscured completely by new behavior patterns.

persons without dementia, they are less effec-

Changes in sleep-wake patterns also may dis-

tive in distinguishing AD from other demen-

rupt normal living patterns. These types of

tias. In these cases, full neuropsychological

symptoms are particularly difficult for the fam-

testing is recommended.

ily and place a great burden on the caregiver.

In the office or hospital, routine mental sta-

Parkinsonian signs such as unsteady gait and

tus testing should include checking the per-

slowed movements are common.

son’s orientation by asking for his or her full

name, the day of the week, the day of the

n SPECIAL CLINICAL POINT: A general

month, the month and the year, where he or

physical decline is not seen until the latest stages

she is, and also his or her age and date of birth.

of the illness. If decline occurs rapidly, which is

Show the individual four or five objects and

associated with a change in gait, parkinsonian

then ask him or her to name them twice (e.g.,

signs, or weakness, other dementing illnesses

a coin, a safety pin, keys, and a comb). Tell the

need to be considered (Fig. 14.1).

person that you will ask him or her to recall

Incontinence may be seen at any time and ini-

the objects in a few minutes. Then check the

tially may reflect the patient’s inability to find

individual’s knowledge of common events by

the bathroom. As the illness progresses, there

asking for the names of well-known public fig-

seems to be a true loss of bladder control and,

ures (e.g., the president, governor, or mayor).

ultimately, a loss of bowel function. Inability to

Ask the person to repeat some numbers (the

walk is also a common occurrence seen at the

typical patient can remember six numbers for-

late stages of the illness. Seizures and an inabil-

ward and three or four backward) and then

ity or unwillingness to eat also may occur in

have him or her do some simple calculations

the later stages of AD.

(e.g., multiplication, addition, and serial sev-

The typical history in AD is a gradually pro-

ens). Have the individual to repeat a simple

gressive dementia over several years. The aver-

phrase, to follow a two-step direction (e.g.,

age patient with AD survives about a decade

point to the ceiling, then point to the floor),

from the time of diagnosis, although the varia-

and to do something with his right hand and

tion may be from a few years to 20 years.

then his left hand (e.g., make a fist with your

There may be plateau periods during which

left hand, followed by salute with your right

deterioration is not obvious; however, a

hand). Ask the individual to write his or her

lengthy plateau would be unusual. There is no

name, to write a brief phrase to dictation (e.g.,

clear evidence that the age of onset determines

today is Monday), and then to draw some-

the natural history. However, younger patients

thing (usually a clock). Also, ask the person to

generally tend to have more speech disorders as

read a simple phrase. Finally, have the patient

the illness progresses. Older patients are more

recall the four or five objects that you showed

prone to age-related medical problems associ-

him or her previously. This mental status test

ated with morbidity and mortality.

can be administered in a few minutes and

should be part of the routine clinical evaluation

Neurologic Examination Formal, standard-

of all older persons. Recommended education-

ized assessment of cognition is required to

adjusted cutoffs have been developed for the

make a diagnosis of dementia and AD. Wide

MMSE and the results can serve as guidelines

294

Chapter 14

n Alzheimer Disease and Other Dementias

to direct further evaluation, and also provide

TABLE 14.1

valuable screening information.

Laboratory Aids in the Differential

Diagnosis of Dementia

n SPECIAL CLINICAL POINT: To make a

diagnosis of dementia, a deficit should exist in

Routine Tests

Optional Tests

more than one area of cognition. Patients with

early AD may have profound memory problems

Chemistry panel

Sedimentation rate

with only mild deficits in other aspects of

Complete blood count

Electrocardiogram

cognition. As the disease progresses, however,

Thyroid function studies

Urinalysis

language and other aspects of cognitive

Vitamin B₁₂ level

Chest x-ray

dysfunction typically become more obvious.

Syphilis serology

Drug levels

CT/MRI of the head

Twenty-four hour urine

The most important function of the neurologic

for heavy metal

examination in evaluating persons with de-

Electroencephalogram

mentia is in diagnosing conditions other than

Cerebrospinal fluid (LP)

AD. The general physical examination and

PET/SPECT

neurologic examination (excluding the mental

HIV testing

status testing) is usually normal in AD. Minor

parkinsonian features, myoclonic jerks, frontal

lobe signs (grasp reflex, snout and glabellar

should be done to rule out a possible infectious

signs), and similar abnormalities occasionally

etiology for the cognitive impairment.

may be seen on examination, especially later in

Morphologic neuroimaging with magnetic

the course of the illness. However, these fea-

resonance imaging (MRI) or computed to-

tures noted in persons with mild memory prob-

mography (CT) is used to look for evidence

lems should alert the physician of a diagnosis

of another disease that can cause or con-

other than, or perhaps in addition to, AD. If a

tribute to cognitive impairment, such as a

person has parkinsonian signs, changes in gait

cerebral infarct or tumor. MRI is superior to

and tone suggestive of rigidity in addition to

CT because it is less subject to artifact, it pro-

memory complaints, the possibility of DLB ex-

vides greater contrast between gray and white

ists. If a person has limb weakness, a visual

matter, and coronal images can provide excel-

field cut, or asymmetric reflexes, one could

lent views of the mesial temporal lobe struc-

consider VaD or a mixed dementia (AD/VaD).

tures vital to mnemonic function. Over

Myoclonic jerks in addition to unsteady gait

the years there has been a strong research in-

could signify a rapidly progressive dementia

terest in using morphologic imaging (quanti-

such as CJD.

tative structural neuroimaging) as a direct

Ancillary Tests

diagnostic tool for AD. In particular, atrophy

of the medial temporal lobe structures, for

n SPECIAL CLINICAL POINT: Currently

example the hippocampus, has been found in

there is no reliable diagnostic test for AD.

patients with AD.

The purpose of laboratory testing is to identify

Another area of neuroimaging research has

other conditions that might cause or exacer-

centered around the detection of amyloid dep-

bate dementia and include a brain scan and

osition in the brain through the use of radioli-

blood tests (Table 14.1). The use of lumbar

gand for positron emission tomography (PET)

puncture in the routine evaluation of elderly

imaging studies of amyloid in the brain of liv-

patients for dementia or AD is not recom-

ing subjects. Similarly single photon emission

mended. However, if the clinical picture is as-

computed tomography (SPECT) and PET scan-

sociated with an acute change in mental status,

ning have shown promise in its ability to differ-

nuchal rigidity, or fever, a lumbar puncture

entiate among dementias. There is literature

295

Chapter 14

n Alzheimer Disease and Other Dementias

attesting to the utility of FDG-PET

(fluo-

hippocampal formation and neocortex in per-

rodeoxyglucose-positron emission tomography)

sons with AD. Tangles also accumulate in the

in differentiating AD from other dementias,

basal forebrain, the major source of cholinergic

specifically that of FTD and the Centers for

neurons that project to the hippocampal for-

Medicare and Medicaid Services have ap-

mation and neocortex. Plaques are composed

proved for reimbursement the use of FDG-PET

of a central extracellular proteinaceous amy-

for this purpose. In the clinical setting, these

loid core, surrounded by dystrophic axon ter-

tests are used to confirm an underlying suspi-

minals. Amyloid comes from a larger precursor

cion of an atypical dementia, to aid in the treat-

protein coded on chromosome 21. Processing

ment and management of the patient and to

of this protein by various secretases (alpha,

assist the family with long-term care issues.

beta, and gamma secretases) can result in either

However, it is probably better for a primary

the putative toxic fragment that is deposited in

care physician to arrange a patient consulta-

the brain or another smaller, benign fragment.

tion with a dementia specialist prior to order-

The major constituents of neurofibrillary

ing an FDG-PET scan.

tangles are paired helical filaments. Evidence

As noted earlier there appears to be a ge-

suggests that these tangles are composed of the

netic component to the development of AD.

microtubule associated protein tau, which is in

Genetic testing can be considered in young

an abnormal hyperphosphorylated state.

onset suspected familial AD. Often these types

of cases are referred to a neurologist and may

Vascular Dementia As alluded to earlier not all

be further referred to a specific AD research

cases of dementia are that of AD. VaD is often

center for more detailed investigation, in addi-

considered by some to be the second most com-

tion to appropriate genetic counseling. In the

mon cause of dementia in older persons ac-

more typical variety of late onset AD (onset oc-

counting from 10% to 20% of the dementia

curring after the age of 65 years), genetic test-

cases. VaD includes all dementia syndromes re-

ing for specific mutations is not useful.

sulting from ischemic, anoxic, or hypoxic brain

damage. Thus, it is not simply an AD-type de-

n SPECIAL CLINICAL POINT: The current

mentia caused by stroke but a constellation of

recommendations by the Academy of

cognitive syndromes that may or may not

Neurology suggest that APOE testing should

mimic AD. The most consistent risk factor for

not be done routinely in asymptomatic

VaD has been advanced age, with some studies

individuals.

suggesting that the prevalence of VaD is higher

Pathology Data suggest that the progressive

in Asians and African-Americans. Similar to

loss of memory and other cognitive abilities

AD, it appears that higher education is a pro-

from AD is a complex function of the accumu-

tective factor. Risk factors for VaD include hy-

lation of pathology (amyloid plaques and neu-

pertension, smoking hypercholesterolemia,

rofibrillary tangles) and neurochemical deficits

and diabetes.

(deterioration of cholinergic system), leading

The traditional teaching and description of

to a loss of neurons and synapses within selec-

VaD is that of a stepwise progression with

tively vulnerable neural systems. Grossly, there

abrupt stroke-like episodes causing abrupt de-

is atrophy and dilatation of the ventricles and

cline and then stabilization until the next

marked atrophy of the hippocampal forma-

stroke-like episode. In clinical practice, this is

tion. Microscopically, there are large numbers

not always readily seen, causing difficulty at

of neuritic plaques and neurofibrillary tangles.

times in making the diagnosis. In addition, be-

Although both of these lesions can be seen in

cause VaD is often combined with AD (mixed

the brains of older persons without dementia,

dementia) signs and symptoms may overlap

they are found in greater numbers in the

and clinical diagnosis may prove to be difficult.

296

Chapter 14

n Alzheimer Disease and Other Dementias

Although there is no typical neuropsycho-

Dementia with Lewy Bodies In some situations,

logic profile of persons with VaD (because the

the dementia and parkinsonian signs appear to

behavioral manifestations are dependent on

develop simultaneously. These cases often are

the vascular territory involved), the cognitive

referred to as having DLB, diffuse Lewy body

pattern in VaD tends to differ as compared to

disease, or the Lewy body variant of AD. These

patients with AD. Rather than the prominent

are all rather unfortunate terms because they

short-term memory loss

(episodic memory

implicate a specific pathology rather than a de-

loss) that is seen in persons with AD, those

mentia syndrome.

with VaD tend to have difficulties with tasks

DLB is considered by some to be the third

that focus on frontal executive dysfunction

most common neurodegenerative dementia

(such as motor planning). Because the MMSE

and tends to be under diagnosed. In some stud-

does not focus on executive dysfunction, it may

ies, DLB accounts for 15% to 20% of the hos-

not be the best screening test for the diagnosis.

pital autopsy cases and 35% of the dementia

One of the most important clinical signs

cases in population studies. As with AD, the in-

noted in VaD is a history or neurologic exami-

cidence of DLB appears to increase with age.

nation consistent with a focal neurologic event

There may be a slight increase in males; how-

such as a stroke. Ideally, the event should have

ever, other differences, such as racial and ethnic

occurred proximate to the onset of cognitive

trends, are not known. The mean survival time

impairment and is confirmed by neuroimaging.

appears to be similar to AD and like AD some

persons may show rapid progression with 1 to

n SPECIAL CLINICAL POINT: The temporal

2 years survival.

relation between a clinical stroke and the onset

People with well-established Parkinson dis-

of cognitive impairment and dementia is the

ease who subsequently develop dementia often

best predictor of VaD.

are simply referred to as having Parkinson dis-

Because subcortical vascular disease often in-

ease with dementia. Although in many cases

volves pathology in multiple subcortical areas,

this is the result of concomitant AD, persons

symptoms are often varied and include slow-

with Parkinson disease also can develop a de-

ness (parkinsonian signs), changes in speech

mentia that appears to be the result of the inva-

(aphasia or dysarthria), mood (depression) in

sion of the limbic system and neocortex with

addition to urinary incontinence, or gait distur-

Lewy bodies.

bance. White matter lesions commonly are

There have been two workshops on criteria

found on MRI or CT in elderly persons, but

for DLB. In addition to dementia and parkin-

their etiology and significance remain contro-

sonian signs, these patients have fluctuating

versial. Many persons with dementia with

cognition, depression, REM (rapid eye move-

white matter changes on MRI or CT have AD

ment) sleep disturbances, hallucinations, sensi-

at autopsy. Therefore, although the presence of

tivity to neuroleptics, and changes on PET

VaD should be supported by evidence of vascu-

scanning (cerebral hypometabolism in the pri-

lar disease on CT or MRI, the presence of these

mary and association visual cortices). The hal-

lesions does not necessarily indicate that the

lucinations can be black or white, often involve

dementia is of vascular origin.

animals and people, and can be very frighten-

Cholinesterase inhibitors have been shown

ing at times.

to be beneficial in patients with VaD. Some

Finally, many persons with AD also develop

studies have shown that persons with VaD

parkinsonian signs. These signs often are the re-

treated with either galantamine or donepezil

sult of concomitant Lewy bodies in the substan-

compared to persons treated with placebo have

tia nigra as seen in Parkinson disease but also

shown a treatment effect to be similar to that

can result from AD changes in the substantia

seen in patients with AD.

nigra or subcortical ischemic cerebrovascular

297

Chapter 14

n Alzheimer Disease and Other Dementias

disease. One feature of DLB is that these pa-

On neurologic examination, early signs may

tients may be subject to onset of parkinsonian

include frontal release signs such as a snout,

signs and symptoms with modest doses of neu-

grasp, or palmomental reflex. Other abnormal-

roleptic medications, and use of neuroleptics

ities include the presence of early MND or

should be limited.

parkinsonian signs. The families with autoso-

mal dominant FTDs with parkinsonism have

n SPECIAL CLINICAL POINT: Three defining

been linked to chromosome 17 and are thought

features useful in making the diagnosis of DLB

to be due to an aberrant coding of the tau pro-

are the presence of marked fluctuations in

tein. The motor findings in persons with FTD-

cognition and behavior, the occurrence of vivid

hallucinations, and the development of

MND are similar to that seen in pure MND,

parkinsonism within one year after the onset

and may precede, coincide with, or follow the

of dementia.

development of cognitive behaviors.

There is substantial evidence that the choliner-

n SPECIAL CLINICAL POINT: Spontaneous

gic dysfunction is a prominent abnormality in

parkinsonism and clinical MND may be

DLB. Therefore, it is not surprising that evi-

encountered in some patients with FTD.

dence suggests that cholinesterase inhibitors,

The pattern of abnormality on neuropsychologi-

the mainstay treatment in patients with AD,

cal testing is different from that seen in AD, VaD,

may be even more efficacious in patients with

and DLB. It can reveal relatively isolated dys-

DLB. Reports of improvement in apathy, som-

function of frontal abilities (impaired set shifting

nolence, and hallucinations are all noteworthy.

or shifting from one set or rules to another) or

In addition, cholinesterase inhibitors have been

dysfunction of language abilities (e.g., naming).

shown to improve cognition and behavior with-

Structural brain imaging, especially MRI, can

out worsening of extrapyramidal symptoms.

support the diagnosis and demonstrate focal and

Although levodopa does not work particularly

sometimes very marked atrophy of the frontal

well in patients with DLB and has the potential

and or anterior temporal lobes, which is often

to worsen hallucinations, and other behavioral

asymmetrical. FDG-PET recently has been ap-

symptoms, a cautious trial can be considered in

proved by the Centers of Medicare and Medi-

those with prominent motor impairment.

caid Services to distinguish FTD from AD.

The pharmacologic treatment of FTD is cur-

rently aimed at behavioral management, with

“off-label” use of acetylcholinesterase inhibitors,

FRONTOTEMPORAL DEMENTIA

antidepressants, and neuroleptics. Several stud-

FTDs are a rare group of conditions that in-

ies have evaluated the use of acetylcholinesterase

clude Pick disease, primary progressive apha-

inhibitors for behavior in FTD and suggest that

sia, and motor neuron disease (MND) with

some patients may benefit from these agents,

dementia. Patients typically are younger than

including donepezil and rivastigmine. Other

those with AD, with a typical age of onset in

small studies have utilized serotonin uptake in-

the late 50s. They present with neurobehav-

hibitors, such as paroxetine or trazodone, and

ioral or “psychiatric features” that are thought

monoamine oxidase inhibitors, such as as mo-

to be of frontal and/or temporal lobe dysfunc-

clobemide, and have had mixed results with re-

tion such as socially inappropriate behavior or

gards to behavior management.

a progressive language deficit, as opposed to

the memory impairment that characterizes AD.

Prion Diseases

Often patients are seen by psychiatrist first be-

cause of behavioral changes and are then re-

Prion diseases are a heterogeneous group of

ferred to a neurologist for further evaluation.

fatal neurodegenerative conditions of sporadic,

298

Chapter 14

n Alzheimer Disease and Other Dementias

infectious, or genetic origin. The transmissi-

MANAGEMENT OF ALZHEIMER

ble agent appears to be composed solely of

DISEASE

the prion protein, encoded by a gene on chro-

mosome 20, without any nucleic acid, mak-

Once AD is diagnosed, the clinician assists indi-

ing it unlike any other known viral or

viduals in developing a network of personal

bacterial agent. The most common prion dis-

care, medical, social service, and legal providers

ease is CJD.

that will become their support foundation. The

network attempts to maintain cognitive abili-

n SPECIAL CLINICAL POINT: CJD is a

rapidly progressive dementia that leads to

ties, preserve functional abilities, control behav-

death within a year.

ioral difficulties, and reduce caregivers’ burden

through education, social and legal services, and

Sporadic CJD presents as a rapidly progressive

treatment interventions (Fig. 14.2).

dementia with myoclonus, cerebellar dysfunc-

tion, parkinsonian signs, and pyramidal tract

Pharmacotherapy

signs. Iatrogenic CJD can follow corneal or

dural transplants or use of implanted stereotac-

Five agents are approved by the U.S. Food and

tic electrodes or human growth hormone. Sev-

Drug Administration (FDA) for the symptomatic

eral forms of autosomal dominant familial

treatment of AD. Four drugs work to enhance

prion diseases can result from mutations in the

cholinergic transmission in the brain by redu-

prion protein gene on chromosome 20. Famil-

cing the degradation of acetylcholine through

ial CJD tends to present younger and has a

inhibition of the enzyme acetylcholinesterase

long preclinical period. In its prodromal stage,

(AchE). The first drug approved in this class of

behavioral symptoms such as mania, paranoia,

agents, tacrine, is no longer clinically used

or psychosis can occur.

because it induces liver toxicity and requires

Dementia—Treatment

Cognition

Behaviors

Medications

Social

Services

Education

Caregiver

Functionality

Burden

FIGURE 14.2 A diagram depicting the need to develop a treatment plan for individuals with

dementia that includes education, social and legal services, and medications to maintain cognitive

abilities, preserve functional abilities, control behavioral difficulties, and reduce caregiver burden.

299

Chapter 14

n Alzheimer Disease and Other Dementias

dosing four times a day. Therefore, it is not dis-

have had “modest” effects on cognitive,

cussed further. One drug works by being a par-

functional, and behavioral function in patients

with AD and none are thought to slow down the

tial glutamate antagonist.

progression of the underlying disease.

Acetylcholinesterase Inhibitors Rivastigmine in-

There are several medical contraindications to

hibits both AchE and butyrylcholinesterase

cholinesterase inhibitors. Patients with serious

(BuChE), whereas donepezil and galantamine

liver disease or active alcohol abuse are not can-

inhibit AchE but have only minimal inhibition

didates for treatment with these agents. These

of BuChE. All of the AchEs except rivastigmine

inhibitors increase gastric secretions and should

are eliminated via the liver. Rivastigmine is elim-

not be used in patients with active peptic ulcer

inated in the urine and may need to be adjusted

disease. They also can increase bronchial secre-

in individuals with chronic kidney disease.

tions and should be avoided in patients with se-

Donepezil administration is once a day start-

vere chronic obstructive pulmonary disease or

ing at 5 mg and increasing to 10 mg after 4 to

asthma. They are vagotonic and can cause

6 weeks. Rivastigmine is administered twice

bradycardia, and they should not be used in pa-

daily, starting at 1.5 mg twice a day, and in-

tients with preexisting bradycardia or sick sinus

creased to 3 mg a day every 2 weeks, as toler-

syndrome. Donepezil metabolism is inhibited

ated, until a dose of 6 mg twice daily is reached.

by quinidine and ketoconazole. Medications

Because of significant nausea and vomiting,

such as carbamazepine, phenytoin, phenobarbi-

dose escalation frequently is done more slowly.

tal, rifampin, and dexamethasone may increase

A patch version of rivastigmine is currently

donepezil’s elimination from the body.

available in doses of 4.6 and 9.5 mg/day for

Partial Glutamate Antagonist Memantine is an

those individuals with difficulty taking oral

uncompetitive, N-methyl-D-aspartate (NMDA)

medications or medications more than once a

receptor channel antagonist that blocks the ex-

day. Galantamine is started at 4 mg twice a day

citatory effects of glutamate. Memantine is ex-

and increased to 8 mg twice a day after 4 weeks.

creted via the kidney and has a half-life of 60 to

Galantamine can be further increased to 12 mg

80 hours. Memantine is titrated over the course

twice a day. An extended release formula of

of 4 weeks from 5 mg once daily to 10 mg twice

galantamine in 8, 16, and 24 mg doses to be

a day. It is also available in an oral solution for-

taken once daily is also available. Oral solutions

mulation. Memantine has received FDA ap-

of rivastigmine and galantamine and a rapidly

proval for the treatment of moderate-to-severe

dissolvable tablet of donepezil are available for

AD alone or in combination with an AchE agent

individuals with swallowing difficulties.

(clinical trials for the indication were done in

All of these drugs have similar efficacy for the

addition to donepezil only). Memantine has the

symptomatic treatment of mild-to-moderate

main side effects of constipation and sleepiness.

AD. Donepezil has received additional approval

No drug-drug interactions are known. How-

for the treatment of moderate-to-severe AD.

ever, memantine is chemically similar to aman-

None of these drugs are thought to slow down

tadine and has the potential to interact with

the progression of the underlying disease. Thus,

dextromethorphan, which is commonly found

patients should be monitored for improvement

in over-the-counter cough suppression agents.

with both formal mental status testing and dis-

cussions with the patient’s family and/or care-

Other Agents Multiple other agents have

giver. In addition, none of these medications

been tested to see if they can slow down the

have proven efficacy among persons with MCI.

progression of AD. Estrogen did not slow

n SPECIAL CLINICAL POINT: Most experts

down the decline of memory loss in women

agree that all of the cholinesterase inhibitors

with AD. In the Women’s Health Initiative

300

Chapter 14

n Alzheimer Disease and Other Dementias

Memory Study, use of a combination of estro-

any time during the course of the dementing ill-

gen and progesterone did not reduce the inci-

ness, they are more common in the middle and

dence of AD. Anti-inflammatory agents such as

late stages. Common psychotic symptoms in-

prednisone, and celecoxib, a Cox-2 selective

clude delusions (e.g., theft of belongings, aban-

anti-inflammatory agent, did not slow down

donment by family, and spousal infidelity),

the decline of AD. Use of naproxen to prevent

misinterpretation of delusions (e.g., characters

the onset of AD in Cache County, UT, was

on television are real, others are living in the

stopped due to safety concerns of use of Cox-2

house [phantom boarders]), or hallucinations.

inhibitors; however, it did not show a preven-

Physical aggression that may result can have

tion of the incidence of AD. The phase 3 stud-

the most severe consequences for the family,

ies of flubriprofen and tramiprosate did not

eventually leading to institutionalization of the

slow down cognitive loss with AD. Statin

patient. Numerous studies have addressed the

agents, specifically simvastatin, have been

pharmacologic management of behavioral dis-

studied with results pending.

turbances among patients with AD. High-

potency antipsychotic agents, such as haloperi-

Alternative Treatments One study suggested that

dol and fluphenazine, have predominantly ex-

a high-dose vitamin E supplement (2000 IU/day)

trapyramidal adverse effects and have fallen out

delayed overall time to one of the following out-

of favor in the treatment of psychosis in pa-

comes: death, institutionalization, loss of the

tients with AD. The atypical antipsychotics

ability to perform basic activities of daily living,

(risperidone, olanzapine, quetiapine, and cloza-

or severe dementia. The mechanism of this ef-

pine) have replaced conventional neuroleptics

fect, and its specificity, remains to be elucidated

as initial pharmacotherapy for psychosis associ-

because vitamin E did not appear to have an ef-

ated with AD. However, these agents have been

fect on cognitive function. Some, but not most,

associated with increased death in clinical trials

studies suggest that Ginkgo biloba may be of

of individuals with dementia and have a “black

benefit in AD. A placebo controlled trial funded

box” warning regarding their use in older indi-

by the National Center for Complementary and

viduals with dementia. Also, the first phase of

Alternative Medicine and the National Institute

the CATIE-AD study sponsored by the Na-

on Aging of 3000 older individuals without

tional Institutes of Mental Health did not show

memory complaints, showed that G. biloba was

any significant benefit of the atypical antipsy-

not effective in reducing the incidence of AD in

chotics in reducing the intensity of behavioral

these individuals. High doses of vitamins B₁₂, B₆,

symptoms over a 6-week time period. There-

and folic acid to reduce homocysteine levels were

fore, these agents are used “off-label” for the

not found to slow down the progression of cogni-

treatment of behavioral symptoms associated

tive loss in individuals with mild-to-moderate AD.

with AD. These agents should be used only if

Other alternative medications such as hu-

environmental interventions have failed, at the

perzine, a Chinese herbal medicine with prop-

lowest doses possible, with documented coun-

erties similar to AchE inhibitors, curcumin, a

seling of the risks, benefits, and alternatives to

chemical compound in tumeric, and docosa-

treatment with the individual and their family,

hexaenoic acid, an omega-3 fatty acid, are cur-

and with careful monitoring for metabolic syn-

rently being evaluated in clinical trials at

drome (including weight gain, diabetes, ele-

various stages.

vated cholesterol, and high blood pressure).

Pharmacologic Treatment of Behavior Symptoms

n SPECIAL CLINICAL POINT: The main

Associated with AD The course of AD often is

behavioral disturbances seen in AD are

punctuated by neuropsychiatric disturbances.

agitation, psychosis, depression, anxiety, and

Although psychotic symptoms may present at

insomnia, all of which are treatable.

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Chapter 14

n Alzheimer Disease and Other Dementias

Depression and alterations of sleep-wake cycles

healthy caregiver can manage a patient with

respond to pharmacologic intervention and

AD longer and better than one who is over-

should be treated. Few controlled studies exist

wrought and exhausted. The caregiver must

from which to guide the dose and duration of

have rest, and other family members should be

pharmacotherapy. In persons with dementia

urged to take turns in caring for the patient.

and depression, agents such as sertraline, citalo-

Family support groups, often sponsored by the

pram, paroxetine, and mirtazapine have been

Alzheimer’s Association

(www.alz.org), are

used. A low dose, sedating narcoleptic may be

also helpful. The National Adult Day Services

preferable for the nondepressed AD patient with

Association (www.nadsa.org) or the Eldercare

a significant sleep disorder. Some studies suggest

Locator (www.eldercare.gov) has information

that melatonin, or phototherapy, may be benefi-

on local or nationwide day-care centers.

cial for sleep disorders associated with AD.

Special care units

(SCUs) have emerged

However, data on the efficacy of these agents in

over the last few years in an attempt to maxi-

AD are limited.

mize the independence of patients by creating

a 24-hour supervised environment that is safe

for disoriented residents and provide struc-

Other Interventions

ture. Nursing home placement with dementia

There are many areas in which intervention can

care units can exist in rest homes or skilled

improve the quality of life for both the patient

nursing facilities and often are chosen by

and the caregiver. Successful intervention re-

most families at the later stages of the illness.

quires that the physicians work effectively with

The family should be advised to seek out a

providers of many other medical and nonmed-

nursing home where activities and exercise

ical services. In general, five issues should be dis-

are stressed and where tranquilizers and re-

cussed with the family: (a) community resources,

straints are minimized.

(b) advocacy, (c) pharmacotherapy, (d) behavior

AD places a tremendous social, economic,

management, and (e) prognosis.

physical, and psychologic burden on the family.

The psychologic stress on the family is frequently

Community Resources Most patients with AD

not dealt with adequately. Stress is placed on the

in the mild-to-moderate stage can be cared for

family in general, and particularly on the care-

at home, assuming a caregiver is available and

giver. The physician should be available and sup-

willing to assume this responsibility. This deci-

portive throughout the course of the illness and

sion can be made only by the family. It is not

urge the family to contact the local chapter of the

appropriate for the physician (or others not in-

Alzheimer’s Association

(contact information

volved in daily care) to insist on home care

available from the national headquarters at

when the family finds this objectionable. Adult

www.alz.org). The association provides infor-

day-care centers provide a structured, compre-

mation regarding local support services for both

hensive program in a protective setting. They

the patient and the caregiver from other people

offer respite for short periods but can provide

facing similar problems. The National Institute

care up to 7 days a week for 12 hours a day.

on Aging also maintains the Alzheimer’s Disease

Most centers serve mixed populations, but

Education and Referral Center (ADEAR) (www.

some are dementia specific. Many patients do

nia.nih.gov/Alzheimers/), which has information

well in the day-care setting, and the use of day

for both family members and physicians.

centers for patients with dementia results in

Persons with AD eventually may lose all deci-

lower levels of stress and improved psychologic

sion-making capabilities. At the time of initial

well-being for caregivers. The caregiver’s men-

diagnosis, it is important that the physician alert

tal and physical health must be maintained.

the individual and family of the need to make

This ultimately benefits the patient because a

decisions regarding advance directives, living

302

Chapter 14

n Alzheimer Disease and Other Dementias

wills and trusts, power of attorney, and

unrecognized dementia among subjects admit-

guardianship. Advance directives should include

ted to the hospital for an unrelated reason. Be-

an open discussion of the person’s wishes re-

cause the hospital setting can be very

garding nursing home placement and aggressive

disorienting, this situation can easily unmask a

intervention at the end of life, including feeding

mild, unrecognized dementia. Thus, in the

tubes, intubations, and resuscitation. The deter-

evaluation of conditions that can cause a delir-

mination of power of attorney or guardianship

ium, the physician should seek detailed infor-

is fundamental to making economic or ethical

mation regarding the patient’s premorbid

decisions regarding the care of the individual.

function. Second, patients with dementia fre-

Many persons with MCI are legally competent

quently become agitated in the hospital setting,

to execute a valid power of attorney, placing in

often to the point of needing physical and/or

the hands of another person decisions regarding

chemical sedation that can frighten patients,

his or her health and estate. A separate power of

attorney for health care and property must be

completed. In addition, the power of attorney

Always Remember

should be “durable,” which means that it re-

mains effective if the individual becomes incom-

• Increased awareness of dementia offers

petent. Guardianship must be imposed on a

neurologists and non-neurologists an

person who has become incompetent and is no

opportunity to improve the lives of patients

longer able to sign for power of attorney. In the

and their caregivers.

event of family discord, the physician should

• The clinical evaluation for assessing memory

avoid siding with one family member over an-

complaints has four objectives: (a) to

other and should refer the family to a competent

determine if the person has dementia; (b) if

and sympathetic attorney.

dementia is present, to determine whether its

presentation and course are consistent with

Prognosis One question that is asked fre-

AD; (c) to assess evidence for any alternate

quently by the family is whether the physician

diagnoses, especially if the presentation and

can predict the course of the illness. No proven

course are atypical for AD; and (d) to evaluate

methods are yet available to make accurate pre-

evidence of other, coexisting, diseases that

dictions, but a few guidelines are available. First,

may contribute to the dementia, especially

clearly, AD is associated with increased risk of

conditions that might respond to treatment.

death among patients in institutions. However,

• After diagnosis, the clinician assists individuals

data from community based studies has shown

with cognitive concerns to develop a

that persons with AD (with mild to moderate

network of personal care, medical, social

impairment) have survival rates comparable to

service, and legal providers that will become

that of persons without the disease. Finally, per-

their support foundation. The network

sons with any of these three signs—severe cogni-

attempts to maintain cognitive abilities,

tive impairment, cachexia, or parkinsonian

preserve functional abilities, control

signs—have a much greater risk of dying.

behavioral difficulties, and reduce caregiver

burden through education, social and legal

services, and treatment interventions.

Special Considerations for

• In general, five issues should be discussed

Hospitalized Patients

with the family upon diagnosis of a dementia:

There are three special considerations regard-

(a) community resources, (b) advocacy, (c)

ing hospitalized patients. First, because many

pharmacotherapy, (d) behavior management,

persons with AD are not diagnosed, hospital

and (e) prognosis.

staff must be sensitive to the possibility of

303

Chapter 14

n Alzheimer Disease and Other Dementias

staff, and family. Thus, whenever possible, one

with no evidence of stroke. Which of the

should avoid hospitalizing patients with a

following is the most likely diagnosis?

known dementia. When hospitalization is nec-

A. Mild cognitive impairment

essary, a geriatric psychiatry unit may be pre-

B. Depression

ferred over a medical floor because the nurses,

C. Alzheimer disease

staff, and setting may be better prepared to

D. Frontotemporal dementia

care for these problems. Family should be en-

The answer is (C). Recent literature suggests

couraged to stay with the patient, and the use

that individuals evolving to dementia gener-

of infusing tubes and machines, including in-

ally will go through a transitional phase of

travenous lines and urinary catheters, should

MCI. In its purest form, memory impairment

be brief.

is the most prominent feature of MCI on cog-

nitive testing, with relatively sparing of other

cognitive functions. This patient’s neuropsy-

QUESTIONS AND DISCUSSION

chologic profile suggests that more than one

cognitive domain is affected (in addition to

1. A 75-year-old man is brought to the

memory problems), and thus an MCI diagnosis

physician by his wife for evaluation of

is incorrect. Because of the lack of depressive

memory problems. She states that over

symptomatology, depression is also not

the last few years he has become more

thought to be a major contributor to the

forgetful and is having difficulty in doing

patient’s memory problem. The notable

some household tasks. Initially his wife

lack of marked behavior or personality

felt this was just the result of getting

changes, and intact language abilities, make

older, but she became more concerned

the diagnosis of FTD less likely. The patient’s

when her husband got lost driving to a

history and clinical and neuropsychologic

store that they both go to regularly. In

examinations are consistent with the early

addition, at a recent party he had

stages of AD.

noticeable problems recalling friends’

2. The patient described in question 1 above

names and did not participate in

is diagnosed with mild Alzheimer dementia.

conversations as much as he had in the

A drug with which of the following actions

past. Family members mentioned that the

is most appropriate for this patient?

patient appears “sad” at times, but no

A. Acetylcholinesterase inhibitor

changes in the patient’s hobbies, sleep, or

B. Anticholinergic

appetite have occurred. Medical history

C. Dopamine blocker

includes hypertension for 5 years

D. Serotonergic agonist

(controlled with enalapril) and a history

of angina. Physical and neurologic

The correct answer is (A). The levels of acetyl-

examinations are unremarkable except for

choline, noradrenaline, serotonin, gamma

an MMSE score of 25/30. Psychometric

aminobuyric acid (GABA), glutamate,

testing reveals mild short-term memory

somatostatin, and substance P have all been

impairment. Attention and orientation are

documented to be reduced in the brains of AD

mildly impaired, and language, and visual

patients. However, reductions in acetylcholine

perception are in the normal range. Mood

and choline acetyltransferase are the most

is not suggestive of depression. A workup

profound and are thought to be the most

for reversible causes of dementia

important with regards to cognitive function.

(including thyroid-stimulating hormone

Acetylcholine reductions may be due to the

and vitamin B₁₂ levels) is normal. An MRI

neuronal loss in the basal forebrain, which is

of the brain reveals mild cortical atrophy

the major region from which cholinergic

304

Chapter 14

n Alzheimer Disease and Other Dementias

projections originate. For the symptomatic

have significant mortality and morbidity risks

treatment of AD, there are currently three

in older persons with dementia. Typical an-

commonly used drugs that enhance choliner-

tipsychotics have significant extrapyridamidal

gic transmission in the brain by reducing the

side effects commonly are not utilized for

degradation of acetylcholine through inhibi-

long-term treatment of psychosis in dementia.

tion of the enzyme AchE. Rivastigmine

The risk of drug-induced parkinsonism and

inhibits both the AchE and BuChE, whereas

tardive dyskinesia is high, and this patient al-

donepezil and galantamine inhibit AchE but

ready is having very mild parkinsonian signs.

have only minimal inhibition of BuChE. Anti-

As the symptoms are mild at this point and

cholinergic compounds would reduce the

there is no indication that the patient or care-

action of acetylcholine on receptors in the

giver is at significant risk for harm, hospital-

brain and would be more harmful than help-

ization is not warranted.

ful. Symptomatic improvement in mood but

not cognitive improvement has been noted

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management of psychosis in this patient?

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A. Selective-serotonin reuptake agents

Neurology. 2002;59:198-205.

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C. Typical antipsychotics

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nitive decline. Neurology. 2006;67:441-445.

and environmental interventions are key

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nonpharmacologic interventions to reduce the

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Alzheimer disease in primary care: a randomized

effects of behavioral syndromes associated

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Cummings JL. Alzheimer’s disease. N Engl J Med. 2004;

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DeKosky ST, Williamson JD, Fitzpatrick AL, et al.

Mendez MF, Shapira JS, McMurtray A, et al. Accuracy of

Ginkgo evaluation of memory (GEM) study invest-

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2003;290:2015-2022.

Behavioral

Neurology

ROBERT S. WILSON AND

CHRISTOPHER G. GOETZ

key points

• Disease involving the Papez circuit often results in

aberrant emotional behavior, memory dysfunction,

or both.

• Temporal lobe epilepsy is characterized by sudden loss

of contact with the environment and brief behavioral

changes.

• Temporal lobe epilepsy may be ushered in by a

stereotypic sensory experience (i.e., aura) and involve

stereotypic motor behaviors (i.e., automatisms).

• All individuals with a sudden change in language

function should be referred to a neurologist.

• Fluent aphasia is usually the result of dominant

temporal or temporoparietal damage, and because of

the temporal lobe involvement, behavioral changes are

often seen.

• All patients with suspected Wernicke encephalopathy

should immediately receive thiamine.

• Transient global amnesia involves the abrupt onset of a

dense anterograde amnesia that typically completely

resolves within 24 hours.

• Anterograde amnesia and bizarre behavioral and

emotional changes are common sequelae of herpes

simplex encephalitis.

izarre or altered

conditions present with remarkably consistent

behavioral patterns traditionally are felt to re-

behavioral abnormalities. These conditions

late to psychiatric disorders or generalized

have equally consistent anatomic substrates,

delirium from drugs, toxins, or metabolic im-

and, when identified by an astute diagnostician,

balances. However, some specific neurologic

they suggest specific causes and treatments. In

307

308

Chapter 15

n Behavioral Neurology

this chapter, five conditions are discussed, each

most important circuit for clinicians dealing

with a prominent behavioral and seemingly

with behavioral abnormalities; familiarity with

psychiatric presentation but with a pathologic

it allows them to think systematically about the

basis related to a specific neurologic dysfunc-

anatomic foundations of behavioral neurology.

tion. These conditions are temporal lobe

The circuit is diagrammed schematically in

epilepsy (TLE), fluent aphasia, Wernicke en-

Figure 15.1A, with anatomic nuclei and paths

cephalopathy, transient global amnesia, and

identified in the sagittal brain section of

herpes encephalitis.

Figure 15.1B. As indicated, the pathway is cir-

These strange disorders are not rare, and their

cular, providing continual reintegration of in-

complexity often relates not to management

formation. The two focal cortical areas most

problems but to accurate identification. The

prominently involved are the cingulate cortex

topic is thus particularly pertinent to the non-

and the hippocampus of the temporal lobe.

neurologist, who is most likely to be the first per-

Diffuse cortical impulses travel into the hip-

son to interview and evaluate these patients.

pocampus, an area felt to be particularly im-

portant to memory and emotional expression.

This information travels forward in the fornix

ANATOMIC BASIS—PAPEZ CIRCUIT

path to the mammillary bodies of the hypothal-

It is well recognized that the ability to recall and

amus and continues to the anterior lobe of the

engender memories is intimately linked to the

thalamus, and further to the midline cingulate

emotional makeup of such memories. Further-

cortex, which finally projects diffusely to corti-

more, several clinical conditions demonstrate

cal regions.

combined and prominent memory-emotional

Familiarity with this circuit is useful be-

alterations, suggesting that the anatomic basis

cause disease anywhere along the pathway can

of these two functions may be linked. In 1937,

be expected to result in aberrant emotional be-

the neuroanatomist Papez published a treatise

haviors, although not necessarily the same pat-

describing an anatomic circuit that linked those

terns. This knowledge allows the clinician to

nuclei and paths that appear important to many

focus immediately on a finite number of nuclei

aspects of emotional-behavioral integration.

and connecting paths to explain abnormal

This circuit, the Papez circuit, is probably the

behavioral symptoms that may have a focal

FIGURE 15.1 Papez circuit. A: Schematic diagram of brain regions connected by the Papez circuit.

B: Anatomic diagram of brain regions numbered in (A), with arrows indicating the direction of

general informational flow.

309

Chapter 15

n Behavioral Neurology

anatomic basis. The term diffuse cortical input

TABLE 15.1

is important because toxic and metabolic en-

Temporal Lobe Foci and Related Auras

cephalopathy often present with agitated be-

Anatomic Focus

Clinical Symptoms of Aura

havior or a change in personality. The other

areas, however, are focal, and identification of

Uncus

Smell, taste

disease at these levels can lead to rapid inter-

Cingulate cortex

Change in emotional

vention. Reference will be made to this circuit

perception—déjà vu

throughout this chapter.

(strange familiarity with

the environment), jamais

vu (strange sense of

TEMPORAL LOBE EPILEPSY

never being in current

environment), euphoria,

Also referred to as psychomotor epilepsy and

sense of sudden doom

partial complex seizure, psychomotor or psy-

Insula

Epigastric rising sensation

chosensory variety, TLE may manifest itself

Amygdala

Pupillary dilatation,

with intermittent spells of bizarre behavior, in-

photophobia, automatisms

cluding babbling nonsense and frank visual

Temporal cortex

Hallucinations

and auditory hallucinations, all related to or-

including auditory

ganic disease of the central nervous system.

cortex and

Differentiation of this disorder from psychotic

association areas

disorders such as schizophrenia can be diffi-

cult, yet it is essential because their treatments

are drastically different. Certain specific char-

acteristics are helpful in establishing abnormal

minutes. Often, before any visible behavioral

behavioral patterns as probable epilepsy, and

change can be appreciated by an observer, the

they are the focus of this discussion.

patient experiences a stereotypic and fixed sen-

TLE represents an abnormal electrical dis-

sation, known as an epileptic aura. The aura

charge that begins in one temporal lobe and

represents the beginning of the seizure and can

usually crosses rapidly to involve both sides of

help in localizing the focus, or source, of the

the brain. To recognize TLE in a patient, the

seizure activity. The aura may be olfactory, in

clinician should attempt to elicit specific infor-

which the patient suddenly smells a strange,

mation in four areas. If information in even

often pungent odor, or it may be a gustatory

one of these areas is characteristic of TLE, the

sensation or a strange abdominal “butterflies”

diagnosis is suggested.

feeling, also called epigastric rising. Emotional

changes of sudden unfamiliarity with one’s en-

1. The distinctive temporal pattern of the spells.

vironment (jamais vu) or sudden intense famil-

2. The presence of an aura, a distinctive feel-

iarity with the surroundings (déjà vu) are seen,

ing, or sensation that regularly precedes or

and there may be intense and vivid auditory or

begins the spells.

visual hallucinations. The aura and the area of

3. The presence of peculiar motor behaviors

the temporal lobe cortex that are felt to relate

called automatisms.

to the seizure focus are listed in Table 15.1.

4. The specific type of loss of consciousness.

The presence of this stereotypic aura and sud-

The distinctive temporal pattern of TLE

den unprovoked change in behavior help to

refers to repeated, but intermittent, and parox-

quickly identify a patient with TLE. The aura is

ysmal changes in behavior, not necessarily

sensed by the patient and is not identified by

linked to any emotional provocation. The be-

the clinician except by interview. The patient

havioral changes are brief, lasting seconds to

may not necessarily link the strange aura to his

310

Chapter 15

n Behavioral Neurology

spells, so that information must be solicited

may recall its beginning and be able to recount,

specifically.

if specifically asked, the details of the aura. Im-

mediately after the spell, the patient is usually

n SPECIAL CLINICAL POINT: The very first

confused and sleepy. If restrained during this

perceived abnormality related to a seizure has

period, he may strike out randomly at people

key importance to localizing the source of the

who try to assist. However, these patients are

epilepsy, so careful interviewing of a typical

generally not violent in a goal-directed manner,

spell, step-by-step is essential.

either during or after their seizures. As strange

The presence of automatisms is also useful in

as their behaviors may be, focused violence,

the diagnosis of TLE. These activities appear

such as tracking a person with a gun or retriev-

as the seizure spreads in the amygdala region

ing a kitchen knife out of a drawer and stab-

of the temporal lobe. The movements may

bing a victim, is far outside the repertoire of

range from rather primitive movements (lip

TLE. Table 15.2 serves as a summary and out-

smacking, eye blinking, or chewing motions)

lines additional guidelines for differentiating

or may be highly complex (dressing and un-

TLE episodes from psychotic bizarre behaviors

dressing, piling objects on top of one another).

of schizophrenia. These patterns are clinically

These are stereotypic and rather fixed from

useful, although no absolute rules hold true.

one spell to another, so a detailed record of

The following example demonstrates that TLE

two or more episodes helps to establish the

patients can be misdiagnosed.

pattern of behavior.

Case: A 16-year-old boy on the psychiatric

The peculiar characteristic of the loss of

unit with a diagnosis of schizophrenia and hal-

consciousness seen in TLE is also helpful. After

lucinatory behavior is evaluated by the neurol-

the aura, which the examiner cannot see unless

ogist because of a single generalized seizure.

it involves automatisms, there is a sudden loss

On being interviewed, this patient says, “It’s

of contact with the environment in TLE. Un-

just like before, but this time much worse.”

like patients who have other generalized

Several times each week, this patient sees “the

seizures, these patients only rarely fall to the

man,” a blurry but discernible bearded man

floor, shake all over, urinate, or bite their

who beckons him forward verbally. As this

tongue. Instead, when they lose consciousness,

happens, everything in the patient’s environ-

they maintain body tone and may walk around

ment becomes suddenly more distinct, clearer,

but “in a daze, out of contact” with the envi-

and more colorful, with a clear sense of famil-

ronment. When the spell is over, the patient is

iarity and warmth. Then a strange feeling of

usually amnestic for the seizure, except that he

dread and a “fog” come over the patient, who

TABLE 15.2

Clinical Distinctions Between TLE Behavior and Schizophrenia

TLE

Schizophrenia

Environmental precipitants

Rare

Frequent

Duration of attack

0.5-5 minutes

May be days

Aura

Usual

Lacking

Injury to others

Rare and undirected

Unpredictable—may be directed

or undirected

Disturbance of consciousness

Present

Lacking or mildly clouded

Symptoms and signs after attack

Sleepy, confused

Lacking

311

Chapter 15

n Behavioral Neurology

then appears to lose touch for approximately

ANATOMY AND CLINICAL FINDINGS

5 minutes. He has no recollection of this period

of losing touch, but his family says that he

The anatomic lesions of TLE naturally relate

walks around in the house mumbling strange

to the temporal lobe and, depending on the

noises that are sometimes prayers, and at the

area damaged, will give rise to different auras

same time he bows his head back and forth in

(Table 15.1). As can be seen, some of these nuclei

a seemingly ritualistic manner. After this, he

are primary portions of the Papez circuit and

lies down and sleeps for approximately 2 hours.

the others have direct input into the circuit.

The same stereotypic pattern occurred immedi-

In examining a patient with TLE, if there is a

ately before the generalized seizure.

tumor, stroke, or space occupying lesion, a find-

This patient again shows the stereotypic

ing may include a homonymous hemianopia, or

aura, which is hallucinatory this time, along

a homonymous quadrantanopsia, especially in

with the sense of emotional familiarity with the

the superior fields (Fig. 15.2). Because the vi-

environment. Stereotypic repetition of episodes

sual fibers pass through the temporal lobe en

and the automatisms with amnesia and sleepi-

route to the occipital cortex, the superior quad-

ness afterward strongly suggest TLE. In regard

rantanopsia should be specifically sought.

to this latter episode in which there was a gen-

Much has been written about psychopathol-

eralized motor seizure with bilateral shaking,

ogy in patients with TLE. Although the seizures

this pattern can be seen with TLE when the

and bizarre behavior are intermittent, interictal

seizure activity spreads throughout both sides

or between-seizure abnormalities are often at-

of the brain. An EEG study with nasopharyn-

tributed to TLE. Problems such as sedation,

geal recordings demonstrated abnormal epilep-

inattention, and depressed mood may be seen

tiform activity. On medication, the patient has

as dose-related side effects of antiepileptic med-

shown remarkable improvement. This case

ications. If toxicity can be ruled out, the most

demonstrates the important interface between

common psychiatric problem in epilepsy is de-

psychiatric symptoms and clear focal neuro-

pression. Although not specific to TLE, re-

logic disease.

search suggests rates of depression as high as

75% in some clinical samples. Paradoxically,

n SPECIAL CLINICAL POINT: The distinctive

depression may appear after seizure control is

behavioral manifestation of these seizures is a

stereotypic loss of contact with the

accomplished, suggesting that seizures, like

environment, often a “dazed” look while

electroconvulsive therapy, may serve to elevate

otherwise apparently awake.

mood, possibly through opioid mechanisms.

FIGURE 15.2. Visual field defect associated with right temporal lobe disease, termed left superior

quadrantanopsia.

312

Chapter 15

n Behavioral Neurology

Aggressive behavior is often attributed to

and present early with characteristic TLE. Sub-

TLE. There is, however, no good evidence of a

acute onset of TLE with fever should suggest

disproportionate level of aggressive or violent

encephalitis, specifically resulting from herpes

behavior in TLE or epilepsy. Aggressive behav-

simplex, which has a predilection for the tem-

ior may be seen following a seizure, but it is typ-

poral lobes. EEG findings are discussed in

ically nondirected and random, occurring when

Chapter 8. Treatment drugs useful in the con-

the patient is aroused or restrained. The hypoth-

trol of TLE are listed in Table 15.3, along with

esis that TLE is characterized by a distinct

usual doses, plasma levels, and common side

personality profile has not been supported by

effects. There are no specific rehabilitation or

recent research. However, psychiatric signs and

alternate medical therapies that are applicable

symptoms in general are seen more commonly

to the treatment of TLE.

in TLE than in other forms of epilepsy, particu-

larly in patients with severe, uncontrolled TLE.

When to Refer Patients to a Neurologist

TLE is a complicated neurologic condition,

and all patients should be referred to a neurol-

ETIOLOGY

ogist at least once to obtain expert opinion on

TLE is often seen in patients with a history of

the nature of the condition and its manage-

birth trauma. Brain tumors, both primary and

ment. The neurologist can provide guidelines

metastatic, also may involve the temporal lobe

to the non-neurologist for drug management

TABLE 15.3

Drugs Used in the Control of TLE: Dosages, Therapeutic Plasma Levels, and Common or

Important Side Effects

Adult Dosage

Plasma Level

Drug

(mg/day)

(mg/mL)

Toxicity

Carbamazepine^a

600-1200

4-10

Diplopia, nausea, vomiting, sedation,

ataxia

Phenytoin

300

10-20

Ataxia, nausea, vomiting, sedation

folate deficiency

Valproic acid^a

750-1500

50-150

Tremor, nausea, weight gain

Lamotrigine

300-500

2-15

Dizziness, diplopia, ataxia, insomnia

Phenobarbital

90-180

15-40

Sedation, hyperactivity in children,

depression

Gabapentin

900-3600

4-8

Somnolence, nausea, weight gain,

vomiting, sedation, depression,

impotence

Primidone^a

750-1000

7-15 primidone

See Phenobarbital toxicity

20-40 phenobarbital

Topiramate

300-600

2-20

Confusion, dysphasia, weight loss

Oxcarbazepine

600-1800

5-50

Diplopia, nausea, dizziness

Zonisamide

200-600

10-40

Confusion, irritability

Levetiracetam

1000-3000

20-60

Irritability, confusion

Pregabalin

300-600

Not applicable

Weight gain, confusion

^aDrug preferentially recommended for TLE as opposed to other forms of seizures.

313

Chapter 15

n Behavioral Neurology

and behaviors that fall within and outside the

temporal lobe is involved in the Papez circuit,

realm of TLE. Because the government guide-

behavioral alterations in fluent aphasias are ex-

lines for driving are different in each state, the

pected and characteristic.

neurologist also can provide the non-neurologist

In contrast to the frustration and depressed

with the specific rules regarding driving limita-

affect common in subfluent aphasia, patients

tions for patients who have seizures.

with fluent aphasia are often seemingly un-

aware of their deficit and are unconcerned. Pa-

Special Challenges for Hospitalized Patients

tients may not realize that their speech is

incomprehensible to others. In extreme cases,

Hospital personnel are unlikely to be familiar

these patients may blame their inability to

with the behaviors that typify TLE; therefore,

communicate to others on the point of frank

the admitting physician must outline the se-

paranoia. Impulsivity is also observed. The

quence of behaviors of the seizure episodes.

combination of such behaviors can result in se-

Seizure precautions and seizure treatment as

rious management problems.

outlined in Chapter

8 should be followed

The evaluation of aphasia is usually rapid

throughout the hospitalized period. When pa-

and requires no unusual implements. Table 15.4

tients have surgery and cannot take medica-

outlines the manner of examination, which has

tions by mouth, alternate routes of medication

three focal points. First, by listening to the pa-

delivery must be used, as outlined in Chapter 8.

tient’s spontaneous speech, the clinician decides

whether the speech is subfluent, slow, and

sparse or fluent, rapid, and free flowing. This

FLUENT APHASIA

evaluation makes no judgment on content of

speech; instead it judges rhythm and ease of

Aphasia is a specific language deficit that oc-

word production. Second, the examiner asks the

curs without weakness of the articulatory mus-

patient to follow a verbal command—“Show

cles, and it is caused by cortical brain disease.

me a spoon,” “Raise your left hand,” and so

The two basic types of aphasia are subfluent

forth—which tests ability to comprehend. This

and fluent. The former group is not difficult to

integration of auditory information helps to

diagnose and would not be confused with psy-

distinguish various aphasias and localizes the

chiatric disease because in most cases an obvi-

disease. The command must be verbal, and the

ous right hemiparesis accompanies the change

investigator must discipline himself not to use

in speech pattern. The fluent aphasias, how-

nonverbal communication during this task.

ever, are not associated with motor problems,

Third, the patient is asked to repeat a sentence—

so that these patients present with behavioral

first a reasonable phrase, such as “Today is

alterations in the form of strange speech. The

Tuesday; tomorrow I will phone Bill,” and then

adage taught to young neurologists—when

a nonsense phrase, such as “No ifs, ands, or

evaluating an acute behavioral change, one

buts.” These three simple maneuvers can be per-

must always rule out fluent aphasia—is appli-

formed by patients who are confused or intoxi-

cable to all clinicians.

cated and by patients with short attention

Aphasic problems occur with focal dominant

spans. However, they are not performed by pa-

hemisphere disorders. For most people, the left

tients with aphasia. Furthermore, the pattern of

hemisphere is dominant for speech, although in

disability in the three tasks isolates the specific

a small percentage of left-handed people, the

areas of dominant cortical dysfunction.

right hemisphere may be dominant. Subfluent

aphasias relate to frontal lobe disease, and flu-

n SPECIAL CLINICAL POINT: Patients with

ent aphasias relate usually to dominant tempo-

dominant hemisphere temporal lobe disease

ral or temporoparietal damage. Because the

and fluent aphasia babble incoherently, but are

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Chapter 15

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TABLE 15.4

Major Types of Aphasia and Guides to their Rapid Identification

Associative

Names

Fluency

Commands Repeat

Focal Damage

Problems

Broca

Subfluent

Yes

Dominant

Right hemiparesis

frontal lobe

Wernicke

Fluent

Dominant temporal

Visual field

lobe

abnormalities, no

weakness

Conductive

Fluent

Yes

Yes for short

Dominant connecting

Visual field

phrases; cannot

fibers between

abnormalities or

repeat “no ifs,

Broca and

mild weakness,

ands, or buts”

Wernicke area

decreased

sensation on

right side of body

and face

often emotionally undisturbed by their

The highlights of this case are the patient’s

language difficulty.

age, the acute onset, the characteristic speech

pattern, and the easily retrieved results of an

A patient with fluent aphasia, known classically

accurate aphasia testing screen. It is impor-

as Wernicke aphasia (not to be confused with

tant to note that in a patient who is 65 years

Wernicke encephalopathy, discussed later in the

old without prior psychiatric history, the new

text under Wernicke-Korsakoff Syndrome), is

onset of schizophrenia, regardless of how

often first diagnosed as confused, agitated, and

bizarre the behavior or speech may be, would

sometimes even schizophrenic. The following

be exceptional.

case history helps to typify this syndrome, and it

emphasizes the common confusion between this

condition and the word salad of schizophrenia.

Case: A 65-year-old hypertensive right-handed

ETIOLOGY

woman was well until 3 hours before an evalua-

tion in the emergency room. Her family lived

Wernicke fluent aphasia is usually seen with

with her and reported that after lunch the pa-

dominant temporal lobe disease in the form of

tient took a 40-minute nap; on awaking, she

cerebrovascular accidents or sometimes tumors.

“began speaking nonsense—crazy talk.” Her

The rapid onset in an elderly individual suggests

past medical and psychiatric histories were neg-

the former, whereas a more indolent course can

ative, and no similar events had ever occurred.

be seen with tumors. When this speech pattern

The patient is alert and talkative, but her

is encountered, the clinician immediately should

speech has no discernible sense. Phrases such as

focus attention on the dominant temporal lobe.

“oh, me,” “why not,” “should we,” “what now,”

Associated findings often include the superior

and “amen Moses” are spoken rapidly and

quadrantanopsia (Fig. 15.2), and temporal lobe

spontaneously. She can follow no verbal com-

seizures may be an associated phenomenon.

mands nor will she repeat simple phrases.

The other fluent aphasia, conduction apha-

The family feels she may be poisoned or has

sia, does not appear to be a psychiatric illness;

gone crazy.

thus, it will not be discussed in detail. These

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Chapter 15

n Behavioral Neurology

patients speak fluently and usually make sense,

incoherent language, although they may not be

except that they mix up words or make new

able to interpret the problem as an aphasia. In an

words (paraphasic errors). Although they can

emergency room or office setting, the physician

repeat simple sentences, they have trouble with

must always be alert to the possibility of a focal

nonsense phrases such as “no ifs, ands, or buts.”

neurologic lesion when there is a sudden change

This disease localizes to the arcuate fasciculus of

in language function. Once the diagnosis and un-

the parietal lobe connecting the temporal and

derlying cause are defined, the management often

frontal speech areas. Strokes and tumors are

can be directed by the non-neurologist with inter-

again the likely causes, although sometimes

mittent consultation back to the neurologist.

Wernicke aphasia, as it resolves, tends to be-

n SPECIAL CLINICAL NOTE: All patients with

come a conduction aphasia. Anomic aphasia, in

a sudden change in language content should be

which the patient is fluent and behaviorally ap-

referred to a neurologist for a consultation.

propriate but has trouble finding the proper

word, is seen as other forms of aphasia resolve.

Special Challenges for Hospitalized Patients

In the hospital, patients with aphasia are a par-

Treatment

ticular challenge. Usually, they are hospitalized

The treatment of aphasia focuses on two ele-

at the onset of the aphasia, and the staff will not

ments: rehabilitation of the speech deficit and

understand the language abnormality or its ori-

treatment of the underlying cause. Because pa-

gin. Staff must be educated to be compassionate

tients with fluent aphasia often do not recog-

and solicitous of the patient’s needs despite the

nize their speech problems, they are difficult

seemingly nonsensical language. In a patient

rehabilitation patients. Speech therapy is used,

with a chronic Wernicke aphasia who must be

but until the patient becomes motivated to

hospitalized, the family often will be more fa-

communicate more effectively, the speech exer-

miliar with the speech deficit than a professional

cises are often fruitless. No medications or al-

staff, and their aid must be sought to maximize

ternate medical treatments are specifically

communication efficiency between staff and pa-

useful. Diagnostic tests, such as MRI scans, will

tient. Because patients with fluent aphasia have

identify the anatomic lesion in the dominant

specific difficulty understanding language, when

(left) temporal lobe, and the contours of the le-

the physician or staff need to explain a proce-

sion will help in suggesting a vascular etiology

dure, treatment, or test, the family member with

(stroke) from tumor, where there is often exten-

authority for the patient’s care must be included

sive edema or multiple discrete lesions. An EEG

for proper consent.

will help define if there are seizures. The treat-

ments will be directed to the most likely cause;

stroke treatment is outlined in Chapter

WERNICKE-KORSAKOFF SYNDROME

tumor therapy is discussed in Chapter 20, and

(WERNICKE ENCEPHALOPATHY)

seizure management is covered in Chapter 8.

Wernicke-Korsakoff syndrome, also known

as Wernicke encephalopathy or, in its extreme

When to Refer the Patient to a Neurologist

form, Korsakoff psychosis, represents a neu-

In contrast to subjects with subfluent aphasia, in

rologic emergency. The important triad of

which the patient cannot produce speech, pa-

Wernicke encephalopathy includes behavioral

tients with Wernicke aphasia speak excessively

alterations, extraocular movement abnormali-

and typically are unconcerned about their speech

ties, and ataxia. These symptoms occur to a

and behavioral abnormalities. The family and

greater or lesser extent with selective memory

medical staff, however, readily recognize the

impairment, and when this memory impairment

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Chapter 15

n Behavioral Neurology

is marked, the syndrome is called Korsakoff

seen. Confabulation is not an essential compo-

psychosis. The two diseases are the same but are

nent of Korsakoff psychosis; the characteristic

referred to with different terms depending on

trait of this condition is the preferential loss of

the degree of memory deficit. The pathogenesis

recent memory.

of this syndrome relates to vitamin deficiency in

The patient with chronic Wernicke-Kor-

the form of vitamin B₁ (thiamine). The primary

sakoff syndrome is typically alert and ori-

patients at high risk for this syndrome are alco-

ented but displays characteristic deficiencies

holics who obtain calories through the alcohol

in recent and remote memory. The recent

but do not receive essential vitamins. Patients

memory deficit is usually profound and con-

with prolonged emesis or with gastric bowel re-

sists of an inability to make an enduring

section or bariatric surgery also can suffer with

record of daily experiences. The remote mem-

thiamine deficiency. Occasionally, voluntary

ory deficit is temporally graded such that

starvation in the form of political protest, psy-

more remote events are relatively more acces-

chotic disturbances, or unsupervised treatment

sible to recall. Thus, a patient asked to name

of obesity also can induce this syndrome. Fi-

presidents since World War II may recall Tru-

nally, and important to surgical patients, hyper-

man and Eisenhower but not their successors.

alimentation can be associated with Wernicke

Confabulation is not typically seen in chronic

encephalopathy when water-soluble B vitamins

patients. Behaviorally, such patients are usu-

are not included in the formula.

ally apathetic and indifferent, with occasional

outbursts of irritability.

n SPECIAL CLINICAL POINT: When a

patient presents with behavioral changes and

n SPECIAL CLINICAL POINT: Memory loss is

has a gait abnormality and abnormalities of eye

the key behavioral abnormality seen in

movements, Wernicke encephalopathy must be

Wernicke encephalopathy.

considered and rapid treatment with thiamine

In diagnosing this syndrome, the neurologic

supplementation is essential to treat this

signs of extraocular muscle palsy or nystagmus

medical emergency.

and ataxia are important features to recognize.

In many ways, the patient with acute Wernicke

The behavioral picture of Wernicke

encephalopathy looks like a drunkard with

encephalopathy-Korsakoff psychosis has three

trouble walking, nystagmus, and altered affect.

different presentations. The patient with acute

Because of the similarity, it is a common adage

Wernicke encephalopathy shows global confu-

that a drunk patient seen in the emergency

sion, and his or her demeanor is usually quiet

room should be given an injection of thiamine

and apathetic. He or she is alert and responsive

(a) to treat possible Wernicke encephalopathy

but inattentive, and the patient appears fa-

and (b) to prevent a future episode of the con-

tigued. Occasionally, a patient may be more

dition. The chronic patient is difficult to manage

agitated, especially if he or she is undergoing

because, although the extraocular movements

delirium tremens associated with alcohol with-

improve quickly with thiamine therapy and

drawal. The usual presentation, however, is

the ataxia improves to a moderate extent, the

one of an affable but dull affect.

memory problems are least abated by thiamine

In the partially treated patient or in the early

therapy.

stages of chronic disease, the affect becomes

more bright, and the patient becomes more lo-

quacious. The memory deficits become more

ANATOMIC BASIS

apparent as the patient is less globally con-

fused. The patient is nonhesitant in his speech,

The unifying basis for this disorder involves the

and it is at this point that the famed confabula-

Papez circuit where there is capillary prolifera-

tory aspects of Korsakoff psychosis may be

tion at the level of the mammillary bodies. In

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Chapter 15

n Behavioral Neurology

some cases in which the mammillary bodies

of alcohol withdrawal in the hospital and its

are spared, the anterior lobe of the thalamus is

consequences including delirium tremens is

involved. Additional pathologic findings may

high. The hospital staff must be aware of these

involve cerebellar and diffuse cortical degenera-

problems and appropriately protect the patient

tion. Although the clinical picture of Korsakoff

against injury and medical complications of al-

psychosis should immediately suggest vitamin

cohol withdrawal, especially in the first 72 hours

deficiency and disease that at least includes the

of hospitalization, as outlined in Chapter 12.

mammillary bodies, it can be seen in diseases

These include a careful attention to the diagno-

that involve other aspects of the Papez circuit.

sis of infection or associated injuries, such as

The same syndrome has been reported in pa-

meningitis or subdural hematomas. Further,

tients who recover from a viral encephalitis with

maintenance of fluid and electrolyte balance is

prominent hippocampus involvement. Such clin-

essential, as well as a watchful attention to the

ical overlap again emphasizes the importance of

possibility of hypoglycemia. Control of agita-

the Papez circuit in localizing diseases that in-

tion is essential to avoid patient and staff in-

volve both memory and affective disorders.

jury. Specific recommendations are outlined in

Chapter 12.

Treatment

All patients with suspected Wernicke encepha-

lopathy must immediately receive thiamine. At

TRANSIENT GLOBAL AMNESIA

least 100 mg intravenous thiamine should be

The syndrome of transient global amnesia oc-

given, followed by 100 mg IM daily for 3 to

curs in middle-aged or elderly patients. A char-

5 days, with a chronic dose of oral thiamine

acteristic triggering event, such as physical or

(50 mg daily) and a multivitamin.

emotional stress or sexual intercourse, often

Once thiamine has been given and good nu-

precedes the amnestic episode.

trition is reestablished, physical and occupa-

When the spell has begun, the patient is un-

tional therapy can be recommended to help in

able to learn new information until it is over.

gait training and coordination. Full neuropsy-

His memory for events that day and the preced-

chologic testing will help in establishing spe-

ing day are almost always poor. Memory for

cific mental deficits and provide data that will

prior events will be better, although memory

be useful for discharge planning. No alterna-

loss during the event sometimes will be de-

tive medical therapies are recommended.

tectable even for events that took place years

When to Refer to a Neurologist

before the amnestic spell. The syndrome of

transient global amnesia typically clears com-

The non-neurologist should never hesitate to

pletely within 24 hours, except for a permanent

treat a patient with components of Wernicke

amnesia for the episode itself. Significantly, the

encephalopathy with thiamine. Clear docu-

patient’s affect is often bland during the episode,

mentation on the chart of the mental status, the

although family members are distressed.

presence of nystagmus or ophthalmoplegia,

Patients with transient global amnesia are

and a description of the gait should be noted.

often brought to medical attention when the

Therefore, the neurologist can be consulted to

family notes that they repeatedly ask the same

corroborate the diagnosis and suggest other

questions and seem unable to remember the an-

treatment or diagnostic evaluations.

swer and sometimes deny that an answer has

been given. At the same time, these patients may

Special Challenges for Hospitalized Patients

perform complex tasks during an episode with-

Because so many patients with Wernicke en-

out difficulty, as long as these tasks were learned

cephalopathy are heavy alcohol users, the risk

prior to the event.

318

Chapter 15

n Behavioral Neurology

These patients are not globally confused. In

Transient global amnesia is most often con-

testing orientation, however, they may report

fused with psychogenic amnestic states. Hysteri-

the wrong answer because they cannot inte-

cal amnesia may occur abruptly but is frequently

grate changes in place and time. When asked to

associated with a specific precipitating event,

do arithmetic calculations or use logical pro-

with retention of memory for other events within

cessing, they respond appropriately.

the time interval. One does not see the profound

yet selective deficit in recent memory, nor the

n SPECIAL CLINICAL POINT: A sudden change

temporally graded retrograde amnesia.

in behavior that involves continual questioning

In the more severe hysterical amnesia, such

with the inability to retain new information in a

as in fugue states, there is the characteristic

patient who is otherwise alert should

dissociative behavior with an additional loss

immediately suggest transient global amnesia.

of personal identity, a feature not seen in tran-

Memory testing during an attack of transient

sient global amnesia. In contrast to the tran-

global amnesia demonstrates a marked inability

sient global amnesia patient, the hysterical

to establish new memories despite preserved at-

patient will often acknowledge that the mem-

tention, language, and higher cognitive function-

ory is poor but will have an inappropriate af-

ing. If the physician leaves the room of a patient

fect, “la belle indifférence.”

with this disorder, he will have to reintroduce

himself when he returns. Recent memory func-

Anatomic Basis

tion is deficient in such patients regardless of

which sensory system is used in the memory

Because the episodes of transient global amne-

tasks, so that visual, tactile, and auditory memo-

sia tend not to recur, no extensive pathologic

ries are disturbed. The retrograde amnesia is

studies have been performed on patients. The

such that the activities of the previous days may

anatomic basis of this syndrome, however, is

be only dimly recollected during the episode. The

felt to relate to temporal lobe dysfunction in

retrograde amnesia is occasionally more exten-

the area involved in the Papez circuit. MRI

sive, affecting memories formed years before the

studies have shown that, despite the transient

episode. Confabulation is notably lacking in

nature of the syndrome, some patients with

these patients. On recovery, there is no recollec-

transient global amnesia show small unilateral

tion of the episode itself, and there is typically a

or bilateral changes on diffusion-weighted

permanent retrograde amnesia for events occur-

MRI in the hippocampal regions within the

ring in the moments prior to the episode.

first 24 to 48 hours following the event. The

This syndrome with its peculiar constella-

etiology of transient global amnesia remains

tion of memory and behavioral features can be

uncertain, but current hypotheses include

highly confusing unless it is recognized.

transient venous or arterial ischemia to the

In patients whose amnesic episodes are brief

hippocampi, and migraine. As noted above,

(e.g., less than 1 hour) and/or recurrent, TLE

patients with epilepsy as the cause of tran-

should be considered, and treatment with anti-

sient amnesia

(transient epileptic amnesia)

convulsant medications can be successful. In

tend to have briefer and more recurrent at-

patients with focal neurologic signs or symp-

tacks than patients with classic transient

toms during or subsequent to the amnesic

global amnesia.

episode, tumors and cerebrovascular disease

should be considered, and the prognosis may

Treatment

be more guarded. If the amnesia includes addi-

tional disorientation and/or inattention, drug

For most patients, the dramatic events of tran-

ingestion, especially of anticholinergic or seda-

sient global amnesia never recur, and therefore,

tive drugs, may be the cause.

treatment is not required. Diagnostic tests to

319

Chapter 15

n Behavioral Neurology

examine for cerebrovascular disease, epilepsy,

HERPES SIMPLEX ENCEPHALITIS

and migraine are important, and MRI and

EEG are both useful tests. A second attack oc-

Herpes encephalitis affects primarily the tem-

curs in less than 25% of subjects, and fewer

poral lobes and leads to necrosis and hemor-

than 5% have more than three episodes. The

rhagic

destruction of brain tissue. The

frequency of seizures or subsequent strokes is

mortality rate in herpes simplex encephalitis

not different from that of a comparable age-

has been reduced, but the prevalence of neuro-

matched group without a prior episode. Unless

logic deficits among survivors remains high.

a specific etiologic diagnosis is made, no treat-

These deficits are almost exclusively in the be-

ment is needed.

havioral realm. Temporal lobe seizures already

described are a common presenting feature of

this disease. Acute or subacute behavioral

When to Consult a Neurologist

changes, including cognitive and memory im-

The isolated event is rarely seen by the neurolo-

pairment, mood alterations, and psychiatric

gist, and often only the emergency room physi-

symptoms, may be the first signs of encephali-

cian actually witnesses the amnestic episode. In

tis. The most common behavioral sequel of

such cases, the neurologist is best utilized as a

herpes encephalitis is an amnesia that can be

consultant to interpret the description of events

isolated, with sparing of other cognitive func-

and guide the non-neurologist in the limited di-

tions. The amnesia consists of an inability to

agnostic tests needed and the usual lack of

form enduring memories. In more severe cases,

needed intervention. A follow-up appointment

the deficit in recent memory is accompanied by

after the event with a neurologist is useful to

alterations in language, perception, and intelli-

document the absence of static neurologic

gence such that global dementia is seen. This

signs; at this appointment, the neurologist can

linguistic disorder typically resembles a fluent

review with the family the relative statistics on

aphasia with poor comprehension and para-

recurrence and the signs or symptoms of stroke,

phasic or nonsensical speech. Profound percep-

migraine, and epilepsy that should alert the

tual problems may also be seen: patients may

family to a second consultation.

be unable to recognize family members or

friends

(prosopagnosia) or common objects

(visual agnosia).

Special Challenges for Hospitalized Patients

The most striking potential sequelae of her-

Most of these patients are seen in emergency

pes simplex encephalitis are a series of often

room settings; therefore, acute care personnel

bizarre behavioral and emotional changes that,

must be aware of the distinctive features of

in the extreme, resemble those reported by

this syndrome. The combination of sudden

Kluver and Bucy in primates after bilateral re-

memory loss without superimposed confu-

moval of the temporal lobes. In humans, the

sion and without language abnormalities

syndrome is sometimes referred to as a limbic

should alert nurses and physicians to this en-

dementia and consists of (in addition to the vi-

tity. Very specific and rapid documentation

sual agnosia) emotional placidity, distractibil-

on the memory loss, affect, and preservation

ity, and alterations in sexual behavior. Thus,

of other mental capacities is essential because

patients are often apathetic with flat affect and

the syndrome clears quickly. Because of its

may show childlike compliance. In humans,

very good prognosis, transient global amne-

the hypermetamorphosis consists of manual

sia must be considered and specifically diag-

and oral exploration of the environment with

nosed while the signs are still present, not

placement of objects in the mouth. Episodes of

afterward when the neurologic examination

bulimia may be seen along with ingestion of

is normal.

inappropriate material. The sexual changes

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Chapter 15

n Behavioral Neurology

consist primarily of inappropriate comments

When to Refer the Patient to a Neurologist

and overtures. The Kluver-Bucy syndrome is

The main experts in this condition are infec-

not diagnostically specific; the symptom com-

tious disease specialists and neurologists.

plex may also be seen with head trauma,

Rapid consultation is essential to order the ap-

Alzheimer disease, and Pick disease. The behav-

propriate cerebrospinal tests and initiate ther-

ioral alterations in herpes simplex encephalitis

apy without delay. With this guidance, the

are typically less extreme than the full Kluver-

non-neurologist often will manage the case

Bucy syndrome, and they consist of episodically

with appropriate reconsultation of these spe-

inappropriate behavior, personality changes,

cialists as needed.

delusions, and hyposexuality. Such behavioral

sequelae frequently are viewed as psychogenic

Special Challenges for Hospitalized Patients

by the family and may be resistant to tradi-

tional forms of psychiatric treatment.

Most patients with herpes encephalitis are hos-

pitalized during the acute illness, and special at-

n SPECIAL CLINICAL POINT: Memory loss is

typical of Herpes encephalitis, and many other

tention must be given to the identification of

behaviors and personality changes can occur in

seizures and preherniation syndromes. Nursing

the acute infection.

staff must be vigilant to the level of conscious-

ness of the patient, vital signs, the strength of

arms and legs, and the size of the pupils. Because

Anatomic Basis

temporal lobe swelling can occur, the develop-

For unknown reasons, herpes encephalitis has

ment of a large pupil, contralateral weakness of

a predilection for the temporal lobes of the

the arm and leg, and change in level of con-

brain; therefore the cortical regions of the

sciousness are significant neurologic changes

Papez circuit are involved. The encephalitis is

and call for emergency intervention. Staff must

not isolated to the temporal lobe, but the major

be educated to observe the patient for involun-

involvement occurs in this area often in an

tary jerking movements, sometimes very subtle,

asymmetric pattern, with one lobe showing

that can indicate seizures.

more hemorrhagic involvement than the other.

The unifying points of this chapter have been

that abnormal behavior can be a manifestation

of focal neurologic disease and the lesions re-

Treatment

sponsible for such behaviors mainly are pre-

Acyclovir is the drug of choice for the treat-

dictably located somewhere in or near the

ment of herpes simplex encephalitis, and the

Papez circuit. Using the Papez circuit as the

standard care is 30 mg/kg/day for a minimum

foundation provides two major diagnostic ad-

of 14 days. Higher doses and longer courses

vantages. First, behavior can be analyzed with a

(3 weeks followed by an oral antiviral agent)

systematic, rigorous discipline provided by neu-

are being investigated. Brain biopsy generally is

roanatomy. Second, because this is an anatomic

reserved for subjects whose diagnosis remains

circuit, there is the plasticity to integrate dis-

unclear despite the diagnostic studies that

eases that may be of different etiologies or that

include MRI scans and polymerase chain re-

may affect different nuclei in the brain and yet

action (PCR) assays of cerebrospinal fluid. An-

that present with similar clinical presentations.

ticonvulsant medications may be needed for

seizure treatment or prevention. After recov-

Future Perspectives

ery, physical, occupational, and speech therapy

may be important to maximize rehabilitation.

There has been new interest in the treatment of

No alternative medical therapies are indicated

memory deficits with presumed cholinergic

for this acute infection.

precursors such as lecithin or choline chloride,

321

Chapter 15

n Behavioral Neurology

but these agents have not been tested exten-

problems, and patients ingesting megavita-

sively. Future diagnostic tools with greater

mins may develop many other problems but

anatomic precision will help delineate the exact

certainly not Wernicke encephalopathy.

area of involvement in the Papez circuit for the

Parkinsonian patients are usually slender, but

entities discussed. The use of such tools as

are not thiamine deficient.

function magnetic resonance imagery (fMRI)

2. A patient says he has a seizure disorder.

will allow patients to be tested during memory

He is under arrest for having destroyed his

or other tasks to define the functional deficits

friend’s apartment and beaten up his

related to this anatomy. A greater understand-

girlfriend. He says, “I didn’t mean to. I

ing of the neurochemical transmitters that link

don’t remember a thing.” This behavior

each nucleus in the circuit will help to design

could represent TLE, or it could be

therapies that are more specific to lesions

antisocial behavior by a patient trying to

within this neurologic circuit.

plead ignorance. Along with an EEG,

which of the following supports a likely

seizure disorder?

Always Remember

A. After an argument, the patient raced

• Damage to the Papez circuit often leads to

after his girlfriend, caught her in the

emotional and memory dysfunction.

parking lot, and beat her up.

• An abrupt change in language function should

B. He was observed to exhibit picking

trigger a neurological consultation.

movements of his hands and lip

• Suspected Wernicke’s encephalopathy should

smacking before any belligerent behavior

be immediately treated with thiamine.

began.

• Memory disorders in conditions involving the

C. The fighting and destructive behavior

Papez circuit are primarily characterized by an

occurred when the topic of visiting his

inability to form an enduring record of recent

college roommate for the weekend was

experience (i.e., anterograde amnesia).

broached.

D. The patient says this happened three

times before: “I know when I’m going

into a spell because I hear my mother

whispering in my ears something about

QUESTIONS AND DISCUSSION

my credit card debt.”

1. Patients at high risk for developing

The correct answer is B. Automatisms like

Wernicke encephalopathy include:

those described in B are common in TLE; the

A. Patients with posthepatitis cirrhosis

aura of primitive auditory sensation like a

B. Hospitalized patients receiving

buzzing sound can be part of a seizure, but a

intravenous hyperalimentation

complex and condemning whispering from the

C. Patients with Parkinson disease

patient’s mother is more complex than typical

D. Health food advocates who consume

seizure auras. The destructive combative be-

large quantities of B vitamins

havior seen in epilepsy is not common and

The correct answer is B. Wernicke en-

when it occurs, it is nondirected. Patients will

cephalopathy relates to thiamine deficiency.

not chase after someone in the midst of a

Patients who do not receive vitamins in hy-

seizure, although if they are restrained or con-

peralimentation eventually will become de-

fined, they may possibly be combative. Run-

pleted, as will patients whose dietary caloric

ning after his girlfriend in the midst of an

intake involves only alcohol. Cirrhosis per se

argument and searching for her in a dark

is not associated with water-soluble vitamin

parking lot is a highly directed violent activity

322

Chapter 15

n Behavioral Neurology

far outside the realm of epilepsy. Epileptic

SUGGESTED READING

spells can be triggered by hyperventilation

and other stimuli, but a specific topic like a

Benson DF. Aphasia, Alexia, and Agraphia. New York:

visit to the former roommate is far too

Churchill Livingstone; 1979.

specific to suggest epilepsy.

Benson DF, Ardila A. Aphasia: A Clinical Perspective.

New York: Oxford University Press; 1996.

3. Transient global amnesia is felt to relate to

Bogen JE. Wernicke’s region—where is it? Ann NY Acad

dysfunction in which of the following brain

Sci. 1976;280:834.

regions?

Edwards S. Fluent Aphasia. Cambridge: Cambridge Uni-

A. Frontal lobes

versity Press; 2005.

B. Parietal lobes

Engel J, Caldecott-Hazard S, Bandler R. Neurobiology of

C. Hippocampal regions

behavior: anatomic and physiological implications re-

D. Occipital lobes

lated to epilepsy. Epilepsia. 1986;27(suppl 2):53.

The correct answer is C. Transient global am-

Flor-Henry P. Lateralized temporal-limbic dysfunction

nesia occurs due to transient dysfunction of

and psychopathology. Ann NY Acad Sci.

1976;280:777.

the hippocampal regions of the temporal lobes,

brain regions involved in recent memory.

Gabrieli JDE. Memory systems analyses in aging and

age-related diseases. Proc Nat Head Sci. 1996;93:

4. Other conditions, besides transient global

13534-13540.

amnesia, that are part of the differential

Geschwind N. Aphasia. N Engl J Med. 1971;284:654.

diagnosis of amnestic syndromes include:

Greenwood R, Bhalla A, Gordon A, et al. Behaviour distur-

A. Anticholinergic drug effect

bance during recovery from herpes simplex encephali-

B. Psychomotor epilepsy

tis. J Neurol Neurosurg Psychiatry. 1983;46:809.

C. Head trauma

Hanibert G. Emotional disturbance and temporal lobe in-

D. Migraine headaches

jury. Compr Psychiatry. 1978;19:441.

E. All of the above

Hodges JR, Warlow CP. The aetiology of transient global

amnesia: a case-control study of 114 cases with

The correct answer is E. It is important to con-

prospective follow-up. Brain. 1990;113:639.

sider all of the listed options in dealing with the

Kinsella LJ, Riley DE. Nutritional deficiencies and syn-

differential diagnosis of amnestic syndromes.

dromes associated with alcoholism. In: Goetz CG, ed.

Textbook of Clinical Neurology. 2nd ed. Philadelphia:

5. During or after herpes encephalitis, which

WB Saunders; 2003:873-888.

of the following occur?

Luria AR, Hutton JT. Modern assessment of the basic

A. Temporal lobe seizures

forms of aphasia. Brain Lang. 1977;4:190.

B. Aphasia

Miller JW, Peterson RC, Metter EJ. Transient global

C. Amnesia

America: clinical characteristics and prognosis.

D. Childlike affect and hypersexual behavior

Neurology. 1987;37:733.

E. All of the above

Papez JW. A proposed mechanism of emotion. Arch

The correct answer is E. During the en-

Neurol Psychiatry. 1937;38:725.

cephalitis, and as a residual, seizures may

Pierce CJ. The anatomy of language: contributions from

occur and they may be difficult to control.

function neuroimaging. J Anat. 2000;197:335-359.

Because there may not be generalized shak-

Pincus JH, Tucker GJ. Behavioral Neurology. New York:

ing, tongue biting, or incontinence associated

Oxford University Press; 1974.

with the spells, they may not be appreciated

Pritchard PB, Lombroso CT, McIntyre M. Psychological

as epileptic aphasia. Especially fluent forms

complications of temporal lobe epilepsy. Neurology.

1980;30:227.

can occur because the dominant temporal

lobe may be diseased, and when both tempo-

Quinette P, Guillery-Girard B, Dayan J, et al. What does

transient global amnesia really mean? Review of the

ral lobes are affected, amnesia and the

literature and thorough study of 142 cases. Brain.

Kluver-Bucy syndrome may occur.

2006;129:1640-1658.

Traumatic Brain

Injury

MICHAEL J. MAKLEY

key points

• Traumatic brain injury (TBI) is the leading cause of

death and disability in young adults.

• The two primary mechanisms of injury in

acceleration/deceleration brain trauma are focal

cortical contusion and widespread neuronal damage

called diffuse axonal injury (DAI).

• The duration of amnesia and confusion termed

posttraumatic amnesia (PTA) is the best predictor of

outcome following TBI.

• Disrupted sleep cycles play a major role in the cognitive

and behavioral deficits that are the hallmarks of

emergence from a moderate-to-severe TBI.

• Although patients with TBI are at an increased risk for

seizures, use of prophylactic anticonvulsants should not

continue beyond one week after injury in most cases.

tations with TBI. Topics covered will range from

EPIDEMIOLOGY AND OVERVIEW

the patient in coma to guidelines for dealing with

sports-related concussion. This overview will pro-

The wide spectrum of possible presentations in

vide the reader with a sense of the breadth of the

traumatic brain injury (TBI) offers several chal-

disease process; an understanding of some basic

lenges to the clinician. Often the clinician is asked

terminology and pathophysiology; and finally,

not only to manage the patient medically but also

some fundamental concepts of managing these

to prognosticate regarding outcome and return to

patients at various levels of disease severity.

former activities such as school, work, or driving.

The aftermath of brain injury has a huge im-

Managing each of these patients is complicated

pact not only on individuals and families but

additionally by various factors that will affect out-

also on society. It has been estimated that 1.5 to

come and recovery, such as the extent and severity

2 million people suffer a TBI each year, with

of injury, age, genetic factors, premorbid learning

nearly a million of these being treated in an emer-

disability, or substance abuse history. This chapter

gency room. In relative terms this is greater than

will discuss this wide spectrum of patient presen-

324

325

Chapter 16

n Traumatic Brain Injury

the yearly incidence of stroke, spinal cord injury,

n SPECIAL CLINICAL POINT: Traumatic brain

and multiple sclerosis combined. The incidence

injury in the younger population is primarily

young males having car and motorcycle accidents

of severe TBI is 14 per 100,000 people, with

while in the older population brain injury is

nearly 60% of these people dying from their in-

generally related to falls and is more evenly

jury. The incidence for moderate and mild TBI is

distributed between males and females.

15 and 131 per 100,000, respectively.

There is a bimodal distribution in regard to

age and TBI. The first peak, in the second and

PATHOPHYSIOLOGY AND

third decade of life, is predominantly related to

OPERATIONAL TERMS

motor-vehicle accidents

(MVA); the second

peak, in the sixth decade of life, is predominantly

To understand TBI at any injury severity level

related to falls. In the younger age groups it is a

it is important to understand some fundamen-

male disease (2:1), whereas in the older age

tal pathophysiology. The two main mecha-

groups it becomes more evenly distributed be-

nisms of injury considered to be at work in

tween genders. TBI is the leading cause of death

acceleration/deceleration injury are related to

and disability in young adults, affecting this pop-

impact injury or focal cortical contusion and

ulation in their peak income-producing and re-

diffuse axonal injury (DAI). In Figure 16.1, an

productive part of their lives. The economic

impact injury, the point of impact is primarily

impact in the United States has been estimated

the bilateral frontal and temporal poles, which

for both direct and indirect costs of lost wages

correspond to the brain overlying the inside of

and productivity at $39 billion per year. Despite

the skull’s orbitofrontal ridge and each wing

this incidence and cost to society there are very

of the sphenoid bone, which cradles the tem-

few well-controlled clinical trials to guide the cli-

poral lobes. These areas of damage ultimately

nician in the management of these patients after

will lead to long-term behavioral sequelae of

acute resuscitation. Often treatment is based on

TBI as manifested by executive dysfunction,

small trials, case reports, and anecdote. The need

specifically deficits in behavior modulation,

for the development of effective treatment is

attention, and memory encoding and retrieval.

made all the more compelling with the return of

Other focal injuries to motor, language, and vi-

soldiers from Afghanistan and Iraq. It is esti-

sual cortex will lead to more obvious neuro-

mated that 10% to 20% of soldiers involved in

logic syndromes such as spastic hemiparesis,

these two wars have sustained a head injury. The

aphasia, and hemianopsia.

enormity of the cost of long-term care and man-

The pathologic hallmark of DAI on a cellu-

agement of these veterans is only beginning to be

lar level is the presence of axonal retraction

realized.

balls (Fig. 16.2). Originally it was thought that

FIGURE 16.1 Hemorrhagic contusion at frontal and temporal lobes after traumatic brain injury.

326

Chapter 16

n Traumatic Brain Injury

FIGURE 16.2 Axonal retraction ball formation seen in

FIGURE 16.3 Diffuse white matter petechial

diffuse axonal injury (DAI).

hemorrhage seen in diffuse axonal injury (DAI) on

gross section.

these occurred with shearing forces to the axon

For every level of injury this secondary cascade

at the moment of impact and that these “balls”

of events also will have an impact on outcome

were just the effect of the axon rolling up like a

and recovery. Anoxic injury in addition to TBI

window shade that was wound too tightly.

is associated with the worst outcome, and the

Postmortem studies, however, have shown that

prognosis for a good recovery is poor. Finally,

these retraction balls are not evident for 12 to

in considering outcome, it is important to keep

24 hours postinjury. It is now thought that im-

in mind that the extent of each person’s recov-

pact causes a perturbation in axoplasmic trans-

ery from TBI may be determined by an individ-

fer that, over several hours, leads to axonal

ual’s genetic makeup. Some research suggests

swelling and finally disconnection and Waller-

that patients carrying a mutant allele of

ian degeneration. This disconnection leads to

apolipoprotein E have increased beta amyloid

widespread deafferentation, which is thought

deposition in the brain and a significantly

to be one of the most significant factors in

longer recovery following TBI.

terms of long-term morbidity and recovery. Al-

Before discussion of patient management, it is

though DAI is a pathologic, postmortem diag-

helpful to define certain terms commonly used

nosis, patients who survive TBI are described

by specialists who treat brain-injured patients.

as having had axonal injury when there is a

Because of the current lack of any specific func-

prolonged loss of consciousness with a normal

tional or structural imaging test that can reliably

computed tomography

(CT) scan or neu-

define the extent of injury, the field has relied pri-

roimaging findings that show diffuse petechial

marily on descriptor scales to describe brain in-

intraparenchymal hemorrhage (Fig. 16.3).

jury severity. Two of the most commonly used

scales in TBI are the Glasgow Coma Scale

n SPECIAL CLINICAL POINT: The primary

(GCS) and the Rancho Los Amigos Scale (RLAS)

mechanism of brain injury in acceleration/

(Figs. 16.4 and 16.5) . The GCS is widely used in

deceleration trauma is focal cortical contusion

trauma centers to describe the level of awareness

and diffuse axonal injury (DAI).

in the patient with TBI. This scoring system oc-

Other factors that contribute to injury sever-

curs over three domains of motor, verbal re-

ity include extra-axial and intraparenchymal

sponse, and eye opening. The lower scores (3-8)

hemorrhage, anoxia, and impact depolariza-

are associated with coma or the minimally re-

tion with widespread release of excitatory neu-

sponsive patient, and the higher scores (13-15)

rotransmitters and generation of free radicals.

describe a person who may be a little confused

328

Chapter 16

n Traumatic Brain Injury

FIGURE 16.5 The Rancho Los Amigos Scale of Cognitive Functioning after traumatic brain injury.

but is oriented and following commands. The

each stage on the scale is directly proportional

GCS also has been used to grade severity of TBI

to the severity of injury. In the least severe in-

(Fig. 16.6). Although commonly used to grade

jury, such as concussion, passage through the

severity, a number of recent studies have shown

first stages may be fairly rapid. In the more se-

that initial GCS is a poor predictor of long-term

vere cases the passage up these stages can be

functional outcome.

months to years, and for some patients their

The RLAS is used primarily in the postacute

progress can stall at any point on the RLAS.

or rehabilitation setting, in which the bottom

Traumatic brain injury is unique among ac-

of the scale, I and II, is associated with a vege-

quired brain disease because of the predomi-

tative state and the top of the scale at VIII is as-

nance of behavioral and memory deficits over

sociated with only mild cognitive deficits. This

motor and sensory deficits. Because of this, it is

scale is a narrative description of emergence

important to understand the concept of post-

stage by stage from DAI where the duration of

traumatic amnesia (PTA), a unique memory

329

Chapter 16

n Traumatic Brain Injury

FIGURE 16.6 Severity of brain injury graded by Glasgow Coma Scale (GCS).

disorder of TBI. PTA is a compound amnestic

While the initial GCS score is a poor prog-

syndrome in which a person has lost both pre-

nostic marker, the duration of PTA has been

viously acquired memory (retrograde amnesia)

linked to severity of injury, long-term func-

as well as the ability to lay down new memory

tional outcomes, and resource utilization. PTA

(anterograde amnesia). PTA is more than a

longer than 24 hours is associated with severe

memory disorder. It is a constellation of behav-

TBI. Data from Katz and Alexander showed

ioral symptoms, which in addition to amnesia

that for those with PTA of less than 2 weeks,

includes poor safety awareness and insight into

76% reached a level of good recovery, whereas

deficits, decreased attention, as well as impulse

22% were moderately disabled and 2% were

dyscontrol. In many ways this state could be

severely disabled at 1 year. For survivors with

considered a delirium. Patients with ongoing

8 to 12 weeks of PTA, only 12% had a good re-

PTA are very difficult to discharge into the

covery at 1 year, whereas 75% suffered moder-

community because of the need for 24-hour su-

ate disability and 13% were severely disabled.

pervision. Because of this, many patients will

No one with PTA longer than 12 weeks had

be discharged to nursing homes or specialized

what was described as a good recovery.

behavioral units until this resolves.

Information about long-range needs for pa-

Obviously the inability to lay down memory

tients following head injury is often identified

has implications for any rehabilitation-training

by loved ones and families of brain-injured in-

program, but the duration of PTA also has

dividuals as essential information they expect

been used to describe severity of TBI as well as

from the clinician. However, the traditionally

predict outcome in terms of disability. One

quoted percentage breakdown between good

neuropsychologic screening test to determine

recovery and disability, as discussed above, can

the duration of PTA is called the Galveston

often be confusing for families. Kothari and

Orientation and Amnesia Test

(GOAT), in

colleagues recently completed a review of the

which a score of 75 or greater is associated

literature on TBI outcomes in order to develop

with resolution of PTA. Another commonly

evidence based “threshold values” for prog-

used tool to measure PTA in the rehabilitation

nostication following head injury based on du-

setting is called the Orientation Log or O-LOG.

ration of both PTA and coma. These values can

The O-LOG is less cumbersome than the

be helpful to the clinician in discussions with

GOAT and can be administered by a clinician

families regarding long-term outcomes. Ac-

other than a neuropsychologist. This particular

cording to this review, severe disability, or

test scores the patient from 0 to 30 and the

being functionally dependant for most care, is

threshold for clearance of PTA is a score of

unlikely with a period of PTA less than the

25. Serial testing using either the GOAT or the

threshold value of 2 weeks. Conversely dura-

O-LOG provides the length of time spent in

tion of PTA greater than 3 months is unlikely

this amnestic state. Length of PTA can be esti-

to be associated with a return to previous level

mated retrospectively by a neuropsychologist.

of functioning and independence. With regards

330

Chapter 16

n Traumatic Brain Injury

to the comatose patient, Kothari’s review sup-

to an overwhelming increase in intracranial

ports the observation that the longer the dura-

pressure from intraparenchymal edema. Even

tion of coma the worse the outcome. In terms

without an expanding mass lesion this type of

of coma threshold values Kothari suggests that

diffuse swelling can rapidly lead to herniation

for coma less than 2 weeks severe disability is

and death. Typically neurosurgeons monitor

unlikely while a good recovery is improbable

this with an intracranial pressure monitor that

for patients in coma longer than 3 months.

is passed through the skull. Patients may be

given hypertonic saline or mannitol and may

n SPECIAL CLINICAL POINT: Families of

be hyperventilated to bring their P down to

people with head injury identify prognostic

CO2

25 mmHg. Pentobarbital coma is often the

information on long-term outcomes as the

next step when these measures fail to bring

most important information they need from

down the pressure. Even with all of these inter-

the clinician after the acute period. Threshold

ventions, patients with severe trauma can con-

values based on duration of PTA and coma can

tinue to have unrelenting elevated pressures.

help present this information in an

understandable way.

The most drastic measure to reverse this

process is craniectomy and duraplasty. This

surgery removes the cranium and places a du-

raplastic patch on the dura that allows the

ACUTE HOSPITALIZATION

brain to expand unimpeded by the calvarium.

Most patients who experience a brief loss of

The skull flap is frozen in the pathology lab

consciousness and present to the emergency de-

and replaced after the swelling has subsided.

partment with a GCS of 13 to 15 will have rou-

Although many patients survive the acute

tine evaluations that should include a complete

edema, carefully controlled studies have not

neurologic examination, CT scan looking for

been done for this dramatic intervention and

evidence of extra-axial blood, and radiographic

long-term outcome data are unknown.

clearance of any neck injuries. Those with a

Another issue that arises in the acute care

normal neurologic and radiographic examina-

setting is seizure prophylaxis. People with

tion often will be sent home after a period of

closed-head injury (CHI) are at a greater risk of

observation. The acute hospitalization of mod-

developing seizures. Various studies have found

erate-to-severe TBI typically will be managed in

between 2% and 12% of patients with CHI

a trauma center and will be provided by a neu-

will develop posttraumatic seizures. For those

rosurgeon or an experienced team of trauma

with dural-penetrating injuries, the rate may be

specialists and intensivists.

more than 50%. In the early 1990s Temkin and

In the acute hospitalized setting the primary

colleagues investigated seizure prophylaxis using

focus of care often will be the management of

a double-blind, placebo-controlled paradigm

increased intracranial pressure and intracranial

in patients presenting with TBI. Their results

hemorrhage. Patients with expanding epidural

showed there was no benefit to phenytoin after

hematomas will be taken to the operating room

the first 7 days in terms of preventing the devel-

immediately. Subdural and intraparenchymal

opment of posttraumatic seizures. However, pa-

blood will be assessed for evacuation according

tients with penetrating head injury, because of the

to the grade and severity as well as the underly-

higher risk of developing posttraumatic seizures,

ing neurologic examination. The blood gener-

should be maintained on seizure prophylaxis for

ally may be removed when it is associated with

6 months to 1 year, depending on the severity of

mass effect and shift of midline structures or a

injury.

deteriorating neurologic examination.

With severe impact injury the secondary

SPECIAL CLINICAL POINT: While patients

cascade of widespread depolarization can lead

with closed head injury should be taken off

331

Chapter 16

n Traumatic Brain Injury

prophylactic seizure medication after 7 days,

complications that come from an immobile,

those patients with dural penetration injury

minimally responsive patient. Such a patient

(i.e., a bullet) should be maintained on seizure

needs provision of aggressive pulmonary toilet,

medications for 6 months to 1 year.

treatment of infections, prevention of decubitus

ulcers, maintenance of adequate nutrition, man-

agement of spasticity, and access to comprehen-

POSTACUTE HOSPITALIZATION

sive family education. The role of the inter-

As methods for acute resuscitation improve

disciplinary therapy team within a specialized

with the development of acute trauma centers

low-level brain injury program is not only for

there has been a dramatic increase in brain-in-

passive range of motion and sensory stimulation.

jured patients at the lowest level of responsive-

Trained therapists also assess the person’s level

ness. Data from the National Traumatic Coma

of responsiveness to his or her environment

Data Bank demonstrated that nearly 10% of

using a systematic scoring tool such as the JFK

the patients discharged from an acute trauma

Coma Recovery Score or other scoring system.

center are in a minimally responsive state, yet

The physician, in addition to treating medical

there is no consensus on their appropriate

issues and spasticity, often will introduce vari-

management. Often these patients are dis-

ous neurostimulants, such as methylphenidate,

charged to nursing homes poorly equipped and

amantadine, bromocriptine, or levodopa/car-

trained to manage the complex needs of these

bidopa (Table 16.1). These agents are thought to

patients. Although functional goals are limited

enhance arousal and attention primarily through

in the minimally responsive patient, there is a

augmentation of the dopaminergic system. An-

role for an interdisciplinary approach to the

other agent used to treat attention-deficit disor-

management of these low-level patients (i.e.,

der called atomoxetine is getting wide use in the

RLAS I to II), particularly just after acute hos-

low-level brain-injured patient. This agent is

pitalization. In one study, 60% of patients ad-

thought to primarily work at the noradrenergic

mitted to a specialized low-level head-injury

receptor by selectively inhibiting reuptake of

program emerged and progressed to an acute

norepinephrine. Exactly how these neurostimu-

rehabilitation program with age being the most

lants work in the low-level TBI patient is not

significant predictor of successful emergence.

clear, although they may correct a severe distur-

In these low-level patients the most impor-

bance of sleep-wake cycle. Although there is

tant medical management issues revolve around

widespread use of these agents in this patient

TABLE 16.1

Commonly Used Neurostimulant Agents for Low-Level Responsive Patients Following TBI

Medicine

Effects

Dosing

Amantadine

Both presynaptic and postsynaptic

100 mg b.i.d.

dopaminergic effect

Max. dose 300 mg/day

Bromocriptine

Dopamine agonist

1.25-2.5 mg b.i.d.

Carbidopa/levodopa

Primary targets are mesial and

Starting dose of 25/100 t.i.d. and

prefrontal dopaminergic pathways

titrate up to 1-1.5 g of levodopa

Methylphenidate

Indirect catecholamine agonist

Starting dose at 2.5-5 mg b.i.d.

Can titrate up to 20 mg/day

Dose at morning and noon

TBI, traumatic brain injury.

332

Chapter 16

n Traumatic Brain Injury

population, there are no large-scale, placebo-

driving is the risk of seizures. In those states

controlled trials that guide their use.

without a formal medical review board deter-

After emerging from coma, patients with se-

mining when a person can return to driving, it

vere TBI may progress to RLAS III to VII behav-

may be prudent to refer the patient to a neurol-

ior. At this stage they will exhibit emerging

ogist for an opinion.

awareness and evolving communication; how-

ever, they will have severe cognitive deficits as

well as deficits in attention, self-monitoring, and

SPECIAL CHALLENGES OF THE

safety awareness. The early part of this period

HOSPITALIZED PATIENT

also is marked by motor restlessness, sleep-

Sleep-Wake Cycle Disturbance (SWCD)

wake cycle disturbance (SWCD), and continued

anterograde amnesia. This phase of an emerging

SWCD is often observed during the subacute pe-

head-injured patient’s recovery is best managed

riod of recovery from moderate-to-severe TBI.

in an acute rehabilitation setting with a dedi-

Populations of neurons implicated in sleep-

cated staff of interdisciplinary specialists experi-

wake cycle generation have been found to be

enced in brain injury providing physical therapy,

widespread across the neural axis. These neu-

occupational therapy, and speech and language

rons range from the raphe nucleus of the brain-

therapy. In addition, a neuropsychologist or be-

stem, and the thalamic reticular nucleus, to

havioral psychologist who can address the be-

the basal forebrain nuclei. Given acceleration/

havioral aspects of these patients is an essential

deceleration forces common to TBI it should not

part of the multidisciplinary team.

be surprising that these centers could be indi-

As their working memory returns and pa-

vidually or collectively injured. In addition,

tients move on to the RLAS VII and VIII levels,

neurotransmitter and second messenger system

they frequently are discharged from an acute

derangements are likely involved in this clinical

rehabilitation setting to their families with

phenomenon. A study in patients with moderate

continued outpatient therapy in the commu-

and severe TBI reported low cerebrospinal fluid

nity. Almost all patients, when discharged from

(CSF) levels of hypocretin 1, an excitatory hypo-

a rehabilitation setting after a moderate-to-

thalamic neuropeptide involved in regulation of

severe injury, will require 24-hour supervision,

sleep-wake cycles and known to be reduced or

which is often a very large burden on the fam-

absent in patients with narcolepsy.

ily and caregivers.

Following resuscitation from moderate-to-

Once in the community, patients should be

severe head injury most patients will be sent to a

connected with resources for vocational or ed-

rehabilitation center for intensive therapy. In this

ucational re-entry. There are regional advocacy

setting, daytime drowsiness can affect a patient’s

groups for patients and families with TBI that

participation in therapy, while nighttime wake-

offer resources and support groups to assist in

fulness makes a patient more prone to adverse

this transition. Frequently school systems have

events when less staff is on duty. There is little

programs in place to reintegrate adolescents

description in the medical literature of SWCD

with TBI into the classroom. Some states have

during this early period of recovery. Most stud-

funded programs for vocational evaluation and

ies of sleep disturbance in brain injury have fo-

placement following head injury. In terms of

cused on 6 months to 1 year postinjury. SWCD

motor-vehicle operation, each state has indi-

reported during this chronic phase after injury

vidual requirements and protocols for return to

includes excessive daytime somnolence, sleep

driving after a head injury, and the physician

phase cycle disturbance, narcolepsy, and sleep

should investigate these particulars before

apnea. Problems with sleep are also common in

clearing the person. In CHI the biggest risk for

the early phase of recovery from TBI. In fact,

333

Chapter 16

n Traumatic Brain Injury

Length of Stay in Acute Care

FIGURE 16.7 The probability of sleep disturbance increases with increasing length of stay in the

acute care hospital. This graph suggests that after 25 to 30 days in the acute care hospital disrupted

sleep is almost certain to be present.

disrupted sleep may play a central role in the

medications have been shown in both animal

memory and behavioral deficits common to this

models and human subjects to be detrimental to

period of recovery. It has recently been shown

the recovering central nervous system after in-

that 68% of patients admitted to a rehabilita-

jury. Patients with excessive daytime somno-

tion unit with the diagnosis of moderate-to-se-

lence have poor attention, which may make

vere CHI had disrupted nighttime sleep. Despite

rehabilitation efforts fall short and in some cases

similar admission Glasgow Coma Score (GCS),

lead to transfer of the patient to a lower level of

patients identified with SWCD had longer stays

care such as a nursing home.

in the acute trauma center and the rehabilitation

Poor sleep, regardless of the underlying

hospital and had lower functional scores on ad-

pathology, can have a significant impact on cog-

mission to rehabilitation suggesting that SWCD

nitive functioning and behavior. Several studies

may be a marker for a more severe injury. As

have shown that sleep fragmentation in healthy

Figure 16.7 shows, the longer the patient is in

adults can lead to an increase in daytime sleepi-

the acute trauma center the more likely they are

ness, decrease in psychomotor performance, de-

to have disrupted nighttime sleep and the clini-

pressed mood and sleep apnea. Similarly, a

cian should be aware of this when treating pa-

study of soldiers during simulated combat train-

tients in this postacute setting.

ing found that sleep deprivation led to severe

The problem of disrupted sleep in CHI pa-

degradation in cognitive and executive function,

tients on an inpatient rehabilitation unit is not

including memory, reaction time, attention, and

trivial. Confused patients who are awake at

reasoning. Gathering evidence in the field of

night are often physically restrained by nursing

sleep research suggests that sleep plays a signifi-

staff to prevent falls and unsafe behavior like

cant role in memory consolidation. Interestingly,

ambulating on a broken limb. Restraints in a

poor memory consolidation, impaired attention

confused, emerging head-injured patient fre-

and executive function seen with disrupted sleep

quently lead to more agitation, which in turn

circumscribe the same constellation of symp-

often requires pharmacologic interventions such

toms that are the hallmarks of PTA in emerging

as benzodiazepines or even antipsychotics. Such

brain-injured patients.

334

Chapter 16

n Traumatic Brain Injury

OLOG

Sleep Eff

Days

FIGURE 16.8 This graph illustrates the improvement in sleep temporally correlated with resolution

of posttraumatic amnesia (PTA is considered resolved at an O-LOG score of 25).

It is of primary importance for the clinician

Hypersomnolence is typically treated with

to be aware of the high prevalence of disor-

neurostimulants or modafinil a medication

dered sleep following brain injury and be alert

commonly used in narcolepsy. Clinicians use

for its presence. Appropriate treatment of

typical sedative hypnotics for their patients

SWCD in these patients will hinge on the clini-

with insomnia such as zolpidem or eszopi-

cian correctly identifying the specific type of

clone. Trazodone is frequently used in these pa-

sleep derangement. SWCD in the subacute pe-

tients and may have some beneficial effect on

riod of recovery can manifest as either hyper-

reducing daytime agitation. In TBI patients it is

somnolence, hypervigilance, or a shift/inversion

of normal sleep phase. A recent study has

shown that as sleep improves in these patients

their memory improves and the syndrome of

PTA resolves (Fig. 16.8). Identification of the

specific type of sleep disruption can be accom-

plished by simple nursing observational logs. A

more objective measure of a patient’s complete

circadian cycles, however, can be obtained

using actigraphy. An actigraph is a small wrist-

watch-sized accelerometer which has been used

in sleep research for more than 20 years. This

device differentiates between sleep and waking

based on the amount of movement in the limb

and has been correlated with polysomnography

(Fig. 16.9).

FIGURE 16.9 This is an actigraph on a patient’s wrist.

335

Chapter 16

n Traumatic Brain Injury

best to avoid anticholinergic medications such

bolus, thyroid disease, and other clinical entities.

as diphenhydramine as this may add to their

Centrally mediated symptoms are thought to be

confusion. The clinician should be alert to the

related to hypothalamic damage and most often

possibility that some patients will have a severe

are treated symptomatically and observed. Typi-

form of insomnia or hypervigilance where they

cally these symptoms remit after emergence from

literally do not sleep for consecutive days.

coma. Beta-blockers often are used for this con-

Many of these patients will subsequently de-

dition and serendipitously may help with agita-

velop acute psychotic symptoms such as para-

tion as the patient emerges to the next level on

noid delusions, hallucinations, and severe,

the RLAS. In patients with neurosweats the

directed agitation. In these patients the use of

physician should watch for dehydration, partic-

sedating atypical neuroleptics such as quetiap-

ularly in the patient receiving nutrition and hy-

ine is often helpful. Treatment of circadian

dration through a feeding tube because the

shift of sleep cycles is often accomplished by

dietitian calculating the diet for the patient fre-

using a combination of sedative and stimulant

quently overlooks this.

medications. Some sleep specialists would ad-

vocate the use of light therapy to try to reset

Hyponatremia

sleep cycles in these patients. While trials in

nursing home patients with dementia have

Low serum sodium is a fairly common occur-

shown some benefit of this approach, there are

rence in people with TBI related to their brain

no trials of this intervention in the emerging

injury or medications. Most often electrolyte

head-injured patient. Although there appears

analysis of serum and urine will show that it is

to be an association between disrupted sleep

related to the syndrome of inappropriate antid-

and PTA in the early stage of recovery follow-

iuretic hormone (SIADH) secretion from the

ing moderate-to-severe brain injury, it is un-

anterior hypothalamus.

clear if aggressively treating SWCD leads to a

Drugs often are implicated in SIADH, particu-

shorter duration of this period of confusion or

larly carbamazepine, so a complete review of the

better long-term outcomes.

patient’s pharmacology should be performed.

Management involves removal of potential phar-

n SPECIAL CLINICAL POINT: Sleep-wake

macologic etiologies such as carbamazepine, se-

cycle disturbance is prevalent in traumatic

lective serotonin reuptake inhibitors (SSRIs), and

brain injury and may contribute to the patient’s

nonsteroidal anti-inflammatory drugs (NSAIDs).

confusion, agitation, and poor memory.

For SIADH, the patient is typically fluid re-

stricted to 1500 cc of fluid per day. In refractory

cases, demeclocycline, a tetracycline that blocks

Dysautonomia

the effect of vasopressin on the renal collecting

In patients with moderate-to-severe head injury

duct, is used.

it is not uncommon to observe tachycardia;

tachypnea; hypertension; profuse neurosweats;

Late-Onset Hydrocephalus

and persistently and markedly elevated tempera-

ture, particularly in patients at low levels of re-

Another late complication in TBI is hydro-

sponsiveness (GCS of less than 8 or an RLAS of

cephalus. Subarachnoid blood blocking the

I or II). These symptoms are often attributed to

egress of CSF in the arachnoid villi is thought to

being centrally mediated, although it must be

be the etiology. This diagnosis should be con-

remembered that, for the most part, this is a di-

sidered in a patient who does not progress in

agnosis of exclusion. Prior to this clinical conclu-

terms of recovery or who was progressing and

sion the patient should be evaluated thoroughly

then stops or regresses. At least one follow-up

for infection, dehydration, pain, pulmonary em-

CT scan should be performed on patients in a

336

Chapter 16

n Traumatic Brain Injury

vegetative state following their acute hospital-

triggers for the patient’s agitation. For exam-

ization or in any patient who regresses in their

ple, limit the number of friends and family

rehabilitation program without a clear etiology.

who visit and keep environmental stimuli to a

It remains controversial as to who will benefit

minimum (i.e., turn down the lights, turn off

from a shunt procedure because it is often not

the Jerry Springer show on the television). Part

clear whether the widened ventricles are ex

of agitation can be iatrogenic, caused by at-

vacuo changes from diffuse neuronal loss and

tempts to keep the patient safe because of their

atrophy or indeed a result of a high-pressure

poor insight, memory, and poor safety aware-

system in need of shunting. Therapeutic spinal

ness. Restraints and locking belts invariably

taps are rarely conclusive to determine whether

escalate problems in the patient who is con-

a person needs a shunt, but they often are per-

fused and delirious, and their use should be

formed. Some neurosurgeons will place a tem-

minimized, although at times they are un-

porary lumbar drain to evaluate for clinical

avoidable.

improvement. Others have advocated placing a

A number of theories have been put forth

shunt as a trial for 4 to 6 months.

about the agitation in TBI. One behavioral the-

ory holds that because of severe frontal lobe in-

n SPECIAL CLINICAL POINT: Regression or

jury, the patient becomes stimulus bound. In

failure to progress in recovery following a brain

other words, because of frontal injury the patient

injury in the subacute period should prompt a

has no block or filter on their reaction to their

head CT to evaluate for late-onset

hydrocephalus.

environment or internal needs. This is com-

pounded by several factors, including their con-

fusional/amnestic state, the strange environment

Agitation

of a rehabilitation hospital, and restraint use.

One of the major management problems for

Another theory of agitation in head injury

the clinician dealing with patients emerging at

holds that it is related to attentional deficits.

an RLAS III to V level is agitation. Typically the

Analogous to the child with attention-deficit

agitation is generalized and related to their

hyperactivity disorder, the patient with TBI is

amnestic state and their impulse dyscontrol.

overwhelmed with sensory stimuli, and that

This type of agitation is very similar to delirium,

causes random, generalized striking out or

and causes for delirium should be explored in

hostile behavior. Advocates of this school of

each of these patients before attempting to treat

thought prescribe stimulant medication to try

agitation thought to be related to emerging

to hone attention and reduce agitation. Although

head-injury behavior. Specific entities the clini-

seemingly paradoxical, for some patients with

cian should watch out for include infection,

prominent attentional deficits, giving stimulants

drug or alcohol withdrawal, metabolic abnor-

works.

mality, and adverse drug reaction. The clini-

Although commonly used for agitation in this

cian should also look for sleep-wake cycle

patient population, it is thought that one should

abnormalities, particularly severe insomnia or

avoid neuroleptic medications in patients with

hypervigilance, as this may be playing a role in

TBI because of experimental evidence suggesting

the patient’s agitation. In the low level and

that these agents have a detrimental effect on

confused patient pain is a commonly over-

brain recovery. The exception to this rule is the

looked although prevalent problem in individ-

patient with paranoid delusions or the violently

uals who are often involved in a multitrauma

agitated patient whose actions endanger staff or

injury with concomitant orthopedic and mus-

themselves. For the patient who is acutely agi-

culoskeletal injuries.

tated, the use of haloperidol intramuscularly or

If possible, agitation should be treated non-

intravenously is indicated. For patients with

pharmacologically by removing all identifiable

paranoid delusions but who are not an imminent

338

Chapter 16

n Traumatic Brain Injury

n SPECIAL CLINICAL POINT: Pharmacology

ication works peripherally on the muscle by

should be used to treat agitation only after

inhibiting the release of calcium from the sar-

other measures have been tried.

coplasmic reticulum, thereby inhibiting excita-

tion contraction coupling between the myosin

and the myosin light chain kinase. To treat focal

Lack of Initiation

spasticity or to try and improve positioning of

At the other end of the spectrum of agitation is

the upper and lower extremities, focal blocks

the patient with TBI without any motivation or

are useful with either botulinum toxin or phe-

self drive, which is described as abulia, derived

nol. These are often very helpful while the ther-

from the Greek word meaning “without will.”

apists try measures such as serial casting.

This describes a patient who is awake but

Although systemic spasmolytics such as ba-

wholly disconnected from his or her environ-

clofen and tizanidine are avoided in brain in-

ment. In the most extreme cases the person is

jury, there are times when spasticity becomes so

completely without motivation or initiation

overwhelming that these agents must be uti-

and, in fact, will starve to death if not fed. As in

lized. An intrathecal baclofen pump should be

the patient who is comatose or in a vegetative

considered in cases of unrelenting spasticity

state, these individuals primarily are treated

when systemic spasmolytics cause intolerable

with dopaminergic agents or serotonergic reup-

sedation. This is a small programmable pump

take inhibitors.

device that is implanted into the abdomen wall.

A silastic catheter comes off the pump reservoir

and is tunneled around the abdomen and in-

Spasticity

serted into the lumbar cistern. The pump can

Spasticity is a frequent and difficult problem

deliver continuous microgram amounts of ba-

for patients, particularly those with severe

clofen directly to the spinal column capillary

head injury. With the onset of increasing tone

beds, thus providing spasticity relief at a much

the therapist in the acute or rehabilitation cen-

smaller total dose while leaving cortical neu-

ter will begin using conservative measures to

rons relatively unaffected. A center specializing

try and counteract spasticity. These measures

in the management of intrathecal pumps will be

include passive range of motion, weight bear-

needed in this case.

ing, and serial casting, in which the affected

limb is casted into a more neutral, or func-

Mild TBI

tional position in the upper or lower extremity.

When conservative measures fail to control

Mild TBI, or those patients with a presenting

spasticity, more aggressive pharmacologic in-

GCS of 13 to 15, compose the largest percent-

terventions will need to be used.

age of all occurrences of brain injury. It is a sig-

In patients with TBI in general one should

nificant public health problem and probably

avoid baclofen because of its gamma-amino-

the most common brain injury presentation to

butyric acid (GABA)-agonist activity as well as

face the primary care physician or non-neurol-

the significant sedation that it frequently

ogist. The American Congress of Rehabilita-

causes. GABA is the primary inhibitory neuro-

tion Medicine delineates specific components

transmitter in the central nervous system, and

of the diagnosis of mild TBI (Fig. 16.11).

many studies have suggested that GABA ago-

The postconcussive syndrome that follows

nists may slow the recovering brain. Also, ba-

a mild head injury has a myriad of associated

clofen may be so sedating as to obscure a

symptomatology with the most common being

person’s emergence from a low level of respon-

headache, vertigo, depression, fatigue, irritabil-

siveness. For these reasons the first-line agent is

ity, sleep disturbance, slowed reaction time,

considered to be dantrolene sodium. This med-

slowed information processing, and loss of

339

Chapter 16

n Traumatic Brain Injury

but perhaps would be handled better by a neu-

rologist or headache specialist. Posttraumatic

cephalgia that does not respond to tricyclics

and NSAIDs should be referred to a specialist.

n SPECIAL CLINICAL POINT: Headaches are

common after head injury and respond well to

low-dose tricyclic antidepressants and NSAIDs.

Vertigo Vertigo, or the sensation of movement

with any turn of the head, is quite common

after head injury of any severity even in minor

concussive injury. It often comes to light in the

outpatient clinic after the person with moderate-

to-severe injury is discharged from the rehabili-

FIGURE 16.11 The American Congress of

tation center. In mild TBI it often can be a

Rehabilitation Medicine’s specific components of the

diagnosis of mild traumatic brain injury.

presenting complaint. Symptoms are thought to

be related to concussive forces knocking otolith

concentration and memory. Subdural or epidural

crystals off of hair cells in the inner ear. Typically

blood, seizures, tremor, or dystonia are rare

patients will report that when they are lying in

occurrences that also have been reported fol-

bed or when they turn their head suddenly either

lowing mild TBI.

they will have a sensation of spinning or have the

Typically these patients present with many

sensation that the room is spinning around them.

subjective symptoms but with a normal neuro-

Nearly all patients will recover after 6 months,

logic examination and unremarkable imaging

and often symptoms are mild and the only treat-

studies. That litigation is not infrequently in-

ment necessary is gentle reassurance. For pa-

volved often colors the clinician’s opinion in

tients whose symptoms interfere with function,

these cases. It is important to keep an objective

any of the vestibular suppressants such as anti-

sense of this symptomatology despite lack of

cholinergics or benzodiazepines can be used;

hard objective findings on examination or con-

however, all of them have the side effect of

ventional neuroimaging studies.

drowsiness, which may worsen other symptoms

associated with mild TBI such as fatigue and

Headaches Posttraumatic cephalgia is one of

mental slowness (see Chapter 21).

the most common complaints after a mild TBI.

These often are described with components of

Sports-Related Concussive Injury The non-neu-

both a tension-type and a vascular- or migraine-

rologist often is asked to clear an athlete fol-

type headache. For instance, a patient may

lowing concussive injury for return to sports.

complain of a daily headache that is pressure in

That decision should be based on the severity of

character and associated with photophobia

the concussive injury and the duration of con-

and nausea and vomiting. These “mixed-type”

cussive symptomatology. The clinician also

headaches respond to low-dose amitriptyline at

should keep in mind that the effects of concus-

bedtime in a dosage range of 25 to 50 mg. It is

sive injury are thought to be additive. Guide-

important to inform patients that amitriptyline

lines published by the American Academy of

is not a pain reliever and should be taken con-

Neurology can help with these decisions. Con-

sistently at bedtime for at least 1 week before

cussive injury is described by grades. Those

titrating up. For pain relief NSAIDs are often

with transient confusion, no loss of conscious-

beneficial. Typical migraine headache will re-

ness, and concussive symptoms that last less

spond to conventional migraine interventions

than 15 minutes are rated as grade 1. People

340

Chapter 16

n Traumatic Brain Injury

with transient confusion and no loss of con-

Posttraumatic Epilepsy

sciousness but concussive symptoms or mental

All patients with moderate-to-severe head in-

status abnormalities that last greater than 15

jury should be informed of their increased risk

minutes are considered grade 2. Grade 3 con-

for epilepsy as a result of their injury, and fam-

cussive injury is anyone with loss of conscious-

ily members or significant others should be

ness of any duration. Any athlete with grade

counseled on basic seizure first aid. First-time

3 concussion should be transported to an emer-

seizure patients should be instructed to go for

gency room for a full evaluation to include

evaluation in an emergency room, including a

a CT scan of the head and neck. It should be

CT scan. Follow up with an evaluation by a

kept in mind that under most circumstances

neurologist that should include an electroen-

the neck should be immobilized until this eval-

cephalogram. Carbamazepine is the current

uation. Grade 2 concussions should eliminate

drug of choice for focal seizures with second-

the athlete from the contest or sporting activity,

ary generalization that result from CHI. Car-

whereas an athlete with a grade 1 injury should

bamazepine is also a mood stabilizer, and for

be watched carefully and only permitted to re-

patients with impulse dyscontrol or agitation

turn to play if all symptoms clear in less than

this may have a secondary benefit. Levetirac-

15 minutes. CT imaging of grade 2 concussive

etam is becoming more widely used mainly for

injuries should be done for those with persistent

its ease of administration. Levels do not need

postconcussive symptoms.

to be followed and there is little in the way of

n SPECIAL CLINICAL POINT: A loss of

drug interactions or side effects of liver toxic-

consciousness of any duration would require

ity. The clinician should be aware that one of

immediate removal from play and transport to

the major adverse reactions is hostility and ag-

an emergency department for a full evaluation

gressive behavior, which may already be a

which should include a CT scan of head and

problem for a patient with brain injury. One

neck.

antiepileptic drug that should be avoided in

this patient population, particularly in the

acute recovery phase, is phenobarbital, which

WHEN TO REFER TO A NEUROLOGIST

has the side effects of both cognitive and mo-

OR OTHER SPECIALIST

toric slowing that only compounds already ex-

isting problems for the brain-injured patient.

Refractory Headaches

Posttraumatic cephalgia is common in CHI and

Neuropsychologic Testing

is usually self-limited or treatable with a combi-

nation of low-dose tricyclic antidepressants and

Formal neuropsychologic testing is always in-

NSAIDs. Those patients with headaches that do

dicated in patients returning to school or any

not respond to doses of tricyclics at 100 mg/

type of high-level management or professional

day probably should be sent to a neurologist

occupation. Information from such testing may

or a headache specialist who might use other

be helpful to reintegrate the student into their

therapeutic options such as occipital nerve

academic track or help modify a work environ-

block, transcutaneous electrical nerve stimulator

ment that allows successful return to employ-

(TENS) units, or antiepileptic medications. Also,

ment or professional life. This testing is of no

patients who develop migraine-type symptoms

use in a period of ongoing PTA and is best-

following their head injury, such as pulsatile

utilized 4 to 6 months after injury. Sometimes

headache with photophobia, scintillating sco-

it is helpful to have the tests repeated at 1 year

toma, and nausea and vomiting, also should be

to see if there are improvements in any do-

referred to a specialist for treatment.

mains of intellect.

341

Chapter 16

n Traumatic Brain Injury

Severe Behavioral Disorder/Depression

motorcycle. His blood alcohol level was

elevated, and he had an open book fracture

In all levels of TBI there are patients who

of his pelvis, a right femur fracture, and a T4

emerge with severe and refractory behavioral

compression fracture. He is transferred, after

disorders that do not resolve. Patients with se-

5 weeks at the trauma center at what the

vere impulse dyscontrol, aggression, agitation,

speech therapist is calling “Rancho 4 level.”

or depression should be referred to a neurolo-

He exhibits a great deal of motor restlessness

gist with experience in TBI or a neuropsychia-

in bed and frequently is found by the nursing

trist who can manage these difficult patients

staff to be attempting to climb out of the

with appropriate pharmacology. Unfortu-

bed. He is nonverbal. The nurses are

nately, some of the most impaired of these pa-

requesting medication for agitation. The

tients will not be able to function outside of a

most likely cause of this agitation is:

structured institutional setting.

A. An acute meningeal infection

Depression is a common occurrence among

B. Part of his brain injury

survivors at all injury levels. Depression com-

C. Alcohol withdrawal

plicated by psychotic features or unresponsive

D. Pain

to first-line agents such as the SSRIs should be

E. Acute paranoid delusions

referred to a psychiatrist for further evaluation

and treatment.

The correct answer is D. Part of the emer-

gence from severe head injury does involve

generalized agitation and motor restlessness,

SUMMARY

but it is important for the physician not to

overlook treating musculoskeletal pain in pa-

TBI is a common problem with life-changing

tients, particularly those who have multi-

consequences for those affected and their fami-

trauma injury and who might not be able to

lies. The cost to society is equally large. Although

communicate their needs. It is well past the

there has been some suggestion of a decline in

point for him to be going through acute alco-

head injury incidence in the United States, there is

hol withdrawal at 5 weeks.

still a great deal to learn on how to effectively

treat survivors of TBI to return them to their

2. A 20-year-old man is involved in a severe

highest level of functioning within their commu-

motor-vehicle accident and is admitted to a

nity. These patients have a number of problems at

rehabilitation center in a vegetative state.

every level of severity that the physician is asked

The therapists who are working with him

to manage—from headaches to agitation and im-

report steady gains in the coma recovery

pulse dyscontrol. Very often victims of CHI are

scoring tool that they are using until week

relatively young and can have a normal life span

5, which is 9 weeks after his injury. They tell

while living with symptoms and the after effects

you he actually is regressing in some parts of

of their brain injury. On the horizon are new

the scoring system. The most likely cause is:

treatments in both the acute center and the out-

A. Vasospasm and infarct

patient arena that may change the ultimate out-

B. Drug-related encephalopathy

come and quality of life for survivors of TBI.

C. Hydrocephalus

D. Depression

E. Expanding epidural hemorrhage

QUESTIONS AND DISCUSSION

The correct answer is C. Hydrocephalus is a

1. A 26-year-old man is discharged to a

late-onset complication from severe head in-

rehabilitation facility after sustaining a severe

jury and is thought to be related to subarach-

closed-head injury after wrecking his

noid blood blocking the egress of CSF from

342

Chapter 16

n Traumatic Brain Injury

the arachnoid villi. Communicating hydro-

their archrivals. One of the senior

cephalus should be suspected in anyone with a

forwards, and leading scorers, takes a stick

decline in function but should be a particular

to the head (National Collegiate Athletic

concern in those at the lowest level of respon-

Association women’s lacrosse rules do not

sivity. Often these patients will respond to

mandate helmets) and for a brief moment is

ventriculoperitoneal shunting. Expanding

knocked unconscious. On the sidelines she

epidural hematoma would be a much more

briefly is confused, but this clears quickly

dramatic change in neurologic functioning

(<5 minutes) and she wants to get back into

and would, under most circumstances, need

the game. She denies headache, dizziness,

rapid neurosurgical intervention.

nausea, or vomiting. She is alert and

oriented. The coach looks at you standing

3. A 32-year-old mother of a newborn comes

on the sidelines and, knowing you are a

in with complaints of dizziness. She was

physician, asks your opinion. Your

involved in a motor-vehicle accident 1 week

recommendation is that:

before, and she reports that she was

A. She should be observed for 15 to

knocked unconscious for a brief period.

30 minutes before being allowed to

She was taken to a local emergency room

return to the field.

for evaluation, where a head CT was done

B. She should not be allowed back in the

that was negative. She was sent home after

game and should be taken to the

a brief period of observation. She has little

emergency room immediately for

recollection of any events before being in

evaluation.

the hospital. She reports that when she is

C. She can return to play, but if she suffers

lying down on the sofa and turns her head

another blow to the head she should be

a certain direction she feels as if the room is

taken out of the game.

spinning. Her neurologic examination is

D. She should be removed from the contest

normal. She most likely has:

and not allowed to return that day.

A. Postpartum depression

The correct answer is B. Any loss of conscious-

B. Subdural hematoma that was missed on

ness is considered a grade 3 or severe concus-

the first CT scan

sion, and an evaluation in an emergency room

C. Dislodged otolith crystals

is warranted. One also should keep in mind

D. Complicated migraine

that if the athlete went down there could be a

E. Postconcussive syndrome

spine injury, and cervical immobilization

The correct answer is C. Although it can be

would be prudent until this can be evaluated in

part of a postconcussive syndrome, this pa-

an emergency room. After a brief grade 3 con-

tient is describing a type of positional vertigo

cussion the athlete should be withheld from

that is common after concussive injury.

play for a minimum of 2 weeks.

The most appropriate treatment for this pa-

tient is:

5. A 50-year-old dairy farmer is up early

A. Gabapentin

milking his cows 1 day and falls off his

B. Diazepam

tractor, approximately 15 feet, suffering a

C. Meclizine

closed-head injury and a fractured right

D. Reassurance and possibly an otolith

humerus. A CT scan in the emergency

repositioning maneuver

room shows a right temporal contusion.

His posttraumatic amnesia resolves within

The correct answer is D.

1 week, and he is discharged from the acute

4. You are at your daughter’s lacrosse game,

hospital to home and outpatient therapies.

which is the last game of the season against

His wife brings him in to your family

343

Chapter 16

n Traumatic Brain Injury

practice for an office visit the week after his

Chang BS, Lowenstein DH. Practice parameter:

antiepileptic drug prophylaxis in severe traumatic

discharge and wants to know how long he

brain injury. Neurology. 2003;60(1):10-16.

needs to be taking the phenytoin. She says

Katz DI, Alexander MP. Traumatic brain injury: predicting

it makes him “foggy.” She relates that to

course of recovery and outcome for patients admitted

her knowledge he never had a seizure and

to rehabilitation. Arch Neurol. 1994;51:661-670.

there is no one in the family who has

Makley MJ, English JB, Drubach DA, et al. Prevalence of

seizures. Your response:

sleep disturbance in closed head injury patients in a re-

A. Because of his advanced age and the

habilitation unit. Neurorehabil Neural Repair. 2008;

22(4):341-347.

location of his contusion he is at a high

risk for seizures and should be

Makley MJ, Johnson-Greene L, Kreuz A, et al. Return of

memory and sleep efficiency following moderate to

maintained for 1 year.

severe closed head injury. Neurorehabil Neural Repair.

B. He needs to see a neurologist to

2009;23(4);320-326.

determine this.

Mysiw WJ, Sandel ME. The agitated brain injured pa-

C. He can stop taking phenytoin.

tient. Part 2: pathophysiology and treatment. Arch

D. He needs to be switched to

Phys Med Rehabil. 1997;78(2):213-220.

carbamazepine, which works better than

Nathan DZ, Douglas IK, Ross DZ, eds. Brain Injury

phenytoin.

Medicine: Principles and Practice. New York:

Demos; 2007.

The correct answer is C. There is evidence

Practice parameter: the management of concussion in

that there is no benefit to the use of anti-

sports (summary statement). Neurology.

seizure medications beyond the first week in

1997;48(3):581-585.

TBI. The patient should be reminded that he

Report of the Consensus Development Conference on the

is still at risk for having a seizure because of

Rehabilitation of Persons with Traumatic Brain Injury.

their head injury, and the patient and family

Bethesda, MD: National Institutes of Health; 1998.

should be informed of this and counseled in

Temkin NR, Dikmen SS, Wilensky AJ, et al. A random-

what to do should their family member have

ized, double-blind study of phenytoin for the preven-

tion of posttraumatic seizures. N Engl J Med.

a seizure.

1990;323(8):497-502.

Zafonte RD, Mann NR. Cerebral salt wasting syn-

drome in brain injury patients: a potential cause

SUGGESTED READING

of hyponatremia. Arch Phys Med Rehabil.

1994;78(5):540-542.

Brown AW, Elovic EP, Kothari S, et al. Congenital and

acquired brain injury. 1. Epidemiology, pathophysiol-

Zaloshnja E, Miller T, Langlois JA, et al. Prevalence of

ogy, prognostication, innovative treatments, and pre-

long-term disability from traumatic brain injury in the

vention. Arch Phys Med Rehabil. 2008;89(3 suppl 1):

civilian population of the United States, 2005. J Head

S3-S8.

Trauma Rehabil. 2008;23(6):394-400.

Neuromuscular

Diseases

DIANNA QUAN AND STEVEN P. RINGEL

key points

• Neuromuscular disorders include diseases affecting

muscle, neuromuscular junction, peripheral nerve, and

their nerve cell bodies.

• Pace of onset and patterns of weakness help guide a

focused evaluation.

• It is important to identify neuromuscular disorders that

have specific disease-modifying therapy.

• For disorders that have no disease-modifying treatment,

accurate diagnosis is important to ensure appropriate

supportive care.

isorders that

diagnostic investigations including genetic test-

result from abnormalities of spinal cord motor

ing (Table 17.1), outpatient treatment princi-

neurons, peripheral nerve, neuromuscular

ples

(Table

17.2), special problems in

junction, or muscle constitute “neuromuscular

managing hospitalized patients, and sugges-

disease.” Weakness is a common symptom, but

tions on when to refer to a neurologist will be

unlike central nervous system (CNS) disorders,

discussed.

neuromuscular diseases may be accompanied

by muscle atrophy and diminished muscle

tone. Patients also may develop muscle pain,

stiffness, cramps, twitching, limb deformities,

CLINICAL PRESENTATIONS

or myoglobinuria.

Weakness

This chapter begins with an overview of the

variable clinical presentations of neuromuscu-

■ SPECIAL CLINICAL POINT: A useful clinical

generalization for neuromuscular disorders is as

lar disease and a description of the tests

follows: all motor neuron, neuromuscular

commonly used to aid in the diagnosis of neu-

junction, and muscle diseases have no sensory

romuscular conditions. Subsequent sections in-

changes accompanying weakness.

clude more detailed descriptions of specific

neuromuscular disorders, excluding disorders

Coexisting sensory loss, dysesthesias, or pares-

of peripheral nerve, which will be covered in a

thesias strongly suggest a peripheral nerve disor-

separate chapter. For each condition, pertinent

der (see Chapter 18, Peripheral Neuropathy).

344

350

Chapter 17

■ Neuromuscular Diseases

The rapidity of onset, location, and progres-

armrests. In arising from the floor or a squat-

sion of weakness are important diagnostic fea-

ting position, they may require one or more

tures. Rapidly developing weakness (hours to

supports with the hands on the floor, knees,

several days) is characteristic of diseases of the

and thighs (Gowers maneuver; Fig. 17.1). The

neuromuscular junction, Guillain-Barré syn-

gait of a person with proximal weakness has a

drome, toxic myopathies, and acute electrolyte

waddling appearance because of hip girdle

disturbances. Acute remissions and relapses

weakness. Knee extensor weakness may cause

may be seen with myasthenia gravis (MG),

the leg to “give out.” Patients may lock their

periodic paralysis, and other channelopathies.

knees to compensate, gradually leading to hy-

Insidious and slowly progressive weakness oc-

perextension

(back-kneeing), which in turn

curs in many diseases affecting muscle or spinal

produces an exaggeration of the lumbar lordo-

cord motor neurons. Three major patterns of

sis. Shoulder girdle weakness produces diffi-

weakness can be encountered: proximal, distal,

culty in elevating the arms and may be

or cranial. Each pattern is associated with typ-

accompanied by scapular winging (Fig. 17.2).

ical symptoms related by the patient and with

With the arms hanging at the sides, the scapu-

some signs easily observed even before individ-

lae may slide laterally to produce a curving

ual muscles are tested.

inward of the shoulders with the backs of the

Proximal weakness is characteristic of many

hands facing forward and an associated oblique

muscle disorders, the spinal muscular atro-

“axillary crease” (Fig. 17.3). The high-riding

phies, and MG. These patients report difficulty

scapulae produce a conspicuous

“trapezius

in climbing stairs or arising from low chairs.

hump”; the clavicles may slope downward and

When arising from a chair, they will lean for-

stand out prominently from the atrophic neck

ward and “push off” with their hands on the

musculature (Fig. 17.3).

FIGURE 17.1 Gowers maneuver displayed in arising from the floor (Duchenne muscular dystrophy).

351

Chapter 17

■ Neuromuscular Diseases

FIGURE 17.3 Shoulder girdle weakness with

“trapezius hump,” “step-sign” with prominent

FIGURE 17.1 (continued)

downsloping clavicles, and an oblique anterior axillary

crease (LGD).

Distal weakness in the presence of atrophy is

commonly seen in amyotrophic lateral sclerosis

(ALS)

(Fig.

17.4), inclusion body myositis

(IBM), and myotonic dystrophy. Patients with

ALS or IBM may present with unilateral symp-

toms but eventually develop weakness bilater-

ally. These patients find it difficult to manipulate

small objects such as buttons or writing or eat-

ing utensils. They may complain of “dragging”

their legs because of “foot drop” or of frequent

tripping, particularly on uneven ground. With

each step, the knees are raised high while the

feet flap limply; shoe soles may show asymmet-

rical wear.

Cranial weakness may manifest as extraocu-

lar, facial, or oropharyngeal muscle weakness

and is an important differential feature in diag-

nosis of various dystrophies (Figs. 17.5 and

17.6). Ptosis and ophthalmoparesis occur in

several myopathic disorders and are very com-

FIGURE 17.2 Winging of the scapulae when the arms

mon in MG. Swallowing and speech changes

are elevated (fascioscapulohumeral dystrophy [FSH]).

can also be early signs of either ALS or MG.

352

Chapter 17

■ Neuromuscular Diseases

FIGURE 17.4 Marked atrophy of the first dorsal

interosseous muscle in motor neuron disease.

FIGURE 17.6 Myotonic dystrophy in mother (note

“hatchet face”) and infant (note “shark mouth”).

Diagnosis first made in the child suggested the same

diagnosis in the mother.

Atrophy and Hypertrophy

The disuse of a limb will produce modest mus-

cle atrophy, as is seen in nonneuromuscular

conditions such as after casting of a bone frac-

ture. The muscle retains much of its strength in

disuse atrophy, and the apparently atrophied

limbs of an elderly person may be surprisingly

strong. In contrast, the striking muscular atro-

phy in patients with neuromuscular disease is

associated with obvious weakness.

Atrophy of the muscles around the shoulder

girdle commonly reveals underlying bony promi-

nences. Flattening of the thenar eminence and

guttering of the interossei can produce a wasted,

clawlike deformity of the hand

(Fig.

17.4).

Several disorders produce characteristic appear-

ances. Examples include “Popeye arms” (very at-

rophied biceps/triceps with a normal-appearing

FIGURE 17.5 Typical facial appearance in myotonic

forearm) in facioscapulohumeral dystrophy, the

dystrophy with frontal balding, temporalis and masseter

“hatchet face” (temporalis wasting) appearance

atrophy, ptosis, and protuberant lower lip.

in myotonic dystrophy (Figs. 17.5 and 17.6), and

353

Chapter 17

■ Neuromuscular Diseases

■ SPECIAL CLINICAL POINT: Most patients

with limb aching and pain without objective

weakness or abnormally elevated muscle

enzymes do not have a neuromuscular disease,

and other possibilities should be considered,

such as joint or soft tissue pathology.

In older patients, pain, aching, and stiffness in

the shoulder and hip girdle muscles should sug-

gest polymyalgia rheumatica, and this disorder

is associated with a very high sedimentation

rate. It is important to recognize because of

its very specific treatment and rapid response

to steroid medications. The diagnosis of fi-

bromyalgia often is evoked, particularly in oth-

erwise healthy individuals who have diffuse

aches and pains without objective signs of

weakness; however, the pathologic foundation

of this entity remains controversial.

Stiffness may be a nonspecific symptom, or

it may be a symptom of myotonia, a phenome-

non consisting of a delayed relaxation of the

muscle following voluntary contraction or per-

cussion. This produces difficulty in releasing

FIGURE 17.7 Pseudohypertrophy of the calves

the grip or initiating movements after a period

(Duchenne dystrophy).

of rest and may point to a myotonic dystrophy

or myotonia congenita.

the enlarged calves of Duchenne dystrophy

Muscle cramp, a prolonged involuntary

(DUD; Fig. 17.7). Diffuse hypertrophy of all limb

contraction, is a universal and generally benign

muscles is commonly seen in myotonia con-

symptom that occurs with increased frequency

genita, rarely in hypothyroidism, or very rarely in

during unaccustomed exercise, “body build-

amyloidosis.

ing,” pregnancy, or electrolyte disturbance. It

also may occur in hypothyroidism, partial den-

ervation due to ALS or other less sinister types

Pain, Stiffness, and Cramps

of nerve injuries, tetany (with hypocalcemia,

Pain is a nonspecific symptom that may be seen

hypomagnesemia, or alkalosis), and certain

in many neuromuscular conditions. Inflamma-

metabolic myopathies.

tory myopathies and other collagen vascular

diseases may produce muscle pain and tender-

Muscle Twitching

ness, but the absence of these symptoms does

not exclude the diagnosis. Some patients may

Fasciculations are contractions of muscle fibers

have difficulty distinguishing between pain and

in a single motor unit. Fasciculations appearing

weakness because pain limits their ability to

in a strong muscle are usually benign and are

perform motor tasks. This may result in per-

exacerbated by many factors, including fatigue

ceived weakness. Such individuals often prove

and caffeine intake. When they occur in a weak

to have normal strength or a “give-away” pat-

muscle, they may be associated with ALS, but

tern of weakness, which suggests lack of full

they also may occur in the setting of root com-

voluntary effort.

pression or peripheral nerve injury.

354

Chapter 17

■ Neuromuscular Diseases

Infantile Hypotonia

malformation of the feet

(e.g., clubfoot,

equinovarus, or pes cavus deformity). Arthro-

The most frequent abnormality causing infan-

gryposis or multiple congenital limb deformi-

tile hypotonia or a “floppy baby” is CNS dis-

ties may occur with various diseases affecting

ease, such as seen after perinatal asphyxia. The

any part of the motor unit.

hypotonic infant may exhibit normal muscle

The syndrome of myoglobinuria consists of

strength, with the ability to lift its head or

weakness and painful swelling of affected

limbs against gravity. In the absence of other

muscles in association with headaches, nausea,

abnormalities, the prognosis for normal devel-

and vomiting. The urine turns reddish brown

opment may be excellent. In infants with obvi-

within 24 hours and is positive for benzidine

ous weakness, the underlying disorder may be

and Hemastix. An elevation of serous creatine

spinal muscle atrophy or one of the congenital

phosphokinase (CK) peaks at 5 to 7 days after

myopathies. Weakness of sucking and respira-

the initial muscle injury. Most episodes are re-

tion are serious concomitant findings, which

lated to acute muscle necrosis due to unusual

are usually fatal if undiagnosed and untreated.

circumstances, such as vigorous exercise (par-

ticularly in deconditioned individuals) or

Deformities

exposure to myotoxic agents such as alcohol,

cocaine, amphetamines, heroin, neuroleptics,

Neuromuscular disorders often are associated

and halothane in susceptible individuals. A

with skeletal deformities and should be sus-

patient with recurrent myoglobinuria should

pected in a patient with unexplained hip dislo-

be evaluated for an underlying metabolic neu-

cation, scoliosis

(Fig.

17.8), contracture, or

romuscular disease.

EXAMINATION FINDINGS

Observing the pattern and distribution of

weakness and reflex findings is an important

first step in formulating a differential diagnosis

for patients with neuromuscular disorders.

Table 17.3 and Figure 17.9 provide some gen-

eral guidance.

DIAGNOSTIC LABORATORY

INVESTIGATIONS

Enzyme Elevation

Muscle necrosis results in elevated levels of

serum CK. Other enzymes including aldolase

may also be elevated. The highest levels occur

in the syndrome of myoglobinuria, Duchenne

muscular dystrophy, and polymyositis with

slightly to moderately elevated values in most

FIGURE 17.8 Scoliosis in chronic infantile spinal

of the other dystrophies and motor neuron

muscular atrophy. The angle of curvature is measured

disorders. The most common causes of a

and followed closely (55 degrees in this patient).

modest CK elevation include recent vigorous

355

Chapter 17

■ Neuromuscular Diseases

TABLE 17.3

Characteristic Examination Findings and Helpful Tests in Neuromuscular Disorders

Neuromuscular Junction

Motor Neuron Disorders

Disorders

Myopathic Disorders

Pattern of

• May be focal in onset especially in

• Symmetrical weakness

• Usually symmetrical

weakness

acquired motor neuron disorders

• Bulbar symptoms, e.g.,

proximal weakness

• May begin in arms, legs, or bulbar

diplopia and ptosis

• Occasionally other

region

common in MG

characteristic patterns

• Limb weakness eventually

occurs in majority and

proximal weakness is

prominent

• Mostly limb and little

bulbar weakness in LEMS

Reflexes

• Hyperactive reflexes common

• Normal in MG

Normal except with

in ALS

• Sometimes mildly

severe weakness

• Normal in lower motor

depressed in LEMS

neuron syndromes

Sensory

No sensory loss

• No sensory loss in MG

No sensory loss

changes

• Occasional mild sensory

loss in LEMS

Helpful

• Nerve conduction studies

• Acetylcholine receptor or

• Creatine phosphokinase

diagnostic

and electromyography

muscle-specific tyrosine

level

tests

• Spine imaging to exclude

kinase antibodies in MG

• Nerve conduction

stenosis or radiculopathy

• Calcium channel

studies and

antibodies in LEMS

electromyography

• Nerve conduction

studies with repetitive

stimulation or single-

fiber electromyography

exercise in an otherwise normal individual and

course of disease. In conditions affecting only

hypothyroidism.

muscle, NCS are abnormal only if significant

loss of muscle tissue causes low-amplitude

compound motor action potential recordings.

Electrodiagnostic Studies

Needle EMG is an essential complement to

Electrophysiologic investigations including

NCS and helps to differentiate neuropathic

nerve conduction studies (NCS), needle elec-

from myopathic disorders (Fig. 17.10). Neuro-

tromyography (EMG) examination, repetitive

pathic disorders resulting from loss of anterior

nerve stimulation, and single-fiber EMG pro-

horn cells or peripheral nerve leave fewer

vide both qualitative and quantitative informa-

motor units available to generate muscle force.

tion about neuromuscular disease states.

This manifests on EMG as a decrease in the

NCS broadly differentiate between primary

electrical interference pattern. In the acute

demyelinating and axonal neuropathies and

period of neuron or axon loss, spontaneous

provide quantitative data for following the

electrical activity from denervated muscle

356

Chapter 17

■ Neuromuscular Diseases

Patient with suspected

neuromuscular disease

Muscle weakness on clinical examination?

yes

Nerve conduction studies

and needle EMG

Consider NMJ disease if

Normal

Abnormal

Normal

findings consistent

Consider

Abnormal CK?

CNS

disease

yes

Consider NMJ

neurogenic

myopathic

disease; if NMJ

testing negative,

neuromuscular

Consider motor neuron

Consider muscle

disease less likely;

disease or neuropathy

biopsy or genetic

consider non-

testing to

neuromuscular

characterize

disorders; observe

disease further

for further changes

FIGURE 17.9 Suggested algorithm for evaluating patients with suspected neuromuscular disease.

fibers may be recorded in the form of fibrilla-

pathic motor units are needed. During volun-

tion potentials and positive sharp waves. Fol-

tary contraction, this is seen as “early recruit-

lowing chronic denervation, surviving motor

ment” of motor unit potentials and the early

axons develop collateral sprouts that reinner-

development of a maximum interference pat-

vate muscle fibers. Spontaneous electrical ac-

tern.

tivity disappears, and the electrical potentials

In disorders of the neuromuscular junction,

produced by these large motor units have high

more specialized testing such as repetitive stim-

amplitudes, long durations, and an increased

ulation studies or single-fiber EMG can be per-

number of phases.

formed. Repetitive stimulation of a peripheral

In myopathic disorders, the random loss of

nerve in these conditions may produce a char-

individual muscle fibers results in decreased

acteristic decrease or increase in the amplitude

motor unit potential amplitudes (Fig. 17.10,

of the compound motor action potential, de-

item 2). To generate the same amount of force

pending on the type of defect. Single-fiber

as a healthy muscle, more of the smaller myo-

EMG may reveal increased “jitter,” a measure

357

Chapter 17

■ Neuromuscular Diseases

FIGURE 17.10 Single motor unit action potentials recorded by electromyography in a voluntarily

contracting skeletal muscle. 1: Normal motor unit action potential. 2: The myopathic potential is brief,

has small amplitude, and is polyphasic. 3: The neuropathic potential is prolonged, has high amplitude, and

is polyphasic. 4: A fibrillation potential is spontaneously produced by a denervated muscle fiber at rest.

of the synchrony of depolarization occurring in

gene mutations that produce motor neuron dis-

muscle fibers from the same motor unit.

eases, dystrophies, muscle storage disorders,

congenital myopathies, and channelopathies.

Muscle and Nerve Biopsy

Further genetic details are provided in subse-

quent descriptions of specific diseases.

Muscle biopsy is performed easily under local

anesthesia as an outpatient procedure, allow-

ing for rapid histologic and histochemical

SPECIFIC NEUROMUSCULAR

preparation to aid in diagnosis. Characteristic

DISORDERS

changes are well described for many conditions

The following section will describe clinical fea-

affecting the motor neuron and muscle.

tures of specific diseases, commonly used diag-

nostic tests, genetics, prognosis, and, when

Genetic Testing

appropriate, specific drug treatment. For the

of Neuromuscular Diseases

motor neuron disorders and genetically deter-

Molecular biology techniques have produced a

mined muscle diseases that have limited or non-

torrent of information describing gene abnor-

existent disease-modifying treatments, we will

malities underlying many neuromuscular disor-

cover general rehabilitation principles for outpa-

ders. Table 17.1 summarizes the more common

tients and hospitalized patients in a later section.

358

Chapter 17

■ Neuromuscular Diseases

Motor Neuron Diseases

X-Linked Spinal and Bulbar Muscular Atrophy

(Kennedy Disease) X-linked spinal and bulbar

The diagnostic confirmation of motor neuron

muscular atrophy (Kennedy disease) is an un-

disease relies heavily on accurate electrodiag-

usual disorder that can be confused with ALS.

nostic studies, which should demonstrate de-

Patients in their thirties and forties present

nervation with needle EMG testing of affected

with swallowing dysfunction, slurred speech,

myotomes; changes may be acute or chronic

perioral and tongue fasciculations, facial weak-

depending on when the test is performed in the

ness, mild limb weakness, hand tremor, gy-

course of disease. Depending on the time

necomastia, and impotence. The disorder is

course and severity of disease, motor NCS

very slowly progressive and, unlike ALS, life

may be abnormal but are frequently surpris-

expectancy is only minimally shortened.

ingly normal, especially in more chronic or

The disorder results from a gene abnormality

slowly progressive conditions. Sensory NCS

on the X chromosome. Thus, only males are af-

are normal unless another superimposed pe-

fected. There is never male-to-male transmission;

ripheral nerve disorder is present. When mus-

and females, although unaffected clinically, are

cle biopsy is carried out in patients with motor

carriers. The disease is caused by multiple

neuron disorders, abnormalities will include

cytosin-adenin-guanine (CAG) trinucleotide re-

distinctive muscle fiber group atrophy and

peats in the androgen receptor gene. As numbers

type grouping, a reflection of motor unit loss

of CAG repeats increase, the age of disease onset

and reorganization. Invasive testing has be-

is earlier, but there is no correlation with disease

come less necessary with the increasing ease

severity. The treatment is supportive since no

and availability of genetic testing for some

specific drug therapies are currently available.

conditions. In all the motor neuron disorders,

serum CK may be modestly elevated but rarely

Amyotrophic Lateral Sclerosis ALS is charac-

rises above 1,000 IU/L.

terized by progressive muscle wasting and

weakness resulting from degeneration of brain

Spinal Muscular Atrophies The spinal muscular

stem and spinal cord lower motor neurons.

atrophies (SMA) constitute a group of heredi-

There is coexisting spasticity and hyperreflexia

tary disorders characterized by a severe reduc-

caused by degeneration of upper motor neu-

tion in spinal cord and cranial motor neurons.

rons in the brain. Although the vast majority of

Patients have normal sensation but chronic pro-

cases are sporadic, between 5% and 10% are

gressive weakness. Virtually all cases are auto-

familial. Initial clinical symptoms may be lim-

somal recessive. Four major clinical phenotypes

ited to asymmetric limb weakness in the pres-

are recognized on the basis of age of onset and

ence of fasciculations. Foot drop or marked

severity of disease (Table 17.1). Types 1, 2, and

hand deformity resulting from interossei wast-

3 are autosomal recessive, resulting from vari-

ing (Fig. 17.4) can be seen. Speech may become

able mutations of the survival motor neuron

slurred or spastic. In addition to hyperreflexia,

(SMN) gene on chromosome 5. Defects in both

there are other pathologic reflexes (Hoffman

SMN alleles are present in about 95% of pa-

response and crossed adductor responses) and

tients with the SMA phenotype. Rarely, there

in some cases extensor plantar responses. Sen-

may be mutations of a closely adjacent neu-

sation is normal. Frank dementia is uncommon

ronal apoptotic inhibitory protein (NAIP) gene.

in ALS, but sophisticated psychological test

Patients with type 4 SMA are rare, and of the

batteries reveal that cognitive deficits, espe-

few studied, SMN mutations are found incon-

cially executive dysfunction, may be seen in as

sistently. Currently, no specific drug treatments

many as 30% of patients.

are available for SMA, but several agents are in

The spread and involvement of different mus-

various phases of clinical trial testing.

cles in ALS occurs in a characteristic pattern,

359

Chapter 17

■ Neuromuscular Diseases

first moving to involve both sides in one region

the 20th century has reduced the frequency of

of the body, and then to contiguous areas cau-

new cases in industrialized countries, many in-

dally and rostrally. Facial weakness may be seen,

dividuals who contracted the disease in earlier

but eye movement is never affected. Weight loss

times have permanent weakness in regions of

is common as swallowing becomes increasingly

the body where the infection destroyed spinal

impaired. Diaphragm weakness often leads to a

cord motor neurons. With normal age-related

critical time in the disease, as vital capacity drops

attrition of the motor neuron pool, progressive

progressively. The average survival after diagno-

weakness may develop after many years of

sis is 3 to 4 years, but 10% survival at 10 years

compensated static deficit, the so-called “post-

has been reported.

polio syndrome.” There is no evidence for viral

The vast majority of ALS cases are sporadic

reactivation, and the condition is best treated

and have no demonstrable genetic defect. Of

with symptomatic rehabilitative measures.

the 10% of patients with ALS who have a pos-

In the last decade, there have been an increas-

itive family history, approximately

10% to

ing number of human West Nile virus infections.

20% have a dominant superoxide dismutase

Most of those infected develop a nonspecific

(SOD1) gene mutation on chromosome 21;

febrile illness and recover uneventfully. Less

more than 110 mutations have been reported.

than 1% develop a neuroinvasive form of the

The ALS phenotype in these individuals results

disease characterized by meningoencephalitis

from a toxic “gain of function” which may

and sometimes anterior horn cell inflammation

trigger reactions that cause premature neu-

and destruction. As in poliovirus infection,

ronal death

(apoptosis). Additional families

more severe loss of anterior horn cells may lead

with non-SOD-1 gene mutations on chromo-

to permanent weakness of the affected my-

somes 2, 9, 15, 16, 18, 20, and X have been de-

otomes. No vaccine or specific treatment is cur-

scribed, though the phenotypes described in

rently available.

many of these kindreds have features that may

not represent classic ALS.

Disorders of the Neuromuscular Junction

The treatment of ALS is primarily sympto-

matic (Table 17.2). Of the many drugs and

Myasthenia Gravis MG is an autoimmune dis-

trophic factors tried, only the oral agent rilu-

order associated with a postjunctional defect of

zole is of value, prolonging survival by an aver-

the acetylcholine receptor (AChR). It may occur

age of 2 to 3 months. Numerous clinical trials

at any age but is most frequent in young

testing other agents are in progress. A trouble-

women and older men. Fluctuating weakness

some symptom in up to 30% of patients with

and fatigue in cranial, limb, or trunk muscula-

ALS is inappropriate laughing or crying,

ture are characteristic. Ocular symptoms,

termed “pseudobulbar affect.” Amitriptyline

including alternating ptosis, diplopia, and

or the combination of quinidine and dex-

blurred vision, are present initially in more

tromethorphan may be helpful in this situa-

than 50% of patients and eventually in 90%.

tion. For cramps, baclofen, quinine, or

Facial muscles are often weak, producing a

benzodiazepines are sometimes successful. For

snarling appearance when laughing. Speech

excessive salivation, nortriptyline or glycopy-

becomes increasingly slurred, nasal, or hoarse

rrolate can help.

as the patient continues to talk, and progres-

sive dysphagia with choking and aspiration of

Infections Affecting Motor Neurons Acute po-

food may occur. Neck muscle weakness may

liovirus infection in nonimmunized individuals

be so prominent that the patient resorts to

leads to a nonspecific febrile illness, followed

using a hand to prop up the head. Generalized

by paralytic symptoms in a minority. Although

MG frequently involves the respiratory

widespread immunization in the latter half of

muscles, producing shortness of breath. The

360

Chapter 17

■ Neuromuscular Diseases

clinical course occasionally is fulminant but

of choice. Initiation of doses greater than 20 to

gradual progression of symptoms with fre-

30 mg/day may result in a transient exacerba-

quent remissions and relapses is more com-

tion of weakness during the first 2 weeks, with

mon. Myasthenic “crisis” or sudden worsening

a potential for respiratory failure; slow titration

of symptoms to life-threatening severity may

of prednisone to target doses is therefore rec-

occur with emotional or physiologic stress,

ommended. High-dose long-term prednisone

such as superimposed infection, electrolyte dis-

therapy is not desirable because of the side

turbance (especially hypokalemia), pregnancy,

effects of weight gain, cataracts, diabetes,

or other systemic illness.

hypertension, and osteopenia. Steroid-sparing

A diagnosis of MG is confirmed by the pres-

immunosuppressants such as azathioprine,

ence of AChR antibodies found in the serum of

mycophenolate mofetil, cyclosporine, and cy-

85% to 90% of patients with generalized MG.

clophosphamide take longer to work than pred-

Approximately 35% of patients who have no

nisone, but have been used successfully in many

AChR antibodies may have antibodies to muscle-

patients with MG.

specific receptor tyrosine kinase

(MuSK).

Thymic tumors in patients with MG should

Many patients with MuSK antibody-related

be surgically removed. Even in patients with-

MG are clinically indistinguishable from those

out thymoma, the thymus is recognized to

with AChR antibodies. However, others may

play a role in disease pathogenesis. For many

have especially severe oculobulbar weakness,

decades, thymectomy has been commonly per-

some with striking facial and tongue atrophy.

formed as a means of reducing disease severity

Other patients may have prominent neck, shoul-

and dependence on immunosuppressive med-

der, and respiratory muscle weakness without

ications, even among patients without thymic

ocular weakness.

tumors. Retrospective data suggest that there

In instances of negative antibodies, electro-

is a beneficial effect on disease in patients

diagnostic testing by repetitive stimulation of a

who have AChR antibodies and generalized

motor nerve may produce a characteristic

weakness, but no prospective studies have

decremental response in the evoked compound

corroborated these observations. The role of

motor action potentials. Single-fiber EMG to

thymectomy in older patients with more surgi-

look for increased “jitter,” a reflection of un-

cal risk factors, patients with purely ocular

stable neuromuscular transmission, may help if

MG, and those with seronegative or MuSK an-

other tests are negative but is only available at

tibody MG is even less clear and requires fur-

centers with specialized neuromuscular expert-

ther study.

ise. A diagnostic intravenous injection of edro-

In the setting of myasthenic crisis with acutely

phonium (Tensilon) should briefly correct ptosis,

worsening weakness, problems with secretions,

ophthalmoparesis, or limb weakness but may

or respiratory distress, artificial ventilatory sup-

be easily misinterpreted.

port may be necessary until emergency treatment

The treatment of MG has changed consider-

takes effect. Plasmapheresis or intravenous im-

ably in the last several decades, with increasing

mune globulin is accepted treatment for MG cri-

recognition of the primary autoimmune distur-

sis. Neither modality is clearly superior to the

bance. High-quality clinical trial data is not

other; both improve symptoms, but the effects

available for most of the treatments used in MG;

generally last only a few weeks, and oral im-

however, older agents have a long track record of

munosuppression must be continued to achieve

use and empiric evidence of efficacy. The anti-

sustained remission.

cholinesterase agent pyridostigmine (Mestinon)

Patients with isolated ocular symptoms (ocu-

is used for symptomatic relief but has no long-

lar MG) may develop generalized MG, but the

term disease-modifying effect. In most cases,

risk is low after 2 years. These patients may not

prednisone is the initial immunosuppressant

require surgery or intensive immunosuppression.

361

Chapter 17

■ Neuromuscular Diseases

MG in childhood differs little from the adult

and tight heel cords with a tendency toward

form but is treated conservatively because ag-

toe walking. When arising from the floor,

gressive treatment may retard growth.

these children demonstrate a Gowers maneu-

ver (Fig. 17.1). Eye movements, swallowing,

Lambert-Eaton Myasthenic Syndrome Lambert-

and sensation are unaffected.

Eaton myasthenic syndrome (LEMS) is a rare

Patients with Duchenne muscular dystrophy

paraneoplastic or autoimmune disease result-

have earlier onset and more severe disease; cogni-

ing from antibodies directed against presynap-

tive developmental delay is common. By age 9 to

tic voltage-gated P/Q-type calcium channels

12 years, increasing proximal weakness makes

(VGCC) at the neuromuscular junction. About

independent walking progressively unsteady and

half of patients have small cell lung carcinoma.

unsafe. Once in a wheelchair, patients develop

Non-small cell lung cancer, thymoma, breast,

progressive kyphoscoliosis, joint contractures,

colon, prostate, and a variety of other cancers

and equinovarus deformities of the feet. In subse-

have also rarely been associated with LEMS. In

quent years, these children become virtually im-

contrast to MG, muscles innervated by the cra-

mobile and require comprehensive, around-the-

nial nerves usually are spared. Patients may

clock care. The combination of weak respiratory

complain of weakness, fatigue, distal paresthe-

muscles and kyphoscoliosis drastically reduces

sias, or dry mouth. Slow (2 to 3 Hz), repetitive

pulmonary reserve, and patients generally suc-

electrical stimulation of motor nerves demon-

cumb by the late teens or early twenties. Becker

strates a decrement in compound motor action

muscular dystrophy has a later onset, and the

potential amplitudes at rest, but after brief

course is more benign with survival well into

muscle exercise or rapid (30 to 50 Hz) repetitive

adulthood. Some patients may remain ambula-

stimulation large incremental responses are seen.

tory, and mental impairment is less common.

The diagnosis mandates a search for malignancy,

Diagnosis is aided by myopathic changes on

but some patients may have a strictly autoim-

electrodiagnostic testing and a sometimes inci-

mune basis for disease and no identifiable cancer.

dental observation of serum CK elevation (20 to

Symptoms may improve with removal of the

100 times normal), even before the disease is clin-

cancer if one is found. Pyridostigmine, guani-

ically evident. Genetic testing to detect a deletion

dine, and 3,4-diaminopyridine (DAP) may ame-

or mutation of the dystrophin gene is routine cur-

liorate symptoms. Guanidine and DAP require

rently. Although less commonly performed for

frequent monitoring of hepatic, renal, hemato-

diagnosis in recent decades, muscle biopsy will

logic, and cardiac function, and DAP is only

show characteristic dystrophic features.

available through special arrangement with the

Weakness is caused by a variety of deletions

manufacturer, Jacobus Pharmaceutical Com-

and point mutations affecting the muscle mem-

pany. Immunomodulatory treatments such as

brane protein dystrophin. Mutations in the

plasmapheresis, prednisone, or azathioprine are

X-linked dystrophin gene may lead to a total

other options in refractory cases.

absence of dystrophin (Duchenne) or the pro-

duction of a smaller molecular weight dys-

trophin in diminished quantity (Becker). For

Myopathies

children suspected of having the disease, a

Muscular Dystrophies

blood specimen will demonstrate a deletion or

Duchenne and Becker Muscular Dystrophy

duplication in 60% to 70% of cases. The ab-

These are X-linked recessive disorders. Boys

normality detected may be specific for either

who are affected have a clumsy waddling gait.

the Duchenne or Becker form of the disease.

Examination reveals a protuberant abdomen

For the remaining 20% to 30% where no dele-

resulting from accentuation of lumbar lordosis,

tion or duplication is found, a small specimen

pseudohypertrophy of the calves (Fig. 17.7),

of skeletal muscle can be obtained and used to

362

Chapter 17

■ Neuromuscular Diseases

determine the quantity and quality of dys-

with symptom onset ranging from early child-

trophin by immunohistochemistry. Female car-

hood to middle age. Numerous inheritance

riers can be identified by testing peripheral

patterns have been identified. Research into

blood for DNA deletions or duplications in the

muscle protein abnormalities underlying the

dystrophin gene. Prenatal diagnosis of the fetus

limb girdle dystrophies has resulted in a very

may be achieved by using cells obtained at am-

complex picture for what was once thought to

niocentesis or chorionic villus biopsy.

be a single disease. There are currently at least

14 identified gene loci in families with reces-

Facioscapulohumeral

(FSH) Dystrophy This is

sively inherited disease (LGMD 2A-2N) and

an autosomal dominant disorder characterized

five gene loci in families exhibiting autosomal

by slowly progressive weakness with predomi-

dominant inheritance (LGMD 1A-1E). In re-

nant involvement of the shoulder girdle mus-

cent decades, there has been a steady advance

cles and variable degrees of facial and foot

in the understanding of the genetics of this het-

dorsiflexion weakness. Symptoms may begin

erogeneous class of muscular dystrophies.

insidiously in the first two decades of life and

In the most common autosomal recessive

progress slowly or may not be noted until later

forms, LGMD 2A and 2B, weakness usually

decades. Common symptoms include diffi-

begins in the proximal legs and later is seen in

culty whistling, blowing up a balloon, or

the arms, along with scapular winging. Facial,

drinking through a straw. The lips often are

tongue, and pharyngeal weakness is usually ab-

pouting (bouché de tapir), and the smile is

sent. An anterior axillary fold and neck flexor

transverse. During sleep, the eyes may remain

weakness is common. Respiratory muscle in-

slightly open. The clavicles are prominent and

volvement may occur in some patients. Clinical

downsloping, and the shoulders droop to pro-

variation of the disorder may be seen within

duce an oblique axillary crease. The scapulae

families, where the proximal pattern is ex-

wing out when the patient attempts to elevate

pressed in some individuals and distal leg

the arms (Fig. 17.2), and the trapezius muscles

weakness is the first and most prominent find-

can be pushed up prominently. Atrophy of the

ing in others. Some families consist entirely of

triceps and biceps contrasts with preserved

patients with predominantly distal weakness,

forearm muscles, producing a “Popeye arm”

so-called “Miyoshi myopathy.” Depending on

appearance. Foot dorsiflexion weakness results

the gene mutation involved, the patient may be

in foot drop in some patients, but hip muscles

severely weakened at an early age and resemble

generally are spared and patients retain the

DUD or simply display mild limb weakness.

ability to walk. The characteristic clinical find-

Electrodiagnostic studies can confirm an un-

ings in a patient with a positive family history

derlying disorder of muscle, but diagnosis rests

make diagnosis fairly straightforward. EMG

on molecular diagnostic techniques on blood

and muscle biopsy usually show mild but non-

and immunohistochemistry on muscle biopsy

specific myopathic changes.

samples. Treatment is supportive and similar to

A mutation in a gene localized on chromo-

that of other inherited muscle disorders; details

some 4 is thought to lead to the clinical weak-

are outlined at the end of this chapter.

ness seen in FSH dystrophy, but the gene has

not been identified to date. Deletions near the

Oculopharyngeal Muscular Dystrophy Patients

telomeric end of chromosome 4 occur in 85%

with oculopharyngeal dystrophy are normal

to 95% of FSH cases and provide laboratory

until their forties or fifties. Symptoms usually

confirmation of the disease.

begin with progressive ptosis developing over

several years accompanied by increasingly re-

Limb Girdle Muscular Dystrophy (LGMD) This

stricted eye movements without diplopia.

is a clinically heterogeneous group of disorders

Swallowing difficulties usually develop, and

363

Chapter 17

■ Neuromuscular Diseases

aspiration can be a serious problem in a minor-

cases may appear in the same family; however,

ity of patients. Mild proximal limb weakness

a commonly observed feature is that patients

occurs frequently. Often, these patients recall

often are unaware that there are other affected

similarly afflicted family members and the

family members, even in obvious cases. About

pattern of an autosomal dominant disease

10% of patients present with severe hypotonia,

emerges. Electrodiagnostic studies show non-

weakness, and mental retardation in infancy.

specific chronic myopathic changes. The diag-

In nearly all patients, other organ systems

nosis is confirmed by the presence of a

are involved. Cataract formation, impairment

polyalanine triplet (GCG) repeat expansion or

of gastrointestinal motility, and endocrine ab-

unique exon duplication in the PABP2 gene

normalities are common. Patients frequently

on chromosome 14. Muscle biopsy shows dis-

are noted to have low intelligence, poor goal

tinctive red-rimmed vacuoles. Treatment is di-

orientation, uneven work histories, and bizarre

rected at the surgical correction of ptosis and

personalities. Progressive cardiac conduction

the prevention of aspiration. A gastrostomy

block may lead to sudden death. Serial electro-

feeding tube occasionally is needed.

cardiograms (EKGs) are recommended, and a

pacemaker-defibrillator should be considered

Myotonic Disorders and Channelopathies Myoto-

for patients with significant abnormalities. A

nia refers to a clinical phenomenon of delayed

reduced ventilatory drive may produce symp-

muscle relaxation after voluntary contraction

toms of alveolar hypoventilation including dis-

or muscle percussion. The clinical suspicion for

turbed sleep. General anesthesia should be

a myotonic disorder can be confirmed electro-

given cautiously because patients are unduly

diagnostically. Needle EMG examination of

sensitive to barbiturates and other medications

affected muscles demonstrates spontaneous

that depress ventilatory drive.

myotonic discharges with a characteristic wax-

Patients who have myotonic dystrophy

ing and waning amplitude and frequency.

2 (DM2 or proximal myotonic dystrophy) show

Some examiners have compared the auditory

distinctive proximal weakness as well as percus-

recording of these discharges to a dive-bomber

sion myotonia, cataracts, and, rarely, cardiac

or revving motorcycle. In some myotonic disor-

conduction defects. Pain may be a prominent

ders, there is also significant muscle weakness,

symptom.

while in others myotonia is predominant.

Genetic testing confirms the disease. DM1 is

an autosomal dominant disorder linked to ex-

Myotonic Dystrophy Two forms of myotonic

cessive CTG trinucleotide repeats in a noncod-

dystrophy have been identified. The most com-

ing part of a gene on chromosome 19. The

mon, myotonic dystrophy 1 (DM1), usually

clinical severity of the disease increases as the

presents in children or young adults with finger

number of repeats becomes larger, but the exact

grip and foot dorsiflexion weakness. This dis-

defect produced in the protein kinase gene

tal weakness is unlike most other dystrophies

product is uncertain. In the DM2, the gene mu-

that begin proximally. Advanced cases have a

tation is found on chromosome 3 and involves

characteristic facial appearance with ptosis;

a CCTG repeat expansion of a section of the

temporalis and masseter wasting; protuberant

gene coding for a ribonucleic acid-binding pro-

lower lip; and thinning of the sternocleidomas-

tein; the DM1 gene region of chromosome 19 is

toid muscle, with a typical “hatchet face” ap-

normal in DM2 patients.

pearance (Figs.

17.5 and 17.6). Percussion

Treatment is symptomatic. Weakness of foot

and grip myotonia are distinctive findings.

dorsiflexion may be improved with ankle foot

Speech is often dysarthric and nasal, and the

orthotics. Individuals with proximal weakness

patient may complain of dysphagia. As in other

that interferes with walking may need motorized

autosomal dominant disorders, mild and severe

scooters or wheelchairs. All patients should

364

Chapter 17

■ Neuromuscular Diseases

receive regular follow-up and treatment for the

may present with similar symptoms of muscle

nonneurologic manifestations of their disease.

pain and stiffness. PMR is not a primary disor-

der of muscle, and CK is normal.

Myotonia Congenita Impaired muscle relax-

ation, especially in the legs, is the cause of

Polymyositis and Dermatomyositis DM and PM

prominent “stiffness” in patients with myoto-

have similar clinical symptoms and signs, with

nia congenita. Patients complain of difficulty in

the exception of the characteristic rash seen only

rapidly opening a clenched fist and slowness in

in DM. The latter disorder may indicate the

initiating activity after a prolonged rest. They

presence of a neoplasm in adults. In patients

also may describe reduction in stiffness after

with an associated collagen vascular disease

exercising a muscle

(“warm-up” phenome-

(i.e., systemic lupus erythematosus, rheumatoid

non). Muscle hypertrophy is frequent and oc-

arthritis, Sjögren syndrome), inflammatory my-

casionally produces a Herculean appearance.

opathy may be a minor or major manifestation

Muscle biopsy is not helpful, and CK levels

of the disease.

are usually normal. More than 50 mutations of

DM is seen in both children and adults,

the chromosome 7 gene coding for the skeletal

whereas PM is almost exclusively an adult dis-

muscle chloride channel (CLCN1) have been

ease occurring in patients in middle and later

described. Most cases are autosomal recessive

life. Both diseases may begin insidiously with

(Becker disease), but autosomal dominant

systemic features such as fever, arthralgias, and

cases are well described (Thomsen disease). Di-

myalgias; Raynaud phenomenon may be seen

agnostic DNA tests are available for some muta-

in DM. Weakness may begin relatively sud-

tions. In patients who have no identifiable DNA

denly and may become profound, but more

mutation, specific diagnosis relies primarily on

commonly there is a subacute progression of

clinical and EMG data. Medications such as

proximal weakness that is not readily distin-

mexiletine, phenytoin, and tocainide may be

guishable from other limb girdle syndromes.

helpful in reducing myotonia, but no rigorous

The presence of muscle tenderness is variable.

clinical trial data exist to support their use.

The rash of DM may take several forms, ap-

pearing before, after, or in association with the

Channelopathies Affecting Skeletal Muscle In re-

onset of weakness. The upper eyelids often have

cent years, a number of skeletal muscle mem-

a lavender or heliotrope discoloration in chil-

brane gene mutations causing sodium, calcium,

dren, and periorbital edema and flushing of the

and chloride channel abnormalities have been

cheeks occur in advanced cases. The chest and

shown to cause distinctive clinical syndromes,

neck may become reddened and develop telang-

many with episodic muscle weakness. Some of

iectasia. Gottren papules are thickened erythe-

these may be associated with clinical or electro-

matous patches that occur over the knuckles

physiologic myotonia. These disorders are

and other joint extensor surfaces. Skin nodules

summarized in Table 17.1.

may break down and exude calcium.

The disease often has a variable course. Oc-

Inflammatory Myopathies An autoimmune dis-

casional patients have an acute episode with

turbance underlies polymyositis (PM) and der-

complete recovery, even without treatment.

matomyositis (DM). Other syndromes of muscle

Other patients demonstrate a relapsing, remit-

inflammation may be caused by coxsackie

ting course with incomplete recovery between

virus, pyogenic bacteria, trichinosis, sarcoid, or

episodes or a chronic progressive course that

tuberculous granuloma. True inflammatory my-

responds poorly to treatment. The serum CK is

opathies should be distinguished from polymyal-

elevated in most cases, particularly those with

gia rheumatica (PMR), an inflammatory process

acute onset. Electrodiagnostic testing typically

that may involve fascia rather than muscle and

shows myopathic changes and may help to

365

Chapter 17

■ Neuromuscular Diseases

identify the best area for muscle biopsy. In both

finding of excess glycogen in skeletal muscle

DM and PM, biopsy shows necrosis of muscle

and sometimes other organ systems. Symptoms

fibers and scattered inflammatory infiltrates. In

do not arise from the presence of glycogen but,

DM, perifascicular atrophy and overt vasculitis

rather, from a defect of energy metabolism in-

are common.

volving the conversion of glycogen to glucose.

Corticosteroids are the usual initial treat-

McArdle disease is the most common of

ment once a diagnosis is confirmed. Treatment

those listed in Table 17.1 and presents in child-

is usually required for several months. Other

hood or early adulthood with symptoms of ex-

immunosuppressants can be added, and once

ercise intolerance because of cramping and

strength improves, a gradual steroid taper may

myoglobinuria. Limb weakness is common in

be attempted. By reducing the steroids to the

McArdle disease and acid maltase deficiency

lowest possible levels, side effects are mini-

but is rare in the other glycogen storage dis-

mized. All adult patients who have DM should

eases. Fixed proximal weakness rather than

be screened periodically for an occult malig-

exercise-induced cramping is a particular fea-

nancy. A home exercise program or physical

ture of acid maltase deficiency, in which early

therapy program may be helpful.

diaphragm involvement in adults may bring the

patient to medical attention because of breath-

Inclusion Body Myositis (IBM) IBM is a disorder

ing difficulty. The other glycogen storage disor-

most commonly seen in men older than age 50,

ders are either fatal in infancy or present at any

but familial and even juvenile cases have been

age, with exercise intolerance and varying de-

documented. Symptoms include asymmetric

grees of muscle weakness (Table 17.1).

handgrip weakness along with proximal leg

Diagnosis of these disorders can be made by

weakness. The CK level is only modestly ele-

muscle biopsy, which will show distinctive

vated. Electrodiagnostic studies in such patients,

glycogen storage and abundant lysosomal ma-

some of whom may be suspected of having motor

terial. The serum CK is elevated in symptomatic

neuron disease, show a mixed neurogenic and

individuals. Gene loci for these disorders are

myopathic pattern. On muscle biopsy, there are

known and inheritance is usually autosomal

distinctive findings of increased connective tissue,

recessive or X-linked (Table 17.1). McArdle

variation in fiber size, isolated patches of inflam-

disease can occur as an autosomal dominant

matory cells, and small red-rimmed vacuoles con-

disease as well, but this is uncommon. Diagnos-

taining amyloid deposits, other degenerative

tic assays for specific enzyme deficits are avail-

proteins, and aggregates of proteinaceous mate-

able commercially.

rial of unknown significance within individual

muscle fibers. No specific drug therapy is avail-

Disorders of Lipid Metabolism Carnitine

able for these patients, though helpful rehabilita-

palmitoyl transferase deficiency (CPT II) may

tive measures are discussed below.

present at any age. Patients may show symp-

The vast majority of IBM cases are sporadic.

toms at birth with a rapidly fatal course. When

In recent years, there have been reports of fam-

onset is in childhood, there are severe but re-

ilies with multiple affected siblings whose biop-

versible metabolic crises. These early onset

sies show typical IBM findings. Inheritance is

cases are quite rare. Onset in adolescence mim-

mostly autosomal recessive with a gene muta-

ics the presentation in glycogen storage dis-

tion on chromosome 9, but rare families have

eases; patients may develop stiffness and pain

shown an autosomal dominant pattern.

(although no cramping) with exercise and then

myoglobinuria. Recurrent myoglobinuria may

Metabolic Myopathies

be precipitated in these patients by general

Glycogen Storage Diseases These rare autoso-

anesthesia, infection, or a high-fat meal. The

mal recessive disorders exhibit the common

diagnosis of CPT II is not always obvious

366

Chapter 17

■ Neuromuscular Diseases

because muscle biopsy may be surprisingly nor-

stroke-like episodes, diabetes, and hearing loss

mal (except after an episode of myoglobin-

may provide clues suggesting an underlying mi-

uria). The specific CPT II enzyme defect can be

tochondrial disorder.

detected in muscle specimens. The gene locus

Muscle biopsy may demonstrate excessive

for this autosomal recessive disorder is on

subsarcolemmal collections of mitochondria

chromosome 1. Treatment is directed at pre-

(ragged-red fibers) or abnormal staining pat-

venting attacks by avoiding extreme exercise

terns with succinate dehydrogenase (SDH) or

and consuming a high-carbohydrate, low-fat

cytochrome c oxidase (COX) reactions. The

diet divided into frequent small meals.

inheritance pattern may be maternal via mito-

A carnitine deficiency disorder results from

chondrial DNA, autosomal dominant, autoso-

reduced or absent carnitine, a carrier protein

mal recessive, or X-linked. On the basis of

vital to the transport of fatty acids into mito-

common phenotypic patterns, known muta-

chondria. The disease may present with only

tions can be assessed using blood or other tis-

limb muscle weakness or as a more serious sys-

sue samples.

temic illness. The myopathic form usually be-

gins in childhood or young adulthood with

Malignant Hyperthermia Patients with malig-

painless, proximal weakness; exercise intoler-

nant hyperthermia are free of symptoms unless

ance; and rarely cardiomyopathy and di-

they are exposed to certain anesthetic agents,

aphragm weakness. The more severe systemic

particularly halothane and succinylcholine.

form has earlier onset; encephalopathy is com-

The syndrome results from abnormally in-

mon, and sometimes severe cardiomyopathy

creased release of calcium from sarcoplasmic

and rapid death occur. Primary carnitine defi-

reticulum and manifests with increased minute

ciency is autosomal recessive and related to de-

ventilation, muscular rigidity, tachycardia,

fective activity in the OCTN2 carnitine

marked lactic acidosis, myoglobinuria, eleva-

transporter encoded by the SLC22A5 gene on

tion in temperature, and refractory cardiac ar-

chromosome 5. On biopsy, the major change is

rhythmias. Untreated cases may be fatal.

a massive accumulation of fat within skeletal

Anesthesia and the surgical procedure must be

muscle, and biochemical assay can detect low

terminated immediately, while dantrolene

or absent carnitine levels. Treatment of either

sodium is administered with cooling measures.

form of the disease entails reducing dietary fat

The disease is autosomal dominant in many

and taking supplements of oral L-carnitine.

patients, and there may be subtle evidence of an

underlying myopathy. The caffein-halothane

Mitochondrial Myopathies All of the mitochon-

contracture test is the gold standard to confirm

drial myopathies share the common feature of

susceptibility. Genetic testing is available to

excessive numbers of abnormal mitochondria in

identify mutations in the ryanodine receptor

skeletal muscle and often in other tissues, arising

gene on chromosome 19; approximately 25%

from mutations in mitochondrial and nuclear

of susceptible individuals have an identifiable

DNA. An ever-increasing number of phenotypes

mutation in this gene, but the absence of a mu-

caused by the resulting faulty energy production

tation does not exclude susceptibility to the

in the mitochondrial respiratory chain have

problem.

been identified.

Besides symptoms and findings of muscle

Toxic Myopathies A wide variety of medica-

disease such as weakness, muscle pain, exercise

tions and toxic compounds can produce either

intolerance, and rhabdomyolysis, other prob-

acute muscle necrosis or a slowly progressive

lems such as myoclonus, developmental delay

chronic myopathy. Alcohol can produce both

or progressive dementia, ataxia, pigmentary

of these syndromes in the same patient and

retinal degeneration, cardiac conduction block,

is the most common myotoxin. The acute

367

Chapter 17

■ Neuromuscular Diseases

myopathy usually follows a binge of drinking

Graves disease may result in weakness and oph-

and may be accompanied by myoglobinuria.

thalmoplegia. Hypoparathyroidism may lead to

Other drugs and toxins associated with acute

carpopedal spasm or tetany. Hyperparathy-

myopathy include ipecac, amiodarone, clofi-

roidism may combine weakness with brisk

brate, heroin, aminocaproic acid, chlorthalidone,

reflexes, which are reminiscent of ALS.

vincristine

(where a sensorimotor neuropathy

usually is superimposed), zidovudine, and any

Congenital Myopathies Congenital myopathies

substance that produces hypokalemia including

constitute a heterogeneous group of muscle

diuretics, purgatives, licorice, carbenoxolone, or

disorders defined by unique structural changes

amphotericin B. A chronic proximal myopathy is

easily identified in histopathologic prepara-

associated with prolonged corticosteroid therapy,

tions on muscle biopsy material. The three

particularly with dexamethasone and fluorinated

most common congenital myopathies are sum-

steroids. The aforementioned drugs associated

marized in Table 17.1.

with acute myopathy also may produce a chronic

myopathy.

The increasingly widespread use of statin

OUTPATIENT TREATMENT PRINCIPLES

cholesterol-lowering agents warrants particu-

lar discussion. Although significant myopathy

■ SPECIAL CLINICAL POINT: The initial

reaction of a patient and family to the diagnosis

is observed in only about 5 per 100,000 statin-

of a neuromuscular disease is often one of

treated patients per year, myalgias with or

despondency and hopelessness. In time, with

without CK elevations may occur in up to 7%

support and understanding, they may

of treated individuals, and asymptomatic CK

understand that a well-balanced rehabilitative

elevations are common. The exact cause of

approach will maximize function, prolong

statin-related myopathy remains uncertain, but

ambulation, limit complications, and create a

may relate to reduced sarcolemmal cholesterol,

more optimistic environment.

mitochondrial dysfunction, or depletion of iso-

The treatment of patients with chronic neuro-

prenoids that control myofiber apoptosis.

muscular weakness is a team effort requiring

Some individuals may have increased geneti-

the expertise of primary care physicians; neu-

cally mediated susceptibility to statin myopa-

romuscular specialists; physical, occupational,

thy related to polymorphisms in cytochrome

and respiratory therapists; orthotists; podia-

P450 enzymes or disease-causing mutations for

trists; orthopaedists; nutritionists; social work-

various metabolic myopathies.

ers; and psychiatrists.

■ SPECIAL CLINICAL POINT: The treatment

for all toxic myopathies is to eliminate the

offending toxin.

Special Considerations in Children

In cases where rhabdomyolysis occurs, support-

For patients with Duchenne or Becker muscu-

ive therapy with hydration should be provided.

lar dystrophy or SMA, most clinicians will opt

Most patients improve with these measures,

to work with an experienced team of child re-

though the time to recovery varies.

habilitation specialists. The central goal is to

improve quality of life for these patients. For

Endocrine Myopathies Thyroid and parathy-

children able to handle controls responsibly, a

roid dysfunction are the main considerations

power-drive wheelchair gives tremendous and

among endocrine causes of myopathy. Hy-

welcomed autonomy. Education is a must for

pothyroidism is associated with cramps, mild

all children with these neuromuscular disor-

weakness, and “hung-up” reflexes. Hyperthy-

ders. The child with SMA is generally of above-

roidism may produce mild weakness, and

average intelligence and will find school

368

Chapter 17

■ Neuromuscular Diseases

enjoyable as long as there is sufficient intellec-

may show poor weight gain, particularly dur-

tual challenge. Patients with Becker dystrophy

ing the first 2 years; even in later years, despite

fall into the same category and often possess sur-

a relatively sedentary existence, weight can

prising levels of intelligence and insight into

plateau despite continuous growth. In contrast,

their illness. In contrast, patients with Duchenne

patients with Duchenne or Becker muscular

muscular dystrophy commonly have cognitive

dystrophy may exhibit substantial weight gain

delay, difficulty in school, and usually require

and obesity, especially in the preteen age years.

special education courses.

Once the weight is there, it is virtually impossi-

The prevention of contractures, particularly

ble to lose. Advice from dietitians is critical to

of the Achilles tendon and iliotibial band, is im-

prevent extremes of weight gain or loss. Often,

portant early in all of these diseases. A surgical

however, despite everyone’s best efforts, the

release of contractures along with the use of long

child continues to eat and is indirectly encour-

leg braces can prolong independent, although

aged to do so by the fact that it is one of few

somewhat precarious, walking for several years

pleasures left in an increasingly circumscribed

in Duchenne or Becker muscular dystrophy but

world.

is rarely an option in children with SMA.

For children with other primary muscle dis-

Adequate and good quality rest is impor-

eases marked by stable but weak limbs or grad-

tant. Patients with severe limb weakness sleep

ual deterioration of strength, or in whom

more comfortably on an air or water mattress

strength is stabilized by drugs (e.g., DM), the

designed to distribute weight evenly, prevent-

principles of strength building and range-

ing unrelenting pressure and decubiti.

of-motion maintenance are the same as for the

When the patient becomes confined to a

patients with SMA and Duchenne and Becker

wheelchair, the development of kyphoscoliosis

muscular dystrophy. Referral to specialists in

(Fig. 17.8) can be slowed with proper upright

children’s rehabilitation is key to maximizing a

positioning and external chest bracing. A great

child’s quality of life. All the principles de-

deal of mobility and comfort is possible for in-

scribed here may apply to anyone with chronic

dividuals confined to a wheelchair, provided

neuromuscular disorders.

the wheelchair is properly designed and fitted.

Detachable arm rests and swing-away elevating

Special Outpatient Problems in Adults

leg rests facilitate transferring and prevent

lower-extremity contractures and edema that

The patient with ALS probably best exemplifies

may develop if the legs are constantly depend-

the need for multiple symptomatic treatments

ent. Once in the wheelchair, however, the central

that improve quality of life during progressive

aim is to prevent the development of restrictive

loss of strength. Early in the disease every pa-

lung disease as pulmonary reserve drops with

tient needs detailed instruction on a home pro-

age. The use of assistive cough devices, chest

gram of exercise for maintaining strength and

percussion, measurements of forced vital capac-

range of motion. The “frozen shoulder” is a

ity, and blood gas measurements are all useful

particularly painful complication that can be

and best coordinated by a pediatric pulmonolo-

minimized by simple range-of-motion exercises.

gist. In some children, scoliosis reaches a criti-

Use of adaptive equipment and bracing, when

cal level where spinal fusion must be done to

indicated, is also helpful. Patients initially may

sustain life. This is not always an easy decision

need a cane for balance but can be expected to

to make in children for whom the risk is high

move on to a walker and a standard push- or

but whose life expectancy might be dramati-

battery-powered wheelchair. In patients with

cally increased by such a procedure.

hip weakness, raising the height of seats with a

The intake of food may present special chal-

toilet seat elevator or electric lift chair makes

lenges in these children. Patients with SMA 2

standing without assistance easier. Patients rely

369

Chapter 17

■ Neuromuscular Diseases

heavily on well-anchored hand supports for

working closely with the neuromuscular neu-

getting up from the toilet, getting out of a tub,

rologist. Nocturnal Bi-PAP using an external

or going up stairs. Weakness of the hands im-

face mask is readily available to and tolerated

pairs the fine dexterity required for eating, writ-

by most patients. By removing carbon diox-

ing, and dressing. Various pieces of adaptive

ide buildup, nighttime sleep is facilitated,

equipment are designed to splint the hand and

daytime sleepiness is avoided, and overall

allow easier grasping. Large-handled utensils, a

quality of life is improved. With increasing

buttonholer, or a pencil attached to the hand

bulbar weakness and difficulty with secre-

with a Velcro strap may be useful. The patient

tions, a cough assist device should be tried;

who has shoulder weakness can use a long-

however, a tracheostomy usually is needed if

handled reaching device to get objects from

aspiration is to be prevented and adequate

cabinets or high shelves. Patients who have se-

ventilation is to be ensured. The thought of

vere dysarthria can develop alternate means of

prolonging life on a respirator is unaccept-

communication with relatively inexpensive

able for many patients, but for others consid-

electronic devices available with the help of a

erable satisfaction still can be gained if the

speech therapist.

environment is supportive. The physician,

Because pharyngeal weakness is common

patient, and family should discuss these op-

in ALS, progressive swallowing dysfunction

tions well in advance. Family counseling and

must be identified early. Clues to swallowing

end-of-life decisions are critical to the care of

dysfunction come from continuing weight

a patient with ALS.

loss in the face of claims that “everything is

eaten,” prolonged eating time (30 to 60 minutes

Specific Issues in Other

per meal), and recurrent pneumonias. If aspi-

Neuromuscular Disorders

ration is suspected, a barium swallow can be

confirmatory. A first step in addressing swal-

■ SPECIAL CLINICAL POINT: Palpitations or

lowing problems is to get the patient “safe

unexplained syncope resulting from heart block

swallowing” counseling from a speech thera-

can occur with various neuromuscular

pist and advice on caloric intake from a dieti-

disorders, particularly myotonic dystrophy, and

tian. At this point, a frank discussion of the

some limb girdle dystrophies and mitochondrial

disorders. These patients may require periodic

pros and cons of gastric tube placement

EKGs or Holter monitoring, and a pacemaker

should be undertaken. Gastric tubes are being

may be indicated.

recommended earlier and earlier in the course

of the disease, although precise guidelines for

With acute generalized weakness, pulmonary

optimal timing of the procedure are still not

and swallowing function should be monitored

available. As a rough rule, weight loss of

carefully. In some conditions like MG, respira-

more than 3 pounds per month and more

tory failure or aspiration can develop rapidly

than one pneumonia episode in the face of

and should be treated in an intensive care unit.

demonstrable aspiration when drinking a

Apart from minimizing the physical handi-

glass of water in the office are reasonable

cap, the physician must be aware of the pa-

grounds for bringing the subject to the atten-

tient’s social, emotional, and sexual needs. A

tion of patient and family.

severely handicapped patient who relies on

Early use of noninvasive ventilation (Bi-

others for eating, hygiene, and elimination un-

PAP) is thought to be beneficial but will have

derstandably will become depressed over this

to be evaluated in a controlled trial. The fail-

extreme dependency. Active counseling of the

ure of breathing in patients with ALS as a re-

patient and family should be directed toward

sult of diaphragm weakness presents specific

solutions to the various problems in “personal

challenges best handled by a pulmonologist

space” and independence that arise.

370

Chapter 17

■ Neuromuscular Diseases

expiratory pressures. When the vital capacity

SPECIAL CHALLENGES IN THE

falls below 50% of predicted and the disorder ap-

HOSPITALIZED PATIENT

pears to be progressing, Bi-PAP or more invasive

ventilatory support should be considered. Bulbar

Because neuromuscular disorders can impair

dysfunction results in a poor cough and increased

such vital functions as speaking, swallowing,

risk of aspiration so that early intubation may be

breathing, and cardiac output, the hospitalized

warranted to protect the patient’s airway. Infre-

patient must be carefully monitored for these

quently, patients with neuromuscular disease

life-threatening complications. For patients

have a superimposed central hypoventilation syn-

with end-stage weakness, treatment decisions

drome that further compromises breathing. A pa-

must consider patient and family wishes.

tient with limited movement of the extremities is

susceptible to deep vein thrombosis and pul-

Swallowing Dysfunction

monary embolism, which can further limit ade-

Acute onset of swallowing dysfunction can

quate oxygenation. Performing range-of-motion

occur in MG and other uncommon neuromuscu-

exercises, wearing compression stockings, and

lar syndromes such as botulism or organophos-

taking subcutaneous heparin may help mitigate

phate poisoning. Recurrent aspiration from

these risks.

chronic progressive dysphagia is a continual con-

cern in patients with ALS, MG, oculopharyngeal

Cardiac Complications

dystrophy, myotonic dystrophy, adult forms of

SMA, and (rarely) inflammatory myopathies.

In a few neuromuscular disorders such as

The integrity of the swallowing mechanism can

Duchenne or Becker dystrophy and some limb

be tested by asking patients to swallow water

girdle dystrophies, myocardial involvement

from a small glass at the bedside. Patients who

leads to impaired contractility and congestive

choke on thin liquid may have a serious swal-

heart failure. Cardiac conduction disturbances

lowing problem, indicating that oral food intake

are frequent in myotonic dystrophy and some

can lead to aspiration and pneumonia. A tai-

limb girdle dystrophies and mitochondrial my-

lored barium swallow should be done to confirm

opathies. A demand pacemaker and defibrilla-

such swallowing problems. If aspiration risk is

tor can be life sustaining.

high, a simple “chin tuck” maneuver may be all

that is needed. With more frequent and persist-

Infectious Complications

ent aspiration, an endoscopically placed gastros-

tomy tube may be needed to guard against

Although pneumonia is more likely in patients

pneumonia and to maintain proper nutrition.

with bulbar dysfunction and/or respiratory

muscle weakness, patients with MG and in-

flammatory myopathies are at even greater risk

Respiratory Complications

because of pharmacologic immunosuppression.

Respiratory depression is to be expected and an-

Common sites of infection include the urinary

ticipated in most hospitalized patients with neu-

and respiratory tracts, but septicemia, peritoni-

romuscular disease. Weakness of the diaphragm

tis, meningitis, and other types of infections

and accessory intercostal muscles of respiration

also may occur. Prophylactic influenza and

compromises ventilation. Symptoms of respira-

pneumococcal immunizations are essential.

tory distress can be mild and nonspecific and

include restlessness, irritability, and confusion.

Rhabdomyolysis and Myoglobinuria

Arterial blood gases and pulmonary function

tests should be monitored closely for drop-

Acute muscle destruction

(rhabdomyolysis)

ping vital capacity and poor inspiratory and

may occur from a variety of insults, including

371

Chapter 17

■ Neuromuscular Diseases

extreme physical overexertion, trauma, and

otherwise endless chain of self-referrals, which

toxins, and far less commonly from inherited

add unnecessarily to medical care costs, and

neuromuscular disorders. Muscle breakdown

needless patient anxiety. This is a particularly

releases myoglobin, which can cause acute

important function in these times when easy

renal failure from tubular necrosis. The result-

access to the medical world via the Internet

ant electrolyte imbalances can produce life-

may compound patient anxieties and lead to

threatening cardiac arrhythmias. Careful

“doctor shopping.” Second, in patients with an

attention should be given to maintaining ade-

organic neurologic disease, an appropriate

quate blood volume, urine flow, and electrolyte

consultation can prevent diagnostic delays that

balance. Renal dialysis may be needed.

might be either overtly dangerous or seriously

compromise appropriate therapy.

End-of-Life Care

■ SPECIAL CLINICAL POINT: Knowing when

to refer a patient to a neuromuscular specialist

The role of the physician in the care of dying pa-

is not a terribly scientific decision. Sometimes it

tients has been the subject of renewed interest

is a reflexive action that occurs when a

and intense debate in recent years. Although

physician realizes that the problem is beyond

physicians understand the importance of reliev-

his or her capabilities.

ing suffering, some remain uncomfortable with

Occasionally, it results from the physician’s

a competent, terminally ill patient’s right to

frustration with a patient who returns repeat-

refuse life-sustaining treatment, including venti-

edly with symptoms that do not respond to

lation, hydration, and nutrition. Similarly, a pa-

treatment or as a result of complaints from un-

tient’s request for morphine or similar agents to

happy relatives or caregivers.

relieve pain or dyspnea can be disconcerting in

Finally, when confronted with a patient who

the face of ventilatory failure. In such circum-

seems to fit the diagnostic criteria for a neuro-

stances, physicians can benefit from consulta-

muscular disorder, ordering one or two labora-

tion with experts in palliative care and

tory tests is appropriate (e.g., a CK for suspected

end-of-life decision making.

dystrophies and inflammatory myopathies,

anti-AChR antibody for suspected MG).

WHEN TO REFER TO A NEUROLOGIST

Electrodiagnostic testing is often very helpful to

distinguish neuromuscular from nonneu-

Primary care physicians often ask themselves

romuscular disease processes and to distinguish

when they should refer the patient with neuro-

neurogenic from myopathic conditions.

muscular symptoms to a neuromuscular spe-

cialist. There is a tendency in this day of

■ SPECIAL CLINICAL POINT:

Electrodiagnostic testing is best performed by

restrictive managed care plans to simply ask

neuromuscular specialists or physicians with

the specialist for informal advice by phone or

specialty qualifications in electrophysiology.

during a chance meeting over coffee in the hos-

pital cafeteria. This can be a prescription for

More expensive or esoteric tests may be de-

disaster. Usually, not all of the critical informa-

ferred until the patient is seen by the specialist.

tion is passed to the would-be consultant who

In this age of cost awareness, allowing the neu-

is asked to render an opinion without either di-

rologic consultant to direct the focused ordering

rect questioning or a complete neurologic ex-

of these specialty tests can result in considerable

amination.

savings, both medical and economic.

A formal consultation with an experienced

The referral of a patient is a cooperative

neuromuscular consultant serves two impor-

venture designed to reach a diagnostic conclu-

tant purposes. First, among patients with non-

sion and offer effective treatment. Referring

neuromuscular problems, it may stop the

physicians and neuromuscular consultants

372

Chapter 17

■ Neuromuscular Diseases

must work in partnership for the good of the

QUESTIONS AND DISCUSSION

patient. These guidelines are meant to be the

first step in developing such a partnership.

1. A 61-year-old man presents with insidious

and painless progression of left foot

weakness. His medical history is

Always Remember

unremarkable. His examination shows

atrophy of the anterior compartment of the

Objective signals that a patient might benefit

left foreleg, left foot dorsiflexion weakness,

from a neuromuscular consultation include the

hyperactive leg reflexes, and extensor

following “red flags.”

plantar responses. Cognition, cranial

In children:

nerves, and sensation are normal. Which of

• The floppy infant or hypotonic infant—think

the following is the most likely diagnosis?

SMA, congenital myopathy

A. Myasthenia gravis

• Child with delayed motor milestones—think

B. Peripheral neuropathy

muscular dystrophy, SMA, congenital

C. Amyotrophic lateral sclerosis

myopathies, metabolic myopathies

D. Inclusion body myositis

• Child with frequent falls, clumsy gait,

The correct answer is C. Painless weakness

abnormal use of hands to assist self, trouble

in the setting of preserved sensation and hy-

getting up from a fall—think muscular

peractive reflexes are ominous symptoms

dystrophy, DM, congenital myopathies

and signs of possible ALS. Alternate consid-

• Child with toe walking—think muscular

erations include a focal nerve or nerve root

dystrophy

lesion, distal myopathy, or a peripheral neu-

In adults:

ropathy predominantly affecting motor

nerves, but these would not be expected to

• Muscle pain—think inflammatory myopathy,

cause hyperactive reflexes, and focal nerve

PMR

or root lesions are usually accompanied by

• Trouble with arising from a chair, climbing

sensory symptoms. A less likely possibility is

stairs, lifting objects over head (“trouble with

a localized central nervous system lesion,

chairs, stairs, and into the air”)—think

but this would not cause significant muscle

proximal limb weakness as in MG and

atrophy.

inflammatory myopathy

A nerve conduction study with needle elec-

• Tripping while running/walking—think foot

tromyography would be extremely helpful to

drop resulting from peripheral neuropathy,

distinguish between a neurogenic disorder as

ALS, myotonic dystrophy

would be expected with ALS or a myopathic

• Grip weakness—think ALS, myotonic

condition. Other useful studies include serum

dystrophy, IBM

CK and a sedimentation rate to screen for sys-

• Slurred speech—think early ALS, MG,

temic inflammatory disease or significant mus-

Kennedy disease

cle disease. The life-changing implications of a

• Swallowing difficulties, especially with thin

suspected ALS diagnosis require that the pa-

liquids—think ALS, MG, Kennedy disease, IBM,

tient be referred to a neuromuscular specialist

oculopharyngeal dystrophy

for further evaluation and treatment.

• Dark urine—think myoglobinuria resulting

from excessive exercise, glycogen storage

2. A 19-year-old pregnant woman reports that

disease, CPT deficiency

two maternal uncles died of muscular

• Muscle atrophy and/or visible twitches—think

dystrophy at the ages of 15 and 16. Of the

ALS

choices below, which neuromuscular

373

Chapter 17

■ Neuromuscular Diseases

condition was the most likely condition

C. Becker muscular dystrophy

affecting the uncles?

D. Fascioscapulohumeral muscular

A. Becker muscular dystrophy

dystrophy

B. Limb girdle muscular dystrophy

The correct answer is B. Myotonic dystro-

C. Fascioscapulohumeral muscular

phy is suggested by the history of grip my-

dystrophy

otonia and systemic complaints. Recurrent

D. Duchenne muscular dystrophy

abdominal pain, gallstones, chronic diar-

rhea, dyspepsia, and dysphagia are common

The correct answer is D. Some cases of mus-

symptoms. Cardiac conduction disturbances

cular dystrophy actually may have been misdi-

may present with dizziness or may be discov-

agnosed SMA. SMA is usually an autosomal

ered on a routine EKG. A careful examina-

recessive disorder, and the risk of the woman

tion for clinical myotonia, as well as for the

or her children developing this disease would

characteristic facial features, would support

be low. Among the muscular dystrophies,

the diagnosis in this case. Myotonic dystro-

death occurring in the teenage years is charac-

phy is a common disorder, although it fre-

teristic of Duchenne dystrophy. This illness in

quently is overlooked.

two male siblings would not be the result of a

spontaneous mutation and indicates that their

4. In the clinical scenario outlined in question

mother, the patient’s grandmother, was a car-

3, an EKG demonstrates complete heart

rier. Genetic linkage analysis requires blood

block. What is the most appropriate

samples from the affected uncles but is not an

immediate course of action?

option in this case.

A. Discharge: She has a genetic condition

Blood samples on the patient as well as fetal

and nothing can be done.

cells obtained by amniocentesis can be screened

B. Observe for 24 hours and schedule for

for the abnormal dystrophin gene. If no dele-

outpatient follow-up in 3 months.

tion is found, linkage analysis can be carried

C. Obtain a cardiac electrophysiology

out to determine the probabilities of family

consultation.

members having the identical X chromosome,

D. Contact the patient’s family and have

but without linkage information from the two

everyone genetically tested.

deceased uncles of the pregnant patient, no ac-

The correct answer is C. A pacemaker may

curate probability can be given concerning her

need to be implanted. Bilateral foot drop is

being a carrier or having passed the abnormal

relieved with ankle bracing. All relatives of

gene on to her fetus. The situation might be

this patient should be evaluated clinically for

clarified if the patient’s CK were significantly

signs and symptoms of this autosomal domi-

elevated, arguing for her being a carrier, but

nant disorder. Symptomatic relatives can be

normal values would not be helpful. In such a

counseled and followed as needed for the dis-

complex situation, the assistance of an experi-

order. Asymptomatic individuals can be given

enced genetic counselor is advised.

information regarding the disease. Should they

3. A 51-year-old woman is admitted to the

wish to know their carrier status with cer-

hospital with symptomatic bradycardia. She

tainty, a DNA analysis of blood can provide

reports frequent “dizzy spells” for about 1

definite information regarding the presence or

year, but she has never fainted. She also has

absence of trinucleotide repeat sequences. This

had lifelong stiffness in her hands and a

information would be of use particularly to

nasal voice, and she trips frequently. Which

asymptomatic mutation carriers who are plan-

of the following is the most likely diagnosis?

ning families. However, the first priority is to

A. Duchenne muscular dystrophy

address the medical needs of the symptomatic

B. Myotonic muscular dystrophy

patient.

374

Chapter 17

■ Neuromuscular Diseases

Lynch DR, Farmer JM. Neurogenetics. Introduction.

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flections from the past and a way forward. Neurother-

2008; 28(2):212-227.

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Miller TM. Differential diagnosis of myotonic disorders.

Chahin N, Klein C, Mandrekar J, et al. Natural history of

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Mitsumoto H, Chad DA, Pioro EP. Amyotrophic Lateral

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Engel AG, Franzini-Armstrong C. Myology. 3rd ed. Vols

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Norwood F, de Visser M, Eymard B, et al. EFNS guideline

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Groh WJ, Groh MR, Saha C, et al. Electrocardiographic

dystrophies. Eur J Neurol. 2007;14:1305-1312.

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type 1. N Engl J Med. 2008;358:2688-2697.

Oskoui M, Kaufmann P. Spinal muscular atrophy.

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Guglieri M, Straub V, Bushby K, et al. Limb-girdle muscu-

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Peripheral

Neuropathy

JOSHUA GORDON AND MORRIS A. FISHER

key points

• History and physical examination are the most

important steps in determining the etiology of a

peripheral neuropathy.

• Neuropathies can be categorized according to type of

modalities involved (motor, sensory, or autonomic) and

distribution (multifocal or diffuse).

• A distal symmetric pattern is the most common

presentation of a polyneuropathy.

• Treatment of peripheral neuropathies is either directed

at the underlying cause or is aimed at reducing the

discomfort that is often associated with neuropathies.

All parts of the PNS are associated with

CLINICAL FEATURES

Schwann cells or the comparable ganglionic

AND SCIENTIFIC BACKGROUND

cells, the satellite cells. This anatomic com-

monality may account for some of the patho-

The peripheral nervous system (PNS) starts as

logic aspects of the PNS. More significantly,

the pia arachnoid ends at the level of the inter-

the normal functions of all parts of the PNS

vertebral foramina and therefore encompasses

are dependent on the proper functioning of the

those parts of the nervous system that lie out-

nerve cell bodies from which the motor and

side the confines of the brain, brainstem, and

sensory axons originate. For example, the foot

spinal cord. It consists of those portions of the

is supplied by nerve fibers whose cell bodies lie

primary sensory neurons, lower motor neu-

at the level of the lower thoracic/upper-lumbar

rons, and autonomic neurons that are outside

vertebrae. A single neuron consists of the mo-

the central nervous system (CNS). Therefore

toneuron and its associated motor axon inner-

the PNS includes the cranial nerves, the spinal

vating a foot muscle. The maintenance of this

nerves with their roots and rami, the periph-

cell extending from the lower back to the foot

eral nerves, and those aspects of the autonomic

is a complex process. There is constant antero-

nervous system that are outside the CNS. Be-

grade transport system from the nerve cell

cause some disease processes preferentially

bodies to their most distal axonal projections,

involve the PNS, it is useful to consider this

and this system is necessary for maintaining

system as a nosologic entity.

375

376

Chapter 18

n Peripheral Neuropathy

normal nerve (and muscle) function. There is

also retrograde transport so that the cell bod-

ies are influenced by distal events. This system

provides the conduit by which agents such as

herpes virus may reach the nerve cell body.

Given the complexity and length of the struc-

tures involved, it is not surprising that the

normal functioning of the PNS frequently is

disturbed.

ANATOMY

Except for the cranial nerves, peripheral

nerves separate at the level of the roots. The

dorsal roots contain sensory afferent

(sen-

sory) fibers that are located either pregan-

glionic or postganglionic to the dorsal root

ganglion on their way to the spinal cord. The

ventral roots consist of efferent (motor) fibers

that originate from the lower motor neurons.

The ventral and dorsal roots joining shortly

after exiting the spinal cord, and the resultant

mixed (motor and sensory) nerves are the

structures for providing information to and

FIGURE 18.1 Drawing of peripheral nerve originating

from the CNS. In the thoracic and upper-

from (1) ventral root with cells of origin in the anterior

lumbar region, these nerves are joined by sym-

horn of the spinal cord and (2) dorsal root with a dorsal

pathetic fibers after these fibers have synapsed

root ganglion. The postganglionic dorsal root fibers pass

in the ganglionic chain adjacent to the verte-

to the dorsal horn or more superiorly in the spinal cord.

The posterior primary ramus extends dorsally, whereas

bral column. The parasympathetic outflow

the anterior primary ramus is the main extension of the

originates either in the cranial region (cranial

peripheral nerve. Sympathetic fibers join the peripheral

nerves III, VII, IX, and X) or in the sacral re-

nerve by way of the sympathetic ganglion.

gion passing distally as the pelvic splanchnic

nerves (Fig. 18.1).

Individual muscles and areas of skin are

membranes. These supporting cells are ubiqui-

supplied not only by particular nerves but also

tous throughout the PNS. In myelinated fibers

by fibers that originate in particular roots. The

the gaps between myelin sheaths from two ad-

PNS distribution in the limbs is superficially

jacent Schwann cells are referred to as nodes of

complex because of the routing that occurs in

Ranvier. Most sensory fibers and all autonomic

the brachial plexus for the upper limb, and the

fibers are either poorly myelinated or unmyeli-

lumbosacral plexus of the lower limb.

nated. Even unmyelinated nerve fibers, how-

Individual nerves are composed of bundles

ever, are ensheathed by Schwann cells.

of individual nerve fibers called fascicles,

Nutrient arteries that arise from adjacent

which, in turn, are surrounded by connective

blood vessels supply nerves. The arterial supply

tissue. All of the motor fibers and many of the

is richly collateralized both to and within the

sensory fibers are surrounded by myelin.

nerves themselves. The result is a system resist-

Myelin is formed by foldings of Schwann cell

ant to large-vessel ischemia.

377

Chapter 18

n Peripheral Neuropathy

between different charts, and one should not at-

INDICATIONS OF NEUROPATHIC INJURY

tempt to fit each patient into a rigidly circum-

scribed view of normal. Patterns of root and

The symptoms and signs of neuropathic injury

nerve distribution in a broad sense are reliable,

can be predicted from the preceding discussion.

and it is important to try to identify these pat-

If nerves to muscles are disrupted, weakness

terns clinically (Fig. 18.2).

may be present, and prominent atrophy of

The muscles of the shoulder girdle are inner-

muscle fibers can occur. Cramping with fatigue

vated mainly by the C5 root, those of the arm

is a common symptom. Reflexes may be de-

by C5 and C6 (triceps brachii, C7), those of the

creased or absent if the afferent or efferent

forearm by C7 and C8, and those of the hand

nerves that subserve the reflex are disturbed.

by C8 and T1. In the lower extremity, the thigh

A wide range of sensory disturbances are

muscles are supplied by the L2, L3, and L4

found. With complete loss of innervation, there

roots. Those muscles of the anterior leg are in-

may be total loss of feeling-anesthesia. This

nervated by L4 and L5 roots, those of the pos-

rarely happens because of the considerable over-

terior leg by S1, and the small muscles of the

lap of sensory nerve supply. More commonly,

foot by S1 and S2.

alterations in sensation are found. Unusual

feelings such as “pins and needles” are called

paresthesias, and unpleasant sensations such as

burning are called dysesthesias. A decrease in

sensation on examination is referred to as hy-

poesthesia; an increase is called hyperesthesia.

Formication refers to the crawling feeling that

some patients may experience. A decrease in

perception of position and vibration indicates

dysfunction in larger fibers, whereas diminished

pinprick and temperature sensation indicates

abnormalities in smaller fibers. Autonomic dys-

function can affect cardiac, vasomotor, gas-

trointestinal, sweating, and sexual functions.

The skin may become smooth and glossy, hair

may decrease (or occasionally increase), and the

nails may become thickened. Because of loss of

feeling, repeated injury and inadequate repair

can result in permanent losses in limbs as well as

of function of joints (Charcot joints).

ANATOMIC DISTRIBUTION

Motor and sensory changes caused by PNS dis-

ease occur in the distribution of nerve roots or

the peripheral nerves themselves. Charts are

readily available that show these distributions.

The information has been obtained indirectly

based on root or nerve injury. Although superfi-

FIGURE 18.2 Sequential nature of the cutaneous

cially complex, with practice the information be-

root distribution as shown with the individual in the

comes readily usable. There is some variability

quadruped position.

378

Chapter 18

n Peripheral Neuropathy

The root sensory distribution can be visual-

muscles of the thenar eminence controlling

ized with the individual in the anatomic posi-

thumb movement. The ulnar nerve innervates

tion. In general, C1-4 innervate the back of the

the remaining intrinsic hand muscles. The me-

head, the neck, and the shoulder region; C5 in-

dian and ulnar nerves supply the cutaneous

nervates the lateral aspect of the arm; C6 inner-

sensibility to the hand. The ulnar territory char-

vates the lateral portion of the forearm

acteristically encompasses the little finger, half

extending into the hand involving the thumb

of the ring finger, and the adjacent palmar sur-

and index finger; C7 innervates the midportion

face, whereas the median nerve provides the

of the hand and ring finger; and C8 innervates

remaining cutaneous innervation

(Fig.

18.3).

the more medial portion of the hand including

Variations, however, are frequently present.

the little finger. The posterior aspect of the

In the lower extremity, the femoral nerve sup-

upper extremity then is supplied by T1 and T2,

plies the knee extensors in the thigh in addition

and the torso is innervated sequentially by

to the cutaneous branches for the anterior thigh

T2-L1, with T5 at about the level of the nipples

and medial aspect of the leg and foot (by way of

and T10 at the umbilicus. The anterior thigh is

the saphenous nerve). The posterior thigh mus-

supplied by L1, L2, and L3; the anterior leg

cles controlling knee flexion, as well as all the

and foot are supplied predominantly by L4 and

muscles of the leg and foot, are innervated by

L5; the posterior aspect of the lower extremity

the sciatic nerve. The peroneal (anterior tibial)

is supplied by S1 and S2; and the region of the

branch of the sciatic nerve supplies the anterior

anus is supplied by S3, S4, and S5.

compartment of the leg—namely, those muscles

The three main terminal nerves of the

that affect dorsiflexion of the ankle and toes as

brachial plexus in the upper extremity are the

well as foot eversion. The tibial portion of the

radial, median, and ulnar nerves. The radial

sciatic nerve innervates those muscles producing

nerve innervates the extensor muscles and pro-

plantar flexion. The cutaneous distribution is

vides much of the cutaneous supply to the ex-

comparable. Branches of the peroneal nerve

tensor surface of the arm, forearm, and hand.

supply the anterior leg and dorsum of the foot,

The median nerve is the predominant nerve

whereas the posterior aspect of the leg and plan-

innervating the forearm flexors as well as the

tar aspect of the foot are innervated by branches

FIGURE 18.3 Cutaneous innervation of the hand by the radial (clear section), median (stippled

section), and ulnar (diagonal lines) nerves.

379

Chapter 18

n Peripheral Neuropathy

of the tibial nerve. The medial plantar aspect of

Table 18.2 shows a schema of the cutaneous

the foot and toes is supplied by the medial plan-

innervation of the limbs. These tables and the

tar nerve, whereas their more lateral aspect is

preceding discussion are designed to provide a

supplied by the lateral plantar nerve. The medial

framework for the clinical evaluation of pe-

and lateral plantar nerves are the terminal

ripheral nerve disorders. To do the examina-

equivalents of the upper-extremity median and

tion well requires considerable experience.

ulnar nerves, respectively.

Obtaining the necessary information from the

Table 18.1 indicates selected muscle move-

patients can be demanding, and the examina-

ments with their main innervation, and

tion itself must be an active process looking for

TABLE 18.1

Selected Muscle Movements and Their Innervation

Joint Movement

Muscles^a

Peripheral Nerves^a

Spinal Segments^a

Upper

Extremity

Shoulder abduction

Deltoid

Axillary

Shoulder external rotation

Infraspinatus

Suprascapular

Elbow flexion

Biceps brachii

Musculocutaneous

C5, C6

Elbow extensin

Triceps brachii

Radial

Radial-ulnar supination

Biceps brachii

Musculocutaneous

Pronation

Pronator teres

Median

Wrist extension

Extensor carpi radialis

Radial

Radial wrist flexion

Flexor carpi radialis

Median

Ulnar wrist flexion

Flexor carpi ulnaris

Ulnar

Thumb adduction

Interossei

Ulnar

Thumb abduction

Abductor pollicis brevis

Median

Thumb extension

Extensor pollicis

Radial

C7, C8

Thumb opposition

Opponens pollicis

Median

Finger adduction

Palmar interossei

Ulnar

Finger abduction

Dorsal interossei

Ulnar

Finger extension

Extensor digitorum

Radial

C7, C8

Index finger extension

Extensor indicis

Radial

Lower

Extremity

Hip flexion

Iliopsoas

Femoral

Hip extension

Gluteus maximus

Inferior gluteal

S1, S2

Leg adduction

Adductor magnus

Obturator

L2, L3

Leg abduction

Gluteus medius

Superior gluteal

L4, L5

Knee extension

Quadriceps

Femoral

L3, L4

Knee flexion

Biceps femoris

Sciatic

Ankle dorsiflexion

Tibialis anterior

Peroneal

Plantar flexion

Gastrocnemius

Posterior tibial

S1, S2

Inversion

Tibialis posterior

Posterior tibial

Eversion

Peroneus longus

Peroneal

Large toe extension

Extensor hallucis longus

Peroneal

^aOnly main controlling muscle, nerve, and roots listed.

Joint action listed because it can be easily tested and muscle, nerve, and root control are relatively simple.

Notes: Terminal divisions of the brachial plexus can be tested at the thumb. Hip action controlled by muscles innervated by L2-S2 roots.

380

Chapter 18

n Peripheral Neuropathy

TABLE 18.2

Schematic Cutaneous Innervation of the Limbs

Lateral

Medial

Posterior

Arm

C5 axillary radial

Medial cutaneous

nerve of arm T2

Forearm

C6 musculocutaneous

Medial cutaneous

nerve of forearm T1

Hand and fingers

Thumb and index C6

Middle C7

Ring C8

Little C8

Thigh

Lateral femoral

Femoral L2, L3

Obturator

Posterior

cutaneous

nerve S2

Leg

Peroneal L5

Saphenous L4

Sural S1, S2

Foot

Peroneal L5

Plantar nerves S1

Portions of the posterior midline areas of the arm and forearm are supplied by branches of the radial nerve.

For cutaneous distribution, see Figures 18.2 and 18.3.

patterns of abnormality. As such, neurologic

distal distribution. The signs and symptoms

consultation for the evaluation of peripheral

start distally in the legs and progress proxi-

nerve disorders is frequently helpful.

mally. Clinical findings in the legs and arms

are related to the distance from the spinal cord

(i.e., from C7 in the arms and T12-L1 in the

PATTERNS OF ABNORMALITY

legs). Sensory loss should extend to the mid-

legs, for example, before such findings are

Derangements of motor, sensory, and auto-

present in the arms. Diabetic polyneuropathy,

nomic function may be present with lesions at

uremia, and drug or toxic exposure are com-

the level of the roots, plexuses, or peripheral

mon examples. One possible cause for this dis-

nerves. Sensory loss, for example, involving the

tribution may be that longer nerve fibers are

lateral aspect of the leg combined with weak-

more vulnerable to disturbances in nutrient

ness of dorsiflexion of the toes would be con-

transport.

sistent with a lesion of the L5 root; motor and

sensory changes in the distribution of both the

n SPECIAL CLINICAL POINT: In most distal

symmetric polyneuropathies the portions of the

axillary and radial nerves would be compatible

nerve that are farthest from the spinal cord are

with injury to the posterior cord of the brachial

affected first and symptoms progress proximally.

plexus; and weakness and atrophy of intrinsic

hand muscles combined with sensory loss in-

Damage to a single nerve is called a mononeu-

volving the medial aspect of the palmar surface

ropathy. An example would be the carpal tun-

of the hand, the little finger, and adjacent half

nel syndrome (CTS) as a result of median nerve

of the middle finger would indicate an ulnar

injury at the level of the wrist. Compressive

nerve lesion.

injury is a frequent cause.

The most common pattern of PNS disease is

A mononeuropathy multiplex indicates dys-

a symmetric polyneuropathy. Sensory, usually

function of multiple single peripheral nerves.

more than motor, signs and symptoms are pres-

This pattern is common in diabetes as well as

ent in a more or less symmetric, predominantly

vasculitides such as polyarteritis nodosa.

381

Chapter 18

n Peripheral Neuropathy

Plexopathies refer to injury at the level of the

which often must then reinnervate denervated

brachial, lumbar, or sacral plexuses. Idiopathic

structures. As a result, recovery may be rela-

brachial neuritis, traumatic injury to the brachial

tively slow and incomplete.

plexus, and retroperitoneal or apical lung tu-

With physical injury to nerves, the injury

mors are common causes. Radiculopathies are

may be limited to focal (paranodal) demyelina-

caused by injury to the roots. Sensory loss is in a

tion with associated conduction block and rapid

dermatome rather than peripheral nerve distri-

recovery

(neuropraxia). If axons are inter-

bution. Disc and vertebral bone disease are

rupted (axonotmesis), degeneration (Wallerian)

among the associated conditions.

of the axons and myelin may occur distal to

An important clinical distinction is whether

the site of injury. If the Schwann cell basal lam-

a process is diffuse or multifocal. In multifocal

ina and endoneurial tissue remain intact, ax-

neuropathies, the length-dependent basis of

onal regeneration commences promptly after

nerve dysfunction in neuropathies is not neces-

injury. If both the axon and surrounding

sarily present. Cranial nerves may be involved,

connective tissue are disrupted (neurotmesis),

the arms may be more affected than the legs,

Wallerian degeneration is inevitable and axon

and there may be prominent differences in the

regeneration may be disrupted by intervening

degree of injury between similar nerves on the

connective tissue. Neuromas and aberrant re-

right or left or between nerves (e.g., tibial and

generation may occur.

peroneal) in comparable areas of a limb.

The potential pathologic processes that affect

the PNS are similar to those that affect other sys-

tems. Metabolic or toxic derangements (e.g., vi-

tamin deficiencies, uremia, alcoholism, heavy

PATHOLOGY

metals, industrial solvents, and certain medica-

Pathologic processes affecting nerves usually

tions) frequently result in nerve dysfunction.

involve both myelin and axons, although at

Vascular abnormalities affecting nerves usually

times the physiologic effects predominantly

involve the medium and small arteries, and these

may reflect injury to one or the other of these

abnormalities may be found in rheumatoid

structures. In demyelinating processes, myelin

arthritis, polyarteritis nodosa, and temporal ar-

may be lost diffusely (e.g., inherited demyeli-

teritis. Diabetic mononeuropathies are probably

nating neuropathies) as well as segmentally

vascular in origin, and the primary pathologic

(e.g., acquired demyelinating neuropathies).

process in diabetic polyneuropathies may be a

There may be marked slowing and blocking of

vascular-based ischemia. Idiopathic polyneuritis

conduction. The axons may be relatively well

(Landry-Guillain-Barré syndrome) is repre-

preserved. As such, clinical recovery in the ac-

sentative of an inflammatory process. This

quired demyelinating neuropathies such as the

probably has an immunologic basis, as do the

Guillain-Barré syndrome (GBS) can be both

neuropathies seen in paraproteinemias and para-

rapid and complete if remyelination occurs.

neoplastic syndromes. Leprosy is a common in-

Prominent axonal degeneration is more

fectious process affecting nerves, as are some of

common than primary demyelination. This is

the neuropathies associated with human immun-

characteristic of neuropathies as a result of a

odeficiency virus (HIV) infection. A genetic basis

large number of exogenous toxins and meta-

for PNS dysfunction such as peroneal muscular

bolic derangements. These processes may af-

atrophy (Charcot-Marie-Tooth disease) is also

fect the nerve cell bodies as well as the axons

not uncommon. Schwannomas and neurofibro-

and may be manifested as a dying back of the

mas are representative tumors. Trauma is a fre-

distal portion of the axon. Secondary demyeli-

quent cause of nerve injury. This includes

nation occurs in those fibers with axonal dam-

entrapment neuropathies—namely, mononeu-

age. Recovery occurs by regeneration of axons,

ropathies resulting from vulnerability because of

382

Chapter 18

n Peripheral Neuropathy

anatomic features of the nerves. CTS is the most

A distal to proximal area of sensory change can

common entrapment neuropathy, but other

be outlined in a similar fashion. Moving relevant

common injuries include the ulnar nerve at the

joints can test position sense. Slight movements

elbow and the peroneal nerve at the fibula head.

of distal joints should be appreciated accurately.

Neuropathies are common. An approach to

A 128-cycles/sec (cps) tuning fork with the base

evaluating these problems is essential in all

placed on bony prominences is used for testing

areas of medicine. Even under the best of cir-

vibration. In neuropathies, vibration is charac-

cumstances, the cause for a neuropathy may

teristically more affected than position. The ex-

not be established in about one-third of these

amination should start from the most distal area

patients. As in other areas of medicine, often

of abnormality. Then one should test vibration

the important thing for management to deter-

in more proximal locations only if the patient

mine is what is not the cause as much as what

does not perceive the full duration of the vibra-

is the cause.

tion at the more distal site. A finger of the exam-

iner touching the same bony region as the tuning

n SPECIAL CLINICAL POINT: Even with a

fork helps evaluate the patient’s sensitivity.

complete neurologic exam and appropriate

As mentioned previously, the sensory exami-

diagnostic testing, up to one-third of

nation may be difficult and confusing. A primary

neuropathies will not have an identifiable cause.

care physician should have a low threshold for

seeking consultation if it could be helpful.

The most valuable ancillary study for analysis

DIAGNOSIS

of PNS disorders is electromyography (EMG).

The physical examination remains a powerful

This is best viewed as an extension of the neuro-

tool for the evaluation of disorders of the PNS.

logic examination. Although an EMG is harm-

The examination need not be subtle, but it

less, it does entail some discomfort. Reliable

must be accurate. Motor and sensory distribu-

information obtained in an efficient fashion is

tions of a polyneuropathy, mononeuropathy,

crucial, and this, in turn, will depend on the ex-

or radiculopathy often can be appreciated.

perience and skill of the electromyographer.

The action of individual muscles should be

Electromyography consists of two basic parts.

tested and rated as to strength. Strength may be

The first is an evaluation of the conduction in

normal (5), mildly decreased (4), moderately

nerves. The second part involves analysis of the

decreased (3) (movement against gravity only),

electrical activity in muscles—the EMG per se.

markedly (1-2) decreased, or absent (0). This is

The data can define the location of a lesion and

a standard numerical system but has the limita-

aid in understanding the pathophysiology.

tion that the overwhelming majority of ratings

Conduction in motor fibers is determined by

are in the range of 3 to 5. Muscle strength test-

stimulating nerves electrically and recording

ing should be concentrated in those areas that

the resultant-evoked motor response. Muscle

aid in the analysis of the particular problem.

fiber contraction is associated with electrical

The sensory examination need not be tedious,

activity caused by the movement of charged

but it must be accurate. Again, concentration on

ions across membranes, and this electrical ac-

areas relevant to the diagnostic question is im-

tivity can be recorded. Latency refers to the

portant. The patient often can best outline a cir-

time from the stimulus to the onset of the elec-

cumscribed area of sensory deficit. This area

trical activity. The latency will be shorter if the

then can be analyzed in more detail for light

stimulus is closer to the muscle than if it is

touch and pain sensations using a finger and a

more distant. The time difference between a

sharp instrument such as a safety pin, respec-

distal and a more proximal latency divided by

tively. (New and separate pins must be used for

the distance between the two stimulating

each patient to minimize risk of infection.)

points enables a conduction velocity (CV) to be

383

Chapter 18

n Peripheral Neuropathy

determined—that is, distance/time = conduc-

than is the latency. Amplitude may be affected by

tion velocity (CV). The time required for trans-

the site of the recording as well as by the amount

mission in slow-conducting terminal fibers and

of tissue between the electrical-activity genera-

across the neuromuscular junction is un-

tor in the muscle or nerve and the recording

known. Therefore, when recording from mus-

electrodes. Nevertheless, the amplitudes of the

cle, a CV can be determined only if stimulation

evoked efferent or afferent responses reflect the

is performed in at least two points. The un-

amount of electrical-activity-generating tissue.

known time for transmission time is then “sub-

Decreased amplitude responses can be defined,

tracted out” (Fig. 18.4).

and side-to-side comparisons of response ampli-

Electrical responses from afferent (sensory)

tudes can be particularly helpful.

fibers also may be recorded. Because the ampli-

The different fibers in a particular nerve con-

tudes of these evoked afferent responses are

duct impulses at different rates. There is a linear

several orders of magnitude less than the

relation between fiber size and CV, with the

evoked motor responses, the sensory potentials

largest fibers conducting at the fastest veloci-

are more difficult to record. At the same time,

ties. If activity in the largest fibers is lost, then

a meaningful CV can be obtained from a single

conduction will be slowed. The maximum de-

latency because a CV may be calculated from

gree of slowing that may be present with axon

the time taken to traverse a particular distance

loss alone, however, is considerably less than

because there is no unknown time in the region

that which may be found with demyelination.

of the neuromuscular junction.

In addition to slowed conduction and de-

The amplitude of evoked motor or sensory re-

creased amplitude, nerve injury can produce al-

sponses is a less accurate indicator of normality

tered configuration and dispersion of evoked

FIGURE 18.4 Evoked motor responses with the shorter-latency L1 resulting from stimulation

closer to the recording site, in comparison with the latency L2 resulting from stimulation of the nerve

at a more proximal site. The conduction velocity (CV) in the nerve is determined by dividing the

distance (d) between the stimulating sites by the latency differences.

384

Chapter 18

n Peripheral Neuropathy

responses. These changes in evoked responses

can define the location of focal nerve dysfunc-

tion. Temporal dispersion is characteristic of

demyelinating injury, as is conduction block. In

the latter, the size of the response is meaning-

fully decreased or even absent during stimula-

tion proximal to the block. The result may be a

striking picture in which nerve function is lost

but conduction studies distal to the region of

conduction block are entirely normal because

those portions of the nerve distal to the block

may be normal.

Studies are available (i.e., H reflexes and

F responses) that monitor conduction in nerve

fibers to and from the spinal cord. These stud-

ies are important because proximal nerve in-

jury may be present even in the absence of

injury to the more distal nerves.

The electrical-activity generated by muscle

FIGURE 18.5 Drawings of motor unit recruitment

contraction can be recorded from the muscle

patterns. A: Normal pattern with increasing number and

surface but is best evaluated by recording from

size of motor units with increasing force of muscle

a needle electrode inserted in the muscle itself.

contraction. B: Repetitive firing of a single large motor

The resultant electrical activity then can be

unit characteristic of neuropathies. C: A “rich” pattern of

monitored, amplified, and displayed.

many small motor units even at low levels of muscle

At rest, there is no electrical activity. Some

tension seen in myopathies. Amplitude calibrations in the

activity usually is seen as a needle is moved

ratio of 1:5:0.5 for A:B:C.

through muscle (insertional activity), but these

responses stop when needle movement stops.

varies with the fineness of control required. For

As muscle contracts, there is increasing activ-

example, there may be only six muscle fibers per

ity. This consists of the firing of motor units. A

motor unit in the eye muscles but up to several

motor unit is composed of a lower motor neu-

thousand in some of the large postural muscles.

ron in the anterior horn of the spinal cord, its

The simultaneous contraction of all the muscle

motor axon, and the muscle fibers innervated

fibers in a motor unit results in the usual

by that axon. Increasing force of contraction

integrated smooth, triphasic electrical response

results primarily from the recruitment of more

(Fig. 18.6). Motor unit size varies not only be-

units, although an increased rate of firing also

tween muscles but also within muscles. The

contributes to the increase in muscle tension.

larger motor units have more muscle fibers, and,

This increased muscle activity with increasing

therefore, with discharge they will generate

force of muscle contraction is readily appreci-

more electrical activity than smaller units. Thus

ated during routine EMG. More electrical ac-

the larger units generally will be of larger ampli-

tivity is seen; the amount of visible baseline

tude. During normal reflex or voluntary recruit-

without motor unit activity decreases; and

ment, motor units are activated sequentially

the audio amplification of the muscle activity

according to size, with the smaller units dis-

becomes increasingly prominent (Fig. 18.5).

charging first. As a muscle contracts, more,

Each motor unit is composed of muscle fibers

larger units are activated. The amplitude of a

scattered widely throughout a particular mus-

particular motor unit is, however, a relatively

cle. The number of muscle fibers in a motor unit

poor indicator of motor unit size because of

385

Chapter 18

n Peripheral Neuropathy

contractions of entire motor units may appear;

these are called fasciculations. They are visible

clinically and can be present in normal individ-

uals, especially with fatigue. They also occur

with axonal injury and are characteristic in dis-

orders of the motor neuron such as amy-

otrophic lateral sclerosis (ALS).

Electromyography using special electrodes

can record electrical activity from single muscle

fibers. This technique is particularly useful for

defining abnormalities of the neuromuscular

junction such as myasthenia gravis. Similar ab-

normalities also may be seen in rapidly progres-

sive neuropathic injury or with reinnervation.

In neuropathies, there is a loss of function-

ing axons. Fewer motor units than normal may

be found on voluntary activation of a muscle.

At its most extreme, only a single motor unit

may be seen to discharge within the recording

field of the electrode, even with maximum

muscle contraction. In association with these

FIGURE 18.6 Tracings of (A), normal triphasic motor

changes, the motor units may be larger than

unit potential; (B) polyphasic potential; (C) fibrillation;

normal. The muscle fibers that have been den-

(D) positive sharp wave. Calibrations: vertical

ervated may be reinnervated by the remaining

(microvolts)—(A) and (B), 500; (C) and (D), 50;

viable axons of remaining motor units. As a re-

horizontal (milliseconds)—(A) and (B), 5; (C) and (D), 2.

sult, these motor units may be larger than nor-

mal and also more complex in configuration.

(a) the potential variation of muscle fiber or-

Small, complex (polyphasic)-appearing motor

ganization within a particular motor unit and

unit potentials, however, also may be found.

(b) the relation of the recording needle to those

Although these potentials are considered more

muscle fibers. Motor unit duration provides a

characteristic of myopathies as a result of loss

better estimate of relative motor unit size be-

of functioning muscle fibers, they also are seen

cause motor unit duration reflects the dispersion

in neuropathic injury during reinnervation. As

of the muscle fibers in an individual motor unit

motor axons grow into muscle that has lost its

within a muscle; larger motor units have larger

innervation, new motor units are formed, and

motor unit durations.

these new units initially will be small and

When there is a disruption of the normal

polyphasic because they include a relatively

connection between nerve and muscle

(i.e.,

limited number of muscle fibers. A reduced

denervation), abnormalities appear at rest 1 to

number of motor units, especially if they are

3 weeks after injury, and EMG can detect

large and associated with electrophysiologic

them. Individual muscle fibers may discharge

evidence of denervation, would be characteris-

at rest, and this type of electrical activity is re-

tic of a neuropathic process.

ferred to as fibrillations or positive sharp

These may be the only electrophysiologic

waves. This activity is not visible clinically.

findings in those neurogenic processes caused

Other types of abnormal spontaneous activity

by loss of motoneurons such as ALS. More

may be present, such as runs of complex poten-

commonly in neuropathies, slowing of conduc-

tials (complex repetitive discharges). Irregular

tion is present and provides evidence of nerve

386

Chapter 18

n Peripheral Neuropathy

dysfunction. Prominent slowing with no or rel-

can be focused. For example, diffuse demyeli-

atively little denervation and preserved re-

nating patterns are characteristic of some inher-

sponse amplitudes would be consistent with a

ited neuropathies; multifocal demyelinating

demyelinating process. Borderline to mildly

patterns are characteristic of acquired neu-

slowed conductions associated with clear and

ropathies such as the GBS, diffuse axonal pat-

relatively diffuse axonal injury would indicate

terns suggest toxic neuropathies; and multifocal

predominant axonal injury. Low-amplitude

axonal patterns suggest vasculitic neuropathies

evoked responses are most characteristic of ax-

such as those occur in collagen diseases.

onal dysfunction because of loss of functioning

nerve or muscle tissue.

n SPECIAL CLINICAL POINT:

The patient’s symptoms may not correlate

Electromyography is best viewed as an

extension of the neurologic examination. Its

with the degree of nerve injury found on EMG.

primary utility is to identify patterns of

The usual electrodiagnostic studies monitor

abnormalities not observable during routine

function only in large fibers. Disabling dyses-

bedside testing.

thesias as a result of small fiber dysfunction

may occur with unremarkable or relatively

Nerve biopsies can be performed. The sural or

minor EMG abnormalities. At the same time,

superficial peroneal nerve is biopsied most com-

severe, diffuse nerve abnormalities may be ac-

monly. At times, the information may be pathog-

companied by few complaints because of

nomonic, such as in infiltrative neuropathies

preservation of sufficient, even if decreased,

(e.g., amyloidosis and metachromatic leukodys-

nerve fibers. In general, electrodiagnostic find-

trophy). In other circumstances, the information

ings will correlate better with motor symptoms

may be important for patient management

and signs (weakness) than sensory dysfunction.

(e.g., defining the presence of chronic demyeli-

Electromyographic studies can provide infor-

nating inflammatory injury).

“Teased” fiber

mation not only about the severity and dura-

preparations allow an examination of individual

tion of a neuropathic process but also about

fibers and thereby more accurate analysis of the

the prognosis of nerve injury.

pathology of nerve injury. Immunologic staining

Normal conduction and lack of denervation

can define the type of antibody and abnormal

several weeks after the onset of nerve dysfunc-

cells present in nerves. Nerve biopsy itself is per-

tion could indicate a good prognosis because

formed under local anesthesia and is essentially a

this pattern would be consistent with functional,

benign procedure, although there can be tran-

but not necessarily structural, abnormalities of

sient uncomfortable residua. Sophisticated judg-

the nerve. This is a common clinical considera-

ment is required for determining when a nerve

tion, for example, in Bell palsy caused by dis-

biopsy is indicated. As such, a nerve biopsy

ruption of facial nerve function.

should probably only be performed in consulta-

At their best, electrodiagnostic studies

tion with someone with expertise in neuromus-

should be considered not only for establishing

cular disorders. Punch biopsy of the skin is also

the presence of a neuropathy—this is usually a

useful in the evaluation of certain neuropathies.

clinical diagnosis—but primarily for establish-

It is particularly sensitive for small fiber neu-

ing the pattern of abnormality. This includes

ropathies and is relatively noninvasive.

not only whether a process is demyelinating or

Antibody testing is increasingly being per-

axonal; this distinction in fact is usually less

formed for evaluation of peripheral neu-

easily established than one might think from

ropathies. This stems from the increasing

reading the literature. Equally important is the

recognition that antibodies can be present

degree of symmetry or asymmetry. If one can

in patients with neuropathies that may be

establish diffuse versus multifocal axonal or de-

pathogenetic for the neuropathies. This is par-

myelinating patterns, the differential diagnosis

ticularly true for those antibodies against

387

Chapter 18

n Peripheral Neuropathy

neural gangliosides. The anti-GQ1b antibody

improve by removing the offending agent. A rep-

is present in about 95% of patients with a par-

resentative list of systemic disorders and toxic

ticular variant of the GBS (the Miller-Fisher

causes associated with peripheral neuropathy is

syndrome). An immunoglobulin M (IgM) GM1

presented in Table 18.3. Disulfiram, dapsone,

antibody is present in about 50% of patients

and vincristine all can cause peripheral neu-

with a variant of a chronic inflammatory

ropathies, but they are used to treat conditions

demyelinating neuropathy (multifocal motor

in which peripheral neuropathy is a common

neuropathy), and a relatively specific neuro-

presentation—alcoholism, leprosy, and carci-

pathic syndrome is present in those with an

noma. Inherited neuropathies such as Charcot-

IgM monoclonal gammopathy and antibodies

Marie-Tooth disease are common. Two specific

to myelin-associated glycoprotein. Neverthe-

neuropathies and their management are dis-

less, the circumstances where these antibodies

cussed in the following sections—acquired

will be present and clinically useful are small.

inflammatory polyradicular neuropathies and

Given their expense and low yield, these stud-

diabetic neuropathies.

ies are probably best ordered by one knowl-

n SPECIAL CLINICAL POINT: Neuropathies

edgeable about their limitations and possible

that are due to metabolic derangements or

clinical usefulness.

vitamin deficiencies can improve with

Given the large number of causes for neu-

correction of these abnormalities.

ropathies, how one approaches the evaluation

of neuropathies will depend on the patients

Treatment of neuropathies also may be sympto-

being seen. If one works in an area with a large

matic. Consultations with physiatrists and occu-

industrial base, the main concerns may be

pational therapists can be rewarding. Bracing,

entrapment and toxic neuropathies. If one

for example, may help a foot drop. Canes, walk-

deals with an elderly population, the concerns

ers, and motorized wheelchairs can be helpful

would include diabetes, hypothyroidism,

for those with gait problems. Useful implements

monoclonal gammopathies, and paraneoplas-

can be made for those with limited finger and

tic neuropathies. B₁₂ deficiency may present in

hand movement. Painful neuropathies are com-

a subtle fashion and is worth evaluating in

mon, and pain is often the reason a patient with

those with unexplained neuropathic sensory

a neuropathy seeks medical attention. Neuro-

disturbances. A recent Practice Parameter eval-

pathic pain can be treated with medications.

uation of screening laboratory studies for neu-

Common medications and their dosages are

ropathies has emphasized the importance in

shown in Table 18.4. The tricyclic antidepres-

distal symmetric sensory polyneuropathies of

sants commonly are used for aching discomfort.

impaired glucose tolerance which can be docu-

The exact mechanism by which these drugs alle-

mented by a glucose tolerance test.

viate pain is unknown. However, they must be

given in high enough doses and for a long

enough period (i.e., several months) to ascertain

Management

whether they will be effective.

If the underlying cause of a neuropathy can be

The anticonvulsants are more commonly

established, treatment of this cause can improve

used for “positive” symptoms such as pares-

the neuropathy. The neuropathies associated

thesias and dysesthesias. The latter reflect ab-

with hypothyroidism, carcinoma, and vitamin

normal discharges in diseased nerves, and

deficiencies, for example, improve with treat-

anticonvulsants presumably help by decreasing

ment. Uremic neuropathies can resolve after

these discharges. Opiates can be helpful. Given

transplantation, and nerve dysfunction related

their potential for abuse, a program of opiates

to drugs (vincristine, heavy metals [lead], and

is probably best instituted in conjunction with

industrial solvents [n-hexane, acrylamide]) can

neurologic consultation. The exception may be

388

Chapter 18

n Peripheral Neuropathy

TABLE 18.3

Disorders of the Peripheral Nervous System

Systemic Diseases

Vitamin Deficiency

Exogenous Toxins

Diabetes mellitus

Thiamine

Alcohol

Hypothyroidism

Pyridoxine

Chloramphenicol

Renal failure

Niacin

Cis-platinum

HIV/AIDS

Riboflavin

Cyanide

Intestinal malabsorption

Folic acid

Dapsone

Acute intermittent porphyria

Vitamin B

Diphenylhydantoin

Amyloidosis

Disulfiram

Acromegaly

Ethionamide

Leprosy

Glutethimide

Diphtheria

Gold

Lyme disease

Hydralazine

Mycoplasma

Isoniazid

Rheumatoid arthritis

Lithium

Systemic lupus erythematosus

Metronidazole

Polyarteritis nodosa

Nitrofurantoin

Wegener granulomatosis

Nitrous oxide

Carcinoma

Paclitaxel (taxol)

Waldenström macroglobulinemia

Perhexiline maleate

Multiple myeloma

Pyridoxine (lack or excess)

POEMS (polyneuropathy,

Thalidomide

organomegaly, M protein,

Vinca alkaloids

skin changes)

Heavy metals:

Cryoglobulinemia

Lead

Paraproteinemia (monoclonal

Thallium

gammopathy of uncertain

Industrial agents

significance—MGUS)

Solvents:

Sarcoidosis

n-Hexane

Whipple disease

Methyl-n-butyl-ketone

Syphilis

2,5-Hexanedione

Carbon disulfide

Trichloroethylene

Acrylamide

Dimethylaminopropionitrile

2,4-Dichlorophenoxyacetic acid

Triorthocresyl phosphate

Organophosphorus compound

tramadol because it has a relatively low poten-

of the neuropathy and loss of pain fibers or be-

tial for abuse. Nevertheless, it is important

cause the neuropathies improve. Patients often

to be sensitive that tramadol is an opioid and

are puzzled by the presence of pain and loss of

has produced problems with addiction. The

feeling in the same area, such as the feet. This is

natural history for painful neuropathies is for

common and reflects the differing effect of

improvement—either because of progression

nerve injury on different nerve fibers.

389

Chapter 18

n Peripheral Neuropathy

TABLE 18.4

Drug Treatment of Painful Neuropathies

Drug

Suggested Starting Dose

Usual Maximum Dose

Antidepressants

Amitriptyline

10-25 mg h.s.; inc. 10-25 mg q7 days

150-200 mg h.s.

Nortriptyline

10-25 mg h.s.; inc. 10-25 mg q7 days

100-150 mg h.s.

Duloxetine

60 mg q.d.

120 mg day

Anticonvulsants

Carbamazepine

100-200 mg b.i.d.; inc. 100-200 mg q3-7d

1200 mg/d (given as t.i.d.)

Gabapentin

300-400 mg q.d.; inc. 300-400 mg q3-7d t.i.d.

3600 mg/d (given as t.i.d.)

Topiramate

50 mg qPM; inc. 50 mg q7d b.i.d.

200 mg/d (given as b.i.d.)

Pregabalin

50 mg t.i.d.

100 mg t.i.d.

Opioids

Tramadol

50 mg q.d.; inc. 50 mg q3-4d q.i.d.

100 mg q.i.d.

for carefully because abnormalities of sensa-

GUILLAIN-BARRÉ SYNDROME

tion help differentiate this syndrome from

other conditions that may appear similar,

Of remitting polyneuropathies, acute inflam-

including hypokalemia, botulism, and po-

matory polyradiculoneuropathy, also known

liomyelitis. Pathologically, there is widespread

as the Guillain-Barré syndrome (GBS), is the

inflammatory segmental demyelination, most

most common, estimated to occur at a rate of

prominent proximally and presumably im-

1.5 per 100,000 people. GBS occurs most com-

munologically mediated. Prominent axonal in-

monly in young adulthood and early middle

jury and marked decrease in evoked motor

age, preceded in almost half of patients by an

response amplitudes argue for a slow recovery.

antecedent infectious illness (such as campy-

Although there are characteristic clinical fea-

lobacter) that usually clears before neurologic

tures, the variability of clinical presentation in

dysfunction begins. The etiology is thought to

actual practice should be emphasized. These in-

be immunologic. Of the patients, 20% to 30%

clude the Miller-Fisher syndrome (ataxia, oph-

have antiganglioside antibodies (GM1, GD1a)

thalmoplegia, and hyporeflexia) as well as

to neural antigens. The hallmarks of the syn-

limited findings such as facial diplegia with car-

drome are ascending progressive, often pro-

diac arrhythmias indicative of focal injury to

found, weakness; complete tendon areflexia;

the facial and vagal nerves. The CSF protein

high spinal fluid protein; possible cranial nerve

may not be elevated initially, and repeated lum-

and respiratory compromise; and substantial

bar punctures may be necessary to demonstrate

or complete spontaneous recovery. Weakness

an increased protein with the associated charac-

develops over hours to days but should not

teristic dissociation between protein and cells.

progress longer than

4 weeks. The severe

Autonomic instability may be a prominent fea-

motor compromise, short duration of progres-

ture and may result in morbidity and occasional

sion, and elevated cerebrospinal fluid (CSF)

mortality. EMG studies may reveal prominent

protein with few (<10 mononuclear cells/mm³)

slowing of nerve conduction, but evidence of

are features that distinguish this syndrome.

conduction block associated with segmental

Sensory loss may be mild but should be looked

390

Chapter 18

n Peripheral Neuropathy

demyelination and proximal conduction abnor-

demyelination, but there is also a loss of myeli-

malities may be the only findings. The EMG ex-

nated fibers. Onion bulbs are found as a result of

amination can have prognostic implications.

repeated episodes of demyelination with re-

GBS is considered idiopathic in origin. Syn-

myelination. The CSF again shows high pro-

dromes similar to GBS, however, may be found

tein and relatively few cells at some stage in the

in conditions such as acute intermittent por-

illness, but it may be normal at the time of a

phyria and Hodgkin disease and less commonly

particular examination. EMG studies charac-

with other neoplasms, hepatitis, infectious

teristically show slowed conduction. Nerve

mononucleosis, Lyme disease, and recently ac-

biopsy may be helpful for the diagnosis. In con-

quired HIV infection. Certain toxic neuropathies

trast to GBS, steroids are thought helpful in

such as with thallium may be similar.

CIDP. Immunosuppressive agents also have been

Although recovery may be slow, the charac-

used, and plasmapheresis and IVIG have pro-

teristic history of GBS is one of almost complete

duced a temporary improvement. The clinical

improvement. As such, the most important

presentation of patients with chronic acquired

treatment is symptomatic, particularly respira-

neuropathies can be quite variable; there are no

tory support and monitoring autonomic dys-

firm diagnostic EMG criteria. The treatments

function. Steroids have been advocated, but

are costly and can have serious side effects, such

they have not been beneficial and are possibly

as with high-dose steroid therapy. As such, the

detrimental. Plasmapheresis or intravenous im-

diagnosis and management of this condition

munoglobulins (IVIG) can hasten recovery and

should be in conjunction with those experienced

appear particularly indicated for those with se-

with these problems.

vere respiratory compromise and if used within

7 days of onset. A total of three to five courses

NEUROPATHIES ASSOCIATED

of plasmapheresis usually is given every other

WITH DIABETES MELLITUS

day; the standard dose for IVIG is 0.4 g/kg/day

for a total of 5 days. There is no proven benefit

Diabetes mellitus is common and often is associ-

to combining both plasmapheresis and IVIG.

ated with nerve dysfunction. Diabetic neu-

ropathies are probably now the most common

n SPECIAL CLINICAL POINT: Intravenous

neuropathies in the Western world. The reported

immunoglobulin and plasmapheresis are

incidence of neuropathic abnormalities in dia-

equally effective treatments for acute

betes has varied widely, most likely as a result of

inflammatory polyradiculoneuropathy

differing criteria and techniques used to diagnose

(Guillain-Barre syndrome).

PNS injury in these patients. A balanced view

probably would indicate a prevalence of 50% to

60% of some form of neuropathy in patients

CHRONIC INFLAMMATORY

with diabetes. The prevalence increases with the

DEMYELINATING

duration of the disease, but diabetic nerve dys-

POLYRADICULONEUROPATHY

function may be the initial sign of diabetes. Given

A syndrome similar to GBS sometimes may

the various presentations and probable patho-

occur in a chronic form termed chronic inflam-

genesis, it is best to think in terms of diabetic neu-

matory demyelinating polyradiculoneuropathy

ropathies rather than in terms of a single entity.

(CIDP). In these patients, the symptoms progress

n SPECIAL CLINICAL POINT: Diabetes is one

for more than 4 weeks. In comparison to GBS,

of the most common causes of neuropathy.

the onset is often more gradual; antecedent infec-

Therefore, in patients with a consistent clinical

tions are less common; and sensory symptoms

presentation, appropriate screening includes a

and signs are more frequent. As in GBS, the basic

fasting blood glucose test and possibly a glucose

pathologic process is an inflammatory segmental

tolerance test.

391

Chapter 18

n Peripheral Neuropathy

Polyneuropathies, mononeuropathies, plexop-

nerve as well as the cranial nerves, particularly

athies, radiculopathies, and autonomic neu-

the extraocular muscles. The onset of symp-

ropathies all are found individually or in

toms in mononeuropathies is characteristically

combination in diabetes, and diabetes there-

abrupt and frequently painful. Diabetes may

fore can be associated with abnormalities at

present as peroneal palsies.

any level of the PNS. Patients with asympto-

The pathogenesis of diabetic neuropathies is

matic diabetes may show decreased nerve con-

complex. Metabolic derangements have been

ductions that can normalize with improved

cited as the basis for the polyneuropathies.

control of blood sugar. A distal sensory or sen-

There is experimental evidence, however, that

sorimotor polyneuropathy is the most common

edema secondary to structural changes in en-

type of diabetic neuropathy. Although com-

doneural blood vessels with associated ischemia

monly described as “symmetric,” careful ex-

may be the primary cause. This may account

amination of these patients frequently reveals

for the asymmetric clinical findings in patients

some, even if limited, asymmetry. Describing

with “symmetric” diabetic neuropathies. The

the findings as “stocking glove” in distribution

abrupt onset of painful, focal lesions in the dia-

is actually somewhat misleading. The findings

betic mononeuropathies is similar to that of

are related to the distance in the limbs from the

other vascular neuropathies and has led to the

spinal cord; sensory loss limited to the hands

concept that these neuropathies are the result of

and feet would be consistent with spinal cord

occlusion of the small, nutrient blood vessels

injury, not peripheral nerve. A loss of position,

supplying nerves. This finding, however, has

vibration, and light touch as well as decreased

not been confirmed pathologically.

reflexes are prominent features of the “large

The natural history of diabetic mononeu-

fiber” pattern. Relatively pronounced loss of

ropathies, amyotrophies, and polyradicu-

pain and temperature sensation, in association

lopathies is one of improvement, even if slow.

with pain, indicate predominant “small fiber”

The course of diabetic polyneuropathies varies:

injury. The pain may have a dull, aching qual-

some diabetic neuropathies improve, many

ity in the limbs and also a distal, burning dis-

plateau, and some steadily progress. A severe

comfort most prominent at night. Rarely, there

disability is the exception. The pseudotabetic

is a pattern of sensory ataxia, pain, and

variety is generally progressive and more dis-

arthropathy

(diabetic

“pseudotabes”). The

abling. Pain, particularly distal burning dyses-

small fiber and pseudotabetic patterns may be

thesias, can be a major problem. Although the

associated with autonomic dysfunction, in-

manifestations of the autonomic neuropathy

cluding an involvement of the gastrointestinal,

may be subclinical, they are not infrequently

cardiovascular, and genitourinary systems. Au-

incapacitating. The prognosis for the auto-

tonomic dysfunction also can occur without

nomic neuropathy is among the worst of the

other evidence for a neuropathy. Postural hy-

diabetic neuropathies.

potension, diarrhea, impotence, urinary reten-

Good metabolic control is probably helpful

tion, and increased sweating are examples of

for both preventing and ameliorating diabetic

symptoms that may be caused by a diabetic au-

neuropathies, and good control of blood sugar

tonomic neuropathy. The painful, asymmetric,

therefore should be a goal in these patients. Ex-

proximal weakness of the legs found in dia-

ercise should be encouraged. Other therapies

betes (diabetic amyotrophy) is probably a re-

are symptomatic. An eye patch is helpful in pa-

sult of the involvement of the lumbar plexus

tients with the self-limited diabetic ophthalmo-

and frequently is found in the context of a his-

plegia, and bracing may be helpful in those with

tory of weight loss. Clinical patterns of a

peroneal palsy. Medications have been helpful

polyradiculopathy may occur. Mononeuropa-

in the painful sensory neuropathies (Table 18.4),

thies can affect almost every major peripheral

and analgesics are reasonable for the acute pain

392

Chapter 18

n Peripheral Neuropathy

associated with mononeuropathies. Trophic ul-

and weakness of thumb abduction. Provocative

cers of the feet may require changes in shoe size,

maneuvers such as percussion of the wrist over

debridement, and antibiotics. Standard medical

the median nerve (Tinel’s sign) or prolonged

regimens should be tried for autonomic dys-

wrist flexion

(Phalen’s sign) may reproduce

function. These regimens include codeine phos-

symptoms of paresthesias in the expected distri-

phate and diphenoxylate for diarrhea, support

bution. These findings are supportive of a diag-

stockings and fludrocortisone or midodrine for

nosis of CTS. Electrodiagnostic findings of

postural hypotension, and regular voidings as-

prolonged distal motor latencies or relative slow-

sisted by suprapubic pressure in those with

ing of median sensory conduction can also be

bladder atony. Nighttime lights can assist walk-

used to support the diagnosis. Conservative

ing in those patients with sensory loss by pre-

treatment often begins with wrist splints that

serving visual cues.

prevent excessive flexion particularly at night.

Local glucocorticoid injections have been shown

to provide modest and temporary relief of symp-

toms. Patients with severe CTS or those with

FOCAL NEUROPATHIES

moderate CTS who do not respond conservative

A patient complaining of numbness, weakness,

therapy may be candidates for surgical decom-

or pain in a very specific distribution may be

pression of the carpal tunnel.

suffering from a focal neuropathy. Appropriate

knowledge of peripheral neuroanatomy, key

Ulnar Neuropathy

historical clues, and findings on clinical exam

will often allow the clinician to identify a focal

The ulnar nerve is also susceptible to compres-

mononeuropathy.

sion, particularly as it passes across the medial

side of the elbow where the nerve is very su-

perficial. The ulnar nerve supplies many of the

Carpal Tunnel Syndrome

intrinsic muscles of the hand and motor symp-

Carpal tunnel syndrome (CTS) is one of the most

toms often predominate. They may include

common peripheral nerve entrapment disorders.

weakness of hand grip and pinch strength.

CTS results from compression of the median

More advanced cases will have associated at-

nerve as it passes through the carpal tunnel at the

rophy of both the thenar and hypothenar emi-

wrist. Symptoms typically include numbness and

nence. There may be preferential weakness of

burning in the hand that may extend into the

the third dorsal interosseous which is respon-

forearm and even the arm and neck. Patients

sible for adduction of 5th finger. The resulting

often report symptoms to be worse at night and

posture is a relative abduction of the 5th fin-

perceive relief with shaking of their hands. In

ger, a posture referred to as the Wartenburg

most of the population sensory fibers of the me-

sign. Patients with this pattern of weakness

dian nerve that pass through the carpal tunnel

may complain of catching their little finger

travel into the hand to supply the volar portions

when trying to put their hand in a pocket. The

of the thumb, index, middle, and the radial half

Benediction posture is another typical posture

of the ring finger. Typical findings on exam in-

associated with advanced ulnar nerve lesions.

clude decreased sensation in the distribution of

It is the result of weakness of the finger adduc-

the median nerve. A particularly useful finding is

tors and a hyperextension at the metacarpal-

a clear decrease in sensation to pinprick in the ra-

phalangeal joints in combination with flexion

dial half of the ring finger in comparison to the

at the proximal and distal interphalangeal

ulnar half. In more severe and long lasting cases

joints of the ring and little fingers. Patients

there may be a flattening of the thenar eminence

who have sensory complaints associated with

393

Chapter 18

n Peripheral Neuropathy

ulnar nerve lesion will complain of pain or

studies help to confirm the area of damage.

numbness in both the dorsal and volar distri-

Management of peroneal nerve palsy depends

bution of the little and ulnar half of the ring

on the underlying etiology.

finger. Percussion of the ulnar groove at the

elbow may reproduce sensory symptoms. Al-

though the elbow is the most common site of

FUTURE PERSPECTIVES

compression, the ulnar nerve is susceptible to

compression along its entire course from the

Our understanding of peripheral nerve disor-

axilla to the wrist. Electrodiagnostic studies

ders and their management remains unsatis-

may help to localize the lesion by identifying

factory. There is the potential for an increased

areas of slowed CV or a significant drop in

understanding of peripheral neuropathies.

amplitude. Treatment is aimed at minimizing

Newer techniques of histopathologic evalua-

compression of the ulnar nerve. For ulnar neu-

tion, including electron microscopy, teased

ropathy at the elbow initial conservative treat-

fiber preparations, and morphometric analysis

ment measures include counseling to avoid

of nerves, already have added meaningfully

prolonged flexion at the elbow, avoidance of

to our understanding of both normal and ab-

positions that put external pressure on the

normal nerves. Similarly, more sophisticated

ulnar nerve, and splints or elbow pads. Pa-

forms of electrophysiologic analysis should

tients who fail to respond to conservative

allow for a better evaluation of nerve dysfunc-

treatment may require surgery.

tion. These techniques include recording from

single muscle fibers (single fiber EMG); com-

puter analysis of motor unit firing, clinically

Peroneal Neuropathy

applicable techniques for evaluating changes

Peroneal neuropathy is the most common

in ion conductances in nerves, and increasing

mononeuropathy of the lower extremity. This

routine study of a wider range of electrophys-

is because it is particularly susceptible to com-

iologic responses and more sophisticated analy-

pression as it passes across the fibular head in

sis in EMG studies. The recording of cortical

the leg. Patients typically complain of inability

responses evoked by peripheral nerve stimula-

to dorsiflex the foot, a condition often referred

tion

(somatosensory evoked responses) not

to as foot drop. Often times the presentation

only allows for a more detailed evaluation of

may be acute after the patient was in a pro-

certain peripheral nerve injuries but also pro-

longed position that allowed for compression

vides a possible technique for evaluation at the

of the common peroneal nerve such as a surgi-

interface between peripheral and CNS dys-

cal procedure. Significant weight loss is also a

function. Immunologic studies are becoming

proven risk factor for development of a per-

increasingly important for understanding the

oneal nerve palsy. Other possible etiologies in-

pathogenesis of nerve disorders and for pro-

clude trauma or less commonly a mass lesion.

viding guides to therapy. Patients with a clini-

Physical examination will reveal weakness of

cal picture similar to ALS but with conduction

foot dorsiflexion as well foot eversion. Impor-

block on electrophysiologic examination and

tantly, in a pure peroneal lesion inversion of

frequently elevated titers of anti-GM1 anti-

the foot will be normal. This finding helps to

bodies have been treated successfully with

differentiate peroneal neuropathy from a L5

immunosuppressive agents. Finally, basic re-

radiculopathy, another condition that com-

search in the physiology, biochemistry, im-

monly presents with foot drop. Sensation may

munobiology, and axonal transport of nerves

be decreased along the lateral aspect of the leg

provides a dynamism and makes an interest in

and the dorsum of the foot. Electrodiagnostic

peripheral nerves rewarding.

394

Chapter 18

n Peripheral Neuropathy

A. Mononeuropathy

QUESTIONS AND DISCUSSION

B. Mononeuropathy multiplex

C. Plexopathy

1. A 64-year-old patient with a 10-year

D. Polyneuropathy

history of insulin-dependent diabetes

E. Radiculopathy

mellitus complains of burning dysesthesias

in the feet. Examination reveals a mild

The correct answer is A. This patient’s current

decrease in strength at the toes and ankles;

history and findings is most consistent with a

absent Achilles reflexes; decreased pinprick

mononeuropathy of the left peroneal (anterior

to the knees and elbows; decreased

tibial) nerve. Clinically, there is sensory loss,

vibration in the legs; and decreased

motor weakness, and EMG abnormalities in

position sense in the toes. Electrodiagnostic

the distribution of that nerve.

studies indicate slowed motor conduction

Diabetes mellitus can produce both a

velocities and absent sensory potentials in

polyneuropathy and a mononeuropathy, not

the legs with evidence of denervation

infrequently in the same patient. The patho-

distally in the lower extremities on needle

genesis of his polyneuropathy is probably

EMG examination. Sensory conductions in

multifactorial, including metabolic derange-

the upper extremities are slowed. Which of

ments and ischemia, whereas the mononeu-

the following is the most likely diagnosis at

ropathy may be secondary to vascular

this time?

infarction of the peroneal nerve.

A. Mononeuropathy

A diabetic polyneuropathy argues for good

B. Mononeuropathy multiplex

diabetic control. Diabetic mononeuropathies

C. Plexopathy

usually resolve with time because of the par-

D. Polyneuropathy

tial nature of the nerve injury secondary to the

E. Radiculopathy

ischemic insult. A short leg brace to aid in

dorsiflexion of the left ankle could be helpful

The correct answer is D. This patient’s clinical

for this patient during the recovery period.

symptoms, signs, and electrophysiologic find-

ings are most characteristic of a polyneuropa-

3. A 50-year-old woman has a 6-month

thy. The clinical and electrodiagnostic

history of intermittent paresthesias and

examinations reveal a diffuse sensorimotor

pain in her right hand. This pain awakens

neuropathic process most prominent distally.

her at night, usually within several hours of

2. Four weeks later, the same patient as in

falling asleep. She has noticed clumsiness in

question 1 develops weakness in the left leg

the use of that hand and complains of

associated with some pain in the region of

paresthesias radiating into the thumb and

the left knee. An examination 3 weeks after

index fingers. Recently, she has noted some

onset reveals relatively more prominent

milder tingling in the left thumb and index

decreased pinprick and touch sensation in

finger. She was recently diagnosed with

the lateral aspect of the left leg and dorsum

hypothyroidism. Examination shows

of the left foot, as well as lack of

paresthesias and pain radiating to the

dorsiflexion and eversion of the left ankle.

fingers on tapping the wrists bilaterally

EMG examination shows no evoked motor

(positive Tinel signs); weakness of right

response stimulating at the fibula head and

thumb abduction (the right abductor

denervation in the left tibialis anterior,

pollicis brevis muscle); and numbness

peronei, and extensor digitorum brevis

involving the right thumb, index finger, and

muscles. Which of the following is the most

middle finger as well as the adjacent one-

likely diagnosis for the patient’s new

half of the ring finger. There is also

symptoms and signs?

numbness involving the lateral half of the

395

Chapter 18

n Peripheral Neuropathy

palmar surface of the right hand. EMG

4. A 55-year-old man undergoing vincristine

examination reveals a prolongation of the

therapy for systemic lymphoma has

median distal motor latencies and slowing

developed progressive weakness over

of median sensory potentials bilaterally,

several weeks, resulting in an inability to

more prominent on the right. Which of the

walk. An examination reveals decreased

following is the most likely diagnosis?

vibration in the legs, decreased pin

A. Brachial plexopathy

sensation to the upper legs and in the

B. Carpal tunnel syndrome

fingers, preserved position sense, absent

C. Cervical radiculopathy

reflexes in the legs, and moderate to marked

D. Cervical spinal cord compression

weakness in the legs and mild-to-moderate

E. Polyneuropathy

weakness in the arms, most marked distally.

Electrodiagnostic studies reveal borderline,

The correct answer is E. This patient’s symp-

slow motor conduction velocities with

toms, signs, and electrophysiologic findings are

considerable evidence of denervation, again

most compatible with a diagnosis of bilateral

most prominent distally. Which of the

carpal tunnel syndrome (CTS), worse on the

following is most likely location of the

right. This syndrome is a mononeuropathy

nervous system lesion in this patient?

caused by “entrapment” of the median nerve

A. Brachial and lumbar plexus

as it passes through the carpal tunnel at the

B. Nerve roots

wrist. A positive Tinel sign is a common clini-

C. Peripheral nerve axons

cal finding in an area of partial nerve injury,

D. Peripheral nerve myelin

and progression of this sign distally can be

E. Spinal cord

used to follow regeneration after a nerve has

The correct answer is C (peripheral nerve

been severed. Characteristic electrodiagnostic

axons). This patient’s history and clinical and

findings in CTS are those that indicate median

electrophysiologic findings would be typical

nerve dysfunction at the level of the wrist—

for a polyneuropathy secondary to vincristine

that is, prolonged motor conduction stimulat-

therapy. The prominent denervation indicates

ing the nerve at the wrist and recording from

disruption of the normal connections between

median-innervated thenar hand muscles as

nerve and muscle. Combined with the border-

well as prolonged median sensory conductions

line slowing of conduction velocities, the pri-

with the level of injury at the wrist. The his-

mary disease is of axons rather than of

tory would suggest a bilateral process—an as-

myelin—that is, an axonal type of neuropathy.

sumption confirmed by the electrodiagnostic

The treatment is to stop the vincristine.

studies. Bilateral involvement in the CTS is

present in approximately 25% of the cases.

5. A 35-year-old man has a 6-month history

This syndrome is frequently part of several sys-

of weakness in the hands that now involves

temic illnesses including hypothyroidism. A

the legs. An examination reveals atrophy

CTS may be presenting complaint in a patient

and fasciculations in the intrinsic muscles

with abnormal thyroid function.

of the hands, weakness that is more

Initial treatment would consist of therapy

prominent distally in the upper than in the

for the hypothyroidism as well as splinting the

lower extremities, hyperactive reflexes, and

wrists to limit movement. If these measures

extensor plantar responses bilaterally.

failed, the transverse carpal ligaments proba-

Sensory testing is unremarkable.

bly should be surgically sectioned. Steroid in-

Electrodiagnostic examination reveals

jections can produce symptomatic relief, but

normal motor and sensory conduction

the long-term effectiveness and the possible

studies in the presence of denervation and

harm of this therapy have been debated.

decreased activation of motor units in all

396

Chapter 18

n Peripheral Neuropathy

FLOW CHART FOR NEUROPATHY EVALUATION AND TREATMENT

Careful history with special attention to distribution and rate of progression of symptoms.

Thorough physical exam to determine if the neuropathy involves sensory, motor, or autonomic fibers and if

it is diffuse or multifocal.

Ancillary testing which may include blood work, electromyography, nerve biopsy, and possibly

genetic testing.

Address underlying cause if it is identifiable and treatable.

Treat neuropathic discomfort with agents proven to be effective (i.e., antiepileptics,

antidepressants, or opioids).

Monitor for progression or improvement of the neuropathy with repeated

physical examinations and symptom evaluations.

four extremities. Many of the motor units

nerve and therefore contains only afferent

are both large and polyphasic. A cervical

fibers.

MRI is normal. Which of the following is

Nerve dysfunction may involve either

the most likely diagnosis?

motor or sensory fibers only. In ALS, the pri-

A. Amyotrophic lateral sclerosis (ALS)

mary pathology is at the lower motor neuron

B. Chronic inflammatory demyelinating

level in the anterior horns of the spinal cord.

polyneuropathy (CIDP)

It may be argued this is not an illness of the

C. Diabetic polyneuropathy

PNS. Conversely, because ALS involves the

D. Guillain-Barré syndrome

cell bodies of efferent fibers with resultant ab-

E. Vasculitic neuropathy

normalities in nerve and muscle, the illness

might be considered a prototypical axonal

The correct answer is A. The history and

neuropathy.

findings are consistent with a diagnosis of

ALS. The extensor plantar responses and hy-

peractive reflexes would indicate some in-

volvement of the long motor system tracts in

SUGGESTED READING

the CNS, but the atrophy and fasciculations

Aids to the Examination of the Peripheral Nervous Sys-

would be consistent with involvement of the

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lower motor neurons. This is confirmed by

Blume G, Pestronk A, Goodnough LT. Anti-MAG

the electrodiagnostic studies, which indicate

antibody-associated polyneuropathies: improvement

a chronic motor neuropathic process not

following immunotherapy with monthly plasma

readily explained by a process primarily af-

exchange and IV cyclophosphamide. Neurology.

1995;45:1577.

fecting peripheral nerves, plexuses, or roots.

The normal conduction velocities indicate

Brown WF, Bolton CF, Aminoff MJ, eds. Neuromuscular

Function and Disease: Basic, Clinical, and Electrodi-

preservation of at least some of the fast-con-

agnostic Aspects. Vols. 1 and 2. Philadelphia: WB

ducting (i.e., largest) motor axons. Because

Saunders; 2002.

the pathologic process involves strictly effer-

Cros D, ed. Peripheral Neuropathy: A Practical Approach

ent (i.e., motor) fibers, a sural nerve biopsy

to Diagnosis and Management. Philadelphia: Lippincott

would not be helpful. The sural is a sensory

Williams & Wilkins; 2001.

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n Peripheral Neuropathy

van Dijk JG. Too many solutions. Muscle Nerve.

Pestronk A. Motor neuropathies, motor neuron disor-

2006;33(6):713-714.

ders, and antiglycolipid antibodies. Muscle Nerve.

1991;14:927.

Donofrio PD, Alber JW. Polyneuropathy: classification by

nerve conduction studies and electromyography.

Ropper AH, Gorson KC. Neuropathies associated

Muscle Nerve. 1990;13:889.

with paraproteinemia. N Engl J Med. 1998;

338:1607.

Gibbons CH, Griffin JW, Polydefkis M, et al. The utility

of skin biopsy for prediction of progression in sus-

Saperstein DS, Katz JS, Amato AA, et al. Clinical

pected small fiber neuropathy. Neurology.

spectrum of chronic acquired demyelinating

2006;66:256-258.

polyneuropathies. Muscle Nerve. 2001;24:

311-324.

Kimura J. Electrodiagnosis in Diseases of Nerve and

Muscle. Philadelphia: FA Davis; 2001.

Stalberg E, Trontelj JE. Single Fiber Electromyography.

Old Woking, England: Miravalle Press; 1994.

Latov N. Pathogenesis and therapy of neuropathies asso-

ciated with monoclonal gammopathies. Ann Neurol.

Sumner CJ, Sheth S, Griffin JW, et al. The spectrum of

1995;37(suppl 1):S32.

neuropathy in diabetes and impaired glucose toler-

Mendell JR, Kissel JT, Cornblath DR, eds. Diagnosis and

ance. Neurology. 2003;60(1):108-111

Management of Peripheral Nerve Disorders. Oxford:

Tuck RR, Schmelzer JD, Low PA. Endoneurial blood flow

Oxford University Press; 2001.

and oxygen tension in the sciatic nerves of rats with

Parry JG. Guillain-Barré Syndrome. New York:

experimental diabetic neuropathy. Brain.

Thieme; 1993.

1984;107:935.

Neurologic

Evaluation of

Low Back Pain

MEGAN M. SHANKS

key points

• Most low back pain is from a nonspecific cause and will

resolve with or without treatment in a few weeks.

• Some less common causes of low back pain should not

be missed—these include cauda equina syndrome,

neoplasm, infection, and unstable fracture.

• Evidence-based reviews of acute back pain increasingly

recommend less initial imaging, less invasive treatment,

and increased patient physical activity.

emphasized here, especially for the 2% to 5%

EPIDEMIOLOGY

of low back pain patients with sciatica or

A majority of doctors will encounter low back

radicular nerve pain that can radiate past the

pain as a patient complaint. It comes second

knee, and other disorders involving the lum-

only to upper respiratory infections for sheer

bosacral nerves such as lumbosacral spinal

numbers of doctor visits and missed workdays.

stenosis and the cauda equina syndrome.

In young and middle-aged adults, it is the lead-

ing cause of activity-limiting illness. In Western

ANATOMY

countries, 50% to 80% of the adult population

will have some level of back pain during their

Much about the mechanics of low back pain

lifetime, and 15% to 30% within the past year.

is not well understood. Other than the spinal

About 2% to 5% of low back pain patients

cord and radicular nerves, structures that are

will develop chronic low back pain (i.e., lasting

known to possess nociceptive (pain) fibers in-

more than 4 to 6 weeks), with psychosocial is-

clude the outer annulus of the disc, the perios-

sues found as an even greater factor in these

teum of the vertebral bodies, the blood vessel

patients. The majority of patients recover

walls, the anterior dura, the posterior longitu-

within 4 to 6 weeks no matter what treatment

dinal ligament, the fibrous capsule of the facet

they receive, but recurrence is also common.

joint, and the sacroiliac joint. Damage to or

The neurologic approach to low back pain is

around these structures often, but not always,

398

399

Chapter 19

n Neurologic Evaluation of Low Back Pain

is a cause of pain. Approximately 85% of low

spinal canal as the cauda equina. The de-

back pain has no clear related injury to these

scending five lumbar, five sacral, and single

structures and is known as nonspecific back

coccygeal nerve roots exit through their corre-

pain. This is sometimes classified as nonspe-

sponding lateral neural foramina. Unlike the

cific degenerative disease, myofascial pain,

cervical nerve roots, the lumbar nerves de-

muscle spasm, or strain. The following details

scend for several levels before exiting below

of spine anatomy may be a helpful reference

the corresponding numbered vertebral body

in understanding the known causes and exam

(the L4 root between the L4 and L5 vertebrae,

findings in more depth.

and so on). Thus, a far lateral L4-5 disc herni-

The low back consists of five lumbar verte-

ation will cause an L4 radiculopathy pattern.

bral bodies, and a single fused bony sacrum,

But more commonly the disc herniates pos-

with the coccyx (tailbone) below. The lumbar

terolaterally within the neural canal, causing

vertebrae are stabilized by various ligaments,

the more medially descending L5 root to be com-

as well as the surrounding musculature, and

pressed (see Figs. 19.3 to 19.5). The most com-

cushioned by intervertebral discs (Fig. 19.1).

mon disc herniation and root syndromes are

The dorsal vertebral spine makes up the

the L4-5 (L5 root) and L5-S1 (S1 root). The

protective neural arch, surrounding the spinal

joint between each lumbar vertebral body is

cord canal and descending nerve roots

the facet (zagopophyseal) joint. The pars artic-

(Fig. 19.2). The adult spinal cord ends as the

ularis is the supportive bony bridge connecting

conus medullaris at L1-2, with the lum-

the superior and inferior articular facets, and

bosacral nerve roots descending through the

is prone to stress fracture (see Spondylosis).

FIGURE 19.1 Anatomic landmarks of lumbosacral spine.

401

Chapter 19

n Neurologic Evaluation of Low Back Pain

FIGURE 19.5 Axial spine MRI showing the same L4-5

disc (A), causing neural foraminal narrowing at the left

FIGURE 19.3 Herniated disc at L4-5 compressing the

nerve root exit (B). Note the normal appearance of the

L5 rootlet.

cauda equina nerve roots (black dots) floating within the

spinal canal (the triangle of white cerebrospinal fluid).

ligamentous change. Discs may also be a site of

infection, or discitis. Disc herniation without

Neurogenic Pain

nerve impingement can cause a focal back pain

without radiation down the legs past the knee, or

This is called “sciatica” or radicular pain. Mul-

be asymptomatic. Pain is typically worse with

tiple etiologies can be the source of nerve im-

bending, coughing, or sneezing (see Neurogenic

pingement. Most commonly disc herniation

Pain, and Neurologic Exam below for symptoms

causes nerves compression either in the spinal

found with specific nerve root impingements).

canal or neural foramen, but narrowing may

also be caused by arthritic change, ligamentous

hypertrophy, or often by a combination of all

three. These areas may also be compromised

by tumor, infection, or inflammatory disease. A

typical presentation is that of a sharp shooting

pain down the leg or legs, often with a tingling

numbness, with a particular pattern of weak-

ness if severe.

n SPECIAL CLINICAL POINT: It is often

stated that radicular pain can be differentiated

from other causes of radiating back pain by

traveling below the knee; this may not be true

for higher lumbar roots L1-3.

Gradual narrowing of the spinal canal in the

lumbosacral region can cause spinal stenosis

around multiple nerve roots. Degenerative dis-

FIGURE 19.4 Sagittal spine MRI showing a

posterolateral L4-5 disc herniation causing spinal canal

ease of bone, disc, and ligaments is the most

narrowing.

common cause. This can cause a specific pattern

402

Chapter 19

n Neurologic Evaluation of Low Back Pain

of pain referred to as “neurogenic claudica-

cause initial flaccid paralysis and areflexia, but

tion.” Like vascular claudication, exercise can

typically also has severe sensory loss.

bring on aching or cramping pain in the back,

buttocks and legs, and sitting or standing still is

Bony Spine Pain

needed to relieve the pain. Patients with neuro-

genic claudication may notice over time that the

Fracture or damage from trauma or osteopenia,

distance they can walk before they are stopped

neoplasm (metastases, primary bony tumors),

by pain becomes progressively shorter. Lumbar

infection or arthritis (inflammatory, degenera-

flexion may ease the pain. Low back pain is typ-

tive, Paget disease) may affect the vertebral

ically seen in neurogenic claudication, but may

bodies, facet joints, pars articularis, or sacroil-

be absent.

iac joints. Osteomyelitis of the spine may

Sudden simultaneous compression of multi-

develop slowly with symptoms of focal, unre-

ple lumbosacral nerve roots causes the cauda

lenting back pain not relieved by rest. Fever and

equina syndrome. It can be caused by disc her-

chills may also be present. This may lead to

niation, tumor, abscess, hemorrhage, spondy-

compressive neurologic symptoms by forming

lolisthesis (vertebral slippage), or fracture.

an epidural abscess. Compression fracture of

the vertebral bodies after minor trauma may

n SPECIAL CLINICAL POINT: Cauda equina

cause a constant focal tender region of the

syndrome is a neurologic emergency requiring

spine. Repetitive stress to the pars articularis

immediate attention to prevent permanent

may cause them to fracture, which is referred to

neurologic damage. It should be suspected if the

as spondylolysis. This can be entirely asympto-

patient complains of sudden back and leg pain

matic, or cause focal back pain with flexion or

with leg weakness, loss of reflexes, saddle

numbness, and bladder or bowel dysfunction

extension. It is notable cause of low back pain

with loss of anal tone.

in athletes. It predisposes patients to spondy-

lolisthesis, which is the slipping forward of one

Spinal cord or conus medullaris compression

vertebral body over the next. This may by itself

have similar symptoms as cauda equina syn-

cause unilateral or bilateral back pain, or cause

drome, but with the addition of upper motor

root irritation with radiating leg pain. Spondy-

signs such as hyperreflexia and spasticity.

losis is arthritic change or bony spurring from

This will be found with lesions in the L1-2 re-

the vertebral margins, and does not cause pain

gion or above, as the cord ends at this level in

unless there is nerve impingement. Facet joint

adults.

arthritis may cause a focal aching tenderness

Involvement of multiple nerve roots that

and pain with movement. Spinal deformities

can be rare causes of severe back pain include

such as scoliosis or kyphosis can increase the

Guillain-Barré syndrome (acute inflammatory

risk of back pain. Sacroiliac joint pain may be

demyelinating polyneuropathy) with progres-

due to arthritis or pregnancy, and causes an

sive weakness and areflexia, arachnoiditis (in-

aching or sharp pain over the low back where

flammatory clumping of the nerve roots), and

the sacrum joins the pelvis. It is worse with

carcinomatous meningitis. Low thoracic or high

standing or walking. Back pain may also be re-

lumbar cord involvement may also cause low

ferred from the hip joints.

back pain, including transverse myelitis and

spinal cord infarct. Cord infarct may spare the

Referred Pain from Abdominal

dorsal columns that carry joint position and vi-

or Pelvic Structures

bration sense, but will affect pain and temper-

ature as well as all strength below the level of

Pyelonephritis, kidney stones or urinary tract in-

infarct. Acute spinal shock from any cause

fection, pancreatitis, abdominal aortic aneurysm

(trauma, cord infarct, transverse myelitis) may

or dissection, gall bladder disease, peptic ulcer

403

Chapter 19

n Neurologic Evaluation of Low Back Pain

disease, prostatitis, endometriosis, and pelvic

nerve, but this latter syndrome is not associated

inflammatory disease can all potentially cause

with shooting pain and the weakness is usually

more pronounced (severe foot drop) than seen in

referred pain to the low back.

L5 radiculopathy.

A distinction can be made between a drop foot

Psychosocial Factors

from an L5 radiculopathy and that of a com-

The levels of life stressors and emotional dis-

mon peroneal neuropathy by checking for foot

tress are key in predicting poor outcomes and

inversion (tibialis posterior). Peroneal palsies

chronic low back pain. This includes job dis-

should spare foot inversion. Weakness of foot

satisfaction, depression, high levels of psycho-

inversion suggests an L5 radiculopathy rather

logical distress regarding pain and disability,

than a peroneal neuropathy.

and medicolegal or compensation disputes.

A neurologic exam of the lower extremities

This is probably one of the most important fac-

is important in any low back pain patient to

tors in nonspecific back pain, but one that is

rule out nerve compromise, particularly if the

more difficult to rate or treat.

clinical history suggests radiating pain or possi-

ble weakness or numbness.

n SPECIAL CLINICAL POINT: Most cases of

low back pain have a benign course, but there

Motor Strength

(See also Table 19.1) Ask the

are some less common causes of low back pain

patient to push against resistance. For L2-4, ask

that should not be missed. These include cauda

them to lift the leg at the hip and push the knees

equina syndrome, neoplasm, infection, and

toward each other. For L5, have them push the

unstable fracture.

knees apart, raise the foot at the ankle (this may

also have some L4), flex at the knee (this may

also have some S1), and tilt the foot inward and

EXAM

outward. For S1, have them push downward

with the foot, or from a supine position have

As a general medical history can point toward

them try to keep the leg on the bed while the leg

the specific causes of low back pain, so too can

is raised. A straight leg raise (SLR) test may also

the general exam. Fever is not always present

be checked at this time with passive lifting of the

in infections in or around the spine, but its

leg to between 30 and 70 degrees to assess for

presence with focal back pain is notable. Ab-

painful radicular nerve stretch. SLR can also be

dominal, pelvic, and hip exam may uncover re-

tested from a sitting position, with gradual

ferred sources of pain.

straightening of the leg. Patrick sign can be tested

Percuss the spine for focal tenderness as can

to check for referred pain from the hip or sacroil-

be seen in fracture, infection, or neoplasm. Pal-

iac joint. Patrick sign is also referred to as FABER

pate the back muscles for spasm and pain. In-

for flexion, abduction, and external rotation of

spect the skin for signs of shingles or bruising.

the hip. Be aware that pain with certain move-

Investigate the curve and mobility of the back

ments may cause the so-called “give-way weak-

movements.

ness” that will resolve when pain is controlled.

Be sure to ask the patient whether any pain is oc-

Neurologic Exam

curring if weakness is found. Give-way can also

be seen in a non-neurologic or diffuse pattern in

n SPECIAL CLINICAL POINT: L5 radiculopathy

embellishment or malingering. Check increased

is the most common radicular syndrome. The

hallmarks are shooting pain into the leg, big toe

tone by lifting the legs at the knees gently to see if

dorsiflexion weakness, and trouble inverting the

the heel drags along the bed or lifts up in a spastic

foot. The main differential diagnosis is peroneal

bouncing fashion. A patient in pain may not be

palsy from a more distal lesion of the peroneal

able to relax enough for this test to be done.

404

Chapter 19

n Neurologic Evaluation of Low Back Pain

TABLE 19.1

Main Nerve Root Motor and Sensory Findings (Some Variations Possible)

Root

Muscle

Action

Reflex

Sensory Finding

L2-4

Quadriceps

Knee extension

Patellar

Anterior thigh

Iliopsoas

Hip flexion

and medial calf

Adductor magnus

Hip adduction

and longus

Gluteus medius

Hip abduction

Hamstring

Lateral calf, medial

Hamstrings

Knee flexion

foot and toes

Extensor hallicus

Lift big toe

Gastrocnemius

Stand tiptoe,

Ankle jerk

Posterior calf,

point foot

and lateral foot

Gluteus maximus

Extend leg back

and toes

Toe flexors

Bend toes down

Sensory Exam Ask the patient if they have any

not prone to infarct, thus sparing the dorsal

numbness, then screen for the main der-

columns that carry joint position sense.

matomes with light touch and pinprick (some-

times one modality may be more affected than

Reflexes Knee reflex can be decreased or lost

another). Be sure to check the anterior and pos-

in L2, L3, or L4 radiculopathies, but may be

terior thighs, lateral and medial calves, and lat-

maintained if only one root is affected. The

eral and medial foot. Check vibration sense in

ankle jerk is a good S1 indicator, but may also

the toes with a tuning fork if available. Propri-

be lost in other conditions such as polyneu-

oception (joint position sense) in the toes and

ropathy, when it will be lost bilaterally. The

feet can be tested instead, but it is a less sensi-

hamstring reflex is rarely checked, as it is diffi-

tive test than vibration sensation. Checking for

cult to elicit. It is usually mediated by the L5

a positive Romberg (swaying with eyes closed)

root, but occasionally also by the S1 root.

is also a test for joint position sense. Peripheral

nerve disease can cause this finding as well.

Rectal Exam Rectal tone is a good indicator

of sacral nerve involvement. This is important

n SPECIAL CLINICAL POINT: Check

to check if spinal cord or cauda equina lesions

vibratory sensation (using a tuning fork) and

are suspected. See Chapter 1 (The Neurologic

joint proprioception to evaluate the spinal cord

Exam) for more details.

dorsal or posterior columns.

The vibratory exam can be extremely helpful in

establishing any dorsal column spinal cord dam-

WORKUP

age as can be seen with B₁₂ deficiency, syphilis,

or HIV. Alternately, complete loss of all function

A recent argument is that the entity of acute

(motor and sensory) in the legs with the excep-

low back pain is overly imaged. As mentioned

tion of vibration and proprioception is strongly

earlier, nonspecific low back pain accounts for

suggestive of a spinal cord infarct. Acute spinal

a majority of all back pain, and by definition,

shock can occur early after cord infarct, how-

no structural cause may be found. There are

ever, and may be pan-sensory. Unlike the ante-

certainly false negatives and false positives

rior spinal artery, the paired posterior spinal

found by any diagnostic modality. For example,

arteries have many collateral vessels and are

an MRI may reveal an unrelated right-sided

405

Chapter 19

n Neurologic Evaluation of Low Back Pain

bulging or herniated disc when the symptoms

or vascular cause. Limitations include the pos-

are clearly on the left or localizable to a differ-

sibility of renal failure or allergic reaction.

ent level. The abnormalities found may not re-

late to the current complaint. This can lead to

CT Myelogram

unnecessary or ineffective invasive treatment,

especially if the clinical history and exam is not

This adds significant improvement of details

kept firmly in mind when reviewing the diag-

regarding the CSF space surrounding the spinal

nostic findings. In addition, it is important to

cord, allowing further information regarding

realize that not every abnormality may be seen

mass lesions, CSF leaks, and nerve root sleeves.

on diagnostic imaging or workup, even some-

Limitations: A lumbar puncture must be per-

thing presumably obvious like a slipped disc.

formed in order to introduce the dye. Post-LP

With that in mind, the modalities discussed

postural headaches may occur. CT myelogram

below are most helpful in specific structural

also has similar renal and dye allergy concerns

causes, particularly those that are the main

as above, but it is also a rare cause of arach-

focus of this chapter, back pain with neurologic

noiditis (inflammation and pain with clumping

signs or symptoms.

of nerve roots).

Spine X-rays

MRI Spine Without Gadolinium Dye

These are most useful for fracture (traumatic or

This provides good identification of soft tissue

spontaneous), tumor

(with bone metastasis,

and details of anatomy, and is the best modality

multiple myeloma, or primary bone tumors),

for visualization of the spinal cord and nerve

osteoporosis, Paget disease, arthritic condi-

roots. MRI is also very good for diagnosis of

tions with bony change (ankylosing spondylitis),

tumor and infectious causes. MRI involves no

spondylolisthesis or spondylolysis, and os-

radiation exposure and is safer in pregnancy.

teomyelitis. Limitations of this test include the

Limitations: MRI shows less bony detail so

following: the soft tissue is not visualized and

fractures are less clear. This cannot be done on

changes from conditions such as osteomyelitis

patients with pacemakers, loose metal, claus-

may take weeks to develop.

trophobes, or over-sized patients. In addition,

low back pain patients may find lying still for

the extended time required for MRI to be intol-

CT Spine

erable. Open and upright MRI imagers are

This modality provides good visualization of

available but with some degradation of the

fractures, and is less affected by motion arti-

image.

fact, and cheaper, than MRI. CT of the spine is

useful for patients where MRI is contraindi-

MRI Spine with Gadolinium

cated (e.g., pacemakers, claustrophobia, over-

size patient, and metal fragments). It has all the

The addition of gadolinium contrast increases

above advantages of spine x-ray with more de-

the information and yield of MRI in cases of

tails available. Limitations of CT of the spine

neoplasm and infection. Gadolinium dye is not

include that soft tissue (and the spinal cord or

required for imaging of degenerative structural

nerve roots) are not well visualized.

causes such as disc herniation or arthritic

change. It can also be helpful in assessing post-

operative scar formation. Limitation: Allergic

CT Spine With IV Dye

reactions are less common than CT dye, but

The addition of intravenous contrast may add

can occur. Patients with renal insufficiency are

details for conditions of neoplastic, infectious,

at risk for nephrogenic systemic fibrosis.

406

Chapter 19

n Neurologic Evaluation of Low Back Pain

Radionuclide Bone Scan

Labs

This can be done if a condition such as

LDH (probably most sensitive but least specific

bony metastatic disease, acute fractures, or os-

in spinal infection) and also ESR and C-reactive

teomyelitis is suspected. Limitations: Findings

protein (CRP) may be helpful. White blood cell

from this modality are nonspecific, and there

count can be elevated or normal in spinal infec-

may be significant false negatives and positives.

tions. Low platelets and increased PT/PTT may

reflect bleeding risk and the possibility of

n SPECIAL CLINICAL POINT: If the patient

epidural hematoma. Increased alkaline phos-

has signs of spinal cord dysfunction (e.g. bilateral

phatase, calcium, and serum and urine immu-

leg spasticity and hyperreflexia, with or without

noelectropheresis may also suggest multiple

arm symptoms), a spine MRI should be done. The

myeloma. Alkaline phosphatase may also be

spinal cord does not usually go below L1-2 in

increased in osteoporosis, hypoparathyroidism,

adults, so a lumbosacral spine MRI will be less

and bony metastases. HLA-B27 is more com-

helpful than a cervical or thoracic spine MRI in

patients with signs and symptoms of spinal cord

mon in inflammatory arthritis

(ankylosing

dysfunction.

spondylitis). Limitations: These laboratory tests

are low yield, playing less of a role in diagnos-

Electrodiagnostic Studies

ing most low back pain.

Electromyogram/Nerve conduction studies

(EMG/NCS): This is a study of the muscle and

nerve, usually referred to as “EMG.” EMG is

TREATMENT

helpful to evaluate lower motor neuron nerve

There is wide variability in the treatment of

damage, that is, damage of the motor nerve

low back pain, both between and even within

(to muscle) and below the sensory nerve cell

specialties. Many treatments in common use

bodies.

may have little or no efficacy. Efforts are being

made to perform systemic reviews of evidence-

n SPECIAL CLINICAL POINT: In typical

based data to correct this, and there are various

radiculopathies, sensory nerve conduction

studies will be normal despite a patient’s

guidelines put out by several groups and agen-

symptoms of numbness, because the sensory

cies available.

cell body in the dorsal root ganglion is below

the level of a typical disc herniation.

Treatment of Acute Low Back

Pain (<4 to 6 weeks)

Limitations: EMG can be a painful study,

motor nerve conductions can remain normal

Emergent evaluation is required if the patient

for 7 to 10 days following an injury, and needle

has signs of cauda equina compression (new

studies of the muscle (which is the most helpful

onset of severe or progressive leg weakness or

part of the test in determining radiculopathies

numbness, saddle numbness, or bowel or blad-

with nerve root damage) can take 14 to 21 days

der dysfunction), or other “red flags” such as

to fully develop.

trauma, fever, or a suspicion for cancer (see

Table 19.2). Surgical consultation should be

n SPECIAL CLINICAL POINT: EMGs are best

considered. If evidence of cauda equina syn-

if done more than 3 weeks after onset of nerve

drome is found, the patient may require surgical

damage.

decompression performed emergently. Similarly,

Upper motor neuron cord lesions will not be

any unstable fractures or spondylolisthesis must

apparent on EMG. Painful lumbar stenosis

be surgically stabilized, and infections treated

without weakness or numbness may not be ap-

with antibiotics (after drainage if due to ab-

parent on EMG.

scess). Tumors may require surgical removal or

407

Chapter 19

n Neurologic Evaluation of Low Back Pain

TABLE 19.2

should be scheduled, with a timely surgical con-

Indications for Possible Serious

sultation (neurosurgical or orthopedic) for com-

Underlying Causes of New-Onset

pressive lesions. For mild motor deficits with

Low Back Pain

acute radicular pain, an urgent spine MRI

should also be considered, and an EMG consid-

Condition

Sign or Symptom

ered if symptoms persist beyond 3 weeks. The

patient may be reassured that most of these

Cauda equina

New onset of severe

or progressive leg

milder cases resolve without surgery. If severe

weakness or numbness,

radicular pain and/or sensory deficits are pres-

saddle numbness, bowel

ent, the usual conservative measures are used

or bladder dysfunction

(see below), with the addition of a brief course

Neoplasm

History of cancer, age >55,

of opioids if pain is intolerable. Although oral

unexplained weight loss,

steroids are frequently recommended, there

constant pain not relieved

is no strong evidence that this is effective. There

by rest or change in

is some conflicting evidence that epidural

position, progressive leg

steroids may hasten improvement in the first

weakness or numbness

few weeks, and little data comparing it to other

Infection

Fever, chills, pain unrelieved

modalities of treatment. Conservative treatment

by rest, immune

suppression, recent

should be used for all nonurgent forms of low

infection (e.g., UTI),

back pain. The most common form of low back

IV drug use

pain is non-neurologic, nonspecific low back

Fracture

Recent trauma, osteoporosis

pain. Conservative measures should be used as

Guillain-Barré

Ascending leg weakness,

outlined below.

syndrome

areflexia, minimal

numbness (pain is unusual)

Conservative Treatment

in Acute Low Back Pain

nerve root decompression, steroids, chemother-

Reassure the patient that most low back pain

apy, or radiation, depending on type and loca-

resolves within a few weeks. They should

tion. The reader is directed to surgery and

avoid heavy lifting, twisting, or other aggra-

oncology texts for more details. Although pain

vating movements, but otherwise stay as active

is unusual in Guillain-Barré cases (acute de-

as possible. Bed rest should be avoided if at all

myelinating polyneuritis), it can be associated

possible. Heat should be applied to the back. If

with severe back pain. Guillain-Barré syndrome

needed, acetaminophen, paracetamol (outside

should be suspected with progressive, ascending

the United Sates), NSAIDs (nonsteroidal anti-

weakness and areflexia, and negative spinal im-

inflammatory drugs), and muscle relaxants can

aging. It can progress to respiratory arrest in

decrease pain levels. Stronger medications

hours or days. Neurologic consultation and a

such as opioids, benzodiazepines, and tra-

lumbar puncture should be considered for con-

madol can be effective, but should be avoided

firmation. Treatment consists of a course of

if possible due to side effects and dependency

plasma exchanges or IVIG (see Chapter 18).

issues. Physical therapy and spinal manipula-

Fortunately the emergent causes of low back

tion may be helpful, although specific back

pain are rare. Somewhat more common are the

strengthening exercises are probably not help-

structural causes of acute low back pain with

ful in the acute period. Spinal manipulation is

nerve involvement, which includes radicu-

not recommended in those with radicular

lopathies or “sciatica.” If significant weakness is

symptoms such as numbness or weakness.

found in a root distribution, a more urgent MRI

There is currently insufficient evidence to

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Chapter 19

n Neurologic Evaluation of Low Back Pain

support massage or acupuncture, and no evi-

ing has a much higher chance of good response

dence to support traction, lumbar supports, or

to surgery. However, use of surgery is contro-

TENS (transcutaneous electrical nerve stimu-

versial given recent findings suggesting a more

lation) in the acute low back pain patient.

rapid recovery, but no long-term benefit over

nonsurgical treatments. In radiculopathy

(chronic sciatica), laminectomy (removal of the

Treatment of Chronic Low Back

vertebral bony arch) with or without discec-

Pain (>4 to 6 weeks)

tomy, partial facetectomy, or spinal fusion, are

If conservative measures fail and back pain per-

the decompressive spinal surgeries most com-

sists, a referral to a physician specializing in

monly performed. A majority of patients have

back pain may be required. Depending on pres-

decreased pain symptoms after decompression

entation, this can include neurologists, physical

for spinal stenosis. However, there is uncertain

medicine and rehabilitation specialists, rheuma-

long-term benefit after several years, except in

tologists, sports medicine specialists, anesthesia

cases with acute onset. There is conflicting evi-

pain specialists, neurosurgeons, and orthopedic

dence for spinal fusion surgery in chronic low

surgeons, among others. If milder, nonprogres-

back pain with nonspecific degenerative spine

sive motor deficits, or disabling back or leg pain

disease. The reader is directed to neurosurgery

persists despite conservative treatment, imaging

or orthopedic surgical texts for more details on

should be performed if not done already.

various surgical approaches.

Conservative treatment measures may still

be employed as in acute back pain, with in-

creased concern over dependency and side-effect

Always Remember

issues of stronger medications. Medications for

• Severe or progressive neurologic deficits

chronic pain, including tricyclic antidepressants

should be evaluated immediately.

such as amitriptyline or nortriptyline may have

• Cauda equina syndrome is a neurologic

some small benefit, although serotonin reuptake

emergency requiring immediate attention to

inhibitors (SSRIs) and trazadone have shown no

prevent permanent neurologic damage.

benefit. There is conflicting data over the benefit

• Patient self-care with back pain education,

of gabapentin or pregabalin for radicular nerve

avoiding bed rest, and application of heat are

pain.

the first steps in the treatment of acute low

Physical therapy and spinal manipulation

back pain.

shows evidence of some benefit, as does exercise

• Psychosocial factors play a major role in

therapy, and possibly massage, acupuncture,

predicting poor outcomes and chronic low

and yoga. Cognitive-behavioral therapy, multi-

back pain.

disciplinary rehabilitation, and back school

(educating patients about back pain), may be

helpful for chronic low back pain. Scant data

suggests spinal manipulation is less effective in

QUESTIONS AND DISCUSSION

sciatica patients. TENS treatments and traction

show no evidence of efficacy in the chronic low

1. A 25-year-old woman presents to the

back pain patient. There is currently insufficient

office with 2 weeks of low back pain that

evidence to support the use of more invasive

began after moving some boxes. She

treatment for chronic low back pain, such as

describes a severe aching pain in the low

trigger point injections, epidural steroid injec-

back that is occasionally sharp with

tions, and facet joint injections.

movement, but without radiation down

Surgical procedures may be reconsidered.

the legs. On examination she has limited

Pain with a clear structural cause seen on imag-

range of motion of her back, no

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Chapter 19

n Neurologic Evaluation of Low Back Pain

FLOW CHART: APPROACH TO ADULT LOW BACK PAIN

STEP 1: Assessment of Acute Low Back Pain (<4 to 6 weeks)

Evaluate history, general, and neurologic exam for serious underlying conditions:

a. Onset associated with trauma, suspected fracture, or fever and chills

b. History suggesting neoplasm, hemorrhage, immunosuppression, IV drug use, or recent systemic infection

c. Severe or progressive weakness, or bowel and bladder dysfunction

If any of the above red flags are present, immediate evaluation is required. Go to Step 2.

Otherwise, go to Step 4.

STEP 2: Emergent Care

a. Spine x-ray or CT spine if fractures suspected, if not, MRI is preferable

b. MRI lumbosacral spine, without gadolinium unless infection or tumor suspected

c. MRI with gadolinium and labs if infection or tumor suspected (ESR, LDH, CRP, CBC, alkaline phosphatase);

bone scan if desired

d. MRI thoracic spine if focal lower extremity upper motor neuron signs present

e. If scans are normal and patient has areflexia, consider Guillain-Barré syndrome or acute spinal shock

If emergent or serious underlying cause found go to Step 3.

If no emergent cause found, go to Step 4.

STEP 3: Interventional Care

Consult or refer to a spine surgeon for decompression and stabilization, or a neurologist, oncologist,

rheumatologist etc. as required to treat specific cause.

STEP 4: Acute Conservative Care

a. Education in self-care: Stay active but avoid aggravating movements. Use heat.

b. If needed use acetaminophen, NSAIDS, muscle relaxants

c. Consider physical therapy or spinal manipulation (unless radicular)

d. Re-evaluate patient in 4 to 6 weeks (Step 5)

STEP 5: Chronic Care (>4 to 6 weeks)

a. Re-evaluate history and exam for serious underlying causes (Step 1)

b. MRI spine without gadolinium if not already performed

c. EMG if radicular or spinal stenosis symptoms present

d. Return to Step 3 (Interventional Care) if indicated

e. Continue Step 4 (Conservative Care) measures with addition of gabapentin, pregabalin, or tricyclics for nerve

pain if needed

f. Consider referral for physical therapy, spinal manipulation, exercise therapy, massage, acupuncture, yoga,

cognitive-behavioral therapy, multidisciplinary rehabilitation, or back school. Consider referral to a

neurologist when a radiculopathy is not responding to conservative measures, or when neurologic signs or

symptoms such as weakness or numbness are present.

weakness, no sensory loss, and normal

B. Continue her usual physical activities as

reflexes. She has a negative straight

tolerated (except heavy lifting), with

leg raise. Which of the following is the

anti-inflammatories as needed.

most appropriate management of this

C. Epidural steroid injections in the lumbar

patient?

spine.

A. Strict bed rest for 2 weeks with codeine

D. MRI of lumbar spine.

as needed, and then start physical

The correct answer is B. The patient has acute

therapy for back strengthening

nonspecific back pain with onset of less than

exercises.

4 to 6 weeks. There is no evidence by history

410

Chapter 19

n Neurologic Evaluation of Low Back Pain

or exam of a more serious underlying cause

The correct answer is B. The patient has

of low back pain, so back imaging is not

chronic low back pain that is likely due to a

indicated at this point. If symptoms do not

lumbosacral radiculopathy, but without

respond in a reasonable time, a search for a

significant neurologic deficits. Many

structural abnormality of the spine would

physicians would also consider answer C. This

then be warranted.

is controversial, as epidural steroid injections

This patient should be reassured that most

are considered by many to be standard care,

low back pain resolves within a few weeks.

but with variable results in formal studies.

She should avoid heavy lifting, twisting, or

Epidural steroid injections are frequently used

other aggravating movements, but otherwise

in nonsurgical radiculopathy cases, with many

stay as active as possible. Bed rest should be

patients reporting pain relief after the injec-

avoided if at all possible. Heat should be

tions. However, there is currently insufficient

applied to the back. If needed, acetaminophen,

evidence to support epidural steroids as a

paracetamol (outside the United States),

treatment for chronic low back pain with

NSAIDs (nonsteroidal anti-inflammatory

radiculopathy symptoms. Back surgery is not

drugs), and muscle relaxants can decrease

usually indicated for a herniated disc without

pain levels. Stronger medications such as

significant neurologic deficits (weakness,

opioids, benzodiazepines, and tramadol can

bowel and bladder dysfunction), although it is

be effective, but should be avoided if possible

sometimes used in cases with severe unremit-

due to side effects and dependency issues.

ting radicular pain. Chronic opioid use should

Physical therapy and spinal manipulation may

be avoided. As mentioned above, physical

be helpful, although specific back strengthen-

therapy shows some benefit, and complete bed

ing exercises are probably not helpful in the

rest has not been found to be helpful.

acute period. Epidural steroids are not

3. A 55-year-old man was in a fistfight

indicated for acute back pain.

2 weeks ago, which caused skin abrasions,

2. A 40-year-old man has low back pain for

but no other injuries or pain. One week

2 months, which began suddenly after

later he developed a constant low

playing basketball. It is not as bad as it was

backache. Two weeks later he presents to

2 months ago, but he complains of an

the emergency department with new-onset

occasional sharp pain radiating down his

bilateral leg weakness, numbness,

left leg and intermittent tingling in his foot.

constipation, and no urine output for

On examination he has limited range of

12 hours. On examination he has bilateral

motion of his back due to some pain, no

3-4/5 leg weakness, patchy sensory loss in

weakness, no objective sensory loss, normal

the legs and saddle region, decreased ankle

reflexes, and a positive straight leg raise on

reflexes, decreased rectal tone, and focal

the left. MRI shows a small leftward

back pain to percussion in the low mid-

herniated L5-S1 disc. Which of the

back. Which of the following is the most

following is the most appropriate treatment?

appropriate emergency test at this time?

A. Strict bed rest for 2 weeks with codeine

A. Radionuclide bone scan

as needed.

B. Spine x-ray

B. Advise the patient to remain active, and

C. EMG

refer to physical therapy.

D. Spine MRI

C. Epidural steroid injections in the lumbar

The correct answer is D. The patient appears

spine.

to have cauda equina syndrome, possibly

D. Surgery for the herniated disc seen on

from an infectious source such as an

lumbosacral MRI.

epidural abscess. Cancer with bone

411

Chapter 19

n Neurologic Evaluation of Low Back Pain

metastases could have a similar presentation

SUGGESTED READING

unrelated to his skin abrasions, so further

history and examination relating to cancer

Available at: http://www.cochrane.iwh.on.ca/ for regularly

should be sought. A CBC and LDH may be

updated evidence-based healthcare reviews of low

back pain (Cochrane Review Back Review Group).

elevated with a focal infection, but are

nonspecific. An x-ray would show fractures,

Chou R, Qaseem A, Snow V, et al. Clinical Efficacy Assess-

ment Subcommittee, Diagnosis and treatment of low

and possibly osteomyelitis. However, plain

back pain: a joint clinical practice guideline from the

radiographs can be normal in early

American College of Physicians and the American Pain

osteomyelitis and will be normal with an

Society. Ann Intern Med. 2007;147:478-491.

acute epidural abscess, disc herniation,

Chou R, Huffman LH. Nonpharmacologic therapies for

hematoma, or other nonbony abnormality.

acute and chronic low back pain: a review of the evi-

dence for an American Pain Society/American College

He had no back pain immediately after his

of Physicians clinical practice guideline. Ann Intern

fight to indicate an acute fracture at that

Med. 2007;147:492-504.

time. An EMG will show evidence for

Chou R, Huffman LH. Medications for acute and chronic

polyradiculopathy in cauda equina syndrome

low back pain: a review of the evidence for an American

in 2 to 3 weeks time, but will not be helpful

Pain Society/American College of Physicians clinical

practice guideline. Ann Intern Med. 2007;147:505-514.

in the acute setting. An emergent MRI of the

spine will show the source of the cauda

Weinstein JN, Tosteson TD, Lurie JD, et al. Surgical vs

nonoperative treatment for lumbar disk Herniation.

equina compression, and allow for immediate

The spine patient outcomes research trial (SPORT): a

presurgical evaluation. To decrease the

randomized trial. JAMA. 2006;296:2441-2450.

possibility of permanent neurologic deficits,

Siemionow K, Steinmetz M, Bell G, et al. Identifying

surgical consultation should be called imme-

serious causes of back pain: cancer, infection, fracture.

diately, and not left until the next morning.

Cleve Clin J Med. 2008;75:557-566.

Dizziness

and Vertigo

ROBERT K. SHIN AND JUDD M. JENSEN

key points

• Dizziness is a nonspecific term that may refer to

presyncope, vertigo, or disequilibrium.

• Presyncope is primarily a cardiovascular problem rather

than a purely neurologic disorder. Causes of presyncope

include hypertension, orthostatic hypotension, vasovagal

depression, and cardiac arrhythmia.

• Many causes of vertigo are benign (e.g., benign

paroxysmal positional vertigo or Ménière disease), but

acute or intermittent vertigo may be a sign of more

serious disorders, such as vertebrobasilar disease.

• Disequilibrium may result from problems with

sensation, vestibular function, central integration, or

motor coordination.

izziness is a

THREE TYPES OF DIZZINESS

common complaint in the outpatient clinic and

the emergency department, one that may be as

Dizziness has traditionally been divided into

anxiety-provoking for the physician as it is for

three categories: presyncope, vertigo, and dise-

the patient. Many causes of dizziness are be-

quilibrium. Distinguishing between these dif-

nign, but dizziness can also be a symptom of

ferent types of dizziness may help point to a

cerebrovascular disease (transient ischemic at-

particular diagnosis. Patients may have diffi-

tack [TIA] or stroke) or other disorders that

culty describing their dizziness in detail, how-

may be potentially life-threatening. Clinicians

ever, and the clinician should keep in mind that

should be familiar with the different causes of

some disorders, for example, cerebrovascular

dizziness to assist in making an accurate diag-

disease, can present with any form of dizziness.

nosis and should be able to recognize “red flags”

that may signal potentially life-threatening

Presyncope

causes of dizziness. Effective therapies for some

dizziness syndromes have been developed,

Patients with presyncope may describe their

which the non-neurologist may find useful in

dizziness as “lightheadedness” or “feeling like

clinical practice.

I’m going to faint.” This sensation may be

412

413

Chapter 20

■ Dizziness and Vertigo

associated with generalized weakness, visual

associated neurologic signs and symptoms in

blurring or blackout, diaphoresis, pallor, short-

order to arrive at the correct diagnosis.

ness of breath, or palpitations. Presyncope is

typically episodic and is caused by a transient

CAUSES OF PRESYNCOPE

reduction in global cerebral perfusion. There-

fore, presyncope is usually a primary cardio-

Presyncope is characterized by lightheadedness,

vascular problem rather than a neurologic one.

visual blurring or blackout, paresthesias, and/or

generalized weakness that may result from a

global reduction in cerebral perfusion from a de-

Vertigo

crease in systemic arterial pressure, failure of car-

Patients who have vertigo experience a false sen-

diac output, or diffuse cerebral vasoconstriction.

sation of movement. Most commonly, they re-

Diaphoresis, palpitations, and nausea often are

port that their environment is spinning around

present as the autonomic nervous system at-

them; however, sensations of tilting, swaying,

tempts to restore cerebral perfusion. Presyncope

and being impelled forward, backward, or to ei-

may occur in a variety of clinical settings.

ther side are also vertiginous. Nausea, vomiting,

and some degree of imbalance are common, as

Hyperventilation Syndrome

are autonomic signs such as diaphoresis, pallor,

and tachycardia. Classically, patients with ver-

Hyperventilation is a common cause of presyn-

tigo are thought to have a disorder of either the

cope typically seen in anxious, pressured individ-

peripheral or central vestibular system, with pe-

uals. Patients with high-grade hyperventilation

ripheral vestibular disorders comprising ap-

tend to have acute episodes of dizziness precipi-

proximately 90% of cases. Cerebellar lesions,

tated by stressful situations or panic attacks.

however, may also cause vertigo and may mimic

They often are aware of breathing rapidly or

a peripheral vestibular problem.

feeling short of breath and may complain of vi-

sual blurring, paresthesias of the lips or fingers,

and generalized weakness. Patients with low-

Disequilibrium

grade hyperventilation have a more protracted

Disequilibrium is a more complex category than

and insidious form of dizziness in which symp-

the previous two. Whereas patients with presyn-

toms tend to wax and wane over longer periods.

cope and vertigo tend to have episodic symptoms

Visual blurring, paresthesias, and generalized

or attacks, patients with disequilibrium typically

weakness are usually absent. Patients are almost

have more continuous symptoms. Patients with

never aware that they are overbreathing, and

disequilibrium are dizzy primarily when standing

they may not feel short of breath.

or walking and tend to improve when seated or

Artificial hyperventilation can be useful in

supine. Disequilibrium may be difficult for pa-

the evaluation of patients with dizziness. Hyper-

tients to describe. Complains of “bad balance,”

ventilation results in a drop in arterial PCO₂

“poor equilibrium,” or “I’m just dizzy” are com-

with subsequent cerebral arterial vasoconstric-

mon. Disequilibrium is the result of dysfunction

tion and global reduction in cerebral blood flow.

at one or more points in the complex system re-

Hyperventilation can be induced by holding a

quired for balance and ambulation.

tissue 12 inches in front of the patient’s mouth

and having the patient blow the tissue with

■ SPECIAL CLINICAL POINT: Distinguishing

rapid and deep breaths for up to 3 minutes. The

between these three types of dizziness can

tissue must be displaced significantly with each

sometimes be difficult for the patient and,

consequently, for the clinician. At times it may

exhalation to ensure hyperventilation. If this

be more important to pay attention to the

procedure exactly reproduces the patient’s dizzi-

acuteness and pattern of the dizziness as well as

ness, hyperventilation syndrome is suggested.

414

Chapter 20

■ Dizziness and Vertigo

Both high-grade and low-grade hyperventi-

symptoms, then the observed drop in blood

lators tend to be very sensitive to even short pe-

pressure may not be the cause of the dizziness.

riods of induced hyperventilation. Reassurance

Diuretics and other antihypertensive medi-

regarding the etiology and benign nature of

cations are common causes of orthostasis.

their symptom complex is the most important

Other causes of this syndrome include auto-

aspect of treatment for these patients. The high-

nomic neuropathy, primary orthostatic hy-

grade hyperventilator may be helped by place-

potension, and multiple system atrophy, also

ment of a paper or plastic bag over the mouth

known as Shy-Drager syndrome.

during the attacks. Supportive psychotherapy

Symptomatic orthostatic hypotension from

or counseling may be helpful in some patients.

antihypertensive medications should be treated

Anxiolytic medication may be appropriate in

by medication adjustments. Neurologic causes

selected patients.

of chronic orthostatic hypotension have several

possible treatments. Raising the head of the pa-

tient’s bed by 10 to 15 degrees or recommend-

Orthostatic Hypotension

ing elastic stockings may be helpful. If these

Orthostatic hypotension is another common

maneuvers do not provide adequate sympto-

cause of presyncope, particularly in the elderly.

matic relief, then sodium chloride tablets can be

The symptoms almost always occur when the

added judiciously if they are not contraindi-

patient is standing and are frequently maximal

cated by hypertension, congestive heart failure,

just after the patient rises from the sitting or

hepatic disease, or renal failure. The mineralo-

supine position. Gravity decreases venous re-

corticoid fludrocortisone acetate can be used in

turn to the heart, resulting in a decline in left

difficult cases, but blood pressure and serum

heart filling. The autonomic nervous system

electrolytes must be monitored closely. The

normally is able to adjust peripheral resistance,

alpha agonist midodrine also can be used in se-

cardiac rate, and contractility so that cardiac

lected patients.

output and blood pressure are maintained, but

if patients are hypovolemic from fluid loss or

Vasovagal/Vasodepressor Presyncope

diuretic therapy, if they have been pharmaco-

logically vasodilated, or if their compensatory

Vasovagal presyncope is probably more cor-

autonomic responses are blunted by medication

rectly called neurocardiogenic presyncope.

or disease, cardiac output and blood pressure

The patient’s history is usually diagnostic.

may fall sufficiently to produce presyncopal

Vasovagal dizziness may occur in a hot

symptoms. In these patients, a significant drop

crowded room or in the setting of sudden pain

in blood pressure usually can be demonstrated

or strong emotion. The patient is almost al-

at the bedside and this procedure often will re-

ways standing and may have premonitory

produce the patient’s symptom complex.

symptoms of yawning, diaphoresis, and pallor.

To evaluate a patient for orthostatic hy-

In vasovagal syncope, reductions in blood

potension, blood pressure should always be

pressure and cerebral blood flow are caused by

checked as the patient goes directly from the

sudden, reflux dilation of the resistance arteri-

supine to the standing position. A drop of

oles. This syndrome usually occurs in young,

greater than 20/10 mm Hg 3 minutes after

otherwise healthy adults but can occur in the

standing is considered abnormal. It is impor-

elderly. Heat favors vasodilation and could

tant to note that asymptomatic but demon-

produce symptomatic hypotension in an eld-

strable orthostatic blood pressure changes are

erly patient with otherwise compensated mild

common in the elderly. If the patient’s history

orthostatic hypotension. The only treatments

does not suggest orthostatic hypotension and

for this syndrome are reassurance and avoid-

orthostatic testing does not reproduce the

ance of the precipitating circumstances.

415

Chapter 20

■ Dizziness and Vertigo

Cardiac Presyncope

presyncope. Thus, it should be considered in

evaluating patients with episodic dizziness.

Cardiac presyncope usually is caused by an ar-

Most patients with symptomatic hypo-

rhythmia that produces a sudden decrease in car-

glycemia are insulin-dependent diabetics who ei-

diac output and a subsequent decrease in cerebral

ther did not consume an adequate caloric load

perfusion. Common offending arrhythmias in-

for their insulin dose or took an excessive dose of

clude sick sinus syndrome, paroxysmal supra-

insulin. Oral hypoglycemic agents are occasion-

ventricular tachycardia, atrial fibrillation-flutter,

ally unpredictable in their action and can pro-

complete heart block, and ventricular tachycar-

duce symptoms of hypoglycemia. Early diabetics

dia. This diagnosis should be strongly considered

who are not yet on therapy can have reactive hy-

in any patient whose presyncope occurs in the sit-

poglycemia from surges of insulin. This typically

ting or supine position. Workup includes an elec-

occurs 2 to 5 hours after eating and is more often

trocardiogram and Holter monitoring, although

manifested by diaphoresis and palpitations than

it sometimes requires repeated or prolonged

lightheadedness or other neurologic symptoms.

monitoring to document the arrhythmia.

The diagnosis is made by documenting serum

Exercise-related presyncope may be caused

hypoglycemia while the patient is symptomatic.

by aortic stenosis or idiopathic hypertrophic

In general, a serum glucose less than 50 mg/dL is

subaortic stenosis. An echocardiogram is used

necessary to produce neurologic symptoms.

for the diagnosis of these conditions. Paroxys-

Rarely, insulin-secreting tumors may present

mal episodes of lightheadedness and dizziness

with repeated episodes of hypoglycemia.

may sometimes be a manifestation of coronary

ischemia, which should be considered in any

patient with unexplained episodes of presyn-

cope and the appropriate risk factors.

VERTIGO

Vertigo is the subjective sensation of movement

Carotid Sinus Hypersensitivity

or spinning when the head is actually station-

Carotid sinus hypersensitivity is primarily a dis-

ary. Vertigo is generally a symptom of disease

order of the elderly in which the carotid sinus in

in the vestibular or cerebellar balance centers.

the neck becomes abnormally sensitive to pres-

The peripheral vestibular apparatus includes

sure and produces episodes of bradycardia and

the labyrinth, which is located in the petrous

reduced cardiac output. Classically, this syn-

portion of the temporal bone, and the vestibu-

drome was described in men who wore tight col-

lar portion of the eighth cranial nerve, which

lars. Such a history, however, will not be present

connects the labyrinth to the brain stem and is

in most patients with this disease. It should be

located in the internal auditory canal and cere-

suspected in middle-aged or elderly patients with

bellopontine angle. The labyrinth is divided

ongoing bouts of presyncope or syncope. The di-

into three semicircular canals that sense head

agnosis is made by carotid massage under strictly

rotation and the otolith organs (utricle and sac-

controlled conditions

(i.e., the presence of a

cule) that sense head position relative to gravity.

crash cart and personnel skilled in cardiopul-

The central vestibular apparatus consists of

monary resuscitation). The treatment is place-

vestibular nuclei at the pontomedullary junc-

ment of a permanent pacemaker.

tion in the brainstem. These nuclei receive im-

pulses from the eighth cranial nerve and have

rich connections with cerebellum and the nu-

Hypoglycemia

clei controlling eye movements.

Although this metabolic derangement does not

Normally, the vestibular system sends bal-

cause a reduction in cerebral blood flow, its

anced tonic impulses to the central nervous

symptom complex is similar to that seen in

system (CNS) from the left and right inner ears

416

Chapter 20

■ Dizziness and Vertigo

regarding the position of the head and its

nystagmus is greatest in amplitude when looking

movements. Vertigo occurs when a pathologic

in the direction of the quick phase for example, a

process acutely disrupts vestibular input on

right-beating vestibular nystagmus will be great-

one side; the resulting discrepancy between

est in right gaze (Alexander’s law).

right and left inputs produces the false sensa-

Nystagmus that changes direction depending

tion of movement—acute vertigo.

on where the patient is looking is gaze-evoked

nystagmus, and it generally signifies cerebellar

dysfunction. Gaze-evoked nystagmus beats in the

direction of gaze (e.g., right-beating in right gaze,

NYSTAGMUS

left-beating in left gaze, up-beating in up gaze,

etc.). Unlike vestibular nystagmus, which often

Vertigo is almost always accompanied by nys-

has a torsional component, gaze-evoked nystag-

tagmus, a rhythmic oscillation of the eyes. Al-

mus is usually purely horizontal (in left or right

though nystagmus may rarely be pendular,

gaze) or purely vertical (in up or down gaze).

more commonly it is characterized by slow

Gaze-evoked nystagmus tends to be larger in am-

movement in one direction followed by quick

plitude and coarser than vestibular nystagmus.

movement in the other direction. This form of

nystagmus (jerk nystagmus) is named for the

■ SPECIAL CLINICAL POINT: A mild form

direction of the quick phase, for example,

of gaze-evoked nystagmus may be observed

“right-beating” or “down-beating.” Two main

normally in extreme gaze. This benign,

forms of jerk nystagmus are vestibular nystag-

physiologic “end point nystagmus” is symmetric

and disappears when gaze is shifted slightly back

mus and gaze-evoked nystagmus.

toward midline. End point nystagmus is not

Vestibular nystagmus, seen with central or pe-

associated with vertigo or dizziness.

ripheral lesions of the vestibular system, is pri-

marily horizontal, but also has a rotatory or

Central or Peripheral Vertigo?

torsional component. Vestibular nystagmus is

unidirectional—the fast component of the nys-

Because peripheral causes of vertigo are typi-

tagmus always beats in the same direction, away

cally benign while central causes of vertigo are

from the vestibular lesion, no matter where the

usually more serious, emphasis has traditionally

patient is looking. For example, with a left

been placed on determining whether vertigo is

vestibular lesion, the quick phase of the nystagmus

of central or peripheral origin. The presence of

will be to the right (“right-beating”) in all direc-

associated signs and symptoms may be helpful

tions of gaze. Although unidirectional, vestibular

in making this distinction (Table 20.1), but the

TABLE 20.1

Distinguishing Peripheral and Central Vertigo

Peripheral

Central

Brainstem signs or symptoms^a

Never

Frequent

Alteration in consciousness

Never

Possible

Nystagmus

Vestibular

Vestibular or gaze-evoked

Positive head thrust test

Frequent

Rare

Gait ataxia

Rare (mild)

Possible (moderate to severe)

Limb ataxia

Rare

Possible

Hearing loss or tinnitus

Possible

Rare

Headache

Never

Rare (may suggest hemorrhage)

^aIncluding double vision, blindness or blurred vision, homonymous hemianopia, slurred speech, trouble swallowing, Horner syndrome, hiccoughs,

hoarseness, and weakness or numbness of the extremities or face.

417

Chapter 20

■ Dizziness and Vertigo

clinician should keep in mind that in rare cases

usually can stand, although they typically

peripheral vertigo may be caused by stroke or

complain of feeling unsteady and often will

TIA and that some causes of central vertigo are

lean to one side when standing. Patients with

benign.

central vestibular disorders often are unable

to stand at all due to associated ataxia. In ad-

Hearing Loss and Tinnitus Peripheral vestibular

dition, prominent finger-to-nose or heel-to-

lesions are frequently associated with hearing

shin dysmetria is suggestive of a cerebellar

loss and tinnitus. These occur in diseases affect-

(and therefore central) process, possibly in-

ing the cochlea, the middle ear, and the acoustic

farction or hemorrhage.

portion of the eighth cranial nerve. Processes that

■ SPECIAL CLINICAL POINT: Any patient

disrupt the vestibular portion of the eighth nerve

with acute vertigo (dizziness) accompanied

in the cerebellopontine angle or in the internal

by ataxia (dysmetria), double vision

auditory canal usually also affect the acoustic

(diplopia), slurred speech (dysarthria),

portion. Likewise, labyrinthine processes also

hoarseness (dysphonia), trouble swallowing

may affect the cochlea or middle ear.

(dysphagia), or numbness of the extremities

Unfortunately, the presence of hearing loss

or face (dysesthesias) should be urgently

does not guarantee that the lesion is peripheral

evaluated for a possible brainstem or

and benign. Rarely, central processes affecting

cerebellar stroke or hemorrhage.

the brainstem and cerebellum may be associ-

ated with hearing loss or tinnitus. Also, occlu-

Head Thrust Test The Halmagyi head thrust

sion of the internal auditory artery may cause

test distinguishes between vestibular and

sudden, profound, unilateral hearing loss and

cerebellar disorders, and can be performed

vertigo indistinguishable from more benign

quickly and easily at the bedside. The patient

causes of peripheral vestibulopathy.

should fixate on the examiner’s nose and

Eighth cranial nerve and cerebellopontine

relax the neck while the examiner holds each

angle mass lesions (e.g., acoustic neuroma) may

side of the patient’s head. The patient’s head

present with progressive hearing loss or tinnitus

is turned slightly (about 10 degrees) to the

associated with facial weakness, facial sensory

right or left of midline, then quickly rotated

loss, and/or a depressed corneal reflex, but

back to the center.

rarely manifest as acute or recurrent vertigo.

Normally, the vestibulo-ocular reflex (VOR)

More commonly, they cause disequilibrium re-

will ensure that the patient’s eyes remain fixed

lated to slow destruction of the vestibular por-

on the examiner’s nose. In the setting of a

tion of the eighth cranial nerve or pressure on

vestibular lesion, however, the patient’s eyes

the brainstem vestibular nuclei.

will move with the head, falling off target, and

a corrective saccade to the examiner’s nose will

Brainstem and Cerebellar Signs When vertigo is

be observed after the head is snapped back to

associated with brainstem or cerebellar symp-

the primary position.

toms and signs, the presence of such additional

A quick saccade (toward the right) after the

findings clearly identifies the vertigo as central in

head is snapped to the left suggests a left

origin. The list of signs and symptoms that

vestibular lesion. A quick saccade (toward the

should raise “red flags” includes double vision,

left) after the head is snapped to the right sug-

blindness or blurred vision, homonymous hemi-

gests a right vestibular lesion.

anopia, slurred speech, trouble swallowing,

In a patient with vertigo, a normal head

Horner syndrome, hiccoughs, hoarseness, and

thrust test (no corrective saccades noted) is sug-

weakness or numbness of the extremities or face.

gestive of cerebellar disease, which by definition

Ataxia may also be an important distin-

is central in origin. An abnormal head thrust test

guishing feature in vertigo syndromes. Pa-

signifies a vestibular disturbance, which is usu-

tients with peripheral vestibular syndromes

ally peripheral, but may rarely be central.

418

Chapter 20

■ Dizziness and Vertigo

PERIPHERAL CAUSES OF VERTIGO

Benign Paroxysmal Positional Vertigo

Benign paroxysmal positional vertigo (BPPV)

is the most common cause of vertigo, particu-

larly recurrent vertigo. Patients report the sud-

den onset of vertigo shortly after a change in

position (often when reclining in bed). The ver-

tigo typically lasts 15 to 30 seconds and then

resolves. The patients also may note that if they

put their heads in the same position a second or

a third time (within a relatively brief interval),

the vertigo will be less intense each time. Key

historical features of BPPV include the change

in head position, the brief duration of the ver-

tigo, a latency to onset of vertigo, and the fati-

gability of the vertigo with repeated trials.

BPPV can be reproduced in the office with

the Dix-Hallpike maneuver (Fig. 20.1). This

maneuver begins with the patient sitting on the

examination table. The head is turned 45 de-

grees to the right, and then the patient is quickly

put in the supine position with the head hanging

over the edge of the table and extended approx-

imately 30 degrees. If the vertigo does not begin

within 30 seconds, the patient is returned to the

sitting position, the head is turned 45 degrees to

the left, and the patient is again made supine

with the head extended. If vertigo is induced, it

FIGURE 20.1 Dix-Hallpike positional test for benign

is associated with an up-beating torsional nys-

positional nystagmus. Patient is moved rapidly from the

tagmus that beats “toward the floor.”

sitting to the head-hanging position. (Redrawn from

BPPV is usually idiopathic but can be seen

Baloh RW, Halmagyi GM, eds. Disorders of the Vestibular

after head trauma. The pathophysiology of this

syndrome is thought to be an accumulation of

Used by permission.)

calcium carbonate crystals (otoconia) within the

labyrinth, usually in the posterior semicircular

posterior semicircular canal into the utricle

canal. With head movement, the debris drifts, re-

using the modified Epley maneuver (Fig. 20.2).

sulting in movement of the endolymph, which in

The Epley maneuver can be performed in the of-

turn induces vertigo. The latency reflects the lag

fice setting and is highly effective in the majority

between the motion of the head and the drifting

of patients. The natural history of this disorder

of the free-floating debris within the semicircular

is typically a waxing and waning course over

canal. With repeated head movement, the cal-

months to years. The treatments will put most

cium carbonate crystals disperse temporarily re-

patients into a “remission,” but the symptoms

sulting in fatiguing of the vertiginous effect.

may recur at some point. Patients can be taught

Treatment of this syndrome is directed at

to perform the Epley maneuver themselves at

moving the calcium carbonate crystals from the

home in case of recurrence.

419

Chapter 20

■ Dizziness and Vertigo

Figure 20.2 Positional maneuver designed to remove debris from the posterior semicircular canal

(debris in left posterior semicircular canal depicted). A: In the sitting position, calcium carbonate crystals

lie at the bottommost position within the posterior canal. B: Movement to the head-hanging position

causes the crystals to move away from the cupula, producing an excitatory burst of activity in the

ampullary nerve from the posterior canal (ampullofugal displacement of the cupula). C: Movement

across to the other head-hanging position causes the crystals to move further around the canal. D:

The patient then rolls onto the side facing the floor, causing the crystals to enter the common crus of

the posterior and anterior semicircular canals. E: Finally, the patient sits up, and the crystals disperse in

the utricle. The patient should not lie flat for 48 hours to prevent the debris from reentering the canal.

(Redrawn from Epley JM. The canalith repositioning procedure: for treatment of benign paroxysmal

positional vertigo. Otolaryngol Head Surg. 1992;107:399, with permission.)

In a classic case of BPPV (with characteristic

tinnitus, or other brainstem signs and should last

head position, latency, and fatigability) with a

for no more than a minute. The presence of any

of these “red flags” should prompt an evaluation

normal neurologic examination and a positive

for an alternate diagnosis, which may include

Dix-Hallpike maneuver, no brain imaging is

neurologic consultation and brain imaging.

necessary. A screening audiogram is advised,

however, to rule out significantly asymmetric sen-

Acute Peripheral Vestibulopathy

sorineural hearing loss, especially high tone loss.

■ SPECIAL CLINICAL POINT: Episodes of

Acute peripheral vestibulopathy (vestibular neu-

BPPV should not be associated with hearing loss,

ritis or labyrinthitis) is the second most common

420

Chapter 20

■ Dizziness and Vertigo

cause of acute vertigo. Acute peripheral vestibu-

Disequilibrium often follows the resolution of

lopathy is generally assumed to be benign, sec-

the vertigo and may persist for days, weeks, or

ondary to viral inflammation of the vestibular

even months, but eventually will resolve in the

nerve or labyrinth, but it may rarely be cause by

vast majority of patients. During this period of

ischemia.

disequilibrium, the neurologic examination

In typical acute peripheral vestibulopathy,

may be quite normal despite the patient’s com-

vertigo is gradual in onset, peaking within

plains of persistent dizziness and imbalance.

hours, and resolving within days. The acute

A classic case of acute peripheral vestibulo-

phase will be marked by a vestibular nystagmus

pathy in a young, healthy adult does not require

beating away from the side of the lesion. Head

brain imaging. Therapy for acute vertigo may

thrust testing will be abnormal when the head is

include bed rest, intravenous fluids, pheno-

quickly turned toward the lesion. There may be

thiazines, antihistamines, and benzodiazepines

mild gait ataxia, with the patient tending to

(Table 20.2). The use of corticosteroids and an-

veer to the side of the affected vestibular appa-

tiviral agents has been studied in patients with

ratus. Hearing loss may accompany labyrinthi-

acute vestibular syndromes but no clear benefit

tis but is not a part of vestibular neuritis.

has been found.

■ SPECIAL CLINICAL POINT: Acute

Ménière’s Disease

peripheral vestibulopathy may be accompanied

by mild ataxia, but prominent gait ataxia, limb

Ménière’s disease is characterized by recurrent

ataxia, or brainstem signs may signal a more

attacks of vertigo, hearing loss, tinnitus, and

serious central process (e.g., brainstem or

aural fullness. Patients usually experience the

cerebellar infarction or hemorrhage).

entire symptom complex with each episode, but

Patients with peripheral vestibulopathy may be

there are atypical cases of Ménière’s disease that

incapacitated acutely by associated nausea and

have only vestibular symptoms (i.e., vertigo)

vomiting, and they typically prefer to remain

without cochlear symptoms (hearing loss and

motionless during this time because head or

tinnitus) and others with cochlear symptoms

body movements may exacerbate the vertigo.

and no vertigo.

TABLE 20.2

Pharmacologic Treatments for Acute Vertigo Syndromes

Drug

Starting Dose

Maintenance Dose

Potential Drug Interactions

Promethazine

25 mg IM/IV/PR/PO

12.5-50 mg q4-8h

Tranquilizers,

antiparkinsonian

medications

Prochlorperazine

10 mg IM/IV/PR/PO

5-20 mg q4-12h

Tranquilizers,

antiparkinsonian

medications

Dimenhydrinate

50 mg IM/IV/PO

25-100 mg q4-8h

Sedatives, tranquilizers,

antidepressants

Meclizine

25 mg PO

12.5-50 mg q4-8h

Sedatives, tranquilizers,

antidepressants

Diazepam

5 mg IM/IV/PO

2-10 mg q4-8h

Sedatives, antidepressants

Lorazepam

1 mg IM/IV/PO

0.5-2 mg q4-8h

Sedatives, antidepressants

IM, intramuscularly; IV, intravenously; PR, by rectum; PO, by mouth.

Note: All of these medications are useful for acute vertigo. However, they may exacerbate the chronic disequilibrium syndrome that often

follows vertigo syndromes.

421

Chapter 20

■ Dizziness and Vertigo

Attacks of vertigo can be as short as a few

(whether central or peripheral, vestibular or

minutes or rarely may last longer than 4 or

cerebellar), making MRV quite nonspecific.

5 hours. The hearing loss fluctuates and usually

improves after the vertigo resolves, but over

Perilymph Fistula

time there may be progressive loss of hearing.

Episodic vertigo, fluctuating hearing loss, tin-

Symptoms typically begin in one ear but ulti-

nitus, or disequilibrium, triggered by Valsalva

mately become bilateral in nearly 50% of pa-

maneuver, exertion, or changes in barometric

tients. Approximately 80% of patients go into

pressure, may suggest a perilymph fistula, an

remission within 5 years, although most of these

abnormal communication between the peri-

will be left with significant hearing loss. Some

lymphatic space of the inner ear and the pneu-

patients will develop chronic disequilibrium.

matized middle ear. Perilymph fistulae may be

The pathologic findings associated with this

caused by trauma, including barotrauma, chro-

syndrome are referred to as endolymphatic hy-

nic ear infections, or as a result inner ear sur-

drops. It is possible, however, that multiple

gery. There is no completely satisfactory test

causes may lead to this common end point.

for this disorder. Diagnosis, therefore, often de-

All patients suspected of having Ménière’s dis-

pends on elicitation of a history of an appropri-

ease should have an MRI of the posterior fossa to

ate inciting event

(e.g., deep sea diving or

rule out a mass lesion. Serial audiograms are very

stapedectomy) and the reproduction of symp-

helpful. As noted, fluctuating hearing loss is typi-

toms with Valsalva maneuver. If conservative

cal. Low-frequency hearing is lost first, but even-

measures fail to result in improvement, then

tually there is a global loss of auditory function.

surgical repair may be considered.

Salt restriction has been shown in some

studies to reduce the frequency of the attacks

■ SPECIAL CLINICAL POINT: All patients

of vertigo and hearing loss. This treatment

with suspected Ménière’s disease should be

should be initiated with a restriction of 1 to 2 g

seen by a neurologist or otolaryngologist with

expertise in vestibular disorders. All patients

of sodium per day. If this level of restriction is

whose history suggests the presence of a

ineffective, then sodium should be reduced to

perilymph fistula should be evaluated by an

less than 1 g/day. Thiazide diuretics and aceta-

otolaryngologist.

zolamide also have been reported to be helpful

in some patients. Smoking and consumption of

caffeinated beverages exacerbate Ménière’s dis-

ease and should be avoided.

CENTRAL CAUSES OF VERTIGO

Some patients have frequent, disabling attacks

Vertigo may be caused by acute injury to the

of vertigo that do not respond to medication.

brainstem or cerebellum and, therefore, is a com-

Chemical labyrinthectomy with intratym-

mon symptom in posterior circulation syn-

panic gentamicin or surgical labyrinthectomy or

dromes, including stroke/TIA (vertebrobasilar

vestibular neurectomy, may be offered in such pa-

insufficiency) and basilar migraine, cerebellar

tients. Though destructive, these treatments help

hemorrhage, and multiple sclerosis. A variety of

to prevent the recurring attacks of vertigo and

brainstem signs and symptoms and ataxia com-

may preserve some auditory function.

monly accompany central vertigo, but a central

process may rarely cause isolated vertigo as well.

■ SPECIAL CLINICAL NOTE: Movement-

The most common cause of central vertigo is

related vertigo (MRV) can be a source of

cerebrovascular disease (vertebrobasilar insuffi-

confusion and occasionally is misinterpreted as

ciency), which should be considered in any pa-

BPPV. In MRV, almost any head or body

movement produces vertigo, with no latency or

tient with persistent vertigo who has risk factors

fatigability, distinguishing it from BPPV. In fact,

for vascular disease (hypertension, diabetes mel-

head movement can worsen any form of vertigo

litus, heart disease, hyperlipidemia, tobacco) or

422

Chapter 20

■ Dizziness and Vertigo

in older patients regardless of the presence of

toms similar to that seen in the PICA syndrome.

risk factors.

Involvement of the more proximal portion of the

Specific central disorders associated with

AICA and the internal auditory artery produces

vertigo will be discussed here. General princi-

lateral pontine infarction with ipsilateral facial

ples of diagnosis and management of vascular

weakness, resembling Bell’s palsy, and sudden,

disease are discussed in Chapter 7, Cerebrovas-

profound hearing loss with severe vertigo.

cular Disease.

Transient Ischemic Attack

■ SPECIAL CLINICAL POINT: Any acutely

vertiginous patient who has risk factors for

Any ischemic stroke syndromes associated with

vascular disease or is more than 50 years old

vertigo may also present as transient ischemic

should be evaluated for possible stroke or TIA by

attacks. An isolated TIA can be difficult to dis-

a neurologist. Vertigo from brainstem ischemia

tinguish from a peripheral vestibular syndrome,

may also occur in younger patients in the setting

especially if all symptoms have resolved, but as

of dissection of the vertebral or basilar arteries.

a general rule, any episode of vertigo lasting

minutes to hours in a patient with risk factors

Lateral Medullary Ischemia

for stroke should be considered a possible tran-

(Wallenberg Syndrome)

sient ischemic attack, especially when other

Occlusion of the posterior inferior cerebellar

central symptoms are reported. Recurrence of

artery (PICA) or, more commonly, the verte-

such episodes would also strongly suggest TIA

bral artery may cause infarction of the lateral

over a more benign etiology.

medulla. Lateral medullary infarction (Wallen-

berg syndrome) is the most common brainstem

Cerebellar Hemorrhage

stroke syndrome and is associated with a wide

Cerebellar hemorrhage is a life-threatening neu-

variety of symptoms including dysarthria, dys-

rologic emergency. Patients with cerebellar hem-

phagia, hoarseness, hiccoughs, Horner syn-

orrhage may present with prominent headache,

drome, diplopia, facial pain or numbness, and

vertigo, nausea/vomiting, diplopia, imbalance,

gait and limb ataxia, in addition to vertigo.

dysarthria, and/or an altered level of conscious-

In classic Wallenberg syndrome, pain and

ness. When suspected, cerebellar hemorrhage can

temperature sensation is decreased on the face ip-

be quickly diagnosed with a noncontrast head

silateral to the infarction with loss of pain and

CT. Patients with this disorder require an urgent

temperature sensation on the contralateral side

neurosurgical evaluation and intensive care unit

of the body. Vertigo, ataxia, nausea, and vomit-

(ICU) monitoring as neurosurgical decompres-

ing represent involvement of the inferior cerebel-

sion is often required and may be life saving.

lum. A small percentage of these patients develop

significant edema in the area of cerebellar infarc-

■ SPECIAL CLINICAL POINT: Cerebellar

tion with resultant brainstem compression. This

hemorrhage must be considered in any

group of patients, like those with cerebellar hem-

patient with acute headache, vertigo, severe

orrhage (see below), must be monitored closely

nausea/vomiting, and other brainstem or

as surgical decompression may be necessary.

cerebellar signs or symptoms. Quick action,

including an urgent noncontrast head CT and

Lateral Pontine Ischemia

neurosurgical consultation, is essential and

potentially life saving.

The anterior inferior cerebellar artery (AICA)

supplies the lateral pons, the vestibular and

Basilar Migraine

cochlear structures via a branch called the inter-

nal auditory artery, and the anterior inferior por-

Because the vestibular nuclei in the brainstem

tion of the cerebellum. Occlusion of the distal

are supplied by branches of the basilar artery,

portion of this vessel produces cerebellar symp-

migrainous vasospasm of the basilar artery

423

Chapter 20

■ Dizziness and Vertigo

can produce vertigo. Hearing loss and tinnitus

with disequilibrium often complain of feeling off

in addition to other neurologic symptoms

balance and are insecure when walking. They

such as scintillating scotoma, homonymous

tend to reach for walls or furniture when ambu-

hemianopsia, cortical blindness, diplopia,

lating at home or in the office. They may feel even

dysarthria, ataxia, paresthesias, and quadri-

more uncomfortable when outside.

paresis may also occur.

Several coordinated elements are necessary to

These patients are usually young, and the

ensure proper maintenance of balance. Primary

history typically is dominated by the severe

sensory input, including vision and propriocep-

headache that follows the vertigo. In some pa-

tion, must be integrated with the vestibular sys-

tients, however, the headache may not be

tem, and an appropriate motor response must

prominent, whereas in others the headache may

be generated. Deficits in one or more of these

not always follow the vasospastic component

physiologic functions result in imbalance or dis-

of the syndrome.

equilibrium. There are, therefore, a number of

As in more common forms of migraine, the

etiologies of disequilibrium, and some patients

diagnosis of basilar migraine is a diagnosis of

have more than one contributing cause.

exclusion that should not be made until other

cerebrovascular disorders, such as vertebrobasi-

Visual Dysfunction

lar dissection, have been ruled out. The treat-

ment of basilar migraine is similar to the

Whereas visual loss alone does not usually pro-

treatment of other migraine syndromes

(see

duce disequilibrium, visual distortion often does.

Chapter 8, Headache Disorders).

Such distortion typically occurs when the visual

input from one eye is significantly different from

the other. Many patients with sudden ophthal-

Multiple Sclerosis

moplegia and resultant diplopia feel off balance

Vertigo may be a presenting symptom of multi-

during ambulation. Some corneal and retinal

ple sclerosis, or may occur in a patient with an

diseases that produce significant asymmetry of

already established diagnosis. The clinical syn-

visual input also can produce disequilibrium.

drome may mimic acute peripheral vestibu-

lopathy. Hearing loss is rare but does occur.

Loss of Proprioception

Previous neurologic symptoms may provide an

important clue—isolated optic neuritis or tran-

Position sense or proprioception of the joints

sient tingling thought to be related to a pinched

and muscles of the lower extremities is necessary

nerve in the past may hint at a relapsing CNS

for normal balance. Peripheral neuropathy can

disorder. Brain MRI may not always demon-

produce proprioceptive loss in the lower extrem-

strate brainstem or cerebellar lesions, but

ities and subsequent disequilibrium. This is most

periventricular white matter lesions usually are

commonly seen with diabetic polyneuropathy

present. The diagnosis and treatment of multi-

but can result from any cause of peripheral neu-

ple sclerosis is discussed in greater detail else-

ropathy. Spinal cord disease, particularly when

where (see Chapter 11, Multiple Sclerosis).

involving the posterior columns, as in vitamin

B₁₂ deficiency, can produce significant proprio-

ceptive loss in the lower extremities and subse-

quent disequilibrium.

CAUSES OF DISEQUILIBRIUM

Disequilibrium is a common problem in the eld-

Vestibular Dysfunction

erly but can be seen in younger patients after an

acute vertigo syndrome or mild head trauma.

The vestibular system provides information re-

The dizziness tends to be constant and is typically

garding movement and the relationship of the

maximal with standing and ambulation. Patients

head to the pull of gravity. Acute, unilateral

424

Chapter 20

■ Dizziness and Vertigo

vestibular disturbances produce vertigo, but

The pyramidal system can be involved at

slowly progressive, bilateral, or healing vestibular

multiple levels. Hydrocephalus, neoplasms, or

lesions may produce a disequilibrium syndrome.

degenerative frontal lobe dysfunction can pro-

Slow-growing neoplasms of the posterior

duce significant gait apraxia. Cervical spondy-

fossa (e.g., acoustic neuroma) may produce a

litic myelopathy is a common cause of lower-

feeling of imbalance as well as hearing loss, fa-

extremity stiffness and spasticity. Parkinson

cial numbness, and facial weakness. There are

disease is associated with bradykinesia, rigidity,

a variety of congenital and hereditary vestibu-

flexed posture, and loss of postural reflexes.

lar disorders that can produce progressive dise-

The cerebellum is involved significantly in the

quilibrium. Idiopathic degenerative vestibular

coordination of gait and can be affected by a

dysfunction is a recognized cause of disequilib-

wide variety of disease processes, which would

rium in elderly patients.

include primary and alcoholic degenerative

A number of drugs are known vestibulotox-

syndromes, cerebellar neoplasms, paraneoplas-

ins. Anticonvulsants and benzodiazepines may

tic syndromes, cerebellar infarction, and de-

produce reversible vestibular dysfunction.

myelinating disease.

Aminoglycoside antibiotics and cisplatin pro-

duce vestibular injury that is often irreversible.

These drugs tend to produce bilateral vestibu-

Always Remember

lar dysfunction, resulting in a disequilibrium

• Although defining the type of dizziness

syndrome rather than acute vertigo.

(presyncope, vertigo, or disequilibrium) may

Patients recovering from an acute peripheral

be helpful, the pattern of the dizziness and

vestibulopathy may have residual dizziness for

associated neurologic signs and symptoms

as long as several weeks. Likewise, patients

may be more important.

with recurrent peripheral vestibular dysfunc-

• Presyncope may be benign (hyperventilation,

tion, as in Ménière’s disease, may have persist-

vasovagal depression) or may be due to

ent disequilibrium between their acute attacks

significant cardiac disease (arrhythmia, aortic

of vertigo and hearing loss.

or subaortic stenosis, coronary ischemia).

• Vertigo is often benign, but may be a

Abnormalities of Central Integration

symptom of a serious cerebrovascular

Any process that produces a global impairment

disorder, especially when associated with

in CNS function can produce disequilibrium.

brainstem or cerebellar signs and symptoms.

Many patients complain of dizziness after

• Vertigo associated with headache, ataxia,

minor head trauma, which may be the result of

vomiting, and other brainstem symptoms may

mild, diffuse cerebral dysfunction from the

signify a cerebellar hemorrhage, a neurologic

head injury. Medications, particularly those

emergency requiring emergent CT imaging

with sedative side effects, may impair central

and possibly neurosurgical intervention.

integration and result in disequilibrium. Simi-

• Disequilibrium may be multifactorial and is

larly, patients with metabolic encephalopathy

often associated with more insidious

of any etiology may experience disequilibrium.

vestibular or cerebral disorders.

Abnormalities of Motor Response

There are three major elements in the human

QUESTIONS AND DISCUSSION

motor system: the pyramidal system, the ex-

trapyramidal system, and the cerebellum. Dis-

1. A 42-year-old man experienced the sudden

turbance in any one of these elements can

onset of vertigo, nausea, vomiting, and

produce a disequilibrium syndrome.

ataxia 3 weeks ago. The vertigo, nausea,

425

Chapter 20

■ Dizziness and Vertigo

and vomiting resolved in 48 hours, but the

The correct answer is D. This patient’s symp-

patient still complains bitterly of

toms are typical of movement-related vertigo,

“dizziness” and states that he cannot go

a nonspecific symptom that can be seen with

back to work because “I walk like a

any vestibular disorder. The gaze-evoked nys-

drunk.” When questioned, he admits that

tagmus suggests cerebellar involvement. The

his dizziness is present only when he is

history of transient neurologic symptoms in

standing or walking and seems to resolve

the lower extremities would make multiple

when he is sitting or supine. He denies

sclerosis a strong diagnostic consideration.

hearing loss and tinnitus. There is no

The position-related vertigo of benign

associated visual blurring, diaphoresis, or

paroxysmal positional vertigo usually is

pallor. His neurologic examination is

produced by a specific head movement, with

normal except that he tends to veer to the

a latency of several seconds. Ménière’s disease

right when walking. How could this

can be associated with movement-related

patient’s current symptom of dizziness best

vertigo, but is typically associated with a

be categorized?

history of hearing loss and tinnitus.

A. Vertigo

3. A 69-year-old man complains of “dizzy

B. Presyncope

spells.” The patient describes 10 to 12

C. Disequilibrium

episodes in the last 6 weeks of sudden

D. Malingering

visual “blackout” and feeling “like I’m

E. Not classifiable

going to pass out.” His wife notes that he

The correct answer is C. The patient’s syn-

breaks out in a cold sweat during the

drome began with vertigo, but has converted

attacks and looks “glassy-eyed.” The

to a disequilibrium syndrome. Disequilibrium

episodes last 30 to 60 seconds, and the

may follow any acute vestibulopathy, but it

patient feels “fine” afterward. There is no

usually resolves over several weeks.

history of vertigo, hearing loss, tinnitus, or

other focal neurologic symptoms. The

2. A 28-year-old woman complains of

spells are not related to body position or

“everything spinning around” for 2 weeks.

exercise and have occurred in many

The episodes are precipitated by any

different situations including watching

movement in the horizontal or vertical

TV and eating in a restaurant. The

plane. The vertigo begins immediately with

patient’s neurologic examination is

each head movement. The patient denies

normal. What is the most likely etiology

hearing loss and tinnitus but does recall a

of this patient’s presyncope?

2-week episode of “numbness” below her

A. Hyperventilation syndrome

waist about 3 months ago. When asked to

B. Vasovagal attacks

follow the examiner’s finger with her eyes,

C. Orthostatic hypotension

coarse horizontal nystagmus was present

D. Cardiac arrhythmia

on lateral gaze bilaterally and vertical

E. Aortic stenosis

nystagmus was present on upgaze. Her

neurologic examination was otherwise

The correct answer is D. The diagnosis of

remarkable only for questionable bilateral

hyperventilation syndrome is generally sug-

Babinski signs. The most likely diagnosis is

gested by the situations of stress or anxiety

A. Depression

in which it typically occurs. Vasovagal or

B. Benign paroxysmal positional vertigo

vasodepressor attacks are also typically

C. Ménière disease

situational (i.e., hot, crowded room, or sudden

D. Multiple sclerosis

emotion) and always occur when the patient

E. Perilymph fistula

is upright. Orthostatic hypotension typically

426

Chapter 20

■ Dizziness and Vertigo

occurs only when the patient is standing.

SUGGESTED READING

Aortic stenosis is possible, but more

commonly results in exercise-related

Baloh RW. Approach to the evaluation of the dizzy

presyncope. Cardiac arrhythmia may cause

patient. Otolaryngol Head Neck Surg. 1995;112:3.

symptoms in any position or situation.

Baloh RW. Vestibular neuritis. N Engl J Med. 2003;

348:1027-1032.

4. A 51-year-old woman complains of

Brandt T, Daroff RB. The multisensory physiological

multiple episodes of isolated vertigo that

and pathological vertigo syndromes. Ann Neurol.

have occurred over the past several weeks.

1980;7:195.

She is not sure exactly how long the vertigo

Epley JM. The canalith repositioning procedure for treat-

has lasted during each episode, “Thirty

ment of benign paroxysmal positional vertigo. Oto-

seconds? A few minutes, maybe?” The

laryngol Head Neck Surg. 1992;107:399.

episodes may occur while she is lying

Furman JM, Cass SP. Benign paroxysmal positional

down, sitting, or standing. She denies any

vertigo. N Engl J Med. 1999;341:1590.

hearing loss. What is the most likely cause

Hotson JR, Baloh RW. Acute vestibular syndrome. N

of her recurrent vertigo?

Engl J Med. 1998;339:680.

A. Transient ischemic attack (TIA)

Magnusson M, Karlberg M. Peripheral vestibular disor-

B. Vestibular neuritis

ders with acute onset of vertigo. Curr Opin Neurol.

2002;15:5.

C. Benign paroxysmal positional vertigo

(BPPV)

Newman-Toker DE, Guardabascio LM, Zee DS, et al.

Taking the history from a dizzy patient: why “what do

D. Cardiac arrhythmia

you mean by dizzy?” should not be the first question

E. Acoustic neuroma

you ask. Acad Emerg Med. 2006;13:S79.

The correct answer is A. Recurrent, unpro-

Newman-Toker DE, Cannon LM, Stofferahn ME, et al.

voked vertigo lasting for minutes to hours is

Imprecision in patient reports of dizziness symptom

quality: a cross-sectional study conducted in an acute

suggestive of transient vertebrobasilar is-

care setting. Mayo Clin Proc. 2007;82:1329.

chemia. Vestibular neuritis is unlikely to

Newman-Toker DE, Kattah JC, Alvernia JE, et al. Normal

be recurrent or so brief in duration. BPPV

head impulse test differentiates acute cerebellar strokes

may be recurrent, but episodes should not

from vestibular neuritis. Neurology. 2008;70:2378.

last for over a minute and are always pro-

Norrving B, Magnusson M, Holtas S. Isolated vertigo in

voked by changes in head position. A

the elderly: vestibular or vascular disease? Acta Neu-

cardiac arrhythmia is more commonly asso-

rol Scand. 1995;91:43.

ciated with presyncope, though very rarely

Sloan PD, Coeytaux RR, Beck RS, et al. Dizziness: state

it may cause vertigo. A slow-growing mass

of the science. Ann Intern Med. 2001;134:823.

lesion such as an acoustic neuroma more

Troost TB. Dizziness and vertigo in vertebrobasilar dis-

commonly results in disequilibrium than re-

ease: peripheral and systemic causes of dizziness.

Stroke. 1980;11:301.

current vertigo.

An Approach

to the Falling

Patient

KATHRYN A. CHUNG AND FAY B. HORAK

key points

• To diagnose the cause for falls, first determine whether

falls are due to acute loss of brain activity/perfusion or

to a balance problem.

• Falls are often due to impairments in multiple

physiologic systems affecting balance.

• Damage to different systems underlying balance control

results in different, context-specific instabilities.

• Effective fall prevention requires an assessment of

contributing intrinsic and extrinsic factors.

• Refer patients to multidisciplinary resources early to

prevent future falls.

h e c l i n i c a l

tions to prevent future falls, including recom-

problem of falls is complex and requires an es-

mendations on when a referral should be made

pecially thorough history and comprehensive

to a neurologist, will be highlighted.

physical examination of the patient. Although

patients with neurologic disorders are particu-

larly prone to injurious falls, many other diag-

DEFINITION

noses and environmental factors also

contribute to falls. When a complaint of falling

The World Health Organization defines a fall

is presented, the clinician must be prepared to

as “An event, which results in a person coming

consider a broad differential diagnosis. This

to rest inadvertently on the ground or other

chapter will review epidemiologic factors

lower level.” While this definition may seem so

about falls, present a practical approach to dis-

intuitive that defining it is redundant, Tinetti

cover the correct diagnosis, and discuss how

et al. (1997) offered an alternative definition

different underlying constraints on balance

that has become widely accepted because it ac-

control can contribute to falls, even when pa-

knowledges that many falls are secondary to

tients have the same diagnosis. Treatment op-

other phenomena, not necessarily just a balance

427

428

Chapter 21

n An Approach to the Falling Patient

problem. Tinetti’s definition of a fall is “A sud-

19 billion dollars in total direct costs annually.

den, unintentional change in position causing an

In the year 2000, 10,300 falls resulted in a

individual to land at a lower level, on an object,

fatality in the United States, illustrating the

the floor or the ground, other than as a conse-

seriousness of this highly prevalent problem.

quence of sudden onset of paralysis, epileptic

While it has been determined that the eco-

seizure, or overwhelming external force.” Illus-

nomic burden of falls is substantial, falls also

trating this concept further, one can consider two

lead to reduced quality of life, as immobility,

broad categories of falls: (a) sudden loss of pos-

loss of recreational activities, social isolation,

tural tone and/or consciousness (collapsing) and

and fear of falling are common after falling.

(b) loss of balance (falling like a tree), or failure

n SPECIAL CLINICAL POINT: Falls in

to recover equilibrium. This distinction repre-

patients with neurologic disorders are three to

sents an important initial branch point in diag-

five times more common than in age-matched

nosing pathologies related to falls, and it would

people without neurologic diagnoses.

be best to consider patients in these categories

This statistic is not surprising, since balance con-

separately. Those who fall because of loss of bal-

trol involves many parts of the nervous system,

ance will be the main focus of this chapter.

and impairments of balance control are a leading

cause of falls. Some neurologic diagnoses are

more associated with falls and fall injuries than

SCOPE OF THE PROBLEM

other diagnoses, suggesting that they impair neu-

Falls are typically a problem that increases

ral areas more critical for balance control. For ex-

with aging. It is estimated that about 30% of

ample, Figure 21.1 shows the relative percentage

community dwellers older than 65 fall at least

of patients with falls in the previous 12 months

once each year; for those in facilities, this num-

for 489 inpatients admitted to a neurology ward.

ber is even higher. As a consequence of falling,

Patients with Parkinson disease (PD) showed the

about 20% of falls result in medical attention

most falls, with syncope and peripheral neuropa-

for serious injury, approximately 10% result-

thy the next most common causes of falls.

ing in a bony fracture. The economic cost of

Severity of neurologic disease is related to fall

falling in the United States is estimated to be

incidence, but not linearly. Early in neurologic

Sync

PNP EPIL

MND MS PSY Stroke Pain

Neurological Diagnosis

FIGURE 21.1 Fall incidence in neurologic patients by diagnosis. PD, Parkinson disease; Sync, syncope;

PNP, peripheral neuropathy; EPIL, epilepsy; SD, spinal disorders; MND, motor neuron disease; MS,

multiple sclerosis; PSY, psychogenic. (From Stolze H, Klebe S, Zechlin C, et al. Falls in frequent

neurological diseases: prevalence, risk factors and aetiology. J Neurol. 2004;251:79-84, with permission.

429

Chapter 21

n An Approach to the Falling Patient

disability, falls increase with the amount of

TABLE 21.1

neurologic damage. However, as the neuro-

Ratios of Increased Fall Risk

Associated with Various Intrinsic and

logic disability leads to immobility, patients

Extrinsic Factors in the Elderly

who are confined to wheelchairs and beds fall

less often. For example, patients with amy-

Increased Risk of

otrophic lateral sclerosis or severe stroke may

Risk Factors for Falls

Falls Due to Factor

not fall because they cannot stand or walk in-

dependently, whereas a person with mild PD

Weakness

4.4

who continues to ski may sustain a severe frac-

Peripheral neuropathy

3.0

ture from a fall. Thus, frequency of falls should

Balance impairment

2.9

always be considered in relationship to how

Slow gait

2.9

mobile and active a patient engages in activities

Cane for impaired balance

2.6

Vision

2.5

of daily living, sports, and outdoor activities.

Arthritis

2.4

Documented deficit in

activities of daily living deficit

2.3

Depression

2.2

RISK FACTORS

Cognitive decline

1.8

Many studies have examined risk factors leading

Ages >80

1.7

to increased falling. It is useful to consider these

>5 Medications^a

1.7

factors as intrinsic or extrinsic. Examples of in-

^aEspecially sedatives, antidepressants, pain medications.

trinsic factors include muscle weakness, balance

dysfunction, cognitive impairment, orthostasis,

gait abnormalities, mobility limitations, de-

lar extrinsic factor in increasing the risk for

creased functional status, and a history of previ-

falling for individual patients will depend upon

ous falls in the last year. Increasing age, especially

their specific type of balance problem. For ex-

those 80 or older, use of an ambulatory device,

ample, a patient who shuffles when walking

such as a cane or walker, arthritis (especially of

will be at particular risk of falling on throw

the feet), and depression are also associated risk

rugs, a patient with leg weakness or knee joint

factors. Table 21.1 summarizes how much vari-

impairments will be at particular risk on stairs,

ous risk factors increase the chance of falling in a

and a patient with multisensory deficits may be

large cohort of older people.

at particular risk of falling in the dark or on an

Extrinsic factors are derived from the exter-

unstable surface.

nal environment, or risky behaviors.

n SPECIAL CLINICAL POINT: An often

overlooked extrinsic factor is polypharmacy,

DIAGNOSING THE CAUSE OF FALLS

with five or more medications significantly

The complaint (often from family members) that

increasing risk of falls in the elderly.

the patient is falling should prompt investigation

Psychotropic medications such as benzodi-

by clinicians, both neurologists and non-neurol-

azepines, antipsychotics, antidepressants, as

ogists. The broad differential can be intimidat-

well as antihypertensives and anticonvulsants

ing, and the following flowchart (Fig. 21.2) can

are especially associated with falling. Another

help navigate the important branch points.

important extrinsic risk factor is an unsafe en-

While it is often suggested that determining if

vironment, especially throw rugs, stairs, dark

loss of consciousness has occurred in association

areas, and clutter or other obstacles. Behaviors,

with the fall is critical, this point may be unclear

such as climbing ladders, working on roofs,

in the patient’s mind and even by observers.

and sports participation, especially skiing, also

While recognizing the limitations of this line of

increase fall risk. The importance of a particu-

questioning, it can help to ask whether the falls

430

Chapter 21

n An Approach to the Falling Patient

Falls

“Falling like a tree”

“Collapsing in a heap” +/- Loss of

(Retained postural tone)

consciousness (Loss of Postural tone)

Confusion or

Prolonged loss of consciousness,

encephalopathy

tonic-clonic movement, incontinence,

post event confusion

YES

Toxic-Metabolic Illness

YES

•

Infection

Seizure

Parkinsonism

•

Medication adverse

events

•

Substance use

Acute neurologic

YES

•

Vitamin deficiency

deficits

•

Parkinson Disease

YES

•

Progressive Supranuclear Palsy

•

Multiple systems atrophy

•

Corticobasal Ganglionic Degeneration

•

Stroke, TIA

Sensory Deficits

•

Seizure with temporary

•

Lewy Body Disease

•

Misc: Huntington’s, post-encephalitic

neurologic paralysis

Syncope

(Todd’s)

YES

•

Reduced Vision

•

Tabes Dorsalis

Orthostatic

Spasticity

•

Neuropathy

symptoms

(proprioceptive dysfunction)

YES

Hypotension

•

Multiple Sclerosis

•

Cervical-thoracic myelopathy

•

Spastic Paraparesis

Ataxia

•

Stroke

•

Endocrine

Cardiovascular

•

ALS/PLS

abnormalities i.e.,

symptoms

YES

•

Previous CNS injury

Addisonian

•

Low cardiac

YES

output states

•

Alcoholic cerebellar degeneration

•

Idiopathic cerebellar degeneration

•

Antihypertensive

•

Secondary cerebellar disease—MS,

excess

tumor, Stroke

•

Autonomic dysfunction

•

Hereditary ataxias (SCA,

i.e., Multiple systems

Weakness

Friedrich’s, ataxia-telangectasia, etc)

atophy, Primary

•

Paraneoplastic cerebellar

autonomic failure

YES

•

Atrial fibrillation

(tachy-brady)

•

Myasthenia Gravis

•

Ventricular arrhythmias

•

Myopathy

•

Aortic stenosis

•

Lower motor neuron

•

Vasovagal

•

Bradyarrhythmias/

Vestibular

syndromes (incl ALS)

•

Asymptomatic

Heart block

symptoms

•

Neuropathy (denervation

cardiac abnormalities

•

Carotid sinus

of muscles)

•

Vertebrobasilar migraine

hypersensitivity

YES

Figure

Abbreviations

• Meniere’s disease

Legends

ALS

: amyotrophic lateral

• BPPV

sclerosis (Lou Gehrig’s disease)

• Acute Labyrinthine Disorders

BPPV : benign paroxysmal positional vertigo

• Otosclerosis

: multiple sclerosis

• Aminoglycoside toxicity

PLS

: primary lateral sclerosis

• Perilymphatic fistula

SCA

: spinocerebellar ataxia

• Internal auditory artery occlusion (stoke)

TIA

: transient ischemic attack

FIGURE 21.2 Flowchart for approach to a falling patient.

431

Chapter 21

n An Approach to the Falling Patient

appear “collapsing” in nature or not. Often col-

as the approach to acute global deficiencies of

lapsing and impaired consciousness go together,

brain perfusion or electrical maintenance. The

and can indicate low cerebral blood perfusion

bulk of this chapter will now focus on the left

or seizure, as shown in the right half of the

half of the flowchart, which can be classified as

flowchart.

the approach to falls due to balance mainte-

If impairment of alertness appears to underlie

nance problems. These types of falls are typi-

a fall, further signs or historical points should be

cally more chronic in their temporal course and

sought, including tonic-clonic or other rhythmic

often, though not always, associated with neu-

movements at the time of the fall, nystagmus,

rologic conditions. An examination focused on

prolonged postevent confusion, or incontinence

the neurologic system can help place the pa-

which could indicate seizure activity. If not, then

tient in broad categories that will lead to an ac-

stroke should be ruled out by assessing for new

curate diagnosis and treatment plan.

neurologic deficits, keeping in mind that occa-

sionally a seizure can be accompanied by a tem-

Parkinsonism Examination findings of rest-

porary period of apparent weakness known as a

predominant tremor, muscular rigidity, and

Todd’s paralysis. Once a stroke or seizure is

slowness of movement

(bradykinesia) signal

ruled out, then syncope becomes the top consid-

parkinsonism, which is a manifestation of an ab-

eration. If evidence of orthostasis is found by

normally functioning basal ganglia. Subjectively,

history or by examination, further investigation

patients experience parkinsonism as tremulous-

of blood pressure instability follows. Frequently,

ness, muscular stiffness, and slowness. Falling is

antihypertensive medication excess contributes

associated with parkinsonism because rigidity

to this problem, but endocrine deficiencies or

and slowness of movement impair balance re-

autonomic dysfunction can also be causative.

sponses and because many important postural

Autonomic dysfunction, for example, may re-

systems are directly affected. A number of diag-

sult in postural hypotension that can lead to col-

noses are characterized by parkinsonism. As the

lapsing falls when patients attempt to quickly

disease advances, cognitive deficits can also

rise from sitting or lying positions. If no sign

contribute to the accumulation of balance

of orthostasis is evident, then cardiovascular

constraints.

causes of syncope need to be considered, which

The most common cause of parkinsonism is

may require a cardiology specialty referral.

Parkinson disease. PD is clinically diagnosed

At times, no cardiovascular causes can be iden-

and considered probable if two out of three

tified, and rarer conditions including verte-

cardinal signs are present. These signs include

brobasilar migraine may need to be considered.

rest-predominant tremor, bradykinesia (slow-

At this point, a neurologic consultation is war-

ness of movement), and rigidity during passive

ranted for the evaluation of these more unusual

motion of the limbs or neck. Postural instabil-

conditions.

ity is also very common, though not at the be-

Sometimes falls are a sign of underlying med-

ginning of the disease course. Indeed, postural

ical illness or an acute side effect of medications

stability deficits usually develop in the middle

like sedative hypnotics, anticonvulsants, antihis-

to later phases of the disease, occurring at least

tamines/anticholinergics, or substances like al-

a few years after other parkinsonian symptoms

cohol. When falls are due to medication side

develop.

effects, confusion or encephalopathy is a useful

n SPECIAL CLINICAL POINT: Early falls are

feature to recognize, and the expectation is that

considered a red flag indicating an alternate

these falls will resolve when the illness has been

parkinsonian diagnosis.

treated or offending medication removed.

So far, this section has focused on the right

While PD accounts for the majority of cases of

half of the flowchart, which can be considered

parkinsonism, the second most common cause

432

Chapter 21

n An Approach to the Falling Patient

is progressive supranuclear palsy (PSP). PSP is

and adductor muscles of the legs, causing foot

important in the context of this chapter because

inversion, toe pointing, and even curling in a pa-

a hallmark feature of the disease is early falling

tient with multiple sclerosis (MS).

and may be the main symptom presented to the

Spasticity can lead to falls by a number of

medical provider’s attention. Falls are typically

mechanisms. Simple reasons may include weak-

backward in direction, as opposed to PD, where

ness of involved muscles because weakness

patients typically fall forward. Other symptoms

often accompanies spasticity as part of an upper

include stiff axial musculature, restricted volun-

motor neuron syndrome (though not always).

tary ocular excursions, particularly in the verti-

Another reason for falls with spasticity may be

cal downward direction, spastic-ataxic speech,

the abnormal posture of a foot, which results in

dystonic facial features, and cognitive deficits

a limited base of support for balance and leads

that are frontal executive in nature.

to missteps and tripping while walking. Exces-

Other less common conditions that may pres-

sive muscle tone can interrupt the normal coor-

ent with parkinsonism include multiple systems

dinated swing cycle of walking and results in

atrophy (MSA) and corticobasal ganglionic de-

weak postural responses and inflexible postural

generation (CBGD). In MSA, combinations of

tone with delayed postural latencies. Acute

parkinsonism, ataxia, autonomic dysfunction,

spasms of muscles can add unpredictable insta-

and pyramidal tract findings can occur. In

bility during stance or gait.

CBGD, apraxia, cortical sensory disturbance,

dystonia, myoclonus, and rigidity present in a

Ataxia Ataxia is the result of hypermetric,

usually very asymmetric pattern of onset. Other

poorly coordinated body movements with poor

conditions that also may be considered include

motor learning associated with abnormal cere-

fragile X premutation tremor-ataxia syndrome,

bellar function. Ataxia can be inherited as a num-

drug-induced parkinsonism, normal pressure

ber of conditions, or can be acquired as a result of

hydrocephalus, and Lewy body disease. If any

injury or damage to brain structures responsible

type of parkinsonism is suspected, a referral to a

for coordination. Clinicians may perceive ataxia

neurologist or movement disorders specialist is

in the common broad standing base that com-

highly recommended. It is important to recog-

pensates for the effects of excessive involuntary

nize that several drugs prescribed by non-

body motions that disrupt equilibrium. Damage

neurologists are dopamine receptor blockers

to the anterior lobe of the cerebellum results in

and can cause drug-induced parkinsonism.

excessive hip and trunk motion during stance and

These agents (see Chapter 12) include antipsy-

ataxic gait involving inconsistent variable posi-

chotic agents, reserpine, and metoclopramide.

tioning of the feet. When the cerebellar hemi-

spheres are involved, ataxia includes the limbs

Spasticity This problem occurs as a result of

with similar inaccurate, hypermetric, jerky, and

damage to the motor tracts originating any-

poorly controlled purposeful movements. Ataxia

where from the motor cortex down to the spinal

leads to falls for many reasons: poor coordina-

cord before the anterior horn cell (lower motor

tion of stepping, loss of righting mechanisms, hy-

neuron of the spinal cord). Spasticity is the ex-

permetric postural responses, and unstable gait

cessive tonic stretch reflex that is detected in a

with head motion. Depending on the cause of

limb with velocity-dependent maneuvers and is

ataxia, somatosensory, visual, and/or vestibular

sometimes described as having a “clasp-knife”

disruptions may also contribute, as may execu-

character. Subjectively, it may be experienced as

tive deficits.

a stiffness or tightness in the involved muscles

The inherited causes of ataxia include autoso-

and can be associated with painful cramping. As

mal dominant, recessive, and X-linked conditions.

a practical illustration, one may see this as the

Spinocerebellar ataxias are a group of genetically

tightness of muscle tone greater in the extensor

determined conditions that may have associated

433

Chapter 21

n An Approach to the Falling Patient

features such as neuropathy, cognitive dysfunc-

unilateral internal auditory artery occlusion lead-

tion, parkinsonism, eye movement abnormali-

ing to a stroke of the vestibular end organ.

ties, and other diverse neurologic signs. Other

Menière disease is a classic example of fluctuat-

inherited ataxic syndromes have been identified

ing vestibular dysfunction, though it may lead to

and a thorough family history is important to ex-

a chronic pattern in later disease. Mechanically

plore, including mental retardation, as a recently

based dysfunction of the semicircular canals or

described condition called fragile X tremor-

otolith organs include benign paroxysmal posi-

ataxia syndrome especially affecting older males

tional vertigo (BPPV) in which otoconia become

can be found in families where fragile X syn-

displaced from the otoliths and float in the

drome has been diagnosed. If an inherited cause

canals, and perilymphatic fistulas or holes in the

is suspected, a referral to a neurologist or med-

round or oval windows.

ical geneticist is warranted.

Patients with vestibular deficits may have very

Acquired causes of ataxia can include toxic

poor control of balance, complaints of dizziness,

exposures like alcohol or anticonvulsants,

and abnormal eye movements, but not frequent

paraneoplastic conditions accompanying can-

falls. Falls can often be avoided in patients with

cers of the lung or gynecologic organs for ex-

vestibular injuries because they increase their de-

ample, structural abnormalities or infections,

pendence on vision and somatosensory function

vitamin deficiencies, and autoimmune condi-

using central compensation processes. However,

tions such as MS. Idiopathic conditions like

if patients with bilateral loss of vestibular func-

MSA or cerebellar degeneration may present

tion or with uncompensated unilateral loss of

with falls early in the course of the disease.

vestibular function find themselves in a dark en-

While cerebellar abnormalities can lead to

vironment standing on an unstable surface, they

ataxia, disruptions in sensory systems can also

may fall “like a tree” without making automatic

result in a similar appearance of ataxia. Neu-

balance responses because of spatial disorienta-

ropathy, especially when proprioceptive func-

tion from lack of sensory information about their

tion is severely disturbed, or some vestibular

body equilibrium. This “context-specific insta-

disorders can result in unsteadiness of stance

bility” is often missed when evaluating vestibular

and gait that resemble ataxia and result in falls.

loss patients in a well-lit clinic on a firm surface.

Vestibular System Disorders The vestibular

Weakness While weakness is common when

system is a bilateral, reciprocal sensory system

in conjunction with other neurologic findings

that contributes to balance control by sensing

such as spasticity in upper motor neuron syn-

position and velocity of head motions, as well

dromes, or atrophy of muscles associated with

as gravity. It is useful to consider peripheral

neuropathy, there are syndromes of lower

vestibular disorders in three broad groupings,

motor neuron, pure muscle disorders, and neu-

those with (a) chronic unilateral or bilateral

romuscular junction dysfunction where weak-

loss,

(b) fluctuating or intermittent dysfunc-

ness is singularly dominant. Muscle disease

tion, and (c) mechanically based vestibular dys-

including endocrine, inflammatory or toxic

function. Falls due to vestibular dysfunction

myopathies, inclusion body myositis, or neuro-

can be due to any of the following components

muscular junction diseases such as myasthenia

including unstable gait with head motion,

gravis can present with varying degrees of

asymmetric limits of stability, poor sense of the

weakness and falls. Less common lower motor

vertical, and loss of sensory feedback.

neuron diseases such as polio, or spinal muscu-

Examples of chronic or permanent loss of

lar atrophy can lead to profound weakness

vestibular function include otosclerosis, stapedec-

especially of the lower extremities. Weakness

tomy, acoustic neuroma, aminoglycoside or other

of muscle activation causes falls because of in-

ototoxicity, vertebrobasilar stroke, or rarely a

ability to sustain strength against the pull of

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Chapter 21

n An Approach to the Falling Patient

TABLE 21.2

Examples for How Each Neurologic Disease is Associated with a Different Set of

Constraints on Postural Control

Constraints on

Cognitive

Balance Systems

PD Spinal Neurop Spasticity Ataxia Vestibular

Disorders

Weak postural responses

X X

High postural tone

X X

Delayed latencies

Small anticipatory adjustments

Abnormal limits of stability

Loss of sensory feedback

Abnormal sensory weighting

Poor sense of vertical

Unstable gait with head motion

Executive deficits

PD, Parkinson disease; Neurop, somatosensory neuropathy; Vestib, bilateral vestibular loss; Spinal, spinal cord injury.

gravity and inability to generate adequate,

related to inability to recover equilibrium when

quick increases in force between their feet and

it is disturbed from external perturbations. Weak

the ground to recover equilibrium with auto-

postural responses result from any problem in-

matic balance responses.

volving postural long-loop pathways from pro-

prioceptors to the motor cortex and back to

Balance Constraints in Neurologic Patients

motoneuronal pools and muscles. High postural

Since balance control is regulated throughout

tone results in co-contraction and stiffness that

the nervous system, many very different neuro-

limits synergic coordination of postural re-

logic diagnoses result in poor balance and falls.

sponses. Delayed postural response latencies

from their normal 100 msec loop time result in

n SPECIAL CLINICAL POINT: Each

ineffective responses to external perturbations

neurologic disease is associated with a different

like a push or trip.

set of constraints on balance control, leading to

Any motor deficits affecting the quick genera-

balance problems for different reasons and,

tion of muscle activation, such as PD, spinal cord

thus, risk for falling under different conditions.

lesions, or spasticity from stroke or MS, are likely

Each type of neurologic pathology can result in

to result in weak postural responses to external

different types of balance deficits because

perturbations as well as weak self-generated

many different neural circuits are responsible

postural movements. To effectively respond to

for different systems underlying postural con-

postural perturbations such as slips or trips, sub-

trol. Examples of constraints on balance sys-

jects need to generate muscle force quickly. The

tems are listed in Table 21.2.

amount of force needed to recover equilibrium is

larger, the larger the individual and the stronger

the perturbation. Despite high background mus-

BALANCE PROBLEMS LEAD

cle tone associated with rigidity or spasticity,

TO FALLS IN NEUROLOGIC PATIENTS

studies show that these motor deficits are associ-

As shown in Table 21.2, fall risk associated with

ated with a slowed rate-of-change of muscle

motor problems such as weak postural responses,

activation for postural correction. Thus, neuro-

high postural tone, or late postural responses is

logic patients with weak postural responses are

435

Chapter 21

n An Approach to the Falling Patient

likely to fall in response to external perturba-

more difficult and results in exaggerated pos-

tions because they generate inadequate forces to

tural responses.

recover equilibrium.

Sensory deficits affecting sensory feedback or

In contrast to deficits in postural response

sensory weighting may result in falls either

loops, small anticipatory postural adjust-

because of failure to generate a timely balance

ments prior to self-initiated movements, such

response or because an inappropriate balance re-

as an arm raise or step, result in disequilib-

sponse is generated. Falls from failure to gener-

rium and falls during fast voluntary move-

ate a timely postural response are common in

ments that require activation of postural

diseases affecting arrival of accurate somatosen-

muscles to compensate for self-induced per-

sory inputs to the nervous system such as periph-

turbations. For example, patients with PD

eral neuropathy or damage to spinal pathways

who show abnormal anticipatory postural ad-

from MS or spinal stenosis. Delays in postural

justments may not be able to adequately un-

responses can also accompany central long-loop

load a leg quickly to initiate a step. Patients

disruptions such as strokes or frontal lobe prob-

with cerebellar ataxia may show such abnor-

lems. A timely, but inappropriate, balance re-

mally large anticipatory postural adjustments

sponse can also result in falls. For example,

prior to each step, but in this situation, they

when subjects with loss of vestibular informa-

accelerate the body too far laterally, requiring

tion stand on a tilting surface with eyes closed,

lateral protective steps to maintain equilib-

they fall because they actively use their so-

rium. Abnormal anticipatory postural adjust-

matosensory system to align their bodies to the

ments prior to voluntary movements also lead

moving support surface, rather than to gravity.

to instability and falls when transitioning

Likewise, some peripheral and central vestibular

from sitting to standing or when attempting

patients fall as they respond to visual motion

to lift a weighted object.

cues because of the inability to distinguish world

Asymmetrical limits of stability make it dif-

motion from self-motion. Loss of sensory feed-

ficult to control position of the body over its

back from muscle proprioceptors is more likely

base of support without changing the base of

to result in frequent falls than loss from vestibu-

support with a step or grasp of a stable object.

lar or visual inputs because postural responses

If patients do not accurately recognize their

are triggered primarily by proprioceptors.

limits of stability, they may not make the pos-

Abnormal sensory weighting results in falls

tural adjustment necessary to maintain equilib-

when subjects change from one sensory envi-

rium. For example, patients with PD have

ronment to another. Healthy subjects rely pri-

particularly small limits of stability in the back-

marily upon proprioceptive information from

ward direction and patients with unilateral loss

the surface for control of stance posture when

of vestibular inputs have asymmetrical limits of

sensory inputs from all three sensory systems

stability, at least acutely, before they compen-

are available. That is why healthy people sway

sate. Normal limits of stability while standing

more on an unstable surface such as compliant

are about 8 degrees at the ankle forward and 4

foam, than when they close their eyes. That is

degrees backward and can be due to central

also why patients with neuropathy affecting so-

causes such as PD, to lack of sensory informa-

matosensory conduction, but not patients with

tion such as in peripheral neuropathy, or

blindness or vestibular loss are most likely to

vestibular loss, or to biomechanical limitations

have large postural sway in stance and falls.

on strength or the base foot support. Reduced

However, healthy people decrease their reliance

limits of stability are also common in patients

on proprioception and increase their reliance

who have fear of falling. Reduced limits of sta-

on vestibular or visual senses when standing on

bility do not allow patients to balance over a

an unstable surface, such as soft sand or a boat.

large area, so the task of balancing becomes

Some cerebellar or dementia patients who cannot

436

Chapter 21

n An Approach to the Falling Patient

quickly increase dependence on their intact

memory, and body mapping can result in falls

vestibular or visual inputs and decrease depend-

because of difficulty making quick decisions,

ence upon proprioception for balance control

affecting mobility in complex environments.

may be stable on a firm surface and only fall

Patients with Alzheimer disease and other cog-

when attempting to balance on an unstable or

nitive deficits have higher rates of falls than

tilted surface. Some patients with peripheral

age-matched controls, even when they do not

vestibular deficits may become overly depend-

have associated sensory or motor deficits. In

ent upon vision as an orientation reference, so

addition, neurologic patients, such as patients

they align their bodies with moving visual sur-

with PD, who also show executive deficits are

round and become unstable or fall. Thus, either

more likely to falls than patients without cog-

a central or peripheral sensory deficit often re-

nitive deficits.

sults in “context-specific” instability, in which

One reason executive deficits are associated

patient can have excellent balance in one sen-

with increased fall risk is that balance control

sory context but very poor balance and falls in

requires central attention. Although much of

another sensory context. Context-specific insta-

healthy control of balance and gait is “auto-

bility explains why it may be difficult to iden-

matic,” patients with balance disorders need to

tify a balance deficit in some neurologic

increase the amount of cognitive attention they

patients in a well-lit clinic on a firm, flat floor

devote to control of balance and gait. Patients

surface, and then they fall when leaving the of-

with executive deficits may have reduced cog-

fice to walk across the parking lot.

nitive reserve, so they cannot increase their at-

Poor verticality causes patients to lean and

tention as needed for a difficulty postural task.

fall as they attempt to align their bodies with

One way to determine the extent to which a

their inaccurate internal representation of ver-

balance or gait task requires attention is to ask

tical. For example, after a stroke resulting in

a patient to do a secondary cognitive task such

hemineglect, it is common for patients to be

as mental arithmetic or listing from a category

unable to sit or stand upright because of strong

while they are walking or performing another

leaning to the hemiplegic side. This leaning is

task involving balance control. The “Walk and

not only due to inability to support the body

Talk” task is particularly sensitive and useful

with weak muscles but also because the patient

when a stopwatch is used to time how long it

may be attempting to align their bodies with

takes to perform a Get Up and Go task with

laterally tilted sense of upright, vertical. Falls

and without a cognitive task. Although a small

due to a tilted internal representation of verti-

amount of gait slowing is normal during a cog-

cal occur in the direction patients lean; for ex-

nitive task, a large amount of slowing is associ-

ample, patients with peripheral neuropathy

ated with increased fall risk.

consistently fall backward and stroke patients

Although Table 21.2 differentiates how differ-

with hemineglect fall to the side of neglect.

ent neurologic diagnoses tend to be associated

Unstable gait with head motion results in

with a different set of postural constraints, even

ataxic missteps and, potentially, falls when sen-

individuals with the same neurologic diagnosis

sors in the head and neck are perturbed. Pa-

may have a different set of constraints on these

tients with cerebellar deficits and vestibular

postural systems. For example, depending on

deficits are especially sensitive to imbalance and

which neural circuits are involved in MS or fol-

falls when they quickly move their heads while

lowing a stroke, the root cause of a patient’s

walking, even if they are relatively stable in

balance problem, and therefore the nature of

walking with their heads facing straight ahead.

their individual fall risk, will vary. The speci-

Executive cognitive deficits affecting atten-

ficity of type of balance problem in each neuro-

tion, ability to change set quickly, navigation

logic patient demands treatments that are also

437

Chapter 21

n An Approach to the Falling Patient

specific to each patient’s set of constraints,

The model shows the decline in mobility

based upon a systematic assessment.

function in patients with a chronic, degenera-

tive neurologic disease, such as PD. Superim-

posed upon the slow, degenerative decline in

FALLS ARE MULTIFACTORIAL

neural function that may affect mobility, such

as bradykinesia and rigidity, are additional

n SPECIAL CLINICAL POINT: Most falls are a

new constraints on balance control. Additional

result of the complex interaction among many

constraints, such as freezing, or impaired

different intrinsic and extrinsic factors.

kinesthesia, may arise from continued progres-

A sudden onset of frequent falling may not nec-

sion of the same neurologic disease or from

essarily be the result of a sudden, significant

new constraints on balance control, such as

fall risk, but may be due to the addition of one

arthritis or neuropathy from diabetes.

more constraint on balance control to the pre-

Each patient with multiple constraints may

vious set of constraints already present, but not

reach that falling threshold at different times

yet bringing the subject to the threshold for

for different reasons, like the proverbial “straw

falling. For example, a patient with PD may

that broke the camel’s back” (compare subject

have impaired balance but not yet falling due

A and subject B). For example, if the threshold

to a combination of autonomic hypotension,

for falling is reached when freezing is added to

weak postural responses, and high postural

the other constraints due to PD, patients are

tone. When he suddenly is given a sleeping pill

likely to fall forward onto their knees while at-

or changes prescription for his glasses, this new

tempting to start walking. In contrast, if the

risk factor may put him over the threshold for

threshold for falling is reached due to the addi-

falling, although this last factor is not the only

tion of neuropathy, falls are more likely to

reason for the fall. Figure 21.3 shows how the

occur when standing on an unstable surface or

gradual addition of multiple constraints on

in response to an external perturbation. This

balance control can bring a patient to the

model can help explain how and why different

threshold for frequent falls.

individual patients with the same neurologic

Threshold for

Balance or Gait

Problem

Postural Instability

Subject A

Subject B

Progression of Disease

FIGURE 21.3 Model of how addition of multiple constraints on balance control eventually results in

reaching the threshold for frequent falls.

438

Chapter 21

n An Approach to the Falling Patient

disease can have different type of balance prob-

Cataract surgery and improving nighttime

lems leading to different type of falls under dif-

lighting in the hallways and bathroom are ex-

ferent situations.

amples of simpler solutions for those with vi-

sual impairments, for example. Conditions on

the right side of the flowchart are often easily

remedied by optimizing medications, place-

TREATMENT TO PREVENT FALLS IN

ment of a pacemaker, or instituting antiseizure

NEUROLOGIC PATIENTS

therapy, for example. Some conditions in the

Applying a useful treatment for falls is of course

left half of the chart can be treated with a high

dependent on making the correct analysis of the

degree of success. For example, if the problem

fall risk problem. The practical approach begins

is myasthenia gravis and late-day falls, then

with recognizing the predominant body system(s)

appropriate immunomodulating therapy will

impairment (see the flowchart). Once a patient is

cause return of muscle strength and lessening

classified, it is then simpler to understand how

of falls. On the other hand, some deficits can-

balance is impaired by considering each individ-

not be fully treated and normal function may

ual’s balance constraints (Table 21.2). The next

be not completely restored. In many cases,

steps are to identify reversible or treatable

there are no significantly useful medical or

factors. For example, a new faller may be exam-

surgical interventions. In these situations, the

ined and found to have sensory deficits includ-

role of rehabilitation becomes paramount.

ing poor proprioception with toe and ankle

joint testing. A diagnosis of diabetes mellitus

Medical Treatment

might be made after applicable testing, for ex-

of Neurologic Causes of Falls

ample. By understanding that delayed sensory

feedback results in failure to general timely pos-

Parkinsonism Although there is an array of

tural responses, one understands the reason for

symptomatic treatments for PD, the chronic

falling better. Treatment (or prevention) of fu-

progressive problem of postural instability re-

ture falls will focus not only on trying to prevent

mains a great source of disability especially in

ascension or worsening of the sensory deficit

the later stages of the disease. While postural

with good glucose control, but also on removing

instability remains very difficult to treat, there

external hazards such as throw rugs, slippery

are other complications in PD that should be

footwear, and uneven surfaces. If severe weak-

addressed and can prevent falls. Freezing and

ness also contributes, an ankle-foot orthotic

gait shuffling, rigidity, tremor, and bradykine-

may be appropriate.

sia can improve with dopaminergic medica-

tions that may need to be started, or in more

n SPECIAL CLINICAL POINT: In general, if

advanced treated patients, optimized with

the patient has external factors contributing to

higher doses or more frequent dosing regi-

falls, these can be the most quickly remedied

mens. Treating autonomic hypotension may

problems.

prevent falls when quickly rising from a sitting

Studies have shown that home visits by thera-

or supine position, but because these treat-

pists or visiting nurses can alter home environ-

ments are complex, referral to a neurologist or

ments to reduce fall risk. Creative solutions can

even a movement disorders neurologic special-

include offloading tasks such as cleaning gut-

ist is recommended.

ters/washing windows to others, by preventing

Occasionally, medications that boost

risky behaviors leading to falls.

dopamine production are useful in other con-

Finding solutions for intrinsic causes for

ditions like MSA, though the effects are usu-

falling is usually more complicated, though

ally not as robust or as enduring as in PD.

simple solutions do exist for many problems.

Avoiding dopamine receptor blockers such as

439

Chapter 21

n An Approach to the Falling Patient

antipsychotic drugs or metoclopramide will

tified due to diabetes, good glucose control can

prevent potential worsening of parkinsonism

modify the incidence and rate of neuropathy

and increased falling.

progression, which should lead to less falling.

Spasticity A number of pharmacologic treat-

Vestibular Depending on whether the vestibu-

ments for spasticity are in use including baclofen,

lar disturbance is “mechanical” or chronic ver-

tizanidine (imidazolines), and benzodiazepines.

sus intermittent will dictate the medical therapy

Botulinum toxin injections to affected muscles

instituted. It is common for vestibular quieting

are another more recent treatment modality

agents (antihistamines) like meclizine to be pre-

that can reduce tone with fewer side effects. A

scribed for vestibular-based dizziness, but this

good example of the use of botulinum toxin

could be counterproductive for balance and

might be injections to the gastrocnemius,

falls since they suppress vestibular function and

soleus, and posterior tibial muscles to reduce

the ability of the central nervous system to com-

spasticity associated with excessive foot plantar

pensate for chronic vestibular loss. Diuretics

flexion and inversion in a patient with cerebral

can improve certain vestibular disorders like

palsy, thereby decreasing falls from tripping.

Menière disease. Treatment of BPPV with

Pharmacotherapy can help reduce spasticity

canalith-repositioning techniques, which can be

in some patients, but in many others, the side

completed in a matter of minutes, shows great

effects of oral medications are a limiting prob-

success in reducing positional dizziness. Surgi-

lem. The development of alternate routes of

cal techniques for certain chronic labyrinthine

delivery has helped many of these patients,

disorders are occasionally utilized.

such as intrathecal delivery mechanisms (ba-

clofen pump). Sometimes orthopedic or neuro-

Weakness The differential diagnosis is broad

surgical treatments

(rhizotomy) to relieve

and therefore the treatment options are also nu-

spasticity are needed.

merous. In general, myopathies due to toxic, in-

In some cases, relieving spasticity does not

flammatory, or endocrine abnormalities have

provide a net benefit on balance, and in fact can

good chances for improvement using appropri-

lead to more falls, especially if the increased ex-

ate medical treatments. Neuromuscular junction

tensor leg tone helps compensate for weakness

impairment conditions like myasthenia gravis

in a stroke patient, for example. Each individ-

are chronic but usually well-treated conditions

ual case must be evaluated to determine the po-

today. Conditions of lower motor neuron failure

tential benefits, and it is not uncommon to

have dismally few medical treatment options.

decide upon no spasticity treatment.

Depending on the etiology, the role of dis-

Rehabilitation to Prevent

ease modification cannot be underestimated.

Falls in Neurologic Patients

For example, prevention of MS exacerbations

is possible with immunomodulating agents, or

The main treatment to prevent falls in patients

anticoagulation in atrial fibrillation to prevent

with neurologic disorders is physical therapy.

stroke is obviously the best antispasmodic

Physical therapists should base their individu-

strategy.

alized treatment on a comprehensive assess-

ment of the constraints on balance control for

Ataxia There are no known medical treat-

each individual patient.

ments that reliably reduce ataxia. It is impor-

tant to prevent further disease progression if

Assessing Fall Risk Several clinical tools can be

known toxic causes are identified. An example

used to determine risk for a fall. For example,

of this is the alcoholic who stops drinking.

the Berg Balance Scale consists of a series of

When neuropathy or “sensory ataxia” is iden-

balance tasks, such as standing on one foot,

440

Chapter 21

n An Approach to the Falling Patient

reciprocal stepping onto a stool, and a 180-

sponding to external perturbations can improve

degree turn, which are related on a four-point

automatic postural responses. Inability to use

scale from normal (4) to very abnormal (0). A

vestibular information for stance balance, in

total score on the Berg Balance Scale above 48

patients who have intact peripheral vestibular

out of 56 has been shown to predict future falls

receptors, may be improved by practicing bal-

in the elderly and in patients with PD. Tinetti’s

ancing with eyes closed on an unstable surface.

Balance and Gait Test was similarly designed to

Patients overly dependent upon vision for

predict falls in the elderly but it also predicts falls

stance balance can practice balancing with “no-

in neurologic patients, such as those with PD. A

body” glasses or dark sun glasses that reduce

quick and easy clinical test of mobility that is

viewing the body and the visual environment.

also related to falls in the elderly is the timed Get

Patients who have balance deficits use more

Up and Go test. Subjects are timed with a stop-

conscious attention to control their balance.

watch for how long it takes them to rise of an

Many aspects of balance and gait are auto-

armless chair, walk 3 m, turn and return to the

matic and require little conscious attention in

chair and sit down. Frailty and falls can also be

healthy subjects. One way to determine how

assessed with the Functional Performance Test,

much attention is used by the nervous system

consisting of timing five times sit-to-stand,

to control balance is to ask patients to perform

stance in tandem, and timed 2-minute walk. Al-

a secondary cognitive task while they simulta-

though these functional balance tests are related

neously control their balance or gait. For ex-

to fall risk, they do not include tests of postural

ample, in the BESTest, the timed Up and Go

responses to external perturbations, balance

test is performed while performing mental

under altered surface or visual conditions, or

arithmetic. The increase in time it takes to per-

balance challenges during gait. These types of

form the test with versus without a cognitive

balance tests can determine whether neurologic

task indicates how much attention is required

patients need balance rehabilitation but not

for control of mobility. A secondary cognitive

what type of rehabilitation is needed.

task, such as counting backward from 100 by

threes or making a list from a category, can be

Balance Training To design an effective exercise

added to almost any balance or gait task, such

program for a neurologic patient with balance

as one-foot standing, standing on foam with

problems, therapists perform a comprehensive

eyes closed, to determine how much it depends

assessment to determine which systems are con-

upon cognitive attention. Patients may im-

tributing to constraints on balance control.

prove doing a balance or gait task while con-

Using the Balance Evaluation Systems Test

currently doing a cognitive task with practice.

(BESTest), therapist can determine which of six

systems underlying posture control are affected:

Strength Training Weakness from a neurologic

biomechanical, verticality/limits of stability, an-

problem may be due to impaired central motor

ticipatory postural adjustments, automatic pos-

commands for voluntary movement from corti-

tural responses, sensory orientation, and

cospinal damage, basal ganglia-related brady-

stability during gait. If biomechanical con-

kinetic or slow movements with difficultly

straints are found, such as muscle weakness or

increasing or decreasing muscle force quickly, ab-

abnormal postural alignment, therapy will

normal coordination of antagonists and syner-

focus on strengthening, increasing range of mo-

gists as in cerebellar impairment, and inability to

tion, and improving postural alignment. Re-

recruit or unavailable large motoneurons in the

duced limits of stability can be increased with

spinal cord. Whatever the pathology responsible,

practice using biofeedback. Practice unloading

if a neurologic patient presents with weakness,

a leg prior to step initiation may improve antic-

progressive resistance exercise focused on the

ipatory postural adjustments and practice re-

weak muscles leading to postural instability can

441

Chapter 21

n An Approach to the Falling Patient

be helpful. The most important muscles for con-

training focused on increasing toe clearance

trol of balance are the ankle muscles with tibialis

and stride length. However, when treadmill

anterior, in particular, important for preventing

training is accompanied by hand or partial

backward falls. Adequate strength in lateral hip

body weight support, the patient is not training

abductor muscles is also important to prevent

their balance control system along with gait

falls during gait and turns, and quadriceps

training.

strength is needed to prevent falls when transi-

tioning from sit-to-stand or stand-to-sit posture.

Assistive Devices The most effective assistive

Even if isometric peak strength is within normal

device to prevent a fall is use of a cane. Many

limits, the ability to generate joint torque quickly

studies have shown that appropriate use of a

is important for adequate postural responses, so

cane can prevent imbalance and falls in neuro-

therapists need to focus on quick, dynamic

logic patients during gait and balancing tasks.

strengthening exercises.

A cane does not prevent falls by acting as a

crutch to support body weight or to catch the

n SPECIAL CLINICAL POINT: In many cases,

person who is falling. Canes prevent falls by

the most effective exercises for improving

increasing the amount of accurate sensory in-

posture and balance may not be isolated muscle

formation to the nervous system about where

strengthening in well-supported conditions but

the body is with respect to earth reference. In

strengthening exercises while practicing

fact, use of a cane is similar to use of light

balancing tasks.

touch on a stable surface to prevent a fall since

For example, wearing a weighted vest while re-

most neurologic patients do not place much

peating sit-to-stand to strengthen quadriceps

support on a cane. Even light touch of less

and pulling the upright body forward from

than 100 g, about the amount needed to read

leaning back against a wall to strengthen tib-

Braille, is sufficient to decrease postural sway

ialis muscles.

in stance even more than opening the eyes to

use vision. Patients who have loss of periph-

Gait Training Fall prevention by gait training

eral sensory feedback from the vestibular, pro-

involves identifying compensatory strategies

prioceptive, or visual systems show the most

and practicing with added balance challenges

immediate improvement in balance, control,

during gait. Normal gait is an efficient ex-

and stability during gait from use of a cane.

change of potential and kinetic energy in which

Use of a cane or trekking pole also makes

subjects spend two thirds of the gait cycle in

walking more energy efficient by decreasing

single leg support. Patients prone to falls, how-

the balance demands of gait. However, use of

ever, tend to slow gait, increase time in the

a cane requires sufficient sensory integration,

double-support phase, increase variability of

strength, coordination, and executive control

spatial-temporal gait parameters, and increase

to be functional.

lateral body sway while walking.

Some patients with central neurologic deficits

Balance challenges can be added to gait

do not benefit from a cane either because they

training by increasing gait speed, decreasing the

cannot take advantage of the additional sensory

footfall width, adding changes in direction such

information, because they cannot coordinate

as turns, sideways and backward walking:

the use of a cane in a reciprocal gait pattern, or

adding head motions, carrying and picking up

because their balance and strength constraints

objects, altering the surface or visual character-

are too great for a cane alone. If a cane is insuf-

istics of the environment, and adding a second-

ficient for safe balance, then therapists can fit

ary cognitive task. PD, stroke, or partial spinal

patients with appropriate walkers or wheel-

lesion patients who fall because of inadequate

chairs. Large-wheel, swivel walkers with carry-

toe clearance may also benefit from treadmill

ing baskets and seats can make walking safer

442

Chapter 21

n An Approach to the Falling Patient

and practical, although they make it more diffi-

cult to take a protective step for balance in re-

Always Remember

sponse to an external perturbation.

• To diagnose the cause for falls, always start

It should be noted that an assistive device is

by determining whether falls are due to

only useful in preventing falls if it is appropri-

acute loss of brain activity/perfusion or to a

ately fitted, tested, and trained for an individual

balance problem.

patient by a licensed physical therapist. A cane

• A single deficit may not explain falling and a

should be the height of the greater trochanter

search for multiple, interlocking deficits must

from the floor and held in the hand opposite to

be pursued.

the leg with the largest gait problem. A cane that

• The context of falls may be the most

is too tall or difficult to control can be more

important clue to the cause, so detailed

hazardous than no cane at all. Many patients

historical information is essential.

need to be taught how to appropriately use a

• Refer patients to multidisciplinary resources

cane so they decrease, rather than increase, fall

early to prevent future falls.

hazard. There are also an increasingly large vari-

ety of types of walkers, so a proper prescription

by an experienced therapist is important.

Patients who continue to fall frequently, de-

spite best efforts at rehabilitation, may benefit

QUESTIONS AND DISCUSSION

from padded clothing to prevent injuries. For ex-

1. A 72-year-old man presents with three falls

ample, padded hip protectors have been shown

in the last 6 months. He has a known

to be particularly useful in preventing hip frac-

history of atrial fibrillation, hypertension

tures in older, osteoporotic patients with demen-

on two antihypertensive medications, and

tia. Kneepads may protect the legs in patients

type II diabetes on a sulfonylurea. His wife,

with PD who tend to fall forward while walking

who witnessed two of the falls, reports one

due to freezing episodes. Helmets can be worn in

occurred while walking in the grocery store

ambulatory patients who cannot protect them-

and appeared to be a sudden “crumple”

selves with their hands while falling.

with a very brief period of unresponsiveness,

some confusion for a few minutes

afterward, but recovery to his normal

WHEN TO REFER TO A SPECIALIST

baseline. The second event occurred shortly

after getting up from his recliner and

Refer a falling patient to a neurologist once

walking to the kitchen. These falls can

you have eliminated the probability that falling

reasonably be explained by which of the

was due to loss of perfusion to the brain from

following mechanisms?

a cardiovascular event, which may require re-

A. Cardiac arrhythmia

ferral to a cardiovascular specialist. Refer a

B. Seizure

falling patient to a neuro-otologist if they com-

C. Hypoglycemia

plain of spinning or positional vertigo, show

D. Orthostasis

abnormal nystagmus, or to rule out a bilateral,

E. All of the above

profound loss of vestibular function in patients

without any vertigo or nystagmus. Refer to an

The correct answer is E. The point here is to

ophthalmologist to determine if visual deficits

recognize that more history and physical is re-

or poor glasses prescription contribute to

quired to narrow this differential diagnosis,

falling. Refer a falling patient to a physical

but the chances are high that a non-neurologic

therapist to remediate balance and gait impair-

cause will be discovered because of the sud-

ments contributing to falls.

den collapsing nature without seizure-like

443

Chapter 21

n An Approach to the Falling Patient

accompaniments or residual neurologic deficits.

3. A 72-year-old man who has had PD for

While seizures are possible, it would be atypi-

10 years presents to you for falls with

cal with such short periods of postfall confu-

injuries three times in the last 3 months.

sion, and without mention of repetitive motor

Prior to this he had a history of falling

activity (though not always present). Similarly

about once per year. Which potential

for hypoglycemia, the short recovery time is

constraints on balance control will you

less likely but can be investigated with random

need to investigate to determine the reason

fingerstick glucose testing. Orthostasis can be

for the increased risk of falls in this

investigated with questions about lightheaded-

patient?

ness during other postural transitions or after

A. New home environment

meals and investigated with orthostatic vitals

B. Progression of disease with added new

3 minutes apart. As negative data accumulate,

freezing or cognitive constraints

the likelihood of an arrhythmia becomes

C. Increase in lightheadedness after

higher. In a patient with a known history of

transitioning to upright positions

atrial fibrillation, the “collapsing” nature of

D. Over-the-counter medication added to

the fall and probable brief loss of conscious-

his antiparkinsonian medications

ness should make one suspicious of sudden

E. All of the above

loss of cerebral perfusion. In this case, long-

The correct answer is E. Both A and D are

term cardiac monitoring revealed bradycardic

examples of extrinsic factors, which could be

periods and pauses; the placement of a pace-

easily remedied by educating about medica-

maker resulted in no further falls.

tion interactions and by having a therapist or

other visiting specialist evaluate the home for

2. An 84-year-old woman presents with a

potentially hazardous features like abrupt sur-

complaint of worsening balance and a

face transitions, loose carpets, etc. B and C

nighttime fall for the first time. She has no

are complications associated with advancing

history of coronary artery disease, diabetes,

PD. These intrinsic factors can be improved

or seizures. She feels unsteady when she

with treatment of orthostasis with volume

stands up and walks, but feels better when

expanders or midodrine, adjusting the tim-

she touches the wall. Her medications

ing/dose of dopaminergic medications to re-

include alendronate, calcium carbonate/

duce freezing, or adding an assistive device.

vitamin D, omeprazole, and hydrochloroth-

iazide. Which of the following is the most

4. A 78-year-old woman comes to the office

likely diagnosis?

because of a year-long history of

A. Orthostatic hypotension

progressive worsening of gait and balance

B. Multiple sensory deficits

progressing to falls in the last few months.

C. Anxiety

She feels “stiff-legged” and cannot walk

D. Vertebrobasilar transient ischemic

quickly to answer a ringing telephone. Her

attack (TIA)

bladder has become more urgent recently.

E. Benign paroxysmal positional vertigo

Some of her examination findings include

(BPPV)

upgoing toes and sustained clonus at the

The correct answer is B, multiple sensory

ankles. You find no abnormalities above

deficits. The history is progressive worsening,

the waist, but you discover some loss of

and not episodic periods of disequilibrium;

proprioception in the feet. Her gait is

thus BPPV and TIA are not correct. Orthosta-

indeed stiff and slow in appearance, with

sis is an important diagnosis to rule out,

the left leg appearing to be externally

but touching the wall would not cause

rotated. She admits to having a sore neck

improvement.

often and attributes it to arthritis. Which

444

Chapter 21

n An Approach to the Falling Patient

of the following tests is the first priority in

6. A 52-year-old woman stays indoors and

diagnosis of this patient?

fears walking in crowds or near moving

A. MRI of the cervical spine

traffic because of disorientation and fear of

B. Nerve conduction studies of the lower

falling. How could this patient’s complaints

extremities

be categorized?

C. Vitamin B₁₂ level

A. Malingering

D. Mammogram

B. Anxiety disorder with panic attacks

C. Presyncope

The correct answer is A. Structural and treat-

D. Visual motion sensitivity associated with

able abnormalities in the cervical cord should

vestibular disorder

be eliminated rapidly. In this case, MRI revealed

central canal stenosis from a compressive disc

The correct answer is D. Classically, those

protrusion, with abnormal signal in the spinal

with visual motion sensitivity are bothered by

cord. A thoracic cord localization is also possi-

complex movement as exemplified by rapidly

ble, though less common. In this case, the spinal

moving traffic. Presyncope is usually more

cord subacute compression caused spastic gait

random in the setting it occurs, and malinger-

abnormalities which led to falls. Surgical de-

ing is quite unlikely without any evidence of a

compression followed by rehabilitation resulted

potential gain. Anxiety is possible, though fear

in excellent improvement but not complete res-

of falling is more consistent with a history of

olution of walking problems. Vitamin B₁₂ defi-

actual falls and a physiologic etiology for dise-

ciency is also possible and should be explored;

quilibrium.

however, a surgically treatable spinal cord le-

sion must be urgently ruled out.

5. A 35-year-old woman with MS presents due

REFERENCE

to a recent fall when attempting to walk

Tinetti ME, Baker DI, Dutcher J, et al. Reducing the

down an incline, resulting in a skull injury.

risk of falls among older adults in the community.

She had been walking by holding onto a

Berkeley, CA: Peaceable Kingdom Press; 1997.

spouse for support. She has unilateral ankle

muscle weakness, delayed somatosensory

conduction up the spinal cord, difficulty

SUGGESTED READING

seeing to read, and complains of dizziness

with head movements. A referral to which

Adkin AL, Frank JS, Carpenter MG, et al. Postural con-

trol is scaled to level of postural threat. Gait Posture.

of the following professionals is most

2000;12:87-93.

appropriate to prevent falls?

Beidel DC, Horak FB. Behavior therapy for vestibular re-

A. Physical therapy for strengthening, gait

habilitation. Anxiety Disord. 2001;15:121-130.

and balance training with a cane

Berg KO, Wood-Dauphinee SL, Williams JI, et al.

B. Optometry for glasses

Measuring balance in the elderly: validation of an

C. Neuro-otology to diagnose a potential

instrument. Physiotherapy Canada. 1989;41(6):

vestibular disorder

304-306.

D. All of the above

Bloem BR, Grimbergen YA, Cramer M, et al. Prospective

assessment of falls in Parkinson’s disease. J Neurol.

The correct answer is A. Her dizziness with

2001;248(11):950-958.

head movements most likely reflects the dam-

Camicioli R, Howieson D, Lehman S. Talking while walk-

age due to a cerebellar lesion. Vision problems

ing: the effect of a dual task in ageing and Alzheimer’s

due to complications of MS often indicate optic

disease. Neurology. 1997;48:955-958.

nerve damage or problems with yoking of eye

Frenklach A, Louie S, Miller M, et al. Excessive postural

movements. These are usually not responsive to

sway and the risk for falls at different stages of Parkin-

optometric treatment with simple glasses.

son’s disease. Mov Disord. 2009;24(3):377-385.

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Gillespie LD, Gillespie WJ, Cumming R, et al. Interven-

2nd ed. New York: Cambridge University Press;

tions for preventing falls in the elderly. Cochrane

2007.

Database Syst Rev. 2003;(4):CD000340.

Lord SR, Ward JA, Williams P, et al. Physiological factors

Grimbergen YA, Munneke M, Bloem BR. Falls in

associated with falls in older community-dwelling

Parkinson’s disease. Curr Opin Neurol. 2004;17(4):

women. J Am Geriat Soc. 1994;42:1110-1117.

405-415.

Parker MJ, Gillespie LD, Gillespie WJ. Hip protectors for

Horak F. Postural ataxia related to somatosensory loss.

preventing hip fractures in the elderly. Cochrane Data-

In: Ruzicka E, Hallett M, Jankovix J, eds. Gait

base Syst Rev. 2004;(3):CD001255.

Disorders, Advances in Neurology. Philadelphia: Lip-

Pickering RM, Grimbergen YAM, Rigney U, et al. A

pincott Williams & Wilkins; 2001:173-181.

meta-analysis of six prospective studies of falling in

Horak FB. Postural orientation and equilibrium: what do

Parkinson’s disease. Mov Disord. 2007;22(13):

we need to know about neural control of balance to

1892-1900.

prevent falls? Age Ageing. 2006;35-S2:ii7-ii11.

Shupert CL, Horak FB. Adaptation of postural control in

Horak FB, Frank JS, Nutt JG. Effects of dopamine on

normal and pathologic ageing: implications for fall pre-

postural control in Parkinsonian subjects: scaling, set

vention programs. J Appl Biomech. 1999;15:64-74.

and tone. J Neurophys. 1996;75:2380-2396.

Stolze H, Klebe S, Zechlin C, et al. Falls in frequent neu-

Horak FB, Macpherson JM. Postural orientation and

rologic diseases—prevalence, risk factors and aetiol-

equilibrium. In: Rowell LB, Shepard JT, eds. Hand-

ogy. J Neurol. 2004;251(1):79-84.

book of Physiology: Section 12, Exercise Regulation

Tinetti ME, Inouye SK, Gill TM, et al. Shared risk factors

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for falls, incontinence and functional dependence: uni-

Oxford University Press; 1996;255-292.

fying the approach to geriatric syndromes. J Am Med

Horak FB, Shupert CL, eds. Role of the Vestibular System

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in Postural Control. Vestibular Rehabilitation. 2nd ed.

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Philadelphia: F.A. Davis; 1999.

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Visser M, Marinus J, Bloem BR, et al. Clinical tests for

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Tijdschr Geneeskd. 2000;144(48):2309-2314.

Neurotoxic

Effects of Drugs

Prescribed by

Non-neurologists

KATIE KOMPOLITI

key points

• Careful assessment of the medication list should be

part of the assessment of any new neurologic

presentation.

• Drug-induced neurologic side effects do not always

resolve immediately after discontinuation of the

offending agent.

• Drug-drug interactions could be responsible for

neurologic side effects by altering the offending agent’s

metabolism, and therefore its plasma concentrations.

• Neurotoxicity can occur even when levels of the

offending agent are in the therapeutic range.

eurotoxicology

mal poisons, venoms, and botanical poisons).

is a growing field of clinical interest, and physi-

Syndromes associated with these toxins, how-

cians increasingly are required to evaluate and

ever, are not frequently encountered by the

treat patients with numerous complications of

non-neurologist. Yet many drugs that are com-

toxic exposure. The usual compounds dis-

monly prescribed by treating physicians may

cussed in a chapter on neurotoxicology would

precipitate neurotoxic signs or exacerbate the

include metals (e.g., lead, mercury, and arsenic),

underlying neurologic disease. The neurologic

industrial toxins (e.g., organic solvents, gases,

complications of drugs commonly prescribed

pesticides, and other environmental toxins), and

for the medical management of ambulatory

biologic toxins (e.g., bacterial exotoxins, ani-

adults are discussed in this chapter.

446

447

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

whether audiometry is used to detect hearing

ANTIBIOTICS

deficits. Aminoglycoside hearing loss is usually

irreversible and may even progress after the

Penicillins

discontinuation of drug therapy.

Penicillin and related agents rarely cause nervous

system toxic effects, although seizures and my-

n SPECIAL CLINICAL POINT: A potentially

fatal neurotoxic effect of all aminoglycosides is a

oclonic jerks have been reported with high intra-

neuromuscular blockade.

venous (IV) doses. Such effects appear more

commonly in elderly patients with compromised

The aminoglycosides act similarly to curare,

renal function. Meningitic inflammation may

blocking the neuromuscular junction. Amino-

enhance neurotoxic effects by promoting the

glycosides also possibly potentiate ether and

penetration of these drugs into the central nerv-

other anesthetics during surgery. Sudden or

ous system (CNS) and decreasing their egress.

prolonged respiratory paralysis resulting from

Polyneuritis, with paresthesias, paralysis, and

aminoglycoside use may be reversed by the ad-

loss of tendon reflexes, also has been reported.

ministration of calcium or neostigmine.

Cephalosporins

Antifungal Agents

Cephalosporins may cause a number of neuro-

The polymyxins are related closely to the

toxic effects, especially in patients with renal

aminoglycosides in structure and neurotoxicity.

dysfunction or in those receiving high doses.

The incidence of neurotoxic reaction has been

Symptoms can include confusion, coma, tremor,

estimated at 7%, and syndromes other than

myoclonic jerks, asterixis, and hyperexcitability.

neuromuscular blockade include paresthesias,

Status epilepticus that did not respond to anti-

peripheral neuropathy, dizziness, and seizures.

convulsant therapy and subsequently resolved

Respiratory paralysis, however, is the most seri-

with discontinuation of cefepime has been de-

ous neurotoxic reaction. An underlying renal

scribed in two patients receiving this fourth-

dysfunction predisposes to the neuromuscular

generation cephalosporin.

blockade induced by this drug group. Signs of

neuromuscular blockade include diplopia, dys-

phagia, and weakness.

Aminoglycosides

Amphotericin B is widely used against sys-

The toxicities of all aminoglycoside antibi-

temic fungal infection. When the drug is used

otics—neomycin, kanamycin, streptomycin,

intrathecally, seizures, pain along the lumbar

gentamycin, tobramycin, and amikacin—are

nerves, mononeuropathies

(including foot

similar. The two major adverse effects are (a)

drop), and chemical meningitis have occurred.

damage of the eighth cranial nerve and hearing

apparatus and (b) a potentiation of neuromus-

Antituberculous Drugs

cular blockade. Cochlear and vestibular dam-

age is the result of direct toxicity of these

Isoniazid (INH) has been associated with neu-

drugs. Auditory toxicity is more common with

rotoxic effects felt to be related to drug binding

the use of amikacin and kanamycin, whereas

of pyridoxine and resultant excessive vitamin

vestibular toxicity predominates following

excretion. A prominent polyneuropathy is as-

gentamycin and streptomycin therapy. To-

sociated with chronic INH administration, and

bramycin is associated equally with vestibular

symptoms include paresthesias; diminished

and auditory damage. The incidence of clinical

pain, touch, and temperature discrimination;

ototoxicity as a result of use of these drugs

and eventual weakness. Seizures, emotional

ranges from

5% to 25%, depending on

irritability, euphoria, depression, headache,

448

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

and psychosis rarely may occur. The neuro-

dine include, confusion, myoclonus, hallucina-

toxic reactions from INH use are dose related

tions, delirium, and seizures. As amantadine is

and are more common in “slow inactivators.”

excreted through the kidney, the presence of

In these patients, neurotoxic reactions can be

renal impairment may reduce its clearance,

prevented or diminished by the administration

causing it to accumulate in the body and result-

of pyridoxine at a dose of 50 mg daily. Patients

ing in amantadine toxicity.

who intentionally or inadvertently overdose

acutely with INH may develop severe ataxia,

generalized seizures, and coma. Supportive

OTHER COMMONLY PRESCRIBED

measures, anticonvulsants, and pyridoxine

ANTIBIOTICS

should be administered to these patients.

Rifamycin frequently is administered with

Sulfonamide, pyrimethamine, and trimethoprim

INH. Neurologic side effects are uncommon

are used mainly in the treatment of urinary tract

but may include headache, dizziness, inability

infections (UTIs). They generally are considered

to concentrate, and confusion. Less commonly,

safe drugs and are not associated with marked

signs of peripheral neuropathy may develop.

neurotoxicity. They may cause headache, fa-

Ethambutol precipitates a reversible optic neu-

tigue, tinnitus, and acute psychosis, however.

ritis as well as a more generalized peripheral

Some signs may mimic meningitis. On the sec-

neuropathy. A metallic taste in the oral cavity

ond or third day of therapy, patients may com-

frequently is associated with ethambutol ther-

plain of difficulty in concentrating and impaired

apy and may be due to the result of an impair-

judgment. Nitrofurantoin also is used com-

ment of receptor activity.

monly in the treatment of UTIs. A polyneuropa-

thy is the major toxic syndrome with this drug.

Like the Guillain-Barré syndrome, this neu-

Antiviral Drugs

ropathy is usually subacute and begins in the

The treatment of selected viral infections in in-

distal extremities, often with sensory complaints

dividuals who are not positive for the human

of paresthesias and numbness. The neuropathy

immunodeficiency virus

(HIV) has become

ascends and involves the motor system, with

possible over the past few years. The neuro-

progressive weakness and areflexia. Discontinu-

logic complications of HIV and the drugs used

ation of the drug is essential, and not all patients

to treat it will be discussed elsewhere.

will recover. The prognosis appears to relate

Acyclovir can be administered either intra-

most significantly to the extent of the neuropa-

venously or orally. Acyclovir is used orally for

thy at the time of drug withdrawal.

the treatment of localized or ophthalmic vari-

Tetracycline can be associated with pseudo-

cella zoster, treatment of minor herpes simplex

tumor cerebri or increased intracranial pres-

virus, and reducing the severity of varicella. It

sure. The syndrome is characterized by

is used intravenously to treat herpes encephali-

headache; papilledema; elevated spinal fluid

tis. Neurologic side effects rarely are associated

pressure; and, in babies, bulging fontanels. Sig-

with oral acyclovir. However, seizures, en-

nificant vestibular toxicity also has been associ-

cephalopathy, hallucinations, and coma have

ated with a tetracycline derivative, minocycline.

been described, as has tremor.

Erythromycin is probably the least toxic of

Amantadine has been used to prevent in-

the commonly used antibiotics from a neuro-

fluenza A infections. This agent appears to

logic perspective. An uncommon side effect is

have, in addition to its antiviral action, anti-

temporary hearing loss. Erythromycin interacts

cholinergic and dopaminergic effects, which

with carbamazepine; thus the anticonvulsant

has led to its use in mild Parkinson disease. The

levels increase rapidly when erythromycin is

neurologic side effects associated with amanta-

introduced.

449

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

Azithromycin, a macrolide antibiotic, also

demonstrates an axonal neuropathy. It may be

has been reported to cause hearing loss. Clar-

difficult to determine the origin of the neuropa-

ithromycin has been reported to precipitate an

thy because HIV infection also can cause a dis-

acute psychotic episode.

tal sensory neuropathy. The treatment includes

Nitrofurantoin therapy has been associated

removal of the offending agent. Myopathy of

with polyneuropathy. Generally seen with pro-

mitochondrial origin has been reported with

longed therapy, neuropathy can occur as early

both the nucleoside reverse transcriptase

as the first week of treatment. It is usually sub-

inhibitors and the nonnucleoside reverse tran-

acute, begins in the distal extremities with

scriptase inhibitors. This is a proximal sym-

paresthesias, and tends to progressively ascend

metric myopathy with a mitochondrial pattern

to involve the motor system with weakness and

of ragged-red fibers. Removal of the offending

areflexia. Although this polyneuropathy clini-

agent is the best treatment.

cally resembles Guillain-Barré syndrome, the

The major neurologic side effects of the

spinal fluid is usually normal, except that 25%

nonnucleoside reverse transcriptase inhibitors

of patients have a slight increase in protein

include dizziness, somnolence, diminished con-

without pleocytosis. When polyneuropathy is

centration, and confusion. The patient also

recognized, drug withdrawal is essential, al-

may experience psychiatric disturbances in-

though 10% to 15% of patients will not im-

cluding agitation, depersonalization, hallucina-

prove and 15% will have only partial recovery.

tions, insomnia, vivid dreams, depression, and

The prognosis appears to correlate with the ex-

euphoria. These symptoms are most severe at

tent of the neuropathy at the time of drug with-

initiation of therapy. They typically resolve

drawal but not to the total dose exposure or

with elimination of the offending medication.

the duration of therapy.

Among the different nonnucleoside reverse

transcriptase inhibitors, efavirenz has been

commonly associated with neurotoxicity.

ANTIRETROVIRAL MEDICATIONS

n SPECIAL CLINICAL POINT: People of

African descent with a variant of hepatic

Patients infected with HIV are living longer

enzyme CYP2B6 may experience slower

than before as the result of a better understand-

clearance of nonnucleoside reverse

ing of the disease process and newer pharmaco-

transcriptase inhibitors and increased

logic agents often used in combination to

neurotoxicity.

control viral loads. The currently available

classes of antiretrovirals for HIV infection in-

clude protease inhibitors, nucleoside reverse

transcriptase inhibitors, nonnucleoside reverse

TRANSPLANT DRUGS

transcriptase inhibitors, and fusion inhibitors.

Cyclosporine

New drug regimens support the use of concomi-

tant medications from each class in HIV-positive

Neurotoxicity is a well-recognized sequela of

individuals to prevent the complications of AIDS.

cyclosporine, and the most common complica-

Most of these agents can have headache as a side

tions are tremor and altered mental status.

effect.

Cyclosporine neurotoxicity can occur in 1 in 10

The major neurologic side effects of nucleo-

patients after liver transplantation. Behavioral

side reverse transcriptase inhibitors include pe-

signs include acute psychosis, restlessness, wide

ripheral neuropathy. This is typically a distal

mood swings with inappropriate crying and

symmetric predominantly sensory neuropathy

laughing, cortical blindness, visual hallucina-

and has been described with zalcitabine, di-

tions, stupor, and akinetic mutism. Addition-

danosine, and stavudine. Electromyography

ally, seizures, extrapyramidal symptoms, action

450

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

myoclonus, and quadriparesis have been re-

However, some patients have experienced perma-

ported. In patients with neurologic signs, cy-

nent or even fatal neurologic damage even after

closporine levels are usually outside the normal

discontinuation of tacrolimus. Occipital white

range, and after lowering the dose or withhold-

matter appears to be uniquely susceptible to

ing administration, neurotoxicity clears in most

the neurotoxic effects of tacrolimus as is the

cases. MRI abnormalities are consistent with

case with cyclosporine. Magnetic resonance

cortical or white matter high-signal changes

imaging has been reported to reveal bilateral

with a predilection for the occipital lobes. The

symmetric regions of signal abnormality with

mechanism of cyclosporine neurotoxicity has

abnormal contrast enhancement. The abnor-

not been fully elucidated. Both the clinical

mal signal was more evident in FLAIR (fluid-

manifestations and the neuroimaging abnor-

attenuated inversion recovery) sequences.

malities of cyclosporine neurotoxicity usually

Epilepsy and cerebral hemorrhage have been

resolve with a reduction or discontinuation of

reported to be associated with tacrolimus-

cyclosporine.

induced neurotoxicity.

Other Transplant Immunosuppressives

Other transplant immunosuppressives include

CARDIAC DRUGS

basiliximab, daclizumab, mycophenolate

Glycosides

mofetil, sirolimus and tacrolimus. Typical neu-

rologic effects of long-term immunosuppres-

Digitalis and related agents are the mainstay of

sion include infections such as meningitis,

treatment for congestive heart failure. Neuro-

encephalitis, and abscess formation and are

logic complications of digitalis therapy have

similar with the newer agents as they were with

been recognized for almost 200 years and are

the older ones. Direct neurologic toxicity is

characterized by nausea, vomiting, visual dis-

more common with tacrolimus, a calcineurin

turbances, seizures, and syncope. Adverse ef-

inhibitor-like cyclosporine, while the others

fects on the CNS reportedly occur in 40% to

exhibit toxicity that spares the nervous system.

50% of patients with clinical digitalis toxicity

Although tacrolimus may be a better im-

and may occur before, simultaneously with, or

munosuppressant than cyclosporine, its neuro-

after the signs of cardiac toxicity develop.

logic effects may be worse. In a multicenter,

The most frequent and often the first sign of

randomized, parallel-group study of 545 pa-

clinical intoxication is nausea, which appears to

tients undergoing primary liver transplanta-

be the result of central mechanisms rather than

tion, tacrolimus was associated with a higher

gastrointestinal irritation. The incidence of

incidence of neurologic symptoms than cy-

digitalis-related visual disturbances has been es-

closporine. The risk of tacrolimus-treated pa-

timated at 40%, and although these symptoms

tients developing tremor was related to the

may occur as an isolated symptom, they usually

initial IV dose, the rate of administration, and

occur concomitantly with other toxic signs.

the total daily dose. Headache was signifi-

Blurred vision, reversible scotomas, diplopia,

cantly correlated with dose, while insomnia

defects of color vision, and total amaurosis rep-

was not. Factors that may promote the devel-

resent the spectrum of optic side effects.

opment of serious complications include

Seizures most commonly are seen in pedi-

advanced liver failure, hypertension, hypocho-

atric patients. The incidence of digitalis-related

lesterolemia, elevated serum levels, hypomag-

seizures is difficult to estimate because other

nesemia, and methylprednisone. The symptoms

seizure etiologies (e.g., arrhythmia) are so high

may be reversed by reducing the dose of

in cardiac patients. Transient mental aberra-

immunosuppressant or by discontinuation.

tions felt to be caused by intermittent cerebral

451

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

hypoperfusion resemble transient global amne-

influences can cause syncope, vertigo, and res-

sia. Syncope, probably the result of conduction

piratory arrest (on rare occasions).

delay or hyperactivity of baroreceptors, also

Lidocaine-induced CNS toxicity occurs

has occurred in digitalis toxicity. Other neuro-

commonly and may relate to its rapid absorp-

toxic reactions include facial neuralgia, pares-

tion across the blood-brain barrier. The syn-

thesias, headache, weakness, and fatigue.

drome appears to relate to a diffuse excitement

Cerebral symptoms consisting of confusion,

of neuronal systems, with an early prodrome of

delirium, mania, and hallucinosis have been re-

altered behavior. Garrulousness and loss of in-

ported in as many as 15% of patients with dig-

hibitions may be the prominent feature, as may

italis toxicity. Although the mechanism for the

agitation or psychosis. Circumoral numbness,

symptoms is unknown, it is felt that they are

diplopia, and tinnitus also may occur, with

not the result of altered cardiac function.

progressive muscle twitches and tremors. Gen-

eralized myoclonic seizures and finally CNS

and respiratory depression are seen with higher

Antianginal Agents

doses. In both cardiac and surgical patients,

Nitroglycerin and nitrate therapy frequently is

hypoxia and acidosis develop rapidly if the li-

associated with headache. According to cur-

docaine syndrome is not reversed. Treatment

rently proposed mechanisms, nitric oxide is the

focuses on adequate oxygenation and support

common mediator in experimental vascular

because the half-life of bolus lidocaine given

headaches. Nitroglycerin produces a throbbing

acutely is 6 to 8 minutes. Because repeated in-

or pulsating sensation in many patients and an

jections change the kinetics of lidocaine and

overt headache in many others. Often, the

prolong its half-life to approximately 90 min-

headaches attenuate or disappear with time,

utes, however, more long-lasting effects can be

but 15% to 20% of patients will not be able to

seen.

tolerate long-acting nitrates because of headache.

Procainamide may cause light-headedness

Patients should be encouraged to use analgesics

and even syncope because of the hypotensive

during the initial days or weeks of nitrate ther-

action. Additionally, a lupus erythematosus syn-

apy and should be educated as to the nature of

drome can develop in patients taking pro-

this problem and its probable resolution with

cainamide, and 80% of patients receiving the

time.

drug for 6 months have antinuclear antibodies;

Nitroglycerin therapy can cause dose-

these antibodies clear with the withdrawal of

related increases in intracranial pressure,

the agent. During lupus-like syndrome, en-

which in rare cases can result in a clinically

cephalopathy with confusion and agitation can

overt syndrome. Furthermore, the hypotensive

develop. Procainamide also has a curare-like ef-

effects of nitroglycerin can result in dizziness

fect at the neuromuscular junction and hence can

and light-headedness or even syncope.

precipitate myasthenia gravis or exacerbate it.

Tocainide hydrochloride is an antiarrhyth-

mic agent that is structurally and pharmacolog-

Antiarrhythmics

ically similar to lidocaine, except that it is well

Quinidine is used mainly to treat atrial fibrilla-

absorbed when given orally. Tocainide has been

tion. Nervous system manifestations are usu-

proven effective in managing various ventricu-

ally not significant, but with overdosage or in

lar arrhythmias; however, because it crosses

susceptible individuals the following may

the blood-brain barrier, it frequently causes

occur: headache, nausea, vomiting, blurring of

several neurologic side effects, which include

vision, ringing of the ears, flushing, palpita-

light-headedness, dizziness, tremor, twitching,

tions, and even convulsions. A precipitous de-

paresthesias, sweating, hot flashes, blurred vi-

crease in blood pressure related to vagal

sion, diplopia, and mood changes. Peak plasma

452

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

concentrations of tocainide occur within 1 to 2

none had sensory or long-tract abnormalities

hours of ingestion; the plasma half-life is 12 to

on examination. Peripheral neuropathy associ-

15 hours in patients with unimpaired renal and

ated with this drug was first reported in 1974

hepatic systems. CNS side effects appear to be

and continues to account for a significant por-

linearly related to the dose.

tion of the neurologic toxicity reported today.

Bretylium is a parenteral antiarrhythmic

The neuropathy is sensorimotor in type and

drug used in the prophylaxis and treatment of

generally causes numbness and tingling of all

ventricular fibrillation and life-threatening

four extremities. Proximal weakness occasion-

ventricular arrhythmias that do not respond to

ally accompanies the paresthesias. Sural nerve

first-line agents such as lidocaine. The antiar-

biopsies have been examined and have re-

rhythmic mechanisms of bretylium in humans

vealed demyelination with mild axonal loss in

are not clearly defined, but in animals it in-

some cases. Lamellated inclusions of lysoso-

creases the ventricular fibrillatory threshold

mal origin were found in all cell types in the

and also the action potential duration and ef-

nerves and are a characteristic finding of this

fective refractory period. It induces a state of

neuropathy.

chemical sympathectomy.

The most significant side effect of this drug

Diuretics

is severe supine and orthostatic hypotension.

Patients report dizziness, light-headedness, ver-

Diuretics are divided into three principal

tigo, and faintness. Bretylium may also rarely

groups: thiazide, loop, and potassium sparing.

cause flushing, hyperthermia, confusion, para-

Diuretics most frequently cause extracardiac

noid psychosis, mood changes, anxiety,

side effects as a direct result of the electrolytes

lethargy, and nasal stuffiness.

lost or retained in the renal system. Each

Amiodarone is an orally effective antiar-

group, however, can cause adverse effects that

rhythmic drug that, like bretylium, slows repo-

are linked indirectly to electrolyte and water

larization in various myocardial fibers and

balance.

raises the threshold for ventricular fibrillation.

The thiazide diuretics have been reported to

Early reports of adverse effects include corneal

cause syncope, acute muscle cramps and pain,

microdeposits, thyroid dysfunction, and cuta-

hyporeflexia, weakness, flaccid paralysis, and

neous photosensitivity. However, toxic neuro-

epileptiform movements. The deterioration of

logic side effects now have been described, and

mental function, including the development of

in a series of 54 patients studied, these side ef-

coma, can be precipitated with thiazide admin-

fects were the most common reason for either

istration in patients being treated for cirrhosis.

altering or discontinuing amiodarone therapy.

Thiazides given concomitantly with triamterene

A reversible syndrome of tremor, ataxia,

and amantadine can increase the likelihood of

and peripheral neuropathy without nystagmus,

neurotoxicity from the amantadine.

dizziness, encephalopathy, or long-tract signs

If loop diuretics, particularly furosemide,

developed in 54% of these patients. Tremor oc-

are given quickly and in high doses, they can

curred earliest and most frequently (29%). The

cause deafness and paresthesias. If they are

6- to 10-Hz flexion-extension movements in

given to a patient who also is receiving lithium

the fingers, wrists, and elbows were indistin-

chronically, loop diuretics can alter the renal

guishable from essential tremor. Of the pa-

clearance of lithium and increase the risk of

tients,

37% reported ataxia associated with

lithium toxicity and fluid electrolyte abnormal-

falls, staggering, and difficulty in dressing the

ities. Loop diuretics also potentially can in-

lower limbs. The ability to walk was seriously

crease the success with which succinylcholine

impaired in 18% of the patients. None of these

blocks the neuromuscular junction in anes-

patients had preexisting gait problems, and

thetized patients.

453

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

Potassium-sparing diuretics,

including

pronounced after the first dose(s) or in

spironolactone and triamterene, have been re-

patients who have had a hiatus from the drug

ported to cause confusion, drowsiness, muscle

and are reinstituting treatment. Hypoten-

weakness, paresthesias, dizziness (although this

sion can be minimized if the initial dose

may be a result of cardiac rhythm changes), and

is small and is given at bedtime. Other CNS

headache.

side effects include headache, dry mouth,

nasal stuffiness, lassitude, hallucinations,

depression, paresthesias, nervousness, and

Sympatholytics

priapism.

Clonidine is an alpha 2-noradrenergic agonist,

and some have suggested that this drug induces

Vasodilators

an overall decrease in norepinephrine release,

possibly through a presynaptic mechanism. Se-

Hydralazine is the only direct-acting vasodila-

dation is the most common adverse neurologic

tor generally available for the treatment of

effect of clonidine. Other less common neuro-

chronic hypertension. The neurologic side ef-

toxic reactions include depression, nightmares,

fects of hydralazine are few and uncommon in

and reversible dementia syndrome.

clinical practice. Peripheral neuropathy charac-

Neuropsychiatric symptoms occur fre-

terized by diffuse numbness and tingling is the

quently during treatment with beta blockers.

only consistent neurotoxic reaction and is felt

The pharmacology of CNS side effects is un-

to be the result of a direct toxic effect of the

clear, although presynaptic and postsynaptic

drug.

adrenergic inhibition has been implicated, as

Calcium channel blockers, particularly flu-

has serotonergic antagonism. Nonselective beta

narizine and cinnarizine, have been associated

blockers seem to cause CNS-related side effects

with dystonia, parkinsonism, akathisia, and

to a greater extent than beta 1-selective blockers.

tardive dyskinesia

(TD). Theoretic explana-

It is unclear to what degree lipophilicity is re-

tions for these events include the inhibition of

sponsible for this kind of side effect. Lassitude or

calcium influx into striatal cells and direct

insomnia and depression are the most common

dopaminergic antagonistic properties. Evi-

reactions, although vivid dreams, nightmares,

dence also suggests that inhibition of proton

hypnagogic hallucinations, and psychotic behav-

pumping and catecholamine uptake are possi-

ior have been reported with high doses (more

ble mechanisms. In addition, the chemical

than 500 mg/day of propranolol). Preexisting

structures of flunarizine and cinnarizine, which

major psychiatric illness and hyperthyroidism

are related to neuroleptics, may explain the

may predispose to the previously mentioned

greater incidence of such side effects with these

symptoms.

agents compared with those of calcium channel

Prazosin competitively blocks the vascular

blockers available in the United States. Sug-

postsynaptic alpha-adrenergic receptors and is

gested risk factors appear to be advanced age

the first of a class of similar antagonists derived

and a family history of tremors or Parkinson

from quinazoline. The selective affinity of pra-

disease, or both. The onset and type of presen-

zosin for alpha-receptors allows it to block the

tation are unpredictable. The long-term evolu-

contractile response of vascular smooth muscle

tion was assessed in a prospective follow-up

to norepinephrine, consequently lowering mean

study of 32 patients with diagnoses of calcium

arterial pressure and peripheral resistance. Like

channel blocker-induced parkinsonism. Eight-

other antihypertensives that cause vasodilata-

een months following discontinuation of the

tion, prazosin causes hypotension; dizziness

offending agent, 44% of the patients had de-

and faintness have been reported in up to 50%

pression, 88% had tremor, and 33% still had

of patients receiving this drug. These are most

criteria for diagnosis of parkinsonism.

454

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

Angiotensin-Converting Enzyme Inhibitors

concomitant medication use and medical con-

ditions that alter statin metabolism as well as

Angiotensin-converting enzyme inhibitors have

the patient’s underlying genetic constitution.

been used in the United States to treat moder-

According to findings from 21 clinical trials

ate to severe hypertension, based on its effect on

providing 180,000 person-years of follow-up

the renin-angiotensin-aldosterone (RAA) axis.

in patients treated with statin or placebo, my-

This cascading hormonal axis simultaneously

opathy (defined as muscle symptoms plus cre-

maintains systemic arterial pressure and sodium

atine kinase [CK] >10 times the upper limit of

balance by detecting and correcting even small

normal) occurs in 5 patients per 100,000 per-

changes in renal perfusion. Alongside the in-

son-years and rhabdomyolysis in 1.6 patients

creased understanding of the RAA axis has

per 100,000 person-years (placebo corrected).

come the discovery of drugs that specifically and

The most common muscle side effects remain

selectively inhibit the RAA cascade.

myalgia (i.e., muscle pain or soreness), weak-

Few neurologic side effects have been re-

ness, and/or cramps without CK elevations.

ported; however, in a large multinational study,

These symptoms are most often tolerable, but

5% of the participating patients reported

occasionally can be intolerable and debilitat-

symptoms of hypotension, including dizziness,

ing, requiring the statin to be withdrawn.

light-headedness, and vertigo. These symptoms

Muscle symptoms have been reported in clini-

were generally transient and mild and most

cal trials to occur in 1.5% to 3.0% of patients

frequently occurred in patients who were

receiving statin therapy, most often without

sodium or water depleted. Dysgeusia occurred

an elevation in the CK level, and at an equiv-

in 2% to 4% of patients participating in this

alent rate in patients given placebo. The inci-

small trial. The incidence of taste change or

dence of muscle complaints among patients

loss increased in patients with impaired renal

being treated in a practice setting ranges from

function.

0.3% to 33% (Bays, 2006). The higher rate

may occur partly because statin-intolerant pa-

tients and those with risk factors for muscle

Cholesterol-Lowering Agents

toxicity are more likely to be excluded from

Clofibrate, an aromatic monocarboxylic acid,

clinical trials.

is capable of inducing myotonia in humans and

n SPECIAL CLINICAL POINT: The potential

experimental animals and is clinically signifi-

of different statins for myotoxicity may be

cant because it is widely used to reduce serum

altered by concomitant medications that alter

triglyceride levels. The mechanism by which it

their metabolism.

induces myotonia is believed to be through a

decrease in chloride conductance.

HMG-CoA reductase inhibitors or statins

have been implicated in causing toxic myopa-

GASTROINTESTINAL AGENTS

thy. Statin myotoxicity ranges from asympto-

matic creatine kinase elevations or myalgias

Common gastrointestinal problems include the

to muscles necrosis and fatal rhabdomyolysis.

hypermotility disorders with vomiting and/or

Statins may also cause an autoimmune my-

diarrhea; hypomotility disorders, with consti-

opathy requiring immunosuppressive treat-

pation; or excessive acid secretion leading to

ment. The mechanisms of statin myotoxicity

“heartburn” or ulcerations. A wide variety of

are unclear. If unrecognized in its early mani-

drugs commonly are recommended for these

festations, complications from continued

disorders. Fortunately, neurologic complica-

statin therapy may lead to rhabdomyolysis

tions from these frequently prescribed agents

and death. Risk factors for myotoxicity are

are infrequent.

455

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

Laxatives

basis, as in the treatment of chronic esophageal

reflux, the potentially irreversible symptoms of

There are only a few neurologic complications

TD even may occur.

associated with the drugs used to treat consti-

pation. Docusate sodium (Colace) is a stool sof-

n SPECIAL CLINICAL POINT:

tener that occasionally causes nausea or a bitter

Metoclopramide (Reglan), prochlorperazine

taste. The long-term use of nonprescription lax-

(Compazine), and promethazine (Phenergan)

atives may cause neurologic complications aris-

induced parkinsonism may take up to 6 months

ing secondary to depletion of electrolytes.

to reverse after discontinuation of the

Profound muscle weakness may occur from the

medication.

potassium depletion following chronic laxative

A different type of agent with predominantly

intake. The irritant purgatives, such as cascara,

anticholinergic effect, scopolamine, is pre-

may damage the myenteric plexus of the colon,

scribed for the treatment of motion-induced

leading to a reduction of intestinal motility and

nausea and vomiting. Scopolamine has become

a worsening of constipation.

available in a long-acting, transdermal patch

preparation. The neurologic side effects of

scopolamine are those associated with block-

Antiemetics

ade of muscarinic receptors. The most frequent

Of the antiemetic drugs, several commonly

is xerostomia. The reduction in saliva produc-

prescribed agents act as dopamine receptor

tion, if severe, can lead to mucosal ulcerations

blockers in a similar fashion to the neuroleptic

and dental problems. Other peripheral effects

drugs described later. Metoclopramide (Reglan),

of scopolamine include blurred near vision re-

prochlorperazine

(Compazine), and promet-

sulting from alterations in accommodation, re-

hazine

(Phenergan) are three widely used

duced sweating, and urinary retention from

antiemetics with neuroleptic properties. Sedation

effects on bladder muscles. A potentially irre-

may occur as an early complaint with the intro-

versible effect of the anticholinergic agents is

duction of these agents. In addition, acute dysto-

the exacerbation of closed-angle glaucoma

nia, with distressing involuntary spasms of head,

with the potential for causing blindness.

neck, eyes, facial, and trunk muscles, may occur,

The CNS side effects of these drugs include

particularly in children treated with prochlorper-

sedation and confusion. Losses in recent and

azine. If not recognized by the clinician, these

immediate memory can occur at high doses. Fi-

acute, sometimes bizarre, symptoms may be in-

nally, with toxicity, delirium and hallucinations

accurately thought to have a psychogenic etiol-

have been described.

ogy. The treatment of the acute dystonia from

the dopamine receptor-blocking antiemetics is

Antidiarrheals

the administration of anticholinergic agents.

In addition to acute dystonia, these dopamine

Drugs used to symptomatically alleviate diar-

receptor antagonist, antiemetic agents may cause

rhea frequently contain morphine or morphine

a parkinsonian syndrome, clinically indistin-

derivatives. These compounds act to reduce the

guishable from idiopathic Parkinson disease.

propulsive contractions of the small bowel and

Those of more advanced age appear to be more

colon. The neurologic adverse effects from these

susceptible to this neurologic complication and

agents include sedation, respiratory depression,

may even be treated with antidopaminergic

and coma, typically with pupillary constriction.

agents if the symptoms are not recognized as

Anticholinergic agents also have been used

being associated with the medication. Akathisia

to treat symptoms of diarrhea. Diphenoxylate-

also may occur as a side effect of these medica-

atropine

(Lomotil) is a widely prescribed

tions. If these agents are used on a long-term

antidiarrheal agent. Overdoses of this agent

456

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

most frequently cause a predominantly opioid

effect of cimetidine—and, to a lesser degree, the

intoxication.

other H₂ blockers—on the cytochrome P450 en-

Some antidiarrheal compounds (e.g., Don-

zymes in the liver may alter the pharmacokinetic

natal) are combinations of morphine deriva-

profile of other drugs undergoing hepatic degra-

tives and from one to three different

dation, including warfarin and phenytoin.

anticholinergic agents. Donnatal contains phe-

nobarbital, hyoscyamine, atropine, and scopo-

lamine. Although each component is present

only in small amounts, patients taking several

RESPIRATORY AGENTS

tablets a day or elderly persons may experience

Adrenergic Drugs

significant side effects.

Bismuth compounds, as found in the nonpre-

Of the three types of adrenergic receptors

scription bismuth subsalicylate (Pepto-Bismol),

(alpha, B1, B2), it is the B2 receptor that medi-

have been recommended for the treatment of

ates bronchodilation. The first sympathomimet-

“traveler’s diarrhea.” The neurologic sequelae of

ics available for the treatment of asthma were

these agents are rare. There have been reports of

not B2 selective (metaproterenol, isoproterenol,

an acute reversible psychotic reaction following

epinephrine, ephedrine); therefore, in addition

excessive use of these compounds as a result of

to dilating the bronchioli, they also produced

acute bismuth toxicity. More commonly, tinnitus

significant cardiac and CNS effects. The intro-

is noted with large doses, arising from the salicy-

duction of B2-selective agents (albuterol, terbu-

late component in this compound.

taline) resulted in a reduction in the number of

adverse effects. These agents are administered

most efficiently by inhalation, resulting in bene-

Antiacidity Agents

fit with minimal side effects. When these agents

The magnesium and aluminum antacids, if

are administered parenterally, there may be nau-

taken in large quantities or with renal impair-

sea, vomiting, headache, and a variable-ampli-

ment, may cause neurologic symptoms second-

tude postural and action tremor associated with

ary to alteration in electrolytes. Sucralfate is an

these agents.

aluminum compound that coats the gastric

mucosa. Although little of this agent is ab-

Xanthine Bronchodilators

sorbed directly, sucralfate may reduce the ab-

sorption of phenytoin and, in those taking this

The xanthine compounds include amino-

anticonvulsant, may result in a drop in pheny-

phylline and theophylline. These agents now

toin levels below the therapeutic range.

are prescribed only for those patients suffering

The H₂ receptor antagonists inhibit acid se-

with chronic rather than intermittent symp-

cretion from the parietal cells. Currently, four H₂

toms of bronchoconstriction. Theophylline is

receptor antagonists are approved for use in the

metabolized primarily in the liver, and drugs

United States. Cimetidine (Tagamet) was the first

that affect hepatic enzymes, including tobacco,

to be developed. More recently developed H₂ re-

may alter the metabolism of theophylline.

ceptor antagonists include ranitidine (Zantac),

Liver disease, heart failure, and pulmonary dis-

nizatidine (Axid), and famotidine (Pepcid). The

ease tend to slow the metabolism of theo-

neurologic complications of these medications

phylline, sometimes resulting in toxicity even

include lethargy, confusion, depression, halluci-

at low dosages. The therapeutic serum concen-

nations, and headache. Individuals treated with

tration of theophylline is 10 to 20 mg/mL. The

these drugs who develop unexplained en-

side effects from theophylline tend to be dose

cephalopathic symptoms may improve with the

related. However, even in the therapeutic

discontinuation of these agents. Additionally, the

range, neurologic side effects may occur. These

457

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

include nausea, nervousness, insomnia, and

and anti-alpha 1-adrenergic properties. The

headache. Although usually associated with

newer, so-called atypical agents include clozap-

toxic levels of theophylline, seizures also may

ine, olanzapine, quetiapine, and risperidone.

occur in the high therapeutic range, particularly

Many newer agents have some affinity for

in the elderly or those with a history of previous

5-HT₂ serotonin receptors as well (clozapine,

brain injury. This latter group is likely to develop

risperidone). The atypical neuroleptic agents

prolonged seizures with a poor outcome. The

have become favored because of their lower ex-

mechanism of theophylline-induced seizures is

trapyramidal side effect profile. Many newer

not clearly understood. In otherwise healthy

agents have some affinity for 5-HT₂ serotonin

asthmatics, the seizures are typically short lived

receptors as well (clozapine, risperidone). Neu-

with a good outcome. A recently described neu-

roleptics, as a class, are associated with a vari-

rologic side effect observed in children is the oc-

ety of important neurologic complications.

currence of acquired stuttering, which resolves

These can be classified as acute, subacute, and

with the discontinuation of this drug.

chronic side effects (Fig. 22.1).

Neuroleptics may cause a toxic confusional

state, especially in the elderly, and confusion

occurs more frequently with the low-potency,

PSYCHIATRIC DRUGS

high-anticholinergic activity subclass

(chlor-

promazine, thioridazine, mesoridazine). These

Neuroleptic Agents

drugs also can produce profound sedation, es-

The neuroleptic agents or major tranquilizers

pecially with initiation of therapy.

exert their antipsychotic activity by blocking

Neuroleptics also lower the seizure thresh-

dopaminergic receptors at the level of the lim-

old and have been associated with exacerba-

bic system, forebrain, and basal ganglia. They

tion of preexisting epilepsy as well as the

also have antihistaminergic, anticholinergic,

de novo appearance of seizures. Clozapine

NEUROLEPTIC

NEUROTOXICITY

ACUTE

SUBACUTE

TARDIVE

Within hours to days

Within weeks

Within months

(at least 3 months on

treatment)

• Akathisia

• Parkinsonism

• Akathisia

• Dystonia

• Neuroleptic

• Chorea*

• Encephalopathy

malignant

• Dystonia

• Lowering of seizure

syndrome

• Myoclonus

threshold

• Tics

• Neuroleptic malignant

syndrome

*classic tardive dyskinesia.

FIGURE 22.1 Acute, subacute, and chronic side effects of neuroleptic agents.

458

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

has been associated with generalized and

cludes ceasing of the offending agent, providing

myoclonic seizures. Seizures were present

supportive measures, and administering dantro-

during the titration phase at low dosages

lene or bromocriptine or a combination of

(<300 mg/day) and at high dosages during the

the two.

maintenance phase (600 mg/day).

Acute neuroleptic-induced dystonia can be

Neuroleptic malignant syndrome (NMS) is

seen early in the course of neuroleptic therapy

associated with neuroleptic use. The pathogen-

or with dose increases. It often is seen following

esis of NMS is not completely understood.

a single parenteral dose of neuroleptics. The

Alterations in dopaminergic transmission,

manifestations can be diverse, although the

changes in sympathetic outflow, alterations in

most typical clinical signs involve oculogyric

central serotonin metabolism, and abnormali-

crises and opisthotonic posturing. Risk factors

ties in muscle membrane function have been

include young age, male gender, and use of

implicated. NMS has been associated with all

high-potency neuroleptics. Acute dystonic reac-

groups of neuroleptics, although high-potency

tions are self-limited, and if they are left un-

agents, specifically haloperidol and fluphena-

treated, they usually subside within 24 hours.

zine, have been cited most frequently. NMS has

Parenteral administration of anticholinergics,

been described with the atypical neuroleptic

such as benztropine or diphenhydramine, offers

medications, clozapine, risperidone, and olan-

immediate relief in the majority of cases, but

zapine. NMS tends to occur with the initiation

oral anticholinergics should be continued for a

of treatment or increases in dose and is more

few days until the causative neuroleptic is

common with depot forms of neuroleptics. Af-

cleared.

fective disorder, concomitant lithium carbon-

Akathisia is a severe form of restlessness as-

ate administration, psychomotor agitation,

sociated with the need to move. Typically, the

dehydration, exhaustion, and mild hyperther-

patient paces incessantly in place and cannot sit

mia seem to increase susceptibility toward this

down without continual volitional movement

condition. The principal features of NMS are

of the legs or feet. The pathophysiology of the

hyperthermia, muscle rigidity, autonomic dys-

syndrome is not well understood but may relate

function, and mental status changes. Labora-

to the development of acute imbalance between

tory findings include elevated creatine kinase;

the dopaminergic and cholinergic systems. This

polymorphonuclear leukocytosis; elevated al-

neuroleptic side effect usually occurs within the

dolase, alkaline phosphatase, lactic dehydroge-

first days of therapy or with dose increases,

nase (LDH), alanine aminotrans ferase (ALT),

and it resolves with withdrawal of the neu-

and aspartate aminotransferase (AST); hypocal-

roleptic agent. Anticholinergics, amantadine,

cemia; hypomagnesemia; low iron; protein-

beta blockers, clonidine, and benzodiazepines

uria; and myoglobinuria. Approximately 40%

also have been used with variable success. Late-

of patients with NMS develop medical compli-

onset akathisia may be a form of TD and may

cations that may be life threatening. NMS is a

be more difficult to treat.

clinical diagnosis based on the presence of the

Neuroleptic-induced parkinsonism is the

proper historical setting and the characteristic

result of striatal dopaminergic underactivity re-

constellation of signs. Disorders with similar

sulting from dopaminergic D₂ receptor block-

features include malignant hyperthermia; heat

ade. Clinically, it cannot be distinguished from

stroke induced by neuroleptics; lethal catato-

idiopathic Parkinson disease, although its de-

nia; other drug reactions; and vascular, infec-

velopment occurs as a subacute syndrome

tious, or postinfectious brain damage.

within the first weeks of drug introduction or

NMS is a potentially fatal disease, and a

drug dosage increase. Parkinsonian symptoms

high index of suspicion is required for early

resolve over a few weeks to 6 months after

recognition and intervention. Treatment in-

stopping the causative agent or with the use of

459

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

antiparkinsonian drugs. Proposed risk fac-

ued, if possible. Alternatively, the patient should

tors for development of neuroleptic-induced

be switched to an atypical neuroleptic such as

parkinsonism are female gender, older age, and

clozapine, which not only does not regularly

the use of high-potency agents. Treatment con-

cause TD but may even improve its symptoms.

sists of discontinuing or reducing the dose of

If neurologic impairment, disfigurement, or dis-

the offending agent. A lower-potency neurolep-

comfort exists, treatment with the dopamine de-

tic or one of several novel neuroleptics that

pleters reserpine or tetrabenazine should be

lack prominent striatal receptor blockade, such

considered. Noradrenergic antagonists (propra-

as clozapine, can be substituted. Anticholiner-

nolol, clonidine); gamma-aminobutyric acid

gics, amantadine, and electroconvulsive ther-

(GABA) agonists (clonazepam, diazepam, val-

apy are also possible treatments.

proate, baclofen); botulinum toxin injections;

TD usually appears after several months

and to a lesser degree, vitamin E, buspirone, and

or years of treatment with antipsychotic med-

calcium channel blockers have been used with

ications and almost never before 3 months. No

variable success.

consistent neuropathologic changes have been

seen in patients with TD, and the predominant

Anxiolytics

hypothesis for its genesis is denervation super-

sensitivity of the striatal dopamine receptors

Benzodiazepines are commonly prescribed

following chronic blockade. Risk factors for

anxiolytic agents. The therapeutic index of

the development of TD include old age; female

these agents is 10 to 30 times that of the barbi-

gender; presence of affective disorders; history

turates and, hence, their absolute toxicity is

of neuroleptic-induced parkinsonism; presence

less. However, because these agents are so

of organic brain disease; high-potency neu-

widely used, adverse reactions frequently are

roleptics use; sufficient duration of treatment

reported. The predominant toxic symptom is

with neuroleptics; and possibly the use of anti-

drowsiness or paradoxical excitation. With-

cholinergic medications, previous electrocon-

drawal seizures also have been reported. Dry

vulsive treatment, and drug holidays.

mouth, tachycardia, dilated pupils, and de-

In addition to the well-known oral-buccal-

pressed bowel sounds may occur early after the

lingual masticatory movements and general-

introduction of benzodiazepines because of

ized chorea, dystonia, akathisia, tics, and

possible anticholinergic effects. Withdrawal

myoclonus have been described. Once TD has

symptoms include excessive apprehension,

appeared, its peak severity is reached rapidly

anorexia, nausea, postural tremulousness, in-

and often is maintained. Following neuroleptic

somnia, and confusion. Withdrawal symptoms

withdrawal, TD may transiently worsen, but

are best handled in the hospital, and barbitu-

this exacerbation is short lived. TD resolves in

rates usually are substituted.

up to 33% of patients within 2 years after

discontinuation of the offending agent. A

Antidepressant Agents

prospective study comparing risperidone and

haloperidol in 350 neuroleptic-naive patients,

Tricyclic antidepressants

(TCAs) induce an

however, showed that each drug had a similar

acute encephalopathy that is characterized by

incidence of dystonia, parkinsonism, akithisia,

agitation, confusion, mydriasis, and sometimes

and dyskinesia.

convulsions. Tremor and myoclonus may be

At present, prevention is the treatment of

prominent motor features of this syndrome.

choice for TD. Therefore, neuroleptic agents

Medical complications of these drugs include

should be used only when specifically needed

complex cardiac arrhythmias and heart block.

and at the lowest possible doses. Once TD de-

Generalized support measures should be insti-

velops, the causative agent should be discontin-

tuted for the patient who takes an overdose of

460

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

TCAs. Physostigmine, a centrally active

sion, it is difficult to draw conclusions; how-

cholinesterase inhibitor, 1 to 2 mg given IV,

ever, it is difficult to exclude the possibility that

often will awaken a patient from coma. This

suicidal ideation occurs as a rare adverse reac-

finding suggests that much of the toxic mental

tion with some drugs.

alteration relates directly to central anticholin-

SSRIs have been shown in vitro and in vivo to

ergic toxicity.

inhibit the P450 system and therefore to result

TCAs also may precipitate a more chronic

in increased levels of drugs that are substrates of

neurotoxic syndrome in which tremor and se-

P450 as well (e.g., TCAs). There has been de-

dation or insomnia are the prominent features.

bate over whether the combination of SSRIs and

The tremor is usually postural or intentional

monoamine oxidase (MAO) inhibitors or TCAs

and resembles that seen with amphetamine in-

can lead to the serotonin syndrome character-

toxication or use of lithium. Currently, most

ized by hyperpyrexia, myoclonus, rigidity, hy-

TCAs can be monitored with plasma levels, so

perreflexia, shivering, confusion, agitation,

that intoxication can be detected at early

restlessness, coma, autonomic instability, nau-

stages.

sea, diarrhea, diaphoresis, flushing, and (rarely)

Newer-generation TCAs have been devel-

rhabdomyolysis and death. This occurrence is

oped to be more selective for the noradrenergic

probably very uncommon but should be

or serotonergic systems. Many of these agents

watched for and handled immediately with sup-

(e.g., trimipramine, amoxapine, or maproti-

portive care and drug withdrawal if it occurs.

line), however, still have significant anticholin-

Several case reports in the literature suggest that

ergic side effects, including blurred vision,

SSRIs can produce extrapyramidal symptoms in

urinary retention, and confusion. Trazodone

the form of akathisia, dyskinesia, acute dysto-

can cause priapism.

nia, and deterioration in Parkinson disease, but

Selective serotonin reuptake inhibitors

controlled clinical studies are needed to deter-

(SSRIs) are potent and selective inhibitors of

mine the validity of these observations.

serotonin reuptake at the presynaptic terminal.

MAO inhibitors are drugs that have been

They currently are considered first-line therapy

used for decades in the treatment of depres-

for depression because of their prescribing ease

sion. The characteristic of acute MAO in-

and superior side effect/safety profile. SSRI-

hibitor intoxication is hyperpyrexia, with

induced side effects are usually transient and

fevers as high as 108°F. Coma, tachycardia,

rarely result in discontinuation of the medica-

tachypnea, dilated pupils, and profuse sweat-

tion. In addition, they appear to be safer than

ing occur. Rapid recovery after hemodialysis

TCAs in overdose.

suggests that this means of therapy is effective.

The major CNS side effects of the SSRIs in-

A second cataclysmic syndrome is the hyper-

clude nausea, headache, dry mouth, insomnia/

tensive crisis associated with combined use of

somnolence, agitation, nervousness, sweating,

MAO inhibitors and tyramine products or

dizziness, tremor, myoclonus, and sexual dys-

other centrally active agents. Cheese, chicken

function. Fluoxetine often is associated with

livers, chocolate, wine, and some forms of her-

anxiety, nervousness, insomnia, and anorexia.

ring have been associated with this syndrome

Paroxetine, fluvoxamine, and nefazodone are

in patients ingesting MAO inhibitors. Much

associated with sedation. Sexual dysfunction

less dramatic and also more common are mild

manifests itself as ejaculatory delay in men and

side effects, such as mild dizziness, a general-

anorgasmia in women. There have been re-

ized weakness, dysarthria, and confusion,

ports suggesting that fluoxetine can induce or

which can occur in patients receiving therapeu-

exacerbate suicidal tendencies, and several

tic doses of these agents.

mechanisms have been proposed. However, be-

Lithium carbonate is well established as an ef-

cause suicide is an important feature of depres-

fective agent in the treatment of manic-depressive

461

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

illness. Neurotoxic effects are not rare, and the

the drugs already mentioned, methaqualone

most common and annoying effect is a fine

with alcohol may have addictive sedating ef-

postural intention tremor, which may be seen

fects. Other drug interactions include en-

even in therapeutic doses. A reduction of the

hanced effect of MAO inhibitors and TCAs.

dosage usually either will eliminate the tremor

Delirium and marked myoclonus also may

or significantly reduce its intensity. The beta-

occur in patients who acutely overdose with

adrenergic blocker propranolol may prove

these drugs.

beneficial. Toxic confusional states also may

Disulfiram is used in the rehabilitation of al-

occur with lithium, and, if this develops,

coholics because high levels of acetaldehyde ac-

lithium blood levels should be checked. Ataxia,

cumulate when alcohol is ingested with the drug.

seizures, and coma can occur at high doses

Chronic disulfiram therapy is associated with two

(serum levels exceeding 2.0 mEq/L). There is

distinct neurotoxic syndromes, an encephalopa-

no specific antidote for severe lithium intoxica-

thy and a neuropathy. The encephalopathy is usu-

tion. After severe intoxication, residual symptoms

ally acute or subacute in onset, characterized by

including ataxia, nystagmus, choreoathetoid

delirium and paranoid and psychotic behavior,

movements, and hyperactive deep tendon reflexes

and it often is confused with the diagnosis of

have been reported.

schizophrenic reaction. The behavioral re-

sponse to neuroleptics or other psychotropic

n SPECIAL CLINICAL POINT: Lithium-

drugs is generally not marked, a finding that

induced tremor does not necessarily present on

should suggest a toxic cause; withdrawal of

toxic levels of the medication and can be seen

disulfiram and mild sedation with supportive

with therapeutic doses.

care (but without neuroleptic therapy) are rec-

ommended in the treatment of disulfiram

Hypnosedative and Other Agents

encephalopathy.

Barbiturates usually are used to manage seizure

Disulfiram also is associated with a rare ax-

disorders but still are used to calm patients and

onal distal sensory/motor polyneuropathy. The

facilitate sleep. Drowsiness is a common com-

recovery after drug withdrawal both clinically

plaint associated with their use, and ataxia

and pathologically suggests a dying-back or

(often without nystagmus) can develop when the

distal axonopathy rather than new degenera-

plasma level rises above 50 mg/mL. At higher

tion secondary to the loss of nerve cells. It is

doses, severe ataxia, nausea, vomiting, and nys-

not known whether disulfiram is the responsi-

tagmus predominate. A second encephalopathic

ble agent or whether a toxic metabolite induces

syndrome occurs in children taking phenobarbi-

the neuropathy. Disulfiram possibly is metabo-

tal and is highly distinctive. Instead of somno-

lized to carbon disulfide, a compound capable

lence, these children develop remarkable

of causing an axonal neuropathy in humans

agitation and hyperactivity. This can give the pic-

and animals.

ture of attentional deficit disorder (ADD), or

childhood hyperactivity. Patients with chronic

toxic exposure to barbiturates show ataxic gait,

slurred speech, and periods of intermittent agita-

ANTIINFLAMMATORY AGENTS

tion. Tremors and confusion, as well as diplopia

Salicylate Compounds

and nystagmus, are characteristic.

Methaqualone may induce transient and

Because of their ready availability in most house-

persistent paresthesias and other signs of pe-

holds, salicylates represent a common source of

ripheral neuropathy. Paradoxic restlessness

intoxication, accounting for the largest yearly

and anxiety instead of sedation and sleep also

number of serious childhood poisonings. In

are reported with this drug. As with many of

acute intoxication, the prominent neurologic

462

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

and respiratory signs may immediately suggest

There is a poor correlation between the

the correct diagnosis and direct prompt and ap-

serum salicylate levels and the clinical severity

propriate intervention. The neurologic manifes-

of intoxication. Despite apparently adequate

tations of salicylate toxicity include a rapid and

treatment and progressive lowering of toxic

dramatic alteration in consciousness and global

plasma salicylate levels, sudden and unex-

function with convulsions and coma. Confu-

plained deaths are not rare.

sion and restlessness are seen early, leading

within a few hours to excitability, tremor, inco-

Steroids

herent speech, and often delirium or halluci-

nosis. This phase has been referred to as a

Steroids induce three neurotoxic syndromes: in-

“salicylate jag” to indicate its similarity to alco-

creased intracranial pressure

(pseudomotor

holic inebriation, although euphoria and ela-

cerebri), toxic encephalopathy, and myopathy.

tion are conspicuously absent with salicylates.

Infants are more likely than adults to develop

After this phase, a gradual depression in the

steroid-related increased intracranial pressure,

level of consciousness occurs with a rapid lapse

hydrocephalus, and papilledema. This syn-

into coma. Seizures are especially common in

drome may occur while patients are receiving

children and are usually generalized. The

steroids or after withdrawal. The pathophysiol-

pathophysiology of the convulsions appears to

ogy of this syndrome is unknown, although it

relate to combined effects of metabolic and res-

may relate to water intoxication. When it oc-

piratory disturbances. In infants, salicylate in-

curs, patients have been treated for weeks or

toxication induces a marked hypoglycemia, and

months with steroid compounds.

seizure activity is especially hazardous in this

In contrast, steroid-induced toxic en-

young age group. Diplopia, dizziness, and de-

cephalopathy may occur within days of steroid

creased visual acuity also can be seen with sali-

introduction. The behavior is varied and fluctu-

cylate intoxication. Involvement of the

ant, ranging over 24 hours from momentary eu-

audiovestibular (eighth cranial) nerve can lead

phoria to depression to fully developed

to tinnitus, vertigo, and complete deafness. This

psychosis. Depersonalization and motor retar-

complication is more common with chronic sal-

dation may make these patients difficult to

icylate intoxication and is seen especially in eld-

manage during the intoxication phase. Para-

erly patients treated for arthritic or headache

noia with visual and auditory hallucination and

conditions where aspirin or salicylate com-

markedly delusional thinking may predomi-

pounds are ingested daily. The treatment of sal-

nate. Although this syndrome typically occurs

icylate toxicity involves minimizing drug

early in the course of steroid therapy, cases exist

absorption, hastening drug elimination, cor-

where mental decline developed after more

recting acid-base disturbance, and treating ex-

than 3 months of treatment. Doses of medica-

isting neurologic or medical complications.

tion do not clearly correlate with symptoms, al-

Induced emesis in the awake patient is the most

though the encephalopathy is generally more

effective means of emptying the stomach. En-

frequent in high-dose treatment groups. Patients

hanced elimination is affected by alkalinization

with a prior history of psychiatric care or de-

of the urine or by peritoneal dialysis or

pression may be at higher risk for encephalopa-

hemodialysis. Careful fluid and electrolyte

thy than other patients. Suicides have occurred,

management is tantamount and depends on the

making this encephalopathy a significant source

age of the patient and the stage of intoxication.

of potential morbidity. Treatment focuses on

The complications of hypoglycemia in infants

withdrawal of the steroid and medical and psy-

must be anticipated and thereby prevented.

chiatric support. Steroids sometimes can be

Seizures usually are treated with phenytoin and

reintroduced later without the reappearance of

phenobarbital.

the problem.

463

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

Steroid myopathy, characterized by proxi-

sought, no communicable agent has been iso-

mal weakness and atrophy, appears unrelated

lated. The meningeal syndrome resolves with

to the actual duration of drug treatment, and

the discontinuation of the nonsteroidal agent,

type II fibers appear to be selectively affected.

only to recur, sometimes more rapidly and se-

Patients complain of progressive weakness that

verely, if treatment is reinitiated.

focuses primarily on the proximal muscles

Indomethacin has proved to be a potent

(shoulders and thighs).

anti-inflammatory drug but appears less effica-

Rapid withdrawal of steroids induces the

cious than salicylates in the treatment of arthri-

behavioral manifestations seen clinically in Ad-

tis and rheumatoid variants. Its mode of action

dison disease. These manifestations are second-

is still uncertain, but it may act by way of inhi-

ary phenomena and are not related directly to

bition of prostaglandin synthesis. CNS toxicity

drug neurotoxicity.

is one of the most frequent dose-limiting fac-

tors, precluding the use of indomethacin in

30% to 50% of patients. Neurotoxic effects

Nonsteroidal Agents

consist of headaches, depression, agitation,

The nonsteroidal anti-inflammatory agents

and (rarely) hallucinations. Ataxia, clumsiness,

(NSAIDs) account for approximately 4% of

and impaired postural reflexes also may occur,

the prescription market. There are a variety of

although slow increases in dosage may prevent

types currently available, and ibuprofen is

their development.

available in low doses as a nonprescription

Naproxen has been associated with adverse

drug. Despite widespread use, these agents in-

neurologic reactions in approximately 8% of

frequently cause significant neurologic adverse

patients. These effects include headache, drowsi-

effects. The most common neurologic side ef-

ness, vertigo, inability to concentrate, and de-

fect is headache. Other rare but serious central

pression. Because of its protein-binding affin-

disturbances include confusion, hallucinations,

ity, naproxen can be associated with phenytoin

and overt psychosis. Although these agents

toxicity in seizure patients. By displacing

have not been evaluated well in controlled

phenytoin from proteins, naproxen causes

studies, it has been suggested that there may be

higher levels of unbound phenytoin to circu-

subtle associated cognitive and memory changes,

late, so that toxic signs develop, although the

particularly in more elderly patients. Another

total serum phenytoin level remains in the ther-

infrequent yet important side effect described is

apeutic range.

the occurrence of aseptic meningitis. Initially

reported in 1978, there have been subsequent

Hormones

case reports in which ibuprofen was the most

commonly associated drug, although sulindac,

Female hormones in the form of oral contracep-

naproxen, and tolmetin also have been impli-

tives or postmenopausal replacement therapy

cated. From these case reports, it appears that

have become widely prescribed. It is clear that

young women with connective tissue disorders

oral contraceptives increase by three to eight

are the most likely to develop this side effect.

times the risk of stroke in women taking them.

The clinical picture is that of aseptic meningi-

Oral contraceptive-associated strokes can

tis, with fever, chills, and meningismus. The

occur in any vascular distribution. Factors pre-

cerebrospinal fluid has an elevated protein con-

disposing to cerebrovascular disease in women

tent, a pleocytosis of granulocytes, and a nor-

taking birth control pills include the use of com-

mal or reduced glucose level. The underlying

pounds containing high levels of estrogen, mul-

mechanism for this syndrome is felt to be a hy-

tiparity, and a change in migraine headache

persensitivity reaction to the drugs. Although

pattern. Of probable but less certain importance

an infectious source for meningitis must be

are previous thrombotic or embolic disease and

464

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

hypertension. Inherited resistance to activated

graine may become classic migraine, with pa-

protein C, which is caused by a single factor

tients experiencing symptoms or signs of focal

V gene mutation, is a frequent risk factor for

cerebral dysfunction at the onset of the

thrombosis. Activated protein C resistance was

headache. In cases in which migraines either

found to be highly prevalent in women with a

appear for the first time, increase in frequency,

history of thromboembolic complications dur-

or become focal, cessation of oral contracep-

ing pregnancy or use of oral contraceptives.

tives is suggested. However, a subgroup of pa-

The gene defect is common in the general pop-

tients with headache find relief of headache

ulation, and the question is raised as to whether

pain while taking oral contraceptives. These

it would be reasonable to perform general

headaches may have a close relationship with

screening for activated protein C resistance

menstruation, and while taking the oral con-

early during pregnancy or before prescription

traceptives, the patient has minimal pain.

of oral contraceptives. Progesterone-only con-

Various other neurologic disorders occa-

traceptives do not increase the risk of stroke.

sionally are associated with the use of oral con-

Hormone replacement therapy with estrogen

traceptives. Seizures may change in pattern of

alone or combined with progesterone increases

frequency. Carpal tunnel syndrome of median

the risk of ischemic stroke with no effect on he-

nerve neuropathy or other pressure neu-

morrhagic stroke. Stroke risk increases with the

ropathies may occur related to the increased

dose of estrogen. The time between menopause

fluid retention associated with oral contracep-

and the initiation of hormone replacement ther-

tives. Drug-induced and reversible myasthenia

apy does not influence ischemic stroke risk.

gravis also has been reported but rarely.

n SPECIAL CLINICAL POINT: Progesterone-

only contraceptives are preferable in women

Vitamins and Additives

with cerebrovascular disease or risk factors for

Caffeine and other xanthine derivatives, in-

cerebrovascular disease.

cluding aminophylline, are CNS stimulants

Chorea is another serious problem related to

that excite all levels of the CNS, the cortex

oral contraceptives. The involuntary movements

being the most sensitive. Caffeine increases en-

appear days or weeks after starting birth con-

ergy metabolism throughout the brain but de-

trol pills and may be more frequent in patients

creases cerebral blood flow, inducing a relative

with a prior history of Sydenham’s chorea. The

brain hypoperfusion. The drug activates nora-

chorea starts abruptly and may involve only

drenaline neurons and may act as a second

one side of the body. A similar phenomenon oc-

messenger at dopamine receptors to affect the

casionally occurs during pregnancy when a

local release of dopamine. Mobilization of in-

woman develops severe involuntary move-

tracellular calcium and inhibition of specific

ments that spontaneously resolve when the

phosphodiesterases occur at high, nonphysio-

pregnancy ends

(chorea gravidarum). Birth

logic concentrations of caffeine. The most

control chorea may disappear within 48 hours

likely mechanism of action of methylxanthine

of cessation of the medication, although the

is the antagonism at the level of adenosine

abatement can take longer.

receptors.

Whereas pseudotumor cerebri can occur in

Caffeine’s psychostimulant action on hu-

patients taking oral contraceptives, another

mans is often subtle and difficult to detect. Its

cause of blurring of the optic disc is pa-

effects on learning, memory, performance, and

pilledema related to venous sinus obstruction.

coordination are related to methylxanthine-

Vascular headaches also may appear for the

induced arousal, vigilance, and fatigue. An

first time or suddenly change in pattern when

increased awareness of the environment or hy-

oral contraceptives are started. Common mi-

peresthesia may be an unpleasant experience

465

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

for some patients. The patient becomes loqua-

supervene, although convulsions are usually

cious and restless and often complains of ring-

not present. If death occurs, it is caused by

ing in the ears and giddiness. At high doses,

paralysis of respiratory muscles. Cardiac ar-

xanthines affect the spinal cord, resulting in in-

rhythmias are significant and are other poten-

creased reflex excitability, tremulous extremi-

tial sources for demise. Chronic intoxication

ties, and tense muscles. Caffeine clearly alters

as a result of nicotine occurs among tobacco

sleep patterns, and if taken within 1 hour of at-

pickers, or “croppers,” consisting of nausea,

tempted sleep, it increases sleep latency, de-

vomiting, dizziness, and prostration. The ill-

creases total sleep time, and worsens the

ness is intermittent and lasts between 12 and

subject’s estimate of sleep quality. Less time is

14 hours; it then clears, only to recur with re-

spent in stages 3 and 4 and more in stage 2.

turn to work. There are no mortalities or long-

Xanthine-associated seizures are seen as a com-

term sequelae, however. During the

1973

plication of aminophylline therapy, especially

harvesting season, an estimated

9% of the

when the drug is administered intravenously.

60,000 tobacco growers in North Carolina re-

They usually are generalized but can be focal.

ported illnesses.

Cessation of the use of products containing

Vitamins are vital trace substances, and neu-

caffeine can cause a withdrawal syndrome of

rologic syndromes generally are associated with

headaches; drowsiness; fatigue; decreased per-

deficiency syndromes. However, because health

formance; and, in some instances, nausea and

enthusiasm has reached passionate proportions

vomiting. These symptoms begin within 12 to

for many individuals, especially Americans, clini-

24 hours after the last use, peak at

20 to

cians are encountering neurotoxic syndromes as-

48 hours, and last approximately 1 week.

sociated with these seemingly safe agents. Of the

Nicotine increases circulating levels of norep-

fat-soluble vitamins, vitamin A is directly associ-

inephrine and epinephrine and stimulates the re-

ated with neurotoxicity, and vitamin D can alter

lease of striatal dopamine. It exerts stimulant

bone and renal metabolism, causing secondary

effects through specific nicotinic receptors,

neurologic dysfunction. Of the water-soluble vi-

whose activation may facilitate dopaminergic

tamins, only pyridoxine (B₆) is established to

transmission centrally. Nicotine has been re-

provoke neurologic complications.

ported to affect a number of neurologic diseases,

Vitamin A, required for normal growth, vi-

such as spinocerebellar degeneration, multiple

sion, reproduction, and maintenance of epithe-

system atrophy, multiple sclerosis, tic disorders,

lium, in high doses accumulates and can induce

parkinsonism, and myoclonic epilepsy.

the syndrome of increased intracranial pressure

Nicotine, despite being a powerful stimu-

(pseudotumor cerebri). Foods high in vitamin

lant, has no major therapeutic application. Its

A include broccoli, cabbage, and liver, al-

high toxicity and presence in tobacco smoke

though dietary hypervitaminosis A is most un-

give nicotine a considerable medical impor-

usual. Medically, vitamin A is used in the

tance, however. Clinically, tremors and convul-

treatment of acne vulgaris and other dermato-

sions are major neurologic signs of nicotine

logic illnesses. Whereas the generally recom-

intoxication. Respiration is stimulated, and

mended daily allowance is 5,000 IU, individual

vomiting is induced. Nicotine also has marked

capsules can contain five times that value, with

antidiuretic activity resulting from direct hypo-

subjects often ingesting 100,000 IU daily. At

thalamic stimulation. If acutely ingested, nico-

these doses, intoxication will develop over sev-

tine can be fatal at a level of approximately

eral months; at 200,000 IU daily, intoxication

60 mg of the base product. Autonomic overac-

may develop within weeks. Publicity about pu-

tivity with dilated pupils, irregular pulse,

tative cancer preventive properties of vitamin A

sweating, and muscle twitching are characteris-

may increase the number of people who expose

tic signs of nicotine toxicity. Coma may rapidly

themselves to this product.

466

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

Early signs of increased intracranial pres-

(premenstrual syndrome). Myalgia and eosino-

sure include headaches, blurred vision, tran-

philia have been reported in numerous patients,

sient obscuration of vision, and sixth cranial

as well as a progressive neuropathy affecting pri-

nerve paresis. On funduscopic examination,

marily the lower extremities with aching weak-

gradual papilledema develops without further

ness. In some instances, patients are so disabled

signs of focal neurologic deficit. No neurologic

that they are wheelchair bound and need ventila-

clue exists to establish the etiology, but the skin

tory assistance. Cessation of exposure to trypto-

changes, organomegaly, and history of vitamin

phan and plasma exchange have been associated

ingestion will establish the diagnosis. Because

with clinical improvement in some cases.

vitamin zealots are often

“antimedication,”

these patients must be questioned specifically

about vitamins.

Always Remember

Vitamin D, when given in massive amounts,

mobilizes bone calcium and phosphorus. When

• Drug-induced neurologic symptoms can be

there is bone demineralization and degeneration,

diagnosed with careful history and vigilance of

nerve root and spinal cord compression can

the examining physician.

occur. Alterations in the calcium balance can

• The physician should be careful to inquire

produce generalized weakness, muscle aches,

about the use of supplements and vitamins as

cramps, and mild metabolic encephalopathy.

the patients do not always volunteer their use.

Meningeal symptoms and trigeminal neuralgia

• Polypharmacy can alter drug levels and

are two additional reported findings without

increase the potential for neurotoxicity.

clear pathogenesis. The latter may relate to bony

• Some side effects appear after a while

foraminal alterations. When renal impairment

following the initiation of the offending

occurs, progressive secondary encephalopathy,

medication and in a similar manner can take a

not directly related to the vitamin, develops, and

while before they resolve.

coma may result.

Pyridoxine, or vitamin B₆, has been impli-

cated in a highly selective toxic syndrome pro-

voking a sensory ataxia and dorsal root ganglia

QUESTIONS AND DISCUSSION

dysfunction. Widely used, especially by women

1. Which one of the following medications can

to treat premenstrual tension and edema, pyri-

cause visual disturbance in as many as 40%

doxine induces this neurotoxic syndrome in oc-

of patients?

casional patients consuming chronic daily doses

A. Propranolol

of 2 g or more. Gradually, the patient notes dif-

B. Digitalis

ficulty walking, with lightning-like dysesthesias

C. Alpha-methyldopa

in the back. Numbness of the extremities oc-

D. Lidocaine

curs, and, importantly, facial dysesthesias, so

uncommon with most toxic neuropathies other

The correct answer is B. Digitalis has promi-

than trichloroethane, quickly develop. Are-

nent visual side effects, and patients often

flexia, stocking-glove sensory loss, and pro-

complain of halos around everything. Propra-

found sensory ataxia with preserved strength

nolol and other beta-antagonists can cause de-

are typical. On electromyography, marked

pression and impotency that can be obscured

slowing of the sensory nerve conduction is seen

in the rehabilitative setting after a myocardial

with normal motor conduction.

infarction or surgery. Alpha-methyldopa can

Tryptophan is an amino acid that has become

cause or aggravate parkinsonism, and lido-

popular for management of insomnia and behav-

caine often is associated with a bizarre and

ioral changes related to the menstrual cycle

alarming change in behavior.

467

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

2. The factor(s) that contribute(s) to the acid-

hypothesized to underlie the chorea as opposed

base abnormality of salicylate intoxication

to the transient chorea, which probably relates

include the following?

to a hormonally induced functional alteration

A. Salicylates initially depress medullary

in dopaminergic sensitivity at the striatum. Pa-

breathing activation.

pilledema, when it occurs in patients taking

B. Salicylates are acids that displace

birth control pills, may have multiple etiolo-

bicarbonate and also can lead to ketosis.

gies, including venous thrombosis and pseudo-

C. Myoglobinuria usually precipitates renal

tumor cerebri. It does not appear to relate to

shutdown and metabolic acidosis.

hypervitaminosis A.

D. All of the above.

4. Which one of the five neurologic

The correct answer is B. Salicylates initially ac-

complications of neuroleptic therapy listed

tivate the medullary breathing center and

can occur as a subacute event, occurring

cause respiratory alkalosis. Later, at high

days, weeks, or a few months after starting

doses, the medullary breathing center can be

the drug?

inhibited. In addition, salicylates induce and

A. Dystonia

enhance the chemosensitive response and are

B. Parkinsonism

acids. The net response is a metabolic acidosis

C. Chorea

with either a respiratory acidosis or alkalosis.

D. Akathisia

Myoglobinuria is not a feature of salicylate in-

E. Oculogyric crises

toxication.

The correct answer is B. The subacute prob-

3. In regards to neurologic disability

lem associated with neuroleptic medications

associated with birth control pills:

is parkinsonism, which may include any of

A. Peripheral neuropathy of the axonal type

the following: tremor, bradykinesia, rigidity,

can mimic multiple sclerosis.

or postural reflex compromise. The acute

B. Cerebrovascular accidents usually relate

neurologic side effects related to neuroleptic

to cardiac valvular vegetations.

drugs are dystonia and akathisia. The con-

C. Chorea often resolves within days or

torted posture of dystonia is frightening to

weeks of drug cessation and is rarely a

see or experience. An oculogyric crisis, with

permanent sequela of oral contraceptive

the eyes thrown back and the neck usually

ingestion.

hyperextended, is only one example of a dys-

D. Papilledema, when it occurs, is caused by

tonic complication of neuroleptics. A late-

steroid-induced hypervitaminosis A.

onset dystonia has been described as within

the realm of tardive dyskinesia, but this is

The correct answer is C. Birth control pills are

probably uncommon. Tardive dyskinesia is

not associated with a peripheral neuropathy;

mainly a choreic or stereotypic disorder but

instead, their toxicity relates predominantly to

may be dystonic and is the major chronic

a CNS function. Cerebrovascular accidents are

side effect of neuroleptic drugs.

an alarming complication of these drugs in

young women and may be of embolic or

5. Which statement is true regarding

thrombotic origin. They do not relate specifi-

antiemetic drugs and neurologic use or

cally to valvular vegetations. Chorea often oc-

adverse effects?

curs within days of the first ingestion of birth

A. Metoclopramide is particularly useful in

control pills and may stop promptly after drug

patients with Parkinson disease with

cessation. Only in rare instances (usually a

nausea secondary to their dopaminergic

hemiballistic syndrome) will the chorea be

medication.

longstanding after drug cessation. In such

B. Children receiving prochlorperazine for

cases, a static cerebrovascular accident is

gastrointestinal distress are less likely

468

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

than adults to have neurologic

increased risk. Congestive heart failure may in-

complications.

crease theophylline levels even when the drug

C. In a patient using a scopolamine patch

is administered at recommended doses. Theo-

who reports acute right eye pain, an

phylline is a xanthine compound without

emergency visit to an ophthalmologist

dopamine receptor activity, and it is not

and removal of the patch should be

known to cause acute dystonic reactions.

recommended.

7. Which of the following antibiotics is

D. Scopolamine may cause drug-induced

associated with a high incidence of

parkinsonism by a mechanism similar to

neurotoxicity?

that of neuroleptics.

A. Penicillin

The correct answer is C. Scopolamine is an

B. Trimethoprim

anticholinergic agent that may exacerbate

C. Minocycline

narrow-angle glaucoma, with painful symp-

D. Erythromycin

toms in the eyes. If not recognized and treated

The correct answer is C. Minocycline provokes

emergently, this may result in blindness. Both

ototoxicity, and women are more susceptible

metoclopramide and prochlorperazine are

to these effects than men. The remaining

dopamine receptor blockers, similar to the

agents are associated with neurotoxic syn-

neuroleptics. Hence, both agents may cause

dromes only on occasion, unless they are given

drug-induced parkinsonism or worsen preex-

by unusual routes or in unusual doses.

isting Parkinson disease. Children treated with

these drugs are at more risk for developing

8. Which condition is associated with vitamin

acute dystonic reactions. In contrast, scopo-

excess?

lamine, being an anticholinergic agent, does

A. Clinical findings of Guillain-Barré

not cause drug-induced parkinsonism.

syndrome

6. In patients receiving theophylline, which of

B. Increased intracranial pressure

the following is true?

C. Myasthenia gravis

A. Seizures occur only if serum levels are in

D. Wernicke-Korsakoff syndrome

the toxic range.

The correct answer is B. Excess vitamin A and

B. Theophylline is a useful agent in an

B₆ are known to cause neurotoxic syndrome. B₆

elderly patient with congestive heart

provokes a sensory neuropathy with loss of

failure and a previous stroke with a

reflexes, but it should not be confused with

history of intermittent asthma.

Guillain-Barré, which predominantly affects

C. A child receiving IV infusions of

the motor system. Vitamin A causes the syn-

theophylline is at increased risk for

drome of pseudotumor cerebri, with increased

developing acute dystonic reactions.

intracranial pressure, often associated with

D. The pharmacokinetics of drugs

headache and other nonfocal neurologic find-

metabolized in the liver may affect the

ings. (Sixth-nerve paresis, unlike other cranial

metabolism and serum levels of

neuropathies, is a “false-localizing” sign. Be-

theophylline.

cause of the long trajectory of the nerve along

The correct answer is D. Theophylline is me-

bony surfaces, a sixth-nerve paresis does not

tabolized by the hepatic enzymes. Other drugs

locate the level or side of neurologic damage.)

metabolized in the liver may alter theophylline

Vitamin D, when given in high doses chroni-

metabolism, affecting the serum levels. The

cally, affects calcium and phosphorus balance,

seizures associated with theophylline may

which may clinically provoke global weakness.

occur in the therapeutic range. In particular,

The classical neuromuscular fatigue typical of

patients with previous brain injury are at

myasthenia and the response to edrophonium

469

Chapter 22

n Neurotoxic Effects of Drugs Prescribed by Non-neurologists

are not seen. Wernicke-Korsakoff syndrome

Lipsy RJ, Fennerty B, Fagan TC. Clinical review of the his-

tamine-2 receptor antagonists. Arch Intern Med.

is related to vitamin deprivation and not to

1990;150:745.

intoxication.

Miller LG, Jankovic J. Persistent dystonia possibly induced

by flecainide. Mov Disord. 1992;7:62.

Neuhaus P, McMaster P, Calne R, et al. Neurological com-

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trations: risk factors for serious outcome in adults.

Pappert EJ. Neuroleptic-induced movement disorders:

Neurology. 1991;41:1309.

acute and subacute syndromes. In: de Wolff FA, ed.

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Neurologic

Complications

of Alcoholism

ALLISON L. WEATHERS

key points

• The potential neurologic consequences of chronic

alcoholism are wide ranging with potential involvement

of both the central nervous system and peripheral

nervous system.

• Wernicke encephalopathy is a neurologic emergency,

whose diagnosis and the decision to treat should be

based on the clinical picture alone. This diagnosis should

be considered in all high-risk patients.

• In addition to the more commonly occurring neurologic

complications of alcoholism such as hepatic

encephalopathy and Wernicke encephalopathy, more rare

manifestations such as pancreatic encephalopathy, pellagra

encephalopathy, and Marchiafava-Bignami disease may

occur and should be considered in the differential of an

alcoholic patient with mental status changes.

thanol is one of

complications ranging from those that may be

the most commonly abused substances in the

considered acute neurologic emergencies, such

United States. Chronic alcoholism results in

as Wernicke encephalopathy, to more chronic,

substantial health consequences for those

insidious processes such as alcoholic neuropa-

who suffer from this disease and overall

thy. Internists, family medicine practitioners,

impacts our medical resources to a significant

and emergency department physicians are usu-

degree. The potential neurologic complica-

ally well versed in the potential neurologic com-

tions of chronic alcoholism are broad, with

plications of acute alcohol intoxication and

both the central nervous system (CNS) and

withdrawal and their management, often more

peripheral nervous system (PNS) possible tar-

so than neurologists. Therefore, this chapter will

gets of the adverse effects of chronic alcohol

focus solely on the neurologic manifestations of

abuse. This chapter will cover these potential

chronic alcohol abuse.

470

471

Chapter 23

n Neurologic Complications of Alcoholism

and signs will progress with increasingly se-

WERNICKE ENCEPHALOPATHY

vere confusion, confabulation, hallucinations,

and ultimately coma and death are possible

Though Wernicke encephalopathy is not one of

outcomes. Though rare, patients may present

the most common neurologic manifestations of

in coma without focal neurologic signs,

alcoholism, its potential for devastating neuro-

mimicking other metabolic encephalopathies,

logic consequences and ultimately death if

unrecognized and untreated makes it one of the

and patients may also present with systemic

most significant possible complications of alco-

signs including hypotension, hypothermia,

hol abuse. It is now recognized that a number

and tachycardia.

of clinical scenarios may result in Wernicke

Although controversy exists surrounding

encephalopathy; however, chronic alcohol use

the pathophysiology of many of the neuro-

remains one of the most common causes of thi-

logic complications of alcoholism, specifically

amine deficiency and therefore is still the

whether they are due to the direct toxic effects

underlying cause in the majority of cases. In

of alcohol and its metabolites or to superim-

this patient population, the onset of Wernicke

posed nutritional and vitamin deficiencies.

encephalopathy is especially likely to occur

Wernicke encephalopathy is known to be the

during concurrent febrile illnesses, during or

result of thiamine deficiency. Thiamine defi-

following treatment of delirium tremens, dur-

ciency is common in this population for a

ing detoxification, with the administration of

number of reasons including decreased gas-

glucose (often as a component of intravenous

trointestinal (GI) absorption of thiamine both

fluids), or during refeeding after prolonged

by chronic alcohol use and by the concurrent

starvation. The unifying feature of all of these

use of alcohol with thiamine administration,

circumstances is that they result in increased

decreased thiamine storage in the liver, im-

metabolic demand or stress. Physicians who

paired transformation of thiamine into its ac-

care for alcoholic patients need to be cognizant

tive form, and independently decreased

of these inciting factors and aware of the wide

absorption due to malnutrition. Thiamine de-

range of clinical features of this illness.

ficiency can occur within weeks without con-

Although the triad of mental status

tinued dietary (or supplemental) intake, and

changes, ophthalmoplegia, and ataxia is well-

symptoms can start within a few weeks of the

recognized as the classic clinical picture of

onset of the deficient state.

Wernicke encephalopathy, in actuality the full

The active form of thiamine, thiamine diphos-

triad occurs in relatively few patients. Mental

phate, plays a critical role in three different

status and personality changes, including

enzyme pathways, which in turn are vital to

insomnia, lethargy, anxiety, apprehension, ap-

a number of biologic functions, such as the syn-

athy, confusion, memory loss, and difficulty

thesis of neurotransmitters, the maintenance of

with concentration, are frequently the initial

myelin sheaths, the production of energy

symptoms. Ocular symptoms, including wa-

through lipid and glucose metabolism, and

vering of vision, double vision (diplopia), and

branched-chain amino acid production. As a

photophobia, may precede the mental status

consequence, thiamine deficiency results in

changes, and nystagmus may be the initial

cerebral energy deficits, focal lactic acidosis,

neurologic finding on exam. Lateral rectus

glutamate-mediated excitotoxicity, blood-brain

palsies, conjugate gaze palsy, complete oph-

barrier breakdown, and free radical formation,

thalmoplegia, pupillary abnormalities, and

which in turn are thought to result in the patho-

ptosis are not as frequently seen. Ataxia may

logic changes seen in Wernicke encephalopathy,

also be a presenting sign, but occurs less

and therefore the clinical picture.

commonly than mental status changes and eye

It is possible to measure thiamine levels, as

signs. If untreated, the neurologic symptoms

well as to assess thiamine status through the

472

Chapter 23

n Neurologic Complications of Alcoholism

measurement of red blood cell transketolase;

syndrome. Patients with this chronic amnestic

however, these studies, though they may

condition will have severe anterograde amnesia

identify at-risk patients, are not diagnostic,

with retrograde amnesia for the months to years

may not be available emergently, and should

prior to the onset of the illness. Confabulation is

not be relied on to make treatment decisions.

a common associated finding in patients with

This holds true for other adjunctive studies

this severe amnestic syndrome.

such as magnetic resonance imaging (MRI) and

Given the potential for a devastating neuro-

lumbar puncture. Although MRI may show

logic outcome, Wernicke encephalopathy is a

signal abnormalities, usually in the medial thal-

neurologic emergency and treatment should

ami, mammillary bodies, and certain regions of

not be delayed.

the midbrain in acute cases, these findings will

n SPECIAL CLINICAL POINT: As treatment

not be seen in all patients. Cerebrospinal fluid

is generally well tolerated and the risk of

(CSF) studies are often normal.

missing the diagnosis is so great, the diagnosis

of Wernicke encephalopathy should be

n SPECIAL CLINICAL POINT: Wernicke

considered in all high-risk patients, including

encephalopathy is a neurologic emergency,

those with hepatic encephalopathy, those with

whose diagnosis, and therefore the decision to

encephalopathy secondary to head trauma, and

treat, should be based on the clinical picture

those with any one of the possible presenting

alone.

clinical symptoms, particularly when the patient

Although the need for thiamine replacement in

presents acutely intoxicated.

these patients is clear, exact treatment recommen-

dations cannot be made on the basis of the litera-

ture. Treatment should be given in parental form

PELLAGRA ENCEPHALOPATHY

in all cases due to the known decreased absorp-

tion from the GI tract in alcoholic patients, and

As with Wernicke encephalopathy, although a

alcoholic patients require higher doses than do

number of medical conditions may predispose

those with other underlying etiologies for the

patients to pellagra, chronic alcoholism has

same reasons that this population is more often

long been known to be the chief underlying

deficient. Alcoholic patients may require several

condition; both for cases in nonendemic areas

hundred milligrams of parental thiamine given

at the height of the epidemic in the mid-20th

up to twice daily for several days. Magnesium is

century and today, despite the enrichment of

a required cofactor in the metabolism of thiamine

bread and flour by niacin. Although vitamin

and is frequently a codeficiency in alcoholics. It

enrichment did greatly reduce the incidence of

should be replenished as well in deficient patients

this disease, it still persists, especially in mal-

to ensure response to treatment. Although par-

nourished, indigent alcoholics, and therefore

enteral thiamine is thought to have a good safety

pellagra encephalopathy should still be consid-

profile, anaphylaxis is a possible reaction and

ered a potential neurologic complication of

treatment should only be given in a setting where

alcoholism.

cardiopulmonary resuscitation and epinephrine

In addition to being associated strongly with

are available emergently.

chronic alcoholism and the result of a vitamin

Generally, the response to adequate treat-

deficiency, pellagra shares other characteristics

ment is fairly rapid, with the eye movement

with Wernicke encephalopathy, including the

abnormalities improving first and resolving

fact that the diagnosis is coupled to a classic

within days, followed by the cognitive deficits

triad of clinical symptoms that does not actu-

and ataxia within weeks to months. A potential

ally occur in the majority of patients. In this

consequence of inadequate and of course a com-

case, the triad is dermatitis, diarrhea, and

plete lack of treatment is Wernicke-Korsakoff

dementia, also known as “the three Ds” of pel-

473

Chapter 23

n Neurologic Complications of Alcoholism

lagra. “Dementia” is often a late characteris-

a crucial role in multiple oxidation-reduction

tic with mild cognitive and personality

reactions in the body, including glycolysis and

changes occurring early in the disease course.

fat synthesis. Multiple other vitamins are

These include fatigue, insomnia, anorexia,

essential for the synthesis of niacin from tryp-

apprehension, anxiety, depression, mania, apa-

tophan, including thiamine, riboflavin, and

thy, and mood lability. Headache, mild mem-

pyridoxine, and a codeficiency of protein or of

ory loss, and vertigo may also be early

one of these other vitamins is likely needed for

neurologic manifestations of this illness. With

the development of the disease. As chronic al-

disease progression, both the psychiatric and

coholics often will be overall malnourished

neurologic symptoms and signs will often

with deficiencies in more than one vitamin, this

increase in severity. Patients may develop acute

population is especially predisposed to the de-

psychosis, paranoid delusions, and hallucina-

velopment of pellagra.

tions, and most will develop confusion with

Niacin deficiency can be assessed in the lab-

disorientation and fluctuations in their level of

oratory, both by the direct blood levels of

consciousness. Neurologic examination may

niacin and tryptophan and by the urinary

reveal spastic weakness, extrapyramidal signs,

metabolites of niacin-dependent pathways, but

hyperreflexia, Babinski sign, myoclonus, gait

these tests are not routinely available or have

abnormalities, gegenhalten tone, tremor, dys-

low specificity or poor reliability.

phagia, and bowel and bladder incontinence.

Seizures may occur. The neuropsychiatric man-

n SPECIAL CLINICAL POINT: As with

Wernicke encephalopathy, pellagra

ifestations of pellagra may occur in isolation,

encephalopathy remains a clinical diagnosis

often making it hard to distinguish pellagra

that can be confirmed by clinical improvement

encephalopathy from other encephalopathies

with replacement therapy.

seen in alcoholic patients, such as delirium

tremens.

Pellagra differs from Wernicke encephalopathy

The “dermatitis” of pellagra is classically a

in that large oral doses of niacin and a diet

symmetric, sharply demarcated, erythematous,

enriched in niacin and protein is sufficient for

photosensitive rash that occurs is sun-exposed

treatment. Niacinamide is frequently used due

areas in the spring and summer, including the

to its improved adverse effect profile compared

face, dorsal surfaces of the hands and

to niacin, including less GI effects and less

arms, and the front of the neck. Other derma-

vasoactive properties (less flushing); however,

tologic manifestations of this disease may

both are U.S. Food and Drug Administration

occur, including desquamation of the skin,

(FDA) approved for the treatment of pellagra.

thickening, mild hyperpigmentation, and

Adequate replacement of the other B vitamins

eczema-like lesions. The classic rash may not

is necessary due to both the frequently associ-

develop in patients who are not exposed to

ated codeficiencies of these vitamins and to the

sunlight. The potential GI manifestations are

requirements for them in niacin metabolism.

also broad, and in addition to diarrhea include

Magnesium may be required, if found to be

abdominal pain, nausea and vomiting, steator-

deficient.

rhea, and constipation. Stomatitis and glossitis

Though relatively rare, pellagra did not

are common clinical features.

disappear with the end of the epidemic in the

Pellagra is the result of niacin deficiency or

mid-20th century. Pellagra encephalopathy often

of a deficiency of tryptophan, the essential

responds rapidly and completely to treatment,

amino acid that is the precursor of niacin.

especially when treatment is started early in the

Niacin, through the enzymes nicotinamide ade-

course of the illness, and has a very high mortal-

nine dinucleotide

(NAD) and nicotinamide

ity rate when untreated. For all of these reasons,

adenine dinucleotide phosphate (NADP), plays

it must be considered in the differential diagnosis

474

Chapter 23

n Neurologic Complications of Alcoholism

of the encephalopathic alcoholic patient and

of the middle stages of the disease process.

the diagnosis should not be discarded on the

Although this is the usual course of disease

basis of the absence of GI and dermatologic

progression, patients may have swift progres-

manifestations.

sion between stages, with rapid evolution to

coma. Though not an absolute, patients often

demonstrate other findings consistent with

liver disease, such as ascites, jaundice, and

METABOLIC ENCEPHALOPATHIES

spider angiomas.

Hepatic encephalopathy is a clinical diagno-

Hepatic Encephalopathy

sis based on the history and physical examina-

Alcohol abuse is a very common cause of cir-

tion; however, adjunctive studies may be

rhosis and therefore a common etiology of

helpful as supportive evidence. Serum ammonia

hepatic encephalopathy associated with cirrho-

levels do not clearly correspond to the level of

sis with portal hypertension or portosystemic

severity of the encephalopathy, though a nor-

shunts. The potential clinical findings of he-

mal level is not consistent with this diagnosis.

patic encephalopathy are broad and may range

Electroencephalogram is useful to rule out un-

from the subtle personality changes and cogni-

derlying seizures, such as in nonconvulsive

tive deficits detectable only on formal neu-

status epilepticus, a potential mimicker of he-

ropsychiatric testing found in minimal hepatic

patic (and other) encephalopathies. It will often

encephalopathy, to coma. The degree of sever-

be abnormal with potential findings including

ity of the encephalopathy is characterized by

diffuse slowing and triphasic waves. Neu-

the level of consciousness, intellectual function,

roimaging with computer tomography (CT) or

and the extent of personality and behavioral

MRI is useful to rule out a structural lesion, but

changes. With progression of the disease

will not confirm the diagnosis. MRI will often

course, patients will usually have worsening of

show high signal on the T1 images in the globus

all of these individual components.

pallidus, likely due to manganese deposition,

The impairment in level of consciousness

but this finding is seen in patients with chronic

will advance from mild fatigue or insomnia to

liver disease and is not in itself specific for the

lethargy to somnolence and then on to coma.

clinical diagnosis of hepatic encephalopathy.

Diminished attention span may progress to

n SPECIAL CLINICAL POINT: A triggering

mild disorientation, amnesia, and mild confu-

clinical event superimposed on chronic

sion, and then further to marked cognitive

underlying liver disease is often responsible for

impairment. Mild irritability and depression

the development of hepatic encephalopathy.

will evolve to clear personality changes with

inappropriate behavior, followed by paranoid

These events include dehydration, GI bleeding,

ideations and hallucinations. Finally, while a

infections, intake of excessive dietary protein,

slight tremor or incoordination may be the

electrolyte abnormalities, surgery, transjugular

only motor findings in the early stage of

intrahepatic portosystemic shunt placement,

hepatic encephalopathy, examination will

and additional hepatic insults.

often evolve to show dysarthria, hyporeflexia,

n SPECIAL CLINICAL POINT: As a result,

and ataxia, and in later stages hyperreflexia,

treatment of hepatic encephalopathy starts

weakness, nystagmus, Babinski sign, clonus,

with a search for and correction of any

and rigidity are all possible. In late-stage

triggering factors.

hepatic encephalopathy, opisthotonus and pos-

turing may be associated with the comatose

After this initial step, pharmacologic treatment

state. Asterixis, a well-recognized feature of

consists of administration of the nonab-

hepatic encephalopathy, is a prominent feature

sorbable disaccharide lactulose and the oral

475

Chapter 23

n Neurologic Complications of Alcoholism

antibiotic rifaximin, which may be adminis-

secondary to dysfunction of the basal ganglia)

tered in combination. Both act by inhibiting

including choreoathetosis, tremor, myoclonus

absorption and production of ammonia.

of the face and limbs, dystonia, rigidity, and

Although there is controversy regarding the

dysarthria. Of the above, tremor, which is

efficacy of lactulose and it is often not well

often coarse, postural, and kinetic; myoclonus;

tolerated by patients given its unavoidable

and mild gait unsteadiness are often the pre-

GI effects, its use remains widespread. Rifaximin

senting symptoms. Frank ataxia, pyramidal

has improved tolerance over other antibiotics.

tract signs, and dementia are later signs. A

Although not as common in chronic alco-

parkinsonian form of AHCD is characterized

holics as hepatic encephalopathy secondary to

by the relatively rapid onset of symmetric

cirrhosis with portal hypertension or portosys-

akinesia, cogwheeling rigidity, and resting

temic shunts, encephalopathy due to fulmi-

tremor in association with a gait disorder,

nant, acute liver failure may occur, most likely

postural instability, and less frequently, focal

due to an acute hepatic insult superimposed on

dystonia. Hepatic myelopathy, also known as

chronic liver disease. This type of hepatic

portosystemic or postshunt myelopathy, pres-

encephalopathy is considered a neurologic

ents with a progressive spastic paraparesis

emergency due to the frequent occurrence of

with associated hyperreflexia and minimal

cerebral edema, which results in increased

sensory involvement.

intracranial pressure. Emergent neurosurgical

AHCD differs from Wilson disease by the

consultation is indicated in the management of

later age of onset, absence of Kayser-Fleischer

these cases for the placement of an intracranial

rings, and normal copper metabolism. However,

pressure transducer, as head CT may be unre-

a diagnosis of Wilson disease should always be

markable. Aggressive treatment of this poten-

excluded when a diagnosis of AHCD is enter-

tial complication is necessary.

tained. Clinical features of cirrhosis including

ascites, spider angiomata, palmar erythema, and

hypoalbuminemia are often present.

Acquired Hepatocerebral Degeneration

As with hepatic encephalopathy, neu-

Acquired (or “non-Wilsonian” to distinguish it

roimaging in patients with AHCD will often

from the classic genetic form) hepatocerebral

reveal hyperintense signal abnormalities on the

degeneration (AHCD) is a neurodegenerative

T1-weighted imaging sequences in the lenticu-

disease comprising chronic neurologic and psy-

lar nuclei, particularly the globus pallidus.

chiatric impairment that occurs as a complica-

These changes correspond to the underlying

tion of chronic liver failure and that is

chronic liver disease and occur regardless of

unrelated to the underlying cause of liver dis-

the existence of clinical neurologic impairment

ease. Its incidence is less than that of hepatic

consistent with a diagnosis of AHCD.

encephalopathy, but it does appear to be an as-

While the pathophysiology of AHCD remains

sociated process as its onset seems to be related

not fully understood, the predominance of

to repeated episodes of hepatic encephalopa-

extrapyramidal symptoms may be due to the loss

thy, and especially of hepatic coma. However,

of dopamine D₂ receptors in the lentiform nuclei

this is not an absolute and overt episodes of

of AHCD patients. It is unknown if the reduc-

hepatic encephalopathy do not always precede

tion in dopamine receptors is a direct effect of

this illness. There may also be a correlation

the abnormal manganese deposition in the basal

between the onset of this syndrome with the

ganglia that is thought to be the culprit of the

degree of portosystemic shunting and the

T1 signal changes seen on MRI. Other metabolic

ammonia level.

derangements such as reduced glucose consump-

The majority of neurologic symptoms and

tion in the basal ganglia may also contribute to

signs may be classified as extrapyramidal (i.e.,

the clinical picture. Chronic exposure to toxic

476

Chapter 23

n Neurologic Complications of Alcoholism

nitrogenous substances that are not being me-

be normal or may show scattered areas of

tabolized by the liver and cumulative damage

signal abnormality on the T2, FLAIR (fluid-at-

from multiple episodes of hepatic encephalopa-

tenuated inversion recovery), and diffusion-

thy are also likely responsible in some way.

weighted images. As none of these studies, even

AHCD is a chronic condition; patients do not

when positive, have findings specific to this di-

generally respond to pharmacologic measures

agnosis, they are more useful to exclude the

used in the treatment of hepatic encephalopathy.

differential diagnoses such as infection, mass

There may, however, be improvement in both

lesion, and status epilepticus.

the cognitive deficits and the extrapyramidal

In addition to the above differential which is

signs following liver transplant.

common to all encephalopathic patients,

patients with pancreatitis are also at increased

risk for electrolyte and calcium abnormalities,

Pancreatic Encephalopathy

pH disturbances, superimposed infections, other

Alcoholism is one of the most frequent underly-

metabolic derangements, and secondary liver

ing etiologies of acute pancreatitis and though

injury. Though rare, osmotic demyelination and

not as common as hepatic encephalopathy,

pancreatitis-induced disseminated intravascular

pancreatic encephalopathy is a well-recognized

coagulation syndrome may complicate acute

neurologic complication of this common med-

pancreatitis and all of these may result in an

ical illness. There are no neurologic findings

encephalopathy. This patient population is also

that are specific to this form of encephalopathy.

at especially high risk for Wernicke encephalopa-

Confusion with disorientation, fluctuating al-

thy, owing to the frequent clinical features of hy-

terations of consciousness, agitation, paranoid

peremesis and anorexia and management with

ideations, and hallucinations are common man-

“pancreatic rest” with holding of oral feedings

ifestations. Less frequently, depressed mood,

and administration of total parenteral nutrition,

seizures, tremor, aphasia, weakness, frontal

in the absence of adequate vitamin supplementa-

release signs, meningismus, ataxia, nystagmus,

tion. Therefore, pancreatic encephalopathy is a

akinetic mutism, and coma may occur. The

diagnosis that the physician should feel comfort-

onset of the encephalopathy is usually within

able with only once all of these other possibilities

2 weeks of the onset of the underlying pancre-

have been excluded. Making this diagnosis even

atitis, often within the first week. Though more

more complicated in alcoholic patients is the fact

unusual, patients may have neurologic symp-

that pancreatic encephalopathy may be strik-

toms develop within the first day of their

ingly similar in presentation to delirium tremens.

GI symptoms. There does not seem to be a clear

Several pathophysiologic mechanisms are

correlation between the severity of the pancre-

thought to be responsible for pancreatic

atitis and the occurrence of encephalopathy.

encephalopathy including the activation of

phospholipase A, which causes a chain of

n SPECIAL CLINICAL POINT: As with the

events that ultimately result in demyelination,

ammonia level for hepatic encephalopathy, the

encephalomalacia, hemorrhage, mitochondrial

degree of elevation of the amylase level does

injury, diminished acetylcholine release, and

not correlate with the presence or severity of

edema due to alterations in vascular permeabil-

the pancreatic encephalopathy; however, this is

ity. Acute pancreatitis may be complicated by

a useful adjunctive laboratory study in an

fat necrosis with fat embolism. Both hypoxia

encephalopathic patient with severe abdominal

due to pulmonary fat embolism and the direct

pain associated with other GI symptoms.

effects of cerebral fat embolism may underlie

EEG is often abnormal with diffuse slowing,

pancreatic encephalopathy.

though again these findings are not specific to

There are no directed treatments based on

this diagnosis. CT and MRI of the brain may

these mechanisms, with treatment instead con-

477

Chapter 23

n Neurologic Complications of Alcoholism

sisting only of supportive and symptomatic ther-

agitation, insomnia, paranoia, delusions, and

apy. Early and aggressive management of the

disinhibited and aggressive behavior. MRI may

acute pancreatitis is recommended. Neurologic

show findings supportive of the clinical diag-

improvement usually mirrors that of the under-

nosis with hyperintensities seen on the

lying pancreatitis, though it may be delayed, fol-

T2-weighted and FLAIR images in the pons and

lowing the resolution of the GI symptoms.

other extrapontine locations.

Mortality is high, occurring in approximately

n SPECIAL CLINICAL POINT: Treatment of

half the cases, and residual neurologic impair-

central pontine myelinolysis is mainly limited

ment without full recovery may occur.

to supportive measures, with an important

component being correction of all other

underlying possible etiologies of

encephalopathy (such as other electrolyte or

CENTRAL PONTINE MYELINOLYSIS

metabolic disorders) and management of

Central pontine myelinolysis (CPM) is a rare

comorbidities such as aspiration pneumonia.

condition most commonly associated with the

Patients will often have some degree of neuro-

rapid correction of hyponatremia, where it

logic improvement with supportive therapy

occurs due to the extracellular sodium concen-

followed by rehabilitation, but this is not

tration increasing faster than the intracellular

always complete.

uptake of electrolytes and organic osmolytes. As

a result, water will shift from the intracellular to

the extracellular compartment, which causes

MARCHIAFAVA-BIGNAMI DISEASE

cell injury and demyelination. CPM is now

more accurately called osmotic demyelination

Once thought to be an extremely rare and uni-

syndrome, as these changes are not restricted to

formly fatal disease seen only in chronic male

the pons. Although classically associated with

drinkers of Italian red wine, Marchiafava-

the clinical scenario described above, other

Bignami disease (MBD), although still rare and

causes of serum hyperosmolality may result in

still most commonly encountered in chronic

CPM, and it may occur even with slow correc-

alcoholics, is now known to be a survivable ill-

tion of hyponatremia. Patients will often have a

ness that can occur in either gender no matter

chronic underlying predisposing condition and

what type of ethanol-containing product is

chronic alcoholism is one of the most frequent.

chronically abused. Though it may also be seen

Clinically, CPM often presents as an acute

in patients who are chronically malnourished

decline in the patient’s neurologic status with

from diseases other than alcoholism, it is still

an acute confusional state. In cases due to rapid

most frequently encountered in male, middle-

correction of hyponatremia, this decline often

aged, malnourished alcoholics. MBD is charac-

follows an initial brief improvement in the

terized by demyelination and necrosis of the

encephalopathy due to the hyponatremia itself.

corpus callosum and was initially a diagnosis

Patients may develop a pseudobulbar affect (in-

that required pathologic confirmation. As neu-

appropriate laughing and crying), and motor

roimaging techniques, especially MRI, have

manifestations may be a prominent feature and

improved and became more helpful in revealing

may include flaccid quadriparesis with progres-

the classic corpus callosum lesions, the historical

sion to spasticity, dysarthria, dysphagia, and a

description provided above has been expanded.

complete locked-in syndrome. With progres-

There are now known to be three clinical

sion of the disease process, stupor and coma

variations of MBD. The acute form is manifested

may occur. Cognitive and psychiatric symptoms

by rapid alteration of consciousness and

may also be more subtle, such as restlessness,

seizures, with swift progression to coma and

emotional lability, apathy, akinetic mutism,

then frequently death within a matter of days.

478

Chapter 23

n Neurologic Complications of Alcoholism

This variant is often associated with diffuse

longstanding alcohol abuse, occurring more fre-

hypertonia and rigidity, dysphagia, and mute-

quently than Wernicke encephalopathy. Alco-

ness. The subacute form is similar, with hyper-

holism is a frequent etiology of acquired

tonia and dysarthria also frequent features, as

cerebellar impairment. The clinical manifesta-

well as facial grimacing and opisthotonus.

tions are usually subacutely progressive over

However, as the name suggests, it differs in its

months, but may occur more rapidly, or more

time course, with patients presenting with a de-

chronically over years.

mentia of rapid onset which then evolves into a

n SPECIAL CLINICAL POINT: The classic

vegetative state. Death may occur within

clinical picture of alcoholic cerebellar

months. In the chronic form, the neurologic

degeneration is that of a very ataxic gait (wide

symptoms and signs may persist for months to

based, unsteady, with shortened steps) and

years, but may then resolve and a wide range of

stance with only minimal to mild cerebellar

clinical manifestations are possible. An inter-

findings in the upper extremities.

hemispheric disconnection syndrome mani-

Cerebellar abnormalities involving speech and

fested by limb apraxia, agraphia, and alexia is

ocular movements are not usually seen. The

common, and a gait disorder, urinary inconti-

pathologic findings correspond to the clinical

nence, hemiparesis, aphasia, disorientation,

manifestations of ACD, with either the degen-

and memory loss may occur. Patients with the

erative changes restricted to the anterior and

acute and subacute form may also present with

superior portions of the cerebellar vermis, or in

an interhemispheric disconnection syndrome.

some cases, with these regions being affected

MRI will usually reveal areas of low signal

earlier and more severely than adjacent areas.

intensity on the T1-weighted images, with anal-

Focal atrophy of the vermis may be seen in

ogous areas of high signal intensity on the T2

chronic alcoholics on the T1-weighted sagittal

and FLAIR images, in a portion of the corpus

MRI images, even in the absence of clinical

callosum; the entire corpus callosum is usually

signs.

not involved. Extracallosal lesions may occur in

Although this is a neurologic complication

the adjacent white matter, hemispheric white

most often seen in longstanding alcoholics,

matter, and middle cerebellar peduncles. Callosal

an exact relationship between the amount of

atrophy may be seen in chronic cases. Cortical

alcohol consumption and the onset of cere-

lesions are not inconsistent with this diagnosis,

bellar symptoms has not been clearly delin-

but are seen more frequently on pathologic stud-

eated. In addition to the direct neurotoxic

ies at autopsy than on neuroimaging.

effects of alcohol and its metabolites such as

Although the exact pathophysiologic mecha-

acetaldehyde, thiamine deficiency and overall

nism of MBD is not known, vitamin B complex

nutritional status are also thought to be con-

deficiencies and vascular injury have been pro-

tributing factors to the development of ACD;

posed as possible underlying etiologies. On the

however, the degree to which each of these is

basis of the former possible mechanism, patients

responsible is not known. Environmental and

may respond to treatment with high-dose

genetic variables and age are thought to play

vitamin B complex supplementation. Cortico-

a role as well. Clinical improvement may

steroids are sometimes administered as well.

occur with abstinence.

ALCOHOLIC CEREBELLAR

DEGENERATION

ALCOHOLIC DEMENTIA

Unlike some of the other neurologic complica-

In addition to cerebellar atrophy, chronic

tions discussed, alcoholic cerebellar degeneration

alcoholics also develop diffuse atrophy that may

(ACD) is not a rare neurologic manifestation of

be evident on neuroimaging by the presence of

479

Chapter 23

n Neurologic Complications of Alcoholism

enlarged ventricles and sulcal widening. The

manifestations tends to be insidious and there-

atrophy is attributed mainly to a decrease in the

fore, they may go undiagnosed. This, in turn,

cerebral white matter and while it is wide-

has considerable clinical implications, because

spread, there is disproportionate involvement of

unlike many of the above discussed CNS com-

the frontal and frontoparietotemporal regions.

plications, there is great potential for signifi-

Chronic alcoholics frequently have cognitive

cant improvement with alcohol cessation

deficits, especially apparent on formal neu-

alone.

ropsychological testing, that are not limited to

one domain and may be seen on tests of mem-

Alcoholic Neuropathy

ory, attention, visual and verbal learning, visu-

ospatial abilities, psychomotor speed, and

Alcoholic neuropathy is a distal axonal senso-

executive functions. The presence or degree of

rimotor polyneuropathy. A wide incidence has

cognitive manifestations of chronic alcoholism

been cited in the literature, with an even

does not clearly correspond to the neuroimaging

greater number of chronic alcoholics found to

findings of atrophy. It is unclear if alcoholics

have evidence for neuropathy when electrodi-

truly have deficits in these individual modalities

agnostic testing is utilized. Like many other

or have an overall deficit of higher-order

peripheral polyneuropathies, such as that due

processes.

to diabetes, a patient’s initial symptom is usu-

Patients may develop cognitive impairment

ally distal paresthesias involving the feet, often

and neuroimaging findings consistent with

with associated numbness, which gradually

atrophy without previous episodes of Wernicke

progress in a proximal distribution. Over time,

encephalopathy and therefore independently

symptoms will progress in intensity, becoming

from a diagnosis of Wernicke-Korsakoff syn-

more painful, and spread to include the fingers.

drome. This supports a pathophysiologic

The pain may become so severe that the

mechanism other than thiamine deficiency as

patient’s activities of daily living are adversely

the etiology of alcoholic dementia. These

impacted. Motor manifestations, including

changes are therefore considered to be due to

weakness and atrophy, develop after the

the toxic effects of ethanol and its metabolites,

sensory symptoms, but do not usually reach

with the exact mechanism of this toxicity not

the degree of the sensory involvement. Auto-

yet fully elucidated. Likely contributing to the

nomic involvement manifested by constipa-

cognitive impairment in many patients is the

tion, urinary retention, impotence, impaired

high comorbidity of head trauma and other

sweating, gastroparesis, orthostatic hypoten-

coexisting encephalopathies. Patients may have

sion, and cardiovascular autonomic dysfunc-

improvement in their cognitive impairment

tion may occur. The autonomic symptoms are

and atrophy with abstinence, with recovery

usually not as frequent and are often more mild

occurring in as early as a few weeks and as late

than the sensory and motor findings. Cranial

as several years after stopping drinking.

nerve involvement is rare.

Neurologic examination reveals early loss of

nociception, with loss of all sensory modalities

being seen in more advanced cases. With loss

PERIPHERAL NERVOUS SYSTEM

of proprioception, patients may have a result-

MANIFESTATIONS OF CHRONIC

ant sensory ataxia with gait instability, and

ALCOHOLISM

Romberg sign may be present on examination.

Although much of the emphasis of this chapter

Loss of the Achilles reflex is a common sign.

has been placed on the potential CNS manifes-

Chronic findings may include the development

tations of chronic alcoholism, complications

of Charcot joints and distal hair loss. The diag-

of the PNS, namely neuropathy and myopathy,

nosis of alcoholic neuropathy may be sup-

are well described. The onset of these

ported by other findings on examination

480

Chapter 23

n Neurologic Complications of Alcoholism

consistent with chronic alcoholism, such as

studies with sustained abstinence. Patients

those findings seen in cirrhotic patients dis-

with mild to moderate neuropathies tend to

cussed previously.

recover more fully. Patients who significantly

Electromyography and nerve conduction

decrease their alcohol intake, without com-

studies will confirm the presence of an axonal

plete abstention, may also recover. The lack of

polyneuropathy. Further invasive studies, such

efficacy of vitamin supplementation in pa-

as nerve biopsy or nerve fiber density, are not

tients who continue to drink further supports

indicated for the routine diagnosis of alcoholic

a direct toxic effect of ethanol and its metabo-

neuropathy. It is critical, however, to consider,

lites as the underlying pathophysiology of

and rule out as appropriate, other underlying

pure alcoholic neuropathy. Concomitantly oc-

etiologies of a painful peripheral neuropathy,

curring diseases such as diabetes will adversely

such as diabetes, amyloidosis, cryoglobuline-

impact prognosis.

mia, HIV, and Fabry disease.

In addition to alcohol cessation, patients

Thiamine deficiency is known to result in a

may have some improvement of their painful

peripheral polyneuropathy, and neuropathy

paresthesias with symptomatic therapies such

is a frequently associated finding in patients

as gabapentin and pregabalin. Topical treat-

with Wernicke encephalopathy. Therefore, al-

ments, such as the lidocaine patch, may also

coholic neuropathy was initially thought to be

provide some pain relief. In patients with a sen-

a direct result of alcoholism-induced thiamine

sory ataxia, physical therapy with gait and bal-

deficiency. The pathophysiology of alcoholic

ance training may result in improved patient

neuropathy is now known to not be this

safety.

straightforward. This is supported by the pres-

In addition to the commonly encountered

ence of alcoholic neuropathy in patients with-

variant of alcoholic neuropathy, alcoholics

out thiamine deficiency, the distinct clinical

with alcoholic neuropathy are also at in-

presentation and pathologic findings of pure

creased risk for superimposed compression

thiamine deficiency neuropathy, and by

neuropathies. A common site of compression

the finding of a dose-dependent relationship

is the radial nerve at the spiral groove, known

between the presence and severity of alcoholic

as the “Saturday night palsy,” which results

neuropathy and total lifetime dose of alcohol.

from falling asleep in a sitting position with

Alcoholic neuropathy is now thought to be, at

their upper extremities dangling over the arms

least in large part, a result of the toxic effects of

of a chair, then awakening with a wrist drop.

ethanol or its metabolites on the PNS. The

Other common sites susceptible to compres-

superimposed presence of thiamine deficiency

sion injury include the peroneal nerve at the

may result in variation of the clinical picture of

fibular head and the ulnar nerve at the elbow.

the classic alcoholic neuropathy described

Very rarely, alcohol neuropathy will present

above.

with an acute or subacute course. In these

Prognosis is often poor in patients who

cases, the main differential diagnosis is Guil-

continue to drink heavily, with further pro-

lain-Barré syndrome, which may be distin-

gression of their alcoholic neuropathy result-

guished from an acute alcoholic neuropathy

ing in worsening pain and gait instability.

by normal CSF protein and evidence of an ax-

Patients may also stabilize with no further de-

onal, not demyelinating, process on electrodi-

terioration, despite continued drinking. The

agnostic studies.

reverse is also true, and patients with severe

alcoholic neuropathy may have a good prog-

Alcoholic Myopathy

nosis with improvement of their symptoms

and resolution of the abnormalities found on

Although alcoholic myopathy often occurs

neurologic examination and electrodiagnostic

concurrently with alcoholic neuropathy, it is a

481

Chapter 23

n Neurologic Complications of Alcoholism

distinct phenomenon with the clinical picture

in the absence of electrolyte abnormalities and

the result of a unique pathologic process. As

therefore this is not a sufficient explanation on

with alcoholic neuropathy, there is an acute and

its own. However, due to the potential to exac-

chronic form, and although the chronic form is

erbate the acute illness, nutritional, vitamin,

much more common than the acute form, the

and electrolyte deficiencies and disturbances

acute form does occur with more regularity than

should be actively sought out and corrected.

the rare cases reported of acute alcoholic neu-

Adequate intravenous fluid replacement and

ropathy. The clinical syndrome of acute

maintenance of a high urine pH may protect

alcoholic myopathy consists of usually proximal

against the renal complications. Neurologic

myalgias (cramping and pain) in association

prognosis is often good with patients able to

with muscle tenderness, swollen muscles, and

recover full strength within days to weeks with

weakness. Calf involvement is not rare. The

avoidance of alcohol, even following repeated

onset of symptoms is usually over hours to days,

episodes; overall prognosis is dependent on

and patients will often have associated myoglo-

how well patients recover from the associated

binuria due to rhabdomyolysis, with markedly

renal failure.

elevated serum creatine phosphokinase (CK).

Chronic alcoholic myopathy is estimated to

Myoglobinuria results in acute tubular necrosis

be one of the most common causes of muscle

and, in turn, renal impairment. This risk for

disease, occurring much more frequently than

acute renal failure is the most clinically signifi-

genetic muscular disorders. It is also one of the

cant aspect of this condition. Patients may have

most frequent neurologic complications of

bulbar and respiratory muscular involvement,

alcoholism. Chronic alcoholic myopathy dif-

especially in the acute diffuse necrotizing form.

fers greatly from the acute variant in its clini-

Acute alcoholic myopathy usually is triggered

cal presentation, not just its time course.

by a severe alcoholic binge, especially in mal-

Progressive proximal muscle weakness

nourished chronic alcoholics or in those who

(mainly involving the shoulder and pelvic gir-

binge after a long period of abstinence, and has

dles) occurs over many weeks to months with

a male gender predominance. There is a wide

minimal to no associated myalgias. Although

spectrum of disease; while patients may have a

this is the usual pattern of muscle involvement,

severe course with acute renal failure, many are

patients may have more widespread involve-

asymptomatic or experience only mild myalgias

ment, with generalized muscle weakness some-

and a milder transient rise in CK.

times seen. A subclinical form also exists in

In addition to serum CK levels, serum and

which patients are not symptomatic, but mild

urine myoglobin may support the diagnosis.

weakness and atrophy may be detected by

Also, evidence for an acute myopathic process

physical examination.

may be seen on electrodiagnostic studies,

Chronic alcoholic myopathy occurs equally in

although these changes may not be apparent

both sexes, most commonly in patients who have

until approximately 2 weeks after the onset of

been drinking heavily for over 10 years. It natu-

symptoms. On pathologic studies (not indi-

rally follows that patients will often have other

cated in the routine diagnosis of this illness),

manifestations of chronic alcohol abuse such as

there is necrosis and phagocytosis of both the

cirrhosis, peripheral neuropathy, and cardiomy-

red and white muscle fibers.

opathy due to cardiac muscle involvement.

Muscle injury is thought to be due to a toxic

Neurologic examination of patients with

effect of ethanol, either through direct injury or

chronic alcoholic myopathy will usually

through impairment of metabolic processes.

reveal atrophy in addition to the proximal

Electrolyte derangements such as hypokalemia

muscle weakness. Fasciculations may be seen.

and hypophosphatemia may contribute to this

Serum CK levels are frequently normal or only

process, but acute alcoholic myopathy occurs

mildly elevated and patients do not have

482

Chapter 23

n Neurologic Complications of Alcoholism

myoglobulinuria. In a chronic alcoholic with

undergo significant gradual recovery. Patients

this clinical picture and without any other un-

may benefit greatly from physiotherapy dur-

derlying etiologies of a myopathy, muscle

ing the recovery period to improve muscle

biopsy revealing atrophy of primarily the type

bulk and motor function.

II muscle fibers and myocyte necrosis is con-

sidered diagnostic. These biopsy findings are

not specific to chronic alcoholic myopathy and

WHEN TO REFER PATIENTS

it is the presence of all of these criteria and not

TO A NEUROLOGIST

the biopsy alone that allows for the diagnosis

to be made. Rarely, however, in clinical prac-

The spectrum of potential neurologic compli-

tice is biopsy necessary, with the diagnosis

cations of chronic alcoholism is broad, ranging

usually made based on the history, examina-

from commonly encountered manifestations,

tion findings, and supporting laboratory and

such as hepatic encephalopathy and cerebellar

electrodiagnostic data.

degeneration, to the more rare manifestations,

Like acute alcoholic myopathy, chronic

such as MBD. Further complicating the diag-

alcoholic myopathy is the result of the direct

nosis and, in turn, the management of these

toxic effects of alcohol on striated muscle and

patients is that they often do not present with

its pathogenesis is not related to nutritional,

“classic” clinical presentations such as the full

electrolyte, or vitamin derangements or to the

triad of Wernicke encephalopathy, and patients

frequently concurrent liver dysfunction. Multi-

suffering from chronic alcoholism will often

ple theories exist for how ethanol results in

not have a singular complication, but rather

muscle disease, including the production of

multiple ones superimposed on each other,

free radicals, alterations of protein and glyco-

involving both the PNS and CNS. Although the

gen metabolism, and impairment of mitochon-

only treatment for many of the possible neuro-

drial function. Likely, a combination of

logic complications of alcoholism is alcohol

multiple different alcohol-induced mechanisms

cessation, some, such as Wernicke and pellagra

results in the final clinical picture. Patient-

encephalopathy, constitute neurologic emer-

specific variables such as gender, nutritional

gencies and therefore need to be recognized

status, and the presence of other disease

promptly. Therefore, practitioners who care

processes may make a patient more susceptible

for this patient population must have a high

to these toxic effects.

index of suspicion for some of the rarer, yet

As with the acute variant, treatment con-

treatable complications of chronic alcoholism.

sists mainly of abstinence; however, correc-

A neurologist may be consulted whenever the

tion of electrolyte, vitamin, and other

primary physician is uncomfortable with the

nutritional deficiencies, such as inadequate

diagnosis or management of the patient, or

calorie or protein intake, may hasten and re-

the patient does not respond to therapy in the

sult in a more complete recovery. Ethanol tox-

expected manner for the presumed diagnosis.

icity on muscle is known to be dose dependent

A neurologist may be consulted prior to the or-

and this applies to recovery as well. Patients

dering of diagnostic studies such as electrodiag-

who are truly abstinent will have improve-

nostic testing or MRI as this testing may not be

ment or at least stabilization of their disease

necessary and is not always helpful in confirm-

and patients who continue to drink heavily

ing the neurologic diagnosis. The evaluation

will have further progression of their myopa-

and treatment of acutely ill patients, such as

thy. Patients who are not fully abstinent but

those in whom Wernicke encephalopathy or

significantly reduce their alcohol intake will

superimposed CNS infection or hemorrhage is

usually also have improvement. With cessa-

suspected, should never be delayed in order to

tion of ethanol use, most patients will

obtain a neurologic consultation.

483

Chapter 23

n Neurologic Complications of Alcoholism

tenderness to palpation and mild proximal

Always Remember

weakness. CK is 850 IU/L. Electrolyte

levels are normal. What is the most

• Wernicke encephalopathy is a neurologic

appropriate initial management of this

emergency, whose diagnosis, and therefore

patient?

the decision to treat, should be based on the

A. Transfer from the emergency room to an

clinical picture alone.

inpatient alcohol rehabilitation program

• As treatment is generally well tolerated and

B. Discharge home with a nonsteroidal

the risk of missing the diagnosis is so great,

anti-inflammatory agent

Wernicke encephalopathy should be

C. Intravenous fluid replacement and

considered in all high-risk patients.

maintenance of a high urine pH

• Pellagra encephalopathy is a clinical diagnosis

D. Phosphorus supplementation

that can be confirmed by clinical

E. EMG and nerve conduction studies

improvement with replacement therapy.

• A triggering clinical event superimposed on

The correct answer is C. This patient’s clinical

chronic underlying liver disease is often

history and his clinical symptoms and signs

responsible for the development of hepatic

are most compatible with an acute alcoholic

encephalopathy. As a result, treatment of

myopathy. Intravenous fluid replacement and

hepatic encephalopathy starts with a search

maintenance of a high urine pH may protect

for and correction of any triggering factors.

against the renal complications of this condi-

• The classic clinical picture of alcoholic

tion. Electrodiagnostic studies may ultimately

cerebellar degeneration is that of a very

be helpful but are not necessary immediately.

ataxic gait and stance, with only minimal to

The overall prognosis in this condition is

mild cerebellar findings seen in the upper

dependent on how well patients recover from

extremities. If there are prominent upper

the associated renal impairment of acute

extremity symptoms, another diagnosis

alcoholic myopathy.

should be strongly considered and searched

2. A man is brought to the emergency room

for (such as a cerebellar infarct or

after being found in the street by the

hemorrhage).

police. He appears to be in his mid-forties

• When diagnosing alcoholic neuropathy, it is

and severely malnourished, smells of

critical to rule out other underlying etiologies

alcohol, and has a laceration on his

of a painful peripheral neuropathy.

forehead with dried blood. He is mildly

lethargic, oriented only to person, and is

dysarthric. CT scan of the head without

contrast does not reveal any acute

QUESTIONS AND DISCUSSION

intracranial pathology. What diagnostic

1. A 56-year-old man who has been a

studies should be performed prior to

recovering alcoholic for a number of years

administering the appropriate treatment in

relapses at a party. He then goes on to

this patient?

drink multiple bottles of hard liquor over

A. Administration of 1 mg of IV thiamine

the next several days. Two days later, he

to ensure that the patient does not have

presents to the emergency room reporting

an anaphylactic reaction prior to

severe cramping and muscle pain of his

administering the full dose

proximal lower extremities which has

B. Lumbar puncture to assess the CSF

progressed over the past day, and an

thiamine level

episode of “cola-colored” urine. On

C. No studies are indicated prior to

examination, he has exquisite muscle

treatment

484

Chapter 23

n Neurologic Complications of Alcoholism

D. Red blood cell transketolase levels in

E. Outpatient initiation of treatment with

serum

rifaximin alone

E. Serum thiamine level

The correct answer is A. A triggering clinical

The correct answer is C. Wernicke

event superimposed on chronic underlying

encephalopathy is a neurologic emergency,

liver disease is often responsible for the devel-

whose diagnosis, and therefore the decision to

opment of hepatic encephalopathy. As a

treat, should be based on the clinical picture

result, treatment of hepatic encephalopathy

alone. As treatment is generally well tolerated

starts with a search for and correction of any

and the risk of missing the diagnosis is so

triggering factors. MRI will often show high

great, this diagnosis should be considered in

signal on the T1 images in the globus pallidus,

all high-risk patients, particularly when the

but this finding is seen in many patients with

patient presents acutely intoxicated. Measures

chronic liver disease and is not in itself specific

of thiamine status, including thiamine levels

for the clinical diagnosis of hepatic

and red blood cell transketolase, are not diag-

encephalopathy.

nostic, may not be available emergently, and

4. A 70-year-old woman presents with

should not be relied on to make treatment

6 months of progressively painful

decisions.

paresthesias that began in the feet and have

spread up to the ankles. She denies any

3. A 60-year-old woman with longstanding

SUGGESTED READING

Pearce JMS. Wernicke-Korsakoff encephalopathy. Eur

Neurol. 2008;59:101-104.

Bartha P, Shifrin E, Levy Y. Pancreatic encephalopathy—a

rare complication of a common disease. Eur J Intern

Preedy VR, Adachi J, Ueno Y, et al. Alcoholic skeletal

Med. 2006;17:382.

muscle myopathy: definitions, features, contribution

of neuropathy, impact and diagnosis. Eur J Neurol.

Burkhard PR, Delavelle J, Du Pasquier R, Spahr L.

2001;8(6):677-687.

Chronic parkinsonism associated with cirrhosis: a dis-

tinct subset of acquired hepatocerebral degeneration.

Sechi GP, Serra A. Wernicke’s encephalopathy: new clini-

Arch Neurol. 2003;60:521-528.

cal settings and recent advances in diagnosis and man-

agement. Lancet Neurol. 2007;6:442-455.

Delgado-Sanchez L, Godkar D, Niranjan S. Pellagra:

rekindling of an old flame. Am J Ther. 2008;15:

Thomson AD, Cook CCH, Guerrini I, et al. Wernicke’s

173-175.

encephalopathy: ‘Plus ca change, plus C’Est a mem

chose’. Alcohol Alcohol. 2008;43(2):180-186.

Fitzpatrick LE, Jackson M, Crowe SF. The relationship

between alcoholic cerebellar degeneration and cogni-

Urbano-Márquez A, Fernández-Solá J. Effects of alcohol

tive and emotional functioning. Neurosci Biobehav

on skeletal and cardiac muscle. Muscle Nerve.

Rev. 2008;32(3):466-485.

2004;30(6):689-707.

Kleinschmidt-DeMasters BK, Rojiani AM, Filley CM.

van der Helm van Mil AHM, van Vugt JPP, Lammers GJ,

Central and extrapontine myelinolysis: then . . . and

Harinck HIJ. Hypernatremia from a hunger strike as a

now. J Neuropath Exp Neurol. 2006;65(1):1-11.

cause of osmotic myelinosis. Neurology.

2005;64(1):574-575.

Kohler CG, Ances BM, Coleman AR, et al. Marchiafava-

Bignami disease: literature review and case report.

Victor M, Adams RD, Collins GH. The Wernicke-

Neuropsychiatry Neuropsychol Behav Neurol.

Korsakoff Syndrome and Related Neurologic Disor-

2000;13(1):67-76.

ders Due to Alcoholism and Malnutrition. 2nd ed.

Philadelphia, PA: FA Davis Company; 1989.

Koike H, Sobue G. Alcoholic neuropathy. Curr Opin

Neurol. 2006;19:481-486.

Wijdicks EFM, Wiesner RH. Acquired (non-Wilsonian)

hepatocerebral degeneration: complex management

Lockwood AH. Hepatic encephalopathy. In: Aminoff MJ,

decisions. Liver Transpl. 2003;9(9):993-994.

ed. Neurology and General Medicine. 4th ed. Philadel-

phia, PA: Churchill Livingstone; 2008:265-279.

Yokota O, Tsuchiya K, Terada S. Frequency and clinico-

pathological characteristics of alcoholic cerebellar

Ménégon P, Sibon I, Pachai C. Marchiafava-Bignami dis-

degeneration in Japan: a cross-sectional study of

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cortical lesions. Neurology. 2005;65(3):475-477.

2006;112:43-51.

Central

Nervous System

Infections

LARRY E. DAVIS

key points

• Meningitis may be viral, bacterial, or fungal. These

different types of meningitis differ in terms of time

course, severity, and recommended treatments.

• Encephalitis is usually viral. Herpes encephalitis in

particular should be treated with acyclovir.

• Brain abscesses are usually bacterial and may cause

significant symptoms based on mass effect.

• Prion diseases (e.g., Creutzfeldt-Jakob) are

characterized by rapidly progressive dementia.

entral nervous

entry through adjacent bone following open skull

fracture or from infected mastoid or air sinuses.

system

(CNS) infections can be caused by

viruses, bacteria, fungi, parasites, and prions,

but bacteria and viruses are the most common

Despite the many infections we develop during

causes. All but one class of human infectious

our lifetimes, organisms rarely reach the brain.

agents

(called prions) possess nucleic acid

For example, transient bacteremias are com-

(DNA, RNA, or both) surrounded by a variety

mon following vigorously brushing teeth, yet

of proteins and lipids to create a particle, single

the bacteria do not cause meningitis. Important

cell, or complex cellular organism. Infectious

protective systems include the reticuloendothe-

agents enter the body by way of the gastroin-

lial system (which efficiently removes bacteria

testinal tract or respiratory tract or following

and viruses from blood), cellular and humoral

skin inoculation (animal or insect bite) and set

immune responses (which destroy organisms

up the initial site of replication in these tissues.

from the blood and primary site of infection),

and the blood-brain barrier (which prevents

entry of organisms into the brain or cere-

n SPECIAL CLINICAL POINT: The majority

of organisms then reach the CNS by way of the

brospinal fluid [CSF]). Organisms that do enter

bloodstream, but occasional organisms reach the

the brain or CSF from blood do so by infecting

brain by way of peripheral nerves or by direct

endothelial cells of the cerebral blood vessels

486

487

Chapter 24

n Central Nervous System Infections

(many encephalitis viruses), penetrating the

n SPECIAL CLINICAL POINT: The time

blood-CSF barrier in the meninges or choroid

course of the meningitis may give clues as to

its etiology. Viral and bacterial meningitis are

plexus (many bacteria) or occluding small cere-

acute illnesses with symptoms developing over

bral blood vessels with infected emboli from the

hours to 1 day. Patients with fungal meningitis

blood (brain abscess organisms). Once the inva-

or tuberculous meningitis develop symptoms

sion has occurred, the brain and CSF have less

over days to 2 weeks.

immune protection than the rest of the body.

Normal CSF has about 1/500th the amount of

antibody as blood and has few white blood cells

Common Laboratory Findings

(WBCs). Thus, individuals who develop a brain

or meningeal bacterial or fungal infection usu-

The WBC in blood usually is elevated, as is the

ally die without antimicrobial intervention.

erythrocyte sedimentation rate. The CSF ex-

Inflammation of the meninges or brain is the

amination is the key to the diagnosis of menin-

hallmark of CNS infection. Inflammatory cells

gitis with ascertainment of the type of

may be present in the meninges, in perivascular

infecting agent, establishment of the etiologic

spaces, or within brain parenchyma such as

agent, and determination of antimicrobial sen-

around an abscess or with encephalitis. The in-

sitivities (Fig. 24.1). Viral, bacterial, tubercu-

flammatory monocytes show specific immune

lous, and fungal infections of the meninges

activity against the infectious agent.

have differing CSF profiles (Table 24.1). CSF

culture determines the etiology of the infection

n SPECIAL CLINICAL POINT: The signs and

as well as antimicrobial sensitivities. In gen-

symptoms of a CNS infection depend on the

eral, cultures for bacteria take 1 to 3 days,

site of the infection—not the organism. The

virus cultures take days to 3 weeks, and tuber-

organism determines mainly the time course

and severity of the infection.

culosis and fungi cultures take 1 to 6 weeks.

Rapid diagnosis of bacteria can be made by

In general, the time course to develop CNS signs

Gram stain of CSF sediment and by testing

depends on the microorganism class: viruses

CSF for common bacterial antigens. The Gram

(hours to 1 day); aerobic bacteria (hours to a

stain will detect bacteria in CSF sediment in

few days); anaerobic bacteria, tuberculosis, and

more than three fourths of patients with acute

fungi (a few days to weeks); parasites and Tre-

bacterial meningitis and often gives clues for

ponema pallidum (syphilis) (weeks to years).

initial antibiotic treatment. Latex agglutina-

tion antigen tests are commercially available

to detect Haemophilus influenzae, Streptococ-

MENINGITIS

cus pneumoniae, Neisseria meningitidis, and

group A beta-hemolytic streptococci. Antigen

A variety of viral, bacterial, fungal, parasitic,

tests have about the same sensitivity as the

chemical, and neoplastic agents may cause in-

Gram stain and may be useful if the patient is

flammation of the meninges. These patients all

already receiving antibiotics. The polymerase

have common clinical features:

chain reaction (PCR) diagnostic test is readily

• Early features: Prodromal illness, fever,

available to rapidly diagnose Mycobacterium

headache, stiff neck, relative preservation

tuberculosis, enteroviruses, and herpes sim-

of mental status, no focal neurologic

plex virus. Many others are available on a re-

signs, no papilledema.

search basis. PCR detects tiny amounts of

• Later features: Seizures, stupor and

nucleic acids of these infectious agents in CSF.

coma, cranial nerve palsies, deafness,

Advantages of the PCR assay is that it can be

focal neurologic signs may develop if the

performed within hours and can detect nucleic

etiology is other than viral.

acid from organisms that may be very difficult

488

Chapter 24

n Central Nervous System Infections

FIGURE 24.1 Flow diagram for LP and CSF tests in suspected bacterial meningitis. (From Davis LE.

Acute bacterial meningitis. In: Weiner WJ, ed. Emergent and urgent neurology. Philadelphia: JB Lippincott,

1992:139, with permission.)

to culture. However, the PCR does not give in-

Viral Meningitis

formation regarding antimicrobial sensitivi-

Enteroviruses

(echoviruses and Coxsackie

ties. Thus, the best diagnostic test is still to

viruses) are the most common cause of viral

culture the CSF and blood for an infectious

meningitis. Less common viruses include herpes

agent and use the isolate to determine antimi-

simplex virus type 2, mumps virus, lymphocytic

crobial sensitivities.

choriomeningitis, and human immunodeficiency

TABLE 24.1

Spinal Fluid Profiles in CNS Infections

Opening

White

Bacterial or

Pressure

Blood Cells

Protein

Glucose

Fungal Culture

Epidural abscess

N or s1 ↑

0-20 (lymphs)

N or s1 ↑

Negative

Subdural empyema

↑

10-1000 (polys)

s1 ↑

Negative

Viral meningitis

N or s1 ↑

20-1000 (lymphs)^a

s1 ↑

Negative

Bacterial meningitis

↑

50-5000 (polys)

↑

Low

Positive

Fungal or tuberculous

↑

50-5000 (polys and

↑

Low

Positive

meningitis

lymphs)

Meningovascular

N or s1 ↑

10-1000 (lymphs)

↑

Negative

syphilis

Brain abscess

↑

0-10 (lymphs and

Negative

polys)

Viral encephalitis

s1 ↑

10-200 (lymphs)

N or s1 ↑

Negative

^aCSF may show poly predominance during the first day.

N, normal; s1 ↑ , slight increase; ↑, increased.

489

Chapter 24

n Central Nervous System Infections

virus. Typically in viral meningitis, the CSF con-

perform a computed tomography (CT) or a

tains a pleocytosis with predominately lympho-

magnetic resonance imaging (MRI) scan before

cytes, mildly elevated protein, normal glucose,

the LP unless the patient is immunosuppressed;

and negative Gram stain of sediment. However,

is elderly; or presents with coma, focal neuro-

in the first day of the meningitis, there may be a

logic signs, or papilledema that places them at

predominance of neutrophils in the CSF. Viruses

increased risk for a focal CNS mass. If there is to

often can be isolated from CSF early in the

be a significant delay before the neuroimaging

meningitis, and PCR analysis of CSF rapidly di-

can be obtained, broad-spectrum antibiotics

agnoses enteroviruses and herpes simplex type 2

should be given before the LP. However, one

viruses. Treatment of most viral meningitis is

always should obtain a blood culture before ad-

usually symptomatic and may include analgesics

ministrating the antibiotics. A blood culture is

for the headache and antiemetics for nausea and

positive in 60% of patients with bacterial menin-

vomiting. In sexually active adults, genital her-

gitis and thus could yield antibiotic sensitivities.

pes simplex may develop accompanied by

The key to treatment of acute bacterial

meningitis, which can recur for years. If herpes

meningitis is the prompt administration of ap-

simplex virus is identified in CSF or in herpetic

propriate antibiotics. General principles in-

vesicles, use of high-dose acyclovir may shorten

volved in the use of antibiotics include the

the duration of the meningitis.

following: (a) the antibiotic should be given

early in the clinical course;

(b) the bacteria

n SPECIAL CLINICAL POINT: Hospitalization

must be sensitive to the antibiotic; (c) the an-

for viral meningitis may not be required if the

tibiotic must cross the blood-brain barrier and

diagnosis is certain, but the patient should be

achieve sufficient CSF concentrations to kill

observed at home by a responsible individual.

The prognosis of viral meningitis is excellent, and

the bacteria. Once the diagnosis of bacterial

most patients fully recover within 1 to 2 weeks.

meningitis is made, one should begin treatment

with broad-spectrum antibiotics, which later

can be modified when antibiotic sensitivities

Acute Bacterial Meningitis

become available. The choice of an antibiotic

for initial treatment depends on several factors:

Both gram-positive and gram-negative aerobic

age, immune status, and predisposing medical

bacteria cause meningitis. S. pneumoniae is the

conditions of the patient; results of CSF Gram

most common bacterium affecting all ages fol-

stain and bacterial antigen tests; knowledge of

lowed by N. meningitidis and H. influenzae.

the types of drug-resistant bacteria in the com-

Since the introduction of H. influenzae type B

munity; and whether the patient is allergic to

and pneumococcal vaccines to children, the in-

any antibiotic. Table 24.2 gives common initial

cidence of meningitis in children has decreased

antibiotic regimens, but one should check ref-

dramatically.

erences such as the Medical Letter for the latest

n SPECIAL CLINICAL POINT: Unlike viral

recommendations.

meningitis, patients with bacterial meningitis

Neurologic injury in bacterial meningitis oc-

will progress to death if untreated with

curs in up to 20% of patients. Mechanisms of

antibiotics. Therefore, prompt diagnosis

cerebral injury include meningeal vasculitis caus-

and treatment are essential.

ing spasm or thrombosis of meningeal arteries,

If bacterial meningitis is suspected, the lumbar

arterioles, veins, or venules. The consequence is

puncture (LP) becomes an emergency procedure

ischemia to the underlying brain resulting in in-

(Fig. 24.1). Although increased intracranial pres-

farctions. Second, a variety of toxins are pro-

sure is common in bacterial meningitis, it rarely

duced within the CSF by the bacteria and

poses a risk of brain herniation that would

inflammatory cells such as endotoxin, reactive

prevent an LP. Thus, it seldom is necessary to

oxidizing chemicals from neutrophil granule

490

Chapter 24

n Central Nervous System Infections

TABLE 24.2

Initial Antibiotic Therapy While Awaiting Identification of Infecting Organisms

Setting

Therapy

Preterm and newborn

Ampicillin plus cefotaxime, or ampicillin plus aminoglycoside

2 months to adulthood

Ceftriaxone or cefotaxime plus vancomycin, usually with ampicillin;

vancomycin and ampicillin can be stopped if the bacteria are

sensitive to cephalosporins; ampicillin is given if Listeria

monocytogenes is suspected

Cranial trauma, recent

Vancomycin, cefepime, ceftazidime, or meropenem

neurosurgery, or CSF shunt

One should always check with references such as the Medical Letter for the latest recommendations because resistance patterns are changing.

release, and cytokines released from mononu-

sone should be given only when the illness and

clear cells that cross the pial barrier to reach

CSF findings are highly suggestive of community

cerebral gray matter causing neuronal necrosis.

acquired bacterial meningitis in an immunocom-

The third mechanism develops from inade-

petent patient without contraindications for

quate cerebral arterial perfusion producing

steroid administration such as a recent GI bleed.

global cerebral ischemia. Cerebral perfusion

In general, the CSF becomes sterile within

pressure results from systemic blood pressure

1 day after antibiotic treatment. The fever usu-

minus intracranial pressure. Increased intracra-

ally disappears within a few days but may

nial pressure can result from increased brain

persist for up to 2 weeks. CSF abnormalities

water from the first two mechanisms, increased

rapidly return toward normal, but the pleocy-

CSF pressure due to obstructive hydrocephalus

tosis and elevated protein may persist for sev-

and from increased cerebral blood from dilated

eral weeks. Dead bacteria may be seen on

meningeal arteries and veins responding to the

Gram stain of CSF for several days as are PCR

inflammation. Systemic hypotension can develop

assays for the offending bacteria.

from shock, hypovolemia, dehydration second-

Even if the patient is treated promptly with

ary to fever and vomiting, and inadequate fluid

appropriate antibiotics and steroids, serious

replacement in the hospital. Meningeal bacteria

complications still may develop. Seizures de-

do not readily penetrate the pia mater and in-

velop in about one third of patients, occur usu-

vade the brain. However, interactions between

ally during the acute phase of the meningitis,

meningeal bacteria and host result in meningeal

and seldom recur after the hospitalization.

inflammation; vascular injury; disruption of the

Causes of seizures in meningitis include cere-

blood-brain barrier; vasogenic, interstitial, and

bral cortex irritation from bacterial toxins or

cytotoxic edema; and disruption of normal

meningeal inflammation, CNS vasculitis, brain

CSF flow. At present, corticosteroids have been

infarction, high fever, and hyponatremia from

shown to have a modest benefit in preventing

the syndrome of inappropriate antidiuretic

neurologic morbidity in children and adults.

hormone coupled with excess fluid administra-

Dexamethasone (0.15 mg/kg intravenously in

tion. Treatment of the seizures is usually with

children every 6 hours and 10 mg in adults

intravenous phosphenytoin or levetiracetam

every 6 hours for 2 to 4 days) commonly is ad-

until hospital discharge. Focal neurologic se-

ministered as early as possible. To minimize risks

quelae include cranial nerve palsies, especially

from administering corticosteroids, dexametha-

cranial nerves VIII (deafness) and VI and III

491

Chapter 24

n Central Nervous System Infections

(diplopia), cerebellar ataxia, and hemiparesis.

Patients develop headaches, cranial nerve

In surviving children and adults, 15% have

palsies (especially the Bell palsy in CNS Lyme

language disorders and 10% have cognitive

disease), and occasionally brain infarctions

problems. CT or MRI of the head is often help-

from thrombosis of cortical blood vessels

ful in the evaluation of these complications and

(meningovascular syphilis). Years later, the

may demonstrate cerebral or cerebellar infarc-

spirochetes occasionally invade the brain caus-

tion, brain necrosis, subdural hygromas, or

ing a low-grade encephalitis (general paresis or

mild ventricular dilatation. Hydrocephalus,

CNS Lyme disease). The CSF contains a lym-

subdural empyema, and brain abscess occur

phocytic pleocytosis, elevated protein, and usu-

but are uncommon. Patients with focal neuro-

ally normal glucose level. Spirochetes seldom

logic damage benefit from rehabilitation fol-

are isolated from CSF, and the diagnosis is

lowing acute antibiotic therapy, especially if

made by serologic tests (CSF-Venereal Disease

deafness is identified. Mortality from bacterial

Research Laboratory or Lyme antibody titers).

meningitis ranges from 5% to 20%, depending

Workup for subacute meningitis is given in

on the strain of infecting bacteria, the age

Table 24.3. Treatment is with high-dose peni-

group, and predisposing illnesses in the patient.

cillin or ceftriaxone for several weeks.

Some bacterial meningitis requires chemo-

prophylaxis of immediate family members

Tuberculous and Fungal Meningitis

and close contacts because of their increased

risk of developing meningitis. In N. meningi-

Patients with tuberculous and fungal meningi-

tidis meningitis, treatment of all close con-

tis usually develop subacute meningitis with

tacts is indicated. Rifampin

(600 mg for

the onset of CNS signs developing over days to

adults or 10 mg/kg for children twice daily

weeks. These infections occur most often in in-

orally for 2 days) or ciprofloxacin (single oral

dividuals who are malnourished, debilitated,

dose of 500 mg for adults) may be given. If the

or immunosuppressed and have been exposed

patient has H. influenzae type B meningitis,

to others with pulmonary tuberculosis. Al-

chemoprophylaxis is indicated for children

though initial entry is usually by way of the

younger than 4 years of age who have been in

lungs, less than 50% will have an active pul-

close contact with the patient and not previ-

monary infection at the time of the meningitis.

ously vaccinated with the H. influenzae type B

The best methods to establish the etiology are

vaccine. Rifampin

(10 mg/kg twice daily

by (a) culture of the CSF, (b) identification by

orally for 4 days) usually is given. All close

PCR infectious agents such as M. tuberculosis,

contacts should be observed carefully for the

next week.

test to detect cells sensitive to TB antigens), (d)

Many cases of bacterial meningitis can be

antigen detection for Cryptococcus neofor-

prevented by immunizing infants and small

mans, and (e) serologic tests for several fungi.

children with H. influenzae type B and pneu-

Because tuberculous or fungal organisms may

mococcal vaccines and by immunizing high-risk

be in low concentrations in the CSF, one should

populations such as college students and mili-

culture a concentrate of 5 to 15 mL of CSF on

tary recruits with the meningococcal vaccine.

several occasions.

Treatment of tuberculous meningitis usu-

ally requires administration of four drugs

Spirochete Meningitis

(rifampin, isoniazid, pyrazinamide, and

Spirochetes produce chronic bacterial meningi-

streptomycin or ethambutol) for 2 months

tis. Borrelia burgdorferi (CNS Lyme disease)

followed by rifampin and isoniazid for an-

and T. pallidum

(neurosyphilis) both cause

other 7 months, depending on the antibiotic

acute and occasionally chronic meningitis.

sensitivities of the M. tuberculosis isolate. Of

492

Chapter 24

n Central Nervous System Infections

TABLE 24.3

Evaluation of Subacute Meningitis

CSF studies: Opening pressure, cell count with differential, glucose, protein, IgG, Gram stain, acid-fast stain, and

cytology; CSF serology includes CSF-VDRL, Coccidioides immitis, Histoplasma capsulatum antibody titers, and

Cryptococcus neoformans antigen titer; PCR assays for M. tuberculosis and other fungi as available;

QuantiFERON-TB Gold test for M. tuberculosis

Skin tests: Intermediate purified protein derivative tuberculin test and anergy skin tests

Serum antibody tests: Brucella, syphilis, toxoplasmosis, Coccidioides immitis, other fungi, Lyme disease, and

human immunodeficiency virus

Cultures for bacteria, M. tuberculosis, and fungi: CSF cultures repeated three times; blood, urine, sputum, or

gastric aspirate; bone marrow biopsy; and skin lesion biopsy

Magnetic resonance image or computed tomograph of head with contrast

Chest x-ray and computed tomograph of abdomen, if indicated

IgG, immunoglobulin G; VDRL, Venereal Disease Research Laboratory.

note, multidrug-resistant tuberculous strains

ENCEPHALITIS

are beginning to cause TB meningitis, espe-

cially in individuals from developing coun-

The majority of infectious agents that cause en-

tries. Their treatment is complex and

cephalitis are viruses that reach the brain by way

difficult. Dexamethasone often is added if the

of a hematogenous route. Once the virus

patient is comatose or has severe neurologic

reaches brain parenchyma, a widely dissemi-

deficits. Patients with fungal meningitis are

nated infection of neurons and glia ensues. Neu-

treated either with broad-spectrum triazoles

ronal necrosis and lysis of glial cells result in

such as fluconazole, itraconazole, voricona-

secondary cerebral edema. The inflammatory

zole, or posaconazole or with liposomal am-

response includes perivascular cuffing with in-

photericin B such as AmBisome for weeks to

flammatory cells and infiltration of lymphocytes

months. Fluconazole has been shown to be

and macrophages into the adjacent brain

nearly as efficacious as liposomal ampho-

parenchyma. The invading immune response

tericin B in the treatment of cryptococcal and

often terminates the infection, but the patient

coccidioidal meningitis. The triazoles have

may be left with permanent neurologic sequelae.

the advantage that they can be given orally

Viruses cause more than

90% of cases.

and have less renal and hematopoietic toxic-

Worldwide, arboviruses (togaviruses) are the

ity. In immunosuppressed or AIDS patients

most common cause. In the United States, West

with fungal meningitis in remission, contin-

Nile virus is the most common etiology. Be-

ued use of fluconazole in a lower dosage may

cause arboviruses require a vector (mosquito or

prevent recurrence. Complications are similar

tick), arbovirus encephalitis often occurs in

to those seen in acute bacterial meningitis.

clusters or epidemics in late spring to early fall.

Mortality rates range from 20% to 50% de-

Herpes simplex type 1 virus is the most com-

pending on the organism and predisposing

mon sporadic cause of encephalitis. Herpes

factors. Survivors may be left with neurologic

simplex virus is a latent infection in most indi-

sequelae similar to those seen in acute bacter-

viduals, following a primary stomatitis infec-

ial meningitis.

tion in childhood. Years later the latent virus

493

Chapter 24

n Central Nervous System Infections

can reactivate to cause encephalitis that occurs

of T2, diffusion-weighted images, or FLAIR

year round. Other causes of encephalitis are the

lesions on MRI that are located mainly in the

result of spirochetes (T. pallidum, B. burgdor-

medial aspect of the temporal lobe is suggestive

feri), parasites

(toxoplasmosis or falciparum

of herpes simplex encephalitis.

malaria), and other viruses (cytomegalovirus,

The diagnosis of viral encephalitis usually is

varicella-zoster, adenovirus).

made by serologic tests or PCR assays. Because

most arboviruses rarely infect humans in the

United States and produce a systemic viral infec-

Clinical Features

tion before producing the viral encephalitis,

n SPECIAL CLINICAL POINT: Acute

immunoglobulin M (IgM) antibodies to the

encephalitis is a febrile illness characterized

virus often are present early in the encephalitis.

by the abrupt onset of headache and mental

The IgM-antibody-capture enzyme-linked im-

obtundation.

munoabsorbent assay (Mac ELISA) can be used

Other common features include seizures, which

to detect arbovirus antibodies in serum and CSF

may be generalized or focal; hyperreflexia; spas-

during the first few days of the encephalitis.

ticity; and Babinski signs. Some patients develop

Acute and convalescent serum titers can be

hemiparesis, aphasia, ataxia, limb tremors, and

determined for many viruses with a fourfold in-

cortical blindness. Patients with West Nile neu-

crease in antibody titer being diagnostic. Sero-

roinvasive disease usually develop the typical

logic tests are not useful in establishing the

clinical picture of encephalitis, but 10% also de-

diagnosis of herpes simplex encephalitis, but the

velop a myelitis that is similar to paralytic po-

diagnosis can be made by detection of herpes

liomyelitis. Patients often have a prodromal

simplex viral DNA in CSF by PCR. Although

illness, which varies with the infectious agent

herpes simplex virus is almost never cultured

and can include parotitis (mumps virus), fever,

from CSF, enough viral DNA leaks into the CSF

malaise, and myalgias (arbovirus). Encephalitis

from the brain infection to be detected by PCR.

differs from meningitis primarily because pa-

The CSF PCR test is quite sensitive even during

tients with encephalitis develop prominent men-

the first few days of the encephalitis.

tal changes and a minimal or absent stiff neck.

Management and Prognosis

Laboratory Findings

All patients require excellent symptomatic care

The electroencephalogram (EEG) is always ab-

to minimize complications. If seizures develop,

normal and usually shows diffuse bilateral

anticonvulsant medications are indicated. If

slowing with occasional seizure activity. An LP

increased intracranial pressure develops from

in a patient with early encephalitis will have an

vascular engorgement and cerebral edema, treat-

opening pressure that is normal or slightly ele-

ment may require hyperventilation or the admin-

vated. The CSF contains five to several hun-

istration of mannitol. Use of corticosteroids is

dred WBC/mm³ (predominantly lymphocytes).

controversial. In patients with herpes simplex

CSF glucose is normal, whereas CSF protein is

encephalitis, treatment with acyclovir signifi-

elevated. Viral cultures are usually sterile.

cantly improves outcome. Acyclovir should be

Early in the course of encephalitis, the CT scan

administered early in the encephalitis course.

may be normal, whereas the T2-weighted MRI

Current recommendations are to give 30 mg/kg/

scan often shows areas of hyperintensity as a

day of acyclovir that is divided into three doses

result of edema from cerebral vascular perme-

per day for 14 to 21 days. The drug should

ability. Later, both scans may demonstrate

be delivered intravenously slowly over 1 hour

areas of necrosis or hemorrhage. The presence

to prevent renal toxicity. Drug complications

494

Chapter 24

n Central Nervous System Infections

include transient renal failure, thrombophlebitis,

organisms. Occasionally, multiple bacteria are

and elevations of serum liver enzymes. For most

found in abscesses. Brain abscesses following

RNA viruses such as arboviruses, no antiviral

head trauma or neurosurgery may contain

treatment is available.

Staphylococcus aureus.

Prognosis of encephalitis depends on the in-

fectious agent. Patients with mumps meningoen-

cephalitis and Venezuelan equine encephalitis

Clinical Features

have an excellent prognosis. Patients with West

n SPECIAL CLINICAL POINT: Symptoms

Nile, western equine, St. Louis, and California

from localized brain infections typically are

encephalitis usually have a reasonable prognosis

subacute in onset and produce symptoms from

(2% to 15% mortality), but up to 25% of pa-

increased intracranial pressure and their

tients are left with dementia, seizures, or focal

location in the brain.

neurologic deficits. Patients with eastern equine,

Japanese B, and Murray Valley encephalitis have

Early symptoms include headaches, lethargy,

mortality rates from 20% to 40%. Patients with

intermittent fever, and focal or generalized

herpes simplex encephalitis who are treated with

seizures. Focal neurologic signs may develop

acyclovir have a 20% mortality rate, and 55%

depending on the lesion site. Thus, lesions in

are left with some neurologic sequelae. Rabies

the frontal cortex may produce hemiparesis,

encephalitis is fatal. Patients with cognitive im-

whereas lesions in the occipital cortex cause

pairment or focal neurologic signs benefit from

homonymous visual defects. As the mass ex-

rehabilitation that may take weeks.

pands, increased intracranial pressure becomes

more pronounced. Psychomotor slowing,

lethargy, and confusion increase in severity. Pa-

BRAIN ABSCESS

pilledema and horizontal diplopia from a sixth-

nerve palsy may be seen. Focal neurologic signs

Although viruses tend to cause diffuse brain in-

become more prominent. Eventually, the ab-

fections, most bacteria, fungi, and parasites

scess expands to cause brain herniation or rup-

cause localized brain disease. Brain abscesses

tures into the ventricle-producing ventriculitis.

may arise by direct extension from other foci of

Both usually result in death.

infection within the cranial cavity (mastoiditis

and sinusitis) and from infections following

skull fracture or craniotomy, or as metastasis

Laboratory Findings

carried by the blood from infections elsewhere

in the body. The infection usually begins as a

CT and MRI scans are extremely helpful in di-

localized encephalitis with focal softening,

agnosing brain abscesses. The CT scan with

necrosis, and inflammation. As the process

contrast usually demonstrates a lesion with a

continues, fibroblasts proliferate at the edges,

low-density necrotic center, a well-developed

forming a capsule wall. A variable amount of

contrast-enhancing capsule, and surrounding

cerebral edema surrounds the lesion. If the eti-

cerebral edema (Fig. 24.2). A somewhat similar

ology is bacterial or fungal, the space-occupy-

picture is seen on MRI scan, and administration

ing lesion slowly expands. If untreated, the

of gadolinium causes the capsule wall to en-

brain mass is lethal. Patients with neurocys-

hance. The EEG is often abnormal, usually pro-

ticercosis develop cysts that usually stop grow-

ducing localized slowing in the region of the

ing after they reach about 10 to 15 mm in size.

abscess. An LP, rarely helpful in establishing the

Anaerobic bacteria are found in more than

diagnosis, is potentially dangerous because it

one half of brain abscesses. Anaerobic strepto-

increases the risk of brain herniation if the in-

cocci and Bacteroides fragilis are common

tracranial pressure is markedly elevated.

495

Chapter 24

n Central Nervous System Infections

Because the most immediate threat from brain

abscesses is the mass effect, surgical aspiration of

pus often reduces the increased intracranial pres-

sure. The simplest method is aspiration of the

pus using a CT-guided stereotactic technique.

The received fluid should be Gram stained and

cultured for anaerobic and aerobic bacteria,

fungi, and tuberculosis. If the brain abscesses are

multiple and small or deep involving the basal

ganglia and brainstem, they occasionally can be

treated only with broad-spectrum antimicrobial

agents. However, careful clinical observations

and repeated CT scans are needed to determine

whether the abscess continues to expand.

Mannitol or corticosteroids may be neces-

sary initially to control cerebral edema. How-

ever, corticosteroids should be used cautiously

and tapered rapidly because they may interfere

with capsule formation and host defenses

against the organism.

Mortality from brain abscesses ranges from

30% to 65%, with the lower rates for patients

FIGURE 24.2 CT scan with contrast demonstrating a

who receive combined therapy with antibiotics

brain abscess in the posterior temporal lobe. Arrow

and surgery. About 50% of survivors have neu-

shows the enhancing capsule with necrotic center. There

rologic sequelae, including seizures and focal

is some low-density surrounding edema.

neurologic deficits. These patients require re-

habilitation.

Management and Prognosis

Treatment of brain abscesses usually entails

PRION DISEASES (CREUTZFELDT-

appropriate antibiotic therapy and surgical

JAKOB DISEASE)

drainage. Broad-spectrum antibiotics, started as

soon as the clinical diagnosis is made, are

Prion disease of the CNS can be divided into

selected for their effectiveness against all likely

clinical categories: Creutzfeldt-Jakob disease

pathogens as well as their ability to pene-

(CJD the most common form, with incidence of

trate brain abscesses and surrounding brain

1/1,000,000 per year); Gerstmann-Straüssler

parenchyma. Broad-spectrum antibiotic cover-

syndrome; fatal familial insomnia; and Kuru.

age should be efficacious against both common

This class of CNS infections breaks all the rules

anaerobic (especially Streptococcus intermedius

for conventional infections of the CNS. First,

and B. fragilis) and aerobic bacteria. Possible

no nucleic agent has been identified in the infec-

combinations include the use of cefotaxime or

tious particle. The infectious agent is a protein

ceftriaxone plus metronidazole or chlorampheni-

normally made by neurons that is somehow

col. If staphylococci are suspected or isolated, an-

misfolded into an abnormal infectious mole-

tistaphylococcal drugs should be given. Once the

cule. Second, patients with the illness do not

bacteria are isolated, therapy should be directed

present with typical signs of an infection. They

by their antibiotic sensitivities. Intravenous an-

lack fever and an elevated WBC and have CSF

tibiotics should be administered for 6 to 8 weeks.

that appears normal on standard tests because

496

Chapter 24

n Central Nervous System Infections

an immune response is not made by the host

against the infectious particle. Third, the infec-

Always Remember

tious particle is not killed by formalin, ethanol,

Follow these steps to diagnose and treat CNS

or boiling (methods that normally destroy in-

infections:

fectious agents) but can be destroyed by auto-

claving. Fourth, most patients present with a

1. Determine the site of infection based on

subacute to chronic progressive dementia that

history, exam, CSF and blood findings, and

is fatal over 6 months to 2 years.

neuroimaging.

The prion infectious agent is present in CSF,

2. Obtain appropriate CSF, blood, or tissue

brain, pituitary, and peripheral nerves that inner-

specimens for culture and serology to

vate cornea and dura. The infectious agent does

determine the type of organism (e.g.,

not appear to be present in saliva, urine, sweat,

bacteria, virus, fungus) and antimicrobial

or stool so isolation of the patient is not neces-

sensitivities.

sary. Blood should be considered infectious, but

3. Begin initial broad-spectrum antimicrobial

no documented human cases of the sporadic dis-

treatment.

ease have occurred from blood transfusions.

4. Determine specific etiology and antimicrobial

sensitivities, and modify treatment if

n SPECIAL CLINICAL POINT: Transmission

necessary.

of a prion infectious disease may occur through

5. Watch for and treat complications.

inoculation via infected human cornea, dura,

pituitary, or surgical instruments, or it may be

hereditary as in familial CJD, Gerstmann-

Straüssler syndrome, and fatal familial insomnia.

In the United Kingdom, rare cases of a variant

QUESTIONS AND DISCUSSION

of CJD (vCJD) appear to be transmitted from

1. Herpes simplex encephalitis

infected cattle with bovine spongiform en-

A. Is best diagnosed by isolation of herpes

cephalopathy (mad cow disease). Fortunately

simplex virus from CSF

the incidence of vCJD continues to fall since

B. Is accompanied by a herpetic blister on

changes were made to the feed of cattle. How-

the lip

ever, most cases of CJD appear to be sporadic

C. Is best treated with acyclovir

without a known source of the transmission.

administered early in the disease

Diagnosis may be difficult because there is

D. Isolation is necessary as the patient is

no simple diagnostic test. CJD should be sus-

infectious to others

pected in an adult with rapidly progressive de-

E. Has characteristic clinical features

mentia, myoclonic jerks, and normal CSF. In

many patients with CJD, the CSF demonstrates

The correct answer is A. Untreated herpes sim-

abnormal 14-3-3 proteins on electrophoresis.

plex encephalitis (HSE) carries a 70% mortal-

An EEG may show characteristic abnormali-

ity rate but early administration of high-dose

ties. MRI shows progressive brain atrophy

acyclovir reduces the mortality rate to about

often with abnormal gadolinium enhancement

25%. Patients with HSE do not present with

of the anterior basal ganglia. Pathologically,

any characteristic history on exam and do not

the brain shows a characteristic spongiform

occur in clusters like arbovirus encephalitis.

encephalopathy without inflammation. Cur-

The diagnosis is best made by detection of

rently, there is no available treatment to stop

herpes virus DNA in CSF by PCR assay. The

disease progression. Patients suspected of hav-

presence of herpes lesions on the lip or virus

ing this disease should not donate blood or au-

isolation from the mouth does not help in es-

topsy organs.

tablishing the diagnosis.

497

Chapter 24

n Central Nervous System Infections

2. West Nile viral encephalitis

4. Enterovirus meningitis

A. Occurs sporadically all year

A. Is transmitted by a bite of an infected

B. Is contagious to others

mosquito

C. Is best diagnosed by virus isolation

B. Is the most common cause of aseptic

from CSF

meningitis

D. Produces widespread but intermittent

C. Follows a prodrome of an upper

death of neurons

respiratory tract infection

E. Is best treated with acyclovir

D. Causes cranial nerve palsies in 30% of

patients

The correct answer is D. West Nile encephali-

E. Is best treated with acyclovir

tis virus in the brain and spinal cord mainly

infects neurons in a widespread fashion, often

The correct answer is B. In the United States,

resulting in their death. West Nile virus is an

enterovirus causes about 75% of cases of viral

arbovirus that is transmitted to humans from

meningitis and the majority of aseptic menin-

the bite of infected mosquitoes during the sum-

gitis cases. The virus is transmitted to the

mer and early fall. West Nile virus is not pres-

gastrointestinal tract from infected water or

ent in urine, saliva, or stool so the patient is

oral spread from infected feces. Most patients

not contagious and does not need isolation.

develop an asymptomatic gastrointestinal

The diagnosis is usually made by detection of

infection. In a few patients a viremia occurs

IgM antibodies to West Nile virus in serum or

that spreads virus to the meninges. No antivi-

CSF as the virus is difficult to isolate from

ral drugs are available for treatment, but the

CSF. Acyclovir offers no benefit to RNA virus

clinical course is benign, with more than 99%

like West Nile virus. Thus, current treatment is

of patients making a complete recovery.

symptomatic and the prevention of severe

increased intracranial pressure.

SUGGESTED READING

3. In a brain abscess, the best way to establish

the etiology is to

Bernardini GL. Diagnosis and management of brain ab-

A. Isolate bacteria from CSF

scess and subdural empyema. Curr Neurol Neurosci

Rep. 2004;4:448-456.

B. Detect specific bacterial antigen in CSF

C. Identify bacteria in CSF by Gram stain

Davis LE. Subacute and chronic meningitis. Continuum.

2006;12:27-57.

D. Isolate bacteria from abscess pus

E. Isolate bacteria from blood or urine

Davis LE, Beckham JD, Tyler KL. North American

encephalitic arboviruses. Neurol Clin. 2008;26:727-757.

The correct answer is D. In a brain abscess,

Davis LE, Kennedy PGE, eds. Infectious Diseases of the

the bacteria are surrounded by a capsule and

Nervous System. Oxford: Butterworth-Heinemann;

confined to the pus. Therefore, the CSF does

2000.

not contain any bacteria or bacterial prod-

Irani DN. Aseptic meningitis and viral myelitis. Neurol

ucts. In a few patients, the blood may contain

Clin. 2008;26:635-655.

the bacteria if the organism reached the brain

Kastenbauer S, Pfister HW. Pneumococcal meningitis in

from a bacteremia. The only certain method

adults: spectrum of complications and prognostic

factors in a series of 87 cases. Brain. 2003;126:

of isolating the bacteria causing the abscess is

1015-1025.

to culture the pus. This can be done by

Kent ME, Romanelli F. Reexamining syphilis: an update

stereotactic aspiration of the pus or from a

on epidemiology, clinical manifestations and manage-

craniotomy and direct surgical aspiration or

ment. Ann Pharmacother. 2008;42:226-236.

drainage. The pus should be cultured for

Knight R. Creutzfeldt-Jakob Disease: a rare disease of

anaerobic and aerobic bacteria, fungi, and

dementia in elderly persons. Clin Infect Dis. 2006;

M. tuberculosis.

43:340-346.

Neurologic

Aspects of

Cancer

DEBORAH OLIN HEROS

key points

• Primary central nervous system (CNS) tumors include

gliomas (astrocytomas, oligodendrogliomas, and

ependymomas), meningiomas, and primary CNS

lymphomas.

• Systemic cancers may affect the CNS via intracranial,

leptomeningeal, or spinal metastases.

• Nonmetastatic cancer effects may include cerebrovas-

cular complications, metabolic and nutritional

complications, and paraneoplastic syndromes.

• Cancer treatment with radiotherapy may be associated

with significant neurologic complications.

ancer is the second

Furthermore, systemic cancer may affect the

leading cause of death in the United States, with

peripheral and central nervous systems as a result

an incidence of more than 1 million cases of

of metastatic involvement of the dura and lep-

cancer each year and resulting in more than

tomeninges, bony metastases resulting in epidural

1 million cancer-related deaths per year. More

spinal cord compression, and peripheral involve-

than 20,500 new cases of primary brain tumors

ment to the brachial and lumbosacral plexuses.

were diagnosed in 2007 in the United States.

Cancer also may result in nonmetastatic com-

Primary central nervous system (CNS) tumors

plications to the CNS, including various vascular

occur in people of all ages; they are the third

disorders, metabolic and nutritional disorders,

leading cause of cancer deaths between the ages

infection, and neurologic complications from

of 15 and 34 years. Statistical data suggest that

cancer treatment. Indirect, or paraneoplastic,

the incidence of primary CNS tumors is increas-

syndromes have been recognized as the result of

ing.

systemic cancer. More than 80% of cancer

Autopsy studies identify metastatic tumors

patients will develop neurologic complications,

to the brain in 24% of patients with systemic

and the resultant impact on their quality of life

cancer, the majority of which are symptomatic.

and survival is significant.

499

500

Chapter 25

■ Neurologic Aspects of Cancer

Identification and treatment of neurologic

Clinical Presentation The clinical presentation

complications may improve the quality of life

of astrocytoma is determined by tumor loca-

and survival of the cancer patient. It is, there-

tion, pathology, and age of the patient. The

fore, very important for any clinician involved

majority of astrocytomas in adults occur in

in the care of cancer patients to be aware of the

the supratentorial compartment. Presenting

neurologic aspects of cancer.

symptoms may include headache, seizure, focal

neurologic deficits, and personality change.

The increasing availability of neuroimaging

PRIMARY CENTRAL NERVOUS

studies with improved resolution has resulted

SYSTEM TUMORS

in earlier discovery of brain tumors.

Primary CNS tumors are classified by the cell

■ SPECIAL CLINICAL POINT: Unexplained

of origin. The incidence of primary intracranial

first seizures in adults, unusual neurologic

tumors is between 2 and 19 per 100,000 persons

symptoms, or an unexplained change in

per year and is dependent on age. In adults,

personality or mood should be investigated

supratentorial tumors are more common,

by either computed tomography (CT) or

whereas the majority of primary intracranial

magnetic resonance imaging (MRI).

tumors of childhood occur in the posterior

Contrast for the appropriate neuroimaging

fossa. The most common primary brain tumors

studies is important if a primary brain tumor is

are glial in origin and include astrocytomas,

in the differential diagnosis (see Chapter 4,

oligodendrogliomas, and ependymomas.

Fundamentals of Neuroradiology). Brainstem

gliomas are less common and may present with

Astrocytoma

sensorimotor abnormalities, coordination diffi-

The most common glial tumor is the astrocy-

culties, or cranial nerve dysfunction. The tumor

toma, which stains positive for glial fibrillary

grade correlates somewhat with the abnormali-

acidic protein

(GFAP) and is classified or

ties on the neuroimaging study. Low-grade

graded according to histologic characteristics

tumors usually do not enhance, and they appear

reflecting aggressiveness and survival. The tra-

hypodense on a computed tomography (CT) scan

ditional classification system is the Kernohan

and have abnormalities on magnetic resonance

grading system of astrocytoma, based on the

imaging (MRI) fluid-attenuated inversion recov-

pathologic characteristics of cellularity, pleo-

ery (FLAIR) and T2-weighted images. Increasing

morphism, proliferation, and necrosis. Kernohan

tumor grade results in increasing contrast

grades I and II represent “low-grade” or “well-

enhancement. Central necrosis, with surround-

differentiated” astrocytoma, Kernohan grade

ing enhancement and peritumoral edema, is

III represents the intermediate or anaplastic

suggestive of a glioblastoma.

astrocytoma, and grade IV astrocytoma is syn-

The most important factors that determine

onymous with a glioblastoma multiforme. In an

the prognosis of a patient with an astrocytoma

attempt to improve the correlation between

include histology, age of the patient, and the level

prognosis and grade of the tumor, the World

of disability or performance status. Patients with

Health Organization (WHO) in 1993 suggested

low-grade tumors have the best prognosis.

a descriptive, three-tier system that includes the

Patients with an anaplastic astrocytoma have a

well-differentiated astrocytoma, anaplastic

significantly better prognosis than patients with

astrocytoma, and glioblastoma multiforme.

a glioblastoma. Younger patients and patients

Because there is a slight difference between the

with less disability do better than their older,

pathologic characteristics described by the two

more disabled counterparts. Less significant

systems, the clinician must know which system

prognostic factors may include a long duration

is being used.

of symptoms prior to diagnosis, presence of

501

Chapter 25

■ Neurologic Aspects of Cancer

seizures, location of tumor, and degree of surgi-

nature of astrocytomas generally prohibits a

cal resection. As our understanding of the genetic

complete resection.

abnormalities of specific tumors increases, the

Postoperative radiation therapy increases the

presence or absence of chromosomal abnormal-

median survival of patients with an anaplastic

ities may provide prognostic and therapeutic

astrocytoma and glioblastoma. Limited-field

information.

brain irradiation with a “radiation boost” to

the most active central portion of the tumor

Treatment Treatment options for astrocytoma

is performed over a course of 5 to 6 weeks.

are determined by pathology, location, clinical

Additional techniques to deliver radiation

presentation, and age of the patient. Often, the

therapy to astrocytomas include radiosurgery,

patient is clinically symptomatic from cerebral

three-dimensional conformal radiation therapy,

edema; therefore, corticosteroids (usually dex-

boron neutron capture therapy, and the use of

amethasone) are started prior to surgery, and

radiosensitizers. The role of these techniques for

they often improve symptoms. Caution should

the treatment of high-grade astrocytomas has

be used if a primary CNS lymphoma (PCNSL)

yet to be defined. Stereotactic radiosurgery,

is in the differential diagnosis because the use

when added to fractionated radiotherapy, does

of corticosteroid therapy prior to biopsy may

not improve clinical outcome.

decrease the chance of obtaining a positive

The role of radiation therapy for low-grade

biopsy. An anticonvulsant to prevent seizures

astrocytomas is even less clear. Statistically,

for supratentorial lesions is also often started

patients with low-grade astrocytomas who have

prior to surgery.

received radiation therapy have improved sur-

A definitive diagnosis is obtained by patho-

vival over those patients not so treated.

logic examination of brain tissue. Surgical

However, the timing is controversial. It is not

debulking is preferred over a biopsy, when

clear whether radiation therapy should be

possible, to reduce the tumor burden, provide

administered at the time of diagnosis (e.g.,

an adequate pathology specimen, and improve

when the neoplasm has been identified after a

symptomatic relief from mass effect. Theoretically,

single seizure or perhaps as an incidental find-

tumor debulking also may improve the chance

ing by a neuroimaging study) or delayed until

to respond to adjuvant therapy. Stereotactic

the tumor is more symptomatic from tumor

biopsy is most often reserved for patients whose

transformation. Studies suggest that the timing

poor medical condition precludes a craniotomy

is not a major prognostic determinant.

and for those with deep-seated lesions or lesions

Historically, chemotherapy has not been a pri-

in neurologically eloquent locations.

mary treatment for malignant astrocytomas, but

the recognition that some subtypes of glial

■ SPECIAL CLINICAL POINT: The primary

tumors (e.g., anaplastic astrocytomas in younger

goals of tumor surgery for astrocytoma are

patients) are chemosensitive has increased enthu-

(a) to determine pathology, (b) to identify

siasm for chemotherapy for primary brain

tumor grade, (c) to identify any subtype of

tumors. The preferred combination of therapeu-

glioma that may affect prognosis and

tic agents for anaplastic astrocytomas has been

treatment options, and (d) to directly

procarbazine, CCNU, and vincristine (PCV regi-

reduce mass effect.

men). Carmustine had previously been the most

The use of neuronavigational systems and

widely used single agent for glioblastoma, but

intraoperative neuroimaging studies have

temozolomide, a recently developed oral alkylat-

improved the ability of the neurosurgeon to

ing agent, has demonstrated significant activity

attain maximal resection with minimal mor-

against malignant gliomas. Temozolomide used

bidity. Survival benefit has been correlated

concurrently with radiotherapy and then contin-

with good tumor resection, but the infiltrative

ued as adjuvant treatment has significantly

502

Chapter 25

■ Neurologic Aspects of Cancer

improved the survival outcome for patients with

anaplasia, and therefore aggressiveness, do occur.

high-grade gliomas.

Most often, the tumor presents as a nonenhanc-

Glioblastoma multiforme is a highly vascular

ing hypodense lesion on CT scan or a hypointense

tumor and demonstrates elevated production of

T1-lesion on MRI scan. Calcifications may be

vascular endothelial growth factor (VEGF).

present. Enhancement may suggest a more

Targeted therapy using angiogenesis inhibitors

aggressive tumor or the presence of a mixed

such as bevacizumab, a monoclonal antibody

oligoastrocytoma. Occasionally, symptom onset

to VEGF, has shown efficacy in the treatment

may be abrupt as the result of hemorrhage.

of recurrent malignant gliomas. Clinical studies

Management of the oligodendroglioma

are being conducted using bevacizumab with

depends on location, clinical presentation, and

radiotherapy and temozolomide as initial therapy

neuroimaging appearance. Surgical resection

in newly diagnosed glioblastoma. Preliminary

generally is attempted if possible. The oligoden-

results are encouraging. Other angiogenic

droglioma has been identified as a chemosen-

inhibitors are also under investigation.

sitive tumor; therefore, chemotherapy has

played a major role in its treatment in recent

■ SPECIAL CLINICAL POINT: Ethical

years. The use of chemotherapy for low-

decisions involving the appropriateness of par-

grade oligodendroglioma is being studied.

ticipation in experimental treatment protocols

Approximately 60% of oligodendrogliomas

for astrocytomas are challenging because

patients and families are often desperate or

demonstrate genetic deletions or “loss of het-

frightened, potentially compromising informed

erozygosity” (LOH) of 1p and 19q chromo-

consent. Furthermore, investigational treat-

somes. The presence of LOH of 1p and 19q is

ments are potentially hazardous and full

an indicator of chemosensitivity and favorable

understanding of risk-benefit ratios is often

prognosis (greater than 90% response rate to

unclear. Given the poor prognosis for patients

chemotherapy and improved overall survival).

with high-grade gliomas, however, it is important

Testing for these genetic abnormalities has

for the clinician caring for these patients to be

become more readily available and an impor-

aware of the clinical protocols available and to

tant part of the neuropathology report for

make an appropriate referral for patients inter-

oligodendroglioma. The chemotherapy most

ested in investigational treatment.

commonly used for this tumor has been the

In a national survey, less than 8% of patients

PCV regimen, but temozolomide is increasingly

with astrocytoma were enrolled in treatment

replacing PCV as first-line therapy. Although

protocols. As participation in investigational

radiation therapy has been shown to improve

protocols by patients with other malignancies

survival of patients with oligodendroglioma, the

has resulted in improved treatment modalities,

role of radiation therapy remains controversial,

it is important to encourage participation.

especially if total resection has been accom-

plished. However, if subtotal resection or a

limited biopsy has been performed, radiation

Oligodendroglioma

therapy may offer some survival advantage.

The oligodendroglioma is a type of glial tumor

derived from the oligodendrocyte, the myelin-

Ependymoma

producing cell within the CNS. Histologically, this

tumor is identified by its characteristic “fried-egg”

The ependymoma is a glial tumor arising from

appearance and a positive stain for myelin basic

the ependymal cells lining the ventricles and the

protein. The tumor tends to be slow growing;

cerebrospinal fluid (CSF)-filled spaces. This

therefore, it is most often considered to be a

tumor usually occurs during childhood in the

low-grade tumor. However, varying degrees of

posterior fossa arising from the floor of the

503

Chapter 25

■ Neurologic Aspects of Cancer

fourth ventricle, but it may present in the spinal

following administration of contrast. Often a

cord or in the cerebral hemispheres along the

dural attachment or “dural tail” can be seen

lining of the lateral ventricles. When an ependy-

radiologically, which helps to identify the tumor

moma occurs in the posterior fossa, it usually

as a meningioma. Significant edema surround-

presents with symptoms of increased intracra-

ing the mass is not typically seen, and its

nial pressure, including headache, nausea, and

presence should raise the suspicion for either an

vomiting, and it often causes obstructive hydro-

atypical, malignant meningioma or another

cephalus. The treatment of choice is surgical

type of tumor such as a metastatic tumor, espe-

resection, and the prognosis depends on the

cially from a breast or prostate primary.

degree of resection. A 45% overall 5-year sur-

Meningiomas are also more common in women

vival is reported in the literature, with an

with breast cancer.

increased chance of long-term survival after

The treatment for meningioma is most often

complete resection. This tumor lines the CSF

surgical resection with the goal of complete

pathways and may seed the neuraxis, although

removal because the risk of recurrence is

the majority of tumor recurrence is local within

directly related to the completeness of the resec-

the posterior fossa. Local radiation therapy

tion. This in turn mainly is determined by the

usually is recommended for supratentorial

location of the tumor; tumors that are not

and spinal lesions. Local or craniospinal radiation

amenable to complete resection have a much

therapy may be appropriate for ependymomas of

greater risk for recurrence. For example, tumors

the posterior fossa. Chemotherapy has been of

over the cerebral convexities are more accessi-

limited benefit in the treatment of ependymoma.

ble surgically as compared to tumors at the base

of the skull, and therefore cerebral convexity

tumors are less likely to recur.

Meningioma

Radiotherapy by conventional fractionated

Meningiomas are tumors derived from the

radiation, stereotactic radiosurgery, or fraction-

arachnoid lining of the nervous system and,

ated radiosurgery may play an important role

therefore, are extrinsic to the neuraxis. The

for incompletely resected or recurrent tumors.

tumors are most often histologically benign and

The role of traditional chemotherapy is lim-

are found more frequently with increasing age

ited, but agents such as hydroxyurea and

as the result of the slow growth rate.

interferon alpha-2b have been described as hav-

ing some activity. Meningiomas may contain

■ SPECIAL CLINICAL POINT: Meningiomas

progesterone and, less frequently, estrogen recep-

may be found incidentally, and observation may

tors. Consequently, meningiomas may enlarge

be appropriate, especially when asymptomatic

during periods of elevated hormonal levels such

or when found in an elderly patient.

as pregnancy. Treatment with antiestrogen or

The incidence increases with age starting in the

antiprogesterone agents such as tamoxifen or

sixth decade. Women are affected two to three

mifepristone (RU-486), respectively, has been

times more than men. Symptoms are dependent

used.

on location, size, and rate of growth. Symptoms

Although the majority of meningiomas are

may include seizures from cortical irritation over

histologically benign, infrequently atypical or

the convexity of the cerebral hemisphere,

malignant variants with more aggressive behav-

headache from pressure within the cranium, or

ior may occur. A subtype of meningeal tumor,

symptoms of cranial nerve or brainstem dysfunc-

the hemangiopericytoma, may present similarly,

tion from direct compression of neural structures.

but it has a high rate of recurrence and a propen-

Meningiomas typically demonstrate homog-

sity to seed the leptomeninges and metastasize

enous enhancement on CT or MRI studies

outside of the CNS.

504

Chapter 25

■ Neurologic Aspects of Cancer

Primary CNS Lymphoma (PCNSL)

the tumor is in the midline or if the lep-

tomeninges are involved. CSF cytology may

PCNSL is a non-Hodgkin lymphoma, usually

help to distinguish between a neoplastic mono-

of B-cell origin, that arises within the brain,

clonal lymphocytosis and an inflammatory

spinal cord, or leptomeninges. This tumor may

process. Intraocular involvement can occur, and

occur in otherwise healthy patients with normal

a slit lamp examination or vitreous biopsy may

immune systems, usually in older men, but it

be helpful in establishing the diagnosis. A sys-

more often occurs in patients with a compro-

temic evaluation including a bone marrow

mised immune system. It has been seen with

biopsy may help to exclude the possibility of

increasing frequency as a result of the growing

systemic lymphoma or other small-cell malig-

population with human immunodeficiency

nancies. Most often, a brain biopsy is indicated,

virus (HIV). This tumor does not tend to metas-

however.

tasize systemically and is a separate entity from

Once the diagnosis of PCNSL has been

systemic lymphoma with CNS metastasis.

established, corticosteroid therapy may offer

Patients with inherited, acquired, or iatrogeni-

improvement of neurologic symptoms. For

cally induced immunodeficient states, particularly

many years, radiation therapy has been the

transplant patients, are at an increased risk for

mainstay of treatment, but the prognosis was

developing this tumor, and it may occur in up

limited. The median survival of immunocompe-

to 10% of patients with acquired immunode-

tent patients with PCNSL is approximately

ficiency syndrome

(AIDS). The clinical

14 months, and it is much less in patients with

presentation may include headache, personality

immunodeficiency. Combined treatment with

changes, seizures, and focal neurologic symp-

chemotherapy and radiation therapy has

toms. Often the lesions are multifocal,

resulted in improved survival. Unfortunately,

frequently involving deep midline structures

relapse remains common, and late neurologic

with contrast enhancement and minimal sur-

toxicity from combined therapy is a significant

rounding edema on neuroimaging studies. The

complication resulting in a progressive dement-

diagnosis usually is established by biopsy, but

ing leukoencephalopathy.

surgical resection is usually not an option. The

Chemotherapy has generally not been used

use of corticosteroid therapy prior to biopsy

in patients with CNS lymphoma associated

may decrease the opportunity to obtain an

with immunodeficiency because of the overall

accurate pathologic diagnosis.

poor prognosis and response rate. PCNSL has

The presentation of PCNSL in an immune-

been associated with the presence of Epstein-

compromised patient may resemble CNS

Barr virus in patients with AIDS. As a result of

toxoplasmosis clinically. It is therefore common

this observation, antiviral therapy has been sug-

to treat a patient with a known immunodefi-

gested for treatment of PCNSL. Recently,

ciency empirically for toxoplasmosis for a

rituximab, a monoclonal antibody that targets

limited period with clinical and radiologic

CD20, has shown some promise as well.

follow-up. If the lesions improve, the assump-

tion is that the patient has toxoplasmosis,

whereas if the lesions progress or do not

METASTATIC COMPLICATIONS OF

improve, then the possibility of CNS lymphoma

SYSTEMIC CANCER

increases and a biopsy may be performed.

Intracranial Metastases

Occasionally, an immune-compromised patient

may have simultaneous toxoplasmosis and

Systemic cancer may spread to the CNS to

CNS lymphoma, complicating the interpreta-

involve the skull, dura, parenchyma, or lep-

tion of the empiric trial. A lumbar puncture

tomeninges. Specific tumors may metastasize

with cytologic examination may be helpful if

in predictable patterns, and understanding

505

Chapter 25

■

Neurologic Aspects of Cancer

these trends is important to correctly diagnose

metastases in order to offer palliative therapy.

■ SPECIAL CLINICAL POINT: Breast cancer,

prostate cancer, lung cancer, malignant

melanoma, and cancers of the head and neck

frequently metastasize to the skull.

Neurologic symptoms are most common if the

tumor involves the base of the skull, resulting

in localized pain, headache, or cranial nerve

dysfunction (Fig. 25.1). Special views on a CT

or an MRI scan may be necessary to identify

skull base metastases. Standard screening stud-

ies may not image this region well, giving the

false impression of a negative study; thus, the

opportunity to offer effective palliative therapy

may be missed. The nuclear bone scan is not a

very sensitive study (despite the fact that the

symptoms are the result of bony metastases)

because of the overlapping nuclear isotope

uptake by the venous sinuses in this region.

Localized radiation often offers effective palli-

ation of symptoms, especially pain.

Intraparenchymal brain metastases occur in

nearly 25% of patients with systemic cancer.

■ SPECIAL CLINICAL POINT: Breast cancer,

lung cancer, and malignant melanoma frequently

metastasize to the brain. Less commonly,

tumors of the gastrointestinal tract, kidney,

or genitourinary system may do so as well.

The majority of tumors metastasize to the cere-

FIGURE 25.1 MRI scan demonstrating metastatic

bral hemispheres and less commonly to the

cancer to the upper cervical spine in a man with lung

brainstem and cerebellum in the posterior fossa.

cancer and severe, localized occipital pain. Metastasis to

Metastases to the pituitary region, often from

the base of the skull was clinically suspected from the

tumors of breast origin, have been described.

location of the pain. However, it is interesting that the

The risk of developing brain metastases from

pain was aggravated by neck movement.

lung cancer varies with the pathology of the pri-

mary lung tumor. Small-cell lung cancer has the

metastases occur with high frequency in both

highest risk (60%), adenocarcinoma has an

lung and breast tumors, brain metastases often

intermediate risk (40%), and squamous cell

occur early in lung cancer (within months),

carcinoma is the least likely to spread to the

whereas brain metastases are more likely to

brain (20%). From 25% to 30% of patients

occur much later in breast cancer

(within

may present with neurologic symptoms without

years). Although malignant melanoma is a rel-

a known primary cancer. Nearly one-half of

atively uncommon tumor, it has a very high

these patients will subsequently be found to

propensity (up to 80% at autopsy) to spread to

have some form of lung cancer. Although brain

the CNS, often with multiple metastases.

506

Chapter 25

■ Neurologic Aspects of Cancer

Brain metastases originate from hematoge-

with an H2-receptor antagonist to reduce the

nous spread, and therefore the majority of

risk of gastric complications from the corticos-

patients develop multiple lesions. Approximately

teroid therapy.

20% to 30% of patients have a single metastatic

An anticonvulsant medication is indicated if

tumor. Treatment options often are determined

the patient has experienced a seizure. The role

by whether the lesion is single or multiple.

of prophylactic use of an anticonvulsant is less

The signs and symptoms are determined by the

clear, and many neurologists prefer to avoid the

size, number, and location of the tumors.

risk of side effects from the medication in

Metastatic tumors of the cerebral hemispheres

patients who have not experienced a seizure. It

may cause progressive hemiparesis, language dis-

may be prudent, however, to consider the use

turbance, confusion, seizures, sensory symptoms,

of a prophylactic anticonvulsant medication for

visual field abnormalities, or personality changes.

lesions in potentially epileptogenic areas of the

The development of depression in a patient with

cerebral hemispheres such as near the motor

cancer could be a sign of brain metastases, partic-

cortex. Serum drug levels should be monitored

ularly if he has never previously been prone

appropriately.

to depression. Tumors in the cerebellum may

Conventional treatment of brain metastases

result in dizziness, unsteadiness of gait, dysarthria,

includes whole brain radiation therapy (3000 cGy

clumsiness of an extremity, or headaches from

over 10 or 15 fractions). The whole brain is

obstructive hydrocephalus. Cranial nerve dysfunc-

treated because of the high likelihood of multiple

tion, motor and sensory signs, unsteadiness, and

lesions and the chance of multiple microscopic

incoordination result from brainstem involve-

foci of metastatic tumor from hematogenous

ment. Hemorrhage into a metastasis may result in

dissemination. Advances in neuroimaging and

the abrupt onset of neurologic symptoms.

neurosurgical techniques and the development

of radiosurgery have increased the options for

■ SPECIAL CLINICAL POINT: Metastatic

treatment of metastatic tumors. The current

tumors with a tendency to bleed include

trend is to use radiosurgery (a) to boost the

melanoma, renal cell carcinoma, choriocarci-

effect of whole brain radiation therapy or (b) to

noma, and some forms of lung cancer.

treat recurrences of metastatic tumors after

The diagnosis of metastatic brain tumor is

whole brain radiation therapy. Some clinicians

established by a neuroimaging study, either

are using radiosurgery alone for the treatment

CT or MRI "(see Chapter 4, Fundamentals of

of metastatic tumors. The maximal number of

Neuroradiology). When a patient presents with

tumors that may be treated with radiosurgery

brain metastases without a known primary

is under investigation.

tumor, diagnostic studies are performed to iden-

In general, surgery is reserved for removal of

tify the primary tumor, with special attention to

a single lesion in a surgically accessible area

imaging of the chest, since approximately one-

(e.g., a tumor in the posterior fossa causing

half of these patients will be found to have a

hydrocephalus or a large tumor in the cerebral

primary lung cancer.

hemispheres) (Fig. 25.2). Shunting also is con-

sidered for treatment of hydrocephalus if the

Treatment Corticosteroids, usually dexam-

cause of the hydrocephalus cannot be surgically

ethasone, are very effective in treating patients

excised. Stereotactic biopsy may be considered

with symptoms that result from vasogenic

in patients presenting with neurologic symp-

edema. The appropriate dosing is determined by

toms without a known primary tumor or in

the number, size, and location of lesions and by

patients in whom the specific tumor type can-

the severity of the symptoms. The most com-

not be established otherwise.

mon initial dosage of dexamethasone is 4 mg

The experience of using chemotherapy

four times daily. It often is used in conjunction

for brain metastases is limited as a result of

507

Chapter 25

■ Neurologic Aspects of Cancer

neoplastic meningitis. Other terms used to

describe this condition include carcinomatous

meningitis and meningeal carcinomatosis, or

lymphomatous meningitis, depending on the

tumor of origin. The incidence of this serious

complication is thought to be increasing as con-

trol of systemic disease improves.

The leptomeninges serve as a sanctuary site

from systemic therapy as a result of the blood-

brain barrier. Neoplastic meningitis may occur

in isolation or in combination with other sites

of CNS involvement, such as intraparenchy-

mal brain metastases. Most commonly, neo-

plastic meningitis is caused by tumors of the

breast and lung and malignant melanoma.

Less commonly, tumors of the gastrointestinal

tract, ovary, prostate, uterus, and bladder

spread to the leptomeninges. Various types of

lymphoma and leukemia also have a tendency

for leptomeningeal spread.

The clinical presentation of neoplastic menin-

FIGURE 25.2 Gadolinium MRI scan demonstrating

gitis is variable and often subtle. Symptoms and

contrast-enhancing single metastasis of the cerebellum in

signs reflect the diffuse involvement of the neuraxis

a patient with gastric carcinoma. His headaches, nausea,

and unsteadiness improved after surgical resection.

at three levels: (a) the cerebral cortex, resulting in

confusion, headache, and seizures; (b) cranial

nerves, resulting in diplopia, facial numbness,

the inability for most chemotherapeutic agents

hearing loss, visual loss, and tongue weakness; and

to penetrate the blood-brain barrier. Temozo-

lomide, an oral alkylating agent that readily

the lumbosacral spine region, resulting in low back

crosses the blood-brain barrier and is used for

pain, leg numbness and weakness, and sphincter

treatment of primary brain tumors, may also be

dysfunction. Communicating hydrocephalus

helpful in treating metastatic brain tumors when

develops in 15% to 20% of patients with neoplas-

used in combination with radiotherapy.

tic meningitis. The diagnosis should be suspected

If untreated, the median survival for patients

in a patient with cancer with neurologic symptoms

with brain metastases is 4 to 6 weeks. Appropriate

and signs at various levels of the neuraxis. Often

therapy offers an improved quality of life and pro-

the findings on clinical examination are multiple

longation of survival. The overall median survival

and out of proportion to the symptoms described

of patients treated for metastatic brain tumors is

by the patient.

6 months. Long-term survival usually is described

The diagnosis of neoplastic meningitis is

in patients treated with surgery. The cause of

established by positive cytology of the CSF.

death in patients with brain metastases is most

Repeated CSF examinations may be necessary

often progression of systemic disease.

to establish the diagnosis. The CSF examina-

tion also may demonstrate elevation of

opening pressure, lymphocytic pleocytosis, a

Leptomeningeal Metastases

depressed glucose level, or protein elevation.

Systemic tumors may diffusely seed the lep-

Elevated biochemical markers may be used to

tomeninges, resulting in a condition known as

diagnose the condition as well as to follow

508

Chapter 25

■ Neurologic Aspects of Cancer

the response of treatment. Such markers

Gadolinium MRI of the brain and spinal

include carcinoembryonic antigen, beta

cord may demonstrate leptomeningeal enhance-

human chorionic gonadotropin, and alpha-

ment, and helps to exclude the possibility of

fetoprotein. If a sufficient number of

intracranial brain metastases that might con-

lymphocytes are present, specific immunohis-

traindicate a lumbar puncture. Bulky disease

tochemical studies may help differentiate

that may be treated with localized radiation

reactive inflammatory lymphocytes from

therapy also may be identified. In general, MRI

neoplastic lymphocytes in patients with lym-

with gadolinium is more sensitive than CT with

phoma and leukemia.

contrast (Figs. 25.3 and 25.4).

FIGURE 25.3 MRI scan of the spine before (A) and after (B) gadolinium, demonstrating enhancing

nodular defects in the leptomeninges of a woman with metastatic breast cancer, who presented with

paraparesis and urinary retention. Cerebrospinal fluid examination from an Ommaya reservoir

confirmed the diagnosis of neoplastic meningitis.

509

Chapter 25

■ Neurologic Aspects of Cancer

In patients with cranial nerve dysfunction, ra-

diotherapy to the basal cisterns may be benefi-

cial. Dexamethasone may improve symptoms.

If untreated, the median survival of neoplas-

tic meningitis is 6 weeks. The overall median

survival with treatment is 4 to 6 months. A

chance for longer survival in select patients has

been described in patients with chemosensitive

tumors such as lymphoma and breast cancer.

Patients with neoplastic meningitis from malig-

nant melanoma have a particularly poor

prognosis. Often, a patient with neoplastic

meningitis will have concomitant progression

of systemic cancer.

Spinal Metastases

Spinal cord dysfunction from metastatic cancer

may be the result of tumor metastasis to vertebral

bodies, extension of a paravertebral mass, or

intramedullary metastases from hematogenous

FIGURE 25.4 Contrast-enhanced CT scan

spread to the spinal cord (5%). The most common

demonstrating multiple metastatic tumors in the

cause of spinal cord compression is metastasis to

woman (with metastatic breast cancer) seen in Fig. 25.3.

the vertebral body from tumors with a tendency

The patient required focal radiotherapy to the cauda

to spread to bone, such as multiple myeloma and

equina, whole brain radiotherapy, and intrathecal

tumors of breast, lung, or prostate origin.

chemotherapy.

Pain is present in the majority of patients,

and may be localized or radicular, often direct-

ing the clinician to the appropriate spinal level.

Treatment Treatment of neoplastic meningitis

■ SPECIAL CLINICAL POINT: The presence

includes the use of intrathecal chemotherapy

of back or neck pain in a patient with known

by lumbar puncture or through an Ommaya

cancer should raise the suspicion of a

reservoir into the lateral ventricles. A limited

spinal metastasis and prompt appropriate

number of chemotherapeutic agents are avail-

investigation.

able for intrathecal use, including methotrexate,

cytosine arabinoside, and thioTEPA. Liposome-

The absence of pain in a patient with spinal

encased cytarabine arabinoside administered in-

cord dysfunction should raise the possibility of

trathecally allows for treatment every 2 weeks,

a different etiology for the patient’s symptoms

in contrast to twice weekly with standard

such as radiation myelopathy, intramedullary

chemotherapy, and has been beneficial for lym-

spinal cord metastases, or a paraneoplastic

phoma and some solid tumors causing neoplas-

syndrome.

tic meningitis. Systemic chemotherapy is not

The neurologic examination is very important

thought to be effective in neoplastic meningitis,

to determine the level of spinal cord involvement

and radiotherapy is reserved for localized treat-

"(see Chapter

5, Neurologic Emergencies).

ment of bulky disease. Patients with sphincter

Symptoms may include motor and sensory

dysfunction may benefit from local radiother-

abnormalities and sphincter dysfunction. The

apy to the conus medullaris and cauda equina.

neurologic examination may demonstrate

510

Chapter 25

■ Neurologic Aspects of Cancer

hyperreflexia and dorsal column signs, with

known cancer or in the setting of deterioration

impairment of position sense and vibration.

despite radiotherapy. Newer approaches to

Spinothalamic dysfunction may result in abnor-

surgical decompression using anterior and an-

malities of pain and temperature sensitivities.

terolateral approaches address the location of

tumor involvement and may be preferred to the

■ SPECIAL CLINICAL POINT: Spinal cord

more traditional posterior surgical decompres-

compression from metastatic tumor is a true

sion. However, often the cancer patient in this

neurologic emergency in the patient with cancer.

situation has extensive systemic disease with a

The rate of progression is variable, and failure to

limited life expectancy and surgery is not well

diagnose and treat spinal cord compression

tolerated.

may result in irreversible neurologic injury, thus

limiting the quality of life as well as potentially

the survival of the patient with cancer.

NONMETASTATIC COMPLICATIONS

In general, the neurologic outcome in spinal

Cerebrovascular Complications

cord compression is determined by the neuro-

logic status at the time treatment is initiated.

Patients with cancer are at increased risk for a

A patient who is ambulatory at the time of

variety of cerebrovascular complications result-

treatment has a good chance of remaining

ing either from the effects of malignancy or

ambulatory, whereas it is unlikely that the non-

from treatment. The cerebrovascular complica-

ambulatory patient will regain significant

tions may be either ischemic or hemorrhagic.

function. Sphincter involvement is considered

Accelerated atheromatous disease resulting

to be a poor prognostic sign and often occurs

in thrombotic strokes may occur following

later in spinal cord compression; early involve-

radiation therapy to the head and neck region.

ment should alert the clinician to consider

Systemic cancer may cause a hypercoagulable

conus medullaris or cauda equina involvement.

state, resulting in arterial or venous sinus

Total spine MRI (cervical, thoracic, and lum-

occlusion. Patients with mucin-producing ade-

bar) with gadolinium is the neuroimaging study

nocarcinomas, in particular, have been

of choice for evaluation of spinal cord dysfunc-

described to be at risk for the development of a

tion because 15% to 30% of patients with

hypercoagulable state and suffer subsequent

spinal cord compression may have involvement

cerebral infarction. Mucin deposits have

at multiple levels. Imaging the entire length of

been found in the venous walls at the sight of

the spine is also useful for optimal planning of

the infarct.

radiotherapy. A gadolinium-enhanced spine

Bacterial endocarditis may occur as a compli-

MRI also may identify leptomeningeal involve-

cation of tumor therapy, because of neutropenia,

ment or intramedullary metastasis.

and it may cause septic emboli resulting in

stroke. Less commonly, a mycotic aneurysm may

Treatment Corticosteroids, usually dexam-

develop with the risk of subarachnoid hem-

ethasone, are administered when the diagnosis

orrhage. Nonbacterial thrombotic endocarditis

of spinal cord compression is made. Initial

is a well-recognized complication of cancer and

doses range between 20 and 100 mg. The sub-

may result in cerebral embolism.

sequent dosing is determined on symptoms,

Thrombocytopenia, either as a direct result

rate of progression, and extent of disease.

of the malignancy (usually one of a hematologic

Radiotherapy and surgery are the main thera-

origin) or a consequence of tumor therapy, may

peutic options. Radiotherapy usually is initi-

cause hemorrhagic complications including

ated urgently in a patient with known cancer.

subdural hematoma, spinal epidural hematoma,

Surgery is appropriate for patients without a

or intracerebral hemorrhage.

511

Chapter 25

■ Neurologic Aspects of Cancer

Chemotherapeutic drugs including beva-

TABLE 25.1

cizumab and cisplatin have been associated

Complications of Corticosteroids

with a reversible posterior leukoencephalopathy

Medical

syndrome also known as posterior reversible

Weight gain, striae

encephalopathy syndrome (PRES). The clinical

Diabetes mellitus

presentation includes headache, visual distur-

Skin fragility

bances, confusion, and alteration of con-

Insomnia

sciousness. Seizures may also occur. This disorder

Infection susceptibility

is thought to be the result of endothelial dys-

Candidiasis (oral thrush, esophagitis)

function and impaired autoregulation of the

Neurologic

posterior intracranial circulation. PRES has

Anxiety, emotional lability

been associated with several other causes

Psychosis, confusion

including severe acute hypertension, preeclamp-

Proximal myopathy

sia, and exposure to immunosuppressive

Spinal lipomatosis (rare)

therapy used in organ transplantation. Neuro-

imaging demonstrates symmetric, predominantly

occipital, white matter changes. Diffusion-

weighted imaging can help differentiate PRES

Corticosteroids are used for a variety of

from ischemia. Recovery is possible with appro-

reasons in the patient with cancer. Systemic

priate management.

and neurologic complications are common

(Table 25.1). Anxiety, insomnia, and emotional

lability, also common, may be managed either by

Metabolic and Nutritional Complications

altering the schedule (e.g., to avoid a late-night

dose that causes insomnia) or by the administra-

Metabolic abnormalities may develop as a

tion of an antianxiety medication such as a

direct result of systemic cancer or may be sec-

benzodiazepine. Chemotherapeutic agents can

ondary to cancer treatment, and can affect both

affect the peripheral and central nervous systems

the peripheral and central nervous systems.

in a variety of ways

(Table 25.2). Toxicity

■ SPECIAL CLINICAL POINT: Metabolic

depends on the age, specific agent, drug dosage,

derangements in cancer patients may cause

and associated therapies. It is imperative that the

an encephalopathy, resulting in generalized

clinician caring for a patient with cancer be

confusion, personality changes, alteration of

aware of the neurotoxicity associated with each

alertness, seizures, and coma. These symptoms

chemotherapeutic regimen.

may fluctuate or be associated with physical

Nutritional status, often poor in the patient

and neurologic exam findings that may include

with cancer, should be addressed if there

tremor, myoclonus, or asterixis.

are neurologic symptoms. Neurologic syn-

The cancer patient often takes multiple medica-

dromes from deficiencies of thiamine and B₁₂

tions, including narcotics for pain management.

are well-recognized.

A thorough review of the medication list is

essential in evaluating the cancer patient with

Paraneoplastic Syndromes

neurologic symptoms. Although narcotics and

pain medications most commonly cause neuro-

Several distinct syndromes have been recog-

logic symptoms in the cancer patient, the

nized in patients with systemic cancer that are

clinician needs to be aware of the potential

not related directly to metastatic disease or

neurologic side effects of all medications the

treatment toxicity. These syndromes are consid-

patient is receiving.

ered to be remote effects of the cancer and are

known as paraneoplastic syndromes. The para-

512

Chapter 25

■ Neurologic Aspects of Cancer

neoplastic syndromes are of clinical significance

a significant impact on the quality and sur-

for two reasons:

vival of life of the cancer patient.

2. The neurologic symptoms may develop

1. The neurologic symptoms may cause

prior to the actual diagnosis of the systemic

significant morbidity and therefore have

cancer; therefore, if the clinician is familiar

with the various paraneoplastic syndromes,

an earlier diagnosis of the systemic malig-

TABLE 25.2

Neurotoxicity of Chemotherapy

nancy is potentially possible.

The disorders are thought to be related to

Cerebral Hemispheres

an autoimmune process, and various specific

Acute encephalopathy

antineuronal antibodies have been identified

Procarbazine

Interferon

(Table 25.3).

Interleukin-1,2

Ifosfamide

Methotrexate (high-dose intravenous or

COMPLICATIONS FROM

intrathecal)

RADIATION THERAPY

Asparaginase

Vincristine

Complications from radiation therapy may

Bevacizumab (PRES)

mimic tumor progression or recurrence. In gen-

Cisplatin (PRES)

eral, radiation therapy is initially well tolerated.

Chronic encephalopathy

An acute encephalopathy may develop, however,

Methotrexate (high-dose intravenous or

particularly if large radiation fractions are

intrathecal)

delivered to a large volume of brain in patients

Fludarabine

with increased intracranial pressure. The patients

Leukoencephalopathy

may complain of increased headaches, somno-

Methotrexate

lence, lethargy, nausea, or worsening of focal

5-Fluorouracil + levamisole

neurologic symptoms. The symptoms of acute

Carmustine (intra-arterial)

radiation toxicity are the result of disruption of

Cerebellum

the blood-brain barrier resulting in cerebral

5-fluorouracil

edema, and usually improve with corticosteroid

Cytarabine

therapy. If the symptoms are not responsive to

Visual System

corticosteroid therapy, the radiation therapy may

Tamoxifen (reversible retinopathy)

need to be postponed temporarily.

Fludarabine (cortical blindness)

Subacute or “early delayed” complications

Cisplatin (cortical blindness)

from radiation therapy usually begin within

Intra-arterial chemotherapy (optic

2 weeks of completing radiation therapy and

neuropathy)

may persist up to 4 months after completion of

Myelopathy

radiation therapy. This disorder is thought to

Methotrexate (intrathecal)

be a reversible injury to the oligodendroglial

Cytarabine (intrathecal)

cells resulting in demyelination, and it is respon-

ThioTEPA (intrathecal)

sive to corticosteroid therapy. During this

Peripheral Nerves

phase, neuroimaging studies may demonstrate

Vincristine

an increased mass effect and increased contrast

Cisplatin

enhancement, suggesting tumor progression.

Paclitaxel

However, symptoms may be controlled with

Suramin

dexamethasone, and the clinical situation may

Etoposide

stabilize over time. This phase of radiation

513

Chapter 25

■ Neurologic Aspects of Cancer

TABLE 25.3

Paraneoplastic Syndromes

Syndrome Associated

Autoantibodies

Associated Tumors

Cerebellar degeneration

Anti-Yo (Anti-Purkinje cell)

Ovarian, breast

Encephalomyelitis

Anti-Hu

Lung

Opsoclonus-myoclonus

Anti-Ri

Breast, bladder, and lung

Sensory neuronopathy

Anti-Hu

Lung

Lambert-Eaton syndrome

Anti-VGCC (antisynaptotagmin)

Lung (small-cell)

injury often is mistaken for tumor progression.

and dementia. Although the ventricles may

Pseudoprogression is a term applied to a delay

appear large on neuroimaging, symptoms of

in improvement or apparent worsening of the

leukoencephalopathy do not improve with

neuroimaging in patients with gliomas treated

shunting. Central endocrinopathies including

with concurrent radiotherapy and temozolo-

central hypothyroidism, adrenal insufficiency,

mide. The MRI study may demonstrate

and decreased sex hormones also may occur as

worsening up to several months after comple-

a late complication of radiation therapy. An ele-

tion of the combined therapy. Functional

vated prolactin level may be seen as the result

MRI is being investigated as a means to differ-

of radiation injury to the hypothalamus.

entiate pseudoprogression from early tumor

progression.

A possible late or “delayed” effect of radia-

SPECIAL CHALLENGES FOR

tion therapy is radiation necrosis. This process

HOSPITALIZED PATIENTS

may be indistinguishable from tumor recur-

rence using contrast-enhanced CT or MRI

The general oncology patient may require inter-

studies. Attempts have been made to differenti-

mittent hospitalization during the course of

ate between the two processes by various

illness as a result of severe nausea and vomiting,

metabolic neuroimaging studies, such as

dehydration, sepsis, pain, or new neurologic

positron emission tomography (PET) and sin-

symptoms. The various medical problems often

gle photon emission computed tomography

cause secondary somnolence, weakness, and

(SPECT).

(Radiation necrosis should be

alternation of mental status. The oncology

hypometabolic, whereas recurrent tumor is

patient often is receiving multiple medications

expected to be hypermetabolic.) Often, both

that may cause somnolence, confusion, or

radiation necrosis and recurrent tumor are

weakness. Clinicians need to be alert and sensi-

present simultaneously. If treatment options

tive to metabolic abnormalities, nutritional and

are available, a biopsy may be necessary.

hydration needs, the possibility of infection,

Reoperation with attempted resection and

and unusual medication schedules that may

debulking may reduce chronic corticosteroid

contribute to any of these problems. The toxic-

needs and improve neurologic symptoms but is

ity profile of cancer therapy, including

usually only considered when additional treat-

radiotherapy and chemotherapy, also needs to

ment modalities are available. Reoperation

be considered.

alone offers very limited benefit.

The patient with a brain tumor may require

Late effects of radiation therapy also may

hospitalization for management of seizures,

result in a diffuse leukoencephalopathy, mani-

increased intracranial pressure, or neurologic

fested by gait disturbance, urinary incontinence,

deterioration with disease progression.

514

Chapter 25

■ Neurologic Aspects of Cancer

to the lung tumor. Four months later, the

Always Remember

patient returns with back pain, urinary fre-

quency, and bilateral leg weakness. Which

• Neurologic symptoms may develop in a

of the following is the most likely cause for

patient with known cancer or may be the

this patient’s new symptoms?

presenting symptoms in a patient with no

A. Radiation myelopathy secondary to the

previous diagnosis of cancer.

chest radiotherapy

• Neurologic symptoms may be the direct or

B. Bony metastases to the spine or epidural

indirect result of the malignancy itself or may

cord compression

develop as a result of treatment for the

C. Steroid myopathy

cancer.

D. Urinary tract infection secondary to

• Any patient with a known malignancy

chronic immunosuppression

who develops unexplained neurologic

symptoms, lethargy, depression, or

The correct answer is B. The major clinical con-

personality changes should be referred to a

cerns are epidural spinal cord compression from

neurologist.

bony metastases. MRI of the spine should be

performed with gadolinium using the clinical

examination to guide localization. Steroid my-

opathy does not cause urinary frequency. Radi-

ation-induced myelopathy is a rare diagnosis

QUESTIONS AND DISCUSSION

usually occurring later, and it should be consid-

1. A 50-year-old woman has an unexplained

ered only if the other direct metastatic compli-

episode of loss of consciousness while

cations have been excluded.

home alone. Upon awakening, she was

aware of being incontinent of urine and

3. A 62-year-old man complains of a 2-month

complained of a very sore tongue. You

history of burning numbness in his legs and

determine that she probably had a seizure.

feet. He has lost 10 pounds and describes

The patient’s MRI with gadolinium demon-

decreased appetite. He has normal cogni-

strates multiple ring-enhancing lesions in

tion. Strength in the extremities is full, and

various parts of the cerebral hemispheres.

coordination is normal. Electrodiagnostic

Infection is ruled out. Which of the follow-

studies (EMG/NCS) reveal a pure sensory

ing is the most likely diagnosis?

neuropathy. The paraneoplastic syndrome

A. Glioblastoma multiforme

that would best fit this clinical picture is

B. Meningioma

A. Anti-Hu

C. Oligodendroglioma

B. Anti-Yo

D. Metastases

C. Anti-Ri

D. Anti-VGCC

The correct answer is D. Most primary brain

tumors present as solitary lesions. Multiple

The correct answer is A. Anti-Hu antibodies

ring-enhancing lesions are suggestive of

in the setting of lung cancer may be associated

metastases and should prompt a workup to

with either limbic encephalitis or a subacute

identify the primary tumor.

sensory neuropathy. Anti-Yo is associated

with cerebellar degeneration. Anti-Ri may

2. The chest CT scan of the patient in

cause opsoclonus-myoclonus. Anti-VGCC is

Question 1 is abnormal, and a diagnosis

associated with Lambert-Eaton myasthenic

of adenocarcinoma of the lung is confirmed

syndrome.

histologically by bronchoscopy. The patient

is treated with high-dose steroids, whole

4. A 52-year-old man is receiving beva-

brain radiation therapy, and radiotherapy

cizumab for adenocarcinoma of the lung.

515

Chapter 25

■ Neurologic Aspects of Cancer

The following day after an infusion he

Hochberg FH, Miller DC. Primary central nervous system

lymphoma. J Neurosurg. 1988;68:835.

became confused, complained of inability

to see clearly, and then became agitated.

Hwu WJ, Raizer J, Panageas KS, et al. Treatment of

metastatic melanoma in the brain with temozolomide

On the way to the hospital, he experienced

and thalidomide. Lancet Oncol. 2001;2:634-635.

a seizure. Which of the following complica-

Kori SH, Foley KM, Posner JB. Brachial plexus lesions in

tions of chemotherapy is most likely to be

patients with cancer: 100 cases. Neurology. 1985;35:8.

present in this patient?

Moll JWB, Antoine JC, Brashear HR, et al. Guidelines on

A. Peripheral neuropathy

the detection of paraneoplastic anti-neuronal-specific

B. Toxic optic neuropathy

antibodies. Neurology. 1995;45:1937.

C. Posterior reversible encephalopathy

Patchell RA, Tibbs PA, Walsh JW, et al. Surgery versus

syndrome (PRES)

radiosurgery in the treatment of brain metastasis.

D. Myelopathy

J Neurosurg. 1996;84:748.

The correct answer is C. The symptoms

Perrin RG, McBroom RJ. Metastatic tumors of the spine.

In: Rengachary SS, Wilkins RH, eds. Principles of

suggest acute dysfunction of the posterior

Neurology. St. Louis: Wolfe; 1994.

cerebral hemispheres. Bevacizumab may cause

Posner JB. Neurologic Complications of Cancer. Philadel-

either thrombosis or hemorrhage, but has

phia, PA: FA Davis; 1995.

also been associated with PRES syndrome.

Raez L, Cabral L, Cai JP, et al. Treatment of AIDS-related

Peripheral neuropathies, optic neuropathies,

primary central nervous system lymphoma with

and myelopathies can result as complications

zidovudine, ganciclovir, and interleukin 2. AIDS Res

of chemotherapy but would not be expected

Hum Retroviruses. 1999;15:713-719.

to cause seizures or altered mental status.

Smalley SR, Laws ER, O’Fallon JR, et al. Resection for

solitary brain metastasis: role of adjuvant radiation

and prognostic variables in 229 patients. J Neurosurg.

1992;77:531.

SUGGESTED READING

Stupp R, Dietrich PY, Ostermann Kraljevic S, et al. Prom-

ising survival for patients with newly diagnosed

Bindal AK, Bindal RK, Hess KR, et al. Surgery versus

glioblastoma multiforme treated with concomitant

radiosurgery in the treatment of brain metastasis.

radiation plus temozolomide followed by adjuvant

J Neurosurg. 1996;84:748.

temozolomide. J Clin Oncol. 2002;20:1375-1382.

Cairncross JG, MacDonald DR, Ramsay DA. Aggressive

Thomas JE, Cascino TL, Earie JD. Differential diagnosis

oligodendroglioma: a chemosensitive tumor. Neuro-

between radiation and tumor plexopathy of the pelvis.

surgery. 1992;31:78.

Neurology. 1985;35:1.

Chamberlain MC. Current concepts in leptomeningeal

Vredenburgh JJ, Desjardins A, Herndon JE, et al. Phase II

metastasis. Curr Opin Oncol. 1992;4:533.

trial of bevacizumab and irinotecan in recurrent malig-

Glusker P, Recht L, Lane B. Reversible posterior leukoen-

nant glioma. Clin Cancer Res. 2007;13:1253-1261.

cephalopathy syndrome and bevacizumab. N Engl

Westphal M, Hilt DC, Bortey E, et al. A phase 3 trial of

J Med. 2007;354:980.

local chemotherapy with biodegradable carmustine

Heros DO. Neuro-oncology. In: Weiner WJ, Shulman LM,

(BCNU) wafers

(Gliadel wafers) in patients with

eds. Emergent and Urgent Neurology. New York:

primary malignant glioma. Neuro-oncol. 2003;5(2):

Lippincott Williams & Wilkins; 1999.

79-88.

Eye Signs in

Neurologic

Diagnosis

ROBERT K. SHIN AND JAMES A. GOODWIN

key points

• Specific patterns of vision loss correlate with specific

lesions along the visual pathway from the eye to

primary visual cortex.

• Distinct higher-order visual processing disorders (e.g.,

visuospatial neglect or an inability to recognize faces)

are associated with specific cortical regions.

• The pupils are under autonomic control. Afferent

(sensory) lesions cause poorly reactive pupils while

parasympathetic and sympathetic efferent (motor)

lesions cause anisocoria (unequal pupils).

• Eye movement abnormalities may be conjugate (eyes

remain aligned) or disconjugate (the eyes are no longer

aligned). Disconjugate eye movement abnormalities are

associated with diplopia (double vision).

• Nystagmus (rhythmic, conjugate eye movements) are

associated with vertigo (subjective feeling of

movement) and oscillopsia (shaking of the visual field).

Different forms of nystagmus suggest specific disorders

of the brainstem or cerebellum.

umans are highly

nerves are involved in coordinating, directing,

visual animals. In order to fully scan the environ-

and protecting these delicate visual organs,

ment, our two spherical, lensed eyes synchro-

which can move faster than any other part of the

nously rotate in three spatial dimensions under

human body. Over a million retinal ganglion

the control of 12 extraocular muscles, guided by

cells carry information from over 100 million

the parietal lobes, frontal lobes, cerebellum, mid-

photoreceptors from each exquisitely formed eye

brain, and pons. More than half of our cranial

to multiple brainstem and subcortical nuclei,

516

517

Chapter 26

n Eye Signs in Neurologic Diagnosis

from which myriad neuronal axons splay out

complains of blurred vision or vision loss, the

into the temporal and parietal lobes and down as

first step is to make sure that the patient has

far as the thoracic spinal cord to connect these

been evaluated by an eye doctor (ophthalmolo-

nuclei to a network of autonomic structures and

gist or optometrist) to rule out an ocular disor-

to primary visual cortex. Visual information radi-

der (a problem with the cornea, lens, vitreous,

ates from the occipital lobe in concentric, widen-

or retina). Once disorders such as refractive

ing circles across the neocortex, approximately

error, glaucoma, cataract, vitreous hemorrhage,

one third of which is involved in higher-order

retinal artery or vein occulusion, and retinal

visual processing, providing us with real-time,

detachment have been ruled out, a neurologic

full-color, panoramic, stereoscopic views of the

evaluation can begin.

world around us.

n SPECIAL CLINICAL POINT: Every patient

Because this elegant but complex system

with vision loss should be evaluated by an eye

involves every lobe of the brain, multiple sub-

doctor to rule out ocular problems before the

cortical structures, multiple brainstem nuclei,

neurologic evaluation begins.

multiple peripheral and cranial nerves, the auto-

nomic nervous system, and even the spinal

cord, it is not surprising that many different

Evaluation of Vision Loss

neurologic problems (stroke, migraine, seizures,

The evaluation of vision loss involves tests of

multiple sclerosis, movement disorders, demen-

visual acuity and color vision, the swinging

tia, traumatic brain injury, neuromuscular

flashlight test, an evaluation of the optic disc

disorders, alcoholism, CNS infections, and can-

appearance, and testing for visual field defects.

cer) affect the visual system in some way, lead-

The information gleaned from these tests must

ing to a wide variety of neuro-ophthalmologic

be combined in order to accurately localize and

disorders.

diagnose the source of the vision loss.

This chapter is a survey of a number of vi-

sual signs and symptoms that are useful in lo-

Visual Acuity Visual acuity, tested with hand-

calization and diagnosis in neurologic disease.

held or wall-mounted Snellen eye charts, is the

Broad categories of neuro-ophthalmologic com-

most basic part of the visual examination. The

plaints that neurologists and non-neurologists

best corrected visual acuity possible is desired

may encounter include: vision loss (blindess or

(patients should wear their glasses or contact

blurred vision), higher-order visual processing

lenses). A pinhole may be used to minimize re-

disorders (cognitive disorders), pupillary abnor-

fractive error if lenses are not available.

malities (poorly reactive or unequal pupils), eye

movement problems (gaze palsies and double vi-

Color Vision Color perception is an extremely

sion), and nystagmus (shaking eye movements).

sensitive, although subjective, measure of optic

Each of these broad categories is organized into

nerve dysfunction. If specialized color plates

smaller subsections, with each subsection focus-

are not available, present a fairly large bright

ing on a limited number of related neuro-oph-

red object and ask the patient if there is any

thalmologic disorders.

apparent difference in the redness of the

object between the two eyes. Patients may re-

port a subjective loss of color intensity (color

desaturation) in one eye compared to the

VISION LOSS

other. Reds may be shifted to a darker amber

Vision loss may range from mild blurred vision

color or bleached toward a lighter, pinkish, or

to complete blindness and may involve one or

yellowish color. Patients can be asked to

both eyes. When approaching a patient who

subjectively quantitate the degree of color

518

Chapter 26

n Eye Signs in Neurologic Diagnosis

FIGURE 26.1 Swinging flashlight test. In the darkness (top) both pupils dilate. A: Under normal

conditions, when light shines is either eye, both pupils constrict equally. B: In the setting of injury to

the left optic nerve, both pupils constrict when light shines in the right eye but dilate when light shines

in the left eye.

desaturation—“If this (covering one eye) is a

If a patient has decreased visual acuity in

dollar’s worth of red, how much is this (cover-

one eye with normal visual acuity and a full vi-

ing the other eye) red worth?”

sual field in the other eye, but has no RAPD,

the possibility of refractive error, cataract, or

Swinging Flashlight Test Damage to the anterior

other media opacity should be considered. If

light pathway (optic nerves, optic chiasm, and

the ocular examination is normal, the absence

optic tract) can be detected by illuminating

of a RAPD could suggest that the monocular

each eye separately with a focal light source.

vision loss is functional (nonorganic).

Swinging the flashlight back and forth provides

n SPECIAL CLINICAL POINT: Cataracts and

a sensitive means of comparing the afferent

other opacities do not produce a significant

function of the two eyes (Fig. 26.1).

RAPD even with major visual loss. This is

Normally, the amount of pupillary constric-

because such opacities diffuse light within the

tion will be the same regardless of which eye is

eye and blur the visual image but do not

being stimulated by the flashlight. In the setting

significantly reduce the total quantity of light

of an afferent defect, however, both pupils may

that reaches the retina.

dilate when the light is swung to the affected eye,

with both pupils constricting when the flashlight

Optic Disc Appearance

is swung to the normal eye. (Remember that

even if only the eye illuminated by the flashlight

Ophthalmoscopy, though a challenging skill to

can be seen, the unseen fellow eye is undergoing

master, is an essential part of any evaluation

the same consensual pupillary constriction and

for vision loss (see Chapter 1). At a minimum,

dilation that is observed in the illuminated eye.)

clinicians should be able to distinguish between

This asymmetry is the relative afferent pupillary

a normal optic disc, optic disc pallor, and optic

defect (RAPD) or Marcus Gunn pupil (see sec-

disc swelling with a handheld direct ophthal-

tion Relative Afferent Pupillary Defect).

moscope (Fig. 26.2).

519

Chapter 26

n Eye Signs in Neurologic Diagnosis

Optic Disc Pallor Damage to the optic nerve is

associated with optic disc pallor

(a loss of

color). Optic disc pallor generally takes time to

develop, and may be associated with a history of

prior optic neuropathy. Gradually progressive

vision loss accompanied by optic disc pallor is

concerning for a compressive optic neuropathy

from an aneurysm or tumor. An optic disc that

is both pale and swollen is concerning for is-

chemic optic neuropathy, particularly arteritic

ischemic optic neuropathy caused by giant cell

arteritis.

Optic Disc Swelling Swelling or edema of the

optic disc may be unilateral or bilateral. Is-

chemic, inflammatory, and demyelinating optic

neuropathies may cause disc swelling, as can

increased intracranial pressure. The key to dis-

tinguishing between disc swelling from optic

neuropathy and disc swelling from increased

intracranial pressure (papilledema) is compar-

ing the visual function of the nerve to its ap-

pearance.

Disc swelling due to optic neuropathy will

be associated with decreased visual acuity, de-

creased color vision, a RAPD (if unilateral or

FIGURE 26.2 Fundus photographs. Photos are displayed

asymmetric), and characteristic optic nerve vi-

as though looking at the patient (right eye on the left, left

sual field defects (see section Visual Pathway

eye on the right). Veins (thicker lines) and arteries (thinner

lines) radiate to and from the optic disc, which lies nasal

and Visual Field Defects). Disc swelling due to

to the macula (visible as a pigmented spot). A: Unilateral

optic neuropathy may be unilateral or bilateral

optic disc pallor following a left ischemic optic neuropathy

depending on its etiology.

(black arrow). B: Bilateral disc pallor in a patient with

Papilledema

(which refers specifically to

multiple sclerosis. C: Bilateral disc swelling in a young

optic disc swelling due to increased intracranial

patient with idiopathic intracranial hypertension

pressure) is typically associated with relatively

(pseudotumor cerebri).

little visual dysfunction, especially early on. Vi-

sual acuity and color vision are often normal or

only mildly affected. No RAPD is usually seen

Normal Optic Disc When decreased vision is

unless significant nerve damage has occurred.

accompanied by other signs of optic neuropa-

Visual fields may show enlargement of the blind

thy (decreased color vision, RAPD, field loss)

spot or nonspecific constriction. Although pa-

but the optic disc is normal, consider the possi-

pilledema is usually bilateral, it is often asym-

bility of acute optic neuritis or a posterior is-

metric (see section Papilledema).

chemic optic neuropathy, both of which may

The combination of a pale optic disc on one

present without disc pallor or swelling. Retinal

side and optic disc swelling on the other is the

disorders may also be associated with a normal

Foster Kennedy syndrome, signifying a mass

optic disc, but rarely present with decreased

lesion (e.g., olfactory groove meningioma) that

color vision or a RAPD.

compresses one optic nerve

(causing disc

520

Chapter 26

n Eye Signs in Neurologic Diagnosis

pallor) and raising intracranial pressure (causing

result in a pale optic disc on one side (due to an

papilledema of the opposite nerve). More com-

old optic nerve injury) and a swollen optic disc on

monly seen is the pseudo-Foster Kennedy syn-

the other (due to an acute optic neuropathy).

drome in which sequential optic neuropathies

(e.g., optic neuritis or ischemic optic neuropathy)

Visual Pathway and Visual Field Defects

Each eye has its own visual field. These visual

fields are slightly different from each other, but

overlap substantially. The retina does not

directly project to the occipital lobe. Instead,

visual information travels along a six-part

Left eye

Right eye

visual pathway (Fig. 26.3).

• Retinal gangion cell (RGC) axons con-

verge to form the optic nerves, which

Right

Left

“punch through” the back of the eye

eye

nasal (medial) to the macula, forming

the optic disc. Because there are no

Optic nerve

photoreceptors on the optic disc itself

Optic chiasm

and due to the optics of the eye (images

are reversed and upside-down), a blind

spot is created temporal (lateral) to cen-

Optic tract

tral fixation in each eye.

LGN

• Both optic nerves cross, forming the optic

chiasm. Within the chiasm are RGC

fibers from both eyes, some of which

cross, others of which remain uncrossed.

Optic

• Beyond the chiasm, crossing and uncrossed

radiations

RGC fibers join to form the optic tracts.

Unlike an optic nerve, which carries infor-

mation from a single eye, each optic tract

Visual

carries binocular information from the op-

cortex

posite (left or right) visual hemifield.

• RGC axons (having formed the optic

nerves, chiasm, and tracts) finally project

FIGURE 26.3 Visual fields and the visual pathway.

onto the lateral geniculate nucleus (LGN)

A: Visual fields are always depicted from the patient’s point

of the thalamus.

of view (right eye on the right, left eye on the left). Note

• Axons from each LGN spread out and

that the temporal field of each eye is larger than the nasal

separate into the optic radiations. Visual

field. A blind spot lies temporal and slightly inferior to the

information from the upper half of the

central fixation point in each eye. B: The visual pathway

visual hemifield travels through the infe-

runs from the retina to the occipital lobe. (The diagram is

rior or temporal radiations (Meyer’s loop);

oriented “radiologically” with the eyes toward the top of

visual information from the lower half of

the page and the left eye toward the right side of the

the visual hemifield travels through the

page.) Retinal ganglion cell axons project to the lateral

superior or parietal radiations.

geniculate nucleus (LGN) of the thalamus via the optic

• The radiations converge on the visual

nerve, optic chiasm, and optic tract. Axons from the LGN

project to the visual cortex via the superior (parietal) and

cortex, where higher-order visual pro-

inferior (temporal) optic radiations.

cessing begins.

521

Chapter 26

n Eye Signs in Neurologic Diagnosis

Right

Left

eye

LGN

Visual

cortex

FIGURE 26.4 Optic nerve visual field defects. A: A lesion of the left optic nerve may result in a

variety of visual field defects. B: Monocular blindness. C: Inferior altitudinal defect. D: Superior arcuate

defect (Bjerrum scotoma). E: Central scotoma.

Due to this complicated anatomic arrange-

ment, lesions within different parts of the vi-

sual pathway are associated with a variety of

specific visual field defects.

Optic Nerve Lesions of the optic nerve always

cause unilateral visual field defects (Fig. 26.4).

Optic nerve lesions are generally also associ-

ated with decreased visual acuity, decreased

color vision, and a relative afferent pupillary

defect.

Optic nerve damage may cause monocular

blindness, a central scotoma (blurring only in

the center of vision), or a centrocecal scotoma

(vision loss in the center of vision that extends

to the blind spot).

FIGURE 26.5 Retinal ganglion cell organization. Diagram

Reflecting the organization of RGC axons

of the fundus of the left eye. (1) The papillomacular

within the retina (Fig. 26.5), visual field defects

bundle carries information from the center of the visual

due to optic nerve damage often respect the

field. Lesions of the papillomacular bundle may result in a

horizontal meridian (midline). Superior and in-

central scotoma. (2) The arcuate bundles arc around the

ferior altitudinal defects affect the entire upper

papillomacular bundle. A lesion of an arcuate bundle may

or lower field of vision respectively. Superior

cause an arcuate defect or Bjerrum scotoma.

522

Chapter 26

n Eye Signs in Neurologic Diagnosis

Right

Left

eye

LGN

Visual

cortex

FIGURE 26.6 Chiasmal visual field defects. A: Lesions of the optic chiasm may cause a variety of

visual field defects. B: Classically, a chiasmal lesion causes a bitemporal hemianopia. C: A superior

bitemporal hemianopia may occur if the chiasm is compressed from below. D: A lesion of the

posterior chiasm may result in a central bitemporal hemianopia. E: A lesion of the left optic nerve

where it joins the chiasm may be associated with a junctional scotoma, a superior temporal defect on

the side opposite the optic nerve visual field defect.

and inferior arcuate defects are curved sco-

retinas (Fig. 26.6). Retinal ganglion cells axons

tomas that follow the anatomic organization of

from either side (right or left) of the macula

the arcuate bundles.

travel together through the optic nerve but

In general, these patterns of visual field loss

separate at the optic chiasm. This divergence

are not specific for any particular type of optic

creates the hemianopic midline and is the rea-

neuropathy (see section Optic Neuropathy).

son that all chiasmal and retrochiasmal visual

Central scotomas, however, are commonly

field defects respect the vertical meridian.

seen with optic neuritis. Bilateral centrocecal

Though the chiasm may be affected by is-

scotomas strongly suggest toxic-metabolic

chemia, infection, or demyelination, most symp-

optic neuropathy. Inferior altitudinal defects

tomatic lesions of the chiasm are compressive.

are often associated with ischemic optic neu-

Pituitary macroadenomas are the most common

ropathy. Arcuate defects (Bjerrum scotomas)

cause of chiasmal compression, but other tumors

can be seen in glaucoma.

(e.g., craniopharyngioma and meningioma) and

aneurysms may also injure the chiasm.

Optic Chiasm Chiasmal injury is classically as-

Bitemporal hemianopias may be complete

sociated with bitemporal visual field defects

(with no vision temporal to fixation in either

due to damage to crossing fibers that carry tem-

eye), but when compression is early or mild,

poral visual field information from the nasal

the hemianopia may be denser superiorly

523

Chapter 26

n Eye Signs in Neurologic Diagnosis

(when the chiasm is compressed from below)

retina of the ipsilateral eye and crossed RGC

or inferiorly (when the chiasm is compressed

axons from the nasal retina of the contralateral

from above).

eye. The optic tract, therefore, carries visual in-

Because crossing macular fibers travel poste-

formation from both eyes but only from the

riorly, a lesion of the posterior chiasm may re-

contralateral hemifield (as opposed to the optic

sult in a central bitemporal hemianopia, sparing

nerve, which carries information from both

the more peripheral temporal fields.

hemifields but only from one eye). Like the

Rarely, an anterior lesion at the junction of

optic chiasm, the optic tract is most commonly

the optic nerve and the optic chiasm can injure

injured by compression from a mass lesion.

crossing fibers from the opposite inferior retina

A lesion of the optic tract results in a homony-

(which loop forward into the optic nerve,

mous hemianopia—a loss of vision in the con-

forming Wilbrand knee before projecting pos-

tralateral visual field of both eyes (Fig. 26.7).

teriorly to the optic tract). As a result, the optic

(For example, a left optic tract lesion will cause

nerve visual field defect in one eye may be ac-

an inability to see to the right of midline in both

companied by a superior temporal scotoma in

eyes—a right homonymous hemianopia.) In

the other eye—the junctional scotoma.

fact, all retrochiasmal visual field defects are

homonymous, meaning that the visual field de-

Optic Tract Each optic tract is comprised of

fects will be in the same hemifield (left or right)

uncrossed RGC axons from the temporal

of both eyes.

Right

Left

eye

LGN

Visual

cortex

FIGURE 26.7 Optic tract visual field defects. A: A lesion of the left optic tract is depicted. B: A left

optic tract lesion results in a right homonymous hemianopia. (Because the temporal field of the right

eye is larger than the nasal field of the left eye, this homonymous hemianopia may be accompanied by

a right relative afferent papillary defect.) C: Homonymous hemianopias due to tract lesions may be

incongruous.

524

Chapter 26

n Eye Signs in Neurologic Diagnosis

In order to distinguish a homonymous hemi-

Also, homonymous hemianopias caused by

anopia due to a tract lesion from one caused by

lesions of the optic tract are often incongruous,

a lesion of visual cortex, it is important to check

meaning that the density and shape of the vi-

for a relative afferent pupillary defect and to as-

sual field defects do not match completely. As a

sess the congruity of the visual field.

rule, visual field defect congruity increases as

Although the optic tract primarily projects

the visual pathway approaches the occipital

to the lateral geniculate nucleus of the thala-

lobe, with visual cortex lesions typically pro-

mus (see below), some RGC axons are diverted

ducing highly congruous visual field defects.

from the tract to the posterior midbrain to con-

Congruity can only be assessed if the homony-

trol the pupillary light response (see section

mous hemianopia is incomplete.

Pupil Anatomy and Function). Furthermore,

because the temporal field is larger than the

Lateral Geniculate Nucleus As with tract le-

nasal field, a homonymous hemianopia causes

sions, lesions of the lateral geniculate nucleus

relatively more visual field loss in one eye than

(LGN) of the thalamus will result in homony-

the other. In the case of a lesion of the left optic

mous visual field defects (Fig. 26.8). Thalamic

tract, the resulting right homonymous hemi-

lesions associated with visual field defects are

anopia will cause a larger defect in the right eye

most commonly vascular.

than in the left eye and may therefore be

Lateral (posterior) choroidal artery occlu-

accompanied by a right relative afferent pupil-

sion has been associated with a wedge-shaped

lary defect.

homonymous scotoma along the horizontal

Right

Left

eye

LGN

Visual

cortex

FIGURE 26.8 Lateral geniculate nucleus (LGN) visual field defects. A: A lesion of the left LGN may

be associated with two different vascular lesions. B: Occlusion of the left lateral (posterior) choroidal

artery may cause a right horizontal sectoranopia. C: Occlusion of the left anterior choroidal artery may

result in a right quadruple sectoranopia.

525

Chapter 26

n Eye Signs in Neurologic Diagnosis

Right

Left

eye

LGN

Visual

cortex

FIGURE 26.9 Optic radiation visual field defects. A: A lesion of the left optic radiations is depicted.

B: A lesion in the left temporal lobe, affecting the inferior radiations (Meyer loop), will cause a right

superior quadrantanopia, also known as a “pie in the sky” defect. C: A lesion in the left parietal lobe,

affecting the superior radiations, will result in a right inferior quadrantanopia.

midline, sparing the upper and lower

both sets of optic radiations to be injured

quadrants—a horizontal sectoranopia.

simultaneously.

Anterior choroidal artery occlusion may re-

A lesion of a single set of optic radiations af-

sult in the exact complement of the other

fects half of the contralateral hemifield, resulting

geniculate syndrome, superior and inferior

in a homonymous quadrantanopia (Fig. 26.9).

homonymous quadrantic defects that spare

Temporal lobe lesions, including strokes, tu-

the area along the horizontal meridian—a

mors, encephalitis, and demyelination, may

quadruple sectoranopia.

damage the inferior radiations as they loop

forward and then back toward the visual cortex,

Optic Radiations Axons radiating outward

producing a superior quadrantanopia, also

from the lateral geniculate nucleus toward pri-

known as a “pie in the sky” defect. Similar lesions

mary visual cortex form two thin but wide

of the parietal lobe may damage the superior ra-

bands that travel separately within the deep

diations, causing an inferior quadrantanopia.

white matter of the cerebral hemispheres. Vi-

sual information from the upper visual field

Visual Cortex The visual pathway ends in the

travels inferiorly through the temporal lobes,

occipital lobe as the superior and inferior

while information from the lower visual field

optic radiations converge on primary visual

travels superiorly through the parietal lobes.

cortex (also known as calcarine cortex or stri-

As a result of this separation, it is unusual for

ate cortex).

526

Chapter 26

n Eye Signs in Neurologic Diagnosis

Right

Left

eye

LGN

Visual

cortex

FIGURE 26.10 Visual cortex visual field defects. A: A left occipital lobe lesion may be associated

with a variety of right homonymous hemianopias. B: Homonymous hemianopias without macular

sparing are common. C: Homonymous hemianopias with macular sparing may occur. D: Incomplete

homonymous hemianopias caused by occipital lobe lesions are highly congruous. E: A small lesion of

the deep (anterior) visual cortex may result in a visual field defect that only involves the unpaired

temporal crescent.

Lesions of the visual cortex, like lesions of the

Occasionally, central vision may be spared

optic tract, frequently result in a contralateral

within the hemianopic field. The classic expla-

homonymous hemianopia

(Fig.

26.10). The

nation for this macular sparing is collateral

most common causes of homonymous hemi-

blood supply to the occipital lobe from a

anopias due to an occipital lobe lesion are pos-

branch of the middle cerebral artery, though

terior cerebral artery infarction, hemorrhage,

there are other possible explanations as well.

trauma, and tumor (Fig. 26.11). Rarely, patients

Rarely, a lesion may selectively affect only

present with homonymous hemianopias but no

the deepest, most anterior part of the visual

abnormalities on MRI, which raises the possi-

cortex, producing a visual field defect that is

bilies of Alzheimer disease or the Heidenhain

limited to the peripheral portion of the tem-

variant of Creutzfeld-Jakob disease.

poral field of the contralateral eye. Involve-

Homonymous hemianopias caused by vi-

ment of the temporal crescent is the only

sual cortex lesions are frequently complete.

situation in which a retrochiamsal lesion re-

When incomplete, homonymous hemianopias

sults in a monocular visual field defect.

tend to be congruous. Homonymous quadran-

(Sparing of the temporal crescent in the set-

tanopias can also be seen when damage to the

ting of a homonymous hemianopia is also

visual cortex is limited.

possible.)

527

Chapter 26

n Eye Signs in Neurologic Diagnosis

FIGURE 26.11 Occipital hemorrhage. A: Axial FLAIR MRI shows a left occipital lobe hemorrhage

secondary to poorly controlled hypertension. B: The patient’s only neurologic deficit was a complete

right homonymous hemianopia.

Optic Neuropathy

Optic neuritis is a clinical diagnosis; MRI of

the orbits is not necessary when the presenta-

Vision loss that is only present in one eye is

tion is classic (a young adult with subacute vi-

generally either an ocular disorder affecting the

sion loss in one eye associated with decreased

structures of the eye itself (above) or an optic

color vision and pain on eye movements). MRI

neuropathy, a lesion of the optic nerve. There

of the brain, however, is useful as a way to

are many different kinds of ischemic, inflam-

identify patients at higher risk to go on to de-

matory, infectious, infiltrative, demyelinating,

velop multiple sclerosis (MS). Patients with a

and toxic-metabolic causes of optic neuropa-

single episode of optic neuritis who have de-

thy (only a few are discussed here), but in all

myelinating lesions on brain MRI are much

cases of optic neuropathy, there should be de-

more likely to go on to develop MS in the fu-

creased visual acuity, decreased color vision, a

ture than patients whose initial brain MRI

RAPD, and visual field defects.

shows no lesions.

The prognosis for recovery from optic neuri-

Optic Neuritis Optic neuritis is a specific de-

tis is excellent. Most patients recover on their

myelinating optic neuropathy, which may be

own. Intravenous corticosteroids may speed up

idiopathic, but is strongly associated with mul-

the recovery of vision but do not provide any

tiple sclerosis (see Chapter 11). Optic neuritis

lasting benefit. Oral corticosteroids should not

typically occurs in young adults (ages 20 to 40)

be used to treat optic neuritis due to an apparent

and is characterized by decreased vision in one

increased risk of recurrence of optic neuritis.

eye that presents subacutely

(over hours to

days) accompanied by a relative afferent pupil-

n SPECIAL CLINICAL POINT: Optic neuritis

lary defect. Pain or discomfort exacerbated by

should not be treated with oral corticosteroids,

eye movement is present more than 90% of the

which provide no benefit and may increase the

time. Patients with optic neuritis usually note

risk of recurrence.

poor color vision in the affected eye. The clas-

sic visual field defect associated with optic neu-

Ischemic Optic Neuropathy Ischemia to the

ritis is a central scotoma, though other patterns

optic nerve head may result in sudden, painless

are frequently seen. Funduscopic examination

loss of vision. Ischemic optic neuropathy may

may reveal mild optic disc swelling or may be

occur in adults over the age of 50, particularly

completely normal.

those with vascular risk factors. Patients often

528

Chapter 26

n Eye Signs in Neurologic Diagnosis

wake up with vision loss. Decreased visual acu-

intracranial pressure. The workup of pa-

ity, decreased color vision, a RAPD, and visual

pilledema includes imaging (to rule out a mass

field defects (often altitudinal defects) are the

lesion, hemorrhage, or hydrocephalus), lumbar

norm. The optic disc is swollen (often with

puncture (to confirm the presence of increased

peripapillary hemorrhages) in anterior is-

intracranial pressure), and visual fields

(to

chemic optic neuropathy (AION) but appears

track any subclinical visual field loss).

normal in posterior ischemic optic neuropathy

The terms pseudotumor cerebri and idio-

(PION). Anterior ischemic optic neuropathies

pathic intracranial hypertension are sometimes

are further subdivided into arteritic AION

used interchangably if no structural lesion is

(caused by giant cell arteritis) and nonarteritic

found on imaging, although the latter term

AION (NAION). Ischemic optic neuropathy

should probably be reserved for cases in which

can usually be differentiated from optic neuri-

no explanation for the increased intracranial

tis by clinical features, such as the age of the

pressure can be found. Known causes of “sec-

patient, the acuity of the vision loss, the pres-

ondary” intracranial hypertension include a

ence or absence of pain, and the presence or

variety of medications

(e.g., retinoids and

absence of disc swelling.

tetracycline antibiotics), sleep apnea, cerebral

venous thrombosis, and dural arteriovenous

n SPECIAL CLINICAL POINT: In acute

malformations. Patients with truly idiopathic

monocular vision loss, ischemic optic

intracranial hypertension are almost always

neuropathy is more likely that optic neuritis if

young, overweight women who benefit from

(1) the vision loss presents very suddenly

(within seconds or minutes), (2) the vision loss

weight loss, but may require medical and surgi-

is completely painless, or (3) funduscopy reveals

cal interventions to prevent vision loss.

pronounced swelling of the optic disc with disc

hemorrhages.

Diplopia

Sometimes patients present complaining of

Amaurosis Fugax

“blurred vision” but actually have diplopia

Transient, painless monocular vision loss

(double vision). The first question to ask in

(amaurosis fugax) lasting for minutes is highly

such a situation is, “Does the blurred vision go

suggestive of an embolic transient ischemic at-

away if you close either eye?”

tack (TIA) related to internal carotid artery dis-

If the blurred or double vision resolves when

ease. Patients often describe the vision loss as a

either eye is closed, the patient has binocular

“shade coming down” over one eye. As with

diploia (only present when both eyes are open),

any other form of TIA, an urgent vascular

a sign of ocular misalignment or strabismus

workup is recommended, given a greatly in-

(see section Vertical Double Vision and Hori-

creased risk of stroke in these patients (see

zontal Double Vision).

Chapter 7).

If the blurred vision goes away if one eye is

covered but is still present when the other eye is

covered, the patient has monocular diplopia

Papilledema

(only present in one eye). For example, if the

Disc swelling secondary to increased intracra-

blurred or double vision goes away if the right

nial pressure, unlike disc swelling from optic

eye is covered, but is present when the left eye

neuropathies, is often associated with surpris-

is covered, the source of the monocular

ingly mild visual symptoms at first. Papilledema

diplopia is the right eye.

may be accompanied by headache, pulsatile

Common causes of monocular diplopia

tinnitus, transient visual obscurations, or hori-

include refractive error

(cataract, astigma-

zontal double vision—all signs of increased

tism, keratoconus) or vitreoretinal disorders.

529

Chapter 26

n Eye Signs in Neurologic Diagnosis

Occasionally monocular diplopia may be a

any conscious perception of vision. They may

functional (nonorganic) complaint. Monocu-

be able to point to or identify objects by

lar diplopia can be bilateral, in which case the

“guessing” while denying that they can see

double vision will be present in each eye

anything, or they may have the ability to detect

when the opposite eye is covered.

the movement of an object without being able

to perceive the object itself (the Riddoch phe-

n SPECIAL CLINICAL POINT: Monocular

nomenon). The existence of blindsight seems to

diplopia (double vision that is present when one

imply that there may be alternative visual path-

eye is covered) is much more likely to be

ways that bypass primary visual cortex, allow-

ophthalmologic or functional (nonorganic) than

neurologic.

ing unconscious visual perception.

Charles Bonnet syndrome Vivid, complex vi-

sual hallucinations may develop in the setting

HIGHER-ORDER VISUAL

of significant vision loss. Thought to be the

PROCESSING DISORDERS

brain’s attempt to compensate for decreased vi-

Even after visual information reaches the oc-

sual stimulation, Charles Bonnet syndrome can

cipital lobe, visual processing continues at a

occur in patients with glaucoma, macular de-

higher level within visual association cortex

generation, and bilateral optic neuropathy, as

and in adjacent visual association areas, allow-

well as in cortically blind patients or in patients

ing a more complex “conscious” visual experi-

with homonymous hemianopias. Patients rec-

ence. Lesions within these cortical areas may

ognize that the hallucinations are not real but

be associated with a number of cognitive visual

are often reluctant to admit their existence.

processing disturbances.

Alexia without Agraphia A lesion of the left oc-

cipital lobe that extends to the posterior corpus

Cortical Vision Loss

callosum (splenium) may cause alexia without

Bilateral visual cortex lesions may cause total

agraphia, a syndrome in which patients can

blindness. Because the problem lies within the

write but are unable to read words, including

occipital lobes, cortically blind patients have

words they have just written. It is thought that

normal pupillary reactions and normal fundus

the lesion within the corpus callosum discon-

examinations. Cortical blindness may be ac-

nects the right visual cortex from language

companied by Anton syndrome, blindsight, or

areas in the left temporal lobe, leaving the

Charles Bonnet syndrome. Unilateral visual cor-

patient unable to decipher the visual image of

tex lesions may, under special circumstances,

the text.

cause alexia without agraphia.

Disorders of Object Recognition

Anton Syndrome Rarely, patients with cortical

blindness actively deny that they are blind,

Lesions within temporo-occipital brain regions

confabulating answers to questions and behav-

interrupt the ventral stream of visual processing

ing as though they can see. Their speech and

(the

“what pathway”) resulting in problems

behavior may be so convincing that the pres-

recognizing objects and object characteristics.

ence of Anton syndrome may be missed for

some time. The cause of Anton syndrome is

Prosopagnosia Prosopagnosia, the inability to

unknown.

recognize faces, is caused by a lesion of the

right fusiform gyrus, located at the temporo-

Blindsight Some cortically blind patients have

occipital junction. Patients with prosopagnosia

the ability to respond to visual stimuli without

have difficulty recognizing family members or

530

Chapter 26

n Eye Signs in Neurologic Diagnosis

celebrities by looking at their faces, but may be

gaze in an orderly manner to scan a visual

able to identify them by the sound of their

scene. The world for them is a fragmentary and

voice or by distinctive hairstyles or clothing.

disordered array of images, none organically

Prosopagnosia may be accompanied by a left

articulated in a meaningful way. The classic

superior quadrantanopia due to involvement

triad of Balint syndrome includes

(1) optic

of the right inferior optic radiations (see sec-

ataxia

(a loss of hand-eye coordination),

tion Visual Pathway and Visual Field Defects).

(2) ocular apraxia (difficulty directing volun-

tary eye movements), and (3) simultanagnosia

Cerebral Achromatopsia Bilateral lesions of

(an inability to perceive multiple images within

the fusiform and lingual gyri in the temporo-

a complex visual scene).

occipital regions of both hemispheres can cause

a loss of color perception—achromatopsia.

Patients with cerebral achromatopsia see the

PUPILLARY ABNORMALITIES

world in black and white and shades of gray,

Pupil Anatomy and Function

and may also suffer from prosopagnosia and

superior visual field defects.

The iris of the eye is an opaque diaphragm with

an adjustable central opening—the pupil. The

pupil can do only two things: it can constrict or

Disorders of Visuospatial Processing

it can dilate. Neither function is under volun-

Lesions within parieto-occipital brain regions

tary control—pupillary control is autonomic.

interrupt the dorsal stream of visual processing

Ocular parasympathetics control pupillary con-

(the “where pathway”) causing defects in spa-

striction; ocular sympathetics control pupillary

tial perception.

dilation.

Visuospatial Neglect Parietal lesions can cause

Pupil Constriction The parasympathetic nerv-

contralateral visuospatial neglect, in which

ous system is responsible for pupillary constric-

patients ignore stimuli in their contralateral

tion in response to light or a near target.

visual field. Visuospatial neglect seems to pri-

The afferent (sensory) arc of the parasympa-

marily occur following right parietal lesions

thetic light reflex is mediated by retinal gan-

(causing left visuospatial neglect). It is possible

glion cell axones that project (via the optic

that the right hemisphere is specialized for at-

nerve, chiasm, and optic tract) to pretectal nu-

tention and spatial processing, though it is also

clei in the midbrain instead of to the lateral

possible that it is harder to identify neglect in

geniculate nucleus of the thalamus.

patients with left parietal lesions, due to coex-

The parasympathetic efferent (motor) arc is

isting aphasia.

mediated by (1) connections from the pretectal

Visuospatial neglect can be difficult to dis-

nuclei to the Edinger-Westphal subnuclei of

tinguish from a homonymous hemianopia but

the oculomotor complex,

(2) preganglionic

may be identified by abnormal clock drawing

parasympathetic fibers projecting to the ciliary

(see Chapter 1) or by visual extinction (the pa-

ganglion via the third nerve, and (3) postgan-

tient can count fingers in each visual quadrant,

glionic projections from the ciliary ganglion to

but when two sets of fingers are presented si-

the pupillary sphincter muscle.

multaneously, the patient ignores the fingers in

Because of crossing of fibers in the optic chi-

the neglected hemifield).

asm and crossing of fibers between the midbrain

pretectal nuclei and the Edinger-Westphal ocu-

Balint Syndrome Bilateral parieto-occipital le-

lomotor subnuceli, light delivered to one eye

sions produce a clinical syndrome in which pa-

causes equal reflexive contraction of both pupils.

tients have special difficulty in directing their

(The direct response is pupillary constriction in

531

Chapter 26

n Eye Signs in Neurologic Diagnosis

the stimulated eye; the consensual response is

be associated with a relative afferent pupillary

pupillary constriction in the opposite eye.)

defect. Damage to the efferent sympathetic or

parasympathetic pathways result in anisocoria

n SPECIAL CLINICAL POINT: A unilateral

(unequal pupils). Brainstem lesions affecting

optic nerve or optic tract lesion will never

the posterior midbrain may interfere with one

cause anisocoria (unequal pupils). Even if an

efferent parasympathetic pathway (light) but

optic nerve is completely transected, causing

not the other (near), causing bilateral light-near

complete monocular blindness, both pupils will

dissociation.

remain equal in size due to crossed light input

from the intact right optic nerve.

Relative Afferent Pupillary Defect

Constriction of the pupils to near stimulation is

approximately as brisk and extensive as that to

The presence of a relative afferent pupillary

light, and is best elicited by having patients at-

defect (RAPD) or Marcus Gunn pupil implies a

tempt to focus on their own thumb (not an ex-

unilateral or asymmetric lesion between the

aminer’s finger) held about 2 or 3 cm from

retina and the midbrain (see section Evaluation

their nose.

of Vision Loss). Technically, pupillary function

is normal in a RAPD (the asymmetric response

Pupil Dilation The sympathetic nervous system

to light accurately reflects a problem within the

controls pupillary dilation, which occurs in the

anterior visual pathway).

absence of parasympathetic stimulation (e.g., in

A pupil that paradoxically dilates to direct

the dark or when the parasympathetic pathways

illumination may be seen in the most severe

have been damaged) or when there are strong

forms of optic neuropathy. More commonly,

emotions (e.g., excitement, fear, or anger).

however, a RAPD may manifest more subtly as

The afferent arc of the sympathetic system is

less early constriction in one eye than in the

not well defined, but presumably involves

other during the swinging flashlight test. Pupil-

ascending sensory pathways and other limbic-

lary constriction may not necessarily be com-

diencephalic interfaces.

pletely abolished in a RAPD; asymmetry in

The sympathetic efferent (motor) arc is a

pupil reaction to light is the critical feature.

three-neuron chain that includes: (1) central

Because the swinging flashlight technique is

projections that descend from the hypothala-

a comparative test that uses the fellow eye as

mus into the brainstem and spinal cord,

an internal control, it may be difficult to inter-

synapsing onto preganglionic neurons in the

pret if both the left and right afferent pathways

intermediolateral cell column of the spinal cord

are equally affected, as in cases of bilateral

at around T1 (ciliospinal center of Budge),

optic neuropathy.

(2) preganglionic neurons projecting to the su-

perior cervical ganglion

(located behind the

Hippus and Early Release Some degree of

carotid bifurcation), and

(3) postganglionic

rhythmic pupillary oscillation (alternating con-

fibers from the superior cervical ganglion that

traction and dilation) can be observed in many

climb within the sheath of the internal carotic

normal individuals during steady illumination

artery to the cavernous sinus, then travel with

of the eyes. Though the term hippus usually is

other cranial nerves into the orbit to reach the

reserved for those pupils that oscillate with

iris dilator.

fairly large amplitude, almost every pupil has

small sinusoidal oscillations of size with steady

Pupil Dysfunction The different types of pupil-

illumination. High-amplitude oscillation is a

lary dysfunction reflect these anatomic consider-

curiosity but is not pathologic.

ations. Lesions of the afferent visual pathways

Frequently, the pupil may dilate slightly

(including the optic nerve and optic tract) may

after initially constricting to a light stimulus.

532

Chapter 26

n Eye Signs in Neurologic Diagnosis

This phenomenon of early release is normal

constricting. This implies an ocular parasym-

and does not necessarily indicate an afferent

pathetic deficit due to a third nerve palsy, tonic

defect. This slight redilatation should, how-

pupil, or pharmacologic dilation.

ever, be equal in amplitude between both eyes

to qualify as a normal variant.

Physiologic Anisocoria Approximately 15% of

normal individuals have anisocoria of up to

1 mm without any lesion in either the sympa-

Anisocoria

thetic or parasympathetic systems. The differ-

Anisocoria (a difference in pupil size between

ence in size remains proportional in bright and

the two eyes) is caused by lesions affecting

dim lighting, which serves to distinguish this

the sympathetic or parasympathetic pupillary

benign anisocoria from pathologic states. The

efferents. When examining a patient with

degree of anisocoria may vary or even switch

pupils of unequal size, the first question to

sides over time.

answer is which pupil is the abnormal one?

Is it the smaller of the pupils or the larger of

Horner Syndrome A lesion of the ocular sym-

the two?

pathetic pathway leads to an inability to

The answer can be determined by examin-

dilate the pupil and the classic triad of ipsilat-

ing the pupils both in darkness and in light

eral miosis (pupillary constriction), ipsilateral

(Fig. 26.12). If the anisocoria remains propor-

ptosis

(eyelid drooping), and ipsilateral an-

tional in both darkness and light, the patient

hidrosis (lack of sweating on the face). Because

likely has physiologic anisocoria. If the relative

the sympathetic efferent arc is a three-neuron

anisocoria increases in darkness, however, the

chain, different causes of Horner syndrome

smaller pupil is not dilating properly, implying

may be grouped by whether the lesions af-

a ocular sympathetic deficit, that is, Horner

fect the central

(first-order), preganglionic

syndrome. If the anisocoria increases in light,

(second-order), or postganglionic (third-order)

the problem is that the larger pupil is not

neurons.

FIGURE 26.12 Anisocoria in light and darkness. A: When anisocoria is more obvious in the darkness

than in the light, the smaller pupil is the pathologic one. In this case, the right pupil’s failure to dilate

suggests a right sympathetic deficit (i.e., Horner syndrome). B: When anisocoria is more obvious in the light

than in the dark, the larger pupil is the pathologic one. In this case, the left pupil’s failure to constrict in the

light suggests a left parasympathetic deficit (i.e., third nerve palsy, tonic pupil, or pharmacologic dilation).

533

Chapter 26

n Eye Signs in Neurologic Diagnosis

Central lesions (e.g., of the hypothalamus,

syndrome and ipsilateral headache or facial

brainstem, or cervical cord) are an uncommon

pain is known as Raeder's paratrigeminal syn-

cause of Horner syndrome, but are easily rec-

drome, and may be a manifestation of internal

ognizable by associated cranial nerve, cerebel-

carotid artery dissection or aneurysm, a cav-

lar, and sensorimotor long-tract findings. A

ernous sinus lesion, or (if no vascular or struc-

classic cause of a central Horner syndrome is

tural lesion can be found) a form of migraine

Wallenberg syndrome (lateral medullary syn-

or cluster headache.

drome), in which Horner syndrome is accom-

In the orbit, the ocular sympathetics inner-

panied by vertigo, dysphagia and dysarthria,

vate small tarsal muscles in the upper and

ipsilateral facial numbness, and contralateral

lower eyelids in addition to the iris dilator mus-

numbness in the arms and legs. Cervical cord

cle. Damage to the ocular sympathetic path-

injuries may also result in central Horner

way results in mild ptosis of the upper lid and

syndrome.

mild elevation of the lower lid. The resulting

Preganglionic sympathetic fibers exit the

narrowing of the palpebral fissure creates the

spinal cord in the chest, and may be affected by

illusion that the affected eye is sunken inward

lesions of the upper chest and the neck. Pregan-

(pseudoenophthalmos).

glionic Horner syndrome may result from can-

The ptosis seen in Horner syndrome is mild

cer in the apex of the lung (Pancoast tumor),

(Figs. 26.13 and 26.14), and the function of le-

penetrating neck wounds, or as an iatrogenic

vator palpebrae (innervated by the oculomotor

complication of neck surgeries (e.g., anterior

nerve) remains normal. Complete unilateral

cervical discectomy).

ptosis (an inability to open the eye at all) is

Postganglionic lesions are commonly associ-

never seen in Horner syndrome and should

ated with pain in the ipsilateral orbit and eye.

raise the possibility of a third nerve palsy or

The combination of postganglionic Horner

myasthenia gravis instead.

FIGURE 26.14 Raeder’s paratrigeminal syndrome.

FIGURE 26.13 Horner syndrome. A: Left-sided ptosis

A: Left-sided ptosis and miosis accompanying a left

and miosis developed after anterior cervical discectomy

migrainous headache. B: The left pupil failed to dilate

and fusion. B: After instillation of 0.5% apraclonidine, the

after instillation of 1% hydroxyamphetamine, confirming

anisocoria has reversed (the left pupil is now larger than

the diagnosis of a postganglionic (third-order) Horner

the right) and the left-sided ptosis has resolved.

syndrome.

534

Chapter 26

n Eye Signs in Neurologic Diagnosis

10% cocaine

0.5% apraclonidine

FIGURE 26.15 Pharmacologic testing in Horner syndrome. A: The anisocoria is greater in the

darkness than in the light, suggesting a left ocular sympathetic deficit (failure to dilate). After

administration of 10% cocaine eye drops (bottom), the right pupil dilates, but the left pupil remains

small, confirming the diagnosis of Horner syndrome. B: In the same clinical setting, 0.5% apraclonidine

eye drops cause dilation of the abnormal pupil, reversing the anisocoria and confirming the diagnosis

of Horner syndrome.

n SPECIAL CLINICAL POINT: Sometimes

nerve terminal, resulting in a failure of pupillary

Horner syndrome is congenital or long-standing

dilation if Horner syndrome is present. The co-

and benign. A careful inspection of old

caine test for Horner syndrome is therefore

photographs, which might reveal pre-existing

“positive” if the suspected pupil fails to dilate

ptosis and anisocoria, may help to avoid an

(Fig. 26.15). In a “negative” cocaine test, both

unnecessary evaluation for tumor, dissection, or

pupils dilate fully, leaving no residual anisocoria.

aneurysm. Iris heterochromia, a difference in the

Apraclonidine, an alpha-adrenergic agonist

color of the two eyes (e.g., one blue, one

used in the treatment of glaucoma, is increas-

brown), is another sign that can help identify a

congenital Horner syndrome.

ingly being used to confirm Horner syndrome

when cocaine is not readily available. Apra-

Pharmacologic testing may be used to confirm

clonidine has little effect on the size of normal

a suspected diagnosis of Horner syndrome or

pupils, but causes dilation in pupils affected by

when the clinical history and examination are

Horner syndrome due to denervation hypersen-

equivocal. A drop of

10% cocaine can be

sitivity (see Fig. 26.15). The apraclonidine test

placed into each eye and a second drop placed

for Horner syndrome is “positive” if there is re-

a minute later, or a single drop of 0.5% apra-

versal of anisocoria (the formerly smaller pupil

clonidine in each eye may be used. Any change

becomes the larger pupil). The ptosis associated

in the size of the pupils should be noted at

with Horner syndrome may also resolve with

30 and 60 minutes.

apraclonidine testing

(see Fig.

26.13). In a

Cocaine blocks the reuptake of norepineph-

“negative” apraclonidine test, there will be no

rine at the postganglionic nerve terminal, caus-

significant change in pupil size or ptosis.

ing pupillary dilation under normal conditions.

Additional pharmacologic testing may aid in

A lesion of any part of the three-neuron ocular

localization, distinguishing between different

sympathetic pathway will significantly reduce

types of Horner syndrome. Hydroxyampheta-

the amount of norepinephrine released at the

mine stimulates the release of norepinephrine

535

Chapter 26

n Eye Signs in Neurologic Diagnosis

1st or 2nd order lesion

3rd order (postganglionic) lesion

FIGURE 26.16 Hydroxyamphetamine testing in Horner syndrome. A: Anisocoria, greater in the

darkness than in the light, due to left Horner syndrome. After installation of 1% hydroxyamphetamine

eye drops (bottom), both pupils dilate, indicating that the lesion is either first-order or second-order.

B: A similar situation, except that after installation of 1% hydroxyamphetamine eye drops, the left

pupil does not dilate, suggesting a third-order Horner syndrome.

from the postganglionic sympathetic neuron. As

and stable, may require chest and neck imaging

long as this postganglionic (third-order) neuron

with CT and MRI. If an aneurysm or dissection

is intact, instillation of 1% hydroxyampheta-

is suspected, vascular imaging with MRA,

mine will result in pupillary dilation. If, how-

CTA, or even conventional angiography may

ever, the postganglionic neuron has been injured

be necessary.

(as in a third-order Horner syndrome), the af-

fected pupil will fail to dilate in response to hy-

Third Nerve Palsy Mydriasis (dilated pupil)

droxyamphetamine

(see Fig.

26.14). In a

may be a sign of compression of the third (ocu-

“negative” hydroxyamphetamine test, both

lomotor) nerve or other third nerve pathology

pupils will dilate. Assuming that Horner syn-

(Fig. 26.17). It is theoretically possible for an

drome is present, the “negative” result indicates

aneurysm or other mass to compress the third

that the lesion is in either the central (first-order)

or preganglionic (second-order) neuron, but fur-

ther localization is not possible (Fig. 26.16).

n SPECIAL CLINICAL POINT: Although

apraclonidine testing for Horner syndrome is

becoming increasingly popular, it should be

used with caution in children younger than

6 months old in whom respiratory depression

and bradycardia may occur.

The workup of Horner syndrome depends on

FIGURE 26.17 Partial right third nerve palsy. Right-

the clinical history and the degree to which the

sided ptosis and mydriasis (pupillary dilation) developed

sympathetic deficit can be localized on

after herpes zoster ophthalmicus. The right eye is slightly

examination. Isolated, unexplained Horner

abducted and depressed (“down and out”) in primary

syndrome that cannot be documented as old

position.

536

Chapter 26

n Eye Signs in Neurologic Diagnosis

nerve in a way that only affects the pupil. Usu-

the patient’s third nerve palsy does not signifi-

ally, however, a dilated pupil due to a lesion of

cantly improve within a month or two, then a

the third nerve will be accompanied by ptosis

diagnosis of microvascular ischemia should be

and weakness of the extraocular muscles mak-

questioned.

ing the diagnosis fairly straightforward

(see

In a critical care setting, large tumors or

section Vertical Double Vision).

swelling following a large stroke or hemor-

Whether the third nerve palsy is complete

rhage may cause uncal herniation, compressing

(complete ptosis and no ability to elevate, de-

the midbrain and the third nerve. A dilated

press, or adduct the eye) or partial, if the pupil

pupil (“blown”) in this setting is known as

is involved (sluggish or dilated) at all, the pa-

Hutchinson pupil and is a sign of impending

tient should undergo a vascular workup that

catastrophe, requiring emergent intervention.

includes MR or CT angiography to rule out an

n SPECIAL CLINICAL POINT: A “blown

aneurysm. If an aneurysm cannot be defini-

pupil” in an obtunded patient may be a sign of

tively ruled out noninvasively, then conven-

impending transtentorial herniation and should

tional angiography may be necessary.

be treated as a medical emergency.

In the past, patients with partial, pupil-

sparing third nerve palsies were watched

closely over time to see if the pupil eventually

Tonic Pupil (Adie’s Pupil) The tonic pupil or

became involved. As noninvasive imaging tech-

Adie’s pupil is a dilated pupil that is poorly re-

niques continue to improve, however, it may be

active to light but tonically constricts to a near

reasonable to go ahead with MR or CT imag-

target (Fig. 26.18). Patients often complain of

ing in any case where an aneurysm is felt to be

glare and blurred vision. Some complain of

a possibility.

discomfort when focusing at near. Tonic pupil

Perhaps the only time a patient with an ocu-

is more common in women than in men. In

lomotor palsy does not clearly need be imaged

some cases, the tonic pupil is accompanied by

is in the setting of a complete, pupil-sparing

areflexia—the combination of these two fea-

third nerve palsy, which, in a patient with clear

tures is known as Adie syndrome.

vascular risk factors, is likely to be caused by

The pupil is often large at first, but slowly

microvascular ischemia.

constricts over time. Under magnification, the

Because the pupillary fibers travel along the

pupil is often irregular with segmental contrac-

outside of the third nerve, they can be spared

tion and atrophy of the pupillary ruff.

by microvascular ischemia of the third nerve,

Tonic pupils are a postganglionic parasym-

which tends to damage the deeper axons

pathetic lesion, possibly secondary to a viral in-

within the third nerve bundle as opposed to

fection of the ciliary ganglion. Due to this

more superficial ones.

parasympathetic denervation, the iris develops

cholinergic supersensitivity. Although a tonic

n SPECIAL CLINICAL POINT: Microvascular

pupil can often be distinguished from other

third nerve palsies (sometimes called diabetic

causes of mydriasis (third nerve palsy or phar-

third nerve palsies) typically resolve over a 2 to

macologic dilation) by its clinical features, di-

3-month period, requiring no treatment other

lute (0.1%) pilocarpine may be used to confirm

than modification of any existing vascular risk

the diagnosis.

factors.

The normal pupil serves as an internal control

Unfortunately, sparing of the pupil does not

in this test. One drop of 0.1% pilocarpine is

guarantee that the etiology of the third nerve

placed in both eyes, and a second drop is applied

palsy is ischemic. If the patient is young

10 minutes later. The pupil size is measured at 30

(<50 years old) or has no history of smoking,

and 60 minutes. While this dose of pilocarpine is

hypertension, diabetes, or dyslipidemia, or if

too weak to influence the normal pupil, the tonic

537

Chapter 26

n Eye Signs in Neurologic Diagnosis

Dilute (0.1%) pilocarpine

FIGURE 26.18 Tonic pupil (Adie’s pupil). A: The anisocoria is more obvious in the light because the

right pupil fails to constrict. Both pupils constrict with convergence (bottom). This unilateral light-near

dissociation distinguishes the tonic pupil from a third nerve palsy or pharmacologically dilated pupil.

B: The diagnosis of tonic pupil can be confirmed by instillation of dilute (0.1%) pilocarpine. The tonic

right pupil constricts due to denervation hypersensitivity.

pupil will constrict due to the presence of dener-

people may intentionally place atropinic drugs

vation supersensitivity (Figs. 26.18 and 26.19).

into their eyes to feign a medical problem.

A pharmacologically dilated pupil is often

Pharmacologic Dilation Atropine, scopolamine,

very large and will not be associated with any

and ipratropium are just a few of the anti-

eye movement abnormalities or ptosis. There

cholinergic compounds

(muscarinic antago-

will be no reaction to either light or a near tar-

nists) that can get into the eye and cause

get. If there is any question about the diagno-

mydriasis (pupillary dilation) and anisocoria.

sis, pharmacologic testing with 1% pilocarpine

Atropine is used to treat certain cardiac ar-

can be used—a pharmacologically dilated

rhythmias and as a long-acting cycloplegic

pupil will fail to contrict, while a tonic pupil or

agent for some eye problems. Scopolamine is

a dilated pupil due to a third nerve palsy will

administered by transdermal patch for the pre-

constrict (Fig. 26.19).

vention of motion sickness. Aerosolized iprat-

ropium is used as a bronchodilator in patients

Bilateral Light-Near Dissociation

with chronic obstructive pulmonary disease.

Datura stramonium (also known as jimson

Light-near dissociation may be noted unilater-

weed, angel’s trumpet, and thorn apple) may

ally in the case of a tonic pupil (see section

grow as a weed in the garden or yard.

Anisocoria), but when the phenomenon is

Medical personnel may be exposed to at-

bilateral, involvement of the posterior mid-

ropine at work. A poorly placed nebulizer

brain is likely. A lesion of the posterior (dor-

mask may blow aerosolized ipratropium into a

sal) midbrain may damage the pretectal nuclei,

patient’s eye. Travelers may forget to wash

interrupting the pupillary light pathway, but

their hands after placing a scopolomine patch

may spare the near pathway, which projects

on their skin. Gardeners may accidentally rub

farther forward to the Edinger-Westphal

their eyes while weeding. In rare instances,

subnucleus of the oculomotor (III) complex.

538

Chapter 26

Eye Signs in Neurologic Diagnosis

Robertson pupils are thought to be caused by

damage to the pretectal area surrounding the

sylvian aqueduct in the posterior midbrain sec-

ondary to neurosyphilis.

n SPECIAL CLINICAL POINT: Observation of

small, unreactive pupils that accommodate

should trigger detailed history-taking and

serologic studies to establish or preclude past

syphilitic infection.

Parinaud Syndrome Compressive lesions of the

dorsal midbrain may cause pupillary paralysis

with medium to large pupils that do not react to

light, but do constrict with accommodation. In

Parinaud syndrome, this light-near dissociation

is accompanied by supranuclear vertical gaze

palsy, lid retraction, and convergence-retraction

nystagmus (see section Conjugate Gaze Abnor-

malities). Parinaud syndrome is classically asso-

ciated with tumors of the pineal gland (located

just behind the midbrain) or obstructive hydro-

cephalus, but may be caused by any type of le-

sion that affects the posterior midbrain.

ABNORMAL EYE MOVEMENTS

FIGURE 26.19 Isolated, dilated pupil. A: Adie syndrome.

(a) The right pupil is dilated and unreactive to light. There

Eye movements are an important component

is no ptosis or extraocular muscle weakness. (b) The

of visual function. Humans have sharp, high-

right pupil constricts more than the left after instillation of

resolution vision only in a small area (2 to

0.1% pilocarpine in both eyes, confirming denervation

3 degrees) in the center of our visual field.

supersensitivity. B: Atropinized pupil. The dilated right

Although motion perception is good in the pe-

pupil failed to constrict after instillation of 1% pilocarpine,

indicating pharmacologic dilation.

riphery, our ability to perceive fine spatial de-

tails declines rapidly the farther the image is

from fixation. Eye movements, therefore, are

Bilateral light-near dissociation is seen with

necessary to allow us to scan our enviroment

Argyll Robertson pupils and in Parinaud

thoroughly without constant head motion.

syndrome (Fig. 26.20).

Abnormal eye movements may be conjugate

(the visual axes of the two eyes remain parallel

Argyll Robertson Pupils Argyll Robertson pupils

and aligned) or dysconjugate

(the eyes no

(syphilitic pupils) are typically small, irregular,

longer move together). Dysconjugate eye move-

and unreactive to light stimulation, with a pre-

ments create strabismus (misalignment of the

served ability to constrict with accommoda-

eyes) which results in diplopia (double vision)

tion. (The pupils “accommodate but do not

that may be vertical or horizontal. Conjugate

react”.) The phenomenon is most commonly

gaze abnormalities, vertical double vision, and

bilateral but may be unilateral when first

horizontal double vision will be discussed sepa-

observed, becoming bilateral over time. Argyll

rately below.

539

Chapter 26

n Eye Signs in Neurologic Diagnosis

FIGURE 26.20 Bilateral light-near dissociation. A: Argyll Robertson pupils are typically small and

unreactive to light, but constrict when gaze is focused on a near target (bottom). B: A similar pattern

of light-near dissociation is seen in Parinaud syndrome without the characteristic miosis seen with

syphilitic pupils.

Conjugate Gaze Abnormalities

the right stimulates the right vestibular nu-

A simplified sense of the anatomic differences

cleus, which sends projections across and up

between voluntary (cortically based) eye move-

the brainstem to the left sixth nerve nucleus,

ments and reflexive (vestibulo-ocular) eye move-

which generates compensatory leftward eye

ments is necessary to understand conjugate gaze

movements (Fig. 26.21).

disorders such as horizontal gaze palsy and

Analogous pathways exist for voluntary and

supranuclear vertical gaze palsy. In each of these

reflexive vertical eye movements, which will

disorders, the eyes remain aligned but have lim-

not be discussed in detail here, except to note

ited movement.

that while horizontal gaze is generated prima-

Voluntary horizontal eye movements are

rily in the pons, vertical gaze is primarily con-

controlled by the frontal eye fields (FEF) in

trolled by the midbrain.

the cerebral cortex. Each FEF is responsible

for horizontal gaze in the contralateral direc-

Horizontal Gaze Palsy Horizontal gaze palsies

tion, sending projections down into the brain-

(an inability to look to one side) may occur

stem and across to the contralateral sixth

with lesions in the ipsilateral pons or in the

(abducens) nerve nucleus, which acts as the

contralateral frontal lobe. In both cases, pa-

horizontal gaze center. For example, the right

tients may tend to look away from the side of

FEF projects down to the left sixth nerve nu-

the gaze palsy. For example, patients with a left

cleus, which projects both to the right third

gaze palsy may be noted to have a right gaze

nerve (which controls the right medial rectus

preference.

muscle) and directly to the left lateral rectus

A pontine lesion that damages the sixth (ab-

muscle via the left sixth nerve to generate left

ducens) nerve nucleus

(whether an infarct,

gaze (Fig. 26.21).

hemorrhage, demyelination, or tumor) may

Left gaze may also be generated reflexively

cause an ipsilateral horizontal gaze palsy in

by head movement through the vestibulo-

which both voluntary and reflexive movements

ocular reflex (VOR). Head movement toward

to that side are abolished. For example, a

540

Chapter 26

n Eye Signs in Neurologic Diagnosis

FEF

III

MLF

VIII

FIGURE 26.21 Voluntary and reflexive horizontal eye movements. A: A simplified diagram illustrating

the connections between the right frontal eye fields (FEF) and the right vestibular (VIII) nucleus to the

left abducens (VI) nucleus. The left abducens (VI) nucleus sends projections to the right oculomotor

(III) nucleus (which in turn projects to the right medial rectus muscle) via the medial longitudinal

fasciculus (MLF) and to the left lateral rectus muscle via the abducens (VI) nerve. B: A lesion of the

left abducens (VI) nucleus results in a left horizontal gaze palsy. The eyes will not cross midline to the

left either voluntarily or reflexively.

lesion of the left sixth nerve nucleus will result

lesions within the pons, gaze palsies caused by

in an inability to look to the left regardless of

frontal lobe lesions can be overcome by the

whether the stimulus is a voluntary attempt to

vestibulo-ocular reflex (see Fig. 26.22). Gaze

look left (from the right FEF) or a reflexive sig-

palsies from frontal lobe lesions may be accom-

nal from the right vestibular nucleus during an

panied by other neurologic signs referrable to

attempted oculocephalic

(“doll’s eyes”) ma-

the cerebral hemispheres. For example, a left

neuver (see Fig. 26.22).

gaze palsy caused by a right FEF lesion may be

These dorsal pontine lesions may be accom-

accompanied by left-sided weakness and numb-

panied by other brainstem signs, including an

ness, a left homonymous hemianopia, or left vi-

ipsilateral facial (VII) nerve palsy (Bell palsy)

suospatial neglect, depending on how extensive

or contralateral hemiparesis. For example, a

the cerebral lesion might be.

left gaze palsy caused by a left pontine lesion

n SPECIAL CLINICAL POINT: An infarct

may be accompanied by a left Bell palsy and

affecting the right frontal eye fields may cause

right-sided weakness.

a right gaze preference; the patient is said to

An horizontal gaze palsy may also occur

be “looking toward the stroke.” Excitation of

after injury (most commonly a stroke) to the

the frontal eye fields produces the opposite

frontal eye fields (FEF) in the contralateral cere-

effect, and therefore a seizure in the right

bral hemisphere. Unlike gaze palsies caused by

frontal lobe may drive gaze to the left, in which

541

Chapter 26

n Eye Signs in Neurologic Diagnosis

FEF

III

MLF

VIII

FIGURE 26.22 Left horizontal gaze palsy due to a lesion of the frontal eye fields (FEF). A: A right

FEF lesion results in an inability to voluntarily move the eyes to the left. B: The vestibulo-ocular reflex

is spared, allowing the eyes to cross midline during oculocephalic (“doll’s eyes”) testing.

case the patient is said to be “looking away

In patients over the age of 50, a supranuclear

from the seizure.”

vertical gaze palsy may develop in association

with axial rigidity and other progressive parkin-

Supranuclear Vertical Gaze Palsy Brainstem struc-

sonian symptoms. This neurodegenerative disor-

tures that mediate vertical gaze are situated in

der is known as progressive supranuclear palsy

the midbrain tectum and pretectal areas above

(PSP) or Steele-Richardson-Olszewski syn-

the level of the third and fourth cranial nerve

drome. Downgaze is affected early in PSP, and,

nuclei. Lesions in this supranuclear midbrain

consequently, patients with PSP may be de-

region may result in impaired voluntary upgaze

scribed as “messy eaters.”

and downgaze. If infranuclear connections be-

Compressive lesions of the posterior mid-

tween the pontine vestibular nuclei and the

brain, affecting the posterior commissure,

midbrain oculomotor nuclei are intact, how-

may cause a supranuclear vertical gaze palsy

ever, the vestibulo-ocular reflex will be pre-

that predominantly affects upgaze

(unlike

served, allowing the eyes to move vertically in

PSP, in which downgaze is usually affected

response to head movement (as in vertical

first). Other features of the dorsal midbrain

oculocephalic testing). The preservation of

syndrome, or Parinaud syndrome, include

these reflexive vertical eye movements when

eyelid retraction, light-near dissociation (see

voluntary vertical gaze is impaired is the defin-

section Bilateral Light-Near Dissociation),

ing characteristic of supranuclear vertical gaze

convergence-retraction nystagmus

(rhyth-

palsy.

mic backward movements of the globes into

542

Chapter 26

n Eye Signs in Neurologic Diagnosis

the orbits on attempted upgaze), and lid

retraction.

n SPECIAL CLINICAL POINT: Parinaud

syndrome, the combination of (1) light-near

dissociation, (2) supranuclear vertical gaze

palsy, (3) lid retraction, and (4) convergence-

retraction nystagmus, implies a lesion of the

dorsal midbrain.

Other rare disorders that may be associated

with supranuclear vertical gaze palsy include

Whipple's disease, Niemann-Pick disease, and

anti-Ma2/Ta paraneoplastic limbic encephalitis.

Vertical Double Vision

Binocular diplopia in which the two images are

separated vertically or diagonally suggests a

problem with the third nerve, the fourth nerve,

or the brainstem (skew deviation).

Third Nerve Palsy The third

(oculomotor)

nerve innervates the levator palpebrae, the pupil

sphincter, and the superior recturs, inferior rec-

tus, medial rectus, and inferior oblique muscles.

A lesion of the third nerve typically causes pto-

sis, pupillary dilation, and an inability to ele-

vate, depress, or adduct the eye (Fig. 26.23).

The third nerve originates from a cluster of

oculomotor subnuclei within in the midbrain.

Because of a mixture of crossed and uncrossed

fibers, a unilateral lesion of the oculomotor nu-

cleus may cause bilateral ptosis and failure of

elevation of both eyes. Nuclear third nerve

FIGURE 26.23

Left third nerve palsy due to

palsies are extremely rare and are caused pri-

ophthalmoplegic migraine. A: There is complete ptosis

marily by small infarctions of medial penetrat-

of the left eyelid. B: When the eyelid is lifted, the left eye

ing vessels from the basilar artery.

is abducted and depressed (“down and out”). There is a

Other midbrain lesions may cause a disrup-

small amount of left pupillary dilation (mydriasis). C: The

tion of the fibers emerging from the third cra-

left eye does not adduct on attempted right gaze.

nial nerve nuclei. These fascicular third nerve

D: Abduction is normal in left gaze.

palsies are generally accompanied by addi-

tional signs and symptoms associated with ad-

jacent midbrain structures. For example, a

contralateral hemiplegia suggests involvement

third nerve palsy accompanied by contralateral

of the cerebral peduncle (Weber syndrome).

ataxia implies involvement of cerebellar pro-

The third nerve exits the midbrain between

jections to the red nucleus (Claude syndrome)

the posterior cerebral artery and the superior

while a third nerve palsy accompanied by

cerebellar artery. It courses forward through

543

Chapter 26

n Eye Signs in Neurologic Diagnosis

the subarachnoid space toward the cavernous

Pupillary involvement in aneurysmal third

sinus, running parallel to the posterior commu-

nerve palsies is common but is not invariably

nicating artery

(PCoA). Like other cranial

present, particularly when the third nerve palsy

nerves, the third nerve may be damaged by in-

is mild or partial. The distinction between

flammation, ischemia, or infection, but is addi-

pupil-involving and pupil-sparing third nerve

tionally vulnerable to compression by PCoA

palsies has already been discussed (see section

aneurysms at the junction of the PCoA and the

Anisocoria).

internal carotid artery.

When the third nerve palsy is injured within

Aberrent regeneration of the third nerve may

the cavernous sinus, it is generally accompa-

rarely occur. When present, it is highly sugges-

nied by additional cranial neuropathies

(in-

tive of a compressive lesion of the third nerve,

volving cranial nerves IV, V₁, V₂, or VI). The

as aberrent regeneration of the third nerve is

differential diagnosis of lesions of the cav-

not seen following microvascular ischemia.

ernous sinus is broad and includes inflamma-

Eyelid elevation or pupillary constriction in at-

tory disorders (e.g., Tolosa-Hunt syndrome),

tempted downgaze or adduction (Fig. 26.24)

aneurysms of the cavernous internal carotid ar-

should trigger an urgent evaluation for possible

tery, and tumors (e.g., meningiomas).

aneurysm or tumor.

n SPECIAL CLINICAL POINT: In the setting of

n SPECIAL CLINICAL POINT: Aberrent

a third nerve palsy, fourth nerve function can be

regeneration of the third nerve is a sign of

tested by having the patient abduct the eye

compression of the oculomotor nerve (from

(assuming that the abducens nerve is intact)

aneurysm or tumor) and is never associated

then look downward. If the fourth nerve is intact,

with microvascular or diabetic third nerve

intorsion will be noted on attempted downgaze.

palsies.

If the eye does not rotate, then the patient may

have both a third and a fourth nerve palsy,

suggesting a possible cavernous sinus lesion.

Fourth Nerve Palsy The fourth (trochlear) nerve

innervates the superior oblique muscle. Lesions

affecting this cranial nerve limit the eye’s ability

to depress and intort. This limitation of eye

movement may be difficult to appreciate visually

but causes the affected eye to be too high (hyper-

tropic), resulting in vertical double vision.

The Parks-Bielschowsky test for fourth

nerve palsy has three steps. First, determine

which eye is higher (hypertropic). Second, de-

termine whether the hypertropia is worse in

right or left gaze. Third, determine whether the

hypertropia is worse with right head tilt or left

head tilt.

n SPECIAL CLINICAL POINT: With a right

fourth nerve palsy, the right eye will be

FIGURE 26.24 Aberrant regeneration following

hypertropic. The hypertropia and double vision

aneurysmal third nerve palsy. A: In primary position,

will worsen in left gaze and right head tilt. With

there is ptosis of the left eyelid and subtle left

a left fourth nerve palsy, the left eye will be

hypotropia. B: In attempted downgaze, the left eyelid

hypertropic. The hypertropia and double vision

elevates (pseudo-von Graefe sign).

will worsen in right gaze and left head tilt.

544

Chapter 26

n Eye Signs in Neurologic Diagnosis

The presence of a head tilt may be helpful. Be-

Skew Deviation Vertical misalignment of the

cause head tilt toward the lesion causes in-

eyes that does not fit the pattern of either a third

creased diplopia, the patient may habitually tilt

or fourth cranial nerve palsy can occur with

the head away from the lesion. For example, in

brainstem lesions. This skew deviation may be

the setting of a right fourth nerve palsy, the pa-

associated with other brainstem signs, including

tient may prefer to tilt the head to the left.

an ocular tilt reaction in which the skew devia-

If a fourth nerve palsy is suspected, it may

tion is accompanied by head tilt and torsion of

be helpful to show the patient a straight hori-

the eyes. Neurologic consultation and MR im-

zontal line and ask the patient to describe the

aging with attention to the brainstem should be

double image seen. Because the superior

requested for any patient with binocular vertical

oblique muscle contributes to intorsion, the

double vision that can not be attributed to a

image from the paretic eye will be tilted as well

third or fourth cranial nerve palsy.

as displaced vertically. The arrowhead formed

by the two lines will “point to” the side of the

Horizontal Double Vision

fourth nerve palsy (Fig. 26.25).

Lateral gaze requires the coordination of the lat-

eral rectus muscle (innervated by the sixth cra-

nial nerve) of one eye with the medial rectus

muscle (innervated by the third cranial nerve)

of the other eye. For example, in order to look

to the left, both the left lateral rectus muscle

(controlled by the left abducens nerve) and

FIGURE 26.25 Right fourth nerve palsy. Because the

right eye is hypertropic and extorted, the second image

the right medial rectus muscle (controlled by the

lies below and is tilted relative to the horizontal line. The

right oculomotor nerve) must act together. The

angle formed by the two lines points to the right—the

brainstem circuitry responsible for horizontal

side of the cranial nerve palsy.

gaze lies primarily within the pons.

The sixth (abducens) nerve nucleus lies me-

The fourth cranial nerve is unique in that it

dial and dorsal in the brainstem within the pons.

exits from the brainstem dorsally and crosses to

Large cells within the abducens nucleus inner-

the other side before encircling the brainstem

vate the lateral rectus muscle directly via the

on the way to the cavernous sinus. (The fourth

sixth cranial nerve, while a small cell population

nerve has the longest intracranial course of all

projects via the medial longitudinal fasciculus

cranial nerves.) This renders it particularly sus-

(MLF) to the contralateral third (oculomotor)

ceptible to trauma in which forces are brought

nerve nucleus, which in turn projects to the

to bear on the dorsal midbrain. Fourth cranial

medial rectus muscle.

nerve palsies can occur secondary to microvas-

Binocular horizontal double vision gener-

cular ischemia, often associated with diabetes

ally suggests either a lesion of the abducens

and long-standing hypertension. Tumors in the

(VI) nerve itself or a lesion of the MLF result-

region of the midbrain tectum also occasionally

ing in an internuclear ophthalmoplegia (INO)

can present with fourth cranial nerve palsies.

(Fig. 26.26).

Occasionally, new double vision may rep-

resent “decompensation” of long-standing or

Sixth Nerve Palsy A lesion of the sixth (ab-

congenital fourth nerve palsies that were

ducens) nerve results in the inability to abduct

never previously symptomatic, making it im-

the ipsilateral eye, causing binocular, horizontal

portant to check childhood photographs to

double vision that is worse when looking to-

search for a head tilt that might indicate a

ward the lesion. For example, an injury to the

long-standing condition.

left sixth nerve will impair abduction of the left

545

Chapter 26

n Eye Signs in Neurologic Diagnosis

FEF

III

MLF

VIII

FIGURE 26.26 Horizontal diplopia. A: A lesion of the left sixth nerve results in no abduction of the

left eye on attempted left gaze. B: A lesion of the right medial longitudinal fasciculus (MLF) results in

no adduction of the right eye on attempted left gaze (internuclear ophthalmoplegia). Both lesions can

cause binocular, horizontal diplopia in left gaze.

eye, which will cause the eyes to be turned to-

Internuclear Ophthalmoplegia

(INO) As dis-

ward each other (esotropia). The associated

cussed above, the sixth (abducens) nerve nu-

diplopia will be worse in attempted left gaze

cleus and the contralateral third (oculomotor)

and at distance (Fig. 26.27).

nerve nucleus communicate via the medial lon-

Sixth cranial nerve palsies caused by microvas-

gitudinal fasciculus (MLF) in the brainstem in

cular ischemia are common, particularly in pa-

order to generate conjugate horizontal gaze. A

tients with vascular risk factors, but the complete

lesion of the MLF between these two nuclei in-

differential diagnosis is broad. Fascicular lesions

terrupts this connection between the two nu-

may occur within the pons due to hemorrhage,

clei, causing an internuclear ophthalmoplegia,

infarction, demyelination, or neoplasia (e.g., pon-

characterized by an inability to fully adduct the

tine gliomas or metastatic tumors). The sixth

eye on the same side as the lesion. In the case of

nerve also may be affected by inflammatory or

a lesion of the right MLF, for example, the

infiltrating lesions of the cavernous sinuses or of

right eye will adduct poorly, causing double vi-

the leptomeninges (e.g., Tolosa-Hunt syndrome,

sion in attempted left gaze (Fig. 26.28). Slow-

Lyme disease, or carcinomatous meningitis).

ing of adduction

(“adduction lag”) and a

Sixth nerve palsies may occur as a false-localizing

dissociated abducting nystagmus are also fea-

tures of INO.

pressure (see section Papilledema), and have oc-

In young adults, the most common cause of

casionally been documented as a transient phe-

an isolated INO is a small demyelinating plaque

nomenon following lumbar puncture.

due to multiple sclerosis (see Chapter 11). In

546

Chapter 26

n Eye Signs in Neurologic Diagnosis

FIGURE 26.28 Right internuclear ophthalmoplegia

(INO). In attempted left gaze, the right eye does not

adduct, signifying a lesion of the right medial longitudinal

fasciculus (MLF) in this patient with multiple sclerosis.

adduct away from the lesion. Only abduction

of the contralateral eye is spared.

Extraocular Pathology Disorders of extraocu-

lar muscles or of the neuromuscular junction

may mimic any form of eye movement disorder

described above. Myasthenia gravis and thy-

roid eye disease should be considered in any

patient who complains of double vision.

Myasthenia Gravis Myasthenia gravis may

FIGURE 26.27 Acute left sixth nerve palsy. A: Right

cause weakness of the eyelid or extraocular

gaze is normal. B: In primary position, the patient is

muscles that may resemble a peripheral cranial

esotropic. C: In attempted left gaze, the left eye is

nerve palsy or internuclear ophthalmoplegia.

unable to abduct.

Fluctuating findings or a clear history of wors-

ening later in the day or when fatigued may

suggest myasthenia (see Chapter 17). As a rule

older patients or patients with vascular risk

there should be no pupillary involvement. If

factors, a small stroke should be suspected.

myasthenia gravis is suspected, referral to a

Tumors and vascular malformations may also

neurologist for evaluation is recommended.

cause INO.

n SPECIAL CLINICAL POINT: An isolated,

n SPECIAL CLINICAL POINT: Fluctuating

bilateral internuclear ophthalmoplegia (INO) is

double vision or double vision that worsens

highly suggestive of multiple sclerosis.

toward the end of the day suggests possibile

myasthenia gravis.

One-and-a-Half Syndrome The combination of

a horizontal gaze palsy and internuclear oph-

Thyroid Eye Disease Hyperthyroidism (most

thalmoplegia is known as one-and-a-half

commonly caused by Graves disease) can be

syndrome. It implies a lesion of both the sixth

associated with an autoimmune reaction that

(abducens) nerve nucleus and the adjacent

causes swelling of the orbital soft tissues. En-

ipsilateral MLF. The result of such a lesion

largement and fibrosis of the extraocular mus-

(whether caused by infarction, hemorrhage,

cles (inferior rectus and medial rectus muscles

demyelination, or tumor) is an inability to look

are the most commonly affected) may lead to a

toward the side of the lesion and an inability to

limitation of eye movements and double vision.

547

Chapter 26

n Eye Signs in Neurologic Diagnosis

When thyroid eye disease is severe, there can be

In other words, unilateral right-beating gaze-

marked proptosis, periorbital edema, conjunc-

evoked nystagmus suggests a lesion of the right

tival injection, lid retraction, and possibly

cerebellar hemisphere.

vision loss from compression of the optic

nerve. CT scanning of the orbits may be helpful

Vestibular Nystagmus A rapid, mixed horizon-

in identifying extraocular muscle enlargement

tal-torsional jerk nystagmus that is unidirec-

when thyroid eye disease is suspected.

tional (e.g., right beating regardless of gaze)

suggests vestibular dysfunction. Vestibular nys-

tagmus beats away from the side of the dys-

function. For example, right-beating vestibular

NYSTAGMUS/VERTIGO/OSCILLOPSIA

nystagmus is seen with left vestibular lesions.

Rhythmic, conjugate movements of the eyes

According to Alexander’s Law, vestibular nys-

(nystagmus) generally signify vestibular or

tagmus is greatest in the direction it is beating

cerebellar dysfunction (see Chapter 20). Nys-

(e.g., right-beating vestibular nystagmus is

tagmus may be associated with a subjective

most prominent in right gaze). Vestibular nys-

sense of movement (vertigo) or “shaking” of

tagmus may be caused by either peripheral or

the visual world (oscillopsia). There are many

central lesions (see Chapter 20).

different specific types of nystagmus, but they

can be divided into two main categories: jerk

Brun’s Nystagmus The combination of gaze-

nystagmus and pendular nystagmus.

evoked nystagmus and vestibular nystagmus is

known as Brun’s nystagmus, which signifies a

lesion of the cerebellopontine angle. For exam-

Jerk Nystagmus

ple, a patient with a coarse right-beating hori-

Jerk nystagmus is the more commonly seen type

zontal nystagmus in right gaze (right-beating

of nystagmus, characterized by a slow phase

gaze-evoked nystagmus implying a right cere-

followed by a corrective quick phase. Jerk

bellar lesion) and a quick left-beating horizon-

nystagmus is named for this quick component,

tal-torsional nystagmus in left gaze (left-beating

for example, “right beating” or “up beating.”

vestibular nystagmus implying a right vestibular

There are two main types of jerk nystagmus:

lesion) should be evaluated for a possible lesion

gaze-evoked nystagmus and vestibular nystag-

of the right cerebellopontine angle (e.g., acoustic

mus. Brun’s nystagmus and downbeat nystag-

neuroma).

mus are other specific types of jerk nystagmus.

Downbeat Nystagmus A specific type nystagmus

Gaze-Evoked Nystagmus Coarse nystagmus that

can be seen with lesions at the cervicomedullary

changes direction depending on the direction of

junction (e.g., Chiari malformation). This down-

gaze (e.g., right beating in right gaze, left beat-

beating nystagmus is most prominent in upgaze

ing in left gaze, up beating in up gaze, etc.) is

and lateral downgaze. Downbeat nystagmus can

gaze-evoked nystagmus. Gaze-evoked nystag-

also be seen with hypomagnesemia and lithium

mus is a gaze-holding problem and implies

toxicity.

cerebellar dysfunction. Alcohol intoxication,

anti-epileptic medications, cerebellar degenera-

Pendular Nystagmus

tive disorders, and cerebellar disorders may all

be associated with gaze-evoked nystagmus. A

Less common than jerk nystagmus, pendular

few beats of symmetric gaze-evoked nystag-

nystagmus is characterized by back and forth

mus in extreme gaze is normal and is known

slow phases. This type of nystagmus may be hor-

as end-point nystagmus. Unilateral gaze-evoked

izontal, vertical, or torsional

(rotational), de-

nystagmus signifies a unilateral, ipsilateral, cere-

pending on the plane of the nystagmus. There

bellar lesion (stroke, hemorrhage, or tumor).

are several notable types of pendular nystagmus.

548

Chapter 26

n Eye Signs in Neurologic Diagnosis

See-saw Nystagmus In pendular see-saw nys-

QUESTIONS AND DISCUSSION

tagmus, one eye moves upward and intorts

while the other eye moves downward and ex-

1. A 58-year-old man presents with a history

torts, back and forth, like two children on a

of pain in the left orbit. He denies double

see-saw. This rare form of nystagmus strongly

vision. The pain is described as intense and

suggests a midbrain or parasellar lesion (e.g.,

“boring” in quality without throbbing. He

pituitary adenoma or craniopharyngioma) and

has no previous neurologic or ophthalmolo-

often coexists with bitemporal hemianopia.

gic history. You have been monitoring him

for 5 years for fairly well-controlled adult-

Oculopalatal Myoclonus Pendular nystagmus

onset diabetes mellitus treated with diet

(typically vertical) associated with rhythmic

restriction alone. There is complete left

contractions of the soft palate implies a lesion

eyelid ptosis, and the left eye is depressed

within the brainstem. This oculopalatal my-

and abducted (“down and out”). The pupil

oclonus typically evolves weeks to months fol-

is 8 mm and fixed (no constriction to light

lowing a brainstem hemorrhage or stroke. It is

or near). The patient is able to elevate and

thought to be caused by injury to the central

depress the eye through only about 10% of

tegmental tract lying within the Triangle of

the expected range. There is no adduction

Guillain-Mollaret (whose corners are the red

past midline, but the left eye abducts fully.

nucleus, inferior olive, and dentate gyrus).

Which of the following is the most likely

diagnosis?

Oculomasticatory Myorrhythmia Slow, pendu-

A. Myasthenia gravis

lar convergence of the eyes associated with syn-

B. Thyroid eye disease

chronous contraction of muscles of the jaw and

C. Third nerve palsy resulting from an

face is highly suggestive of, if not pathogno-

intracranial aneurysm

monic for, Whipple's disease.

D. Third nerve palsy secondary to diabetes

mellitus

The correct answer is C. Thyroid eye disease

Always Remember

and myasthenia gravis can cause a variety of

• Visual acuity, color vision, the presence or

eye movement problems, and myasthenia

absence of an afferent pupillary defect

gravis may present with ptosis. Pupillary in-

(RAPD), the appearance of the optic discs,

volvement, however, would not accompany ei-

and visual fields must all be evaluated to

ther. The combination of ptosis, and impaired

determine the cause of vision loss.

adduction, elevation and depression suggests a

• Higher-order visual processing problems

third (oculomotor) nerve palsy. Diabetes is

provide insight into the organization of

often associated with a pupil-sparing ischemic

specialized cortical regions.

or microvascular third nerve palsy, but in-

• The different causes of anisocoria can be

volvement of the pupil in this case strongly

sorted out on examination, but

suggests the possibility of aneurysmal com-

pharmacologic testing may help to confirm

pression of the third nerve.

the diagnosis.

2. An 18-year-old student, brought in by her

• Patterns of abnormal eye movements and

mother, reported that she had transiently

diploia allow fairly precise lesion localization.

gone blind in her right eye. The episode

• The many types of nystagmus fall into a

occurred in school and lasted 20 minutes.

limited number of categories, each associated

She noted that the right half of a large

with specific pathology.

word on the blackboard seemed to be

549

Chapter 26

n Eye Signs in Neurologic Diagnosis

missing and that “everything seemed to be

to see in even moderate illumination. If aniso-

shimmering and wavy.” Other than a mild

coria is more noticeable in the darkness than

headache, she noted no other symptoms.

in the light, a reasonable next step would be

She is in good general health, and the

pharmacologic testing with either 10% co-

neurologic examination is normal. Which

caine or 0.5% apraclonidine to confirm ocular

of the following would be the most

sympathetic dysfunction. Imaging studies may

appropriate next step for this patient?

be useful once a diagnosis of Horner syn-

A. Cerebral angiography

drome has been made in order to help deter-

B. Carotid duplex examination

mine its etiology.

C. CT or MRI of the brain with contrast

4. A 30-year-old woman presents complaining

D. Reassurance and a follow-up visit in 1

of vertigo and “bouncing vision.” She is on

month or sooner should symptoms recur

no medications. Her past medical history is

The correct answer is D. Patients frequently

unremarkable. On examination she has a

interpret a homonymous hemianopia as vision

rapid horizontal and torsional nystagmus

loss in one eye or the other. In this case, the

on right gaze and a coarse, purely

patient’s inability to see the right half of a

horizontal nystagmus in left gaze. What is

word written on the blackboard strongly sug-

the most likely diagnosis?

gests a right homonymous hemianopia, not

A. Acoustic neuroma

monocular vision loss. For this reason, a vas-

B. Cerebellar hemorrhage

cular workup in search of a focal lesion of the

C. Vestibular neuronitis

right carotid artery or ophthalmic artery

D. Chiari malformation

would not be indicated. The patient’s symp-

The correct answer is A. The patient has a

toms are highly suggestive of migraine. Given

combination of vestibular and gaze-evoked

her classic presentation and her young age, the

nystagmus, known as Brun’s nystagmus,

likelihood of a structural lesion is small. Neu-

which is highly suggestive of a lesion at the

roimaging can be deferred unless her symp-

cerebellopontine angle. Cerebellar hemorrhage

toms worsen or progress. Return visits are

would be associated with more severe symp-

advisable, however, to ensure against missing

toms and a unilateral gaze-evoked nystagmus.

progressive symptoms.

Vestibular neuronitis would produce a

vestibular nystagmus. Chiari malformation is

3. A 62-year-old man presents for a routine

commonly a cause of downbeat nystagmus.

examination. He has no head or neck

symptoms, but an examination reveals 1 to

2 mm of left ptosis. In a well-lighted

examination room, the pupils appear to be

SUGGESTED READING

equal in size at 2 mm. The patient denies

awareness of the lid droop and denies head

Asbury AK, Aldridge H, Hershberg R, et al. Oculomotor

or neck trauma. Which of the following

palsy in diabetes mellitus: a clinicopathologic study.

would be the most useful next step?

Brain. 1970;93:555.

A. Chest x-ray

Giles CL, Henderson JW. Horner’s syndrome: an analysis

B. MRI/MRA of the head and neck

of 216 cases. Am J Ophthalmol. 1958;46:289.

C. Examination of the pupils in a dim room

Goodwin J. Disorders of higher cortical visual function.

D. Pharmacologic testing

Curr Neurol Neurosci Rep. 2002;2(5):418-422.

The correct answer is C. The pupils should be

Keitner JL, Johnson CA, Spurr JO, et al. Baseline visual

field profile of optic neuritis: the experience of the

examined in darkness, since pupillary anisoco-

Optic Neuritis Treatment Trial. Arch Ophthalmol.

ria due to Horner syndrome may be difficult

1993;111:231.

Principles of

Neuro-

rehabilitation

D AV I D S . K U S H N E R

key points

• Disablement involves the complex relationship

between disease, impairment, disability, and handicap.

• Functional disabilities are targeted in neurorehabilitation.

• Neurorehabilitation encompasses medical, physical,

social, educational, and vocational interventions pro-

vided in institutional or community settings.

• Ongoing and thorough patient assessment is crucial

throughout the neurorehabilitation process.

• Rehabilitation goals and the management plan are regu-

larly assessed and modified when necessary to

maximize patient potential.

• Patients having disabilities due to an acute, chronic, or

progressive neurologic condition may benefit from

neurorehabilitation.

he World Health

TABLE 27.1

Aspects of Disablement

Organization has described disablement in terms

of disease, impairment, disability, and handicap

Disease: a condition or pathologic process that may

(Table 27.1). In this conceptual model, disease is

result in an impairment

an underlying condition or pathologic process

Impairment: an abnormality in physical or

that results in an impairment. Impairment is an

psychological capacity

abnormality in physical or psychological capac-

Disability: limitations in function resulting from an

impairment

ity. Disability is the limitation an impairment

Handicap: social disadvantages that result from

places on an individual’s ability to perform

disabilities

necessary routine daily functional activities.

Handicap is the social disadvantage that results

from disabilities that prevent an individual from

fulfilling his or her expected role in society.

551

552

Chapter 27

n Principles of Neurorehabilitation

Disease

Impairment

Physical

Psychological

Motor

Sensory

Emotional

Cognitive

Disability

Mobility

Self-care

Communication

Perception

Cognition

Handicap

Physical

Social/cultural

barriers

Social

disadvantage

FIGURE 27.1 Process of disablement.

Handicap is influenced in a society by physical

Neurologic disorders can occur at any point in

barriers, social and cultural factors, and the atti-

an individual’s lifetime and the pathology may

tudes of those involved (Fig. 27.1).

involve any part of the nervous system, from the

central nervous system (CNS) (including the

n SPECIAL CLINICAL POINT: A host of neu-

brain or spinal cord) to the peripheral nervous

rologic conditions that may be developmental,

system and the muscle (resulting in impairments

hereditary, infectious, autoimmune, metabolic,

such as disorders of strength, endurance, balance,

degenerative, vascular, neoplastic, or traumatic

exist that can result in static or progressive

coordination, mobility, cognition, perception,

impairments.

communication, swallowing, and sensation). The

553

Chapter 27

n Principles of Neurorehabilitation

same neurologic impairments can vary in inten-

TABLE 27.2

sity among individuals depending on the

Goals of Neurorehabilitation

pathologic cause or the region of the nervous

Treatments to reduce neurologic impairments

system affected. Similarly, the prognosis may dif-

Compensatory strategies for residual disabilities

fer with similar impairments but with different

Prevention of secondary complications

pathologic processes at work. For example, hemi-

Maintenance of function

paresis resulting directly from an area of brain

Patient/caretaker education

infarction would be less likely to resolve than

would hemiparesis resulting from demyelination

or edema involving the same region of the brain.

limitations of treatment will vary with the type

Disabilities that may result from neurologic

and extent of the disabilities. The objective is to

impairments can involve mobility, self-care,

match patient needs with capabilities of avail-

communication, cognition, and perception.

able programs. This chapter will focus on

Deficits of mobility may include problem with

principles of neurorehabilitation, including a

bed mobility, transfers, and ambulation. Deficits

broad overview of the role of ongoing patient

of self-care may include problems with any of the

assessment, acute-care intervention, the determi-

routine daily functions of an individual from

nation of rehabilitation need and an appropriate

ordinary self-care tasks, including grooming, toi-

setting, the rehabilitation management plan, and

leting, bathing, dressing, and feeding, to the more

issues pertaining to community transition and

complex tasks of independent living, including

neurorehabilitation outcomes. In addition, case

financial management, shopping, home making,

presentations will be given in the Questions and

and the ability to use a telephone or drive a car.

Discussion section to explore potential benefits

Pathology at different sites of the nervous system

and limitations of neurorehabilitation in a vari-

can result in similar functional disability manifes-

ety of neurologic conditions.

tations between individuals. For example,

disorders affecting balance, coordination, cogni-

tion, or strength all may separately result in the

ROLE OF ASSESSMENT IN

inability of an individual to walk or to effectively

NEUROREHABILITATION

perform routine self-care activities.

Ongoing and thorough patient assessment is a

crucial aspect of the neurorehabilitation

n SPECIAL CLINICAL POINT: In neuroreha-

bilitation, functional disabilities are the focus of

process. The goals of assessment change over

medical, restorative, adaptive, environmental,

the clinical course of rehabilitation from the

and social interventions.

acute hospitalization, to the transfer to a reha-

bilitation facility or program, to the transition

Neurorehabilitation encompasses medical,

back to the community. Initial concerns often

physical, social, educational, and vocational

include patient survival, level of consciousness,

interventions that can be provided in a variety

and response to acute treatments. Later con-

of institutional and community settings.

cerns focus on specific neurologic impairments

Professionals include specialized physicians,

and a patient’s functional abilities.

nurses, therapists, psychologists, social work-

ers, dietitians, and orthotists. Goals include the

n SPECIAL CLINICAL POINT: Patient evalua-

prevention of secondary complications, treat-

tion throughout the neurorehabilitation process

involves clinical examinations and well-validated

ment to reduce neurologic impairments,

standardized measures performed by various

compensatory strategies for residual disabilities,

members of the interdisciplinary team of reha-

patient and caretaker education, and mainte-

bilitation specialists.

nance of function (Table 27.2). Anyone with

neurologic impairments can benefit from neu-

This team often is composed of the physician

rorehabilitation, but the setting, approach, and

(neurologist or physiatrist), nurses, a social worker,

554

Chapter 27

n Principles of Neurorehabilitation

therapists

(including physical, occupational,

of assessment after discharge include the evalu-

speech, and recreational/vocational), and a psy-

ation of patient adaptation to the home

chologist.

environment and community setting, the deter-

The non-neurologist primary care physician

mination of the need for further rehabilitation

will likely benefit from a neurorehabilitation

services, and the assessment of caregiver burden

consultation for evaluation of all patients

and needs.

admitted to the hospital with acute neurologic

Standardized assessment instruments in neu-

impairments resulting in functional deficits. In

rorehabilitation complement the neurologic

addition, patients with chronic medical or neu-

examination in evaluating functional recovery.

rologic conditions with functional deficits that

Standardized measurement scales facilitate

may be related to deconditioning weakness,

reliable documentation of severity of functional

reduced joint mobility, or progression of the

disabilities, help to increase consistency of

condition also may benefit from rehabilitation.

treatment decisions, facilitate communication

In principle, a neurorehabilitation evaluation

between therapists, and provide a reliable basis

should be obtained for all hospitalized or

for monitoring progress. Scales exist to

ambulatory clinic patients with functional

measure many areas of neurologic function,

decline in any routine daily functions including

such as consciousness, cognition, perception,

mobility; transfers; ambulation; or the ability to

communication, strength, mobility, balance,

dress, bathe, feed, groom, speak, or carry out

coordination, somatosensation, and affective

previously routine duties such as vocational or

function. For example, the Rancho Los Amigos

homemaking responsibilities.

Cognitive Scale often is used to document levels

The objectives of neurorehabilitation assess-

of cognitive recovery following a traumatic

ment during the acute hospital admission include

brain injury, and the Functional Independence

documentation of the diagnosis, the impairments,

Measure Scale often is used to assess levels of

and the disabilities as well as identification of

independence in areas of basic daily function.

treatment needs. Subsequent reevaluation focuses

In addition, many other scales exist to help

on response to acute-care treatments and any

measure and quantify specific functional

changes in neurologic or medical status. Once

impairments and disabilities. Limitations of

patients are medically stable, the evaluation is

various standardized measurement scales often

geared toward identifying those who will benefit

are counterbalanced by use of other scales and

from further rehabilitation intervention and

the neurologic examination.

determining the appropriate rehabilitation set-

Another important aspect of patient assess-

ting. Recommendation may be made for referral

ment in neurorehabilitation is the clarification

to an interdisciplinary rehabilitation program, in

of the complex relationship that exists between

an inpatient or an outpatient facility, or for

disease, impairment or severity of objective

selected individual rehabilitation services in an

deficits, and disability or the impact of disease

ambulatory care setting.

on function in any individual patient.

On admission to a neurorehabilitation pro-

Specific neurologic impairments may play a

gram, assessment is performed to help develop

role in multiple functional disabilities. For

a rehabilitation management plan with realistic

example, a patient’s inability to adequately self-

goals and to document a baseline level of func-

feed, dress, or propel a wheelchair could

tion for monitoring progress. Periodic weekly or

separately result from impairments in strength,

biweekly reassessment during the rehabilitation

endurance, cognition, comprehension, percep-

program allows patient progress to be moni-

tion, sensation, coordination, balance, lack of

tored, treatment regimens to be adjusted when

motivation, or the presence of pain or fatigue.

necessary to maximize patient potential, and

Furthermore, individual impairments may

discharge planning to be facilitated. Objectives

have multiple possible etiologies. For example,

555

Chapter 27

n Principles of Neurorehabilitation

fatigue may result directly from a neurologic

TABLE 27.3

disease process or it may indirectly result from

Neurorehabilitation during

Acute Care

depression, sedative side effects of various med-

ications, or a lack of adequate sleep. Similarly,

Prevention of secondary complications

a patient’s inability to effectively concentrate

Deep vein thrombosis/pulmonary embolism

and attend to therapies may result from impair-

Skin breakdown

ments of cognition or perception resulting

Joint contractures/dislocations/subluxations

directly from neurologic disease or indirectly

Pneumonia

Falls

from depression, the side effects of medications,

Autonomic dysfunction

or the distraction of pain. Thus, the role of

Malnutrition/dehydration

assessment in neurorehabilitation includes clar-

ification of etiologies contributing to a patient’s

Maintenance of homeostasis

disabilities so that appropriate therapeutic

Normalization of sleep

interventions may be undertaken at any point

Normalization of bowel/bladder function

Normalization of nutritional states

during the rehabilitation process. In addition,

Promotion of early mobilization and return to

certain treatments may be contraindicated or

self-care

recovery may be limited by comorbid chronic

conditions such as cardiovascular disease,

chronic pulmonary disease, cancer, muscu-

loskeletal disorders, or psychiatric conditions.

vent deep vein thrombosis (DVT), pulmonary

Evaluation and treatment of poorly controlled

embolism, skin ulcerations, orthostasis, develop-

comorbid medical conditions also will improve

ment of joint contractures, and pneumonia,

neurorehabilitation outcomes.

which all may result from impaired mobility. In

those patients with disorders of swallowing or

cognition, efforts also are undertaken to prevent

Neurorehabilitation During Acute Care

malnutrition and dehydration. The prevention of

n SPECIAL CLINICAL POINT:

recurrent stroke is a concern in those individuals

Neurorehabilitation intervention should begin

with acute cerebrovascular disorders. Autonomic

following an acute hospitalization once a neuro-

dysreflexia is of concern in individuals with spinal

logic diagnosis has been established and

cord injury or disorders. Autonomic dysfunction

life-threatening problems are controlled.

including cardiovascular dysfunction is of

Highest priorities are the prevention of second-

concern in patients with the acute Guillain-Barré

ary complications, maintenance of general

syndrome

(acute demyelinating polyneu-

health functions, early mobilization, and

ropathies). In addition, efforts to prevent falls and

resumption of self-care activities (Table 27.3).

accidental fractures or joint dislocations are

Immediate neurorehabilitation concerns include

undertaken in all patients who may be at risk.

the maintenance of homeostasis and the preven-

tion of complications that could result from the

Maintenance of Homeostasis

particular neurologic condition. Maintenance of

homeostasis is a priority in all neurologic patients

Dehydration and malnutrition may be conse-

in the acute-care hospital setting. Routine contin-

quences of neurologic disorders resulting in

uous monitoring of basic health functions can

dysphagia, inability to self-feed, confusion, or

help to prevent further disability. Included in

inability to communicate hunger or thirst.

any rehabilitation program are efforts to ensure

Reduction of risk may include monitoring

regulation and adequacy of nutrition and hydra-

daily intake of liquids and calories, weekly

tion, bladder and bowel function, and sleep. In

determinations of body weight, and supervision

addition, measures usually are undertaken to pre-

with meals. A formal dysphagia assessment may

556

Chapter 27

n Principles of Neurorehabilitation

be indicated in certain patients (see Management

Prevention of Deep Vein Thrombosis

of Dysphasia and Aspiration, below).

Acute prolonged immobility, and particularly

Bladder dysfunction is another possible

the paralysis of one or both legs, places an

consequence of neurologic disease. Bladder

individual at risk for deep vein thrombosis

dysfunction may result from neurologic condi-

(DVT) and pulmonary embolism. Randomized

tions causing bladder hypertonicity, bladder

trials have shown effective risk reduction

hypotonicity, and areflexia or hyperactivity of

with use of subcutaneous low-dose heparin or

the internal or external sphincters. Often, a

low-molecular-weight heparin products. In

urologic consultation and urodynamic testing

addition, warfarin, intermittent pneumatic

is necessary. Treatment may involve a program

compression, early mobilization, and elastic

of bladder training that may include intermittent

stockings have been shown to be effective.

bladder catheterization, certain medications,

Management of DVT risk in neurorehabilita-

and toileting at regular intervals. Use of

tion often includes early mobilization; elastic

indwelling Foley catheters is avoided with the

stockings; and, in the absence of contraindica-

exceptions of urinary retention that cannot

tions, mini-dose subcutaneous heparin.

otherwise be controlled, in patients with exten-

sive skin ulcerations, or if incontinence

Prevention of Skin Breakdown

interferes with fluid and electrolyte balance

monitoring.

Risk factors for skin breakdown include

Bowel dysfunction, and particularly consti-

impaired cognition, poor mobility, incontinence,

pation or fecal impaction, may occur in

spasticity, and obesity. Steps to maintain skin

neurologic disease as a result of immobility,

integrity in those at risk include systemic daily

inadequate nutrition (food or fluid), cognitive

inspection, gentle routine skin cleansing, protec-

impairment, neurogenic bowel, and even

tion from moisture, maintenance of hydration

depression or anxiety. Treatment measures

and nutrition, efforts to improve patient mobil-

include the assurance of adequate intake of flu-

ity, frequent turning and repositioning of

ids and fiber, establishment of a regular

immobile patients, and avoidance of skin pres-

toileting schedule, and judicious use of stool

sure or friction. Prior to discharge from the

softeners or laxatives.

acute-care hospital setting, patients or caretak-

Insomnia may occur as a direct result of a

ers should be educated on skin care issues.

neurologic disorder, or it may result indirectly

from comorbidities including depression, agi-

Prevention of Joint Contractures

tation, anxiety, the side effects of medications,

muscle spasms, pain, inability to move in bed,

A patient’s potential for functional recovery

urinary frequency or incontinence, or interrup-

may be limited by the restriction of movement

tions related to the hospital environment.

or pain that results from joint contractures. The

Inadequate sleep can result in daytime drowsi-

joints of spastic paretic limbs are most at risk

ness and inability to fully benefit from

for contractures. Simple prolonged disuse of an

rehabilitation therapies. Goals of management

extremity also can result in contractures. For

include determination and treatment of a spe-

example, a comatose individual with spastic

cific etiology if one exists; alteration of the

hemiparesis is at risk for bilateral plantar flexion

environment if necessary to reduce distur-

contractures, with one plantar flexion contrac-

bances of sleep; adjustment of type, timing,

ture related to spasticity and the other related to

and dose of offending medications; and if all

simple disuse. Spasticity often develops in indi-

else fails, limited judicious use of hypnotic

viduals with so-called “upper motor neuron

medications.

lesions” that result from disorders involving the

557

Chapter 27

n Principles of Neurorehabilitation

brain or spinal cord. Spasticity may involve one

lowing dysfunction can occur as a result of im-

extremity (monoparesis) to all four extremities

paired cognition or from incoordination or

(quadriparesis), depending on the underlying

weakness of the muscles of deglutition. Thus,

pathologic process.

swallowing is assessed prior to oral feedings in

those patients who may be at risk (patients

n SPECIAL CLINICAL POINT: Routine pre-

with strokes, brain injuries, neuromuscular

vention of contractures often includes antispastic

diseases, etc.). Signs of possible dysphagia in-

limb positioning, frequent range-of-motion exer-

clude dysarthria, confusion, frequent coughing,

cises with passive or active stretching, and

splinting or bracing where necessary.

choking on fluids, nasal regurgitation, and

pneumonia. Currently, the gold standard of di-

Other treatment options to further limit the

agnosis is a modified barium swallow study,

effects of spasticity or reduce early contractures

which can help clarify the phase of swallowing

may include medications, progressive casting, sur-

that may be impaired. Goals of dysphagia man-

gical correction (i.e., tendon release procedures),

agement include the prevention of aspiration,

motor point blocks, botulinum toxin injections,

dehydration, and malnutrition and the restora-

or an intrathecal baclofen pump. Antispasticity

tion of the ability to chew and swallow safely.

medications exist with various sites of action,

Treatment includes oral motor exercises, com-

ranging from effects at the CNS to effects at the

pensatory feeding strategies, modification of

muscle. Patients with early contractures in a

food textures, or alternative methods of feeding

monoparesis or hemiparesis pattern may benefit

such as nasogastric tubes or percutaneous endo-

from botulinum toxin injections of involved mus-

scopic gastrostomy tubes.

cles. Patients with spastic quadriparesis may

benefit from placement of an intrathecal

Prevention of Falls, Fractures, and

baclofen pump. In general, botulinum toxin

Dislocations

or intrathecal baclofen may be indicated if reduc-

tion of spasticity/early contractures will improve

A goal of neurorehabilitation intervention

functional independence, hygiene, or comfort or

includes ensuring patient safety by preventing

will decrease the risk of skin breakdown.

falls. The risk of falls is increased in patients with

sensorimotor deficits, confusion, or difficulty

Prevention of Pneumonia

with communication. Methods to prevent falls

vary with the type and severity of the disabilities.

Pneumonia is a common complication of neu-

rologic illness. Risk factors include depressed

n SPECIAL CLINICAL POINT: A fall risk

reduction program may include supervision of

cognition, swallowing disorders, and impaired

high-risk patients, toileting at regular intervals,

mobility. Risk reduction programs include

supervision of transfers and ambulation,

efforts toward early mobilization as well as pre-

adapted nurse call systems, and patient and

vention of aspiration through modification of

family education.

diet, alteration of means of nutrition intake if

necessary, and proper positioning during feed-

The use of restraints is avoided whenever pos-

ings. Prolonged bed rest can result in poor

sible because restraints may lead to other

aeration of the lungs, atelectasis, and a greater

injuries or cause greater agitation in those

likelihood for development of pneumonia. Early

already restless.

patient mobilization can minimize this risk.

Another concern is prevention of shoulder

dislocations in patients with paretic upper

Management of Dysphagia and Aspiration Dys-

extremities. There is a tendency for subluxa-

phagia occurs in certain neurologic conditions

tion to occur at the shoulder joint capsule as a

and may lead to aspiration pneumonia. Swal-

result of the gravitational pull from the weight

558

Chapter 27

n Principles of Neurorehabilitation

of a paretic arm. Preventive measures include

acute autonomic dysreflexia includes blood

maintenance of normal scapulohumeral posi-

pressure stabilization as well as determination

tioning through physical measures, use of lap

and correction of the etiology.

trays on wheelchairs, use of pull sheets during

Autonomic dysfunction also may occur in the

bed positioning, and avoidance of excessive

setting of acute demyelinating polyneuropathy

range-of-motion exercises. Caution must be

(Guillain-Barré syndrome). Autonomic symp-

taken with lap trays because improper use can

toms including sinus tachycardia, bradycardia,

lead to nerve injuries or wrist flexion contrac-

facial flushing, hypotension, or hypertension;

tures; furthermore, sling arm supports may

profuse diaphoresis; or even anhydrosis can

promote upper-extremity flexion contractures

occur. In addition, urinary retention also may

if used improperly. The differential diagnosis

occur in some patients. The autonomic dys-

for shoulder pain in those with paretic upper

function associated with acute demyelinating

extremities also includes rotator cuff tears,

polyneuropathies often remits after a few weeks.

adhesive capsulitis, bicipital tendonitis, reflex

Treatment is supportive and expectant.

sympathetic dystrophy, arthritis, and previous

injuries.

Early Mobilization and Return to Self-Care

Another goal of acute neurorehabilitation inter-

Prevention in Specific Neurologic Disorders

vention is early patient mobilization and the

Patients who have had an ischemic stroke are

encouragement of self-care activities.

at substantial risk for a recurrent stroke.

n SPECIAL CLINICAL POINT: Early mobiliza-

Often, the acute-care team will determine the

tion helps to prevent DVT, skin breakdowns,

need for carotid endarterectomy or anticoag-

pneumonia, joint contractures, and constipa-

ulation with warfarin, ticlopidine, or aspirin.

tion; it promotes early ambulation, better

Neurorehabilitation can help with patient and

orthostatic tolerance, and performance of basic

family education regarding potential modifi-

activities of daily living.

able risk factors including hypertension,

diabetes mellitus, cigarette smoking, alcohol

Early participation in self-care activities can help

consumption, drug abuse, obesity, high serum

to increase strength, endurance, awareness, com-

cholesterol, coronary artery disease, left ven-

munication, problem solving, and social activity.

tricular hypertrophy, and atrial fibrillation.

Mobilization and the encouragement of self-care

Spinal cord injuries and disorders can result

is beneficial as soon as a patient’s medical and

in a potential for autonomic dysreflexia. This is

neurologic condition is stabilized, and, if possible,

more likely with high-level cord pathology.

within 1 to 2 days of admission to the hospital.

Autonomic dysreflexia manifests as precipitous

Early mobilization is delayed or approached with

drops or elevations in blood pressure or pulse,

caution in patients with coma, obtundation,

often accompanied by a pounding headache,

evolving neurologic signs, intracranial hemor-

hyperventilation, and flushing or sweating

rhage, DVT, or persistent orthostasis.

above the level of the lesion. The cause is usu-

Mobilization may be passive or active at

ally a noxious stimulus involving a numb

first, depending on a patient’s condition. It will

portion of the body detectable only to the auto-

progress variably from ability to move in bed,

nomic nervous system. Possible causes may

to sitting in bed, to sitting up, to transferring,

include a full bladder, a fecal impaction, tight-

to operating a wheelchair, to standing and bear-

fitting clothing or shoes, a skin irritation, a

ing weight, and eventually to walking. Basic

DVT, or an infection. Prevention includes a rou-

self-care activities, including feeding, grooming,

tine bowel and bladder program, daily skin

toileting, bathing, and dressing, are encouraged

inspection, and careful dressing. Treatment of

as soon as possible. Training in compensatory

559

Chapter 27

n Principles of Neurorehabilitation

strategies and use of adaptive devices is offered

stable impairments and disabilities also may be

to any patient with persistent disability with

referred from ambulatory care settings. The

any aspect of mobility or self-care.

rehabilitation specialist physician often will

be consulted to help facilitate the evaluation

and transfer process. Determination of the

Discharge from Acute Care

most appropriate rehabilitation setting is based

Ideally, acute-care discharge planning should

on strict criteria.

begin shortly after admission. Objectives of

Threshold criteria for admission to any

rehabilitation involvement in the discharge

active rehabilitation program include medical

process include determining need for further

stability, one or more persistent disabilities, the

rehabilitation services, helping to select the best

ability to learn, and the endurance to sit sup-

discharge environment, educating the patient

ported at least

1 hr/day. More debilitated

and caretakers regarding pertinent issues, and

patients may benefit from rehabilitation serv-

ensuring continuity of care. Patients or caretak-

ices at home or in a supported living setting.

ers should be instructed on the effects and

Candidates for intense interdisciplinary inpa-

prognosis of the neurologic condition, the pre-

tient rehabilitation require total to moderate

vention of potential complications, and the

assistance in either mobility or self-care func-

need and rationale for further treatments. The

tion and are able to tolerate at least 3 hours of

patient and family are included in the discharge

active daily therapy. Candidates for outpatient

decision-making process whenever possible.

rehabilitation programs include patients with

limited mild functional deficits who are other-

wise able to live independently and those

Determination of Rehabilitation

requiring supervision to minimal assistance

Need and Setting

with mobility or self-care. Patients having com-

n SPECIAL CLINICAL POINT: A patient’s

plex medical problems are candidates for

medical condition and the extent of functional

inpatient programs with

24-hour medical

disabilities are the most important determinants

supervision.

of need for neurorehabilitation services and the

In general, the inability to learn that results

choice of an appropriate rehabilitation setting.

from a fixed static lesion is a contraindication

The neurologic condition, medical comorbidi-

to active neurorehabilitation. However, some

ties, ability to tolerate physical activity, and

patients may have cognitive deficits that are

ability to learn are all important considerations.

temporary and that have the potential to clear

Rehabilitation services can be provided in a

over time as a lesion resolves (e.g., some cases

variety of programs and settings following dis-

of brain swelling, multiple sclerosis, or trau-

charge from acute care. Neurorehabilitation

matic brain injury). In such cases, a trial

may continue in an inpatient rehabilitation hos-

admission to an active rehabilitation program is

pital or the rehabilitation unit of an acute-care

warranted. Also, some patients who are unable

hospital, in a nursing home, in the patient’s

to learn still may benefit from a course of pas-

home, or in an outpatient facility. Determination

sive rehabilitation, such as those with severe

of an appropriate program is based on patient

spasticity who recently may have received bot-

needs and capabilities.

ulinum toxin injections or an intrathecal

baclofen pump. In cases such as those, vigorous

passive range-of-motion exercises may further

Rehabilitation Program Criteria

help to reduce early contractures to allow better

Referrals for neurorehabilitation programs

hygiene, to help decrease pain and discomfort,

usually are made on patients in an acute-care

and to prevent skin breakdown. In addition,

hospital setting, but patients with chronic

families and caretakers of such patients can

560

Chapter 27

n Principles of Neurorehabilitation

benefit from education regarding pertinent care

sive programs. Services and intensity vary with

issues, including a program of passive range-

patient needs from 1 hour to several hours of

of-motion exercises as well as other preven-

therapy per day, from 1 to 5 days per week. Team

tive care.

care plan conferences often are held monthly to

review patient progress. These programs allow a

patient to reintegrate into home life while provid-

Programs And Settings

ing necessary therapies, rehabilitation equipment,

Freestanding rehabilitation hospitals and reha-

social contact, and peer support.

bilitation units in acute-care hospitals usually

Home rehabilitation programs vary in capa-

offer intense comprehensive programs staffed

bilities from comprehensive services to selected

by a full range of rehabilitation professionals.

rehabilitation therapies. These programs are

A physician certified in neurorehabilitation or

designed for patients who are medically stable.

psychiatry is available at all times for patient

Advantages include that skills will be learned

management issues. General practitioners and

and applied at home where they are most nec-

specialist medical consultants are generally

essary, and some patients may function better in

available as needed. Weekly interdisciplinary

a familiar environment. Disadvantages include

team care plan conferences are held and

absence of peer support (fellow patients), limited

attended by the physician, nurse, and therapists

availability of specialized rehabilitation equip-

to establish goals, to develop a plan to achieve

ment, and increased burden on caregivers.

goals, to assess patient progress, to identify bar-

riers to progress, and to facilitate revision of

goals and the management plan when neces-

REHABILITATION MANAGEMENT PLAN

sary. These programs are active and require

On admission to a neurorehabilitation pro-

greater physical and cognitive effort from

gram, a patient management plan is formulated

patients than would be necessary in other reha-

by the rehabilitation physician and the therapy

bilitation settings.

team. The rehabilitation management plan

Rehabilitation programs also exist at nursing

includes a clear description of a patient’s

facilities, which also may be hospital based or

impairments, disabilities, and strengths; explicit

freestanding. Staff, rehabilitation services, and

short- and long-term functional goals; and spec-

physician coverage vary between facilities.

ification of treatment strategies to achieve goals

Usually, supportive care and low-level rehabili-

and to prevent secondary complications. The

tation services (so-called “subacute rehabilitation

objective is to devise short-term and long-term

programs”) are offered. Programs may provide

goals that are realistic in terms of patient

1 hour of selected rehabilitation services 5 days a

potential. Overly ambitious goals can set a

week, or they may provide comprehensive thera-

patient up for failure, and overly modest goals

pies that may include physical, occupational,

can limit a patient’s potential for recovery.

speech, psychology, and recreational therapies

several hours per day. Interdisciplinary team care

n SPECIAL CLINICAL POINT: A rehabilita-

plan conferences usually are held every 2 weeks.

tion management care plan is reevaluated on a

These programs can accommodate patients who

regular basis on the basis of patient progress,

have the potential to later become suitable can-

and it may be adjusted as needed to suit patient

didates for further rehabilitation at an inpatient

needs (Table 27.4).

hospital, at home, or in an outpatient rehabilita-

tion program.

Typically, in an intense multidisciplinary inpa-

Outpatient rehabilitation facilities also may be

tient program, the management plan and

hospital based or freestanding and can provide

patient progress are reviewed on a weekly basis;

selected rehabilitation therapies or comprehen-

in less intense rehabilitation programs, the care

561

Chapter 27

n Principles of Neurorehabilitation

TABLE 27.4

Impairments, Disabilities, and Treatments

Impaired mobility/self-care

Management of impaired mobility

Abnormal muscle strength/tone

Remediation/facilitation (volitional movement present):

Loss of joint range of motion

Traditional exercises

Psychomotor delay

Resistive training

Abnormal muscle synergy/sequencing

Forced sensory stimulation

Abnormal coordination/balance

Compensatory strategies (volitional movement absent):

Loss of endurance

Use of unaffected limbs

Sensory impairments/pain

Use of orthotics or braces

Abnormalities of cognition

Use of adaptive equipment

Task-specific retraining (motor apraxias):

Components of above strategies

Environmental cues to enhance performance

Pharmacologic interventions

Impaired cognition

Management of impaired cognition/perception

Poor concentration/attention

Identify/treat causal factors (e.g., sedation)

Disorientation

Cognitive retraining

Impaired memory, perception, executive function

Substitution of intact abilities

Fatigue/apathy/sedation

Compensatory strategies

Emotional dysfunction

Pharmacologic interventions

Distracters (pain, diplopia, anxiety, etc.)

Impaired communication

Management of communication disorders

Aphasias

Aphasias:

Enhancement of comprehension/expression

Compensatory strategies

Adjustment issues

Caregiver/patient communication issues

Right-hemispheric language disorders

Right-hemisphere language disorders:

Increase awareness of deficits

Reinstate pragmatics of communication

Compensatory strategies

Dysarthrias

Dysarthrias:

Oral motor exercises

Manipulation of vocalization/articulation/

respiration/prosody

plan is reviewed monthly. Pharmacologic inter-

cle synergy patterns, abnormal muscle contrac-

ventions in neurorehabilitation vary on the

tion sequencing

(motor apraxia), abnormal

basis of a patient’s condition (Table 27.5).

coordination or balance, lack of endurance,

pain, and sensory impairments (especially pro-

prioception). Prior to treatment, the specific

Management of Impaired Mobility

cause of motor dysfunction and impaired

Disabilities involving mobility may result from

mobility must be determined. Options for treat-

impairment that can include muscle weakness,

ment may include a program of remediation/

abnormal muscle tone, loss of joint range of

facilitation, compensation, or task-specific

motion, delayed response time, abnormal mus-

motor retraining.

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Chapter 27

n Principles of Neurorehabilitation

TABLE 27.5

Pharmacologic Treatments in Neurorehabilitation

Medication Class

Reasons

Antispasticity medications

Tone reduction/contracture prevention; analgesia

Analgesics

Pain relief

Psychostimulants

Enhancement of concentration, attention, arousal

Antidepressants

Depression relief; improvement of motivation; pain relief

Antipsychotics

Enhancement of reality testing; reduction of agitation/hallucinations/delusions

Cholinergics

Improvement of memory/cognition

Anticonvulsants

Management of seizures/mood disorders/pain

Antithrombotics

Prevention of deep vein thrombosis/stroke/pulmonary embolism

Dopaminergics

Enhancement of arousal/cognition; improvement of mobility in patients with

Parkinson disease

Some degree of volitional movement is

In summary, patients with some voluntary

required in an affected limb for remediation/

motor control are encouraged to use an affected

facilitation to be effective. This approach includes

limb in functional tasks. Patients unable to use an

traditional exercises, resistive training, and forced

affected limb are taught compensatory strategies.

sensory stimulation modalities to improve limb

Adaptive devices are used if more natural meth-

strength and function.

ods are not available or cannot be learned, and

In the compensation approach, the goal is to

orthotic devices or braces are indicated if joint or

improve a patient’s level of functional independ-

limb stabilization will help improve function or

ence in performing self-care activities by teaching

ambulation.

compensatory strategies that involve the unaf-

fected limbs. The compensation approach can

Management of Impaired Cognition

result in learned nonuse of an impaired limb and

therefore is reserved for patients with a poor

Limitations in cognition or perception are

prognosis for recovery of sensorimotor function

important in planning and conducting rehabil-

or those whose motor recovery has reached a

itation efforts, in preparing for functional safety

plateau.

on discharge, and in predicting a patient’s abil-

A program of task-specific motor retraining

ity to resume vocational activities. Cognitive

involves some components of both remediation/

deficits may involve difficulties of concentra-

facilitation and compensation and use of envi-

tion, attention, orientation, memory, perception,

ronmental cues to assist in enhancement of

and executive function.

performance of specific tasks. This approach

Causes may include specific brain lesions and

may be helpful for patients with motor apraxias.

environmental or nonenvironmental distractors.

The effectiveness of these functional

Nonenvironmental distractors may include

approaches may be enhanced by treatment of

chronic pain, vertigo, lack of motivation,

specific causes of impaired mobility, such as spas-

diplopia, visual loss, hearing loss, fatigue, impul-

ticity, contractures, or chronic pain, and use of

siveness, the side effects of medications, the effect

orthotic devices, braces, and adaptive equipment

of emotional disturbances (e.g., depression, anx-

when necessary. Adjunct modalities that also may

iety, or agitation), or intermittent seizures such

aid in functional recovery include biofeedback,

as nonconvulsive seizures or brief absence or

functional electrical stimulation, and various

psychomotor seizures. Environmental distractors

computerized retraining devices.

can include aspects of the hospital routine that

563

Chapter 27

n Principles of Neurorehabilitation

may prevent adequate sleep at night such as late

The etiology of emotional dysfunction

medications or busy or noisy therapy areas.

complicating a neurologic condition may be

Prior to treatment, specific etiologies are

multifactorial. Possible causes include organic

identified and a relevant management plan is

brain damage, exacerbation of a preexisting

devised. A cognitive remediation program often

psychiatric condition or personality disorder,

includes the efforts of an occupational thera-

the side effects of medications, acute medical

pist, a speech therapist, and a psychologist.

conditions

(e.g., electrolyte disturbances,

Treatments emphasize cognitive retraining,

hypothyroidism, or hyperthyroidism), chronic

substitution of intact abilities, and compensa-

pain, environmental factors (e.g., interruption

tory strategies. Irreversible cognitive deficits

of sleep), or a reaction to functional loss.

that absolutely preclude learning are a con-

Emotional dysfunction can adversely affect

traindication to active neurorehabilitation (see

participation in active rehabilitation and long-

Rehabilitation Program Criteria, above).

term outcomes. Effective treatment depends on

an accurate diagnosis of etiology. A psychiatry

consultation may be indicated.

Management of Communication Disorders

Management may include psychotherapy, a

Impairments of speech and language may include

brief course of a psychoactive medication, a

aphasias, disorders of pragmatics (right-hemi-

program of maladaptive behavior modification,

sphere communication disorders), and difficulties

and addressing specific etiologies. A behavior

related to dysarthria. Management varies with

modification program will involve the interdis-

etiology and often involves the services of a

ciplinary team in redirecting and discouraging

speech therapist and a psychologist. Treatment of

socially inappropriate behaviors while encour-

aphasia targets problems of comprehension or

aging appropriate conduct.

expression. Specific goals variably include

improving ability to speak, comprehend, read, or

Management of Chronic Pain

write; developing strategies to compensate for

persistent problems; addressing associated

The physiologic and psychological causes and

adjustment issues; and teaching caregivers to

effects of chronic pain are quite complex. Pain

communicate with the patient. Goals of treat-

occurs in many forms and may involve any

ment for right-hemisphere language disorders

portion of the body. The stimulus for pain may

(i.e., right-hemispheric strokes with left hemine-

arise at the level of the peripheral nerves, the

glect) include increasing the awareness of deficits,

autonomic nervous system, or the CNS.

reinstating the pragmatics of communication,

Etiologies may include static or progressive

and providing appropriate compensatory strate-

disorders involving soft tissues, joints, bones, the

gies. Treatment goals for dysarthria include

viscera (internal organs), the peripheral nerves

improving intelligibility of speech through special

or nerve roots, and the CNS. Pain could result

exercises and compensatory strategies such as

from pathology related to the postoperative

manipulation of respiration, phonation, res-

state, trauma, burns, and a host of other condi-

onation, articulation, and prosody.

tions including degenerative, inflammatory,

infectious, metabolic, or neoplastic disorders.

Environmental factors may interact with inter-

Management of Emotional Dysfunction

nal factors to result in pain. For example,

Emotional disturbances such as depression,

individuals with muscle spasticity, contractures,

anxiety, apathy, mania, agitation, delusions,

or decubitus skin ulcers often experience pain

hallucinations, personality changes, and

when being moved or repositioned. Also, the per-

obsessive-compulsive behavior may occur in

ception of pain may be modified by certain

association with certain neurologic conditions.

psychological factors, which can contribute to the

564

Chapter 27

n Principles of Neurorehabilitation

onset, severity, exacerbation, and maintenance of

neous electrical nerve stimulation, massage,

chronic pain.

progressive joint mobilization, acupressure or

It is known that chronic anxiety or depression

acupuncture, biofeedback, relaxation exercises,

can adversely influence the subjective experience

and movement education regarding proper

of pain, and similarly chronic pain can result in

body mechanics. Consultation with an anesthe-

the onset of chronic anxiety or depression. The

sia or pain specialist for local anesthesia,

pattern of behavior resulting from chronic pain

regional blocks, epidural analgesics, or sympa-

may include irritability, anger, dysphoric moods,

thetic nerve blocks may be helpful to break a

loss of self-confidence or self-esteem, poor treat-

cycle of pain. Refractive cases may require a

ment compliance, and deterioration of important

surgical consultation. For example, orthopaedic

social relationships

(possibly including the

surgeons may be able to replace painful degen-

doctor-patient relationship).

erative joints. Neurosurgeons may be able to

The subjective experience of chronic pain

correct or ablate sources of chronic neuro-

may also adversely affect cognitive functioning

pathic pain. Finally, compensation issues also

and overall functional recovery outcomes.

should be considered in certain cases as a pos-

Concentration, attention, mental alertness, and

sible source of chronic pain.

capacity to perform complex neuropsychological

tasks may be reduced by the direct distraction of

Discharge Planning

pain or may be indirectly impaired by associated

fatigue, sleep deprivation, depression, anxiety,

Discharge planning is an integral part of a reha-

poor motivation, or the effects of analgesics. In

bilitation management plan and involves the

addition, physical capacity, including mobility

interdisciplinary team, the patient, and the family

and the ability to perform self-care activities, may

or caregivers. Objectives include the education

be diminished by chronic pain.

of the patient or caregivers and the determina-

tion of the best living environment if other than

n SPECIAL CLINICAL POINT: The treatment

home, family or caregiver capabilities, home

of chronic pain involves the identification and

accessibility, special equipment needs, disability

correction of causal factors whenever possible.

entitlements, the ability to return to work or to

A course of opioid or nonopioid analgesic, anxi-

school, driving issues including handicap parking

olytic, or antidepressant medications may be

needs, need for further rehabilitation therapies

useful. Long-term use of narcotic or anxiolytic

such as vocational rehabilitation, and necessary

medications should be avoided with few excep-

tions (e.g., cancer pain).

community services including appropriate med-

ical follow-up.

Often, a psychological evaluation and course of

Discharge occurs when reasonable treatment

psychotherapy may be beneficial for adjustment

goals have been achieved. Reasonable treatment

issues and associated affective dysfunction. If

goals can include the progression from one level

there are prominent signs of affective dysfunc-

of functional dependence to a more independent

tion, a psychiatry consultation may be necessary.

level that is realistic for that patient. For example,

Pain and other somatic complaints rooted

discharge may be indicated when a patient who

in emotional dysfunction may be refractive to

initially required total assistance in certain mobil-

traditional treatments but responsive to psy-

ity or self-care activities progresses to a level of

chopharmacologic intervention.

moderate or minimal assistance or supervision.

Physical modalities that may be helpful in a

In general, inpatients are discharged from intense

pain management program include ther-

comprehensive rehabilitation programs when

motherapy (hot packs, ultrasound, analgesic

they progress to a level of minimal assistance in

creams), cryotherapy (cold packs), transcuta-

mobility, which may include proficiency in wheel-

565

Chapter 27

n Principles of Neurorehabilitation

chair operation or progression to ambulation

cally ill spouse may not be able to care for the

with the physical assistance of another person

patient unless full-time help is available at

with use of an assistive device, and have the abil-

home. Also, patients who previously lived inde-

ity to assist caregivers with transfers.

pendently may no longer be able to do so. In

Discharge from an outpatient program often

addition, some patients may require temporary

occurs when a level of supervision to independ-

placement in a transitional living program in

ence is reached in mobility and self-care

preparation for more independent living. In

activities. Absence of patient progress in mobility

other cases, the availability of home health care

or self-care function on two successive care plan

services including a home health aide and a vis-

evaluations suggests a functional plateau and a

iting nurse may allow a patient to be discharged

need to reconsider the treatment regimen or the

to the home setting.

rehabilitation setting. Interdisciplinary care plan

Another important objective of the discharge

conferences are held weekly in intense compre-

planning process is patient or caregiver educa-

hensive inpatient programs and bimonthly to

tion and training regarding pertinent care issues

monthly in outpatient or subacute rehabilitation

and community transition. This includes pre-

programs. These meetings are held to allow

vention of complications, necessary techniques

interdisciplinary team members the chance to

such as safe car transfers, home exercises,

update one another on patient progress and

proper use of necessary adaptive equipment or

potential problems. The care plan meetings

braces, routine care needs such as bladder

facilitate the formulation of individualized reha-

catheterization or the use of alternative feeding

bilitation management plans, modifications of

devices, instruction on medication administra-

existing plans, and the discharge planning

tion or potential side effects, information

process.

regarding specific precautions such as driving

A crucial aspect of the discharge planning

or the use of machinery, information regarding

process is the determination of the best living

sexual issues, information regarding available

environment and family caregiver capabilities.

community services that may include vocational

Therapeutic weekend day passes often are

or recreational programs and support groups,

encouraged during a comprehensive inpatient

and instructions regarding discharge follow-up

rehabilitation program to allow a patient and

and continued therapy needs.

caregivers the opportunity to test their abilities

The importance of continuity of care is

at home and in the community. Thus, problem

emphasized. Usually, the team case manager will

areas of community transition may be identi-

assist the patient and caregivers in arranging for

fied, allowing therapists to focus special

necessary community services such as home

attention prior to discharge. In addition, some

health care and outpatient therapies. In addition,

programs allow therapists to perform home

arrangements are made for important medical

consultations to determine potential safety haz-

follow-up that often includes the primary med-

ards and special home equipment needs (e.g.,

ical physician, the neurorehabilitation specialist,

wheelchair ramps, grab bars), to help patients

and all other treating specialist physicians.

and caregivers rehearse the daily routine, and

Prior to discharge, a patient’s functional base-

to assess accessibility of community facilities

line is documented to help monitor subsequent

that still may be used by the patient following

progress and maintenance of function. Also, dis-

discharge. Whether a patient is discharged to

ability entitlements are addressed, such as

home or to an alternative living facility depends

handicapped parking needs, certification of dis-

in part on patient or caregiver preferences and

abilities, and clarification of a patient’s ability to

a realistic assessment of patient or caregiver

return to work or school. If necessary, arrange-

capabilities. For example, an elderly, chroni-

ments are made for special education or

566

Chapter 27

n Principles of Neurorehabilitation

vocational programs. Whenever possible, adap-

medical comorbid conditions or the neurologic

tive equipment or strategies are offered to allow

disorder or from lack of stimulation, lack of

individuals the ability to return to work or school.

self-confidence, physical barriers to activity, or

inadvertent suppression of initiation by over-

protective caregivers.

Neurorehabilitation Follow-Up And

The need for continued or additional rehabil-

Community Transition

itation services also must be considered. Further

Gaps in medical follow-up increase risks for

outpatient rehabilitation needs vary with a

institutionalization of patients with certain dis-

patient’s progress in an existing program and

abilities. Therefore, routine medical follow-up

the extent of remaining disabilities. Goals of

is encouraged following discharge from a neu-

further rehabilitation services may include

rorehabilitation program. The frequency of

encouragement of recreational activities and the

recommended follow-up varies with patient

return to work, school, or driving.

needs. Responsibility for coordination of out-

Specific rehabilitation programs exist to

patient medical care, rehabilitation services,

assess the capacity to perform certain activi-

and determination of further rehabilitation

ties such as the ability to drive or to return to

needs rests with the primary care physician,

work-related physical activities. Work-capacity

who may be the previous treating family physi-

assessments are available. In addition, driving

cian, internist, pediatrician, or rehabilitation

programs for handicapped people exist to assess

specialist.

driving safety as well as to teach adaptive strate-

Goals of follow-up include assessment of a

gies. The ability to drive is influenced by an

patient’s health status, safety at home and in the

individual’s impairments, including visual/spa-

community, and maintenance of function. In

tial and cognitive function. Adaptive driving

addition, if applicable, the follow-up physician

instruction programs are available for appropri-

should assess the adequacy of family or caregiver

ate patients.

interventions. Areas of concern include medical,

Another follow-up concern includes sexual

physical, cognitive, emotional, and social func-

function issues. Adaptive strategies, devices, and

tion. Problems may develop once an individual

counseling can enhance sexual function in

begins to attempt resumption of previous com-

patients with disabilities and can even allow sex-

munity activities and social relationships. This is

ual reproduction for patients with spinal cord

when the full impact of disabilities resulting from

injuries.

a neurologic condition may become apparent to

In summary, in an attempt to maximize the

the patient or the family.

quality of life and functional independence, neu-

Changes in traditional family roles also may

rorehabilitation outpatient follow-up concerns

have profound consequences on the patient or the

include medical, physical, cognitive, emotional,

family members. Support groups and psychother-

and social aspects of patient function during the

apy may be useful in certain situations. Also, the

transition back into the community.

ability of a family member or caretaker to provide

effective care for a patient with severe disabilities

When to Refer a Patient to a

must be reevaluated constantly. Even committed

Neurorehabilitation Specialist

caregivers may reach a point of desperation when

providing continuous support without relief.

The most common disease processes for which

Another concern is a patient’s ability to

neurorehabilitation interventions are warranted

maintain functional levels previously achieved

include stroke, multiple sclerosis, traumatic brain

during a rehabilitation program. Loss of func-

injury, and postoperative conditions following

tion may occur secondary to exacerbation of

neurosurgery. In addition, all individuals with an

567

Chapter 27

n Principles of Neurorehabilitation

acute (e.g., stroke), chronic (e.g., multiple scle-

but who have experienced a decline in their level

rosis), or progressive (e.g., Parkinson disease)

of functional independence.

neurologic disorder may benefit at least to some

degree from neurorehabilitation treatment to

Special Challenges for Hospitalized Patients

enhance function and to improve the quality of

life.

Hospitalizations for intercurrent illnesses pose

The primary care physician is the usual

special challenges to individuals with neurologic

gatekeeper for patient referrals to the neurore-

conditions who may have been undergoing

habilitation specialist. Patient referrals to a

rehabilitation treatment. Functional decline

neurorehabilitation specialist can be made at any

commonly results from an acute intercurrent ill-

point during an individual’s disease process, from

ness in patients who already have chronic

the time of the acute hospitalization to the time

impairments due to a neurologic disorder or dis-

following discharge to home care. As previously

ease. For example, individuals with a history of

outlined in this chapter, neurorehabilitation can

stroke, multiple sclerosis, Parkinson disease,

be carried out in a variety of settings, ranging

spinal cord injury, or brain injury who may

from inpatient to outpatient care settings. Early

require hospital treatment for an intercurrent ill-

patient referrals for neurorehabilitation treatment

ness such as pneumonia, heart disease, or

can enhance functional outcomes. For example,

urosepsis usually will experience a setback in

studies have shown that beginning rehabilitation

their functional status. In addition, the more

as early as possible after a stroke produces better

prolonged a hospitalization for an intercurrent

results than if rehabilitation treatment was

illness may be, the more profound will be the

started later. However, the primary care physician

setback in that individual’s functional recovery.

should never consider it too late to refer a patient

Aspects of a rehospitalization that are coun-

for an evaluation with a neurorehabilitation spe-

terproductive to the functional recovery process

cialist to determine whether there may be helpful

include a number of factors. Prolonged bed rest

physical, pharmacologic, or adaptive interven-

and immobility are among the single most dam-

tions that may improve function and quality of

aging factors. The risks associated with bed rest

life for that individual.

and immobility were discussed at length earlier

Primary care physicians always should be

in this chapter and include the possibility for the

aware that patients with impairments and

development of DVT, joint contractures, skin

disabilities resulting from neurologic conditions

breakdown, pneumonia, deconditioning weak-

may benefit at least to some degree from neurore-

ness, and orthostatic intolerance. Impaired

habilitation interventions. Also, it is important

nutritional status resulting from an intercurrent

that primary care physicians closely monitor their

illness may also negatively affect motor function

outpatients with neurologic conditions for any

recovery and lead to muscle wasting and wors-

deterioration in function either related to the dis-

ened weakness. Infections such as pneumonia or

ease process, aging, or other intercurrent illnesses

urinary tract infections may result in exacerba-

because these patients also may benefit from fur-

tions of confusion in patients with brain injuries

ther neurorehabilitation interventions.

or encephalopathies.

Hospitalizations for a second stroke or hos-

n SPECIAL CLINICAL POINT: Ideally, primary

pitalizations for exacerbations of multiple

care physicians should request a neurorehabilita-

sclerosis can have obvious detrimental effects in

tion evaluation for all their patients with

impairments or disabilities related to a neuro-

a patient who had been undergoing rehabilita-

logic condition who have not yet undergone

tion treatment. Measures to prevent the

rehabilitation treatment and for those patients

complications of immobility should be instituted

who have undergone rehabilitation treatment

in all patients with neurologic conditions who

568

Chapter 27

n Principles of Neurorehabilitation

may require a hospitalization for an intercurrent

disorders such as stroke and traumatic brain and

illness. In addition, early rehabilitation interven-

spinal cord injury. National collaborative reha-

tions by rehabilitation specialists and therapists

bilitation outcome studies should continue to

during the rehospitalizations are critical to

provide useful data for determination of model

enhance functional recovery once the patient is

systems of care for a host of neurologic condi-

stabilized.

tions and disorders.

Neurorehabilitation Outcomes

Always Remember

The effectiveness of a medical treatment may be

• Disablement is best understood in terms of

measured in terms of biologic or functional

the complex relationship between disease,

changes in an individual and cost efficiency. The

impairment, disability, and handicap.

biologic effectiveness of a medical treatment can

• Neurorehabilitation targets disabilities result-

be assessed in terms of changes in an impairment

ing from disease-related impairments to

rating such as the degree of sensory loss, spastic-

reduce handicaps.

ity, or weakness. The functional effectiveness of

• The neurorehabilitation process encompasses

a medical treatment may be measured by changes

medical, physical, social, education, and voca-

in disability or handicap scores. The cost effi-

tional interventions that can be provided in a

ciency of a medical treatment may be measured

variety of institutional or community settings.

in terms of relative monetary savings or losses to

• Ongoing and thorough patient assessment is

the payer in relation to the outcome, which may

a crucial aspect of the neurorehabilitation

include length of hospital stay or an individual’s

process from the acute hospitalization, to the

ability to return to work, school, or independent

transfer to a rehabilitation facility or program,

living. Variables that may complicate the assess-

to the transition back to the community.

ment of a specific medical treatment outcome on

• Short- and long-term rehabilitation goals and

an individual may include age, sex, social factors

a management plan are formulated and regu-

such as prior education, coexistent chronic med-

larly revised as needed to maximize patient

ical or psychological problems, the effects of

potential at all stages of recovery.

other treatments, and patient compliance.

• Neurorehabilitation evaluation is warranted

Numerous prior and ongoing outcome studies

for all patients having disabilities related to an

exist regarding the effectiveness of neurorehabil-

acute, chronic, or progressive neurologic

itation in terms of various neurologic

condition who have not yet undergone reha-

impairments, disabilities, handicaps, and cost

bilitation treatment and for those having new

efficiency. The goal of these studies has been to

functional deficits.

determine the most effective and cost-efficient

• The neurorehabilitation plan always involves

neurorehabilitation approaches for a host of spe-

the patient and key caregiver, so that goals

cific neurologic impairments or disorders, while

of the effort fit with the short-term and

considering possible individual variables.

long-term goals of the family.

Already, a number of specific neurorehabilitation

interventions have been shown to be effective for

a variety of impairments (e.g., various speech

therapy language exercises for certain aphasias

QUESTIONS AND DISCUSSION

or dysphasias and various occupational therapy

and physical therapy interventions for certain

1. A 51-year-old woman with a history of

problems of mobility). In addition, the multidis-

multiple substance abuse developed diffi-

ciplinary rehabilitation team approach has been

culty swallowing. Two days later, she

shown to be effective in a variety of neurologic

developed an acute onset of paraplegia and

569

Chapter 27

n Principles of Neurorehabilitation

was admitted for an evaluation. She was

education, prevention of secondary complica-

diagnosed with an extensive retropharyn-

tions, strengthening of deconditioned mus-

geal abscess with compression of the

cles, and provision of compensatory

cervical spinal cord. She underwent surgical

strategies to overcome functional disabilities.

drainage of the abscess and was prescribed

Long-term prognosis for recovery of ambula-

broad-spectrum intravenous antibiotics.

tion in this patient is fair because there is al-

One month later, she presents for neurore-

ready some movement and sensation present

habilitation with incomplete quadriplegia

in both legs.

with four-fifths strength in both arms and

2. A previously healthy 49-year-old man devel-

two-fifths strength in both legs. A low cervi-

oped progressive weakness that started in

cal sensory level is present, below which

his legs following a flulike illness. A workup

there is partial pinprick and light touch sen-

included a lumbar puncture, which demon-

sation to the toes. An indwelling Foley

strated an elevated protein, and an

catheter is in place, and there is a small area

electromyographic nerve conduction study

of superficial skin breakdown at the sacrum

that showed nerve demyelination with

involving only the epidermis. Which of the

axonal involvement. He was diagnosed with

following statements is correct?

Guillain-Barré syndrome and underwent a

A. Urologic consultation is unnecessary at

course of plasmapheresis. On admission

this point.

for neurorehabilitation 2 months later, he

B. The indwelling Foley catheter should not

presents with flaccid quadriplegia, with the

be removed while localized skin break-

ability to shrug his shoulders. Proprioception

down is present.

is intact down to the ankles but is absent at

C. Short-term rehabilitation goals should

the toes. Reflexes are absent. Bulbar muscles

include strengthening of deconditioned

are not involved. Which of the following

muscles.

statements is correct?

D. The long-term prognosis for recovery of

A. Dysautonomia may develop months into

ambulation is poor.

his recovery

The correct answer is C. The indwelling Foley

B. The patient is at risk of developing

catheter should be removed on admission, and

pneumonia.

a program of bladder training should be

C. Ambulation should be set as a long-term

started. Initially, bladder catheterizations

neurorehabilitation goal.

should be performed at least every 6 hours,

D. After 2 months, quadriplegia is likely

and postvoid residuals should be monitored

permanent.

closely. Bladder catheterization frequency may

be tapered as postvoid residuals diminish. A

The correct answer is B. He is at risk for com-

urology consultation may be helpful in deter-

plications of immobility including pneumonia,

mining medications that may hasten recovery

contractures, DVT, and skin breakdown. In

of bladder function. Superficial skin break-

addition, he is at risk for orthostasis and

down is not a contraindication to removal of

dysautonomia. The latter is a rare complica-

the Foley catheter. However, if the area of skin

tion of Guillain-Barré syndrome that occurs

ulceration penetrated through the dermis into

most often during the acute illness rather than

the soft tissue or muscle, then Foley catheter

the convalescence.

removal might be contraindicated. Moisture

Ambulation would be an unrealistic long-

from urine incontinence can contribute to fur-

term rehabilitation goal at the time of his ad-

ther skin ulceration.

mission because he is presenting as a flaccid

Short-term neurorehabilitation goals in

quadriplegic. However, many patients with

this patient would include patient and family

acute demyelinating polyneuropathies present

570

Chapter 27

n Principles of Neurorehabilitation

for rehabilitation with flaccid quadriplegia

study is performed to evaluate for aspiration.

1 to 2 months after onset of their illness and

Previous history of pneumonia is suggestive of

later recover the ability to ambulate. There-

aspiration. A modified barium swallow study

fore, ambulation would not be an impossibil-

can be performed to document safety in all

ity in this patient.

phases of swallowing with various food

Short-term rehabilitation goals here would

textures. Compensatory swallowing strategies

include patient education, prevention of sec-

are available for certain types of dysphagia,

ondary complications, and gradual mobiliza-

but a temporary alternative means of feeding

tion with passive range-of-motion exercises to

may be necessary in patients at high risk for

help strengthen deconditioned muscles and

aspiration.

prevent development of contractures. Motor

Gradual recovery of some functional abili-

recovery may be delayed in this patient be-

ties is likely in this patient. Prognosis for func-

cause his polyneuropathy involves both de-

tional recovery is best in those with the ability

myelination and axonal nerve damage. Motor

to comprehend and learn. Rehabilitation is still

recovery occurs more rapidly in those individ-

possible, although more difficult, in patients

uals with only demyelination.

with receptive aphasias or hemineglect.

3. A 70-year-old woman underwent a coro-

4. A 14-year-old boy was involved in a motor

nary artery bypass graft and suffered a

vehicle accident. He remained comatose for

left-hemispheric stroke 3 days later. Her

5 days following admission. He was found

hospital stay was complicated by pneumo-

to have a left ankle fracture and diffuse

nia. Three weeks later, she is transferred for

axonal brain injury. Three weeks later, on

neurorehabilitation with a nasogastric feed-

transfer for neurorehabilitation, he is rest-

ing tube in place, expressive aphasia, a

less and agitated with poor concentration

flaccid right arm, and two-fifths strength

and attention. He is nonverbal but attempts

present in the right leg. She is able to fol-

to follow some simple commands. There is

low simple commands. Mood and affect

diminished movement on the left side. A

are flat to tearful. Which of the following

nasogastric feeding tube is in place due to

statements is correct?

dysphagia and risk for aspiration, and the

A. The patient should be taught compensa-

left ankle is in a cast. Which of the follow-

tory strategies.

ing statements is correct?

B. The nasogastric feeding tube should be

A. The patient is at risk of elopement from

removed, and a trial pureed diet with

the rehabilitation facility.

thickened liquids should be started.

B. Cognitive improvement at this point is

C. Bracing and splinting should be avoided

unlikely.

to encourage mobility.

C. Restraints should be avoided to prevent

D. The patient’s expressive aphasia will sig-

agitation.

nificantly impede rehabilitation.

D. One-to-one supervision is necessary to

ensure safety.

The correct answer is A. Short-term rehabili-

tation goals in this patient should include

The correct answer is D. This young man is

compensatory strategies to overcome func-

confused, restless, and agitated, which places

tional disabilities, bracing and splinting to en-

him at risk for falls and inadvertent removal

hance function and prevent contractures,

of the nasogastric tube. Elopement from the

prevention of secondary complications, and

facility is less likely because he is hemiparetic

patient and family education.

and confused.

There is a nasogastric feeding tube in place

Initial measures to ensure safety may

that should not be removed until a swallowing

include one-to-one supervision, a low bed,

571

Chapter 27

n Principles of Neurorehabilitation

and a right-hand mitt restraint. Redirection

Science Foundations for Physical Therapy in Rehabili-

tation. Rockville, MD: Aspen; 1987.

alone is unlikely to be successful because he is

confused with poor attention and concentra-

Granger CV, Black T, Braun SL. Quality and outcome

measures for medical rehabilitation. In: Delisa JA, ed.

tion. Although restraints could result in further

Rehabilitation Medicine. Principles and Practice. 4th

agitation, a right-hand mitt will be necessary to

ed. Philadelphia: Lippincott Williams & Wilkins;

help prevent the otherwise likely removed of the

2005: 151-164.

nasogastric feeding tube. A low bed will limit

Granger CV, Hamilton BB. UDS report: the uniform data

the risk for serious injury should this patient fall

system for medical rehabilitation report on the first

admissions for 1990. Am J Phys Med Rehabil.

out of bed. Medications may be effective if one-

1992;71:108-113.

to-one supervision fails to ensure safety and to

Gresham GE, Duncan PW, Stason WB, et al. Post-stroke

redirect impulsive or aggressive behavior.

rehabilitation: clinical practice guideline. Rockville,

Cognitive improvement is expected. Cogni-

MD: U.S. Department of Health and Human Services,

tive function most likely will improve in pa-

Agency for Healthcare Policy and Research; 1995.

tients with traumatic brain injuries in which

Hamilton BB, Laughlin JA, Granger CV, et al. Interrater

coma lasted 13 days or less. These individuals

agreement of the seven level functional independence

measures (FIM). Arch Phys Med Rehabil. 1991;72:790.

generally will have selective impairments on

neuropsychological testing at 1 year following

Hobart JC. Evidence-based measurement: which disability

scale for neurologic rehabilitation? Neurology. 2001;

injury. Those individuals in a coma lasting

57(4):639-644.

2 weeks to 29 days are more likely to have

Kesselring J. Neurorehabilitation: a bridge between basic

impairments in all areas of cognitive function

science and clinical practice. Eur J Neurol. 2001;

at 1 year following trauma. More than

8(3):221-225.

one-half of those individuals with coma last-

Kushner D. Neurorehabilitation. In: Evans RW, ed. Saun-

ing more than 29 days will remain severely

ders Manual of Neurologic Practice. Philadelphia: WB

impaired in all areas of cognitive function

Saunders; 2003.

1 year following injury.

Kushner D. Neurorehabilitation of brain injuries. In:

Evans RW, ed. Saunders Manual of Neurologic Prac-

tice. Philadelphia: WB Saunders; 2003.

SUGGESTED READING

Macdonell RA. Neurologic disability and neurologic re-

habilitation. Med J Aust. 2001;174(12):653-658.

Braddom RL, ed. Physical Medicine and Rehabilitation.

Philadelphia: Saunders Elsevier; 2007.

Taub E, Uswatte G. New treatments in neurorehabilita-

tion founded on basic research. Nat Rev Neurosci.

Delisa JA, ed. Physical Medicine and Rehabilitation: Prin-

2002;3(3):228-236.

ciples and Practice. 4th ed. Philadelphia: Lippincott

Williams & Wilkins; 2005.

Thompson AJ. Neurological rehabilitation: from mecha-

nisms to management. J Neurol Neurosurg Psychiatry.

Dikmen S, Machamer JE. Neurobehavioral outcomes and

2000;69(6):718-722.

their determinants. J Head Trauma Rehabil. 1995;10:

74-86.

Umphred DA, ed. Neurological Rehabilitation. St. Louis:

CV Mosby; 1990.

Dobkin BH. Impairments, disabilities, and bases for neu-

rological rehabilitation after stroke. J Stroke Cere-

Wade DT. Measurement in Neurological Rehabilitation.

brovasc Dis. 1997;6:221-226.

Oxford: Oxford University Press; 1992.

Gordon J. Assumptions underlying physical therapy inter-

World Health Organization. International Classification

vention: theoretical and historical perspectives. In:

of Functioning, Disability and Health: ICF. Geneva:

Carr J, Shepherd RB, Gordon J, et al, eds. Movement

WHO; 2001.

Medicolegal

Issues in the

Care of Patients

with Neurologic

Illness

MARIA R. SCHIMER AND

LOIS MARGARET NORA

key points

• Excellent communication skills, including the ability to

listen effectively, are among the most important risk

management skills that the physician can employ.

• Treating physicians have a legal duty to their patients to

possess a reasonable degree of skill and knowledge, to

use care and diligence in exercising this skill and

knowledge, to employ approved methods in general

use, and to use their best judgment.

• Informed consent is a process that has essential legal

requirements including a legally and clinically competent

patient, who is given adequate and understandable

information about the proposed medical intervention

by the treating physician and who voluntarily agrees to

the intervention.

• Competent patients, or their surrogate decision makers,

may withdraw their consent for a medical intervention.

• When determining death using neurologic criteria, the

clinical evaluation should be done by experienced

examiners who adhere to the recognized practice

572

573

Chapter 28

n Medicolegal Issues in the Care of Patients with Neurologic Illness

parameters and follow institutional requirements to

establish the diagnosis.

• Documenting advice and directives that are given to a

patient with neurologic disease who wishes to drive is

an important risk management strategy. All states have

Department of Motor Vehicle Web sites that can

provide information helpful in determining driving

regulations for patients who are impaired for any

reason.

n recent years, legal

malpractice occurred in a federal facility (e.g.,

aspects of medical practice

a Veterans Administration hospital), the matter

have become increasingly visible and impor-

is heard in a federal court because of the provi-

tant, particularly in the care of patients with

sions of the Federal Tort Claims Act.

neurologic disease. Although some physicians

Most medical malpractice actions allege

are intimidated by medicolegal issues, knowl-

that the physician (Defendant) was negligent in

edge of legal aspects of medical practice can

the care of the patient (Plaintiff).

give the clinician a greater sense of mastery and

n SPECIAL CLINICAL POINT: To win a lawsuit

may reduce the defensive practice of medicine

alleging professional negligence, the Plaintiff

and thus promote better patient care.

must demonstrate by a “preponderance of the

Three important types of law affect medical

evidence” (greater or stronger evidence) (a) that

practice: case law, statutory law, and adminis-

the physician had a duty of care to the patient,

trative law. Case law (also known as the com-

(b) that the physician breached that duty, (c)

mon law) is developed by both the state and the

that the breach proximately caused injury to the

federal courts (the judicial system) through the

Plaintiff, and (d) that the injury resulted in

resolution of various criminal and civil matters.

damage to the Plaintiff.

The decisions of these courts form a body of

Duty arises at the beginning of a patient-

law that is binding within a given jurisdiction

physician relationship and continues until the

because of a legal doctrine known as stare deci-

relationship is appropriately concluded through

sis, or the doctrine of precedent, which requires

proper written notification to the patient by the

courts to follow earlier court decisions when

physician or patient withdrawal from the rela-

the same legal question arises again. A court’s

tionship. Generally, a patient-physician relation-

jurisdiction is the geographic or subject matter

ship arises when a physician first sees a patient

area over which that court has decision-making

in a patient care setting and agrees to be the pa-

authority. Within any jurisdiction, courts are

tient’s physician. The concept of duty in this

divided into trial courts and appellate courts.

context has several components including the

Physicians are often most concerned with

duties to (a) possess a reasonable degree of skill

the law developed by the judicial system be-

and knowledge, (b) use reasonable care and

cause this is where the majority of law in the

diligence in exercising this skill and knowledge,

area of medical malpractice arises. The law

which is developed in this area has a substan-

and (d) use his or her best judgment.

tial impact on malpractice insurance premiums

for physicians. Medical malpractice is gener-

n SPECIAL CLINICAL POINT: The injury

ally a civil action heard in a court that is part of

alleged must have been caused by some

a state court system. However, if the alleged

particular thing that the Defendant either did or

574

Chapter 28

n Medicolegal Issues in the Care of Patients with Neurologic Illness

failed to do which a physician of ordinary skill,

The Health Insurance Portability and Ac-

care, and diligence would or would not have done

countability Act (HIPAA) is an example of a

under like or similar circumstances. It must then

federal law that is administered by the Office

be proven that the injury was directly and

of Civil Rights at the Department of Health

proximately caused by the Defendant’s action or

and Human Services through multiple adminis-

inaction; attorneys often call this the “but for”

trative regulations. These regulations dramati-

test. Expert medical testimony is provided by

cally affect the patient care environment and

another physician who, through experience and

expand upon the longstanding responsibilities

education, has developed sufficient skill and

knowledge in a particular area of medicine to be

of physicians to honor patient confidentiality.

able to form and give an opinion that will assist

For example, the HIPAA privacy rules regulate

the judge or jury in deciding the case.

the gathering of information from patients,

electronic sharing and storage of information

The second body of law affecting a physician’s

in the medical record, and communication of

medical practice is statutory law. Statutory law

such information with patients’ family mem-

is the body of law developed by local, state, or

bers and others. HIPAA rules impose substan-

federal legislative bodies; this body of law ap-

tial penalties for noncompliance by physicians

plies to persons within the jurisdictional bounds

and organizations.

of those legislative bodies. Examples of such

The remainder of this chapter addresses

statutory laws include the federal and state

three specific areas at the intersection between

statutes concerning medical malpractice, abor-

medical and legal matters and the care of pa-

tion, advance directives (living wills and health

tients with neurologic illness. These areas are

care powers of attorney), and termination of

(a) informed consent, a legal principle that af-

treatment. Laws must be consistent with the

firms patient self-determination; (b) the use of

United States Constitution, which is the most

neurologic criteria to declare death; and (c) the

fundamental and organic source of law, and

licensing of drivers with neurologic disorders,

with the individual state’s constitution. When a

with a focus on seizure disorders.

statute is unclear or when it is in conflict with

the Constitution (federal or state) or another

statute, the judicial system is employed to clarify

INFORMED CONSENT

or interpret the statute or to resolve conflicts.

Informed consent is a fundamental legal con-

n SPECIAL CLINICAL POINT: Administrative

cept based on medical ethics. The purpose of

law is a body of law with three distinct

components: the enabling legislation that creates

obtaining informed consent is to promote the

the governmental agency and gives it its powers;

autonomy of the patient in medical decision

the rules and regulations that are promulgated

making. Informed consent involves two dis-

by the agency in accordance with the power

tinct legal rights of the patient: the right to ob-

granted to it; and the body of opinions, reports,

tain information and the right to make a

and orders that the agency issues.

decision. The informed consent process, which

is best thought of as shared decision making,

An example of an agency that regulates some as-

requires that the treating physician disclose

pects of clinical practice is the U.S. Food and

sufficient information to enable the patient to

Drug Administration (FDA). Among other areas

evaluate a procedure before consenting to it.

of authority, the FDA regulates pharmaceuticals

and medical devices. Another agency, the Office

n SPECIAL CLINICAL POINT: Informed

for Human Research Protections (OHRP), has

consent is predicated on several important

regulatory authority over much of the research

assumptions. These assumptions are that the

involving patients.

patient (a) is competent, (b) is free from duress,

575

Chapter 28

n Medicolegal Issues in the Care of Patients with Neurologic Illness

must, in most cases, be sought from their

information from the treating physician in a

guardians, usually their parents. However, there

manner that renders the information

are exceptions. A minor who has been legally

understandable, and (d) has voluntarily given

emancipated is considered legally competent to

permission or made a choice.

make medical decisions. In addition, minors

To give informed consent, a patient must be

may be legally competent for certain interven-

competent. The President’s Commission for the

tions but not for others. For example, in some

Study of Ethical Problems in Medicine and Bio-

states adolescents are considered legally compe-

medical and Behavioral Research wrote that

tent to make reproductive health decisions, even

competence involves the possession of a set of

though they lack legal competence to make

values and goals, the ability to communicate

other medical care decisions.

and understand information, and the ability to

n SPECIAL CLINICAL POINT: Legal

reason and deliberate about one’s choices. Al-

competence, by itself, is not enough. A person

though this is an excellent standard by which to

must also be clinically competent.

measure competence, the clinical practitioner

often deals with situations in which the patient’s

Clinical competence implies that the patient can

abilities fluctuate over time and vary depending

understand information, formulate a decision,

on the functional domain. It is helpful to under-

and communicate that decision. Assistive de-

stand the construct that the patient must be both

vices (e.g., hearing aids, glasses, or communica-

legally and clinically competent to provide in-

tion devices) can be helpful in maintaining a

formed consent for a medical intervention.

patient’s clinical competence. Clinical compe-

Adults are presumed to be legally competent

tence is a medical decision. In some situations, a

unless they have been declared legally incom-

person may be legally competent but not clini-

petent by a court of law. When a person has

cally competent. Dementia, encephalopathy,

been declared incompetent by the court, the

and other conditions may render the patient in-

court names a guardian who stands in the place

capable of providing informed consent for a

of the incompetent person (ward) for all pur-

variable period.

poses set forth in the guardianship documents.

In situations where it is impossible to secure

Although many well-meaning family members

consent from the patient because the patient is

confuse the two, the practitioner must be care-

incompetent, the physician must consult a sur-

ful to distinguish between documents signify-

rogate decision maker for the patient. This per-

ing that a person is under guardianship and

son is often the patient’s next of kin. The

those signifying that a person has given an-

decision maker may also be a person appointed

other person the power to act for him or her in

earlier by the patient through a written ad-

the event of incompetence, that is, a health care

vance directive, or a court-appointed guardian.

power of attorney. A physician’s failure to se-

n SPECIAL CLINICAL POINT: Two distinct

cure consent before providing treatment may

legal standards have been established for

result in charges of battery (criminal, civil, or

surrogate decision makers. These standards are

both) and malpractice.

the substituted judgment standard and the best

interest standard.

n SPECIAL CLINICAL POINT: The general

rule is that a competent adult may consent to,

The substituted judgment standard requires the

refuse to consent to, or withdraw consent for

surrogate decision maker to review the patient’s

treatment in any form.

known beliefs, previous actions, statements,

Generally, minors are not considered legally

and any available documentation, to determine

competent. Consent for the treatment of minors

what decision the patient would have made. Put

576

Chapter 28

n Medicolegal Issues in the Care of Patients with Neurologic Illness

simply, the surrogate decision maker must “put

as a serious disadvantage. The most appropri-

himself or herself in the place of the patient.”

ate approach is probably a hybrid of the two

The best interest standard requires the surro-

standards.

gate decision maker to look at all of the facts

n SPECIAL CLINICAL POINT: Physicians

and circumstances surrounding the case and to

should communicate those risks that occur

attempt to identify the action that, in the minds

often enough or that are so severe, even if they

of most persons in the jurisdiction, would be in

occur infrequently, that a patient would usually

the best interest of the incompetent patient.

wish to know of them.

The second requirement for informed con-

sent is that adequate information be provided

For example, patients should be advised of the

to the patient in an understandable fashion. In-

possibility of hirsutism and gingival hyperpla-

formation provided to the patient should in-

sia with phenytoin use, and they should be

clude the nature and purpose of the proposed

given information about spinal headaches be-

intervention, its risks and anticipated benefits,

fore undergoing lumbar puncture. In addition,

alternatives to the proposed interventions,

if a physician is aware of a particular character-

prognosis without the intervention, and prog-

istic of a patient that would make a potential

nosis with alternative interventions. The pa-

adverse effect more important to that patient,

tient should be told of the right to refuse and to

this adverse effect should be communicated,

withdraw consent at any time.

even if the physician would not have discussed

it with other patients. For example, potential

n SPECIAL CLINICAL POINT: Although

teratogenic effects of medications should be

other health care personnel may be involved in

discussed with female patients who may be-

obtaining consent, the physician remains

come pregnant.

responsible for ensuring the provision of

The third requirement of informed consent

adequate information and for the other aspects

is that the patient must give consent voluntar-

of the informed consent process.

ily. Coercion and duress invalidate consent. A

The adequacy of information provided to a pa-

physician should provide patients with advice

tient can be an issue in malpractice suits. Two

and guidance regarding proposed therapies,

legal standards of information disclosure are

but this must be done in a noncoercive manner.

recognized: the professional standard and the

No explicit or implicit threat of loss of medical

material risk standard. The professional stan-

or nursing care should be linked to a decision.

dard requires the physician to give the patient

The consent discussion should be docu-

information that other physicians of the same

mented in the patient record. A patient-signed

specialty, in the same community, would give to

consent document is not required for valid con-

patients considering the same intervention. At

sent, but it provides at least some evidence of

trial, expert testimony is necessary to determine

decision making by the patient. Although pre-

the nature and extent of this information. This

pared consent forms can be helpful, the value

is the more traditional of the two standards and

of these documents should not be overesti-

is currently preferred in most jurisdictions.

mated. Courts and juries are often suspicious

The material risk standard requires the physi-

of complicated consent documents that appear

cian to provide any information that a reason-

to be written more to protect the physician

able person in the patient’s position would want

than to inform the patient.

disclosed or would use in making a consent

Care must be taken that interventions re-

decision. Advocates of this standard identify its

main within the scope of the consent given by

emphasis on the patient’s need for information.

the patient. Consent should be secured for a

Opponents point to its retrospective application

given procedure, for other procedures that are

577

Chapter 28

n Medicolegal Issues in the Care of Patients with Neurologic Illness

within the scope of that procedure, and for

beneficial medication because of a severe, but

procedures that can or should be reasonably

unlikely, side effect.

expected. Consent usually is given to a particu-

Physicians must be extremely cautious in their

lar person and to those working with that per-

use of therapeutic privilege. Courts may not be

son. The physician should not overextend the

sympathetic to physicians’ defending their use of

consent to procedures that are not logically as-

therapeutic privilege when confronted by an un-

sociated with the consent or to personnel not

informed patient who has suffered severe ad-

reasonably anticipated by the patient.

verse effects. If a physician believes that the use

of therapeutic privilege is absolutely necessary,

n SPECIAL CLINICAL POINT: In emergency

involving the patient’s family in the decision may

situations, the guidelines for informed consent

be beneficial, but this involvement must not vio-

do not strictly follow the standard informed

late the patient’s privacy. Complete disclosure to

consent principles.

the patient at the earliest opportunity is also ad-

When a patient is unconscious or incompetent

visable. The physician should maintain contem-

(by reason of mental impairment) and has sus-

poraneous and clear documentation of the

tained injuries that are likely to result in the im-

reasons for the decision.

minent loss of life, and no surrogate decision

n SPECIAL CLINICAL POINT: The right of a

maker is available, the health care profession-

competent patient to give informed consent

als caring for the person are required to act in

carries with it an obvious recognition of the

accordance with reasonable medical standards

patient’s right of informed refusal. Patients have

to save the patient’s life.

a legal right to refuse interventions, even if the

It is also important to recognize that a com-

refusal will result in the patient’s death.

petent patient may “waive” the right to in-

formed consent by “letting the doctor decide”

Physicians must inform patients of potential

what course of action to take in a given situa-

problems related to refusing a potential interven-

tion. For example, the patient may say, “I am

tion, and this action should also be documented.

not a physician. I trust you; that is why I came

Education and persuasion of the patient are two

here. Do what you think is best.” Some would

important tools available to the physician when

argue that this is not a waiver at all, but rather a

a patient refuses consent. When a physician is

conscious decision on the part of the patient to

confronted by a patient refusal that may result in

let another make a critical judgment. Although

serious adverse consequences for the patient and

courts recognize the right of a patient to waive

the physician is uncertain whether the refusal is

informed consent, physicians should make sure

the result of a patient’s inability to perceive the

that waiver decisions are carefully documented,

nature and extent of his or her clinical predica-

and they should have the patient put the waiver

ment (e.g., where the patient is in a state of early

in writing.

to mid-stage dementia), a psychological or psy-

Therapeutic privilege is another exception

chiatric consult may be helpful.

to informed consent. This exception is used

Informed refusal is not an absolute right.

when the physician determines that an in-

Certain exceptions to the patient’s right to re-

formed consent discussion will prove so detri-

fuse an intervention have been recognized,

mental to the patient’s health that it should not

and judicial intervention is possible in certain

be undertaken. For example, some physicians

situations. Courts will not permit the use of in-

have used this exception to justify not disclos-

formed refusal as a means of committing sui-

ing the risk of tardive dyskinesia when neu-

cide and may override a patient’s refusal if

roleptic medications are prescribed to certain

such an action is deemed necessary for the pro-

patients who, they fear, will refuse a potentially

tection of innocent third parties. The court

578

Chapter 28

n Medicolegal Issues in the Care of Patients with Neurologic Illness

may modify a patient’s refusal to protect the

• Informed consent is a process; written doc-

standards of the medical profession or of an

umentation is evidence of the process.

• The better the quality of the process and

institution.

documentation of the process, the more

Legal proceedings against physicians for fail-

likely the physician is to prevail in any legal

ure to obtain informed consent may take two

action against him or her.

forms. First, a physician may be sued for bat-

tery, the intentional touching of a person (the

In the case of legal incompetence, guardians

patient) by another (the physician) without con-

should be approached for consent. When a pa-

sent. Because battery is generally an intentional

tient is legally competent but clinically incom-

tort, punitive damages

(monetary damages

petent, medical care may proceed if consent is

meant to punish the physician, not merely to

given by a surrogate decision maker who is em-

recompense the patient) may be available if a

ploying the correct standard for decision mak-

physician is found liable. Except in extreme

ing. In a limited number of circumstances,

cases in which no consent was obtained or in

intervention by the courts may be necessary in

which misrepresentation or fraud was used to

determining nonemergency care for incompe-

obtain the consent, it is unlikely that battery will

tent patients. In most emergency situations,

be alleged. The fact that malpractice insurance

reasonable medical care should be rendered to

coverage is usually not available for intentional

preserve life and limb.

torts also may limit the use of a battery action

In the case of informed refusal, care must be

by Plaintiffs.

taken to inform the patient of the risks of re-

Second, and more commonly, failure to ob-

fusal. If the patient, in the judgment of the treat-

tain informed consent can lead to a medical

ing physician, does not appreciate the nature

malpractice (negligence) suit. To win, the Plain-

and extent of his or her clinical predicament, an

tiff must demonstrate by a preponderance of

appropriate mental health professional should

the evidence that (a) the injury sustained was a

be consulted. However, if the patient is both

known risk of the therapy, (b) the physician

legally and clinically competent, informed refusal

failed to meet the applicable standard of care

(even though life threatening) is the patient’s

regarding information about the risk that

right, except in very limited circumstances. Pa-

caused the injury, and (c) the patient would not

tients whose informed refusal may result in

have consented to the therapy if the informa-

death remain entitled to receive excellent med-

tion had been provided. If these things are

ical and nursing care until the end of life (e.g.,

proved, the Plaintiff can succeed, even if the

palliative and supportive care). Documentation

sustained injury (and damage) was a known

in such circumstance is essential.

complication of the intervention and did not

result through any fault of the physician.

n SPECIAL CLINICAL POINT: Five primary

DECLARING DEATH BY USING

guiding principles should maximize effective

NEUROLOGIC CRITERIA

informed consent:

(BRAIN DEATH)

• Physicians remain responsible for in-

Traditionally, death was defined clinically by

formed consent even when others are

the absence of cardiac and pulmonary func-

involved in obtaining it.

tioning. Today, medical and technologic ad-

• Information given to patients should be

vances make artificial ventilation, continued

adequate and understandable.

• Patients must be legally and clinically com-

cardiac rhythm, and the continued oxygena-

petent, and their consent to interventions

tion of many of the body’s tissues possible after

must be given voluntarily.

the death of the entire brain.

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n Medicolegal Issues in the Care of Patients with Neurologic Illness

The concept that death might be defined

The brain death discussion in this chapter is

using neurologic criteria was first articulated

focused on adult patients. Pediatric experts

by the Harvard criteria in 1968. A 1977 Na-

should be consulted when the brain death of a

tional Institutes of Health Collaborative Study

child must be determined.

and a 1982 President’s Commission for the

The diagnosis of brain death is established in

Study of Ethical Problems in Medicine and

three interrelated steps. First, an irreversible

Biomedical and Behavioral Research further

cause must be established, and certain conditions

explored the issues. In 1980, the United States

that can mimic brain death but are reversible

Uniform Determination of Death Act codified

must be excluded. Second, an extensive neuro-

the use of neurologic criteria (brain death) as

logic evaluation of the patient must be carefully

an acceptable method of determining death. In

performed. Third, ancillary laboratory tests may

the United States, there has been gradual and

be used to confirm the diagnosis and the progno-

substantial acceptance of the use of brain

sis. Rigorous attention to these three steps will

death criteria as an appropriate means of de-

ensure that complete cessation of brain function-

termining the death has occurred. Practice

ing and its irreversibility are established. Physi-

parameters and diagnosis guidelines for using

cians should also be aware of institution-specific

neurologic criteria to declare death have been

requirements related to diagnosing brain death.

developed.

Surprisingly, the requirements for making this di-

All 50 states currently define death either as

agnosis vary widely across institutions; for ex-

the irreversible cessation of circulation and res-

ample, some institutions require the completion

piratory functioning or as the irreversible ces-

of a formal check list or the performance of spe-

sation of all functions of the entire brain,

cific ancillary tests.

including the brain stem. These definitions do

The reason for the patient’s condition must

not imply that there are two types of death but

be known. In general, brain death should not

rather two methods of determining death.

be diagnosed if the cause is not clear. Common

Two elements are crucial to the determina-

causes of brain death are head trauma, intrac-

tion of brain death: (a) total cessation of func-

erebral hemorrhage, and anoxia during car-

tioning of the entire brain

(including the

diopulmonary arrest. Careful history-taking, a

brainstem) and (b) irreversibility of the condi-

detailed examination, and various laboratory

tion. Potential legal difficulties related to brain

tests and imaging studies (e.g., magnetic reso-

death can be avoided by a rigorous medical ap-

nance imaging) may be helpful in determining

proach to establishing the condition and distin-

the cause of brain death.

guishing it from other neurologic conditions.

Medical conditions that can mimic brain

Clear and considerate communication with

death must be ruled out before brain death is

family members and loved ones of the brain-

diagnosed. These medical conditions include

dead patient contributes to optimal care and

hypothermia, metabolic dysfunction, and drug

the avoidance of legal problems.

intoxication. In the setting of hypothermia, the

core body temperature must be corrected be-

n SPECIAL CLINICAL POINT: The diagnosis

fore the diagnosis can be made. Barbiturate

of brain death should be made by a physician

and anesthetic agents are the drugs most fre-

experienced in this process, usually a neurologist,

quently implicated in this setting, but multiple

neurosurgeon, or critical care specialist. Any

other medications, including tricyclic antide-

physician with a real or perceived conflict of

pressants, may also be involved. When a med-

interest in the diagnosis (e.g., a member of a

ical condition exists that can mimic brain

transplant team or a relative of a potential

organ recipient) should not be involved in

death, the condition should be corrected be-

making this diagnosis.

fore the diagnosis is made. If correcting the

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Chapter 28

n Medicolegal Issues in the Care of Patients with Neurologic Illness

condition is impossible, ancillary tests demon-

Although brain stem reflexes are com-

strating the lack of cerebral circulation are

pletely absent with brain death, certain spinal-

necessary.

mediated reflexes can be preserved. The

The second component of the brain death

presence of these reflexes does not preclude the

evaluation is the clinical examination. The

diagnosis, but to the inexperienced eye some of

complexity of the neurologic examination for

these reflex activities may imply brain activity.

establishing brain death mandates that the ex-

It is very important that the health care team

aminer be experienced. The clinical examina-

have a common understanding about what

tion establishes the total absence of brain

these reflex movements may look like, what

(cerebral and brain stem) function and helps

they represent, and that they are neither pur-

rule out those conditions that may mimic brain

poseful activity nor mediated by the brain. This

death. These conditions may be medical, as dis-

common understanding also will allow the

cussed above; neurologic conditions that are

health care team to most effectively communi-

sometimes misdiagnosed as brain death include

cate these facts to the family members.

locked-in syndrome and the vegetative state.

The third component of a brain death eval-

There have been unfortunate instances when

uation is laboratory testing and imaging stud-

patients in vegetative states have been wrongly

ies. These tests can help rule out conditions

declared brain dead; this underscores the im-

that mimic brain death, confirm the neurologic

portance of qualified, experienced examiners

examination, and establish irreversibility of the

making the diagnosis and rigorously adhering

condition. Although laboratory tests are usu-

to established criteria.

ally considered optional, confirmatory labora-

The patient must be unresponsive to any

tory tests are mandatory in some situations, for

external stimuli, including pain. Any form of

example, when specific components of clinical

purposeful response, seizure activity, or decorti-

testing cannot be reliably evaluated, when a

cate posturing is inconsistent with the diagnosis

cause for the diagnosis is not established, and

of brain death. All activities mediated by the

when local regulations require such testing.

cortex and the brain stem, including reflexes,

The electroencephalogram (EEG) has been

must be absent. Pupils are usually midpoint.

used as part of brain death evaluation for many

The light reflex must be absent. Other brain

years. Great care must be taken to ensure ade-

stem reflexes, including doll’s eyes, caloric,

quate technical quality of these studies. Cere-

corneal, gag, swallow, and cough reflexes, must

bral blood flow studies can be very helpful in

be absent.

the diagnosing of brain death and are often

The brain stem controls respiration, and the

easier to complete than EEG studies. Blood

evaluation of brain death should include for-

flow studies that demonstrate no intracranial

mal apnea testing to rule out the ability of the

circulation for at least

10 minutes provide

brain stem to maintain respiration. Formal

compelling and conclusive evidence of irre-

apnea testing should be performed only by

versible brain death.

physicians familiar with and experienced in

It is crucial to allow adequate time for

performing this test. The patient must be pre-

complete evaluation and serial observations

oxygenated before apnea testing and should re-

of the patient during the determination of

ceive oxygen during the test. The ventilator is

brain death. Repeated clinical examinations

disconnected long enough for the PaCO

are recommended. The time required for

2 to in-

crease to at least 60 mm Hg. When the PaCO

reaching the diagnosis will vary depending on

2is

at this level, no spontaneous attempts at respi-

the cause of the patient’s condition, the clini-

ration should be evident before it can be deter-

cal expertise of the examiner, and the use of

mined with confidence that the patient has no

various diagnostic tests. Some states and cer-

spontaneous respiration.

tain institutions may have local rules about

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Chapter 28

n Medicolegal Issues in the Care of Patients with Neurologic Illness

reexamination. Pressure for organ harvesting

a patient or a patient’s family has religious

and other concerns should not prevent the

or cultural objections to the use of neurologic

careful and thorough processes necessary for

criteria to diagnose death. Several states have

reaching the diagnosis.

created laws that either preclude the use of

neurologic criteria to diagnose death when

n SPECIAL CLINICAL POINT: One of the

there are religious objections to these criteria

most frequent errors in the clinical setting, as

or mandate procedures for accommodating

well as in the published literature about brain

such objections.

death, is the suggestion that the brain-dead

Often brain death is diagnosed in conjunc-

patient is somehow still alive.

tion with a decision that the patient or dece-

This suggestion is usually made inadvertently

dent may serve as an organ donor. Although

when a health care provider refers to the brain

organ harvesting is possible in the absence

as “dead” but to the body as “alive.” For ex-

of familial consent (e.g., with a valid donor

ample, a family member may be told that the

card), physicians usually will not harvest or-

“patient is dead [because of brain death], but

gans without this consent. Such restraint is

we are keeping him [or her] alive [because of

appropriate from a risk management perspec-

the desire for organ donation].” This informa-

tive. When organ donation is a possibility, it

tion is confusing to the family and is made

should be discussed with the family early in

more so by the chest movements that result

the care process by persons who are unin-

from the ventilator and by the cardiac rhythm

volved, and who will remain uninvolved, in

that continues to appear on the monitor. The

the diagnostic and treatment decisions.

situation becomes even more complicated if ac-

Organ procurement programs have specially

tivities around the bedside stimulate some form

trained professionals work with families to

of spinal reflex response.

facilitate the organ donation decision. In no

It is extremely important to communicate

event should undue pressure be exerted to

that neurologic criteria can be used to diagnose

convince family members to consent to organ

death and that brain death is death. Families

harvesting.

must be helped to understand that their loved

When organ harvesting is not being consid-

one is dead. Continued pharmacologic and

ered, there may be less inclination to declare

technologic support should be described in

the patient brain dead and to discontinue me-

terms of perfusing organs (particularly when

chanical perfusion of the remaining organs,

the specific organs are being considered for do-

particularly if the family does not wish to dis-

nation) rather than as keeping the patient alive.

continue the use of a ventilator. Nonetheless,

Pharmacologic and technologic support should

this course of action must be weighed against

be discontinued as soon as feasible after the di-

the ethics of using limited medical resources

agnosis of brain death. Allowing families to say

(including nursing and ancillary support staff)

their goodbyes before discontinuation of ma-

to support a corpse.

chinery may be appropriate; extended techno-

logic support of a dead body is not.

It must be recognized that some persons,

LICENSING OF DRIVERS

and some religious traditions, debate the va-

lidity of using neurologic criteria to diagnose

Driving a car is an important life activity for

death. The situation is made more complicated

most adults, and limitations on driving exert

because studies have shown that physicians

important occupational and social impacts.

often lack a rigorous approach to completing

Physicians often become engaged in discussions

all steps in making a diagnosis of death using

about whether patients with neurologic dis-

neurologic criteria. Care must be taken when

eases—including epilepsy, movement disorders,

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Chapter 28

n Medicolegal Issues in the Care of Patients with Neurologic Illness

and dementia—should drive. This discussion

commonly require a physician statement, indi-

will focus on licensing of drivers (noncommer-

cating that the patient’s condition is under suf-

cial) with seizure disorders because this is a

ficient control to permit the safe operation of a

common issue and the discussion has parallels

motor vehicle. Most states either require peri-

with other neurologic conditions.

odic medical updates or give the DOMV the

Most patients with controlled seizures can

discretion to require such an update from the

drive safely and without incident. However,

licensed person.

some types of seizures pose a risk of injury and

Restricted licenses are available in many

death to the patient who is driving, to passen-

states. Examples include licenses that permit

gers, and to others on the road. It is part of

the person to drive only in an emergency, to

good medical practice for physicians to inform

only to and from work, or to drive only during

patients with seizures about any recommended

daylight hours. These restricted licenses may

lifestyle, recreational, or occupational limita-

allow patients to drive even though they can-

tions related to the seizure disorder. It is com-

not meet the statutory seizure-free interval.

mon to recommend that patients abstain from

n SPECIAL CLINICAL POINT: The physician

driving after a seizure, particularly if the seizure

should make individualized medical judgments

involves an alteration in consciousness or a loss

about necessary driving limitations for each

of motor control.

patient, and state requirements should be

Several questions of legal interest are related

considered in formulating any recommendations

to the management of the patient with seizures

that the physician makes to the patients.

who wishes to drive. What are the Department

of Motor Vehicle (DOMV) requirements in the

If a restricted license or some other exception to

state in which the patient is obtaining a license?

the state rules appears appropriate, the physician

How does the physician participate in the pa-

can work with the patient and the state agency.

tient’s obtaining and maintaining a license?

Any recommendations about driving restrictions

How should the physician document the advice

and other occupational and recreational limits

given to patients about their driving activities?

should be carefully documented in the patient’s

If a person with an active seizure disorder

chart. One effective method of documentation is

drives against medical advice, how does the

to have the patient record his understanding of

physician balance the duty to maintain patient

the physician’s advice and to incorporate this

confidentiality with the duty to warn others

document into the chart. This process encour-

about behavior that places the patient and oth-

ages discussion between the patient and the

ers in danger?

physician, and it also provides clear evidence of

Most states require a mandatory seizure-

the patient’s involvement and understanding.

free interval before licensing is allowed. These

The physician may find that direct interac-

mandatory seizure-free periods range from 3 to

tion with the state’s DOMV or similar agency

18 months; 6 months is the most common in-

is necessary. In several states, physicians are

terval. Some states do not require a mandatory

required to report patients with seizure disor-

seizure-free interval before licensure; instead,

ders to the DOMV or another state agency.

decisions are based on individualized determi-

Mandatory reporting is, however, uncommon

nations. In such states, important findings con-

and is considered unwise for many reasons. It

sidered in each decision include the length of

infantilizes the patient, diminishes patient re-

time since the last seizure, the type of seizure,

sponsibility, and interposes a third party into

precipitants, and other factors reasonably ex-

the patient-physician relationship. Nonetheless,

pected to affect the applicant’s ability to con-

when such requirements exist, physicians must

trol a motor vehicle. Additionally, these states

comply with them. Physicians who do not

583

Chapter 28

n Medicolegal Issues in the Care of Patients with Neurologic Illness

comply can be penalized by the state and could

sure. In all states, the denial of a license can be

be held liable if third parties are injured as a re-

appealed.

sult of a seizure of unreported seizure disor-

Perhaps the most difficult problem that the

ders. Even when the physician is immunized

physician faces occurs when a patient with

from suit for providing such information to the

poorly controlled seizures persists in driving de-

state, the patient should still be told that the in-

spite medical advice. In states with mandatory

formation will be transmitted.

reporting, the physician is not only allowed to

In general, no information about a pa-

report such behavior but may be required to do

tient’s medical condition should be released

so. A model driver licensing statute developed

without the express consent of the patient.

by the Epilepsy Foundation of American pro-

Many states require that the physician com-

poses that physicians be immunized from suit

plete initial and periodic reports on persons

for reporting, in good faith, patients with

with seizures who drive. Physicians must fill

seizures who drive despite loss of consciousness

out these forms honestly and usually are im-

or loss of bodily control. Many states have in-

mune from suit for doing so. Office staff

corporated such language into their law. Al-

should be aware that complying with a state

though the law is not settled in all jurisdictions,

DOMV request neither violates nor lessens

it seems unlikely that a court would find a

the responsibility of maintaining the patient’s

physician liable for breaching confidentiality if

expectations of confidentiality.

the physician notified the state when a patient

Physicians should be aware of the proce-

refused to comply with medical advice and con-

dures for obtaining a driver license in their

tinued driving despite ongoing seizures that

state. Typically, applicants for initial or renewal

made such driving unsafe.

licensure complete forms developed by the

Physicians may be liable to persons other

DOMV. These forms may specifically inquire

than their own patients. Most physicians are

about a seizure or epilepsy. However, in some

aware of the Tarasoff case in which a health

jurisdictions, the questions are more general—

professional was found liable for not notifying

asking about disorders characterized by “lapses

a specifically identified potential victim that a

of consciousness” or “episodes of marked con-

patient was threatening her. Plaintiffs have at-

fusion” that may be recurrent—and as such

tempted to hold physicians liable for injuries

encompass epilepsy and other medical condi-

suffered in automobile accidents with defen-

tions. When a seizure disorder (or other med-

dant patients. Plaintiffs have sought to hold

ical problem) is identified, DOMV personnel

physicians liable under a number of theories,

may act on available information or may ask

including telling patients that they could drive,

for additional input.

failing to warn patients that they could not

Once adequate information is available,

drive, failing to warn a patient about the ad-

DOMV personnel may grant the license, re-

verse effects of medications, and failing to

fuse it, or refer the question to a medical advi-

comply with statutory requirements. The law is

sory panel, a group of experts who advise the

not settled in this area.

state about the correct procedures to follow

Additional information about the status of

and about individual cases. If DOMV person-

state and federal laws in this ever-changing area

nel refuse to grant a license, the applicant

can be found at www.epilepsyfoundation.org.

may be able to appeal to the medical advisory

In addition, information for individual states

panel, and this body may contact the physician

can be accessed through individual state’s

for more information. On the basis of the

DOMV Web sites. A case history and recom-

panel’s recommendation, the applicant may

mendations for the physician are considered in

subsequently may be granted or denied licen-

Figure 28.1.

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Chapter 28

n Medicolegal Issues in the Care of Patients with Neurologic Illness

Two weeks ago, a 22-year-old college student had a first seizure following a period of substantial sleep

deprivation (while preparing for college final exams) and heavy alcohol intake (after the last exam was completed).

Today, he is in his family doctor’s office and mentions that he drove to the physician’s office in his new car.

What should the family physician do? What are the key issues to consider? Will a neurologist help?

Make a medical judgment about what, if any, driving restrictions you believe are appropriate for this patient. Issues

to consider may include: the type of seizure; whether or not the patient is on medication; neurologic examination;

other medical conditions. A neurologist may be helpful in considering this issue. The patient asks if you will report

him to the state authorities? How will you respond?

Be aware that all states have laws about patients who drive and have episodes involving altered consciousness

and loss of motor control. Know the specific rules about driver licensing for your state. Check the Epilepsy

Foundation of America Web site or the Department of Motor Vehicles Web site for your state to make sure that

you are aware of the latest rules for your state. After checking your state’s requirements, if they seem overly

stringent, what are your medical options?

Advise the patient of your own medical advice regarding driving. Also, advise the patient of the relevant state rules

regarding driving. From a risk management perspective, you should not give the patient any advice or directives

that are less restrictive than the state law. If you believe that a less restrictive option is indicated in this patient,

you can offer to participate in a special petition to the relevant DOMV medical board but you must stress that the

state restrictions must be followed. The patient accepts this advice, but still wants to know if you are obligated to

report him to the authorities and even if you are not obligated, will you file a report to the driving bureau.

Advise the patient of any state reporting requirements that you, as the physician, must follow. These may include

mandatory reporting of the patient (with or without the patient’s consent) and completing inquiry forms from the

DOMV. Be honest with your patient and tell him exactly what you will do. Are there any other safeguards that you

should complete before the patient leaves?

Document your advice to the patient in the chart. Ideally, have the patient document his understanding of your

advice and make this part of the chart. Another potential option is to document your advice and have the patient

sign the chart page. If the patient drove himself to the office, ensure that the patient has an opportunity to call

family or friends for a ride home. After the patient leaves, you will need to complete state or local documentation

requirements if there are any. If your medical judgment is that less restrictive rules about driving should be applied

to this patient’s case, you can participate in the patient’s initiated request to the state for official review and

assignment of less restrictive rules.

FIGURE 28.1 Legal approach to a new patient with seizures who is driving.

585

Chapter 28

n Medicolegal Issues in the Care of Patients with Neurologic Illness

the patient has waived the information provi-

Always Remember

sion or when the physician has used the thera-

peutic privilege exception (which should be

• The most important risk management

used only cautiously). Answer C is incorrect—

practices for any physician are to maintain

although informed consent should be docu-

clinical competence and to employ excellent

mented, a specific form and witnessing is not

communication.

absolutely necessary. Informed consent forms

• While many neurologic diseases can be

may be useful in demonstrating consent, but

effectively managed by the primary care

they are not foolproof, and if they are not “user

physician, the diagnosis of death using

friendly,” they actually can do more harm than

neurologic criteria should only be made by a

good. In all cases, informed consent is invalid if

physician knowledgeable in the techniques

the person giving the consent is incompetent.

and experienced in making the diagnosis. In

order to avoid misdiagnosis, rigorous

2. An adult patient is competent to provide

adherence to practice parameters and any

consent unless he has been judged

institution-specific guidelines should occur.

incompetent in legal proceedings. True or

• While informed consent forms can be helpful

false?

in documenting a consent discussion, these

The above statement is false. A patient must

forms cannot, and should never, replace a

be both clinically and legally competent to

dialogue between the patient and the physician

provide informed consent. An adult patient is

about the medical intervention that is being

presumed to be legally competent unless he has

considered; the potential benefits and risks of

been found incompetent in judicial proceed-

the intervention; the alternatives to the

ings. Clinical competence is a medical deci-

intervention (including doing nothing) and the

sion. A patient may be clinically incompetent

potential benefits and risks of those alternatives;

although legally competent.

and a decision on the part of the patient.

• Physicians who have patients with seizure

3. A 50-year-old man is found collapsed on a

disorders, and other illnesses that can impact

city street by paramedics who initiate

awareness or motor control, must be aware

cardiopulmonary resuscitation and take

of their state’s licensing rules and comply with

him to the hospital. One hour later, he is in

those rules.

the emergency room on a ventilator, totally

unresponsive to all stimuli and without

brain stem reflexes. He has a completed

donor card. The most appropriate action at

QUESTIONS AND DISCUSSION

this time is:

A. To pronounce brain death and call the

1. For informed consent to be valid:

transplant team to come in and recover

A. Without exception, it must be given after

the organs

information is supplied to the patient in

B. To call the family to see if they agree

an understandable fashion.

with the organ donation

B. It must be given voluntarily.

C. To observe the patient in the emergency

C. It must be accompanied by a witnessed

department for 2 more hours to ensure

form.

that there is no change in the

D. The person providing consent does not

examination

have to be competent.

D. To transfer the patient to an intensive

The correct answer is B. Answer A is correct or-

care setting for further evaluation and

dinarily, but there are exceptions, namely when

workup

586

Chapter 28

n Medicolegal Issues in the Care of Patients with Neurologic Illness

The correct answer is D. There is no clear

The correct answer is E. Patient education is

etiology for this patient’s clinical condition;

an important aspect of handling driving restric-

there is no indication that conditions that can

tions because of uncontrolled seizures. When a

produce this clinical picture, but that might be

patient with uncontrolled seizures persists in

reversible (e.g., drug overdose), have been

driving despite warnings of the risk to self and

ruled out. It is unlikely that a complete exami-

others, the physician should inform the patient

nation to establish death (using neurologic cri-

of the need to report to the state. Some states

teria) has occurred in this setting. This patient

provide immunity for the physician who re-

should receive additional evaluation prior to

ports in these instances. Although not all states

being declared dead.

provide immunities, it is unlikely that a suit for

Although the family’s consent for organ

breach of confidentiality would be successful.

retrieval is not absolutely necessary in the pres-

In some states, a physician may be found liable

ence of a valid organ donor card, most physi-

for failing to report dangerous behavior on the

cians wish to obtain consent of next of kin

part of the patient.

prior to organ retrieval.

4. In a state with mandatory reporting of

persons with seizure disorders, the physician

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Index

Page numbers followed by f indicate figures; those followed by t indicate tabular material.

treatment of, 476

Abducens nerve (CN VI), 544

versus Wilson disease, 475

coma and, 95, 96

Acquired immunodeficiency syndrome (AIDS), 504

eye muscles and, 7

dementia and, 291

Abductor dysphonia, 243

Acute alteration of mental status, 69-74

Abnormal sensory weighting

causes of, 71

falls associated with, 435

cerebellar stroke and, 70-71

Abscess

characterizations of, 69

brain, 494-495

delirium and, 69

clinical features, 494

diagnostic testing for, 73

laboratory findings, 494

herpes simplex encephalitis and, 69-70

management and prognosis, 495

intracranial hematoma and, 70

in posterior temporal lobe, 495f

metabolic encephalopathies and, 71

symptoms, 494

neuroimaging and, 73

treatment of, 495

neurologic examination and, 73

Absence epilepsy

patient history and, 72

children and, 145

treatment of, 73-74

Abulia

Acute bacterial meningitis, 489-491

TBI and, 338

diagnosis of, 489

Academy of Neurology, 295

risk factors, 491

ACD. See Alcoholic cerebellar degeneration

treatment of, 489, 490-491

Acetazolamide

seizures, 490

Ménière disease and, 421

Acute demyelinating polyneuropathy

Acetylcholine receptor (AChR), 359

neurorehabilitation intervention and, 558

Acetylcholinesterase (AchE)

Acute disseminated encephalomyelitis (ADEM), 200

AD and, 298, 299

Acute epidural hematoma, 70

AchE. See Acetylcholinesterase

CT brain scan and, 70

Achilles tendon reflex, 11

Acute hospitalization

AChR. See Acetylcholine receptor

TBI and, 330

Acid maltase deficiency

Acute intermittent porphyria

McArdle disease and, 346t, 365

Guillain-Barré syndrome vs., 81, 82, 82t

Acoustic nerve (cranial nerve VIII), 8-9

Acute intracranial hypertension

assessment of, 9

causes of

dysfunction of, 9

herniation risks and, 75, 75t

testing methods, 9

cranium components of, 74

Acoustic neuroma

symptoms and signs of, 75, 76

neighborhood signs and, 424

treatment of, 76-77

Acquired hepatocerebral degeneration (AHCD)

Acute ischemic stroke

alcoholism and, 475-476

hierarchy of, 110, 110t

diagnosis, 475

interventional therapy for rt-PA and, 109

pathophysiology of, 475

Acute necrotizing hemorrhagic encephalopathy

symptoms and signs, 475

(ANHE), 200

588

589

Index

Acute neuroleptic-induced dystonia

Agitation

anticholinergics and, 458

TBI and, 336-338, 337f

neuroleptic therapy and, 458

AHCD. See Acquired hepatocerebral degeneration

risk factors for, 458

AHI. See Apnea-hypopnea index

Acute optic neuritis, 519

AICA. See Anterior inferior cerebellar artery

Acute peripheral vestibulopathy

AIDS (acquired immunodeficiency syndrome)

as cause of vertigo, 419-420

ICH and, 118

pharmacologic treatments for, 420f

AION. See Anterior ischemic optic neuropathy

Acute spinal cord compression

Akathisia

causes of, 77, 77t

anti dopaminergic agents and, 458

diagnosis of, 78

Akinesia

symptoms of, 77-78

Parkinson’s disease and, 231

treatment of, 78-79

Akinetic rigid syndrome, 226

Acute subdural hematomas, 70

Akinetic seizures, 144

Acyclovir

Albuterol

herpes simplex encephalitis and, 69

neurologic complications and, 456

side effects of, 448

Alcohol abuse

encephalitis, 493

due to cirrhosis, 474

viral meningitis and, 489

Alcoholic cerebellar degeneration (ACD)

AD. See Alzheimer’s disease

alcoholism and, 478

ADC. See Apparent diffusion coefficient

cerebellar abnormalities in, 478

ADD. See Attentional deficit disorder

Alcoholic dementia

Additives

alcoholism and, 478-479

neurotoxic effects of, 464-466

Alcoholic myopathy

ADEAR. See Alzheimer’s Disease Education and

versus alcoholic neuropathy, 481

Referral Center

alcoholism and, 480-482

ADEM. See Acute disseminated encephalomyelitis

as cause of muscle disease, 481

Adenocarcinoma

clinical syndrome of, 481

brain metastases and, 505

diagnosis, 481

Adenosine receptors

neurologic examination of, 481-482

caffeine and, 464

risk factors, 481

ADHD. See Attention deficit hyperactivity

treatment of, 482

disorder

Alcoholic neuropathy

Adie’s pupil, 536-537, 537f

alcoholism and, 479-480

Administrative law

due to thiamine deficiency, 480

health care and, 574

neurologic examination of, 479

Adrenergic drugs

prognosis, 480

neurologic effects of, 456

signs and symptoms, 479

Adrenergic receptors

treatment of, 480

three types of, 456

variant of, 480

Adult-onset craniocervical dystonia, 247

Alcohol intoxication, 470

Adult-onset primary dystonia, 247

acute alteration in mental status and, 71-72

Adults

cluster headache and, 131

precipitants of SE in, 65

coma and, 93t, 94

Advanced-sleep-phase syndrome, 170

dementia and, 291

AED. See Antiepileptic drug

early morning awakening, 170

Afebrile seizure, 143

hypnotic drugs and, 165

Affect

toxic myopathies and, 366

mania and, 3

Alcohol intoxification

Aging

ET and, 255, 258

falls increases with, 428

Aldolase, 354

590

Index

Alexander’s law

disequilibrium and, 423

for vestibular nystagmus, 547

gait examination with, 15

Alexia without agraphia

American Academy of Neurology

in cortical blindness, 529

concussive injury and, 339

Alkaline phosphatase, 406

laboratory and, 40

Almotriptan

Parkinson’s therapy and, 229

migraine and, 134

American Congress of Rehabilitation Medicine,

Alpha agonist midodrine

338, 339f

orthostatic hypotension and, 414

Amikacin

Alpha EEG arousal, 175

side effects of, 447

Alpha-fetoprotein, 507

Aminoglycoside antibiotics

Alpha receptors

disequilibrium and, 424

prazosin and, 453

neurotoxic effects of, 447

Alprazolam

Aminoglycosides hearing loss, 447

ET and, 258, 259

Aminophylline

MS and, 217

bronchoconstriction and, 456

sleep and, 164

Amiodarone

ALS. See Amyotrophic lateral sclerosis

neurotoxic effect of, 452

Alternative therapies

Amitriptyline (Elavil), 339

MS and, 218

early morning awakening and, 170

sleep cycle and, 166

MS and, 217

Alveolar hypoventilation syndrome

Ammonia, 6

OSA and, 174

Amniocentesis

Alzheimer, A.

Becker dystrophy, 362

dementia and, 287

Amphetamines

Alzheimer’s Association, 301

ICH and, 118

Alzheimer’s disease, 287, 320, 526

narcolepsy and, 180

alternative treatments for, 300

Amphotericin B

ancillary tests, 294-295

systemic fungal infection and, 447

clinical symptoms of, 292-294

Amsler grid

community resources for, 301-302

MS and, 202

diagnosis of, 293-294

Amyotrophic lateral sclerosis (ALS), 351f,

epidemiology of, 292

358-359, 385

hospitalized patients and, 302, 303

cause of, 358

MCI and, 288

family history of, 358-359

neurologic examination and, 293-294

pseudobulbar affect in, 359

pathology of, 295-297

weakness and, 358

prognosis, 302

Anaerobic bacteria

treatment of, 298-301, 298f

in brain abscesses, 494

pharmacologic, 300-301

Analgesics

Alzheimer’s Disease Education and Referral Center

rebound headache and, 130, 130t

(ADEAR), 301

Anaplastic astrocytoma

Amantadine

radiation therapy and, 501

HD and, 265

therapeutic agents for, 501

Parkinson’s disease and, 228

Anesthesia

side effects of, 448

hypersomnia and, 184

sleep-wake cycle and, 331, 331t

malignant hyperthermia and, 366

TD syndrome and, 283

MS and, 217

Amaurosis fugax, 528

treatment of refractory SE and, 68

AmBisome, 492

Aneurysmal rupture, 120

Ambulation

complications of, 121t

591

Index

Aneurysmal sac

Anticholinergics

cerebral aneurysms and, 121

acute neuroleptic-induced dystonia, 458

Aneurysmal subarachnoid hemorrhage

dystonia and, 252

epidemiology and, 120

Anticoagulant therapy

Angiography

in ischemic stroke, 116

catheter, 36-37

TEE and, 112

magnetic resonance, 36

Anticonvulsants

Angiotensin-converting enzyme inhibitors

disequilibrium and, 424

neurologic effect of, 454

in vestibular dysfunction, 424

RAA axis for, 454

Antidepressant agents

ANHE. See Acute necrotizing hemorrhagic

neurologic effects of, 459-461

encephalopathy

Antidiarrheals

Anisocoria, 532-537

neurologic effects of, 455-456

Horner syndrome, 532-535, 533f

Antidopaminergics, RLS and, 171

in light and darkness, 532, 532f

Antiemetics

pharmacologic dilation, 537

neurologic effects of, 455

physiologic, 532

Antiepileptic drugs (AED)

third nerve palsy mydriasis, 535-536, 535f

discontinuing, 153

tonic pupil, 536-537, 537f

individual, 151-152

“Ankle jerk.” See Achilles tendon reflex

levels of, 150-151

Anosagnosia, 24

for management of HSE, 70

Anoxia

properties of, 150t

comatose patient and, 100

SE and, 66

Anoxic injury

seizures and, 148

and TBI, 326

Antifungal agents

Antacids, aluminum

neurologic effect of, 447

neurologic symptoms from, 456

Antiinflammatory agents

Antacids, magnesium

hormones, 463-464

neurologic symptoms from, 456

neurologic effects of, 461-466

Antalgic gait, 27

nonsteroidal agents, 463

Anterior horn cells, 355, 359

salicylate compounds, 461-462

Anterior inferior cerebellar artery (AICA)

steroids, 462-463

vertigo and, 422

vitamins and additives, 464-466

Anterior ischemic optic neuropathy (AION), 528

Antineuronal specific antibodies, 512, 513t

Anterocollis, 248

Antiretroviral medications

Antiacidity agents

neurologic effect of, 449

neurologic effects of, 456

Antituberculous drugs

Antianginal agents

neurologic effect of, 447-448

neurologic effect of, 451

Antiviral drugs

Antiarrhythmics

neurologic effect of, 448

neurologic effect of, 451-452

Anton syndrome

Antibiotics

in cortical blindness, 529

aminoglycosides, 447

Anxiety

antifungal agents, 447

MS and, 217

antituberculous drugs, 447-448

Anxiolytics

antiviral drugs, 448

neurotoxic effects of, 459

bacterial meningitis and, 489, 490t

Aortic stenosis

brain abscess and, 495

exercise-related presyncope and, 415

cephalosporins, 447

Aphasia, 3, 22

penicillins, 447

Apnea

Antibody testing, 386

coma and, 94

592

Index

Apnea-hypopnea index (AHI)

temozolomide for, 501-502

sleep apnea severity and, 175

treatment of, 501-502

Apnea testing

Asymmetric extensor toe signs

brain death and, 580

coma and, 98

Apneustic respiration

Ataxia, 14

coma and, 94

acquired causes of, 433

Apolipoprotein e4 allele

AED and, 151

AD and, 288, 292

falling associated with, 432-433

Apoptic cell death

medical treatment for, 439

HD and, 264

gait disorders and, 28

Apparent diffusion coefficient (ADC), 35

inherited causes of, 432-433

Appearance and behavior

midline cerebellar dysfunction and, 14

mental status examination and, 2

phenytoin and, 151

Apraclonidine

in vertigo, 417

for glaucoma, 534

Ataxic gait, 15

Aqueductal stenosis, 50f

Ataxic respirations

Arbovirus

coma and, 94-95

encephalitis and, 496

Atherosclerosis

Areflexia

ischemic stroke and, 114

Adie’s pupil and, 536, 537f

Atherosclerotic plaque

Guillain-Barré syndrome and, 12, 81

ischemic stroke risk and, 114

Argyll Robertson pupils, 538

Atonic seizures, 144

Aripiprazole

ATP7B

TD syndrome, 281

WD and, 269

Arrhythmia

Atrophy of muscles, 351-352

cardiac presyncope and, 415

Atropine

Arteriovenous malformations (AVMs), 34, 106

for cardiac arrhythmias, 537

embryonal development and, 121-122

pupillary size and, 95

Arthritis

Attentional deficit disorder (ADD), 461

medication side effects of, 463

Attention deficit hyperactivity disorder (ADHD)

Artificial hyperventilation, 413

GTS and, 275, 278

Aseptic meningitis

Auditory toxicity

ibuprofen and, 463

drugs and, 447

Asomatagnosia, 24

Auras, 144

Aspiration

Autoimmune disease

management of

MS and, 196

neurologic illness and, 557

Autoimmune process

Aspirin

systemic cancer and, 512, 512t

ischemic stroke and, 116

Automatisms

stroke prevention and, 115

TLE and, 310

Assistive device

Autonomic dysfunction

fall prevention by, 441-442

neurorehabilitation intervention and, 558

Asterixis

Autonomic dysreflexia

in hepatic encephalopathy, 474

neurorehabilitation intervention and, 558

Asthma

Autonomic neuropathies

propranolol and, 257

orthostatic hypotension and, 414

Astrocytoma, 500-502

Autosomal recessive disorder, 366

chemotherapy for, 501

AVMs. See Arteriovenous malformations

clinical presentation, 500-501

Avonex

diagnosis, 501

MS and, 209, 210, 211, 212

Kernohan grading system of, 500

Axial dystonia, 243

radiation therapy for, 501

Axon

593

Index

and TBI, 326

Becker dystrophy, 361-362

Azathioprine

Behavior

MG and, 360

mental status examination and, 2

Azithromycin

Behavioral disorders

neurotoxicity and, 449

GTS and, 275

severe

TBI and, 341

Behavioral neurology

Babinski’s sign, 10, 12

anatomic lesions of, 311-312

HD and, 260

etiology of, 312

MS and, 202

overview, 307-308

Backward spelling

Papez circuit, 308-309, 308f

for working memory testing, 3

refer neurologists, 312-313

Baclofen

TLE and, 309-311

dystonia and, 253

Behavioral sequelae

spasticity treatment and, 214t, 215, 439

of TBI, 325

Bacterial endocarditis

Behavioral therapies, insomnia and, 161-162

blood cultures and, 112

Bell palsy, 8, 386, 540

as complication of tumor therapy, 510

Benign paroxysmal positional vertigo (BPPV),

Bacterial meningitis, 489-491

418-419, 433

focal neurologic signs of, 489

treatment of, 418

infecting organisms in

Benzodiazepines, 333

initial antibiotic therapy for, 490t

acute alteration in mental status and, 74

Bacteroides fragilis

alcohol and

brain abscess and, 494

acute alteration in mental status and, 72

BAEP. See Brainstem auditory evoked potential

disadvantage of, 68

BAER. See Brainstem auditory evoked response

dystonia and, 253

Balance disorders, 27

liver function and, 166

Balance Evaluation Systems Test (BESTest), 440

neurologic effects of, 459

Balance systems

SE and, 65, 66, 68

constraints on, 434, 434t

sleep and, 162

falling associated with, 434-437

for spasticity, 439

Balance tests, 15, 440

in vestibular dysfunction, 424

Balance training

Berg Balance Scale, 439-440

fall prevention by, 440

BESTest. See Balance Evaluation Systems Test

Balint syndrome, 530

Beta-blockers

Barbiturates, 150, 153

head injuries and, 335

neurologic effects of, 461

migraine and, 135

Barotrauma

MS and, 216

perilymph fistula syndrome and, 421

side effects of, 258

Basal ganglia

TBI and, 337

dystonic movements and, 243

Beta human chorionic gonadotropin, 507

GTS and, 276

Beta interferons (IFNα)

HD and, 264

MS and, 210-211, 210t

postural stability, 14

Betaseron

Basal skull fracture, 94

MS and, 209, 210

Basilar migraine

Bevacizumab, 511

in vertigo, 423

Bilateral decerebrate posturing

Basiliximab

coma and, 98

neurologic effect of, 450

Bilateral light-near dissociation, 537-538

Battle’s sign

Argyll Robertson pupils, 538

coma and, 94

Parinaud syndrome, 538

594

Index

Bilevel positive airway pressure (BiPAP), 80

cervical dystonia and, 253

sleep apnea and, 178

ET and, 259

Bilevel positive airway pressure in spontaneous-timed

Botulinum toxin B

mode (BPAP-ST)

cervical dystonia and, 253

central sleep apnea and, 178

Botulism

Biofeedback

Guillain-Barré syndrome vs., 82, 82t

primary headaches and, 133

Bowel dysfunction

Biopsy

MS and, 204

of brain tissue, 39

treatment in, 216

muscle, 39-40, 357

neurorehabilitation and, 556

oculopharyngeal dystrophy, 363

BPAP. See Bilevel positive airway pressure

nerve, 39-40, 357

BPPV. See Benign paroxysmal positional vertigo

skin, 40

Brachial dystonia, 243

Biopterin

Brachial plexus, 376

DRD and, 251

terminal nerves of, 378

BiPAP. See Bilevel positive airway pressure

Bradykinesia

Bitemporal hemianopias, 6, 522-523

levodopa induced dyskinesia v., 231

Bitter orange (Citrus aurantium)

Parkinson’s disease and, 225

ephedrine and, 183

Brain

Bladder dysfunction

evaluation of, 47

MS and, 203-204

MS, 204, 205t

treatment of, 215-216

Brain abscess, 494-495

neurorehabilitation and, 556

clinical features, 494

Blepharospasm, 243, 247

dementia and, 291

features aggravating, 247

laboratory findings, 494

GTS and, 273

management and prognosis, 495

myectomy of orbicularis oculi for, 253

in posterior temporal lobe, 495f

toxic injection for, 253

symptoms, 494

Blepharospasm-oromandibular dystonia syndrome.

treatment of, 495

See Meige syndrome

Brain biopsy, 39

Blindsight

Brain death

in cortical blindness, 529

aspects determining, 578-581

Blinking

diagnosis of, 578-581

coma and, 95

laws governing, 578-581

Blood-brain barrier

Brain hemorrhage

levodopa and, 227

low platelet count and, 118

Blood pressure

Brain herniation

stroke and, 107, 114

mass lesions associated with, 75, 75t

Blood urea nitrogen (BUN)

Brain injury. See also Traumatic brain injury

comatose patient and, 99

low-level, 331

Bony spine pain, 402

postacute hospitalization, 331

Borrelia burgdorferi, 491

primary generalized epilepsies and, 144-145

Botulinum toxin (BoNT)

RLA and, 328

dystonia and, 253

severity of, 329f

focal dystonias and, 253, 254

Brain metastases, 507f

GTS and, 278

chemotherapy for, 506-507

injections of

diagnosis of, 506

spasticity, 439

radiation therapy for, 506

TD syndrome, 283

risk factors, 505

migraine and, 136

signs and symptoms, 506

Botulinum toxin A (Botox)

treatment of, 506-507

595

Index

Brain scan. See also Computed tomography

intracranial metastases, 504-507, 505f

imaging; Magnetic resonance imaging

leptomeningeal metastases, 507-509

AD and, 294

spinal metastases, 509-510

Brainstem auditory evoked potential (BAEP), 38

nonmetastatic complications

Brainstem auditory evoked response (BAER), 38

cerebrovascular, 510-511

MS and, 208

metabolic and nutritional, 511

Brainstem lesions

paraneoplastic syndromes, 511-512, 513t

characteristics of, 24

primary CNS lymphoma, 504

Brainstem reflexes

primary CNS tumors

brain death and, 580

astrocytoma, 500-502

Brain tumor

ependymoma, 502-503

dementia and, 290

meningiomas, 503

Breathing

oligodendroglioma, 502

sleep apnea and, 175, 177

radiation therapy, complications from, 512-513

Bretylium

Cane

neurologic effect of, 452

fall prevention by, 441-442

Broca aphasia, 3

Carbamazepine, 340

Bromocriptine

dystonia and, 252-253

Parkinson’s disease and, 227

seizures and, 151

Parkinson’s therapy and, 229

Carbidopa

sleep-wake cycle and, 331, 331t

Parkinson’s disease and, 227

TD syndrome, 283

Carbidopa-levodopa (Sinemet)

Brun’s nystagmus, 547

complications of, 230-232

BuChE. See Butyrylcholinesterase

dosage of, 238

Bulbar dysfunction

Parkinson’s disease and, 229, 232

pneumonia, 370

RLS and, 168

BUN. See Blood urea nitrogen

side effects of, 168

Bupropion

sleep-related eating disorders and, 186

MS and, 217

toxicity associated with, 230t

Butyrophenones

Carcinoembryonic antigen, 507

HD and, 265

Carcinomatous meningitis, 506

Butyrylcholinesterase (BuChE)

Cardiac arrhythmias

AD and, 299

seizures vs., 149

status epilepticus and, 65

Cardiac complications

neuromuscular disorder and, 370

Caffeine

Cardiac conduction block

herbal medicinal products with, 183

DMI and, 363

neurotoxic effects of, 464-465

Cardiac conduction disturbances

Caffein-halothane contracture test

in myotonic dystrophy, 370

for malignant hyperthermia, 366

Cardiac drugs

CAG. See Cytosin-adenin-guanine

angiotensin-converting enzyme inhibitors, 454

CAG trinucleotide repeat

antianginal agents, 451

huntingtin protein and, 263, 264

antiarrhythmics, 451-452

Calcium channel blockers

cholesterol-lowering agents, 454

GTS and, 278

diuretics, 452-453

migraine and, 135

glycosides, 450-451

neurologic effect of, 453

sympatholytics, 453

Cancer, 499

vasodilators, 453

challenges for, 513

Cardiac dysrhythmias

metastatic complications of systemic

phenytoin IV and, 66

596

Index

Cardiac evaluation

complications of, 68

embolism and, 112

convulsive, 64

Cardiac presyncope, 415

CT brain scan and, 68

Cardiogenic attacks

defined, 64

seizures vs., 149

morbidity, 64

Cardiogenic stroke, 106

mortality rate, 64

Cardiovascular diseases and OSA, 174

nonconvulsive, 64

Carnitine deficiency

patient history and, 68

symptoms of, 366

precipitants of, 65

Carnitine palmitoyl transferase deficiency

refractory, 68

(CPT II), 365

treatment of, 65-69, 66t, 67t

Carotid dissection syndromes

type of, 64

secondary headache disorders and, 137

WD and, 268

Carotid endarterectomy

Central neurogenic hyperventilation

stroke prevention and, 113, 115

coma and, 94

Carotid ischemia

Central pontine myelinolysis (CPM)

vertebrobasilar distribution ischemia vs., 113, 113t

alcoholism and, 477

Carotid sinus hypersensitivity

signs and symptoms, 477

as cause of presyncope, 415

treatment of, 477

Carotid syndromes

Central scotoma, 521

headache and, 137

Central sleep apnea

Carpal tunnel syndrome (CTS), 380, 392

respiratory control and, 174

Case law, 573

treatment of, 178

Cataplexy, 179

v. OSA, 174

tricyclic antidepressants and, 183

Central vertigo, 416-417, 416t, 421

Catathrenia, 186

associated with brainstem, 417

Catechol-O-methyltransferase (COMT)

causes of

Parkinson’s disease and, 227

basilar migraine, 423

Catechol-O-methyltransferase (COMT) inhibitors

cerebellar hemorrhage, 422-423

Parkinson’s disease and, 230, 232

lateral medullary ischemia, 422

Catheter angiography, 36-37

lateral pontine ischemia, 422

Catnip (Nepeta cataria)

multiple sclerosis, 423

sleep cycle and, 166-167

transient ischemic attack, 422

Cauda equina syndrome, 402

cerebellar signs in, 417

surgical consultation, 406

Centrocecal scotoma, 521

CBF. See Cerebral blood flow

MS and, 202

CBGD. See Corticobasal ganglionic degeneration

Cephalosporins

Celecoxib

neurologic effect of, 447

AD and, 300

Cerebellar hemorrhage

Centers for Medicare and Medicaid Services,

in vertigo, 422-423

295, 297

Cerebellar kinetic tremor, 256-257

Central herniation syndrome, 75

Cerebellar outflow rubral tremor, 257

Central integration, abnormalities of

Cerebellar stroke, 70-71

in disequilibrium, 424

acute alteration of mental status and, 70-71

Central nervous system (CNS), 45, 91, 375

management of, difficulties in, 70-71

lesions

Cerebellar tremor

MS and, 204

types of, 256-257

MS and, 192

Cerebellum

secondary dystonia and, 251

disorders of

status epilepticus, 63-65

ataxic gait and, 27

causes of, 64, 65

metastasis of, 507f

597

Index

Cerebral achromatopsia, 530

Channelopathies, 363

Cerebral aneurysm

affecting skeletal muscle, 364

anterior circulation and, 120

Charcot-Marie-Tooth disease, 381, 387

Cerebral aneurysm, ruptured

Charles Bonnet syndrome

clinical manifestations of, 120-121

in cortical blindness, 529

complications of, 121t

Chelation therapy

Cerebral arteriography

Parkinson’s disease and, 236

aneurysm and, 120, 120f

WD and, 272

Cerebral blood flow (CBF)

Chemotherapy

intracranial hypertension and, 74

neurotoxicity of, 512t

Cerebral dysfunction

Cheyne-Stokes respiration

acute alteration in mental status and, 71

coma and, 94, 99t

Cerebral hypoperfusion

CHI. See Closed-head injury

intracranial hypertension and, 74

Chiari malformation

Cerebral infarction

MS v., 209

consciousness and, 91

Chiasmal injury, 522-523, 522f

secondary dystonia and, 251

Childhood-onset dystonia, 242

Cerebral perfusion pressure (CPP)

Children

intracranial hypertension and, 74

anticholinergics and, 252

Cerebral somatostatin

delayed-onset dystonia in, 251

dystonia and, 252

disorders of arousal and, 185

Cerebral vascular accident (CVA)

DM and, 363, 364

pallidotomy and, 233

DUD and, 362

Cerebral venous occlusion

epilepsy syndromes in, 145

headache and, 137

hypnotic drugs and, 165-166

secondary headache disorders and, 137

neuroleptics and

Cerebrospinal fluid (CSF), 65, 332, 389

tics and, 278

Alzheimer’s disease and, 288

neuromuscular disease and, 367-368

CNS infections and, 496

phenytoin and, 151

inflammation and

seizure and, 144, 146

PP-MS and, 198

EEG diagnoses of, 148

lumbar puncture and, 70

with type 2 SMA, 368

neoplastic meningitis and, 507-508

Cholesterol-lowering agents

Cerebrospinal fluid (CSF) pressure

neurologic effects of, 454

secondary headache disorders and, 137

Cholinergic crisis, 79

Cerebrospinal fluid rhinorrhea

Cholinesterase inhibitors

coma and, 94

AD and, 299

Cerebrovascular complications

Chorea, 242, 464

as result of malignancy, 510-511

HD and, 260, 261, 265

Ceruloplasmin

Parkinson’s disease and, 230, 231

WD and, 268

TD syndrome and, 283

Ceruloplasmin level

Chorea, 11

WD and, 269

Choreiform movement disorders, 251, 285

Cervical dystonia, 243, 248-249, 248f, 249f

HD and, 260

BoNT and, 253

Parkinson’s disease and, 237

characterization of, 248, 248f

TD syndrome and, 280, 283

ET v., 256

Chorionic villus biopsy

factors that exacerbate, 248-249

Becker dystrophy, 362

Cervical neck fracture

Chromosome

coma and, 94

disorder and, 358

Cervical spine, 400f

Chromosome 5, 358

598

Index

Chromosome 19

neurologic effect of, 453

AD and, 292

TD syndrome and, 283

Chronic active hepatitis

Clopidogrel

WD and, 267

stroke prevention and, 115

Chronic daily headache

Closed-head injury (CHI), 330

clinical subtypes of, 130

Clozapine, 238

Chronic disulfiram therapy, 461

dystonia and, 253

Chronic inflammatory demyelinating polyradicu-

ET and, 259

loneuropathy (CIDP), 39, 390

GTS and, 277

Chronic insomnia, 160

HD and, 265, 266

Chronic migraine, 129

HD related psychosis, 266

comorbid conditions with, 129

neurologic effects of, 457-458

Chronic obstructive lung disease

Parkinson’s disease and, 231

propranolol and, 257

TD syndrome and, 279, 281, 282, 283

Chronic paroxysmal hemicrania (CPH)

Cluster breathing

indomethacin and, 137

coma and, 94

treatment of, 137

Cluster headache

Chronotherapy, 161

clinical features of, 131

CIDP. See Chronic inflammatory demyelinating

migraine headache vs., 131, 131t

polyradiculoneuropathy

treatment for, 136-137

Cimetidine (Tagamet)

acute, 136t

neurologic effects of, 456

preventive, 136, 136t, 137

Cinnarizine

CNPase. See Cyclic nucleotide

neurologic effect of, 453

3′-phosphohydrolase

Ciprofloxacin, 491

CNS. See Central nervous system

Circadian rhythm sleep disorders, 160

CNS infections, 486-496

Cirrhosis

brain abscess, 494-495

alcohol abuse due to, 474

encephalitis, 492-494

WD and, 267

identification of, antibiotic therapy for, 490t

Cisplatin, 511

meningitis, 487-492

Citalopram

prion diseases, 495-496

MS and, 217

spinal fluid profiles in, 488t

CJD. See Creutzfeldt-Jakob disease

CNS lymphoma, primary, 504

Clarithromycin

CNS tumors, primary

neurologic effect of, 449

astrocytoma, 500-502

Claude syndrome, 542

ependymoma, 502-503

Clinical competence

meningiomas, 503

medical decision of, 575

oligodendroglioma, 502

Clofibrate

Cocaine, 534

neurologic effects of, 454

ICH and, 118

Clomipramine

Coccyx, 399

cataplectic attacks and, 183

Cochlear nerve, 8

Clonazepam

Coenzyme Q10

dystonia and, 253

HD and, 265

ET and, 258, 259

Cognition

GTS and, 278

abnormalities of, 4-5

RBD and, 186

Cognitive domains, primary

sleep-related eating disorders and, 186

executive function, 3

Clonidine

memory, 3-4

adverse effects of, 278

perceptual disturbances, 4

GTS and, 278

speech and language, 2-3

599

Index

Cognitive function

aneurysm and, 120, 120f

old age and, 287

rapture of, 120-121

Cognitive therapy

comatose patient and, 100

insomnia and, 162

DBS and, 259

primary headaches and, 133

rt-PA and, 109, 115, 116t

Cogwheel rigidity

SAH and, 109

Parkinson’s disease and, 225, 232

SE and, 68

Collagen vascular disease

VaD and, 296

inflammatory myopathy and, 364

WD and, 270

Color desaturation, in eye, 517

Computed tomography (CT) scan

Color vision test, 517-518

intraparenchymal hemorrhage on, 326

Coma. See also Hepatic coma

spine and, 405

anatomy of, 91

TBI and, 326

causes of, 92t, 93t

COMT. See Catechol-O-methyltransferase

clinical examination with, 93-99

Concussive injury, sports-related grade of,

emergency treatment for, 99

339-340

etiology of, 91-93, 92t, 93t

Conduction velocity (CV), 383

laboratory evaluation of, 99, 100t

motor responses with, 383f

patient history and, 93

Congenital muscular dystrophy

pentobarbital and, 330

symptoms of, 346t

prognosis of, 102

Congenital myopathies, 367

states of, 90

Conjugate gaze abnormalities

treatment of, 99-101

horizontal gaze palsies, 539-541, 540f, 541f

Coma recovery score, 331

supranuclear vertical gaze palsy, 541-542

Comatose patient

Conjugate vision pathways, 95, 96f

treatment of, 101t

Consciousness, defined, 90

Comatose patient, 2

Constipation

Communicating hydrocephalus, 49

MS and, 204, 216

Complete blood count (CBC)

Content

comatose patient and, 99

abnormalities of, 4

SAH and, 109

Context-specific instability, 436

sleep apnea and, 175

Continuous positive airway pressure (CPAP)

Complex motor tics, 273

hypersomnia and, 184

Complex partial seizures, 144

OSA and, 177

phases of, 146

Contractures

Complex sleep apnea, 174

rehabilitation and neuromuscular diseases

Complex vocal tics

and, 368

GTS and, 273

Contrast agents

Computed tomographic angiography (CTA), 36, 46

gadolinium-based, 47

infarct evaluation and, 59, 60f

versus noncontrast agents, 46-47

Computed tomography (CT), 34-35

Contusion, hemorrhagic

advanced techniques for, 46

TBI and, 325

contrast agents used in, 46-17

Convulsions

infarct evaluation and, 56-60

temporal lobe injury and, 146

versus MRI, 44-46, 45f

Coordination, 14-15

in pregnant patients, 46

neurologic examination and, 1, 1t

Computed tomography (CT) imaging

pediatric neurology and, 16

acute epidural hematoma and, 70

Copaxone

acute spinal cord compression and, 78

MS and, 210t, 211

acute stroke evaluation and, 110

Copper

AD and, 294

WD and, 266, 268, 269

600

Index

Coprolalia

Cryptococcus neoformans, 491

GTS and, 273

CSF. See Cerebrospinal fluid

Copropraxia

CSF analysis

GTS and, 273

MS and, 206-208

Cord infarct, 402

CT. See Computed tomography imaging

Cortical sensory functions

CTA. See Computed tomographic angiography

sensory examination and, 14

CT imaging. See Computed tomography imaging

Cortical vision loss, 529

CT myelogram, 405

Corticobasal ganglionic degeneration (CBGD)

CTS. See Carpal tunnel syndrome

as cause of parkinsonism in falling, 432

Cumulative cardiotoxicity

Corticospinal tracts

mitoxantrone and, 211

lesions of, 24

Cup test

Corticosteroids

tremor and, 255

acute intracranial hypertension and, 76

Cutaneous root distribution

acute spinal cord compression and, 78

sequential nature of, 377

for brain metastases, 506

Cutaneous sensation

comatose patient and, 100

pathways for, 25-26

complications of, 511t

CV. See Conduction velocity

for dermatomyositis, 365

CVA. See Cerebral vascular accident

MS and, 213, 214-215

Cyclic nucleotide 3′-phosphohydrolase (CNPase)

myasthenic crisis and, 80

MS and, 195

use in cancer, 511

Cyclosporine

Counseling

neurologic effect of, 449-450

sleep disorders and, 161

Cytochrome c oxidase (COX), 366

COX. See Cytochrome c oxidase

Cytosin-adenin-guanine (CAG), 358

CPH. See Chronic paroxysmal hemicrania

Cytotoxic edema, 51f

CPK. See Creatinine phosphokinase

versus vasogenic edema, 50-51

CPM. See Central pontine myelinolysis

CPP. See Cerebral perfusion pressure

CPT II. See Carnitine palmitoyl transferase

deficiency

Daclizumab

Cramps, occupational, 250

neurologic effect of, 450

Cranial dystonia, 247-248

DAI. See Diffuse axonal injury

Cranial nerve(s)

DAP. See 3,4-diaminopyridine

functions of, 5-6, 5t

Dapsone, 387

neurologic examination, 1, 1t

Datura stramonium, 537

pediatric neurology and, 16

DBS. See Deep brain stimulation

Cranial nerve VIII. See Acoustic nerve

DDAVP. See Desamino-D-arginine vasopressin

Cranial neuropathy, 21, 21t

Death

C-reactive protein (CRP), 406

physicians and, 371

C-reactive protein (CRP) level

Decerebrate (extensor) posturing

stroke and, 113

coma and, 98

Creatinine phosphokinase (CPK), 84

midbrain dysfunction and, 98

Creutzfeldt-Jakob disease (CJD), 37, 292, 298,

Decorticate posturing

495-496, 526

coma and, 98

variant of, -496

Deep brain stimulation (DBS)

CRP. See C-reactive protein

dystonia and, 253

Crural dystonia, 243

ET and, 259

clinical presentation in, 246

Parkinson’s disease and, 233

Cryptococcal meningitis

Deep hemispheric lesions, 24

dementia and, 291

Deep tendon reflexes (DTRs), 11-12

601

Index

grading, 11-12, 11t

patient history and, 289

neurologic examination of, 1, 1t

of pellagra, 472-473

pediatric neurology and, 16

treatment of, 298, 298f

segmental innervation of, 11t

Dementia with Lewy bodies (DLB), 291, 296-297

Deep vein thrombosis

diagnosis of, 297

neurorehabilitation and, 556

Demyelination

Defibrillator

MS and, 194, 194f, 195

cardiac complications and, 370

Dental structures

Deformities

headache and, 137

neuromuscular disorder and, 354, 354f

secondary headache disorders and, 137, 137t

Degenerative osteoarthritis

Department of Motor Vehicle (DOMV)

cervical dystonia and, 249

seizures and, 582-583

Dehydration

Depression, 341

neurorehabilitation and, 555-556

dementia and, 290

Delayed-onset dystonia

dystonia and, 252

children and, 251

early morning awakening and, 170

Delayed postural response latencies, 434

MS and, 203

Delayed sleep-phase syndrome, 160

treatment of, 216-217

Delayed-type hypersensitivity (DTH) reaction

reserpine and, 283

MS and, 197

seizures and, 146

Delayed word recall

sign of, 3

for long-term memory testing, 3

St. John’s wort (Hypericum perforatum) and, 166

Delirium, 69

WD and, 267

acute alteration of mental status and, 69

“Dermatitis” of pellagra, 473

dementia vs., 290

Dermatomyositis (DM), 40, 364-365

diagnosis of, 69

PM v., 364

differential diagnosis of, 69

Dermatomyositis (DM), juvenile

drug toxicity and, 291

symptoms of, 364-365

hyperactive, 69

Desamino-D-arginine vasopressin (DDAVP)

hypoactive, 69

sleep-related enuresis and, 186

subtypes of, 69

Desmopressin

treatment of, 73-74

MS and, 216

Delusions, 4

Devic disease, 199-200

Demand pacemaker

Dexamethasone, 490, 492

neuromuscular disorder and cardiac

acute intracranial hypertension and, 76

complications in, 370

Dextroamphetamine

Dementia

narcolepsy and, 180

alcoholic, 478-479

Diabetes mellitus

algorithm, approach to memory concern,

propranolol and, 257

289, 289f

stroke and, 106

brain tumor and, 290

Diabetes mellitus, neuropathy with, 390-392

causes of, 290

natural history of, 391

defined, 288

nerve dysfunction of, 390

delirium vs., 290

pathogenesis of, 391

depression and, 290

Diagnostic and Statistical Manual of Mental

differential diagnosis of, 289

Disorders, 4th edition (DSM IV), 69

laboratory aids in, 294t

Diagnostic testing

evaluation for, 288

acute alteration of mental status and, 73

HD and, 260

secondary headache disorders and, 137-138,

neurologic examination and, 290

137t

Parkinson’s disease and, 234-235

3,4-diaminopyridine (DAP), 361

602

Index

Diazepam

Distal axonal projections, 375

dystonia and, 253

Disulfiram, 387

MS and, 217

neurologic effects of, 461

SE and, 66

Diuretics

sleep and, 164

as cause of orthostasis, 414

Didanosine

neurologic effect of, 452-453

neurologic effect of, 449

stroke prevention and, 114

Diet

Dix-Hallpike positional test, 418, 418f

epilepsy and, 153

Dizziness

MS and, 218

categories of, 412-413

Parkinson’s disease and, 232

disequilibrium, 413

Diffuse axonal injury (DAI), 325

overview, 412

Diffuse brain injury

presyncope, 412-413

seizures and, 146

causes of, 413-415

Diffusion-weighted imaging (DWI), 35, 44

as symptom of cerebrovascular disease, 412

acute stroke evaluation and, 111

vertigo. See Vertigo

Digit span

DLB. See Dementia with Lewy bodies

for measurement of working memory, 3

DM. See Dermatomyositis

Diphenhydramine, 335

DM1. See Myotonic dystrophy 1

Diphenoxylateatropine (Lomotil)

DNA tests

neurologic effects of, 455-456

myotonia congenita and, 364

Diphtheric neuropathy

Docusate sodium (Colace)

Guillain-Barré syndrome vs., 82, 82t

neurologic effects of, 455

Diplopia, 79, 528-529

DOMV. See Department of Motor Vehicle

horizontal, 545f

Donepezil

Disablement

AD and, 299

aspects of, 551t

GTS and, 278

neurologic conditions and, 552-553

Dopamine

process of, 552f

DRD and, 252

Discharge planning

GTS and, 276

neurorehabilitation and, 564-566

loss of, 239

Disc herniation, 400-401

Parkinson’s disease and, 227, 228, 229

at L4-5, 401f

TD syndrome and, 280-281

Disease-modifying therapy

Dopamine agonists

Parkinson’s disease and, 234-235

HD and, 265

Disequilibrium

Parkinson’s disease and, 228t, 229

causes of

RLS and, 168

abnormalities of central integration, 424

TD syndrome and, 280, 283

abnormalities of motor response, 424-425

tics syndrome and, 277

loss of proprioception, 423-424

Dopamine receptor

vestibular dysfunction, 424

drug-induced Parkinsonism, 233-234

visual dysfunction, 423

TD syndrome and, 280, 281, 282

Dislocations

Dopaminergic therapy

prevention of

choreiform movement, 237

neurorehabilitation intervention and, 557-558

psychiatric side effects of, 231

Disorders of arousal

Dopaminergic ventrotegmental area (VTA)

parasomnias and, 185

sleep and, 156, 157

Disorders of partial arousal

Dopamine transporter single-photon emission

parasomnias and, 184

computed tomography (SPECT)

Disorders of sleep-stage transition

DRD and, 251

parasomnias and, 184

Dopa-responsive dystonia (DRD)

603

Index

clinical features of, 250-251

DWI. See Diffusion-weighted imaging

genetic links of, 251

Dynorphin

Downbeat nystagmus, 547

GTS and, 276

D-penicillamine

Dysarthria

WD and, 270

treatment goals for, 563

Driving restrictions

WD and, 267

epilepsy and, 583

Dysarthric speech, 2

Droperidol

Dysautonomia

neuroleptic malignant syndrome and, 171

head injury and, 335

Drowsiness, 90

Dysdiadochokinesia, 14

medicinal and toxic contributions to, 184

Dysesthesias, 377

Drugs

Dyskinesias, 239

acute alteration in mental status and, 71

drug-induced, 238

anesthetic

drug-related

malignant hyperthermia, 366

levodopa and, 230, 231

antidepressants

Parkinson’s disease and, 229

early morning awakening and, 170

involuntary movements in, 242

antidopaminergics

Parkinson’s disease and, 232

RLS and, 171

Dysphagia

antiepileptic

management of

TBI and, 340

neurologic illness and, 557

antiplatelet

MG and, 359

stroke prevention and, 115

neuroleptic malignant syndrome and, 84

antipsychotics

Dyspnea, 371

TD syndrome, 279, 281, 282, 283

propranolol and, 257

antithrombotics

Dystonia, 242. See also Early-onset dystonia

stroke prevention and, 114

classification of, 244-245, 244t-245t, 246t

cardiac. See Cardiac drugs

drug-induced, 251

GABA-agonist

ET v., 256

TD syndrome, 283

genes and, 245

immunosuppressive

HD and, 260

MS and, 213

hospitalized patients, challenges for, 254

neurotoxic effects of, 446-466

neurochemistry of, 251-252

overdose of

neurologist referral for, 254

coma prognosis in, 102

pathology of, 251-252

sleep and, 160

treatment of, 252-254, 252t

sleep apnea and, 176

types of, 243

sleep inducing

Dystonia-plus syndrome, 245

choice of, 162-164, 163t-164t

Dystonic cramps, 249

toxic myopathies and, 367

Dystonic movements, 242, 243

transplant. See Transplant drugs

pathophysiology of, 243

Drug screen

Dystonic postures, 237, 238

comatose patient and, 99

Dystonic tics

Drug therapy

GTS and, 273

MS and, 213-218, 214t

DYT1 dystonia, 246-247. See also Crural dystonia

urinary retention in, 215-216

pathophysiology of, 246-247

DTH. See Delayed-type hypersensitivity reaction

DYT6 dystonia, 247

DTRs. See Deep tendon reflexes

DYT1 gene, 246, 247

Duchenne dystrophy (DUD), 352

DYT6 gene, 247

Duchenne muscular dystrophy, 350f, 354, 361-362

DYT7 gene, 247

DUD. See Duchenne dystrophy

DYT13 gene, 247

604

Index

Embolic stroke

EAE. See Experimental allergic encephalomyelitis

thrombotic stroke vs., 109, 109t

Early morning awakening

Embolism

drugs for, 170

cardiac evaluation and, 112

Early-onset dystonia, 244

Embryonal development

clinical spectrum of, 246-247

AVM and, 121-122

Eating disorders

Emergency room (ER)

sleep and, 186

stroke presenting in, 107

Edema

EMG. See Electromyogram; Electromyography

from infarction and gliosis/encephalomalacia,

EMG biofeedback for insomnia, 161

EMG/NCS. See Electromyogram/Nerve conduction

mass effect and, 48

studies

Edrophonium (Tensilon)

Emotional disturbances

MG and, 360

neurorehabilitation and, 563

EEG. See Electroencephalogram; Electroen-

Encephalitis, 492-494

cephalography

causes of, 492

Ehlers-Danlos syndrome type IV

clinical features, 493

aneurysmal rupture and, 120

laboratory findings, 493

EKG. See Electrocardiograms

management and prognosis, 493-494

Eldercare Locator, 301

Encephalopathy, 20-21, 21t, 69. See also Delirium

Elderly

Endocrine encephalopathy

advanced-sleep-phase syndrome, 170

acute alteration in mental status and, 71

hypnotic drugs and, 166

End-of-life care

Elderly patients

physician and, 371

chronic subdural hematomas in, 70

Endolymphatic hydrops, 421

Electrical potentials, 356

Endovascular coiling

Electrocardiograms (EKG)

cerebral aneurysms and, 121

DMI and, 363

Entacapone

Electroencephalogram (EEG)

Parkinson’s disease and, 228

comatose patient and, 101

Parkinson’s therapy and, 230

HSE and, 70

Enteroviruses, 488

metabolic encephalopathy and, 73

Enuresis, sleep-related, 186

nonconvulsive SE and, 64

Enzyme elevation, for muscle necrosis, 354-355

of NREM sleep, 157

EOG. See Electro-oculogram

of REM sleep, 158

Ependymoma, 502-503

SE and, 65, 68

treatment of, 503

seizures and, 143, 147

EPH. See Episodic paroxysmal hemicrania

Electroencephalography (EEG), 37

Ephedra

Electromyogram (EMG), 157

weight loss and, 183

Electromyogram/Nerve conduction studies

Epidural abscess

(EMG/NCS)

acute spinal cord compression and, 78

of muscles and nerve, 406

Epidural hematomas, 55, 55f

Electromyography (EMG), 37-38, 382

location of, 53-54

BoNT injections using, 254

Epilepsy

degree of nerve injury, 386

AED and, 150-152, 153

disryption of, 385

diagnosing, 147-148

single motor unit action potentials, 357f

differential diagnosis of, 148

using electrodes, 385

licensing of drivers with

Electro-oculogram (EOG), 157

legal considerations of, 581-583

Eletriptan

neurologist referral and, 154

migraine and, 134

patients with, challenges for managing, 153, 154

605

Index

posttraumatic head injury and, 340

Executive function

treatment of, 148-150, 149t

mental status examination and, 3-4

surgical therapies for, 152-153

Experimental allergic encephalomyelitis (EAE)

women and, 153

MS and, 196

Epilepsy syndromes, 144-147

Expressive aphasia, 3

Epileptic aura, 309

Extra-axial lesions, 52, 52f

Epileptic seizures

intra-axial lesions versus, 51-53, 52f

status epilepticus and, 63

Extraocular pathology, 546

Episodic paroxysmal hemicrania (EPH)

Extrapyramidal symptomatology (EPS)

indomethacin and, 137

GTS and, 278

treatment of, 137

Eye movements, 538

Epley maneuver, 418, 419f

coma and, 95, 96, 97

EPS. See Extrapyramidal symptomatology

conjugate gaze abnormalities, 539-542

Equipment, special

examination, 7

rehabilitation and neuromuscular diseases

horizontal double vision, 544-547

and, 369

vertical double vision, 542-544

ER. See Emergency room

Ergotamine tartrate

rebound headache and, 130, 130t

Ergot derivatives

Facial diplegia, 389

migraine and, 134

Facial masking

Erythrocyte sedimentation rate

Parkinson’s disease and, 223, 224f, 225f

stroke-like symptoms and, 112

Facial nerve (CN VII)

Erythromycin, 448

integrity of, 8

Escitalopram

Facial weakness, 8

MS and, 217

Facioscapulohumeral (FSH) dystrophy, 362

Esotropia (“crossed eyes”), 7

mutation with chromosome 4, 362

Essential tremor (ET), 242, 284, 285

symptoms of, 362

classification of, 254

Fall(s), 427-442

clinical features of, 254-256

aging and, 428

differential diagnosis of, 255t, 256-257

associated with ataxia, 432-433

dystonia and, 249

medical treatment for, 439

genetics and, 256

autonomic dysfunction, 431

hospitalized patients, challenges for, 260

balance problems associated with, 434-437

neurologist referral for, 259-260

definitions, 427

Parkinson’s disease v., 256

diagnosing cause of, 429-434, 430f

pathology of, 256

due to medication side effects, 431

pathophysiology of, 256

economic cost in U.S., 428

patient evaluation and, 257

incidence in neurologic patients, 428-429, 428f

treatment of, 257-259, 258t

multifactorial, 437-438

Estrogen

overview, 427-428

migraine and, 129

associated with Parkinsonism, 431-432

Eszopiclone, insomnia and, 165

medical treatment for, 438-439

ET. See Essential tremor

prevention of

Evoked potentials, 38

neurorehabilitation intervention and, 557-558

MS and, 208

psychotropic medications for, 429

Excitotoxicity

risk factors for, 429, 429t

HD and, 264

extrinsic, 429

Excitotoxic neuronal injury, 64

intrinsic, 429

Executive cognitive deficits

associated with spasticity, 432

associated with falls, 436

medical treatment for, 439

606

Index

Fall(s) (Continued)

Flunarizine

Tinetti’s definition of, 427-428

neurologic effect of, 453

treatment to prevent

Fluorodeoxyglucose- positron emission

medical treatment, 438-439

tomography (FDG-PET)

rehabilitation, 439-442

AD and, 295

associated with vestibular system disorders, 433

Fluoxetine

medical treatment for, 439

GTS and, 278

associated with weakness, 433-434

MS and, 216

medical treatment for, 439

serotonin uptake and, 183

Famotidine (Pepcid)

sleep apnea syndromes and, 176

neurologic effects of, 456

sleep-related eating disorders and, 186

Fascicles, 376

Flurazepam, 164

Fasciculations, 353

Flycatcher’s tongue

Fatigue

TD syndrome and, 279

MS and, 203

FMRI. See Function magnetic resonance imagery

treatment of, 217

Focal cervical dystonia, 247

FDA. See Food and Drug Administration

Focal cortical contusion

FDG-PET. See Fluorodeoxyglucose- positron

TBI and, 325, 326f

emission tomography

Focal dystonia, 244

Federal Tort Claims Act, 573

DBS and, 253

FEF. See Frontal eye fields

Focal epilepsy, 146, 153

Female hormones

Focal neuropathies, 392-393

neurotoxic effects of, 463-464

carpal tunnel syndrome, 392

Fentanyl

peroneal neuropathy, 393

neuroleptic malignant syndrome and, 171

ulnar neuropathy, 392-393

Fetal malformations

Focal orbital pain

AED and, 153

cluster headache and, 131

Fetal tissue implants (mesencephalon)

Focal seizures, 144, 145

Parkinson’s disease and, 233

Folate

Fever

AED and, 152

MS and, 217

Folstein Mini-Mental Status Examination

Fibrillation potentials, 356, 357f

acute alteration of mental status and, 73

Fibromyalgia, 327

Food and Drug Administration (FDA), 165,

Finger to nose test, 14

473, 574

MS and, 206

AD and, 298

tremor and, 254

botox and, 253

FLAIR. See Fluid-attenuated inversion recovery

medical and law, 574

FLAIR sequence, 44, 450

Foot dorsiflexion weakness

Flight of ideas, 4

gait disorders and, 27

Fluconazole, 492

Forced vital capacity (FVC), 80

Fluent aphasia, 308

Foster Kennedy syndrome, 519

etiology of, 314-315

FOUR (Full Outline of UnResponsiveness) score,

evaluation of, 313

98, 99t

for hospitalized patients, 315

“4-4-4” rule, 6

language difficulty, 314

Fourth nerve palsy

overview, 313

in vertical double vision, 543-544, 544f

refer neurologists, 315

Fractures

treatment of, 315

prevention of

types of, 314t

neurorehabilitation intervention and,

Fluid-attenuated inversion recovery (FLAIR), 35

557-558

MS and, 205, 206

Fragile X tremor-ataxia syndrome, 433

607

Index

Free radicals

Gait examination

HD and, 264, 265

clinical assessment in, 14-15

Frontal eye fields (FEF), 539

neurological examination and, 1, 1t

Frontal lobe disorders, 27

Gait spasticity, 15

Frontal lobes

Gait testing, 15

damage of, 4

Gait training

Frontotemporal dementia (FTD), 291, 297-298

fall prevention by, 441

neurologic examination and, 297

Galantamine

pharmacologic treatment of, 297

AD and, 299

prion diseases, 297-298

Galveston Orientation and Amnesia Test (GOAT)

Frozen shoulder

PTA and, 329

rehabilitation and neuromuscular diseases

Gamma-amino-butyric acid (GABA), 151

and, 368

dystonia and, 252

FSH. See Facioscapulohumeral dystrophy

sleep and, 156

FTD. See Frontotemporal dementia

TBI and, 338

Full Outline of UnResponsiveness (FOUR) score,

TD syndrome and, 281

98, 99t

Gamma-amino-butyric acid (GABA) levels

Fulminant hepatitis

HD and, 264

WD and, 267, 272

Gastroesophageal reflux

Function magnetic resonance imagery

insomnia and, 171

(fMRI), 321

Gastrointestinal agents, 454

Fungal meningitis, 491-492

antiacidity agents, 456

FVC. See Forced vital capacity

antidiarrheals, 455-456

antiemetics, 455

laxatives, 455

neurotoxic effects of, 454-456

GABA. See Gamma-aminobutyric acid

Gastrostomy feeding tube

Gabapentin, 480

oculopharyngeal dystrophy and, 363

ET and, 259

Gastrostomy tube, 370

RLS and, 168

Gaze-evoked nystagmus, 416, 547

seizures and, 151-152

GBS. See Guillain-Barré syndrome

side effects of, 168

GCG. See Polyalanine triplet

SUNCT syndrome, 137

GCS. See Glasgow Coma Scale

GAD. See Glutamic acid decarboxylase

GdDTPA. See Gadolinium diethylenetriaminepen-

Gadolinium, 35

taacetic acid

Gadolinium diethylenetriaminepentaacetic acid

Generalized dystonia, 244

(GdDTPA)

Gene test

MS and, 206

HD and, 261, 262

Gadolinium dye, 405

Genetic canine narcolepsy

Gadolinium-enhancing lesions

genes in, 180

MS and, 199

Genetic mapping

Gadolinium MRI

ET and, 256

of brain and spinal cord, 508, 508f

Genetics

Gag reflex, 9

Becker dystrophy and, 361-362

Gait

carnitine deficiency and, 366

HD and, 260, 261, 265

congenital muscular dystrophy and, 346t

proximal weakness and, 350

CPT II and, 365

unstable, with head motion

DM and, 363

falls associated with, 436

dystonia and, 245

Gait disorders, 27-28

HD and, 261-263

non-neurologic causes of, 27

LGMD and, 362

608

Index

Genetics (Continued)

Globus pallidus

malignant hyperthermia and, 366

dystonia and, 243, 253

McArdle disease and, 365

GTS and, 276

mitochondrial myopathies and, 366

HD and, 264

MS and, 196

Glossopharyngeal nerve (CN IX), 9

muscle biopsy and, 357

Glutamate antagonists

myotonia congenita and, 364

HD and, 264, 265

narcolepsy and, 180

Glutamatergic agents

oculopharyngeal muscular dystrophy and,

TD syndrome and, 283

362-363

Glutamic acid decarboxylase (GAD)

SMA and, 358

HD and, 264

Genetic testing

Glycogen

AD and, 295

skeletal muscle and autosomal recessive disorders

Genomic imprinting

and, 365

GTS and, 276

Glycogen storage diseases

Gentamycin

CPT II v., 365

neurologic effect of, 447

Glycoprotein

GFAP. See Glial fibrillary acidic protein

myelin-associated, 387

Gilles de la Tourette syndrome (GTS),

Glycosides

242, 284

neurologic effect of, 450-451

associated behavioral disturbances in,

GOAT. See Galveston Orientation and Amnesia Test

274-275

Gotu cola (Centella asiatica)

diagnosis of, 275

sleep cycle and, 167

differential diagnosis of, 275

Gowers maneuver, 350, 350f

environmental factors in, 276

weakness and, 350

genetics and, 275-276

Grand mal seizure

hospitalized patients, challenges for, 279

causes of, 143

maternal influences on, 276

Graphesthesia, 14

neurologist referral for, 279

Guanfacine

pathophysiology of, 275-276

GTS and, 278

tics and, 273-274

Guillain-Barré syndrome (GBS), 21, 38, 81-83,

treatment for, 276-279, 277t

381, 389-390, 402, 407, 480

Ginkgo biloba

acute intermittent porphyria vs., 81, 82, 82t

AD and, 300

botulism vs., 82, 82t

Parkinson’s disease and, 236

clinical presentation of, 81

Ginseng (Panax ginseng—Korean ginseng)

differential diagnosis of, 81-82, 82t

ephedrine and, 183

diphtheric neuropathy vs., 82, 82t

Glabellar reflex, abnormal, 4

IVIG and, 83

Glasgow Coma Scale (GCS), 33, 98, 99t

mortality rate, 81

acute alteration of mental status and, 73

origin of, 390

scoring sheet, 327f

patient history and, 81

TBI and, 326

poliomyelitis vs., 82, 82t

Glatiramer acetate (Copaxone)

recovery of, 390

MS and, 211

tick-bite paralysis vs., 82, 82t

Glial fibrillary acidic protein (GFAP), 500

treatment of, 82-83

Glioblastoma multiforme, 502

Guillain-Mollaret triangle, 548

Gliosis

HD and, 263, 264

Gliosis/encephalomalacia, 48

Global aphasia

Haemophilus influenzae, 487, 489

coma vs., 91

Hallucinations, 4

609

Index

Hallucinosis

Hemiparetic gait, 15

Parkinson’s disease and, 232

Hemiplegia, 22

Halmagyi head thrust test, 417

Hemispatial neglect

Haloperidol

sensory examination and, 14

acute alteration in mental status and, 74

Hemispheric motor cortex lesions

dystonia and, 246t

etiology of, 23-24

HD and, 265

Hemorrhage

side effects of, 277

intracranial, 53-56

tics syndrome and, 277

risk of, 56

Halothane

types of, 53

malignant hyperthermia of, 366

Heparin

Hand

ICH and, 119

cutaneous innervation of, 378f

Hepatic encephalopathy

Hatchet face, 363

acute alteration in mental status and, 71

HD. See Huntington’s disease

alcoholism and, 474-475

HD (Huntington’s disease) gene, 261

asterixis in, 474

Headache. See also Tension-type headache

diagnosis, 474

aneurysmal rupture and, 120

etiology of, 474

case studies and, 124-125

treatment of, 474-475

hospital care and, 133t

Hepatic WD

hospitalization for

diagnosing, 269

criteria for, 138, 139t

presentations of, 267

inpatient care with, 139, 139t

Hepatitis WD, 267

intracranial hypertension and, 76

Herbal medicinal products

treatment of, 138

caffeine and, 183

Headaches

Hereditary-degenerative syndromes, 245

mild TBI and, 339

Herniation

refractory, 340

and mass effect, 47-49, 48f

Head injury. See also Brain injury; Traumatic brain

Herniation syndromes

injury

types of

hospitalized patient with special challenges of,

intracranial hypertension and, 75

332-335

Herpes encephalitis, 308

seizure prophylaxis and, 330

Herpes simplex encephalitis (HSE), 69-70,

vocational programmes and, 332

319-321

Head motion

acute alteration of mental status and, 69-70

unstable gait with, 436

AED therapy for treatment of, 70

Head thrust test, 417

bizarre behavioral and, 319

Head titubation, 257

diagnostic testing for, 69-70

Health care

for hospitalized patients, 320

administrative law and, 574

overview, 319

Health Insurance Portability and Accountability

refer neurologists, 320

Act (HIPAA)

treatment of, 320

medical law and, 574

Herpes simplex type 1 virus, 492

Hearing loss

Herpes simplex virus (HSV)-1, 69

in peripheral vestibular lesions, 417

Heterozygotes

Heel-to-shin testing, 14

WD and, 269

Hemicrania continua

High postural tone, 434

indomethacin and, 137

HIPAA. See Health Insurance Portability and

Hemidystonia, 244

Accountability Act

Hemiparesis, 22

Hippus, 531

intracranial hypertension and, 75

HIV. See Human immunodeficiency virus

610

Index

HIV infection

pathology of, 263-264

antiretrovirals for, 449

treatment of

HIV testing

disease-modifying agents in, 265

stroke-like symptoms and, 112

symptomatic therapy in, 265-266

HMG-CoA reductase inhibitors

Hydralazine

neurologic effects of, 454

neurologic effect of, 453

Homonymous hemianopia, 6, 523, 526, 526f

Hydrocephalus, 49, 50f

Horizontal double vision, 544-547

evaluation of, 49

extraocular pathology, 546

versus volume loss, 49-50

hyperthyroidism in, 546-547

Hydrocephalus, late onset

internuclear ophthalmoplegia, 545-546

TBI and, 335-336

myasthenia gravis, 546

Hydroxyamphetamine

one-and-a-half syndrome, 546

in Horner syndrome, 534-535, 535f

sixth nerve palsy, 544-545, 545f

Hyperactive delirium, 69

Horizontal gaze palsies, 539-541, 540f, 541f

Hyperactive reflexes, 11

Horizontal oculocephalic maneuvers

Hypercoagulable state

coma and, 97

evaluation for, 112

Horizontal sectoranopia, 525

“Hyperdense MCA sign,” 57

Hormones

Hyperesthesia, 377

neurotoxic effects of, 463-464

Hyperpnea

Horner syndrome, in anisocoria, 532-535, 533f

Cheyne-Stokes respiration and, 94

apraclonidine test for, 534

Hyperreflexia

hydroxyamphetamine testing for, 534-535, 535f

acute alteration of mental status and, 73

pharmacologic testing in, 534, 534f

MS and, 206

postganglionic lesions in, 533

Hypersomnia

preganglionic sympathetic fibers, 533

hospitalized patients, special challenges for, 184

ptosis in, 533

sleep specialist and, referral to, 184

Raeder’s paratrigeminal syndrome, 533, 533f

Hypersomnolence, 334

Hospitalization

sleep disorders associated with, 172

GCS and, 330

Hypertension

Hounsfield units (HU), 44

MS and, 216

H₂ receptor antagonists

OSA and, 174

neurologic effects of, 456

Hyperthermia

HSE. See Herpes simplex encephalitis

neuroleptic malignant syndrome and, 84

HSV-1. See Herpes simplex virus

Hyperthyroidism

HU. See Hounsfield units

ET and, 257

Human immunodeficiency virus (HIV), 381, 504

in eye disease, 546-547

dementia and, 291

Hypertrophy, 352-353

Human leukocyte antigen (HLA) allele

Hyperventilation

narcoleptics and, 179

intracranial pressure and, 76

Huntingtin protein

Hyperventilation syndrome

CAG trinucleotide repeat and, 264

as cause of presyncope, 413-414

Huntington disease (HD), 242

symptoms of, 413

characteristics of, 260

Hypnosedative agents

clinical features of, 260-261

neurologic effects of, 461

differential diagnosis of, 262t

Hypnosis

genetics of, 261-263

epilepsy and, 153

hospitalized patients, challenges for, 266

Hypnotic drugs for insomnia

neurochemistry of, 263-264

children and, 165-166

neurologist referral for, 266

efficacy of, 162

pathogenesis of, 263-264

half-life of, 164, 165

611

Index

Hypoactive delirium, 69

Indian sida (Sida cordifolia), ephedrine and,

Hypocretin-containing neurons, narcolepsy and, 180

183

Hypoesthesia, 377

Indomethacin

Hypofibrinogenemia

CPH and, 137

ICH and, 118

EPH and, 137

Hypoglossal nerve (CN XII), 9-10

hemicrania continua and, 137

Hypoglycemia

neurotoxic effects of, 463

as cause of presyncope, 415

Infantile hypotonia, 354

comatose patient and, 100

Infant(s)

Hypokalemia

hypotonia, 354

MS and, 214

Infarcts

Hyponatremia

acute cerebral, 57f, 58f

acute alteration in mental status and, 72

evaluation of, 56

TBI and, 335

and vascular imaging, 56-60

Hypoparathyroidism, 367

recent versus chronic MCA, 58f

Hypotension

treatment, 56

phenobarbital IV and, 68

Infections

phenytoin IV and, 66

common sites of neuromuscular disorders

SE and, 68

and, 370

Hypothalamus, sleep and, 156, 157

neuromuscular disorders and, 370

Hypothermia

Inferior arcuate defects, 522

comatose patient and, 100

Inflammatory myopathies, 364

Hypothyroidism

muscles and, 353

dementia and, 291

Informed consent, 574-578

Hypotonia, 354

INH. See Isoniazid

Hypoventilation, 174

Inherited disease, 285

Hypoxia

Inherited syndrome

delayed-onset dystonia and, 251

DYT1 dystonia and, 246

INO. See Internuclear ophthalmoplegia

INR. See International normalization ratio

Insomnia

IBM. See Inclusion body myositis

hospitalized patients, special challenges for,

ICH. See Intracerebral hemorrhage

171-172

ICP. See Intracranial pressure

medical conditions and, 171

ICSD-2. See International Classification of Sleep

neurorehabilitation and, 556

Disorders-2

pattern of, 160

ICU. See Intensive care unit

sleep disorders associated with, 159-160

Idiopathic dystonia

sleep specialist and, 171

secondary dystonia v., 251

treatment of, 161-162, 164-165

Idiopathic insomnia, 159

“Insular ribbon sign,” 57

Idiopathic intracranial hypertension, 528

Intensive care unit (ICU), 65

IgM. See Immunoglobulin M

Internal capsule lesions

Illusions, 4

characteristics of, 24

Imaging

International Classification of Sleep Disorders-2

of spine, 53

(ICSD-2), 159

Imipramine

division of sleep disorders in, 159

cataplectic attacks and, 183

International Headache Society’s (IHS)

Immunoglobulin M (IgM), 387

classification of headaches and, 128, 128t

Immunosuppressives, transplant, 450

criteria for MOH, 130t

Inclusion body myositis (IBM), 351

International normalization ratio (INR)

muscles biopsy and, 365

SAH and, 109

612

Index

Internuclear ophthalmoplegia (INO), 97, 544,

Ischemic stroke, 105

545-546

hematologic factors associated with, 112

MS and, 202

hemorrhagic transformation of, 116, 117f

Intra-arterial cerebral arteriography

prevention of

extracranial circulation and, 111

neurorehabilitation intervention and, 558

Intra-arterial mechanical thrombectomy, 56

treatment of, 114-117

Intra-arterial thrombolytic therapy, 56

Ischemic stroke syndromes

Intra-axial lesions, 51, 52f

associated with vertigo, 422

versus extra-axial lesions, 51-53, 52f

Isoniazid (INH)

Intracerebral hemorrhage (ICH)

neurotoxic effects of, 447

causes of, 117, 117t

Itraconazole, 492

clinical approach to, 117-118

IVIG. See Intravenous immune globulins

CT scan and, 118

IVMP. See Intravenous methylprednisolone

treatment for, 118-119

Intracranial aneurysm, 120

Intracranial hematoma

acute alteration of mental status and, 70

Jacobus Pharmaceutical Company, 361

Intracranial hemorrhage, 53-56

Jaw jerk reflex, 7, 8

Intracranial hypertension. See Acute intracranial

Jaw strength

hypertension

testing of, 7-8

Intracranial metastases, 504-507, 505f

Jerk nystagmus, 547

diagnosis of, 506

Brun’s nystagmus, 547

risk factors, 505

downbeat nystagmus, 547

signs and symptoms, 506

gaze-evoked nystagmus, 547

treatment of, 506-507

vestibular nystagmus, 547

Intracranial pressure (ICP). See also Acute intracra-

JFK Coma Recovery Score

nial hypertension

brain injury and, 331

hyperventilation and, 76

Joint contractures

measurements of, 76

prevention of

Intramedullary spine lesions, 54f

neurologic illness and, 556-557

differential diagnosis of, 53

Judgment

Intraparenchymal hemorrhage

mental status and, 4

differential diagnosis of, 55-56, 56f

Junctional scotoma, 523

etiology for, 55

Juvenile myoclonic epilepsy, 145

location of, 53

pallidotomy and, 233

Intrathecal baclofen

dystonia and, 253

Kanamycin

Intrathecal immunoglobulin (Ig) synthesis

neurologic effect of, 447

MS and, 206-208

Kava kava (Piper methysticum), insomnia and, 166

Intravenous immune globulins (IVIG), 390

Kayser-Fleischer (KF) ring

GBS and, 83

WD and, 267, 268, 268f, 269

myasthenic crisis and, 80-81

Kearns-Sayre syndrome (KSS)

Intravenous (IV) benzodiazepine administration, 65

syncope and, 369

Intravenous methylprednisolone (IVMP)

Kennedy disease, 358

MS and, 214, 215

Kernohan grading system, 500

Intravenous TPA, 56

Ketoconazole

Involuntary movements

AD and, 299

TD syndrome and, 282

Ketogenic diet

Iron deficiency, RLS and, 167, 168

epilepsy and, 153

Ischemic optic neuropathy, 527-528

Kinetic tremor, 235, 257

613

Index

Kleine-Levin syndrome, sleepiness and, 184

Leptomeningeal metastases, 507-509

Kluver-Bucy syndrome, 320

symptoms and signs, 507

Knee extensor weakness, 350

Lethargy, 90

“Knee jerk.” See Patellar reflex

Leukoencephalopathy, 513

Knee reflex, 404

Level of consciousness

Korsakoff psychosis, 316

alterations in, 21-22

Korsakoff syndrome

mental status examination and, 2

dementia and, 291

Levels of consciousness

Kyphoscoliosis

assessment of, 90

poliomyelitis and, 175

Levetiracetam, 340

rehabilitation and neuromuscular diseases

seizures and, 152

and, 361

Levodopa

DLB and, 297

DRD and, 250, 251

dystonia and, 252, 252t

Laboratory testings

Parkinson’s disease and, 227, 228, 229, 233

neuromuscular diseases and, 406

TD syndrome and, 283

Lactulose

Levodopa-carbidopa, 239

WD and, 272

sleep-wake cycle and, 331, 331t

Lacunar-type stroke

Lewy bodies

indications of, 114

Parkinson’s disease and, 226

Lambert- Eaton myasthenic syndrome (LEMS), 361

LGMD. See Limb girdle muscular dystrophy

immunomodulatory treatments for, 361

LGN. See Lateral geniculate nucleus

Lamotrigine

Lhermitte’s sign, 26

seizures and, 149, 152

MS and, 203

SUNCT syndrome and, 137

Licensing of drivers, 581-583

Landry-Guillain-Barré syndrome, 381

Lidocaine-induced CNS toxicity, 451

Language

Ligaments pain, 400

mental status examination and, 2-3

Limb girdle muscular dystrophy (LGMD)

Large artery thrombotic stroke, 106

symptoms of, 362

Laryngeal dystonia, 243

Limbs

Late-onset dystonia, 244

cutaneous innervation of, 380t

Lateral geniculate nucleus (LGN), 520

Lingual dystonia, 243

visual field defects in, 524-525, 525f

Lipid metabolism

Lateral medullary infarction, 422

disorders of, 365-366

as cause of vertigo, 422

Lipohyalinosis

Lateral pontine ischemia

lacunar-type stroke, 114

as cause of vertigo, 422

Lithium carbonate

Laterocollis, 248

neurologic effects of, 460-461

Lavender (Lavandula angustifolia), sleep cycle

Liver failure, 272

and, 167

Liver function tests

Lawsuits. See Medical malpractice suits

comatose patient and, 99

Laxatives

Liver transplant, 272

MS and, 216

Lobar hematoma, 118

neurologic effects of, 455

surgery and, 119

LDN. See Low-dose naltrexone

Lobar hemorrhage

Leber optic neuropathy

aneurysms vs., 118

dystonia and, 245t

Localization-related epilepsies, 145

LEMS. See Lambert-Eaton myasthenic syndrome

LOH. See “Loss of heterozygosity”

Lenticular nuclei

Long-term memory

WD and, 268

testing, 3

614

Index

Loop diuretics

Magnetic resonance angiography (MRA), 36, 46

neurologic effect of, 452

acute stroke evaluation and, 111

Loosening of associations, 4

infarct evaluation and, 59, 59f

Lorazepam

Magnetic resonance imaging (MRI), 35

SE and, 66

acute spinal cord compression and, 78

sleep and, 164

AD and, 294

“Loss of heterozygosity” (LOH), 502

advanced techniques for, 46

Loss of proprioception

comatose patient and, 100

in disequilibrium, 423-424

contrast agents used in, 46-47

Low back pain

versus CT, 44-46, 45f

anatomy of, 398-400

GTS and, 276

causes of new-onset, 407t

herpes simplex encephalitis and, 69-70

epidemiology of, 398

infarct evaluation and, 56-60

examination for, 403

mitoxantrone and, 211

motor, 403

MS and, 193, 204-206, 205t, 206f, 207f, 212,

sensory, 404

213, 213f

vibratory, 404

pathologic correlations with, 195-196

neurologic examination for, 403-404

PP-MS and, 198

psychosocial factors, 403

in pregnant patients, 46

structural causes of

VaD and, 296

ligament pain, 400

WD and, 270, 271f

muscle pain, 400

Magnetic resonance venography (MRV), 36

referred pain, 402-403

Major histocompatibility complex (MHC)

treatment of, 406-408

MS and, 210

conservative, 407-408

Malignant hyperthermia, 366

4 to 6 week, 408

Malnutrition

Low-dose naltrexone (LDN)

neurorehabilitation and, 555-556

MS and, 218

Mandibular branch (V₂), of trigeminal nerve,

Lower motor neuron lesions

7, 8f

symptoms of, 24-25

Mania

Lower motor neuron signs, 10

sign of, 3

LP. See Lumbar puncture

Mannitol

L5 radiculopathy, 403

acute intracranial hypertension and, 76

Lumbar puncture (LP), 36

MAO-B. See Monoamine oxidase B

AD and, 294

MAO inhibitors. See Monoamine oxidase in-

CSF evaluation for, 38, 70

hibitors

SAH and, 109

MAP. See Mean arterial blood pressure

technique for, 39

Marburg disease, 199

Lumbosacral spine, 400f

Marchiafava-Bignami disease (MBD)

anatomic landmarks of, 399

alcoholism and, 477-478

Lupus erythematosus syndrome, 451

callosal atrophy in, 478

Lymphomatous meningitis, 506

clinical variations of, 477-478

diagnosis, 477

extracallosal lesions in, 478

Marcus Gunn pupil, 518

Macrocytosis

MS and, 202

AED and, 151

Marfan syndrome

Macular sparing, 526

aneurysmal rupture and, 120

MAG. See Myelin-associated glycoprotein

Mass effect

Magnesium

and herniation, 47-49, 48f

PLMs and, 170

Maxillary branch (V₂), of trigeminal nerve, 7, 8f

in thiamine metabolism, 471

MBD. See Marchiafava-Bignami disease

615

Index

MBP. See Myelin basic protein

Meningovascular syphilis

McArdle disease, 365

ICH and, 118

acid maltase deficiency and, 346t, 365

Menstruation-associated hypersomnia, sleepiness

symptoms of, 365

and, 184

Mc-Donald diagnostic criteria

Mental status, 1

MS and, 204, 205t

appearance and, 2

MCI. See Mild cognitive impairment

and cognition, 1-5

Mean arterial blood pressure (MAP)

diagnostic process and, 21-22

intracranial hypertension and, 74

neurologic examination, 1, 1t

Meclizine

pediatric neurology and, 15

for vestibular-based dizziness, 439

Metabolic abnormalities

Medial longitudinal fasciculus (MLF), 544, 545

as result of malignancy, 511

Medical malpractice suits, 573-574

Metabolic depression

Medical Research Council (MRC)

coma and, 91, 92

grading of muscle strength, 10t

Metabolic encephalopathies, 92

Medication overuse headache (MOH)

acquired hepatocerebral degeneration, 475-476

features of, 130, 130t

acute alteration of mental status and, 71

IHS criteria for, 130t

alcoholism and, 474-477

treatment of, 133-134, 133t

decerebrate posturing and, 98

Medulla

EEG and, 73

ET and, 256

hepatic encephalopathy, 474-475

sleep and, 156

pancreatic encephalopathy, 476-477

Meige syndrome, 247-248, 284

Metabolic myopathies, 365-366

ET and, 249, 256

glycogen storage diseases, 365

Melatonin

lipid metabolism, disorder of, 365-366

pineal gland and, 157

mitochondrial myopathies, 366

sleep cycle and, 166

Metabolic profile

Memantine

SAH and, 109

AD and, 299

Metallothionein levels

Memory

WD and, 270, 271

components of, 3

Metastases

mental status examination and, 3-4

intracranial, 504-507, 505f

MS and, 203

leptomeningeal, 507-509

Ménière disease

spinal, 509-510

as cause of vertigo, 420-421

Methamphetamine, narcolepsy and, 180

symptoms, 421

Methaqualone

vestibular dysfunction and, 433

neurologic effects of, 461

Meningeal carcinomatosis, 506

Methazolamide

Meningiomas, 503

ET and, 259

chemotherapy for, 503

Methylphenidate (MPH)

focal motor seizures and, 145

ADHD and, 278

radiotherapy for, 503

narcolepsy and, 180

symptoms, 503

OCD and, 275

treatment for, 503

sleep-wake cycle and, 331, 331t

Meningitis, 487-492

Methylprednisolone

acute bacterial, 489-491

acute intracranial hypertension and, 76

etiology of, 487

Metoclopramide

features of, 487

Parkinson’s disease and, 236

laboratory findings, 487-488, 488f

Metoclopramide (Reglan)

spirochete, 491

neurologic effects of, 455

tuberculous and fungal, 491-492

Metoprolol

viral, 488-489

ET and, 257-258

616

Index

Mexiletine

Modafinil

dystonia and, 253

mechanism of action, 181

MG. See Myasthenia gravis

narcolepsy and, 180, 181

MHC. See Major histocompatibility complex

stimulants v., 181

Microelectrode recordings

MOG. See Myelin oligodendrocyte protein

dystonia and, 243

MOH. See Medication overuse headache

Midazolam

Monoamine oxidase B (MAO-B)

SE and, 68

Parkinson’s disease and, 227

Migraine

Monoamine oxidase (MAO) inhibitors

basilar, in vertigo, 423

neurologic effects of, 460

Migraine headache

Monocular blindness, 521

acute treatment of, 134-135, 134t

Mononeuropathy multiplex, 380

categories of medications, 134t, 135t

Monoparesis, 22

classification of, 128-129

Monoplegia, 22

clinical symptoms of, 129

Monozygotic twins

cluster headache vs., 131, 131t

MS and, 196

comorbid conditions associated with, 129

Montreal Cognitive Assessment (MoCA),

defined, 128

5, 73

pathogenesis of, 129, 129t

Mood

pharmacologic treatment of, 134

depression and, 3

preventive treatment of, 135-136, 135t

Mood disorder

Migraine with aura

epilepsy and, 146

characterizations of, 128

Mortality rate

Migraine without aura, 128

of Guillain-Barré syndrome, 81

Mild cognitive impairment (MCI), 288

of myasthenic crisis, 79

AD and, 288

of NMS, 85

AIDS and, 291

of status epilepticus, 64

causes of, 289

Motoneuron, 375

clinical evaluation of, 288

Motor cortex

Mild TBI, 338-340

dystonia and, 243-244

Miller-Fisher syndrome, 389

Motor dysfunction

Mini-mental status examination (MMSE), 4-5

MS and, 202

Mini-mental status examination (MMSE) scores

Motor examination

MCI and, 288

motor system dysfunctions and, 10-11

Mirtazapine

pediatric neurology and, 16

ET and, 259

Motor fluctuations

Mitochondrial DNA

Parkinson’s disease and, 232

mitochondrial myopathies and, 366

Motor nerve

Mitochondrial dysfunction, 367

response of, 382-383

HD, 264

Motor neuron diseases (MND), 297, 358-359

Mitochondrial myopathies, 366

Motor neuron lesions

Mitoxantrone (Novantrone)

lower, symptoms of, 24-25

MS and, 211

upper, symptoms of, 23-24

Mixed apnea, 172

Motor response, abnormalities of

Miyoshi myopathy, 362

in disequilibrium, 424-425

MLF. See Medial longitudinal fasciculus

Motor strength, 403

MMSE. See Mini-mental status examination

Motor task

MMSE scores. See Mini-mental status examination

writer’s cramp and, 250

scores

Motor tics

MND. See Motor neuron disease

GTS and, 273

MoCA. See Montreal Cognitive Assessment

Motor unit potentials, 356, 357f

617

Index

Motor-vehicle accidents (MVA), 325

MRI and

Movement-related vertigo (MRV), 421

pathologic correlations with, 195-196

Moyamoya disease

neurobehavioral manifestations of,

angiography and, 112

216-217

MPH. See Methylphenidate

pathology of, 193-196, 194f

MRA. See Magnetic resonance angiography

precipitation factors of, 200

MRC. See Medical Research Council

prognosis, 199

MRI. See Magnetic resonance imaging

psychiatric manifestations of, 203

with gadolinium

sensory symptoms of, 203

of spine, 405

spasticity treatment for, 214t, 215

of L4-5 disc, 401f

symptoms of, 200-204, 200t, 201t

without gadolinium dye

therapy in, 209-219, 210t

of spine, 405

variants of, 199-200

MRV. See Magnetic resonance venography;

in vertigo, 423

Movement-related vertigo; Venography

Multiple sclerosis (MS) plaque

MS. See Multiple sclerosis

pathogenesis of, 194-195, 194f

MSA. See Multiple system atrophy

Multiple Sleep Latency test (MSLT), 179

MSLT. See Multiple Sleep Latency test

Multiple system atrophy (MSA), 226

Multifocal brain injury

as cause of parkinsonism in falling, 432

seizures and, 146

Muscle atrophy, 351-352

Multifocal dystonia, 244

motor neuron disease and, 350f

Multiple motor tics, 274

weakness and, 351

Multiple sclerosis (MS), 527. See also National

Muscle biopsy. See Biopsy, muscle

Multiple Sclerosis Society; Progressive-re-

Muscle bulk examination, 10

lapsing multiple sclerosis; Relapsing-remit-

Muscle contraction

ting multiple sclerosis; Secondary

electrical-activity generated by, 384

progressive multiple sclerosis

Muscle cramp, 353

alternative therapies and, 218

Muscle disease

brain abnormality

alcoholic myopathy as cause of, 481

MRI criteria for, 204, 205t

Muscle hypertrophy, 10

case studies, 219-220

Muscle injury

cerebellar signs of, 202-203

alcoholism and, 481

clinical patterns of, 197-199, 197t

Muscle movements

cognitive symptoms of, 203

innervation of, 379, 379t

combination therapy in, 213

speed and dexterity examination, 11

corticosteroids and, 213, 214-215

Muscle necrosis, 354

diagnosis of, 204-209

Muscle pain, 353, 400

errors in, 208-209, 208t, 209t

Muscles

disease course of, 197-199, 197t

dystonia and, 243

disease-modifying therapies for, 209-212, 210t

Muscle spasm, 399

epidemiologic studies, 193, 193f

Muscle stiffness, 353

etiology and immunopathogenesis and,

Muscle strength

196-197

examination, 10

experimental immunomodulatory

grading of, 10-11, 10t

approaches, 218

Muscle strength testing, 382

fatigue treatment in, 217

Muscle stretch reflexes. See Deep tendon reflexes

genetics and, 196

Muscle tone

history of, 192-193

defined, 10

hospitalized patients with, 217-218

examination, 10

immunology of, 196-197

Muscle twitching, 353

Mc-Donald diagnostic criteria, 204, 205t

Muscle wasting, 10

618

Index

Muscular dystrophies

Myotonic dystrophy 1 (DM1)

in adult, 368-369

symptoms of, 363

causes of, 361-362

in children, 367-368

diagnosis of, 361

Muscular weakness

NAbs. See Neutralizing antibodies

central nervous system and, 22-23

NAD. See Nicotinamide adenine dinucleotide

Mutant Huntingtin

NADP. See Nicotinamide adenine dinucleotide

CAG trinucleotide repeat and, 263, 264

phosphate

MVA. See Motor-vehicle accidents

NAION. See Nonarteritic AION

Myasthenia gravis (MG), 7, 350, 359-360, 546

NAIP. See Neuronal apoptotic inhibitory protein

diagnosis of, 360

Naproxen

drugs exacerbating, 79, 79t

AD and, 300

swallowing dysfunction in, 370

neurotoxic effects of, 463

treatment of, 360

Narcolepsy

Myasthenic crisis, 79-81

diagnosing, 179

mortality rate, 79

questions about, 187, 188-189

treatment of, 80-81

symptoms of, 179

Mycobacterium tuberculosis, 487

treatment of, 180-181, 181t, 182t, 183

Mycophenolate mofetil

twin studies and, 180

neurologic effect of, 450

Nasal obstruction, sleep apnea and, 178

Myectomy of orbicularis oculi

Natalizumab (Tysabri)

blepharospasm and, 253

MS and, 211-212

Myelin, 376

National Adult Day Services Association, 301

MS and, 195

National Center for Complementary and Alternative

Myelin-associated glycoprotein (MAG)

Medicine, 300

MS and, 195

National Institute on Aging, 300, 301

Myelin basic protein (MBP)

National Institutes of Health (NIH) Stroke Scale

MS and, 195

neurologic examination and, 109

Myelin oligodendrocyte protein (MOG)

National Institutes of Mental Health, 300

MS and, 195

National Multiple Sclerosis Society (NMSS)

Myelography, 35-36

recommendation of, 212

Myelopathies, 21, 21t. See Spinal cord lesions

National Traumatic Coma Data Bank, 331

cervical dystonia and, 249

Nausea

Myoclonic jerks

due to clinical intoxication, 451

AD and, 294

NCS. See Nerve conduction study

Myoclonic seizures, 144

Needle EMG

Myoclonus, 242

NCS and, 355

comatose patient and, 100

Neomycin

Myofascial pain, 399

neurologic effect of, 447

Myoglobinuria, 354, 370-371

WD and, 272

CPT II v., 365-366

Neoplastic meningitis, 506

Myopathies, 21, 21t, 25

diagnosis of, 506

toxic, 366-367

treatment of, 509

Myotonia, 353

Neostigmine

Myotonia congenita, 364

myasthenic crisis and, 80

Myotonic disorders, 363

Nephrogenic fibrosing dermopathy, 35

Myotonic dystrophy

Nephrogenic systemic fibrosis (NSF), 35, 47

facial appearance in, 352f

Nerve biopsy, 39-40, 386

syncope and, 369

Nerve conduction study (NCS), 37

weekness and, 352f

Nerve root motor, and sensory findings, 404t

619

Index

Nervous system

AD and, 293-294

ET and, 254

coma and, 94

Neurocardiogenic presyncope. See Vasovagal

coordination and gait, 14-15

presyncope

cranial nerves, 5-10

Neurocardiogenic (vasovagal) syncope

dementia and, 290

seizures vs., 148

DTRs, 11-12

Neurodiagnostic studies, 34t

FTD and, 297

Neurogenic claudication, 402

mental status and cognition, 1-5

Neurogenic pain, 400

motor function, 10-11

Neuroimaging

organization of, 1, 1t

acute alteration of mental status and, 73

pediatric neurology and, 15-16

Neuroimaging tests, 34-36

coordination, 16

computed tomography (CT), 34-35

cranial nerves, 16

magnetic resonance imaging, 35

DTRs, 16

myelography, 34-35

mental status, 15

Neuroleptic agents

motor examination, 16

acute, subacute, and chronic side effects of,

sensory system, 16

457t

primary generalized epilepsies and, 144

neurologic effects of, 457-459

rt-PA and, 109

Neuroleptic-induced parkinsonism, 458

sensory examination, 12-14

Neuroleptic-induced (tardive dystonia), 251

TBI and, 330, 339

Neuroleptic malignant syndrome (NMS),

Neurologist

83-86, 458

dystonia and, 254

acute alteration in mental status and, 74

ET referral to, 259-260

causes of, 83, 83t

GTS referral to, 279

diagnosis of, 86

HD and, 266

differential diagnosis of, 84

MS referral to, 209

features of, 84

Parkinson’s disease referral to, 235

cardiovascular complications and, 85

referral to, 102

respiratory complications and, 85

referring to

metabolic factors and, 84

epilepsy and, 154

mortality rate, 85

stroke management and, 122

risk factors, 458

TD syndrome and, 284

RLS and, 171

WD and, 273

treatment of, 84-86

Neurology, pediatric, 15-16

Neuroleptics, 285

coordination examination in, 16

acute alteration in mental status and, 74

cranial nerves examination in, 16

TD syndrome and, 281, 282, 283

mental status examination in, 15

tics and, 278

motor examination in, 16

Neurologic diagnosis

reflex examination in, 16

elements of, 21

sensory examination in, 16

patient history and, 20

Neuromuscular diseases

role of temporal course of neurologic illness in,

algorithm for, 356f

28-29

challenges in the hospitalized patient,

symptoms and, 20

370-371

Neurologic disorders, 552-553

clinical presentations of, 344-352

involuntary movements and, 242

electrodiagnostic studies, 355-357, 371

Neurologic dysfunction

enzyme elevation in, 354-355

descriptive terms in, 20-21, 21t

gene abnormalities in, 345t-347t

Neurologic examination

motor neuron diseases, 358-359

acute alteration of mental status and, 73

nerve and muscle biopsy, 357

620

Index

Neuromuscular diseases (Continued)

goals of, 553t

outpatient treatment principles, 367-369

homeostasis maintenance and, 555

overview, 344

hospitalization following

pharmacologic treatments in, 348t-349t

special challenges in, 567-568

refer to neurologist, 371-372

outcomes of, 568

Neuromuscular disorders

pharmacologic treatments in, 562t

differential diagnosis for patients with, 354

Neurorehabilitation intervention

findings and helpful tests in, 355t

acute-care discharge and, 559

hospitalized patient, special challenges in,

determination of rehabilitation setting and, 559

370-371

management plan for, 560-561, 561t

scoliosis in, 354f

return to self-care, 558-559

specific issues in, 357-359

Neurorehabilitation specialist

Neuromuscular junction

patient referral to, 566-567

myasthenia gravis in, 38

Neurotoxicology, 446

Neuromyelitis optica (NMO), 199-200

Neutralizing antibodies (NAbs)

Neuronal apoptotic inhibitory protein (NAIP), 358

MS and, 210, 211

Neuron-specific enolase (NSE), 102

Niacin deficiency

Neuropathic disorder

pellagra and, 473

myopathic disorder v., 354

Nicotinamide adenine dinucleotide (NAD)

Neuropathic injury

role of, 473

indications of, 377

Nicotinamide adenine dinucleotide phosphate

Neuropathies

(NADP)

characteristics of, 21, 21t

role of, 473

Neurophysiologic tests, 37-38

Nicotine

electroencephalography (EEG), 37

neurotoxic effects of, 465

electromyography (EMG), 37-38

Nicotine patches

Neuroprotection

GTS and, 278

MS and, 218

Niemann-Pick disease, 542

Neuroprotective therapy

Nightmare, REM sleep and, 185

Parkinson’s disease and, 234

Nigral neuron

Neuropsychologic testing

parkinsonism and, 235

TBI and, 340

NIMV. See Non-invasive mechanical ventilation

Neuroradiology, 43-60

Nitrate therapy

contrast versus noncontrast, 46-47

neurologic effect of, 451

CT versus MRI, 44-46

Nitrofurantoin therapy

cytotoxic versus vasogenic edema, 50-51

neurologic effect of, 448, 449

herniation and mass effect, 47-49, 48f

Nitroglycerin

hydrocephalus versus volume loss, 49-50, 52f

neurologic effect of, 451

infarct evaluation and vascular imaging, 56-60

Nizatidine (Axid)

intra-axial versus extra-axial lesions, 51-53, 52f

neurologic effects of, 456

intracranial hemorrhage, 53-56

NMDA. See N-methyl-D-aspartate

overview, 43

N-methyl-D-aspartate (NMDA), 299

spine imaging, 53

NMO. See Neuromyelitis optica

Neurorehabilitation, 551

NMO-IgG. See NMO serum biomarker

acute care, 555, 555t

NMO serum biomarker (NMO-IgG), 199-200

assessment role in, 553-555

NMS. See Neuroleptic malignant syndrome

chronic pain in, 563-564

NMSS. See National Multiple Sclerosis Society

communication disorders in, 563

Nociceptive (pain) fibers, 398

discussion questions about, 568-571

Nonarteritic AION (NAION), 528

emotional dysfunction in, 563

Nonbenzodiazepine hypnotics, advantages of,

follow-up and

165, 166

community transition and, 565

Non-Hodgkin lymphoma, 504

621

Index

Non-invasive mechanical ventilation (NIMV)

Obstructive hydrocephalus, 49

central sleep apnea and, 178

Obstructive sleep apnea (OSA), 172-175, 173f

Nonmetastatic complications

cardiovascular diseases and, 174

cerebrovascular, 510-511

causes of, 175

metabolic and nutritional, 511

chronic obstructive pulmonary disease (COPD)

paraneoplastic syndromes, 511-512, 513t

and, 174

Nonnucleoside reverse transcriptase inhibitors

diagnosis of, 174, 175

neurologic side effects of, 449

question about, 189-190

Nonspecific back pain, 399

sleep architecture of, 176f

Nonspecific degenerative disease, 399

symptoms of, 173-174

Nonsteroidal anti-inflammatory agents (NSAIDs),

treatment of, 177

335, 407

CPAP in, 177

MS and, 211

surgical techniques in, 178

neurotoxic effects of, 463

v. central sleep apnea, 174

Noradrenergic antagonists

waking respiratory functions and, 174

TD syndrome and, 283

Occipital focus, 144

Norepinephrine

Occipital nerve blocks

dystonia and, 252

cluster headaches and, 136, 136t, 137

Normal pressure hydrocephalus (NPH)

primary headaches, 132, 132t

dementia and, 290

Occupational therapy

Nortriptyline, cataplectic attacks and, 183

ET and, 259

Novantrone

OCD. See Obsessive-compulsive disorder

MS and, 210t, 211

OCT. See Optical coherence tomography scan

NPH. See Normal pressure hydrocephalus

Ocular bobbing, 97

NREM sleep

Ocular dysmetria

stages of, 157-158, 159f

MS and, 202

NSAIDs. See Nonsteroidal antiinflammatory drugs

Oculocephalic responses

NSE. See Neuron-specific enolase

metabolic encephalopathy, 102

NSF. See Nephrogenic systemic fibrosis

Oculomasticatory myorrhythmia, 548

Nuchal rigidity

Oculomotor nerve (CN III), 7

coma and, 93t, 94

lesion of, 7

Nucleoside reverse transcriptase inhibitors

Oculomotor syndromes

neurologic side effects of, 449

MS and, 202

“Numbness”

Oculopalatal myoclonus, 548

symptom of, 25

Oculopharyngeal dystrophy

Nutrient arteries, 376

symptoms of, 362-363

Nystagmus, 7, 416. See also Vertigo

Oculovestibular responses

AED and, 151

coma and, 97, 98

end point, 416

metabolic encephalopathy, 102

gaze-evoked, 416

Office for Human Research Protections (OHRP),

jerk, 547

574

MS and, 202

OHRP. See Office for Human Research Protections

pendular, 547-548

Olanzapine

vestibular, 416

HD-related psychosis, 266

neurologic effects of, 458

TD syndrome and, 281, 282

tics and, 278

Obesity, sleep apnea and, 173

Olfaction

Obsessions, 4

loss of, 6

Obsessive-compulsive disorder

Olfactory nerve (CN I)

GTS and, 275, 276, 278

olfaction and, 6

HD and, 260

Oligodendrocyte, 502

622

Index

Oligodendroglioma, 502

Orthostatic hypotension

management of, 502

as cause of presyncope, 414

One-and-a-half syndrome, 546

patient evaluation for, 414

ONTT. See Optic Neuritis Treatment Trial

symptoms, 414

Ophthalmic branch (V₁), of trigeminal nerve,

OSA. See Obstructive sleep apnea

7, 8f

Osmotic agents

Ophthalmoparesis, 351

acute alteration in mental status and, 76

Ophthalmoscopy, 518

Osmotic demyelination syndrome, 477

Opiate

Osteomyelitis, 402

GTS and, 278

Otorrhea

Oppenheim dystonia, 246

coma and, 94

Optical coherence tomography (OCT) scan

Overlap syndrome, 174, 177

MS and, 202

Oxazepam, sleep and, 164

Optic atrophy, 7

Oxcarbazepine

Optic chiasm, 520

seizures and, 152

visual field defects in, 522-523, 522f

Oxybutynin

Optic disc appearance, 518-520, 519f

urinary urgency and, 214t, 216

Optic disc pallor, 519

Oxybutynin chloride, sleep-related enuresis and, 186

Optic disc swelling, 519

Oxygen, sleep apnea and, 176

in papilledema, 519

Oxygenation

Optic nerve (CN II), 6-7

evaluation of, SE and, 65

lesion of, 6

lesions of, 521, 521f

Optic neuritis, 527

clinical diagnosis of, 527

PABP2 gene, 363

MS and, 200, 202, 215

Pain

prognosis for, 527

acute spinal cord compression and, 77

Optic Neuritis Treatment Trial (ONTT)

bony spine, 402

MS and, 215

in ligaments, 400

Optic neuropathy, 519, 527-528

management of

in pseudo-Foster Kennedy syndrome, 520

rehabilitation and, 563-564

Optic radiations, 520

MS and, 203

visual field defects in, 525, 525f

treatment in, 215

Optic tracts, 520

in muscles, 400

visual field defects in, 523-524, 523f

nervous system structures and, 25-27

Oral contraceptive

neurogenic, 401

epilepsy and, 153

radicular

Oral contraceptives

cervical processes and, 26

neurotoxic effects of, 463-464

referred, from abdominal, 402-403

Oral trail making

Pain sensation

assessment of, 3-4

sensory examination and, 13

Orbital MRI, 35

Pallidotomy

Orexin in waking, 156

complication from

Organ donation

Parkinson’s disease and, 233

brain death and, 581

Palmar grasp reflex, presence of, 4

Organ harvesting

Palmomental reflex, presence of, 4

brain death and, 581

Palpitations

Orobuccolingual (OBL) dyskinesia

neuromuscular disorder with, 369

TD syndrome and, 279-280

Pancreatic encephalopathy

Oromandibular dystonia, 243, 248

alcoholism and, 476-477

BoNT and, 254

diagnosis, 476

623

Index

pathophysiology of, 476

Parkinson’s disease with dopaminergic adverse

treatment of, 476-477

events, 237

PANDAS. See Pediatric autoimmune neuropsychi-

Parks-Bielschowsky test

atric disorders associated with streptococcal

for fourth nerve palsy, 543

infection

Paroxetine, serotonin uptake and, 183

Panic attacks

Paroxysmal hemicrania, 186

seizures vs., 148

Partial thromboplastin time (PTT)

Papez circuit

comatose patient and, 99

behavioral neurology and, 308-309, 308f

SAH and, 109

Papez loop, 3

Patellar reflex, 11

Papilledema, 528

Patient history

in optic disc swelling, 519

acute alteration of mental status and, 72

Paramedian pontine reticular formation (PPRF)

dementia and, 289

coma and, 95, 96

Guillain-Barré syndrome and, 81

Paraneoplastic syndromes, 511-512, 513t

SE and, 68

Paraparesis, 22

stroke and, 106

Paraplegia, 22

Patrick sign, 403

Parasomnias

PCNSL. See Primary CNS lymphoma

pathophysiologic mechanism of, 184-186

PCoA. See Posterior communicating artery

specialist referral for, 186

PCR. See Polymerase chain reaction

Parcopa, RLS and, 168

PD. See Parkinson’s disease

Paresis, 22

Pediatric autoimmune neuropsychiatric disorders

Paresthesias

associated with streptococcal infection

MS and, 203

(PANDAS)

Parinaud syndrome, 538

GTS and, 276

Parkinsonism, 226-227

Pediatric neurology. See Neurology, pediatric

dopamine system and, 234

Pellagra encephalopathy

drug-induced

alcoholism and, 472-473

anticholinergics, 280

treatment of, 473

diagnosis of, 234

Wernicke encephalopathy versus, 473

Parkinson’s disease v., 233-234

Pendular nystagmus, 547-548

falling associated with, 431-432

oculomasticatory myorrhythmia, 548

medical treatment for, 438-439

oculopalatal myoclonus, 548

neuroleptic-induced, 458

sea-saw, 548

Parkinson’s disease (PD)

Penicillamine therapy, 270, 272t

basal ganglia dysfunction of, 27

adverse effects of

case studies of, 237-240

WD and, 270

as cause of parkinsonism in falling, 431

Penicillins

clinical features of, 222-226, 223f, 224f

neurologic effect of, 447

complementary therapies for, 235-236

Pentobarbital coma, 330

DBS surgery and, 233, 239-240

Perceptual disturbances

disease-modifying therapy and, 234-235

mental status examination and, 4

ET v., 255, 255t, 256, 257, 259

Perfusion-diffusion mismatch, 111

hospitalized patients and

Pergolide

challenges of, 236

Parkinson’s disease and, 227, 229

Lewy bodies and, 296

Perilymph fistula

mechanisms of, 226-228

as cause of vertigo, 421

neurologist referral for, 235

Perindopril

resting tremor and, 254

stroke prevention and, 114

surgery and, 233

Periodic, lateralized, epileptiform discharges

treatment for, 228-230, 228t

(PLEDs), 70

624

Index

Periodic limb movement (PLM) disorder, 157

Phosphenytoin

Peripheral nerve lesions

phenytoin IV vs., 67-68

sensory symptoms of, 26

SE and, 66, 67-68

Peripheral nerves

Physical examination

anatomy of, 376

acute alteration of mental status and, 72

Peripheral nervous system (PNS), 375

Physical therapy

disorder of, 388t

MS and, 218

manifestations of chronic alcoholism,

Physiologic anisocoria, 532

479-482

Physostigmine

myasthenic crisis, 79-81

neurologic effects of, 460

Peripheral neuropathy

PICA. See Posterior inferior cere bellar artery

alcoholim and, 387

Pick disease, 297, 320

anticonvulsants used for, 387

Pimozide

clinical features of, 375-376

GTS and, 277, 278

with diabetes mellitus, 390-392

side effects of, 278

diagnosis of, 382-389

Pineal gland, melatonin and, 157

drug treatment of, 389t

Pinpoint pupils, 95

future prospectives, 393

PION. See Posterior ischemic optic neuropathy

pathology of, 381-382

Pituitary macroadenomas, 522

patterns of abnormality, 380-381

Plantar response

questions and discussion with,

assessment of, 12

394-396

Plasma

symptoms and signs of, 377

ICH and, 119

Peripheral vertigo, 416-417, 416t

Plasma homocysteine level

causes of

stroke and, 113

acute peripheral vestibulopathy,

Plasmapheresis, 360, 390

419-420

myasthenic crisis and, 80

BPPV, 418-419

Platelet count

Ménière disease, 420-421

SAH and, 109

perilymph fistula, 421

PLEDs. See Periodic, lateralized, epileptiform

hearing loss in, 417

discharges

tinnitus in, 417

Plegia, 22

Peroneal neuropathy, 393

Plexopathies, 381

Personality disorders, sleep and, 160

PLM. See Periodic limb movement disorder

PET. See Positron emission tomography

PLMs of wakefulness (PLMW), 167

Phalen’s sign, 392

PLMW. See PLMs of wakefulness

Pharmacologic therapy

PLP. See Proteolipid protein

primary headaches, 132, 132t

PM. See Polymyositis

Pharyngeal dystonia, 243

PMR. See Polymyalgia rheumatica

Pharyngeal weakness

Pneumonia

neuromuscular diseases and, 369

with bulbar dysfunction, 370

Phenobarbital IV

neurorehabilitation and, 557

SE and, 68

PNS. See Peripheral nervous system

Phenothiazines

Poliomyelitis

HD and, 265

Guillain-Barré syndrome vs., 82, 82t

Phenytoin

sleep apneas and, 175

ataxia and, 151

Poliovirus infection, 359

children and, 151

Polyalanine triplet (GCG), 363

phosphenytoin vs., 67-68

Polycystic kidney disease

SE and, 66

aneurysm rupture and, 120

Phobias, 4

Polycythemia, complete blood count and, 175

625

Index

Polymerase chain reaction (PCR)

Potassium-sparing diuretics

herpes simplex encephalitis and, 320

neurologic effect of, 453

Polymyalgia rheumatica (PMR), 364

PP-MS. See Primary progressive multiple sclerosis

Polymyositis (PM), 354, 364-365

Pramipexole

Polymyxins

dyskinesia and, 239

neurologic effect of, 447

Parkinson’s disease and, 227, 229, 232

Polyneuropathies, 25, 448

Pramipexole (Mirapex)

Polyradiculopathies, 25

doses, 168

Polysomnogram (PSMG), 157, 158f, 175, 176f

RLS and, 168

sleep and, 157, 158f

Prazosin

sleep apneas and, 175, 176f

neurologic effect of, 453

Polysomnographic finding

Prednisone

for endogenous v. bipolar depression, 170

AD and, 300

Polysomnography, 334

cluster headache and, 137, 137t

Poor verticality

MS and, 214

falls associated with, 436

myasthenic crisis and, 80

Popeye arms, 352

recommended dosage of, 137t

Posaconazole, 492

Prednisone therapy

Positive sharp waves, 356, 385

for MG, 360

Positron emission tomography (PET), 513

Pregabalin

dementia and, 294

seizures and, 151-152

ET and, 171

Pregabalin, 480

GTS and, 276

Pregnancy

Postacute hospitalization

AED and, 153

TBI and, 331-332

hypnotic drugs and, 165

Postanoxic coma

MS and, 200

prognosis of, 102

RLS and, 167

Postconcussive syndrome, 338

WD and, 272

Posterior communicating artery (PCoA), 543

Premature awakening, 160, 170

Posterior inferior cere bellar artery (PICA), 422

Prenatal testing

Posterior ischemic optic neuropathy (PION),

HD and, 263

519, 528

PRES. See Posterior reversible encephalopathy

Posterior reversible encephalopathy syndrome

syndrome

(PRES), 511

Presyncope, 412-413

Postpolio syndrome, 359

cardiac, 415

sleep apnea and, 175

carotid sinus hypersensitivity and, 415

Posttraumatic amnesia (PTA)

causes of, 413-415

TBI and, 328

hyperventilation syndrome and, 413-414

Posttraumatic cephalgia

hypoglycemia and, 415

mild TBI and, 340

orthostatic hypotension and, 414

Posttraumatic epilepsy, 340

vasovagal/vasodepressor, 414

Posttraumatic hemidystonia, 251

Primary brain injury

Postural adjustments

coma secondary to, 92t

small anticipatory, 435

Primary CNS lymphoma (PCNSL), 504

Postural reflexes

Primary CNS neoplasm

Parkinson’s disease and, 225-226, 226f,

ICH and, 118

238-239

Primary dystonias

Postural responses

classification of, 244-245

associated with falls, 434-437

epidemiology of, 242-244

Postural tremor, 254, 285

Primary generalized epilepsy

ET v., 256

case reviews for, 154

626

Index

Primary headaches

Protriptyline

classifications of, 128-129, 128t

cataplectic attacks and, 183

treatment of, 132, 132t

sleep apnea syndromes and, 176

nonpharmacologic, 132-133

Pseudobulbar syndrome

Primary hemorrhage stroke, 106

MS and, 217

Primary inherited dystonias, 245-247

Pseudohypertrophy of claves, 353f

Primary intracerebral hemorrhage (ICH), 105

Pseudoprogression, 513

Primary memory. See Working memory

Pseudoseizures

Primary progressive aphasia, 297

EEG in, 37

Primary progressive multiple sclerosis (PP-MS)

seizures vs.

clinical symptoms of, 198

AED treatment and, 148

Primary torsion dystonia, 246

Pseudotumor cerebri, 528

Primidone

PSMG. See Polysomnogram

ET and, 258, 258t

PSP. See Progressive supranuclear palsy

side effects of, 258

Psychiatric drugs

Primitive coma, 90

antidepressant agents, 459-461

Prion diseases, 297-298, 495-496

anxiolytics, 459

Prions, defined, 486

hypnosedative, 461

PR-MS. See Progressive-relapsing multiple

neuroleptic agents, 457-459

sclerosis

neurotoxic effects of, 457-461

Procainamide

Psychiatric symptoms

neurologic effect of, 451

MS and, 203

Procarin

WD and, 267, 269

MS and, 218

Psychogenic seizures

Prochlorperazine (Compazine)

AED treatment and, 148

neurologic effects of, 455

Psychogenic unresponsiveness (hysterical coma),

Prodrome, 128

Progressive-relapsing multiple sclerosis

Psychomotor epilepsy, 309

(PR-MS)

Psychophysiologic insomnia, 159

clinical symptoms of, 198-199

Psychosis, drug-induced

Progressive sinus bradycardia, OSA and, 174

Parkinson’s disease and, 231

Progressive supranuclear palsy (PSP), 226,

Psychotherapy

238, 541

primary headaches and, 136

as cause of parkinsonism in falling, 432

PT. See Prothrombin time

posture and, 238-239

PTA. See Posttraumatic amnesia

Promethazine (Phenergan)

Ptosis, 79, 351

neurologic effects of, 455

PTT. See Partial thromboplastin time

Pronator drift

Pulmonary function studies, primary hypertension

testing for, 11

and, 175

Propofol-infusion syndrome, 68

Punch biopsy

Propranolol, 285

of skin, 386

ET and, 257, 258, 258t

Pupil constriction, 530-531

TD syndrome, 283

Pupil dilation, 531

Proprioception

Pupil dysfunction, 531

assessment of, 15

Pupillary abnormalities, 530-538

Prosopagnosia, 529-530

anisocoria, 532-537

Proteolipid protein (PLP)

bilateral light-near dissociation, 537-538

MS and, 195

pupil constriction, 530-531

Prothrombin time (PT)

pupil dilation, 531

comatose patient and, 99

pupil dysfunction, 531

SAH and, 109

relative afferent pupillary defect, 531-532

627

Index

Pupillary response

Ranitidine (Zantac)

coma and, 95

neurologic effects of, 456

Pyridostigmine, 360

RAPD. See Relative afferent pupillary defect

MG and, 360

Rasagiline

myasthenic crisis and, 80

Parkinson’s therapy and, 230

Pyridoxine, 466

Rash, skin

WD and, 270

AED and, 151

Pyrimethamine

lamotrigine

neurologic effect of, 448

seizures and, 152

RBC. See Red blood cell

Rebif

MS and, 209, 210

Quadrantanopia, 525, 525f

Rebound, 168

Quadrantanopias, 6

Rebound headache. See Medication overuse

Quadruple sectoranopia, 525

headache

QuantiFERON-TB Gold test, 491

Receptive aphasia, 3

Quetiapine, 457

Recombinant tissue plasminogen activator

HD and, 265

(rt-PA), 106

HD related psychosis, 266

acute ischemic stroke interventional therapy

Parkinson’s disease and, 231

and, 107

TD syndrome and, 281, 282

case studies and, 123-125

tics and, 278

complications with, 117

Quinidine

contraindications for, 109

neurologic effect of, 451

indications vs. contraindications for, 115, 116t

Rectal exam, 404

Red blood cell (RBC), 70

RAA axis. See Renin-angiotensin-aldosterone axis

Referred pain, from abdominal, 402-403

Rabies encephalitis, 494

Reflexes

Raccoon eyes

HD and, 260

coma and, 94

Rehabilitation

Radiation necrosis, 513

children and neuromuscular disease and,

Radiation therapy

367-368

complications from, 512-513

determining need for, 559

late effects of, 513

discharge planning and, 564-566

Radicular pain

program criteria for, 559-560

cervical processes and, 26

Rehabilitation, fall prevention by

Radiculopathy

assistive devices use, 441-442

cervical dystonia and, 249

balance training, 440

characteristics of, 21, 21t

fall risk assessment, 439-440

Radionuclide bone scan, 406

gait training, 441

Radiotherapy

strength training, 440-441

AVM and, 122

Rehabilitation programs

Raeder’s paratrigeminal syndrome, 533, 533f

home, 560

Ramelteon, insomnia and, 165

management plan for, 560-561, 561t

Ramipril

impaired cognition and, 562-563

stroke prevention and, 114

impaired mobility and, 561, 562

Rancho Los Amigos Scale (RLAS)

nursing facilities with, 560

brain injury and, 326

outpatient, 560

cognitive function after TBI, 328

settings for, 560

Range-of-motion exercises

Rehabilitative therapies

neuromuscular diseases and, 368, 370

epilepsy and, 153

628

Index

Relapsing progressive multiple sclerosis, 199

Rhabdomyolysis, 370-371

Relapsing-remitting multiple sclerosis (RR-MS)

status epilepticus and, 64

clinical symptoms of, 197-198

Riddoch phenomenon

Relative afferent pupillary defect (RAPD), 6, 518

in cortical blindness, 529

in optic tracts, 524

Rifampin, 491

in pupillary abnormalities, 531-532

Rifaximin

Remacemide

used in hepatic encephalopathy, 475

HD and, 265

Right hemispheral destructive lesion, 103

Remission

Rigidity

cervical dystonia and, 248

HD and, 260

REM sleep, 158

Riluzole

hypnosedatives and, 162

HD and, 265

narcolepsy and, 179

Rinne test

Remyelination

for acoustic nerve, 9

MS and, 218

Risperidone

Renal dialysis

GTS and, 277, 278

rhabdomyolysis and, 371

HD and, 265

Renal failure

HD-related psychosis, 266

status epilepticus and, 64

Risperidone, 457

Renin-angiotensin-aldosterone (RAA) axis, 454

neurologic effects of, 458

Rescue therapy

Rivastigmine

for SE patients, 65

AD and, 299

Reserpine

RLAS. See Rancho Los Amigos Scale

depression and, 283

Romberg test, 15

dystonia and, 252

Rooting reflex, 4

GTS and, 278

Ropinirole (Requip)

HD and, 265

doses, 168

side effects of, 252

RLS and, 168

TD syndrome and, 283

Rotigotine

Respiratory agents

Parkinson’s disease and, 229

adrenergic drugs, 456

RR-MS. See Relapsing-remitting multiple sclerosis

neurotoxic effects of, 456-457

Rt-PA. See Recombinant tissue plasminogen

xanthine bronchodilators, 456-457

activator

Respiratory depression, 370

Ryanodine receptor gene, 366

neuromuscular disorders and, 370

Respiratory patterns

coma and, 94

Resting tremor, 254

Sacroiliac joint pain, 402

WD and, 266

SAH. See Subarachnoid hemorrhage

Restless legs syndrome (RLS), 167-170

Salicylate compounds

causes of, 167

neurotoxic effects of, 461-462

diagnosis for, 167

“Salicylate jag,” 462

pathophysiology of, 167-168

SCA. See Spinocerebellar ataxias

prevalence of, 167

Scapular winging

treatment of, 168-170, 169t

weakness and, 350, 350f

Reticular-activating system in waking, 156

Schizophrenia, 309

Retinal gangion cell (RGC), 520

psychotic bizarre behaviors of, 310

Retrobulbar neuritis

TD syndrome and, 281

MS and, 202

TLE behavior and, 310t

Retrocollis, 248

Schwann cells, 375, 376

RGC. See Retinal gangion cell

Sciatica, 401

629

Index

SCN. See Suprachiasmatic nucleus

“Sensory ataxia,” 439

Scoliosis

Sensory disturbance

in chronic infantile spinal muscular atrophy

MS and, 203

and, 354f

Sensory exam, 404

Scopolamine

Sensory feedback

neurologic effects of, 455

loss of, 435

SCUs. See Special care units

Sensory system

SDH. See Succinate dehydrogenase

evaluation of, 12

SE. See Status epilepticus

nerves

Sea-saw nystagmus, 548

peripheral distribution, 12-13, 13f

Secondary dystonia, 243

neurologic examination of, 1, 1t

diagnosis of, 251

pediatric neurology and, 16

etiology of, 244t, 245

syndromes

Secondary headaches

nervous system structures and, 25-27

classification of, 128-129, 128t

Sensory tics

conditions that produce, 128t

GTS and, 273

diagnostic testing and, 127-128, 127t

Sensory weighting

Secondary memory. See Long-term memory

abnormal, 435-436

Secondary progressive multiple sclerosis (SP-MS)

falls associated with, 435

clinical symptoms of, 198

Serologic testing

Sedatives

MS and, 208

comatose patient and, 101

Serotonin reuptake inhibitors (SSRI), 338, 408

Segawa dystonia, 242

Sertraline

Segmental dystonia, 244

serotonin uptake and, 183

Seizure disorders

Serum creatine kinase (CK)

sleep and, 186

Becker dystrophy and, 361

Seizure(s)

muscle necrosis and, 354

AED treatment and, 148

PM and, 364

dietary therapy for, 153

Severe metabolic coma

DOMV requirements for, 582-583

drugs and, 97

in pediatric patients, 450-451

Severe orthostatic hypotension, 235

rehabilitative therapies for, 153

Sexual dysfunction

surgical therapies for, 152-153

MS and, 204

treatment of, 149, 149t

treatment in, 216

types of, 143-144

Short tau inversion recovery (STIR) images

WD and, 267

MS and, 205

Westphal variant and, 260

Short-term memory loss

Selective neuronal degeneration

MS and, 203

HD and, 264

Shoulder girdle, 377

Selective serotonin reuptake inhibitors (SSRIs)

Shy-Drager syndrome, 414

CNS side effects of, 460

SIADH. See Syndrome of inappropriate antidiuretic

migraine and, 136

hormone

MS and, 216

Siberian ginseng (Eleutherococcus senticosus)

OCD and, 278

ephedrine and, 183

TBI and, 335

Sildenafil

Selegiline

MS and, 214t, 216

GTS and, 278

Simple motor tics

narcolepsy and, 181

GTS and, 273

Parkinson’s therapy and, 229-230

Simple partial seizures, 144, 145

Sensation

Simple vocal tics

cutaneous, pathways for, 25-26

GTS and, 273

630

Index

Single-photon emission computed tomography

Sleep latency, drugs and, 162, 163t, 164t

(SPECT), 513

Sleep maintenance, 164

dementia and, 294

Sleep-maintenance insomnia, 160

DRD and, 251

temazepam and, 164

GTS and, 276

Sleep-onset delay, 160-161

Sirolimus

circadian rhythm and, 160-161

neurologic effect of, 450

drug induced, 160

Sixth nerve palsy

insomnia and, 160

in horizontal double vision, 544-545, 545f

psychological factors in, 160

Skeletal muscle

treatment of, 161-162

channelopathies affecting, 364

Sleep-onset insomnia, 160

mitochondrial myopathies and, 366

triazolam and, 164

Skew deviation

Sleep paralysis, 179

in vertical double vision, 544

Sleep-phase syndrome, 160

Skin biopsy, 40

Sleep position, sleep apnea syndrome and,

Skin breakdown

176-177

prevention of, 556

Sleep restriction, 162

Skull flap, 330

Sleep-state misperception, 159

Sleep

Sleep terror, 185

insufficient, 183-184

Sleep-wake cycle

laboratories, use of, 157

agitation and, 336

neurochemistry of, 157

Sleep- wake cycle disturbance (SWCD), 332

stages of, 157-159, 158f, 159f

SLR. See Straight leg raise test

structures facilitating, 156

SMA. See Spinal muscular atrophies

Sleep apnea syndrome, 172

Small artery thrombotic (lacunar) stroke,

diagnosis of, 175

105

drugs for, 176

“Small-fiber” nerves, 12

evaluation of, 175

SMN. See Survival motor neuron gene

frequent awakenings and, 171

Smoking

hypnotic drugs and, 165

cessation

oral appliances for, 178

aneurysm and, 120

postpolio syndrome and, 175

Snoring, UPPP and, 178

question about, 188-189

Snort arousals in obstructive sleep apnea, 173

treatment of, 176-179, 177t

Snout reflex, 4

types of, 172

Sodium oxybate

central, 172, 174

cataplexy and, 181, 183

mixed, 172

narcolepsy and, 181

obstructive, 172-175, 173f

Somato-sensory evoked potential (SSEP), 38

Sleep architecture

MS and, 208

of obstructive sleep apnea syndrome, 176f

Somatostatin

REM and, 157-158, 159f

HD and, 264

Sleep attacks, 168

Somnambulism, 185, 186

in narcolepsy, 179

Somnolence

Sleep-disordered breathing, 160

medical causes of, 184

Sleep disorders

question about, 188

classification of, 159

Spasm, 400

questions about, 187-190

Spasmodic dysphonia, 243

tests available for, 157

BoNT and, 253-254

Sleep fragmentation, causes of, 171

Spasmodic movement, 248, 249

Sleep hygiene, 161

Spasmodic torticollis. See Cervical dystonia

Sleepiness, syndromes causing, 184

Spasms. See Spasticity

631

Index

Spasticity

Staphylococcus aureus, 494

falling associated with, 432

Stare decisis, 573

medical treatment for, 439

Statins

MS and, 206

stroke prevention and, 114

treatment of, 214t, 215

Status epilepticus (SE), 63-65

TBI and, 338

causes of, 64, 65

Special care units (SCUs)

complications of, 68

AD and, 301

convulsive, 64

SPECT. See Single-photon emission computed

CT brain scan and, 68

tomography

defined, 64

Speech

morbidity, 64

mental status examination and, 2-3

mortality rate, 64

Speech therapy, 315, 320

nonconvulsive, 64

WD and, 272

patient history and, 68

Sphenoid sinus disease

precipitants of, 65

secondary headache disorders and, 137

refractory, 68

Sphenoid sinuses

anesthesia for treatment of, 68

headache and, 137

EEG monitoring and, 68

Spinal accessory nerve (CN XI), 9

treatment of, 65-69, 66t, 67t

Spinal cord compression, 402. See Acute spinal

type of, 64

cord compression

Statutory law, 574

Spinal cord injury

Stavudine, 449

neurorehabilitation intervention and, 558

Steele-Richardson-Olszewski syndrome, 541

Spinal cord lesions, 26

Stem cells

MS and, 212-213, 213f

MS and, 218

Spinal deformities, 402

Stereognosis, 14

Spinal metastases, 509-510

Stereotactic techniques

treatment of, 510

ET and, 259

Spinal muscular atrophies (SMA), 358

Stereotypy, 242

Spinal reflex response

Steroid myopathy, 463

brain death and, 581

Steroids

Spinal stenosis, 401

cluster headache and, 136

Spine

neurotoxic effects of, 462-463

CT scan, 405

Stimulus control therapy, 162

MRI with gadolinium, 405

STIR. See Short tau inversion recovery images

MRI without gadolinium dye, 405

Stokes-Adams attacks

x-rays of, 405

seizures vs., 148

Spine imaging, 53

Straight leg raise (SLR) test, 403

Spine lesions, 53, 54f

Strain, 399, 400

Spinocerebellar ataxias (SCA), 235

Strength training

Spirochete meningitis, 491

fall prevention by, 440-441

SP-MS. See Secondary progressive multiple sclerosis

Streptococcus pneumoniae, 487, 489

Spondylolysis, 402

Streptomycin

Sports-related concussive injury

neurologic effect of, 447

mild TBI and, 339-340

Stress

Sprain, 400

tics syndrome and, 274, 275, 279

SSEP. See Somato-sensory evoked potential

Striatal dopamine receptor

SSRI. See Selective serotonin reuptake inhibitors

Parkinson’s disease and, 235

St. John’s wort (Hypericum perforatum), 166

Stroke

Stability

case studies and, 123-125

asymmetrical limits of, 435

clinical evaluation, 108-110

632

Index

Stroke (Continued)

Surgery

diagnostic evaluation, 110-113

cerebral aneurysms and, 121

epidemiology of, 105-108

dystonia and, 253

patient challenges with, 122-123

ET and, 259

prevention

hypersomnia and, 184

pharmacologic treatment for, 114-115, 115t

malignant hyperthermia, 366

primary etiologies for, 106t

Parkinson’s disease and, 233

recurrent

Surgery DBS

predictors of, 107

Parkinson’s disease and, 239-240

risk factors for, 107t

Survival motor neuron (SMN) gene, 358

Stroke management

Swallowing dysfunction

standard measures for, 116, 117, 117t

neuromuscular disorder and, 370

Stupor, 90

SWCD. See Sleep- wake cycle disturbance

Stuporous patient, 2

Swinging flashlight test

Subacute meningitis

for vision loss, 518, 518f

evaluation of, 492t

Sydenham chorea. See also Chorea

Subarachnoid hemorrhage (SAH), 105, 120-122

GTS and, 276

cause of, 55

Sydenham’s chorea, 464

CT brain scan and, 109

Symmetric polyneuropathy, 380

location of, 53

Sympatholytics, 453

with suprasellar cistern, 55, 55f

Syncope

Subdural hematomas, 55, 55f

due to clinical intoxication, 451

location of, 53, 54

neuromucular disorders with, 369

Subfalcine herniation, 47, 48, 48f

Syndrome of inappropriate antidiuretic hormone

Substantia nigra, 239

(SIADH), 335

Parkinson’s disease and, 226

Syphilis serology

Subthalamic nucleus

stroke-like symptoms and, 112

DSB and, 233

Systemic depression

Subwakefulness, 172

coma and, 91, 92

Succinate dehydrogenase (SDH), 366

Succinylcholine, 366

malignant hyperthermia, 366

Sucralfate

Tacrine

neurologic effects of, 456

AD and, 298

Sulfonamide

Tacrolimus, 450

neurologic effect of, 448

neurologic effect of, 450

Sumatriptan

Tardive dyskinesia (TD), 242

migraine and, 134

classification of, 279

SUNCT syndrome

clinical features of, 279-280

treatment of, 137

hospitalized patients, challenges for, 284

Sunflower cataract

pathophysiology of, 280-281

WD and, 268

prevention of, 281-282

Superior arcuate defects, 522

treatment of, 282-283

Superoxide dismutase (SOD1) gene mutation

Tardive dyskinesia (TD) syndrome, 237, 238

on chromosome 21, 359

TBI. See Traumatic brain injury

Superselective vascular catheterization

TCAs. See Tricyclic antidepressants

AVM and, 122

TCD. See Transcranial Doppler

Suprachiasmatic nucleus (SCN)

TD syndrome. See Tardive dyskinesia

circadian sleep rhythm and, 157

TEE. See Transesophageal echocardiography

Supranuclear vertical gaze palsy, 541-542

Temazepam, sleep and, 164

633

Index

Temozolomide

Thiazide diuretics

for astrocytoma, 501-502

neurologic effect of, 452

Temperature sensation

in vertigo, 421

sensory examination and, 13

Third nerve palsy

Temporal arteritis, 381

mydriasis, 535-536, 535f

Temporal dispersion, 384

in vertical double vision, 542-543, 542f

Temporal lobe epilepsy (TLE), 308,

Thomsen disease, 364

309-311

Thoracic cord compression, 77

drug used in, 312t

Thoracic radiculopathies

for hospitalized patients, 313

causes of, 26

refer neurologists, 312-313

Thought blocking, 4

Temporal Lobe Foci, 309t

Thought form

Temporal lobe herniation

abnormalities of, 4

coma and, 95

Threshold values

Temporal lobe injury

and TBI, 329

convulsions and, 146

Thrombocytopenia

Temporomandibular structures

differential diagnosis of, 118

headache and, 137

as result of malignancy, 510

TENS. See Transcutaneous electrical nerve

Thrombotic stroke

stimulation; Transcutaneous electrical

embolic stroke vs., 109, 109t

nerve stimulator

Thrombus

Tension-type headache

occurrence of, 57

classification of, 129

Thymectomy

Tentorium cerebelli

in patients with MG, 360

intracranial hypertension and, 75

Thymic tumors

Terazosin

in patients with MG, 360

MS and, 216

Thyroid eye disease, 7

Terminal insomnia, 160

Thyroid function studies

Tetrabenazine

ET and, 257

depression and, 283

TIA. See Transient ischemic attack

GTS and, 278

Tiagabine

HD and, 265-266

seizures and, 152

Meige syndrome and, 252

Tick-bite paralysis

TD syndrome, 283

Guillain-Barré syndrome vs., 82, 82t

Tetracycline, 448

Tics syndrome, 242

Tetrahydrobiopterin

characteristics of, 273-274

DRD and, 251

classification of, 273

Tetrathiomolybdate (TTM)

clinical spectrum of, 274

WD and, 272, 272t

etiology of, 275

Thalamic lesions, 26

GTS and, 273

Thalamotomy, dystonia and, 246t

medical therapy for, 277t

Thalamus, sleep and, 156

movement disorder v., 273

Theophylline

stress and, 279

neurologic effects of, 456-457

Time of flight (TOF) technique, 47

“The three Ds” of pellagra, 472-473

Tinel’s sign, 392

Thiamine deficiency

Tinetti’s Balance and Gait Test, 440

alcoholic neuropathy due to, 480

Tinetti’s definition of fall, 427-428

alcoholism and, 471

Tinnitus

Thiamine diphosphate

in peripheral vestibular lesions, 417

role in enzyme pathways, 471

Tissue biopsy, 39-40

634

Index

Tissue plasminogen activator (TPA), 56

pathologic studies, 318

Tizanidine

treatment of, 318-319

migraine and, 136

Transient insomnia, 160

spasticity treatment and, 214t, 215, 439

Transient ischemic attack (TIA), 528

TLE. See Temporal lobe epilepsy

patient challanges with, 122-123

TMN. See Tuberomammillary histaminergic

routine studies performed with, 110, 110t

neurons

stroke and, 107

Tobramycin

Transient RBD, drug intoxications and, 185

neurologic effect of, 447

Transient tic disorder, 274, 276

Tocainide hydrochloride

Transitional multiple sclerosis, 199

neurologic effect of, 451-452

Transplant drugs

Todd’s paralysis, 431

cyclosporine, 449-450

TOF technique. See Time of flight technique

immunosuppressives, 450

Tolcapone

Transplant immunosuppressives, 450

Parkinson’s disease and, 228, 228t

Transtentorial herniation, 47, 48, 48f

Parkinson’s therapy and, 230, 232

sequelae of, 49f

Tolterodine

Trauma

urinary urgency and, 214t, 216

coma and, 92t

Tongue protrusion

Trauma, perinatal

HD and, 261

delayed-onset dystonia in, 251

Tonic-clonic epilepsy

Traumatic brain injury (TBI), 324

juvenile myoclonic epilepsy as, 145

abulia and, 338

Tonic-clonic seizures

acute hospitalization, 330

causes of, 143

agitation, 336-338, 337f

Tonic pupil, 536-537, 537f

behavioral disorder/depression, 341

Tonsillar herniation, 47, 48, 48f

discussion questions for, 341-343

Topiramate

dysautonomia, 335

adverse effects of, 259

epidemiology of, 324-325

ET and, 259

hyponatremia, 335

GTS and, 278

late-onset hydrocephalus, 335-336

seizures and, 151, 152

neuropsychologic testing, 340

SUNCT syndrome, 137

neurostimulant agents for, 331

Torticollis, 243, 248

overview, 324-325

GTS and, 273

pathology of, 325-330

secondary dystonia v., 251

postacute hospitalization, 331-332

Toxic compounds

refer neurologists, 340-341

toxic myopathies, 366-367

spasticity and, 338

Toxic myopathies, 366-367

SWCD, 332-335

TPA. See Tissue plasminogen activator

Trazadone, 408

Transcranial Doppler (TCD), 36

Tremor, 11, 237, 242

Transcutaneous electrical nerve stimulation

botulinum toxin and, 249

(TENS), 408

cervical dystonia and, 249

Transcutaneous electrical nerve stimulator

DBS and, 259

(TENS), 340

differential diagnosis of, 255t

Transesophageal echocardiography (TEE)

Parkinson’s disease and, 223, 224

anticoagulant therapy and, 112

voice, 255

Transformed migraine, 129

Treponema pallidum, 487, 491

Transient global amnesia, 308, 317-319

Triazolam, sleep and, 164

consult neurologists, 319

Tricyclic antidepressants (TCAs)

for hospitalized patients, 319

cataplexy and, 183

memory testing during, 318

early morning awakening and, 170

635

Index

migraine and, 136

United States Uniform Determination of Death Act

MS and, 217

brain death and, 579

neurologic effects of, 459-460

Upper airway patency, 174

sleep-related enuresis and, 186

Upper airway resistance syndrome (UARS), 174

Tricyclics

Upper motor neuron lesions

discontinuation of, side effects of, 183

symptoms of, 23-24

Trientine

Upper motor neuron signs, 10

WD and, 270, 272t

UPPP. See Uvulopalatopharyngoplasty

Trigeminal autonomic cephalgias

Uremic encephalopathy

characterization of, 132, 132t

acute alteration in mental status and, 71

Trigeminal cervical connection

Uremic neuropathies, 387

headache and, 137

Urinary tract infections (UTIs)

Trigeminal nerve (CN V)

antibiotics used in, 448

distribution of, 7, 8f

Urination

functions of, 7-8

MS and, 204

Trihexyphenidyl

UTIs. See Urinary tract infections

dystonia and, 252

Uvulopalatopharyngoplasty (UPPP), 178

side effects of, 252

Trimethoprim

neurologic effect of, 448

Trimipramine, early morning awakening and,

VaD. See Vascular dementia

170

Vagus nerve (CN X), 9

Triple flexor response

Valproate

coma and, 98

seizures and, 149

Triptans

side effects of

medication overuse headache and, 130, 130t

seizures and, 151

migraine and, 134

Valproate IV

Trochlear nerve (CN IV), 7

SE and, 68

lesion of, 7

Variant of CJD (vCJD), 496

Truncal dystonia, 243

Vascular dementia (VaD), 291, 295-296

Tryptophan, 466

risk factors for, 295

TTM. See Tetrathiomolybdate

Vascular endothelial growth factor (VEGF), 502

Tuberculous meningitis, 491-492

Vascular imaging, 36-37

treatment of, 491-492

catheter angiography, 36-37

Tuberomammillary histaminergic neurons

computed tomographic angiography, 36

(TMN), 156

infarct evaluation and, 56-60

sleep and, 156

magnetic resonance angiography, 36

T1-weighted images, 35, 44, 45f

magnetic resonance venography, 36

T2-weighted images, 35, 44, 45f

ultrasonography, 36

Type 2 diabetes and OSA, 174

Vasodilators

Tyrosine hydroxylase

neurologic effect of, 453

DRD and, 251

Vasogenic edema, 52f

Tysabri

acute intracranial hypertension and, 76

MS and, 210t, 211-212

cytotoxic edema versus, 50-51

Vasospasm

cerebral aneurysms and, 121

Vasovagal presyncope, 414

UARS. See Upper airway resistance syndrome

VCJD. See Variant of CJD

Ulnar neuropathy, 392-393

Vegetative state

Ultrasonography, 36

locked-in syndrome, 90, 91

Uncal herniation syndrome, 75

VEGF. See Vascular endothelial growth factor

636

Index

Venlafaxine

Vestibular nystagmus, 416, 547

MS and, 217

Vestibular system disorders

Venography (MRV)

falling associated with, 433

acute stroke evaluation and, 111

medical treatment for, 439

Ventilation

Menière disease and, 433

neuromuscular diseases and, 369

Vestibulocochlear nerve (CN VIII), 8-9

Ventricular trapping, 48f

Vestibuloocular reflex (VOR), 417, 539, 540, 541

Ventrolateral preoptic nucleus (VLPO)

Vestibulotoxins, 424

sleep and, 156

VGCC. See Voltage-gated P/Q-type calcium

VEP. See Visual evoked potential

channels

Verbal fluency

Vibratory exam, 404

assessment of, 3

Vincristine, 387

Vertebral bodies

Viral meningitis, 488-489

compression fracture of, 402

Vision loss, 517-518

Vertebral dissection syndromes

cortical, 529

headache and, 137

evaluation of, 517-518

secondary headache disorders and, 137

Visual acuity

Vertebrobasilar distribution ischemia

testing of, 6

carotid ischemia vs., 113, 113t

Visual acuity test

Vertical double vision, 542-544

for vision loss, 517

fourth nerve palsy, 543-544, 544f

Visual cortex

skew deviation, 544

radiations converge on, 520

third nerve palsy, 542-543, 542f, 543f

visual field defects in, 525-526, 526f

Vertigo, 413

Visual disorders

associated with brainstem, 417

cortical vision loss, 529

ataxia in, 417

of object recognition, 529-530

central, 416-417, 421

of visuospatial processing, 530

basilar migraine, 423

Visual dysfunction

cerebellar hemorrhage, 422-423

in disequilibrium, 423

lateral medullary ischemia, 422

Visual evoked potential (VEP), 38

lateral pontine ischemia, 422

MS and, 208

multiple sclerosis, 423

Visual field defects, 6

transient ischemic attack, 422

in lateral geniculate nucleus, 524-525, 525f

cerebellar signs in, 417

in optic chiasm, 522-523, 522f

distinguishing peripheral and central, 416t

optic nerve defects, 521f

Dix-Hallpike positional test for, 418, 418f

in optic radiations, 525, 525f

Halmagyi head thrust test in, 417

in optic tracts, 523-524, 523f

hearing loss in, 417

in visual cortex, 525-526, 526f

mild TBI and, 339

Visual fields, 520-527, 520f

nystagmus and, 416

testing of, 6

peripheral, 416-417

Visual pathway. See Visual field

acute peripheral vestibulopathy, 419-420

Visuospatial neglect, 530

BPPV, 418-419

Visuospatial processing

Ménière disease, 420-421

mental status examination and, 3

perilymph fistula, 421

Vitamin A, 465

pharmacologic treatments for, 420t

Vitamin B₆, 466. See Pyridoxine

symptoms, 415

Vitamin B₁₂

tinnitus in, 417

MS and, 218

Vestibular dysfunction

Vitamin C therapy

in disequilibrium, 424

Parkinson’s disease and, 234

637

Index

Vitamin D, 465

herbal, 183

MS and, 200

sleep apnea and, 176

Vitamin E

Wernicke aphasia, 3, 314-315

HD and, 265

Wernicke encephalopathy, 308. See Wernicke-

TD syndrome and, 283

Korsakoff syndrome

Vitamin E therapy

acute alteration in mental status and, 72

Parkinson’s disease and, 234

alcoholism and, 471-472

Vitamins

dementia and, 291

neurotoxic effects of, 464-466

diagnosis of, 472

VLPO. See Ventrolateral preoptic nucleus

versus pellagra, 473

Vocal tics

symptoms, 471

GTS and, 273

treatment of, 472

Voice tremor, 255

Wernicke-Korsakoff syndrome, 479

Voltage-gated P/Q-type calcium channels

behavioral picture of, 316

(VGCC), 361

comatose patient and, 100

Volume loss, 49

diagnosis of, 316

hydrocephalus versus, 49-50

overview, 315-316

Voluntary conjugate gaze (PSP), 235

refer neurologists, 317

VOR. See Vestibuloocular reflex

treatment of, 317

Voriconazole, 492

West Nile virus, 492

VTA. See Dopaminergic ventrotegmental area

Westphal variant

HD and, 260

Whipple’s disease, 542, 548

WHO. See World Health Organization

Wakefulness after sleep onset (WASO), 165

Wilbrand knee, 523

Wake-promoting hypocretin system in waking,

Wilson disease (WD), 237, 238, 242

156

AHCD versus, 475

“Walk and Talk” task, 436

clinical manifestations of, 266-268

Wallenberg syndrome, 533. See Lateral medullary

diagnosis of, 269-270

infarction

genetics of, 268-269

Wallerian degeneration, 326

neurologist referral for, 273

Warfarin

neuropathology of, 268

ICH and, 119

new-onset dystonia and, 251

stroke prevention and, 115

pathogenesis of, 268-269

Wartenburg sign, 392

treatment of, 270-272, 272t

WASO. See Wakefulness after sleep onset

Women’s Health Initiative Memory Study, 300

Wax and wane

Working memory

GTS and, 274, 275

testing, 3

Weakness

World Health Organization (WHO)

falling associated with, 433-434

definition of fall by, 427

medical treatment for, 439

disablement and, 551, 551t

MS and, 206

Writer’s cramp

neurologic diagnostic process and, 22-25

cervical dystonia and, 249

shoulder girdle, 350, 351f

dystonia and, 249-250, 250f

Weak postural responses, 434

Weber syndrome, 542

Weber test

for acoustic nerve, 9

Xanthine bronchodilators

Weight loss

neurologic effects of, 456-457

HD and, 261

X-linked dystrophin gene, 361