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part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means,

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Illustrations by Yvonne Wylie Walston, CMI © Creative Imagery, Inc.

Library of Congress Cataloging-in-Publication Data

Davis, Larry E. (Larry Ernest)

Fundamentals of neurologic disease : an introductory text / Larry E.

Davis, with Molly K. King, Jessica L. Schultz ; illustrations by Yvonne

Wylie Walston.

p. cm.

Includes bibliographical references and index.

ISBN 1-888799-84-6 (pbk. : alk. paper)

1. Neurology. 2. Nervous system—Diseases.

[DNLM: 1. Nervous System Diseases. WL 300 D262f 2005] I. King, Molly

K., 1962- II. Schultz, Jessica L., 1974- III. Title.

RC346.D385 2005

616.8—dc22

2004030159

CONTENTS

Disorders of the brainstem and cerebellum

Lateral medullary infarction (Wallenberg syndrome)

Spinocerebellar ataxia (SCA 1)

Disorders of the cerebrovascular system

Ischemic strokes (embolic and lacunar)

Transient ischemic attacks

Hemorrhagic strokes

Spontaneous intracranial hemorrhage

Saccular aneurysms

Disorders of myelin

101

Myelin 101

Multiple sclerosis

102

Guillain-Barré syndrome

105

Disorders of higher cortical function

109

Prefrontal lobe

110

Limbic system

110

Parietal lobe

111

Aphasias

113

Intelligence

115

Neurologic changes of normal aging

115

Dementia

116

Alzheimer’s disease

117

Mental retardation

120

Disorders of the extrapyramidal system

123

Essential tremor

124

Parkinson’s disease

126

Huntington’s disease

130

Central nervous system infections

133

Bacterial meningitis

134

Brain abscess

137

Herpes simplex virus encephalitis

139

Prion diseases

141

CONTENTS

Brain tumors

145

Brain herniation syndromes

145

Cerebral edema

146

Glioblastoma multiforme — malignant astrocytoma

147

Meningioma

149

Pituitary adenoma 150

Cerebral metastases

152

Seizures and status epilepticus

155

Primarily generalized tonic-clonic seizures and secondarily generalized

partial seizures (Grand mal seizure)

156

Absence seizure (Petit mal seizure)

158

Infantile spasms (West’s syndrome)

159

Complex partial seizure (Localization-related, temporal lobe, or

psychomotor seizure)

160

Status epilepticus

161

Coma and cerebral death

165

Coma

165

Cerebral death

171

Disorders of the developing nervous system

173

Anencephaly

174

Chiari type I and II malformations

176

Phenylketonuria (Phenylalanine hydroxylase deficiency)

178

Tay-Sach’s disease (Hexosaminidase A deficiency)

179

Down syndrome

181

Traumatic brain injury and subdural hematoma

185

Traumatic brain injury

185

Chronic subdural hematoma

190

Neurologic complications of alcoholism

193

Drunkenness and alcoholic coma

194

Alcoholic tremulousness and hallucinosis

194

Alcohol-withdrawal seizures

195

Delirium tremens

195

Wernicke’s encephalopathy and Korsakoff ’s psychosis syndrome

195

Preface

This textbook is intended for students who wish to

The later chapters are divided into chapters that

learn the basic principles of neurology and to

review common diseases present at different neu-

understand common neurologic diseases. We

roanatomic sites along the neuroaxis from muscle

selected 58 neurologic diseases based on their fre-

to the cerebral cortex and chapters on diseases that

quency, ability to represent that category of neuro-

have a similar pathophysiology. Each chapter

logic disease, value in teaching neuroscience

begins with an overview to understand the com-

concepts, and diagnostic importance.

mon features of this group of diseases. Selected

We recognized that most introductory courses

diseases are then discussed with an emphasis on

on neurologic diseases are short and lack suffi-

the pathophysiology, major clinical features, major

cient time for a student to extensively read a com-

laboratory findings, and the principles of disease

prehensive neurology textbook. In addition, while

management. Our book covers both adult and

abbreviated versions of neurology textbooks cover

pediatric neurologic diseases.

a myriad of neurologic diseases in telegraphic

This book does not cover detailed aspects of dis-

style, they are difficult to comprehend unless one

ease variants, all possible laboratory tests, drug

already knows about the disease. Thus, many stu-

dosages, or many related neurologic diseases as it is

dents finish the course with a spotty understand-

not designed for the specific treatment of neuro-

ing of neurology.We designed our book to be read

logic patients. Our goal is to provide broad and

from cover to cover, giving the reader a more

integrated coverage of the fundamentals of com-

thorough understanding of the fundamentals of

mon neurologic diseases in the context of a

neurology.

competent examination strategy, the disease patho-

The first chapters cover the basic approach a

physiology, and the principles of disease manage-

neurologist takes when encountering a patient with

ment. We hope that students will find the book

a neurologic problem, the key elements of the neu-

structure and context useful in their studies and that

rologic exam, and an overview of common neuro-

it will contribute to the instructors’ efforts to sup-

logic tests. We discuss how to use the history and

port students in their learning.

neurologic exam to localize the patient’s problem to

specific neuroanatomic site(s) and to use the neu-

Larry E. Davis, M.D.

roanatomic information along with results of

Molly K. King, M.D.

appropriate laboratory tests to establish a diagnosis.

Jessica L. Schultz, M.D.

vii

Acknowledgments

Dr. Davis is indebted to his late father, Lloyd, for

Finally, we thank everyone who helped in the

his years of encouragement in his pursuit of schol-

preparation of this book. In particular, we are

arly endeavors; to his wife, Ruth Luckasson, for her

grateful to Yvonne Walston, CMI, of Creative

support, ideas, patience, and encouragement dur-

Imagery, Inc. whose artwork improved the clarity

ing the many hours of writing this book; and to his

of the chapters, to Dr. Blaine Hart, who con-

children Meredith, Colin, and Charles.

tributed neuroimaging illustrations, to Drs. Mark

Dr. King thanks Dr. Joe Bicknell for his enthu-

Becher and Mario Kornfeld who contributed neu-

siastic mentoring and Dr. Kurt Fiedler for his

ropathology illustrations, and to Diana Schneider,

inspiring, never-ending pursuit of knowledge. Dr.

PhD, President of Demos Medical Publishing, who

Schultz would like to thank her husband, Brandon,

supported the creation of this book.

for his support and unfailing patience during the

creation of this book.

Foreword

A detailed patient history and physical examina-

anatomical and pathological correlation and pro-

tion remain the underpinnings of neurologic diag-

vides many tables and line drawings that help in

nosis. Imaging and laboratory testing are

understanding the anatomy and physiological

important, but the ability to piece together clues in

basis of disease and the differential diagnosis of

the patient’s story and to localize lesions by the

neurologic illnesses. Too often introductory vol-

findings on the neurologic examination still sepa-

umes on neurology are overwhelming in bulk and

rate the good neurologist from the main body of

complexity. The authors of this volume have suc-

physicians. Medical students who choose neurol-

ceeded in presenting a gentler and concise intro-

ogy for a career often cite two factors that have

duction to this fascinating subject.

influenced them—first, the spectacular basic and

clinical advances in the understanding and treat-

Richard T. Johnson, MD, FRCP

ment of neurologic illnesses and, second, the con-

Distinguished Service Professor of Neurology,

tinued reliance on clinical skills and the

Microbiology and Neuroscience

formulation of diagnoses at the beside or in the

The Johns Hopkins University School of

clinic.

Medicine & Bloomberg School of Public Health

This condensed volume introduces the reader

Baltimore, Maryland

to neurologic diseases; it emphasizes the clinical

APPROACH TO THE PATIENT

WITH A NEUROLOGIC PROBLEM

Key Steps in Neurologic Diagnosis and Treatment

When helping a patient with a neurologic disorder,

ment. The expert clinician often is able to estab-

a clinician uses clinical skills (taking the history,

lish the correct diagnosis by listening to the his-

conducting the physical and neurologic examina-

tory, forming a hypothesis, and confirming that

tion, and ordering of appropriate tests), knowl-

hypothesis based on the neurologic exam. How-

edge of neuroanatomy, and an understanding of

ever, the medical student seldom possesses these

the pathogenesis of the neurologic disease process

skills, as they come with experience. Fortunately,

(Figure 1-1). The goals are to alleviate signs and

following eight logical steps can help one arrive at

symptoms and to restore and keep the patient in

the same diagnosis. This avoids costly mistakes

the best possible health.

due to ordering inappropriate laboratory tests,

To achieve these goals, one must establish the

establishing an incorrect diagnosis, and prescrib-

correct diagnosis and initiate appropriate treat-

ing the wrong treatment.

Figure 1-1

Approach to the neurologic patient.

FUNDAMENTALS OF NEUROLOGIC DISEASE

Steps in Diagnosing

in which damage to any lobe produces similar

symptoms.

Neurologic Conditions

The nervous system can be divided into discrete

anatomic compartments that give rise to a specific

1. Determine whether the condition involves

constellation of signs and symptoms. This book

the nervous system

follows the neuroanatomic outline below:

2. Determine an anatomic localization

3. Establish the time course of symptoms

Muscle

4. Determine the most likely disease cate-

↓

gory(s)

Neuromuscular junction

5. Make a clinical diagnosis or differential

↓

diagnoses

Peripheral nerve

6. Order appropriate laboratory or neuroimag-

↓

ing tests

Nerve root

7. Establish definite diagnosis

↓

8. Begin appropriate etiologic and sympto-

Spinal cord

matic treatment

↓

Brainstem

↓

1. Determine Whether the

Cerebellum

Condition Involves the

↓

Basal ganglia and thalamus

Nervous System

↓

Cerebral cortex

The first step is to determine whether the patient’s

↓

signs and symptoms are due to an illness involving

Meninges and cerebrospinal fluid

the nervous system. This decision is based on the

history and physical exam coupled with knowl-

In defining the neuroanatomic site, the clini-

edge of general medical diseases. For example, syn-

cian should establish the highest and lowest points

cope causes loss of consciousness, but the etiology

of the nervous system that can give rise to the

can be from cardiovascular disease.

patient’s signs and symptoms. Helpful keys in

determining the most likely neuroanatomic local-

ized site include:

2. Determine an Anatomic

1. Finding the earliest signs and symptoms of

Localization

the illness, which usually denote anatomi-

Another important step based on the history and

cally where the disease began.

physical examination is to establish the most likely

2. Determining the anatomic site where weak-

neuroanatomic site that could cause the patient’s

ness and/or sensory changes likely are pro-

problem. While experts may bypass this step, it is

duced. Motor and sensory systems are

helpful to the beginning clinician. Knowledge of

multisynaptic long-tract systems commonly

the site enables the clinician to narrow the list of

involved in many diseases. Weakness pro-

differential diagnoses and to determine which lab-

duced by dysfunction of the motor system at

oratory and neuroimaging tests will yield the most

the motor cortex, brainstem, spinal cord,

useful information.

peripheral nerves, neuromuscular junctions,

Neurologic localization is possible because the

and muscle has unique characteristics that

nervous system is organized such that each major

help localize the site of the problem.

neuroanatomic location gives rise to specific

3. Identifying accompanying nonneurologic

signs and symptoms. As such, the nervous system

signs and symptoms that may help localize

differs from many other organs such as the liver,

the site.

CHAPTER 1—Approach to the Patient with a Neurologic Problem

Although there are many neurologic signs and

Applying the acronym VINDICATES is one way to

symptoms that point to a given neuroanatomic

classify etiologic groups. Table 1-2 lists common

site, some of the more common clinical features

clinical features seen in each category. Again, diseases

are provided in Table 1-1. However, not all the

in each category may not express all the features.

signs and symptoms are present in a given patient,

and certain diseases do not follow those specified

5. Make a Clinical Diagnosis or

in this table.

Differential Diagnoses

At this point the clinician uses the information

3. Establish the Time

gained from the history and neurologic examina-

Course of Symptoms

tion, most likely disease category, and knowledge

of neuroanatomy and neurophysiology to estab-

The time course of the patient’s symptoms is an

lish a clinical diagnosis or list of relevant differen-

important part of the history and can be difficult to

tial diagnoses. In essence, the clinical diagnosis is a

obtain. The patient often may not have recognized

working diagnosis that allows the clinician to

early symptoms or attributed them to other causes.

determine which laboratory or neuroimaging

Patients also rarely describe their symptoms in a

tests, if any, are necessary for establishing a definite

clear time line. Determination of the time course

diagnosis. While this book gives the reader consid-

helps with urgency of the work-up, disease cate-

erable basic information about common neuro-

gory classification, and prognosis. In children it is

logic diseases, the reader should refer to journal

often difficult to determine whether the disease is

articles and comprehensive neurology textbooks

progressive or static. Static lesions may be misinter-

preted as progressive when children fail to reach

for complete information on specific diseases and

their expected age-related milestones.

details about treatment.

The differential diagnosis should focus on diag-

noses considered most likely. The adage, “Think of

4. Determine the Most Likely

horses, not zebras, when you hear hoof beats,

unless you are in Africa” is true in neurology.

Disease Etiology(s)

Common diagnoses are common but may present

Most neurologic diseases fall into one disease cat-

with atypical features. The differential diagnosis

egory, and each category has common clinical fea-

list should contain diseases that you intend to rule

tures that allow selection of the category. Below are

in or out by appropriate laboratory tests. One can

useful questions to establish the most likely disease

always add more diseases to the differential diag-

category:

nosis list as the work-up proceeds.

• Is the problem new or has it occurred in the

past?

6. Order Appropriate Laboratory

• Was there a trigger for the onset or episode?

and/or Neuroimaging Tests

• What aggravates and alleviates the symptoms?

• Was onset acute, subacute, or gradual?

• Are signs rapidly progressive over hours to 2

Neurologic tests should serve to: (1) establish the

days, subacutely progressive over days to a

etiologic diagnosis when several likely diagnoses

few weeks, slowly progressive over months to

exist; (2) help make therapeutic decisions; and (3)

years, or static and not progressive?

aid in following the results of treatment. Knowl-

• Are signs unilateral or bilateral?

edge of the approximate neuroanatomic location

• Is pain a feature, what are its characteristics,

and the most likely category of disease process

and where is it located?

enables the clinician to order appropriate tests. As

• Is there a family history of similar problems?

neurologic tests are expensive, time-consuming

• Is lesion likely a mass or nonmass?

and occasionally dangerous or uncomfortable to

• Is the location focal, multifocal, or diffuse?

the patient, thought must be given before ordering.

Table 1-1

Common Clinical Features of Neurologic Illness by

Neuroanatomic Site

Muscle

Weakness without sensory loss

Proximal muscles weaker than distal muscles

Weakness that is often slowly progressive

Muscle atrophy

Neuromuscular Junction

Fatigue (especially to chewing and in proximal limb muscles)

Weakness without sensory loss

Ptosis with changing diplopia

No muscle atrophy

Peripheral Nerve

Mixture of motor and sensory findings

Distribution of signs either in a single nerve or in many nerves

Distal limb signs more pronounced than proximal signs

Trunk uncommonly involved

Pain in feet or along a single nerve distribution

Sensory loss due to pain and temperature, or vibration and position sense, or to all modalities

Muscle atrophy and occasionally fasiculations corresponding to involved nerve

Nerve Root

Dermatomal distribution of sensory loss

Neck or back pain that may extend into limb

Loss of deep tendon reflex associated with that root

Weakness only in muscles supplied by that root

Spinal Cord

Sensory level is present

Weakness that may involve both legs or all limbs

Bowel and bladder signs

Autonomic nervous system dysfunction

Loss of reflexes at the level of cord involvement with hyperactivity below that level

Babinski signs

Leg spasticity

Brainstem

Cranial nerve involvement (especially facial weakness, facial sensory loss, dysphagia, dysarthria,

hoarseness, and diplopia)

Vertigo

Tetraparesis with four limb weakness and spasticity

Coma or semicoma

Changes in blood pressure, heart rate, and respiratory rate

Cerebellum

Ataxia of limbs and gait

Vertigo

Nystagmus

Basal Ganglia and Thalamus

Extrapyramidal signs (bradykinesia, shuffling gait, masked facies, etc.)

Movement disorder (chorea, athetosis, or tremor, which may be unilateral or bilateral)

Cerebral Cortex

Unilateral focal neurologic signs such as hemiparesis, hemihypesthesia, homonymous hemianopia

Aphasia

Memory loss

Apraxia

Dementia

Seizures

Meninges and Cerebrospinal Fluid

Headache—usually diffuse

Meningismus

Cranial nerve signs—often with multiple nerves involved

CHAPTER 1—Approach to the Patient with a Neurologic Problem

Table 1-2

Common Clinical Features of Neurologic Illness by Etiologic Group

Vascular

Sudden onset

Asymmetrical signs

Symptoms worse at beginning and then improve

Hemiparesis and hemihypesthesia (but not anesthesia) common

Inflammatory/Infectious

Fairly rapid onset and progression

Fever common

Signs usually involving meninges or cerebral cortex

White blood cell count and erythrocyte sedimentation rate elevated

Neoplastic

Slowly progressive

In adults, mainly involving cerebral cortex, while in children, mainly involving cerebellum and brainstem

Unilateral focal signs common early in disease

Degenerative/Hereditary

Slowly progressive

Symmetrical signs

Diffuse signs

Pain seldom prominent

Family history of similar illness may be present

Clinical features varying, but often including dementia, parkinsonism, and weakness

Intoxication or Withdrawal

Gradual onset of symptoms over hours to weeks

History of unusual drug or substance usage

Altered mental activity (confusion, delirium, stupor, or coma)

Distal symmetrical polyneuropathy common

Focal neurologic signs less common

Congenital/Developmental

Present at birth or early childhood

Family history of similar disease common

Mainly static but can appear progressive in childhood as child fails to gain developmental milestones

Mental retardation, seizures, and spasticity common

Autoimmune/Demyelinating

Onset over days

Prominent motor, sensory, visual, and/or cerebellar signs common

Symmetrical or diffuse clinical features

Trauma

Abrupt onset

History of trauma present

Coma or loss of consciousness common

May cause motor and sensory dysfunction of one peripheral nerve

Clinical improvement eventually occurs

Endocrine/Metabolic

Gradual onset

Slowly progressive

Systemic disease common, especially in liver, lung, or kidney

Symmetrical signs

Abnormal lactation common

Social/Psychologic

Past or present history of psychiatric illness, especially depression

History of abuse

Waxing and waning of symptoms

Nonphysiologic exam

Secondary gain

Positive review of systems with multiple somatic complaints

FUNDAMENTALS OF NEUROLOGIC DISEASE

The overall goal should be to establish the diagno-

blood-brain barrier, they would have difficulty dif-

sis efficiently in both time and money. The shotgun

fusing any distance into the cerebral cortex.

approach (where many tests are ordered in hopes

Management of the patient with a neurologic

of finding the diagnosis) is both expensive and

disease can be divided into four categories: pre-

often unhelpful.

vention, etiologic treatment, symptomatic treat-

ment, and rehabilitation. The key to success is

management of the patient’s complaints and not

7. Establish Definite Diagnosis

just the laboratory tests.

The definite or etiologic diagnosis implies that

Prevention

the diagnosis is firm and no further diagnostic

tests are indicated. Combining information

“An ounce of prevention is worth a pound of cure”

gained from the history and physical exam, the

is particularly pertinent in neurologic disease. A

results of appropriate laboratory and neuroimag-

major effort in neurology focuses on early disease

ing tests, and knowledge of the anatomy and

detection and prompt treatment to minimize later

pathophysiology of the disease in question helps

complications. For example, the treatment of

the clinician arrive at the definite diagnosis. For

hypertension markedly reduces the incidence of

some diseases, there may be a single diagnostic

subsequent strokes. Treatment of the patient with

test that establishes the etiology. For example,

a transient ischemic attack with aspirin reduces

growth of Streptococcus pneumoniae from the

future strokes in many patients by 13-20%. Immu-

cerebrospinal fluid of a patient with meningeal

nization of children with poliovirus vaccine pre-

symptoms establishes the definite diagnosis of

vents subsequent paralytic poliomyelitis.

pneumococcal bacterial meningitis. For other

diseases, for example, classic migraine headache,

Etiologic Treatment

there may be no diagnostic test that establishes

the etiology and definite diagnosis must rest on

Treatment of the etiology should be the goal in the

the history, physical exam, and knowledge of the

care of every patient. Often it is possible to reverse

disease in question.

or halt the underlying disease process. This may

cure the patient, such as by removal of a menin-

gioma. Once the etiology is established, current

8. Begin Appropriate Etiologic and

treatment options are easily found in standard

Symptomatic Treatment

medical or neurologic textbooks or recent review

articles in journals. Unfortunately, for many neu-

Treatment of neurologic disease differs from treat-

rologic diseases the etiologies are unknown, and

ment of diseases of other organs in several aspects.

hence treatment options are poor.

First, neurons do not divide after birth. Thus the

brain cannot replace lost neurons. Second, damaged

Symptomatic Treatment

central nervous system (CNS) myelin or oligoden-

drocytes have limited ability to remyelinate naked

Treatment should be aimed not only at the etiol-

axon segments. Third, surgical removal of a brain

ogy but also at relieving the patient’s signs and

lesion may not be possible because the lesion is in

symptoms, as they are what brought the patient to

part of the brain that is inaccessible due to its deep

the doctor. Symptomatic treatment often brings

anatomic location or because the lesion is sur-

considerable improvement in the quality of the

rounded by critical brain areas (eloquent brain).

patient’s life. For example, administration of L-

Fourth, any drugs given systemically to the patient

dopa greatly improves the disturbing features of

must be capable of crossing the blood-brain barrier.

Parkinson’s disease. However, symptomatic treat-

This barrier severely limits many otherwise effective

ment is not etiologic treatment. While L-Dopa

medications that could be given to the patient. Even

improves the symptoms of Parkinson’s disease, it

if the drugs were given intrathecally into the cere-

does not halt disease progression. Similarly, nar-

brospinal fluid

(CSF) space to bypass the

cotics relieve the pain of a brain tumor but do not

CHAPTER 1—Approach to the Patient with a Neurologic Problem

cure the tumor. When treating the patient, it is

aware that the brain has considerable capacity for

important to observe for side effects.

recovery from damage. There are many factors

Symptomatic treatment should also address the

involved in recovery. An important one is neuro-

psychologic aspects of the illness. Fear or worry

plasticity. The term neuroplasticity means that

about the disease frequently causes anxiety or

other neuronal populations take over the function

depression that may incapacitate the patient. Even

of the damaged part of the brain. At present we

if the disease cannot be cured and is fatal, the

have little understanding of how the brain can

patient should know that the physician cares and

alter synaptic pathways to accomplish this. In gen-

will do everything possible to minimize symptoms.

eral, children have a greater capacity than adults

for neuroplasticity. Increasing evidence suggests

that it can be enhanced through active stimulation,

Neurorehabilitation

motivation, and rehabilitation of the patient. In

Neurorehabilitation should not be overlooked as

addition, rehabilitation can help the patient learn

an important therapeutic tool in the care of the

new methods to compensate.

neurologic patient. We are becoming increasingly

NEUROLOGIC EXAMINATION

cooperate, the remainder of the mental status

Overview

exam should be interpreted cautiously. For exam-

ple, problems with memory may be due to the fact

The physical examination begins the instant you

that the patient never paid attention to the infor-

meet the neurologic patient. Much information is

mation presented.

gleaned from observing the patient during the

Memory problems are suggested by a vague

interview and noting the patient’s speech pattern,

imprecise history, inability to recall current events,

mentation (mental activity), behavior, and pres-

or not remembering the events of the day. One can

ence of abnormal motor movements. The neuro-

ask the patient to repeat three objects (like apple,

logic exam is divided into specific components

table, and penny) immediately and then after 5

that are usually written separately in the chart.

minutes. Normal subjects usually can repeat at

Below are the neurologic tests commonly done.

least two of the objects at 5 minutes, especially

For each area there are many additional tests that

with prompting.

can be done (see comprehensive neurology text-

Cognition should be evaluated relative to the

books for details).

patient’s education and socioeconomic back-

ground. In general terms, it is an estimate of the

patient’s general mental capability that includes

Mental Status Examination

reasoning, planning, solving problems, thinking

abstractly, comprehending complex ideas, learning

The depth to which the mental status exam is pur-

quickly, and learning from experience. If a deficit is

sued depends on the presenting problem and your

detected, critical questions include whether it is of

observations while taking the history. Compo-

recent onset, or progressive, or static.

nents of the mental status exam include: alertness,

One useful screening test of mental status is

attention, cooperation, memory, cognition, mood

called the Folstein Mini Mental Status Examina-

and affect, and speech and language.

tion (Table 2-1). This test is not sensitive for mild

Alertness, attention, and cooperation are evalu-

cognitive impairment, as scores as low as 22/30

ated during the history. If the patient fails to

may be normal depending on education and

demonstrate the ability to attend, stay awake, or

socioeconomic background.

FUNDAMENTALS OF NEUROLOGIC DISEASE

Table 2-1

Folstein Mini Mental Status Examination

Task

Instructions

Scoring

Date Orientation

“Tell me the date?” Ask for omitted items.

One point each for year, season,

date, day of week, and month

Place Orientation

“Where are you?” Ask for omitted items.

One point each for state, county,

town, building, and floor or room

Name three objects slowly and clearly.

One point for each item correctly

Ask the patient to repeat them.

repeated

Serial Sevens

Ask the patient to count backward

One point for each correct answer

from 100 by 7. Stop after five answers.

(or letter)

(Or ask them to spell “world” backwards.)

Recall three Objects

Ask the patient to recall the objects

One point for each item correctly

mentioned above.

remembered

Naming

Point to your watch and ask the patient

One point for each correct answer

“What is this?” Repeat with a pencil.

Repeating a Phrase

Ask the patient to say “No ifs, ands,

One point if successful on first try

or buts.”

Verbal Commands

Give the patient a plain piece of

One point for each correct action

paper and say, “Take this paper in your

right hand, fold it in half, and put it

on the floor.”

Written Commands

Show the patient a piece of paper with

One point if the patient’s eyes close

“CLOSE YOUR EYES” printed on it.

Writing

Ask the patient to write a sentence.

One point if sentence has a subject,

a verb, and makes sense

Drawing

Ask the patient to copy a pair of

One point if the figure has ten

intersecting pentagons onto a

corners and two intersecting lines

piece of paper.

Scoring

A score of 24 or above is considered normal.

Adapted from Folstein et al. Mini Mental State. J Psych Res 1975;12:196-198.

Important moods and affects to note are depres-

tives or adverbs and has garbled speech. Receptive

sion and inappropriate jocular behavior. Symp-

aphasia usually produces normal-sounding speech

toms of depression often include somatic

but the content does not make sense relative to the

complaints. Inappropriate affect may suggest

question. In both aphasias, there is difficulty in

frontal lobe dysfunction.

repeating phrases such as “No ifs, ands, or buts.”

Speech and language abnormalities are divided

Aphasia affects ability to write and read. Language

into dysarthria and dysphasia. Dysarthria results

abnormalities and apraxias are covered in Chapter

from poor articulation—like talking with rocks in

11, “Disorders of Higher Cortical Function.”

your mouth. The sentence makes sense but the

sound is garbled. Abnormalities of the mouth

(poor dentition) or of cranial nerves (CNs) IX, X,

Cranial Nerve Examination

and XII are common causes. Dysarthria does not

affect the ability to write or read. Dysphasia

CN I

implies dysfunction in understanding or forming

sentences. In expressive aphasia, the patient often

Olfactory nerves are seldom routinely tested unless

speaks short, truncated sentences without adjec-

a patient has a complaint of poor taste or smell, or

CHAPTER 2—Neurologic Examination

a history suggesting problems with frontal lobes or

then follow them into the optic disc itself. Color and

facial bones. First, ensure there are no obstructions

size of the disc and the presence of papilledema are

in the nasal passages by inspection with an oto-

particularly important. Papilledema is suggested by

scope. Smell cannot be tested in each side since

swollen optic disc heads with the margins appearing

both sides of the nose communicate. Ask the

blurred or raised, with reasonable vision in that eye.

patient to close his or her eyes and identify

Pupil size and the light reflex involve CN II and

whether he or she can smell an odor and then

autonomic eye nerves. Observe the pupils in dim

identify the odor’s name. Common substances

light with illumination from below. The pupils

such as coffee grounds, unlit cigarettes, and per-

should be round and be within 1 mm of each other

fumed soap are convenient to use in testing. Alco-

in size and constrict equally when the patient

hol and ammonia should not be used, as these

attempts to look at his or her nose (accommo-

odors stimulate CN V and give a false-positive test.

date). Anisocoria or unequal pupil sizes signifies

dysfunction of either the sympathetic nerve (small

pupil or miosis) or parasympathetic nerve (large

CN II

pupil or mydriasis). In the light reflex, one tests a

Optic nerve function is usually divided into visual

direct light reflex (the pupil constricts when a light

acuity, visual fields, and fundoscopic exam. To test

is shined into it) and then a consensual reflex (the

the patient’s visual acuity in each eye while wear-

opposite pupil constricts when a light is shined

ing their glasses, one can use a Snellen eye chart or

into the other eye). Both pupils should constrict

a near-vision card. The ability to read standard

briskly and equally to light. Shining the light into

newsprint suggests 20/40 or better acuity. If the

one eye and failing to see both pupils constrict

patient’s glasses are not available, a pinhole card

implies ipsilateral retina or CN II dysfunction; fail-

(paper with pin pushed through the center) can

ure of the ipsilateral iris to constrict implies dys-

improve vision. If visual acuity is 20/50 or better,

function of the ipsilateral sympathetic nerve; and

the problem is usually ocular and not neurologic.

failure of the contralateral pupil to constrict sug-

Visual fields are evaluated by confrontation test-

gests dysfunction of the contralateral sympathetic

ing each eye separately. Having the patient stand

nerve.

about 4 feet away with one eye closed and looking

at your nose, ask him or her to count the number

CNs III, IV, and VI

of fingers (one, two, or five) presented in the four

visual quadrants. Confrontational testing detects a

Oculomotor, trochlear, and abducens nerves inner-

homonymous hemianopia or quadranopia but not

vate the extraocular eye muscles. They are evalu-

constriction of visual fields from glaucoma.

ated by observing eye movement when the patient

On fundoscopic examination, carefully observe

is asked to follow your finger in all nine directions

the retinal vessels for hemorrhages and exudates and

of gaze (Figure 2-1). Observe whether the eye

Superior

Inferior

Superior

Rectus

Oblique

Rectus

(III)

Lateral

Medial

Lateral

Rectus

(VI)

(III)

(VI)

Inferior

Superior

Inferior

Rectus

Oblique

Rectus

(III)

(IV)

(III)

Figure 2-1

Directions of gaze.

FUNDAMENTALS OF NEUROLOGIC DISEASE

Right 6th Nerve Palsy

Figure 2-2

Right CN VI palsy. The right eye fails to abduct when the patient looks to the right.

movements are conjugate (eyes move together),

on both sides. The corneal reflex (touching the

move the entire range, and are smooth. Presence of

edge of the cornea over the outside of the iris with

double vision in one gaze direction suggests dys-

a wisp of cotton or a soft facial tissue) should pro-

function of a given nerve or eye muscle. Figure 2-

duce prompt blinking of both eyes. Failure to blink

2 demonstrates a patient with a right CN VI palsy.

in either eye suggests an afferent problem in the

Nystagmus often is normal when seen at end of

stimulated CN V, failure of the ipsilateral eye but

horizontal eye movement but abnormal if present

not the contralateral eye to blink suggests dysfunc-

in near mid position.

tion of ipsilateral CN VII, and failure of the con-

The size of the palpebral fissure

(distance

tralateral eye to blink but not the ipsilateral eye

between upper and lower eyelid) depends on CN

suggests dysfunction of contralateral CN VII. Hav-

III and sympathetic nerves. Marked drooping of

ing the patient open his or her jaw and attempt to

the upper eyelid (ptosis) that interferes with vision

move the jaw laterally against resistance test motor

implies CN III dysfunction or prior eye trauma.

fibers of CN V.

Mild ptosis without obstruction of vision implies

sympathetic nerve dysfunction. When mild ptosis

CN VII

is combined with ipsilateral miosis, the lesion is

called Horner’s syndrome.

Facial nerve function is evaluated by testing facial

muscles. Ask the patient to open his or her eyes

wide, close them shut tightly, and pull back his or

CN V

her lips. The muscles of facial expression, inner-

Trigeminal nerve function is tested by evaluating

vated by CN VII, should show equal and symmet-

face sensation. Lightly touch the three divisions of

rical movement on both sides of the face.

CN V with a cotton tip, your fingers, or a cool tun-

A lower motor neuron lesion (facial nerve or

ing fork. The patient should perceive these as equal

nucleus) produces weakness of both the upper and

CHAPTER 2—Neurologic Examination

lower face. An upper motor neuron lesion (corti-

CN XII

cobulbar tract above the level of CN VII nucleus)

Hypoglossal nerve function is evaluated by asking

causes weakness only of the lower face because

the patient to protrude the tongue straight out and

forehead muscles receive bilateral innervation.

move it from side to side. Deviation of the tongue

The chorda tympani nerve branch can be tested

to one side with atrophy and fasciculations on that

by determining whether the patient can detect the

side of the tongue suggest an ipsilateral lower

taste of sugar or salt placed on the anterior two

motor neuron lesion.

thirds of one side of the tongue.

The patient should be able to smoothly flex his

or her neck to touch the chin on the chest and

CN VIII

rotate the head fully toward the shoulders. In

meningitis, the patient cannot flex or resists flex-

Auditory nerve hearing evaluation is tested by

ing the neck, while in cervical arthritis, there is

masking the opposite ear with a finger or sounds

restricted rotation of the neck.

and determining whether the patient can hear

whispers (mid sound frequencies) or rubbing fin-

gers (higher sound frequencies) in the other ear. If

Motor Examination

there is hearing loss, the external auditory canal

should be inspected with an otoscope. Vestibular

A complete motor examination involves evaluat-

nerve testing is described in Chapter 21 “Disorders

ing muscle bulk, tone, strength, and gait, plus

of the Vestibular System.

looking for involuntary movements. Muscle bulk

compares the size of muscles on each side. In par-

CN IX

ticular, observe the hands for atrophy of small

intrinsic muscles and feet for atrophy of intrinsic

Glossopharyngeal nerve function is tested by ask-

foot muscles, seen by permanent elevation of toes

ing patient to say, “aah” and observing whether

at the second metatarsal joints (hammer toes).

the soft palate and uvula rise symmetrically.

Atrophy from lower motor neuron lesions (dener-

Deviation of the uvula and soft palate to one side

vation) shrinks a muscle by two thirds of its nor-

indicates a lesion on the contralateral nerve,

mal size. If the denervation is active, fasciculations

unless the person has scarring from a prior ton-

are seen. Upper motor neuron lesions, disuse, or

sillectomy. One can also touch the pharynx with

deconditioning reduces bulk by only one third,

a cotton swab and observe for a gag reflex from

without fasciculations.

CN IX and CN X.

In evaluating muscle tone, the patient is asked to

relax like a “rag doll” while you move the limbs

CN X

through extension, flexion, and rotation. Think of

Vagus nerve function is tested by listening for

tone as a rubber band and decide if the patient is

hoarseness in the patient’s voice. If present, vocal

floppy (hypotonic), normal, or too tight (exhibit-

cord movements can be visualized by otolaryngo-

ing spasticity or rigidity). Hypotonia suggests a

logical methods to confirm paralysis.

cerebellar or lower motor neuron lesion. Spasticity

is increased tone similar to opening a pocketknife.

The initial movement of the blade is hard, fol-

CN XI

lowed by an easy movement that fully opens the

Accessory nerve function is tested by shoulder

blade. Rigidity is resistance to limb movement that

shrug and head turn. Ask the patient to shrug his

is consistent through the entire range (like bend-

or her shoulders to the ears and then push down.

ing a lead pipe), as seen in Parkinson’s disease.

Strength should be even. Then ask the patient to

Muscle strength is commonly evaluated using

turn his or her head to either side while you apply

the British Medical Research Council method,

resistance with your entire hand on the lower jaw.

where strength is graded on a relative scale of 0 to

Again, strength should be even. Remember that

5 (Table 2-2). In this relative system, the muscle

the right sternocleidomastoid muscle turns the

strength of both a healthy grandmother and

head to the left.

weight lifter would be 5. The value of this scoring

FUNDAMENTALS OF NEUROLOGIC DISEASE

increases. Giving way or suddenly letting go of a

Table 2-2

British Medical Research

position by a patient may indicate pain in a limb or

Council Method of Scoring

reluctance to give “full effort.”

Muscle Strength

Weakness comes from many anatomic loca-

Score Strength Finding

tions. Figure 2-3 shows the key anatomy of the

corticospinal tract, which produces upper motor

No movement

neuron lesions. Later chapters on the approach to

Flicker movements

the patient (Chapter 1) and disorders of muscle

Movement with gravity eliminated

(Chapter 4), neuromuscular junction (Chapter 5),

Movement against gravity only

peripheral nerve (Chapter 6), spinal cord (Chapter

Full movement against some resistance

7), brainstem (Chapter 8), and cerebrovascular

disease

(Chapter 9) provide additional ways to

Full movement against full resistance

evaluate the motor system.

Gait evaluation is the most useful screening test

system is that it is highly reproducible between

of the motor system. Ask the patient to get out of

examiners. The disadvantage is that it is insensitive

the chair and walk normally, then on toes and heels,

to slight worsening of mild weakness since both

and turn. One can also ask the patient to hop or

would be scored 4.

walk backward. Observe for smoothness of gait,

Since there are over 600 muscles in the human

attitude of the trunk and arms, steadiness during

body, it is useful to group muscles into proximal

turns, appropriate arm swings, and balance. The

and distal muscles (Table 2-3). It is helpful to ask

presence of an asymmetrical gait or limp may reflect

the patient to flex or extend the limb and hold it

a hemiparesis, leg joint arthritis, old fractures, bal-

there against the examiner’s force. Start with min-

ance problems, or leg pain that must be sorted out.

imal pressure and then increase until maximal or

Balance can be evaluated by using the Romberg

the limb gives way. True weakness tends to be

position and tandem gait. In the Romberg test, the

gradually overcome as the examiner pressure

individual is asked to put the feet together and balance

Table 2-3

Muscles Commonly Tested and Their Nerve Root and

Peripheral Nerve

Limb

Muscle (Function)

Nerve Root

Peripheral Nerve

Arm Proximal

Deltoid (shoulder adduction)

Axillary

Biceps (elbow flexion)

Musculocutaneous

Triceps (elbow extension)

Radial

Distal

Flexor carpi radialis and ulnaris (flexion wrist)

C6-7

Median and ulnar

Extensor carpi radialis and ulnaris (extension wrist)

C6-8

Radial

Abductor pollicis brevis (thumb abduction)

Median

Abductor digiti minimi (little finger abduction)

Ulnar

Leg Proximal

Iliopsoas (hip flexion)

L2-4

Femoral

Quadriceps (knee extension)

L2-4

Femoral

Hamstrings (Knee flexion)

L4-S1

Sciatic

Distal

Tibialis anterior (ankle dorsiflexion)

L4-5

Peroneal

Gastrocnemius (ankle flexion)

S1-2

Tibial

Tibialis posterior (ankle inversion)

Tibial

Extensor hallucis longus (great toe dorsiflexion)

L5-S1

Peroneal

Foot flexors (dorsiflexion of all toes)

L5-S1

Tibial

FUNDAMENTALS OF NEUROLOGIC DISEASE

with the eyes open. If the balance is normal, the

touch), and cortical sensory functions (stereogno-

patient is asked to close the eyes, thus assuming the

sis, graphesthesia, and two-point discrimination).

Romberg position. Marked sway or loss of balance

Normally, the tests are performed on the hands and

with eyes closed, but not when open, is the Romberg

feet unless the history or exam suggests damage to

sign. This sign is usually due to poor position sense

particular nerves or roots (Figures 2-4a and 2-4b).

in the feet. In tandem walking, the patient attempts

Pain is usually tested with a new safety pin; the

to walk heel to toe in a straight line. Abnormal tan-

patient is asked to determine whether the gentle

dem gait implies dysfunction of inner ear, position

prick was “sharp” from the pin edge or “dull”

sensors in the feet, vestibular brainstem or cerebellar

from clip edge. One compares the sides and other

nuclei or tracts, or orthopedic leg problems.

areas of the limb. Always discard the safety pin

Involuntary movements should be noticed dur-

when finished.

ing the history and exam and most commonly

Temperature is usually tested with a cool metal

involve the arms. In general, the movements

object such as a tuning fork. The control tempera-

should be evaluated to determine whether they (1)

ture for comparison is the face or upper arm. The

are unilateral or bilateral, (2) involve arms, legs, or

patient is asked whether the test skin area is as cool

the head, (3) are continuous or intermittent, (4)

as the control skin area. The test is usually done on

occur at rest, during static position of the limb, or

the dorsum of the foot and moves up the leg until

during purposeful movements, and (5) can volun-

the temperature is perceived as cool.

tarily be abolished. Types of involuntary move-

Vibration is tested with a 128-Hz tuning fork by

ments include tremor, dystonia, chorea, ballismus,

pressing the stem over the great toe and placing

tics, and myoclonus. Most involuntary movements

your finger beneath the toe. The patient is asked to

are due to disorders of the basal ganglia. Chapter

say when the vibration disappears, which should

12 “Disorders of the Extrapyramidal System”

be when the clinician can no longer feel it vibrate

describes these involuntary movements.

in his or her finger. The tuning fork is moved up

the leg proximally until the patient perceives the

vibration well. If the toes have normal vibration

Coordination

sensation, testing the fingers is seldom necessary.

Position sense is determined by grasping the

For coordination to be tested, the patient must have

great toe on the sides and instructing the patient to

normal or near-normal muscle strength in their

respond “up” or “down” from where the toe was

limbs. The finger-nose-finger test asks the patient

last time. Move the toe only a millimeter or two. If

to touch the tip of the index finger to the nose, then

the patient has trouble distinguishing up or down,

to the examiner’s finger, and back to the nose again.

one can move the toe in a larger arc until satisfied

Cerebellar dysfunction causes a tremor perpendicu-

that the patient can detect movement. If the toes

lar to the direction of movement that intensifies as

are normal, testing the fingers is seldom necessary.

the finger nears the target. The heel-to-shin test

Touch evaluation comprises two tests. Stereog-

asks the patient to place a heel on the opposite knee

nosis is tested with the eyes closed and asking the

with the ankle dorsiflexed and then slide the heel

patient to identify simple objects placed in the

down the front of the shin to the great toe. Again

hand, such as coins or a key. Graphesthesia is tested

cerebellar dysfunction causes the heel to move per-

with the eyes closed and asking the patient to iden-

pendicular to the line of heel movement. The rapid

tify numbers or letters written on the palm of each

alternating movement test asks the patient to pat

the knee with the palm and then the back of the

hand. These tests require normal primary sensation

hand as he or she gradually increases the speed.

and abnormalities imply dysfunction in the con-

tralateral sensory cortex or parietal lobe (see Chap-

ter 11 “Disorders of Higher Cortical Function”).

Sensation

The evaluation of sensation is often divided into

Reflexes

small nerve fiber peripheral nerve functions (pain

and temperature), large nerve fiber peripheral

Deep tendon reflexes (DTRs), or stretch reflexes,

nerve functions

(vibration, position sense, and

evaluate a local circuit from muscle spindles to

CHAPTER 2—Neurologic Examination

Ophthalmic n.

Maxillary n.

Great auricular n.

Mandibular n.

Transverse colli n.

Supraclavicular nn.

Axillary n.

Intercostal nn.

Ant. cutaneous rami

Lat. cutaneous rami

Med. brachial cutaneous

& intercostobrachial n.

Lat. brachial cutaneous n.

Med. antebrachial cutaneous n.

Iliohypogastric n.

T10

Ilioinguinal n.

T11

T12

Lat. antebrachial cutaneous n.

Radial n.

Median n.

Ulnar n.

Genitofemoral n.

Lat. femoral cutaneous n.

Obturator n.

Ant. femoral cutaneous n.

Lat. sural cutaneous n.

Saphenous n.

Superficial peroneal n.

Sural n.

Deep peroneal n.

Medial plantar n.

Figure 2-4

Dermatomes and peripheral nerve distributions. (a) Anterior view. (Continues)

spinal cord level and back to the appropriate mus-

the feet just touching the exam step or the floor.

cles. The most common reflexes tested are biceps

Using a long, well-balanced hammer with a soft

jerk (BJ), triceps jerk (TJ), knee jerk (KJ), and ankle

percussion tip, tap the tendon to deliver the stimu-

jerk (AJ) (Figure 2-5). Position the patient comfort-

lus. The key is to be consistent in the application of

ably, usually with the arms resting on the thighs and

force. If the reflex is difficult to attain, it can be aug-

FUNDAMENTALS OF NEUROLOGIC DISEASE

Greater occipital n.

Lesser occipital n.

Great auricular n.

Transverse colli n.

Cutaneous branches of

dorsal rami of spinal nn.

Supraclavicular n.

Lat. cutaneous branches

of intercostal nn.

Axillary n.

Post. brachial cutaneous n.

Med. brachial cutaneous &

intercostobrachial nn.

Lat. antebrachial

T10

cutaneous n.

T11

Post. antebrachial

T12

cutaneous n.

Med. antebrachial

cutaneous n.

Iliohypogastric n.

Radial n.

Ulnar

Clunial n.

Median n.

Obturator n.

Ant. femoral cutaneous n.

Lat. femoral cutaneous n.

Post. femoral cutaneous n.

Lat. sural cutaneous n.

Sural n.

Saphenous n.

Calcaneal nn.

Saphenous n.

Plantar branches of tibial n.

Figure 2-4

(b) Posterior view. (Continued)

mented by asking the patient to grit his or her teeth

The extensor plantar reflex or Babinski sign

or make a fist with the other hand. Children and

suggests damage to the corticospinal tract (upper

young adults, especially if anxious or cold, tend to

motor lesion) in children older than 2 years and

have brisk reflexes, while the elderly often have

adults. It is elicited by scratching the sole of the

diminished reflexes. DTRs are scored per Table 2-4.

foot (usually with a key) from the heel, along the

CHAPTER 2—Neurologic Examination

A. Biceps

B. Triceps Reflex

C. Knee Reflex

D. Ankle Reflex

Figure 2-5

Deep tendon reflexes.

lateral aspect of the foot, and finally arching across

Withdrawal from “tickling” tends to be erratic, does

the ball of the foot to the great toe. The Babinski

not look the same way each time, and is often trig-

sign is present if the great toe extends with fanning

gered by touching the sole of the foot anywhere.

of the other toes. A Babinski sign is stereotypical

Frontal lobe release signs imply bilateral frontal

and similar each time you perform the maneuver.

lobe damage. The grasp reflex is elicited by nonvol-

untarily persistent grasping of the examiner’s fin-

gers when placed or lightly stroked across the

patient’s palm. Other frontal lobe release signs are

Table 2-4

Scoring Deep Tendon

discussed in the Chapter 11 “Disorders of Higher

Reflexes

Cortical Function.”

Score

Reflex Finding

Absent

Pediatric Neurologic Exam

Diminished, often requiring reinforcement

Normal or physiologic

The most striking difference in the pediatric and

adult neurologic exams is that the age of the

Normal for age and brisk without clonus

patient requires very different exam techniques

Abnormally brisk, usually with clonus

and elements. The key portions of the exam are

FUNDAMENTALS OF NEUROLOGIC DISEASE

testing the same systems, albeit in different ways.

Also using the ophthalmoscope or a penlight,

As a child gets older, the clinician can incorporate

check for the pupillary light response.

more and more of the adult exam into the pedi-

atric exam. Therefore, the infant exam will be pre-

Mouth

sented, as it is the most disparate of the pediatric

stages as compared with the adult.

Using a gloved little finger, check for the suck

reflex. Infants should latch on and the examiner’s

finger should not slip from the mouth during

General

suck. While this finger is in the infant’s mouth, also

Observe the baby. How does he or she act? Is the

check for palate height. At some point during the

patient irritable, easily consoled, sleeping and easy

exam, the baby will probably cry. Use this oppor-

to arouse, or somnolent? Encephalopathy in the

tunity to assess palate elevation.

infant often presents as hyperirritability. Do the

face or other features appear dysmorphic? Note

Tone

the set of the eyes and ears.

Always assess tone when the head is midline.

When the head is turned, this triggers the asym-

Skin

metric tonic neck reflex (fencer posture), produc-

Always get the clothes off the infant. Look for

ing increased tone on the side opposite the head

hyper- or hypopigmentation. Check the base of

turn. Passively move the arms and legs. The child

the spine for dimpling or hair tufts. Examine the

should move somewhat in response and not be

diaper area; note the morphology of the genitalia.

totally limp. The examiner should pick up the

baby, with hands around the infant’s chest. Does

the baby slip through the fingers or stay between

Head

the hands without holding onto the chest? The

Always measure head circumference. This should

former demonstrates hypotonia. Hypertonia is

be compared with all previously obtained meas-

evident when the child’s legs scissor when verti-

ures if possible. The parents can be measured as

cally suspended. For further tone assessment, turn

well. Large-headed parents can produce large-

the baby on his or her belly with a hand and sup-

headed children.

port the stomach and chest. Does the patient flop

The anterior fontanel should be soft, not tense

over your hand, arch the back and neck slightly or

or sunken. Some pulsation is normal. The poste-

stay rigidly extended? These are signs of hypoto-

rior fontanel should not be palpable after birth.

nia, normal tone, and hypertonia, respectively.

Now place the infant on its back. A normal pos-

Eyes

ture in the infant is flexion of all four extremities.

As a baby gets older, the limbs assume a more

Check eye movements by giving the child some-

extended posture. Take the baby’s hands and pull

thing to observe. In infants, faces work well at a dis-

to a seated position. Resist the urge to support the

tance of about 6 inches. In older babies, round, red

head. Even at birth, the full-term infant will flex

objects can catch their attention. Check for smooth

the extremities and pull the head up.

movements and the extent of tracking. Tracking

past midline begins around age 2 months. Vertical

Reflexes

tracking begins around 3 to 4 months.

Fundoscopic exam is important to identify the

Always assess reflexes when the head is midline for

red reflex. To do this, while looking through the

the same reasons as above. Check the deep tendon

ophthalmoscope, aim at the child’s eye. If the red

reflexes as in the adult; however, these can usually

of the retina can be seen, there is a red reflex. This

be tapped with the fingers in infants. Ankle clonus

screens for congenital cataracts and retinoblas-

is usually present in infants. Three to four beats

toma. If the infant is cooperative, the clinician may

bilaterally are normal. Sustained clonus or asym-

actually be able to examine the back of the eye.

metries should be noted.

CHAPTER 2—Neurologic Examination

Primitive Reflexes

Table 2-5

Primitive Reflexes

After checking for the suck reflex, one should also

with Expected Time

check Moro, grasp, and step reflexes.

of Appearance and

Disappearance

MORO

Appears by

With the infant on his or her back, grab the hands,

(Gestation

Gone by

lift the baby slightly off the bed, and then allow to

Reflex

Period)

(Approximate)

drop back onto the bed. The response should be a

Suck

34 wk

4 mo

symmetric brisk extension of arms and legs and

Root

34 wk

4 mo

then drawing of the arms back to midline.

Palmar Grasp

34 wk

6 mo

GRASP

Plantar Grasp

34 wk

10 mo

Place a finger into the baby’s palm. The infant

Tonic Neck

34 wk

4-6 mo

should firmly grasp it, equally on both sides.

Moro

34 wk

3-6 mo

STEP

Automatic Step

35 wk

2 mo

Lift the infant to standing position on the examin-

ing surface

(with the examiner supporting the

weight). The baby should take automatic steps on

the table or bed.

RECOMMENDED READING

ROOT

British Medical Research Council. Aids to the Exam-

Brush the side of the child’s cheek. The head will

ination of the Peripheral Nervous System. 4th ed.

turn toward the check touched.

Philadelphia: W. B. Saunders;

2000. (Superb

Table 2-5 shows the timing of appearance and

booklet that outlines how to test each muscle,

disappearance of these primitive reflexes. Always

describes areas of sensation for all peripheral

remember to re-dress and swaddle the baby after

nerves, and easily can be kept in doctor’s bag.)

finishing.

COMMON NEUROLOGIC TESTS

abnormal neurologic functioning of the patient.

Overview

The neurologic exam also gives information about

the general anatomic location of the disease and

Neurologic tests serve to (1) establish a diagnosis

the likely type of disease process. In some diseases

when several possible diagnoses exist, (2) help clini-

(e.g., migraine headache, trigeminal neuralgia,

cians make therapeutic decisions, and (3) aid in fol-

schizophrenia) the neurologic history and exam is

lowing the results of treatment. In broad terms,

the only test that yields the diagnosis. For optimal

neurologic tests can be divided into those that eval-

results, this test requires the patient to be alert,

uate function, structure, and molecular/genetic con-

cooperative, and not aphasic or demented. The test

cerns. For example, the neurologic examination is

is safe, inexpensive, comfortable, and can be

the most exquisite test of neurologic function yet

repeated frequently. A complete history and phys-

devised. While it will provide clues as to the general

ical exam requires 30 minutes to 1 hour (see Chap-

location of the disease process, it is less reliable than

ter 2, “Neurologic Examination”).

other tests. Cranial magnetic resonance imaging

(MRI) and computed tomography (CT) precisely

locate abnormal brain tissue but cannot decipher the

Neuropsychologic Tests

physiologic consequences of the tissue abnormality.

Neuropsychologic tests evaluate higher cortical

In this chapter, the major neurologic tests are

function and do so with a higher degree of preci-

briefly discussed in terms of their basic principles,

sion and certainty than usual bedside testing. A

indications, cost, and side effects.

certified clinical neuropsychologist usually admin-

isters these tests. A variety of tests have been devel-

oped and standardized to enable better evaluation

Functional Neurologic Tests

of different aspects of cortical function (Table 3-

1). While neuropsychologic tests are sensitive indi-

Neurologic Examination

cators of a cognitive disorder, they do not highly

This test is the entry point into the diagnostic and

localize the part of the cerebral cortex that is dys-

therapeutic process. The history and neurologic

functional. Although the tests are quantitative, the

examination yield information about normal and

score does not highly correlate with size of a lesion.

FUNDAMENTALS OF NEUROLOGIC DISEASE

inhibitory and excitatory postsynaptic potentials

Table 3-1

Neuropsychologic Tests

of pyramidal cells. Electrodes are placed over the

and Functions Evaluated

scalp in precise locations to record the brain’s elec-

Function

trical activity when awake and often during sleep.

Best

Differences in voltage between 2 selected elec-

Test

Evaluated

trodes plotted over time are produced as continu-

Weschler Adult Intelligence

Intelligence

ous digital waveforms on a computer monitor or

Scale-III and Weschler

as similar analog waveforms on long sheets of

Intelligence Scale for Children-III

paper. The complete EEG tracing is made up of

Weschler Memory Scale

Frontal lobe

waveforms from several different source elec-

Milan Sorting Test

Frontal lobe

trodes. A trained technician performs the EEG and

Porteus Maize Test

Frontal lobe

a neurologist interprets the tracing.

Information derived from an EEG is divided into

Weschler Block Design

Parietal lobe

waveforms that suggest epileptiform brain activity

Benton Figure Copying Test

Parietal lobe

and those that suggest an encephalopathy (meta-

Halstead-Reitan Battery (parts)

Temporal lobe

bolic or structural in origin). Epileptiform brain

Milner’s Maze Learning Task

Temporal lobe

waves (spikes and sharp waves) are paroxysmal,

Minnesota Multiphasic Personality

Personality

repetitive, brief, and often of higher voltage than

inventory

background activity. Background activity is divided

Rorschach Test

Personality

into 4 different frequencies (in Hz): β (>12 Hz), α

(8-12 Hz), θ (4-7 Hz), and δ (0-3 Hz) that range

from fast to slow. The α frequency is the dominant

EEG frequency seen in occipital leads when an

These tests are used to (1) divide cognitive

awake individual has his or her eyes closed.

abnormalities into specific subtypes that may

Most encephalopathies produce slowing of

assist in establishing a diagnosis, (2) determine a

background activity, often into the δ range. EEG

quantitative score on specific tests so that repeated

electrical activity only comes from intact respond-

tests can measure disease progression or improve-

ing neuronal populations and does not emanate

ment, (3) distinguish dementia from psychologic

from brain tumors or dead neurons in infarcted

illnesses such as depression, and (4) determine an

brain. However, localized brain masses (tumor or

intelligence quotient

(IQ) score for legal or

abscess) produce a localized slowing (δ waves)

medicosocial reasons. For the usual patient with

from dysfunctional neurons located around the

marked dementia from Alzheimer’s disease, neu-

mass. Some drugs

(especially barbiturates)

ropsychologic tests add little. One should clearly

increase background activity into the β range.

state the reason for ordering the testing so the neu-

While an EEG gives considerable information

ropsychologist can construct the most useful bat-

about abnormal brain function, it provides limited

tery of tests to give the patient.

information as to the precise location of the brain

Neuropsychologic tests are safe, inexpensive,

dysfunction. Since electrical currents flow by a

and comfortable to the patient. Testing takes 1 to 4

path of least resistance, the actual source of the

hours depending on the extent of the battery.

electrical activity may not be directly beneath the

These tests can be repeated occasionally but can-

recording electrode. In general, conventional

not be administered frequently as repeated testing

methods localize the EEG source to a 2-cm cube.

at short intervals would produce a “learning

Under some circumstances, the EEG is coupled

effect” that could falsely improve the score.

with a video monitor so the patient’s behavior can

be correlated with EEG findings. The EEG is often

performed during wakefulness and sleeping as

Electroencephalogram (EEG)

epileptiform discharges are usually more frequent

The EEG is a tracing of electronically amplified

during sleep. The EEG can also study patients dur-

and summated electrical activity of the superficial

ing sleep to evaluate sleep abnormalities, such as

layers of the cerebral cortex adjacent to the calvar-

narcolepsy. Under special circumstances, elec-

ium. This electrical activity comes primarily from

trodes can be surgically placed over the cortical

CHAPTER 3—Common Neurologic Tests

surface or within the brain to search for specific

concentric needle while a monopolar needle com-

foci of seizure genesis.

pares the fibers’ electrical signal with that of a refer-

With the advances in CT and MRI, indications

ence electrode on the skin surface. Electrical activity

for ordering an EEG have diminished. Present indi-

from muscle fibers is recorded and amplified to

cations for ordering a routine EEG include (1)

appear on an oscilloscope as a tracing of voltages

evaluating unwitnessed episodes of loss of con-

versus time with accompanying sound. Physicians

sciousness for likelihood of seizures, (2) character-

need special training to perform the EMG.

izing interictal (between seizures) brain activity to

Abnormal motor units or individual muscle

better determine the type of seizure disorder, (3)

fibers demonstrate changes in duration, amplitude,

distinguishing encephalopathy from frequent

and pattern of the waveform that occur during nee-

seizures (status epilepticus) in a stuporous or com-

dle insertion, rest, or voluntary contraction. An

atose patient, (4) distinguishing nonepileptic events

EMG distinguishes normal muscle from disease

from true seizures, and (5) determining brain death.

due to nerve damage or muscle disease. An EMG is

The routine EEG is safe, inexpensive, and com-

safe, somewhat uncomfortable to the patient, inex-

fortable to the patient and takes about 2 hours to

pensive, and requires 30 to 60 minutes. To mini-

complete. An EEG can be repeated as often as neces-

mize patient discomfort, the patient should receive

sary. Figure 3-1 demonstrates typical EEG changes.

a clear description of what will happen and fre-

quent reassurance. The following is a description

of the types of findings seen on EMG.

Electromyogram (EMG)

NORMAL MUSCLE

The EMG is the evaluation of the electrical function

of individual muscle motor unit potentials at rest

Insertion of a needle into a normal muscle injures

and during muscle contraction. It is performed by

and mechanically stimulates many muscle fibers,

inserting a recording needle electrode into the belly

producing a burst of action potentials of short

of a muscle. The needle tip is the recording electrode

duration (<300 msec). At rest, normal muscle is

and the needle shaft is the reference electrode in a

electrically silent as normal muscle tone is not the

Figure 3-1

Electroencephalogram typical of seizure.

FUNDAMENTALS OF NEUROLOGIC DISEASE

result of electrical contraction of muscle fibers. As

(phases) and a maximum amplitude of 0.5 to 5

an electrical impulse travels along the surface of a

mV (Figure 3-2). The shape and duration of a

single muscle fiber toward the recording electrode,

given MUAP remain quite constant on repeat fir-

the impulse becomes positive (downward deflec-

ings and generally appear different from other

tion by convention) relative to the reference elec-

nearby MUAPs.

trode. As the impulse comes beneath the electrode,

DENERVATED MUSCLE

the waveform becomes negative (upward deflec-

tion) and then becomes slightly positive and

Immediately after complete nerve transection,

returns to baseline as the impulse travels past the

the muscle is paralyzed, unexcitable by nerve

electrode (Figure 3-2). A single muscle fiber con-

stimulation, and electrically silent by EMG

traction lasts about 2 to 4 milliseconds and is less

except for insertion potentials. Beginning 2 to 3

than 300 µV in amplitude. The firing of a single

weeks after a muscle loses its innervation, spon-

muscle fiber (called fibrillation, which does not

taneous individual muscle fiber contractions

cause visible muscle movement) does not occur

may appear. The EMG demonstrates fibrillations

normally and is a sign of muscle membrane insta-

and positive sharp waves (brief monophasic pos-

bility either from denervation or myopathy. In

itive spikes). Until the motor unit completely

normal muscle, an electrical impulse travels from a

degenerates, spontaneous firing of the MUAP

spinal cord anterior horn neuron (lower motor

(fasciculation, which produces a visible muscle

neuron) along its axon to eventually innervate 10

twitch) also occurs. If the nerve damage is

to 1,000 muscle fibers (called a motor unit). The

incomplete and occurred several months earlier,

number of muscle fibers innervated depends on

the denervated muscle fiber induces adjacent

the muscle, with proximal limb muscles having the

motor nerves to branch or sprout and send a

highest number of innervated muscle fibers. Dur-

nerve branch to reinnervate the denervated mus-

ing mild voluntary muscle contraction, an entire

cle fiber (called “sprouting”). MUAPs suggestive

motor unit fires almost simultaneously, producing

of sprouting are of longer duration, contain

a motor unit action potential (MUAP). A typical

more phases, and may be of higher maximum

MUAP has 3 to 4 excursions across the baseline

amplitude than normal (Figure 3-3c).

MYOPATHY

Death or dysfunction of scattered muscle fibers

results in MUAPs during voluntary muscle con-

traction that are of shorter duration and lower

amplitude than normal

(Figure

3-3b). Some

MUAPs may be polyphasic from loss of synchro-

nous firing. In myositis, there may be accompany-

ing fibrillations due to inflammatory damage to

2 ms

adjacent motor nerve endings.

In myopathies that cause myotonia (such as

myotonic dystrophy), insertion of the needle pro-

duces a train of high-frequency repetitive dis-

charges in a positive sharp waveform that diminish

Ref.

in frequency and amplitude over a few seconds.

When heard over a speaker, myotonic discharges

sound like a “dive-bomber.”

Nerve Conduction and Neuromuscular

Junction Studies

Nerve conduction studies are undertaken to evalu-

Figure 3-2

Electromyogram recording of a single

muscle fiber with electrical activity following the

ate the functioning of motor, autonomic, and sen-

dashed arrow.

sory nerves and neuromuscular junctions. It is

FUNDAMENTALS OF NEUROLOGIC DISEASE

technician under a physician’s supervision. The

moving the stimulating electrode along the nerve

test is safe, inexpensive, mildly uncomfortable for

pathway, differing latencies

(in milliseconds) to

the patient, and takes ¹/₂ to 1 hour.

muscle contraction are determined. By measuring

Indications for ordering nerve studies include

the distance along the nerve pathway between two

(1) determining whether a neuropathy is general-

exciting stimuli, one can divide the nerve distance

ized or multifocal, (2) determining whether a neu-

(in mm) by the latency difference (in milliseconds)

ropathy is mainly from demyelination or axonal

to obtain the nerve velocity (in m/s). Normal motor

loss, (3) localizing the site of a nerve conduction

velocity of the median and ulnar nerves is 50 to 60

blockade, and (4) determining and characterizing

m/s and 40-50 m/s in the sciatic nerve. Slowing of

neuromuscular junction abnormalities. In the

the motor nerve velocity may reflect loss of myelin

common types of distal sensorimotor peripheral

along the nerve (often causing slowing of velocities

neuropathy, nerve studies seldom help establish

to 20 to 30 m/s) or loss of the fastest motor nerves

the etiology.

(lesser degree of velocity slowing). Slowing of a

motor nerve may occur along the entire nerve path-

MOTOR NERVE FUNCTION

way or at a localized point of nerve compression,

Motor nerve conduction velocity studies measure

such as the ulnar nerve at the elbow.

the velocity of the fastest motor nerve axons at var-

SENSORY NERVE FUNCTION

ious points along a peripheral nerve. Peripheral

nerves can be stimulated to fire by application of an

Evaluating sensory nerve function is more difficult

electrical impulse to the skin overlying the nerve.

as the normal signals are weaker and more diffuse

When a muscle contracts, its electrical signal can be

following an electrical stimulus because the con-

detected by placing an electrode on the skin above

duction velocities of different sensory axons vary

the muscle belly. The muscle electrical signal is

considerably. Sensory nerves may be unmyelinated

recorded and the time from electrical stimulus to

and conduct at ¹/₂ to 2 m/s or be thinly myelinated

muscle contraction (latency) can be determined

and conduct at 10 to 20 m/s. The most common

and displayed on an oscilloscope. A motor nerve

sensory nerve test determines the latency time from

velocity is determined as follows (Figure 3-4). By

surface electrical stimulation of the interdigital

Stimulus

B (mm)

Velocity (m/sec) = --------------------------

2 (msec) - 1(msec)

Reference

Recording

Site

Stimulation

Site 1

Site 2

Figure 3-4

Motor nerve conduction velocity.

CHAPTER 3—Common Neurologic Tests

branch of the median nerve to a skin surface elec-

nose cancer involving the meninges, (3) diagnose

trode site over the median nerve just proximal to

herpes simplex encephalitis and other encephali-

the wrist. A delayed median nerve sensory latency

tides, (4) diagnose a small subarachnoid hemor-

suggests compression of the nerve at the carpal

rhage, and

(5) introduce medications into the

tunnel.

subarachnoid space or contrast media for a myelo-

gram. In addition, there are several diseases where

NEUROMUSCULAR JUNCTION FUNCTION

CSF examination helps make a specific diagnosis.

Information about the function of the neuromuscu-

These diseases include multiple sclerosis, Guillain-

lar junction can be obtained from repetitive nerve

Barré syndrome, and paraneoplastic syndromes.

stimulation studies. Placement of a skin recording

The LP is not limited to establishing diagnoses.

electrode over the belly of a muscle and stimulating

Antimicrobial and anticancer drugs can be deliv-

the motor nerve produces a compound muscle

ered intrathecally into the lumbar or cisternal CSF

action potential (CMAP). If the nerve stimulation is

to treat patients with some forms of infectious

repeated, the CMAPs appear identical on the oscillo-

meningitis or meningeal carcinomatosis. The LP is

scope. In diseases of the neuromuscular junction, the

safe, mildly uncomfortable, moderately expensive

amplitude of the CMAPs may decrease or increase.

depending on tests ordered, and takes up to 1 hour.

In myasthenia gravis and botulism, repetitive nerve

CONTRAINDICATIONS FOR LP

stimulation produces a decremental response in the

CMAP. The test is safe, inexpensive, somewhat

There are times when it is not safe to perform an

uncomfortable, and takes about 15 minutes.

LP. If the individual has a localized mass in the

brain or meninges or obstructive hydrocephalus

SENSORY EVOKED POTENTIALS

that is creating marked increased intracranial pres-

Occasionally there are indications to evaluate the

sure, removal of CSF from the lumbar space will

integrity of central conduction along major sen-

lower the CSF pressure below the foramen mag-

sory pathways (visual, auditory, and peripheral

num. This in turn may allow the brain to move

sensory system); these are called evoked potentials.

through the tentorium (uncal herniation or tento-

As noted above, actual conduction velocities can-

rial herniation) or force cerebellar tonsils into the

not be obtained, but central modality-specific

foramen magnum. To minimize this risk, a com-

latencies can. Evoked potential tests record com-

plete history and neurologic examination should

puter averages of the EEG that are time locked to

always be done before the LP. If the patient has

repeated (100-500 trials) specific sensory stimuli

signs of marked increased intracranial pressure

such as sound, light, or electrical stimulation of

(papilledema), focal neurologic signs (especially

the peripheral nerve. The computer averaging

hemiparesis, aphasia, or ataxia), or is comatose,

reduces background EEG electrical activity to 0

elderly, or immunocompromised, it is usually

while enhancing the time-locked stimulus signal.

advisable to first obtain a neuroimage (usually a

Abnormalities are characterized by a delay for the

CT scan) to rule out a focal intracranial mass or

time-locked signal average to reach its destination

obstructive hydrocephalus.

or distortions (usually a prolongation of the wave-

If the patient has a bleeding disorder, takes anti-

form and loss of signal amplitude). Sensory

coagulants, or has a blood platelet count below

evoked potentials are safe, inexpensive, and com-

50,000/mm³, there is a risk of developing an

fortable. The major indication is the evaluation of

epidural or subdural hematoma at the site of the

possible diseases that cause central nervous system

LP that occasionally compresses the lumbar and

(CNS) demyelination of these sensory pathways.

sacral nerve roots. These conditions should be cor-

rected as much as possible prior to the LP.

Structural Neurologic Tests

ANATOMY AND PHYSIOLOGY OF THE CSF SPACE

CSF is primarily a clear ultrafiltrate of plasma pro-

Lumbar Puncture (LP) and Cerebrospinal

duced by choroid plexus cells. Proteins of low

Fluid (CSF) Examination

molecular weight (MW) reach CSF better than

Five important reasons for examining CSF are to

those of high molecular weight. As such, CSF has

(1) diagnose infections of the meninges, (2) diag-

more albumin (MW 69 kd) than immunoglobu-

FUNDAMENTALS OF NEUROLOGIC DISEASE

lins (MW 150 kd). In addition, some proteins are

energy requirement, such as the glucose trans-

made by the choroid plexus (transthyretin) and

porter) and generally maintain their respective

secreted into CSF. Finally, complex transport sys-

molecules within narrow concentrations. For the

tems exist in blood vessels of the brain and the CSF

above reasons, the CSF-to-plasma concentration

pathways to remove ions or proteins (such as

ratios vary greatly between molecules.

potassium) or deliver molecules (glucose) to the

Approximately 2/3 of CSF is produced by the

CSF. These transporter systems may be active

choroid plexuses located in the lateral and fourth

(requiring energy such as potassium-sodium

ventricles (Figure 3-5). The source of the remain-

transporter from mitochondria) or passive (no

ing CSF is unclear. Choroid plexus CSF travels

Arachnoid Granulations

Superior Sagittal Sinus

Choroid Plexus of

Lateral Ventricle

Dura Mater

Choroid Plexus of

3rd Ventricle

Lateral Aperture

Subarachnoid

Choroid Plexus of

4th Ventricle

Central Canal of Spinal Cord

Filum Terminale

Lumbar Cistern

Figure 3-5

Cerebrospinal fluid flow in the central nervous system.

CHAPTER 3—Common Neurologic Tests

from the lateral ventricle into the third ventricle,

TECHNIQUE OF LP

and along the aqueduct of Sylvius to reach the

Written permission following informed consent is

fourth ventricle. From the fourth ventricle, CSF

highly recommended and often required. An

passes via the foramina of Luschka and Magendie

explanation of what will transpire will often reas-

to exit the cerebellum into the subarachnoid space.

sure a patient and make the procedure more com-

Blockage of CSF pathways up to this point pro-

fortable. Occasionally, a mild sedative is helpful in

duces obstructive hydrocephalus. In the subarach-

the anxious patient. Whenever possible the LP

noid space, CSF travels up through the tentorium

should be performed in the lateral recumbent

opening and over the cerebral convexities to reach

position as this allows an accurate measure of the

the superior sagittal sinus. Blockage of CSF path-

opening pressure. The patient, lying on a firm sur-

ways in the subarachnoid spaces is usually called

face that does not sag, should be placed on the side

communicating hydrocephalus since air introduced

with the knees curled toward the chin. The spinous

into the lumbar subarachnoid space can reach the

processes should be in a horizontal line with the

lateral ventricle. At the superior sagittal sinus, CSF

two iliac crests forming a perpendicular line. The

passes through arachnoid villi or pacchionian

intersection is usually the L3-L4 intervertebral

bodies to reach the sinus. Thus, CSF forms from

space (Figure 3-6).

blood and returns to blood.

The LP needle is usually inserted in the L3-L4

In adults, the total CSF volume is approxi-

space or the L4-L5 space. The skin over these areas

mately 140 mL. The ventricles contain 25 mL, the

should be thoroughly cleaned with an antiseptic

spinal cord subarachnoid space 30 mL, and the

solution such as betadine or alcohol. Wear sterile

remaining 85 mL are in the subarachnoid spaces

gloves during the procedure. Lidocaine may be

around the brain. CSF is produced at a rate of 20

injected intradermally and subcutaneously at the

to 25 mL/h or 500 to 600 mL/d. Thus, CSF turns

over about 4 times a day. CSF production is inde-

anticipated LP needle entry site. Normally a 20-

pendent of CSF pressure (until a pressure of 450

gauge needle is used as this needle does not bend

mm CSF), but CSF absorption is dependent on

during insertion and allows accurate measurement

CSF pressure in a linear fashion.

of CSF pressure. Occasionally, smaller needles are

In adults the spinal cord descends to about

used, but they may not allow accurate CSF pres-

T12-L1, but in small children the spinal cord may

sure measurement. The LP needle is inserted bevel

descend as low as L2. Below that level, nerve roots

up through the skin and then angled slightly

travel to exit appropriate neural foramina. It is at

cephalad toward the umbilicus. It is important to

the level of the nerve roots that it is safe to perform

keep the needle horizontal with the patient during

a lumbar puncture.

insertion. There is usually a “pop” sensation as the

Figure 3-6

Patient placement for lumbar puncture.

FUNDAMENTALS OF NEUROLOGIC DISEASE

needle passes through the dura into the subarach-

advisable to collect an extra tube containing sev-

noid space. One can stop the procedure at any step

eral ml of CSF and mark “save” on the tube in the

and remove the stylet to see if CSF returns. If

event that additional tests are needed. In many lab-

blood is encountered, the needle should be with-

oratories, the “save” CSF tube is kept frozen for at

drawn and the patient repositioned before the next

least 1 month.

try, often at the next higher interspace.

The CSF should promptly be taken to the clini-

Once CSF is encountered, attachment of a

cal laboratory, since white blood cells begin to

three-way stopcock and a manometer (which usu-

degenerate and lyse after ¹/₂ hour and glucose lev-

ally comes with a commercial CSF kit) allows

els may fall due to metabolism by white blood cells

measurement of the CSF pressure. If the pressure

(WBCs). A procedure note should immediately be

is elevated, relaxation of the patient and slight

recorded in the patient’s chart that includes indica-

uncoiling the legs often reduce the pressure back

tions for the LP, the location of the puncture,

to normal levels. CSF is then collected sequentially,

whether or not the spinal tap was traumatic, open-

using 4 to 5 tubes. In adults, 10 to 35 mL are usu-

ing pressure, amount of fluid obtained, appearance

ally collected, depending on the tests to be ordered.

of the fluid, and a list of tests ordered on the CSF.

In small children, 3 to 5 mL are sufficient for stan-

NORMAL CSF VALUES

dard tests in hospitals that have microchemistry

facilities. Figure 3-7 lists the commonly ordered

Table 3-2 lists common normal findings in adult

CSF tests and the tube number the tests is often

CSF. Neonates transiently have more cells in their

ordered from. Tube 1 is the most likely to have a

CSF and higher protein levels. In general for

skin bacterial contaminant and exogenous red

adults, the upper limit of the CSF protein level

blood cells (RBCs) from the LP needle puncture,

equals the patient’s age. Determination of normal

which may produce misleading reports if this tube

CSF glucose level is difficult when blood glucose is

is used for bacterial cultures or cell counts. It is

markedly elevated because high blood glucose sat-

Figure 3-7

Outline of lumbar puncture algorithm.

CHAPTER 3—Common Neurologic Tests

Table 3-2

Normal Lumbar Cerebrospinal Fluid (CSF) Findings in Adults

Test

Normal finding

Appearance

Clear and colorless against a white background

Opening Pressure

70-180 mm CSF in recumbent position

Red Blood Cells (RBCs)

< 5 RBC/mm³

White Blood Cells (WBCs)

5-10 WBC/mm³

Differential

Mainly mononuclear cells

Total Protein

<45-<60 mg/dL depending on assay technique (<30 mg/dL if cisternal CSF,

<25 mg/dL if ventricular CSF)

Percent Immunoglobulins

<15% of total protein

Oligoclonal Bands

None or rarely one band

Glucose

>40 mg/dL (usually >60% of blood glucose)

Gram Stain

Negative

Cultures

Sterile for bacteria, mycobacteria, fungi, and viruses

CSF-VDRL test

Non reactive

Cytology

No malignant cells

* VDRL = Venereal Disease Research Laboratory.

urates the blood-CSF glucose transporter. CSF

located on the dorsal side of the spinal subarach-

polymerase chain reaction assays are increasingly

noid space. When this happens, fresh RBCs and

being used to diagnose infections of the CNS even

serum proteins from the blood and CSF enter the

when the infectious agent cannot be isolated from

needle. Often the number of RBCs rapidly

CSF (see Chapter 13, “Central Nervous System

decreases from tube 1 to tubes 3 or 4. However,

Infections”).

this fresh blood may falsely elevate CSF WBC and

protein levels. If the RBC and WBC counts and

COMPLICATIONS OF LUMBAR PUNCTURE

protein measurements are done on the same tube,

A traumatic lumbar puncture occurs in 10% to

one simple rule of thumb is to subtract

1-2

20% of LPs. It most commonly occurs when the

WBC/mm³ and 1 mg/dL of protein for every 1,000

LP needle hits a tiny vein in Batson’s plexus,

RBCs/mm³. Table 3-3 (analysis of bloody CSF)

Table 3-3

Analysis of Bloody Cerebrospinal Fluid

CSF finding

Traumatic Lumbar Puncture (LP)

Subarachnoid Hemorrhage

Color

Tube 1 pink to red

All tubes uniform color

Tube 3 clearer

Red Blood Cell Count

Higher in tube 1 than in tube 3

All tubes uniform

Color of Supernatant Fluid

Nearly colorless

Xanthochromic (yellow color)

Bilirubin

Absent

Present after first day

Clot

May occur on standing

Absent

Repeat LP at Higher Interspace

Often clear or nearly clear

Same as initial LP

Head Computed Tomography

No blood in subarachnoid space

Blood may be seen in

subarachnoid spaces

FUNDAMENTALS OF NEUROLOGIC DISEASE

gives a useful approach to distinguishing a trau-

from the foot of the bed. Thus, the right side of the

matic LP from a subarachnoid hemorrhage.

brain is located on the left side of the brain image.

While not life threatening, post-LP headaches

CT uses a beam of x-rays shot straight through

may be quite uncomfortable. The headache begins

the brain. As the beam exits the other side, it is

several hours after the LP and may last for several

blunted or attenuated slightly because it has hit

days. The headache is usually frontal and develops

dense living tissues on the way through the head.

when the patient moves from a lying to a sitting or

Very dense tissue, like bone, blocks many x-rays;

standing position. Returning to a lying position

the brain blocks some; and CSF and water block

relieves the headache. The incidence of post-LP

even less. As with conventional x-ray, bone appears

headache is highest in young adult women and is

bright because its high density blocks x-rays from

uncommon in children and the elderly. In young

darkening the film. Conversely, less-dense objects,

adults the incidence is about 10%. The risk of a

such as CSF or fat, appear dark since x-rays can

post-LP headache increases when larger-size LP

penetrate to expose the film. X-ray detectors posi-

needles are used. There is little evidence that

tioned around the circumference of the scanner

drinking large quantities of water or lying prone

collect attenuation readings from multiple angles,

prevents a post-LP headache, but lying prone for a

and a computerized algorithm constructs the

few hours may be of benefit. With simple bed rest,

image of each slice. A standard CT creates hori-

the headache usually disappears.

zontal (axial) brain slices that are about 1 cm thick

A brain herniation from lumbar puncture is the

and in a different plane than that used by MRI.

most-feared complication, but fortunately is quite

The total x-ray exposure from CT is about that of

rare (less than 2% even if the CSF pressure is ele-

a chest x-ray. Presently only a few seconds are

vated). If the patient has markedly elevated pres-

required to obtain one brain slice and 15 to 20

sure, it is still important to collect at least 5 mL of

minutes for the entire brain.

CSF for diagnostic tests before withdrawing the LP

MRI uses different physical principles than CT

needle. Once the needle is withdrawn, CSF begins

to create brain images. When brain protons are

to leak out the hole in the dura. If the CSF pressure

placed in a magnetic field, they oscillate. The fre-

is unexpectedly markedly elevated, there are sev-

quency of oscillation depends on the strength of

eral things that should be done immediately after

the magnetic field. Protons are capable of absorb-

the LP. The patient should be observed closely for

ing energy if exposed to electromagnetic energy at

signs of neurologic deterioration over the next 8

the frequency of oscillation. After the proton

hours. Prompt neuroimaging (CT or MRI) often

absorbs energy, the nucleus releases or reradiates

identifies the cause of elevated CSF pressure. A

this energy and returns to its initial state of equi-

secure intravenous line may be established should

librium. The reradiation or transmission of energy

mannitol administration be required. Notification

by the nucleus is what is observed as the MRI sig-

of a neurosurgeon that a potential problem exists

nal (Figure 3-8).

is helpful should a surgical cause of the increased

The return of the nucleus to equilibrium occurs

CSF pressure be identified. If brain herniation

over time and is governed by 2 physical processes:

begins, the patient should be given intravenous

(1) T1, the time for relaxation back to equilibrium

(IV) mannitol, intubated, and hyperventilated to

of the component of the nuclear magnetization

lower intracranial pressure.

that is parallel to the magnetic field and (2) T2, the

time for relaxation back to equilibrium of the

component of the nuclear magnetization that is

Neuroimaging Tests

perpendicular to the magnetic field. Contrast

between brain tissues depends upon the proton

CT and MRI are the most widely used imaging

density, T1, and T2. MRI signals can be “T1- or

techniques because they yield high resolution of

T2-weighted” to accentuate select properties by

the brain and surrounding structures, they are

changing the way the nuclei are initially subjected

safe, they are performed in a reasonable period of

to electromagnetic energy.

time, and they are widely available in the United

T1-weighted images yield the sharpest and

States. Both CT and MRI images are to be pre-

most accurate brain anatomy but less information

sented as if one is looking at the patient upward

about brain pathology. T2-weighted images better

CHAPTER 3—Common Neurologic Tests

Energy in from MRI radio

Energy out when proton

frequency pulse tips proton

returns to alignment with

in magnetic field

MRI magnetic field

Figure 3-8

Basic principles of magnetic resonance imaging (MRI).

demonstrate brain pathology but are less suitable

pacemakers are contraindicated. Most modern

for brain anatomy. Table 3-4 gives tissue types that

surgical clips and orthopedic appliances are MRI

are bright and dark on T1- and T2-weighted

safe, but older neurosurgical clips may dangerous.

images. When brain pathology is located adjacent

Should a medical emergency occur while the

to ventricles with CSF, it may be difficult to distin-

patient is within the magnet, the patient must be

guish CSF from the lesions on T2-weighted

removed from the MRI scanner room before

images. In these cases, intermediate-weighted

attempting resuscitation since ventilators, crash

images (proton density images) or fluid-attenu-

carts, and emergency personnel often carry ferro-

ated inversion recovery (FLAIR) images are help-

magnetic objects.

ful. Diffusion-weighted MRI scans help identify

As seen in Table 3-5, MRI is the superior neu-

acute infarctions.

roimaging test for most neurologic illnesses. Table

The key to identifying the type of MRI image

3-6 compares the advantages of MRI and CT. In

lies in the CSF. On T1-weighted image CSF is dark

several new applications of magnetic resonance,

and on T2-weighted images, CSF is bright.

magnetic resonance spectroscopy

(MRS) can

Patient safety is of some concern when the

evaluate levels of brain metabolites such as N-

patient is around the MRI machine due to the

acetylaspartate, choline, creatine, myoinositol,

magnet’s high magnetic field. Most MRI machines

and lactate. Often the magnet employed is of

are

1.5 Tesla, meaning the magnet has a field

higher strength (2.0-4.0 Tesla). MRS presently has

strength 30,000 times that of earth. Ferromagnetic

few clinical indications but researchers are exam-

objects on the patient’s or attendant’s clothing can

ining methods of biochemically identifying brain

become missiles and fly inside the magnet. Cardiac

abnormalities such as brain tumors, abscesses, etc.

FUNDAMENTALS OF NEUROLOGIC DISEASE

Table 3-4

Signal Intensities and Densities of Tissue Types in Neuroimaging

Neuroimaging

Bright

Dark

MRI

Fat

Bone or dense calcium

T1 weighted

Methemoglobin

CSF

Gadolinium contrast

Edema or water

Air

Flowing blood

MRI

Edema or water

Bone or dense calcium

T2 weighted

CSF

Air

Methemoglobin (extracellular)

Fat

Flowing blood

Iron-laden tissues

Hemosiderin

Deoxyhemoglobin

Methemoglobin (within RBC)

Bone

CSF

Blood not in vessels

Edema or water

CT contrast material

Fat

Thrombosis of major vessels

Air

CSF = cerebrospinal fluid; CT = computed tomography; MRI = magnetic resonance imaging; RBC = red blood cell.

Functional magnetic resonance imaging (fMRI)

Brain, Nerve, and Muscle Biopsy

evaluates changes in cerebral blood flow in

response to local changes in neuronal firing pat-

A small piece of brain, meninges, peripheral sen-

terns. Thus, fMRI gives information about struc-

sory nerve, or muscle is surgically removed for his-

ture and indirect information about function.

tologic examination and culture for infectious

Neuroimaging tests are safe, expensive, comfort-

agents. Indications for a biopsy include (1) deter-

able, and take up to 1 hour.

mining the etiology of a brain mass, (2) culturing

a suspected brain infection that has not been iso-

lated from CSF or other body sites, and (3) estab-

Single-Photon/Positron Emission

lishing a specific diagnosis of a myopathy or

neuropathy. Since the biopsy destroys tissue, it is

Computed Tomography

performed usually when other safer diagnostic

(SPECT or PET)

tests fail or during surgery to debulk a brain tumor

of unknown type. A biopsy is expensive, uncom-

When radiolabeled compounds are intravenously

fortable to the patient, and has a risk of complica-

injected in tracer amounts, their photon emissions

tions. For example, a brain biopsy has a 5% risk of

can be detected, much like x-rays in CT. The

subsequent seizures, and all biopsy sites can

images are often shown in a color scale that repre-

become infected.

sents the amount of the labeled compound accu-

mulated in specific brain regions. Various

compounds may reflect blood flow, oxygen or glu-

Molecular/Genetic Neurologic Tests

cose metabolism, or concentrations of specific

neurotransmitter receptors. These tests are safe,

The completion of the Human Genome Project

expensive, mildly uncomfortable, and take 1 hour.

and improving methods to link disease pheno-

CHAPTER 3—Common Neurologic Tests

Table 3-5

Commonly Ordered

Table 3-6

Comparison of Magnetic

Neuroimaging for

Resonance Imaging (MRI)

Neurologic Conditions

and Computed Tomography

(CT) Techniques

Test Commonly

Imaging Indications

Ordered

Advantages of MRI

Head Trauma

• Better imaging of brain located adjacent to bone

Acute

• Superior brain anatomy

Old

MRI

• Detection of smaller brain lesions

Cerebral Hemorrhage

• Better detection of subtle central nervous system

CNS Infection

MRI with

pathology such as low-grade tumors

gadolinium

• Can visualize major neck and cerebral arteries

Acute Stroke

MRI with diffusion-

and veins (magnetic resonance angiography)

weighted images

• No ionizing radiation so safer than CT, especially

Seizures

MRI

during pregnancy

Brain Tumor

MRI with

Advantages of CT

gadolinium

• Faster imaging time so restless, uncooperative

Multiple Sclerosis

MRI

patients can be scanned with fewer movement

Dementia

MRI

artifacts

Back Pain with

MRI

• Ferromagnetic objects may be in or on the patient

Radiculopathy

• Less claustrophobia

Spinal Cord Disease and

MRI

• Better detection of subarachnoid hemorrhage,

Myelopathy

brain calcifications, and bone fractures

Atypical Headaches

MRI

CNS = central nervous system; CT = computed tomog-

raphy; MRI = magnetic resonance imaging.

results in metabolic diseases affecting brain devel-

opment or preventing normal turnover of brain

proteins, allowing them to abnormally accumulate

types to specific gene loci enable the diagnosis of

in neurons. Dominantly inherited genetic diseases

many neurologic genetic diseases. Most disease-

are mainly caused by mutations affecting impor-

causing mutations consist of single base substitu-

tant proteins.

tions leading to amino acid substitutions

The genetic mutations of many genetic neuro-

(missense mutations; neurofibromatosis type 1),

logic diseases can be detected using non-CNS host

premature translation stop signals

(nonsense

tissues, such as WBCs, skin biopsy, or mouth

mutations; Duchenne and Becker muscular dys-

mucosa cell scrapings. Assays for specific enzymes

trophies), or abnormal ribonucleic acid (RNA)

can be performed, such as hexosaminidase A to

transcript splicing. Other clinically important

diagnose Tay-Sachs disease. Chromosomal band-

mutations come from deoxyribonucleic acid

ing and spectral karyotyping can detect gross dele-

(DNA) deletions, DNA duplications (Down syn-

tions or duplications of chromosomal DNA.

drome), or abnormal expansion of unstable trinu-

Cellular DNA can be screened for specific genetic

cleotide repeats

(Huntington’s chorea and

mutations by several methods, including poly-

spinocerebellar atrophy). Recessive genetic dis-

merase chain reaction (PCR) assays, automated

eases usually derive from mutations, causing pro-

fluorescent sequencing, Southern blotting, and

duction of abnormal enzymes from both

fluorescence in situ hybridization (FISH).

chromosomes so the normal enzyme from the

While these tests are constantly improving and

opposite chromosome cannot compensate. Total

new genetic mutations are being identified, molec-

or severe loss of important enzyme functions

ular genetic tests have limitations: (1) failure to

FUNDAMENTALS OF NEUROLOGIC DISEASE

detect a given mutation does not rule out the sus-

tides, and heat-stable DNA polymerase are added

pected disease, as the mutation site may be differ-

to the DNA mixture, which contains DNA from the

ent from those searched for in the assay;

(2)

microorganism in question. The mixture is heated

different mutations in the same gene can produce

to melt and separate the double-stranded DNA and

different phenotypes; and (3) mutations in the

then cooled, allowing the primers to hybridize to

same gene can produce different phenotypes. In

their complementary sequences on the separated

addition, incomplete penetrance, age-dependent

strands of the microorganism’s DNA. The DNA

onset, and other genes often modify the disease’s

polymerase enzyme adds nucleotide bases to the

phenotypic expression and rate of progression.

ends of the primers to create a long segment of

A major advance in the diagnosis of infectious

double-stranded DNA. Third, another application

agents affecting the CNS is the PCR assay. These

of heat splits the new DNA fragments apart to

assays now exist for many viruses, bacteria,

allow the cycle to repeat doubling the number of

mycobacterium, fungi, and protozoa. Since the

DNA templates. Using automated equipment, it is

PCR assay identifies only a small, but unique, frag-

possible to make millions of copies of the desired

ment of the infectious agent DNA or RNA, the

template within hours. Fourth, since the DNA tem-

nucleic acid does not have to be fully intact or part

plate molecules are all the same length and compo-

of an infectious organism. As such, the PCR test

sition, they can be detected by gel electrophoresis

often is positive when culture of the infectious

or other methods.

agent is negative. The test is performed on CSF or

biopsy tissue. Compared with conventional isola-

tion methods, the PCR assay is sensitive, rapid (can

RECOMMENDED READING

be completed in hours to 1 day), less expensive, and

safer (does not require infectious organisms).

Fishman RA. Cerebrospinal Fluid in Diseases of the

PCR works on the following basic principles.

Nervous System.

2nd ed. Philadelphia: WB

First, unique short DNA fragments, called primers,

Saunders; 1992. (Excellent compendium of nor-

are chemically synthesized as oligonucleotide

mal CSF values and changes that occur in many

primers. Second, the primers, free DNA nucleo-

diseases.)

DISORDERS OF MUSCLE

sis), some involve distal to a greater extent than

Overview

proximal muscles (distal and myotonic muscular

dystrophies), some produce myotonia or sustained

The human body has over 600 muscles; their bulk

muscle contractions (myotonic muscular dystro-

comprises about 40% of the total body weight.

phy), and some involve specific muscle groups (lid

Muscles are divided into skeletal muscles (respon-

muscles and swallowing muscles in oculopharyn-

sible for voluntary movement and innervated by

motor neurons of the anterior horn or brainstem),

smooth muscle (involuntary muscles of the gas-

trointestinal tract, genitourinary tract, blood ves-

Table 4-1

Common Features of

sels, and skin innervated by autonomic nerves),

Primary Skeletal Muscle

and cardiac muscle (heart muscle innervated by

Diseases

autonomic nerves). Each muscle type has distinct

morphologic and biochemical characteristics that

• Proximal weakness greater than distal weakness

separate them and enable diseases to involve one

• Symmetrical weakness

or more muscle types. In simple terms, a muscle

• Muscle atrophy proportional to degree of

fiber is a long multinucleated cell that contains

weakness

myofibrils for contraction and abundant mito-

• Doughy feel to muscle on palpation

chondria for energy production. Diseases of skele-

• Hypotonic muscle

tal muscle are called by several general names:

myopathy, implying all types of muscle disease;

• Slow progression of weakness

myositis, implying inflammation in the muscle;

• Weakness rarely painful

and muscular dystrophy, implying degeneration of

• Loss of deep tendon reflexes proportional to

muscle, often hereditary.

degree of weakness

The first step in diagnosing a muscle disease is to

• No sensory loss

distinguish it from other causes of weakness (Table

• Serum creatine kinase often elevated early in

4-1). However, there are exceptions to Table 4-1.

disease

For example, some skeletal muscle disorders are

• Electromyography shows myopathic features

episodic (hyper- or hypokalemic periodic paraly-

FUNDAMENTALS OF NEUROLOGIC DISEASE

geal muscular dystrophy). Thus for unknown rea-

onset, sex distribution, location of maximal mus-

sons all skeletal muscles are not equally susceptible

cle atrophy, and phenotypic signs. The most com-

to a given type of muscular dystrophy in spite of

mon and most serious muscular dystrophy is

their apparent similarity in structure.

Duchenne muscular dystrophy (DMD), a lethal

Table 4-2 lists differences between the various

childhood disorder associated with a marked defi-

types of weakness that are helpful for localizing

ciency or absence of dystrophin. A large gene on

weakness due to a muscle disorder.

the X chromosome at Xp21 encodes dystrophin.

Muscle diseases are divided into 4 broad cate-

DMD is the most common disease associated with

gories: muscular dystrophy due to genetic abnor-

genetic mutations of the dystrophin gene. Collec-

malities; channelopathies with abnormal sodium,

tively these diseases are called dystrophinopathies.

calcium, or potassium membrane ion channels;

As DMD is transmitted by X-linked recessive

inflammatory myopathies; and secondary endocrine

inheritance, nearly all patients are male. About

myopathies.

10% of female carriers have mild muscle weakness.

The incidence of DMD is 30/100,000 male

births, with prevalence in the general population

Duchenne Muscular Dystrophy

of 3/100,000. New mutations account for about

1/3 of cases.

(Muscular dystrophies)

Introduction

Pathophysiology

Muscular dystrophies are genetically determined

The dystrophin gene is among the largest known,

disorders that have a wide variation in age of

spanning about 2.3 megabases of DNA or almost

Table 4-2

Distinguishing Characteristics of Limb Weakness

Upper Motor

Lower Motor

Neuron

Neuro-

(Corticospinal

(Peripheral

Distal Poly-

muscular

Skeletal

Characteristic

Tract)

Nerve)

neuropathy

Junction

Muscle

Muscle Involved

Distal more than

Distal more

Proximal more

Proximal

proximal and

proximal

than proximal

than distal

often unilateral

than distal

Muscle Atrophy

Minimal

Marked

Moderate

Minimal

Moderate

Normal Strength

Yes

that Quickly

Fatigues

Fasciculations

Common

Deep Tendon

Increased

Decreased to

Normal or

Normal to

Reflexes

absent

slightly

decreased

proportional

to weakness

Sensory Loss

May be unilateral

Yes

Positive Family

Uncommon

Common

History

CK Elevation

Yes

EMG and nerve

None

Denervation on

Abnormal EMG

Minimal

Myopathic

conduction

EMG or slow

and nerve

changes on

motor units

findings

motor nerve

studies

EMG or

on EMG

conduction velocity

nerve studies

CK = creatine kinase; EMG = electromyogram.

CHAPTER 4—Disorders of Muscle

1% of the entire X chromosome. Muscle dys-

Dystrophin gene mutations that cause DMD

trophin is a large 427-kd molecular weight protein

result in either the absence of dystrophin protein

3,685 amino acids that is found primarily

production or markedly truncated proteins that

within skeletal, smooth, and cardiac muscle. Dys-

cannot attach to the transmembrane protein com-

trophin isoforms are also present in cortical neu-

plex and are rapidly catabolized. The net result is

rons, Purkinje cell neurons, glia, and Schwann

the virtual absence of dystrophin and the dys-

cells. Dystrophin accounts for 5% of sarcolemmal

trophin-associated protein

(DAP) complexes

cytoskeletal proteins in muscle. The protein is rod

along the sarcolemmal membrane. Quantitative

shaped and resides just beneath the sarcolemmal

studies of dystrophin have shown less than 3% of

membrane as two parallel fibers (Figure 4-1). The

normal dystrophin content is present in DMD

amino terminus is attached to actin and the car-

muscle (Figure 4-2).

boxyterminus binds to a transmembrane protein

The absence of dystrophin leads to membrane

complex that is located on the transmembrane. In

instability, myofiber leakiness of creatine kinase

muscle, dystrophin links myofibrillar elements

(CK), and susceptibility to injury from normal

with the sarcolemma, affording stability and flexi-

muscle contractions. Over time, the damaged

bility to the muscle fiber of patients with DMD.

muscle cell wall allows abnormal influxes of cal-

Of these patients, 75% demonstrate large-scale

cium and subsequent activation of cell proteases

deletions in the gene or have partial gene duplica-

with amplification of disturbed calcium home-

tions; the remainder are poorly characterized. Nearly

ostasis. This results in fiber necrosis, secondary

80% of deletions occur in the center of the protein.

inflammation, and apoptosis.

The remaining 25% of patients have small or point

Although mature muscle fibers are postmitotic,

mutations. Frame-shift mutations usually produce

skeletal muscle contains mononuclear muscle pre-

truncated molecules lacking the carboxyterminus

cursor cells that proliferate and fuse in response to

and thus produce DMD. Non-frame-shift muta-

stimuli from degenerating muscle fibers. Since

tions usually result in an abnormal protein that has

these regenerating muscle fibers also lack dys-

a carboxyterminus and can partially function. Muta-

trophin, the process repeats itself. Over time, fibro-

tions of this type are often seen in Becker muscular

sis and scarring develop in the muscle, and fat cells

dystrophy, a milder form of DMD where the

invade, replacing the degenerating muscle cells.

amount of dystrophin is less than normal but not

The net process may transiently give rise to

absent. Thus, the old adage of “1 gene = 1 protein =

enlarged doughy muscles that have a pseudohy-

1 disease” is an oversimplification.

pertrophic appearance.

Sarcolemma

Membrane

Syntrophin

Dystrophin

F-Actin

Figure 4-1

Dystrophin molecule beneath external muscle membrane (sarcolemma).

FUNDAMENTALS OF NEUROLOGIC DISEASE

Figure 4-2

Quantitative studies of dystrophin have shown less than 3% of normal dystrophin content is present in

Duchenne muscular dystrophy muscle (Courtesy of Alan Pestrank, MD).

Major Clinical Features

About 25% of children have IQ scores below 75

and the average IQ score is 1 standard deviation

Although children with DMD have disease activity

below the mean. Some children develop smooth

in the neonatal period (elevated serum CK and

muscle involvement with gastric hypomotility and

necrosis on muscle biopsy) they rarely have clini-

constipation. Cardiomyopathy, cardiac muscle

cal symptoms until age 3 to 4 years. Parents usually

damage, slowly develops. Kyphoscoliosis and

report difficulty in running or climbing, frequent

weakness of respiratory muscles produce a

falls, and enlargement of the calf muscles, which

decreasing lung vital capacity and low maximal

feel firm and rubbery. By 4 to 5 years of age, the

inspiratory and expiratory pressures.

gait becomes wide-based and waddling and the

The terminal stages of DMD are characterized

child often walks on his or her toes because of heel

by recurrent pulmonary infections and often con-

cords contractures. The weakness is greatest in

gestive heart failure. The age of death ranges from

proximal muscles, producing a Gowers maneuver

10 to 30 years, with a mean of 18 years. Only 5%

(placing hands on the knees and climbing up the

live beyond 26 years.

thighs to stand) (Figure 4-3).

Female carriers are usually normal, but 10%

In the early school years, the limb weakness

demonstrate mild weakness of proximal muscles.

progresses and is accompanied by excessive lordo-

Carriers usually can be identified by pedigree

sis. There is relative clinical sparing of extraocular

analysis and presence of mildly elevated serum CK

muscles and muscles of bladder and bowel sphinc-

levels. (CK elevation is not seen in all carriers.)

ters, as for unknown reasons these muscles lack

dystrophin. By age 10 to 12 years, the child is

unable to walk and is confined to a wheelchair.

Major Laboratory Findings

Deep tendon reflexes are lost and joint contractors

appear at the hip flexors and heel cords. By late

In young children, serum CK level is always

teens the weakness is profound, scoliosis is

markedly elevated, often 100 times above the nor-

marked, and joint contractures are frequent.

mal upper limit. In the late stages of DMD, the CK

CHAPTER 4—Disorders of Muscle

Figure 4-3

Gowers maneuver.

level falls as muscle mass disappears. The electro-

onic villus tissue. If the type of DMD mutation is

cardiogram is abnormal in 2/3 of patients.

unknown, experimental studies of 19-week fetal

The EMG demonstrates myopathic motor unit

muscle biopsies can determine the presence or

potentials and occasionally fibrillation potentials

absence of dystrophin.

from segmental necrosis of muscle fibers

(see

Chapter 3, “Common Neurologic Tests”).

Principles of Management and

Muscle biopsy demonstrates a mixture of fiber

Prognosis

sizes, containing necrotic, regenerating, and large

hyaline (hypercontracted, opaque, or large dark)

Management must be multidisciplinary. No drugs

fibers. Necrotic fibers have a glassy appearance

have yet proven to reverse the pathologic process.

from loss of the intermyofibrillar membranous

However, corticosteroid administration may

network and are invaded by macrophages (Figure

improve strength and performance for up to 1

4-2). Fiber type grouping of remaining muscle

year. Management involves use of joint bracing

fibers is normal. Electron microscopy of non-

and prevention or release of contractures to main-

necrotic muscle fibers demonstrates defects in the

tain walking for as long as practical. The wheel-

plasma membrane, where abnormal calcium

chair should be viewed as a passport to mobility

influx occurs. Later in the disease, fibrosis and fatty

and not a failure to walk. Once the child is con-

replacement of muscle fibers is seen. Immunohis-

fined to a wheelchair, attention should be directed

tochemical staining demonstrates absence or near

toward posture and bracing to minimize scoliosis.

absence of dystrophin along the sarcolemma

Occasionally, surgical procedures to improve pos-

membranes.

ture or correcting joint contractures are indicated.

It is now possible to use PCR analysis to

Education should proceed in a normal fashion.

detect deletions in the dystrophin gene to

Terminally, attention is directed to maximizing

account for about 75% of all DMD cases. How-

pulmonary function and minimizing respiratory

ever, the PCR study does not determine whether

infections.

there is a frame-shift abnormality. This makes it

Considerable research is underway to replace

more difficult to separate DMD from Becker’s

the mutated dystrophin gene by introduction of a

dystrophy, which contains the carboxyterminus.

normal gene into muscle fibers via a plasmid or

If the DMD mutation is a deletion, prenatal

viral vector or by inoculation of genetically normal

diagnosis can be made by PCR studies of chori-

myoblasts, which fuse with the patient’s regenerat-

FUNDAMENTALS OF NEUROLOGIC DISEASE

ing muscle fibers. To date all results have been dis-

tidyl transfer (t)-RNA synthetase can be seen in

appointing.

serum of both polymositis (PM) and DM. The clin-

ical significance of these autoantibodies is unclear.

However, an elevated anti-Jo-1 antibody titer may

Dermatomyositis (Inflammatory

signal increased disease activity and an increased

risk of developing interstitial lung disease.

myopathy)

Introduction

Major Clinical Features

Inflammatory myopathies are a heterogenous

Typically, weakness is proximal and first noted in a

group of diseases characterized by muscle inflam-

symmetrical fashion in muscles of the shoulder and

mation. In some, there is an infectious etiology

pelvic girdle. Muscle pain and soreness is uncom-

(trichinosis or viral myositis) but in most the etiol-

mon. As the disease progresses, the patient may

ogy is unknown. Dermatomyositis (DM) has an

develop dysphagia and neck weakness. Occasionally

immune-mediated pathogenesis. While DM can

respiratory muscles may become involved. The early

occur at any age, children from ages 5 to 14 years are

skin rash is characterized by erythema (heliotrope

the most likely to become symptomatic. As in most

appearance) accompanied by edema of the subcuta-

autoimmune disorders, females are more often

neous tissue affecting mainly the periorbital, perio-

affected, but the majority of patients lack a family

ral, malar, and anterior chest regions. Skin exposed

history of the disorder. The estimated incidence is

to sunlight may also develop a similar rash. The rash

0.6/100,000, but the incidence is

1/100,000 in

often progresses to cause scaling, pigmentation,

adults. African Americans appear to be more com-

depigmentation, and skin with a brawny indura-

monly susceptible than caucasian Americans.

tion. Linear erythematosus discoloration may sur-

Patients with DM have a slightly higher incidence of

round nail beds.

malignancies found at the time or within a few years

Interstitial lung disease occurs in about 10% of

of diagnosis. An association of collagen vascular

patients, usually after years of disease. Patients

diseases such as systemic lupus erythematosus and

experience a nonproductive cough and dyspnea

Sjögren syndrome has been noted.

from bronchiolitis obliterans, interstitial pneumo-

nia, and/or diffuse alveolar damage.

Pathophysiology

Major Laboratory Findings

The etiology of this disease is unknown, but is

thought to be the consequence of differing

Serum CK levels are elevated (3-30 times above

immune-mediated processes of blood vessels.

normal). A few patients have autoimmune antibod-

Dermatomyositis appears to be an antibody-

ies, including anti-Jo-1 antibodies and anticyto-

mediated disease in which complement is acti-

plasmic antibodies, anti-signal-recognition particle

vated by deposition of membrane attack

antibodies, and antibodies against Mi-2 antigens.

complexes in blood vessels. Destruction of the

The EMG demonstrates an irritative myopathy

blood vessels leads to ischemia, producing muscle

with myopathic changes (brief, small-amplitude,

fiber necrosis, microinfarcts, and perifascicular

abundant, polyphasic motor units) and signs of

atrophy (at the edges of a muscle fascicle). Capil-

denervation from the associated inflammation

lary destruction is not limited to muscles, but

(fibrillations and positive sharp waves).

may occur in skin (heliotrope rash of face, eye-

Muscle biopsy in DM demonstrates muscle

lids, and sun-exposed areas) and other organs

changes in the perifascicular region. Myopathic

such as the lungs (interstitial lung disease) and

changes include necrosis and regeneration, muscle

heart (cardiomyopathy).

fiber atrophy

(Figure

4-4), and a reduction in

Patients may have autoimmune antibodies that

cytochrome

oxidase activity. Inflammatory

are directed against poorly characterized cellular

changes are seen but do not correlate with severity

targets such as cytoplasmic molecules, signal-recog-

of muscle disease.

nition particles, and myositis-specific epitopes. For

Blood vessels demonstrate perivascular col-

example, anti-Jo-1 antibodies targeted against his-

lections of inflammatory cells, arteritis,

CHAPTER 4—Disorders of Muscle

Figure 4-4

Muscle biopsy of dermatomyositis. (Courtesy of Alan Pestronk, MD.)

phlebitis, intimal hyperplasia of arteries and

immunosuppressants such as azathioprine or

veins, and occlusion of vessels by fibrin thrombi.

methotrexate. These drugs may require 3 to 6

Adjacent to occluded vessels are ischemic and

months of treatment before they are effective.

infarcted muscle fibers. In the majority of chil-

Human immune globulin (IVIg) may be given ini-

dren with DM and in some adults with DM,

tially to severely affected individuals.

there are immune complexes containing IgG,

The duration of DM disease activity in children

IgM, and complement (C3) within the walls of

is variable and may last several months to 4 years

arteries and veins. These muscle and skin angio-

before becoming inactive. In adults the 5-year sur-

pathic changes at the electron microscope level

vival is 90% and the 10-year survival is 80%. Indi-

are virtually diagnostic.

viduals with malignancies, interstitial lung disease,

or cardiomyopathy fare worse.

Principles of Management and Prognosis

Before treatment, a clear diagnosis is needed,

Primary Hyperkalemic Periodic

which usually requires a typical clinical history,

Paralysis (channelopathies)

characteristic EMG findings, and a muscle biopsy

showing inflammatory myopathy or diagnostic

Introduction

blood vessel damage. Corticosteroids represent the

first line of therapy, with an initially high dose that

Channelopathies are a group of diseases with

is tapered as the patient regains muscle strength

abnormal channels resulting from genetic disor-

and the CK level falls. If corticosteroids fail or

ders. Channels are pores in cell membranes that

adverse reactions develop, patients are given

allow ions to enter or exit a cell to depolarize or

FUNDAMENTALS OF NEUROLOGIC DISEASE

hyperpolarize the cell. These macromolecular pro-

muscle cell. The excess intracellular sodium in

tein complexes with the lipid membrane are

turn produces a prolonged depolarization. The net

divided into distinct protein units called subunits.

result is that the depolarized muscle fiber becomes

Each subunit has a specific function and is

paralyzed, electrically unexcitable, and nonrespon-

encoded by a different gene. A channel may be

sive to future nerve stimulation.

non-gated, directly gated, or second-messenger-

The sodium influx allows efflux of intracellular

gated. Important directly gated channels include

potassium into the extracellular space and also

voltage-gated channels (sodium, potassium, cal-

causes extracellular water to enter the muscle fiber,

cium, and chloride) and ligand-gated channels

resulting in hemoconcentration. Both result in a

(acetylcholine, glutamate, γ-aminobutyric acid

further rise in serum potassium level. The elevated

(GABA), and glycine).

potassium level triggers more muscle fibers to

Genetic mutations in critical areas of a channel

become persistently depolarized and the entire

can produce an abnormal gain of function (addi-

muscle rapidly becomes paralyzed. The cycle ends

tional properties not present in the normal pro-

when the serum potassium level returns to normal

tein) or loss of function (loss of properties present

by the kidney’s excretion of potassium and likely

in the normal protein). Channelopathy diseases

by other corrective measures. The duration of

primarily affect excitable cells such as muscle fibers

paralysis may be 15 minutes to hours.

and neurons and produce signs and symptoms

Normal individuals can develop muscle paraly-

that are often episodic.

sis if their serum potassium level rises above 7

Primary hyperkalemic periodic paralysis (hyper-

mmol/L. Hyperkalemia may occur in renal failure,

kalemic PP) belongs to a group of channelopathies

adrenal insufficiency, and exposure to the diuretic

with mutations in the voltage-gated sodium chan-

spironolactone.

nel. Other sodium channelopathies include famil-

ial generalized epilepsy with febrile seizures,

Major Clinical Features

paramyotonia congenital, and hypokalemic peri-

odic paralysis.

The paralysis attacks usually begin in the first

decade of life and are infrequent. With increasing

age the attacks become more frequent. In severe

Pathophysiology

cases, they occur daily. Most episodes occur in the

Hyperkalemic PP is due to a dominant mutation

morning before breakfast. Attacks during the day

in chromosome 17q35 that affects the α-subunit

are often precipitated by strenuous exercise fol-

(SCN4A) of the sodium channel (Figure 4-5). Of

lowed by rest. Other triggers include consumption

all cases, 90% are the result of two mutations, one

of excess potassium, emotional stress, fasting, a cold

of which produces both periodic flaccid weakness

environment, and corticosteroid administration.

and myotonia.

At the start of an attack the patient may experi-

The muscle membrane in a patient with hyper-

ence paresthesias or sensations of increased muscle

kalemic PP contains 2 types of sodium channels. A

tension. The patient then develops a flaccid gener-

normal channel from the normal gene activates

alized weakness and cannot move the arms, legs,

(opens) and then inactivates

(closes) rapidly.

and trunk. The weakness spares respiration mus-

However, the mutated sodium channel activates

cles, cranial nerves, and bladder and bowel sphinc-

appropriately but inactivates abnormally slow.

ters. The attack lasts 15 minutes to 1 hour before

In normal muscle, hyperkalemia causes a few

spontaneously disappearing. Afterwards, strength

normal sodium channels to open. The subsequent

returns to normal and the individual commences

slight membrane depolarization is rapidly cor-

normal activity. Over years, patients with severe

rected as the channels close before the depolariza-

hyperkalemic PP may develop permanent muscle

tion is sufficient to cause muscle contraction.

weakness.

However, in hyperkalemic PP muscle, the hyper-

One mutation causes varying amounts of

kalemia opens both the normal sodium channel

myotonia between attacks. The clinical symptom of

and the mutated sodium channel. The mutated

myotonia is essentially a slowing of relaxation of a

sodium channel remains open for a prolonged

normal muscle contraction and is commonly inter-

period, allowing excess entry of sodium into the

preted by the patient as “stiffness.” Commonly the

CHAPTER 4—Disorders of Muscle

Hyperkalemic

Normal

Periodic

Paralysis

Activation

Gate

A. Resting

State

K+

Na+

Channel

Inactivation

Gate

Na+

B. Depolarizing

Phase

Na+

K+

B2 Delay in

Na+

Inactivation

K+

Gate

C. Repolarizing

Phase

Na+

K+

D. Hyperpolarization

K+

Figure 4-5

Hyperkalemic periodic paralysis is due to a dominant mutation in chromosome 17q35 that affects the α-

subunit (SCN4A) of the sodium channel.

patient cannot easily release a grip on an object. A

Between attacks, the serum potassium level is

cold environment often makes myotonia worse.

usually in the upper normal range and the urinary

potassium level is normal.

During an attack, EMG studies of paralyzed

Major Laboratory Findings

muscle show electrical silence. Between attacks, the

During an attack, the serum potassium level rises

EMG finding in the most common mutation is

up to 5 to 6 mmol/L but rarely reaches cardiotoxic

normal, while myotonia is seen in the less-com-

levels. The serum sodium level falls slightly as the

mon mutation. In myotonia, insertion of the EMG

ion enters muscle fibers. Renal excretion of potas-

needle into a muscle causes a train of rapid electri-

sium occurs, with elevated urine potassium levels.

cal discharges that have a falling amplitude and

The serum CK level is normal to slightly elevated

frequency and sound like a “dive-bomber” when

during an attack.

heard on the EMG speaker. Myotonia is due to

FUNDAMENTALS OF NEUROLOGIC DISEASE

increased excitability of muscle fibers from the

may benefit from chronic administration of thi-

channelopathy

(sodium channels or potassium

azide or acetazolamide diuretics, which lowers the

channels in other myotonic diseases), producing

serum potassium level.

repetitive action potentials in individual muscle

fibers.

Muscle histology may be normal or demon-

RECOMMENDED READING

strate nonspecific changes to muscle fibers. In

patients who develop permanent myopathy, mus-

Davies NP, Hanna MG. The skeletal muscle chan-

cle fibers may show vacuolations in muscle fibers,

nelopathies: basic science, clinical genetics and

focal myofibrillar degeneration, and central nuclei.

treatment. Curr Opin Neurol 2001;24:539-551.

Since the gene for hyperkalemic PP is known,

(Recent review of all channelopathies that affect

blood tests are available for detection of the most

muscle.)

common mutations. However, the diagnosis is

Emery AEH. The muscular dystrophies. Lancet

commonly made in a patient with periodic paraly-

2002;359:687-695. (Nice review of current status

sis who has a dominant family history and tran-

of all muscular dystrophies.)

sient elevation of serum potassium level during an

Hilton-Jones D. Inflammatory muscle disease.

attack.

Curr Opin Neurol 2001;14:591-596. (Reviews

dermatomyositis, polymyositis, and inclusion

body myositis.)

Principles of Management and Prognosis

Pestronk, Alan. www.neuro.wustl.edu/neuromus-

Since most attacks are brief, many patients do not

cular

(Outstanding, accurate, current online

require any drug treatment. Some patients can

information on clinical, laboratory, pathology,

abort or shorten an attack by consuming carbohy-

and treatment of all muscle and peripheral nerve

drates or performing mild exercise at the start of

diseases.)

an attack. Patients with severe frequent attacks

DISORDERS OF THE

NEUROMUSCULAR JUNCTION

hours or days, as when a receptor stimulates intra-

Overview

cellular second messengers that enzymatically

affect intracellular pathways.

In humans, all nerve-to-nerve, nerve-to-muscle,

Synaptic disorders may occur from chemical or

and peripheral sensory receptor-to-nerve commu-

biologic toxins, antibodies directed against synaptic

nication occurs via synapses. An electrical signal

receptor molecules, or genetic mutations in the

traveling along a nerve axon is converted at a spe-

synaptic receptor or membrane channel. Synaptic

cialized nerve ending called a synapse. At the

disorders due to mutations in calcium, potassium,

synapse the electrical signal triggers release of a

and sodium ion channels (called channelopathies)

neurotransmitter into the synaptic cleft. The neu-

are responsible for such episodic disorders as

rotransmitter then crosses the synaptic cleft to

seizures, migraine-type headaches, ataxia, myoto-

attach to a specialized receptor that is part of an

nia, and weakness from Lambert-Eaton syndrome.

ionic channel, resulting in either local depolariza-

Synaptic disorders often have several suggestive

tion or hyperpolarization of the postsynaptic cell.

clinical features: (1) excessive inhibition or excita-

When sufficient ionic channels have been stimu-

tion of one transmitter pathway, (2) signs and

lated by neurotransmitters, the postsynaptic cell

symptoms that are episodic or fluctuate consider-

either completely depolarizes or becomes inhib-

ably, and (3) signs that increase with continuing

ited from depolarizing. In summary, all neural

firing of the synapse.

communication results from electrical-to-chemi-

This chapter focuses on diseases that result

cal-to-electrical transmission.

from toxins and antibodies affecting the neuro-

There are at least 30 different types of neuro-

muscular junction to produce weakness.

transmitters, with the greatest number occurring

in the CNS. In simple terms, neurotransmitters are

classified into simple chemicals

(acetylcholine,

Myasthenia Gravis

norepinephrine, and dopamine), amino acids

(GABA, glycine, and glutamine), or peptides (sub-

Introduction

stance P and endorphins). The duration of the

neurotransmitter effect may be milliseconds, as in

Myasthenia gravis (MG) is the most common dis-

a brief opening and closing of an ionic channel, to

order affecting the neuromuscular junction. MG is

FUNDAMENTALS OF NEUROLOGIC DISEASE

not from a toxin; it originates from autoantibodies

Anti-Acetylcholine

directed against the acetylcholine receptor (AchR).

Receptor Antibody

There are over 30,000 individuals with MG in the

United States, with a prevalence of

10/100,000

adults. The epidemiology of MG demonstrates 2

Acetylcholine

peaks. The first peak, mainly in women, occurs

between ages 10 and 40 years. The second peak has

a male predominance and occurs from ages 50 to

75 years.

Acetylcholine

MG is considered the classic humoral autoim-

Binding Site

mune disease, based on well-characterized autoan-

tibodies and the observation that these patients

frequently develop other autoimmune diseases

such as thyrotoxicosis, rheumatoid arthritis, and

systemic lupus erythematosus.

Receptor

Postsynaptic

Molecule

Pathophysiology

Membrane

The etiology or initial event that begins the onset

Figure 5-1

In myasthenia gravis, acetylcholine recep-

of MG remains unknown. However, the weakness

tor antibody blocks the acetylcholine-binding site.

results from 3 factors. The most important one is

circulating antibodies directed against the AchR

on the postsynaptic membrane of the neuromus-

Of these patients,

75% have an associated

cular junction. Some of these antibodies attach to

abnormality of the thymus gland. About 85% of

the AchR located on key parts of the sodium/

these patients have thymic hyperplasia with germi-

potassium channel, thereby interfering with open-

nal center lymphocyte proliferation, and 15% have

ing the sodium/potassium channel (Figure 5-1).

a thymoma. The role of the thymus gland in pro-

When sufficient AchRs are blocked by antibodies,

ducing the abnormal antibodies is poorly under-

the muscle will not depolarize sufficiently to trig-

stood. The current hypothesis is that the AchR

ger contraction of the muscle fiber. A second fac-

antibody is a T-cell-mediated antibody response.

tor contributing to the weakness is that AchR

Surgical removal of the thymus gland often results

molecules have a faster rate of degeneration. When

in clinical improvement and a reduction of the

AchR antibodies simultaneous attach to two adja-

number of circulating antibodies.

cent AchRs, a cell signal initiates internalization of

MG can occur in infants. Infants born to moth-

both receptors and degrades them. The turnover

ers with MG may have sufficient circulating anti-

rate is faster than replacement of new membrane

bodies to cause the infant to become floppy, weak,

AchRs, resulting in a net loss of available AchRs at

and have a poor suck. This transient syndrome

the synapse. The third factor develops because the

lasts for several weeks until the maternal antibody

antibody attached to the AchR triggers serum com-

disappears. Other infants have congenital MG that

plement activation, producing secondary damage to

is due to genetic mutations in the AchR. These

the synaptic membrane. As a consequence of years

infants remain persistently weak and do not

of complement damage, the postsynaptic mem-

respond to immunosuppressive drugs.

brane loses its rich invaginations and becomes sim-

plified in structure

(Figures 5-2a and 5-2b). In

Major Clinical Features

severe chronic cases, the postsynaptic membrane

may have a 2/3 reduction in the normal number of

Clinical features result from blockade at the neu-

AchR molecules, a number insufficient to initiate

romuscular junction and affect skeletal muscles in

depolarization and contraction of the muscle fiber

a fluctuating and fatigable manner (Table 5-1).

even if no acetylcholine antibodies were present. In

The disease usually has a subacute onset. Earliest

these patients, pyridostigmine usage does not

symptoms are ptosis and diplopia. Patients com-

improve the probability of muscle fiber contraction.

plain of droopy eyelids and double vision that

CHAPTER 5—Disorders of the Neuromuscular Junction

Axon of motor neuron

Vesicle

Acetylcholine (ACh)

ACh Receptors

Acetylcholinesterase

(AChE)

Endplate

Muscle

Axon of motor neuron

Vesicle

Acetylcholine (ACh)

ACh Receptors

Acetylcholinesterase

(AChE)

Endplate

Muscle

Figure 5-2

Neuromuscular junction. (a) Normal. (b) Myasthenia gravis with simplified postsynaptic membranes.

varies during the day and worsens as the day pro-

to a greater extent than distal muscles. Although

gresses. In 15% of patients, the disease does not

brief maximal muscle testing may appear normal,

progress beyond ocular problems. For most other

patients often cannot hold their arms outstretched

patients, other signs of bulbar muscle weakness

for even a minute without fatigue. In severe cases,

appear, with trouble chewing, swallowing, and

patients cannot walk and develop respiratory

speaking loudly. Some patients find they eat their

weakness. Sensation, mentation, and deep tendon

big “dinner” meal for breakfast as they have trou-

reflexes are not affected.

ble chewing meat by the end of the day. Limb

Maximal weakness appears within the first 3

weakness is common and affects proximal muscles

years of clinical onset. About

10% of patients

FUNDAMENTALS OF NEUROLOGIC DISEASE

Principles of Management and Prognosis

Table 5-1

Cardinal Features of

Myasthenia Gravis

The goal of treatment is to improve strength and

to reduce or eliminate circulating antibodies

Weakness

against the AchR. Symptomatic treatment aimed

• Bulbar muscles: ptosis, diplopia, dysarthria,

at improving strength is accomplished with anti-

dysphagia, and chewing difficulty

cholinesterase drugs. These drugs do not reduce

• Limb muscles: proximal greater than distal

weakness

circulating antibody titers, but are the first line to

improve the patient’s strength. Pyridostigmine

Fatigability of skeletal muscles

(Mestinon^®) is the main oral drug; it is given to the

• Increased weakness in afternoon or after

exercise

patient several times a day. Anticholinergic med-

ications act by interfering with acetylcholine

Normal mentation, sensation, and deep tendon

esterase, the enzyme that cleaves acetylcholine in

reflexes

the synaptic cleft. Partial inhibition of this enzyme

results in a longer time period that acetylcholine

molecules can remain in the synaptic cleft to find

experience a spontaneous remission, which occurs

unblocked AchR and increase the probability that

within the first 2 years. However, the remainder of

sufficient AchR channels will open to fully depo-

patients have a life-long chronic illness that fluctu-

larize and contract the muscle fiber. Too much

ates in severity.

pyridostigmine, however, can block all the acetyl-

choline esterase such that acetylcholine cannot be

Major Laboratory Findings

cleaved and removed once it attaches to an AchR.

Serum antibodies directed against the AchR are

The inability to remove acetylcholine from the

found in over 85% of patients. A few additional

receptor causes a depolarizing muscle weakness

MG patients have a blocking antibody. The level

that is called a “cholinergic crisis.”

of antibody titer does not always reflect disease

A number of treatments are aimed at reducing

severity, as the test detects all AchR antibodies,

the amount of circulation antibody. Thymec-

including those that do not interfere with the

tomy, the surgical removal of the thymus gland,

functioning of the channel. However, for a given

in a moderately severe patient often results in

patient, a falling titer does reflect clinical

clinical improvement and a fall in antibody titer.

improvement.

Corticosteroids and other immunosuppressive

X-ray or CT of the chest may demonstrate a thy-

drugs (azathioprine and cyclosporine) are com-

moma. Elevated thyroxin blood levels indicating

monly given to lower the antibody titer and

thyrotoxicosis are found in up to 5% of patients.

improve strength. IVIg and plasma exchange by

Repetitive nerve stimulation (at rate of 3/s) of

plasmaphoresis will temporarily reduce circulat-

proximal muscles (often the trapezius muscle)

ing antibody and improve strength for several

usually demonstrates a decremental fall of

weeks. These temporary methods can be used for

greater than

15% in the compound muscle

patients requiring prompt clinical improvement

action potential (see Chapter 3, “Common Neu-

such as for elective surgery, pneumonia, or a

rologic Tests”).

“myasthenic crisis.”

The tensilon test, which can be performed in

Patients with MG should avoid drugs such as

the office, is helpful for establishing the diagnosis

aminoglycoside antibiotics, chloroquine, and

of MG when there are clear ocular signs. Edropho-

anesthetic neuromuscular-blocking drugs (pan-

nium (Tensilon^®) is a brief-acting anticholinergic

curonium and D-tubocurarine), which affect the

drug that is slowly given intravenously to a patient.

neuromuscular junction.

For the next 5 to 10 minutes, an untreated MG

Using various combinations of pyridostigmine

patient should have a clear objective improvement

and immunosuppresants to lower circulating anti-

in ptosis. Often a saline injection precedes the

body levels, most patients lead fairly normal lives.

administration of edrophonium to evaluate for a

Death is now uncommon and generally develops

placebo effect.

from pneumonia or acute respiratory failure.

CHAPTER 5—Disorders of the Neuromuscular Junction

Botulism

flaccid paralysis due to interrupted transmission of

peripheral motor and cholinergic autonomic

Overview

nerves at their synapses. Human disease occurs

mainly from consumption of preformed botu-

Toxins have long been recognized as having the

linum toxin (foodborne botulism) and growth of

ability to affect the neuromuscular junction,

Clostridium botulinum in the gastrointestinal tract

resulting in paralysis or muscle spasms. Drugs

of infants with subsequent absorption of the toxin

such as curare are known to block the postsynap-

(infant botulism). However, cases of wound botu-

tic excitatory AchRs in the peripheral nervous sys-

lism are increasing primarily in heroin addicts who

tem, producing paralysis. Hyperexcitable states

subcutaneously (“skin popping”) inoculate C. bot-

result from intoxication with tetanus toxin or

ulinum spore-contaminated heroin (Figure 5-3).

lysergic acid diethylamide (LSD). Tetanus toxin

The incidence of botulism varies by type. About

blocks the inhibitory glycine receptor between the

1,000 cases of foodborne botulism are reported

spinal cord Renshaw cell and the anterior horn

annually around the world and about 32 cases

cell. Lack of inhibition on anterior horn neurons

annually in the United States. About 40 cases/yr of

causes them to repeatedly fire upon minor excita-

wound botulism are reported mainly from south-

tion, producing profound muscle spasms. LSD

western states as a consequence of the use of Mex-

appears to cause profound hallucinations by inter-

ican black tar heroin contaminated with C.

fering with CNS serotonin synaptic receptors.

botulinum spores. Nearly 70 cases/yr of infant bot-

Botulinum toxin is the most potent biologic

ulism occur in the United States.

toxin known. The 50% lethal dose (LD₅₀) for

humans has been calculated to be 0.1 µg for intra-

Pathophysiology

venous or intramuscular inoculation (wound bot-

ulism), and 70 µg for oral exposure (foodborne

The bacterium C. botulinum is a spore-forming

botulism). Botulism is a descending, symmetric,

anaerobic gram-positive bacillus that is com-

GI Colonization from

Foodborne

C. Botulinum spores

Botulinum toxin

Infants 1-6 mo. &

rarely adults with

abnormal GI System

Wound

C. Botulinum spores

Figure 5-3

Types of botulism.

FUNDAMENTALS OF NEUROLOGIC DISEASE

monly found in soil and water sediment around

synapse.As a consequence of the light chain cleav-

the world. C. botulinum produces 7 types of neu-

ing SNARE proteins, the muscle fails to contract

rotoxins; humans are intoxicated mainly by types

and the cholinergic parasympathetic nerve fails to

A, B, or E.

function. The resulting synaptic failure continues

Botulinum toxin is an odorless and tasteless

for weeks to 6 months. The high potency of botu-

150-kd molecule that is comprised of a heavy

linum toxin results from its high specificity to

chain (100 kd) and a light chain (50 kd) held

attach to only a few membrane sites and the fact

together by a disulfide bond (Figure 5-4). In food-

that the toxin is an enzyme that cleaves critical

borne botulism, the toxin is protected from stom-

proteins needed for synaptic function.

ach acid by other proteins released by C.

Clinical recovery occurs over 2 to 3 months and

botulinum that loosely attach to the toxin. In the

is due to terminal sprouting, where the incoming

upper intestine, the toxin is actively transported

axon at the paralyzed neuromuscular junction

through intestinal lining cells by receptor-medi-

sends a new branch to the same muscle fiber,

ated transcytosis (crossing the cells as an intact

forming a new synapse, or by the neuronal cell

molecule via a vesicle). Upon reaching the blood-

body producing new SNARE proteins and sending

stream, toxin circulates until it reaches a periph-

them by axoplasmic flow to the distal terminal.

eral acetylcholine synapse. The toxin does not

The pathophysiology of infant botulism is

cross the blood-brain barrier, so it does not affect

unique in that the disease results from growth of

brain cholinergic synapses. The heavy chain pos-

C. botulinum in the gut with production of toxin

sesses a highly specific domain that attaches to the

rather than consumption of the preformed toxin.

presynaptic side of the synapse (Figure 5-5). The

Infant botulism occurs in children only during the

toxin is then internalized into the cytoplasm via

first

12 months of life, with a peak at 2 to 3

an endocytotic vesicle. As the pH within the vesi-

months. After that age, the normal gastrointestinal

cle lowers, the toxin reconfigures and the heavy

(GI) tract will not allow colonization of C. botu-

chain penetrates the vesicle wall, allowing the light

linum. The infant consumes C. botulinum spores

chain to pass through the vesicle wall and release

by eating dust, honey, or other food substances

into the cytoplasm. The light chain, a zinc-con-

that contains spores. In the immature gut, the

taining endopeptidase enzyme, subsequently

spores germinate, colonize, and produce botu-

cleaves docking proteins called soluble N-ethyl-

linum toxin, which is slowly absorbed.

maleimide-sensitive factor attachment protein

receptor

(SNARE) proteins. SNARE proteins

Major Clinical Features

enable vesicles containing quantal amounts of

acetylcholine to fuse with the presynaptic mem-

FOOD-BORNE BOTULISM

brane to release acetylcholine into the synaptic

After ingestion, the mean incubation period is 2

cleft. Thus, botulinum toxins block stimulus-

days, with a range from 0.5 to 6 days. The longer

induced and spontaneous quantal acetylcholine

the incubation period, the milder the symptoms.

release on the presynaptic side of the cholinergic

Botulism classically presents with symmetric,

descending flaccid paralysis with prominent bul-

bar palsies in an afebrile patient with a normal

sensorium. Prominent bulbar palsies include

Zinc

Channel-forming

diplopia, external ophthalmoplegia, dysarthria,

endopeptidase

domain

dysphonia, dysphagia, and facial weakness. Blurry

vision from paresis of accommodation and

Light chain

Heavy chain

diplopia from CN VI palsy are early signs. Limbs

(50 kda)

(100 kda)

become weak over 1 to 3 days and may become

completely paralyzed. Deep tendon reflexes

become depressed or absent. Weakness of respira-

Binding site

domain

tory muscles develops and may be severe enough

to require intubation and mechanical ventilation.

Figure 5-4

Botulinum toxin.

Smooth muscle paralysis typically involves consti-

CHAPTER 5—Disorders of the Neuromuscular Junction

1. Toxin attachment

to membrane receptor

Acetylcholine

Synaptic vesicle

2. Toxin

within

endocytotic

vesicle

3. Light chain

exits vesicle

Synaptobrevin

4. Zinc endopeptidase

SNAP-25

cleaves SNARE proteins,

preventing vesicle

Syntaxin

SNARE

fusion

proteins

Figure 5-5

Action of botulinum toxin at the synapse.

pation, paralytic ileus, and urinary retention. In

The definitive diagnosis is the demonstration of

wound botulism, the clinical picture is similar.

botulinum toxin in serum, stool, or suspected food

or isolation of C. botulinum from a wound site.

INFANT BOTULISM

The most sensitive diagnostic test for the presence

Infants develop an illness that progresses over

of botulinum toxin is a biologic test involving

hours to 20 days (mean 4 days) that is character-

mice. These tests are positive in about ³/₄ of clini-

ized by constipation (no defecation for 3 or more

cally diagnosed cases.

days), lethargy, hypotonia (floppy infant), poor

cry, poor feeding, and loss of head control.

Principles of Management and Prognosis

Treatment should begin promptly after there is a

Major Laboratory Findings

suspicion of botulism or after a clinical diagnosis is

The CSF and blood typically are normal. The

made. Aims of treatment are to (1) support respi-

clinical diagnosis is made on a characteristic clin-

ration, (2) prevent progression of the paralysis by

ical picture and abnormal nerve studies. Nerve

use of antitoxin, and (3) prevent pulmonary or

conduction studies show widespread low-ampli-

other complications until spontaneous recovery

tude compound muscle action potentials with

occurs.

normal distal latencies, conduction velocities,

Weakness and respiratory failure may rapidly

and sensory nerve action potentials. If the nerve

progress within hours. Patients should be hospital-

receives

10 seconds of fast repetitive electrical

ized in an intensive care unit with careful moni-

stimulation (30-50 Hz), there is an increment in

toring of respiratory function. Intubation and

the compound muscle action potential amplitude

mechanical ventilation is required in over ¹/₂ of

secondary to increased release of acetylcholine

patients. Use of a ventilator averages about 2 weeks

quanta.

but can be as long as 2 months.

FUNDAMENTALS OF NEUROLOGIC DISEASE

State health officials should be immediately noti-

eign protein. Use of BIG has been shown to shorten

fied to bring antisera and to help should there be

the time on a ventilator and hospitalization.

additional cases, as seen in a common source out-

Excellent nursing care will minimize complica-

break of foodborne botulism. For botulism in

tions. Yet despite everything, the mortality rate is

adults, administration of equine trivalent (types A,

5% to 15%. Patients who survive will regain nor-

B, and E) botulism antitoxin should be as soon as

mal muscle strength but often complain of fatigue

possible without waiting for laboratory confirma-

for years.

tion. The antitoxin eliminates circulating toxin but

does not remove toxin that has already entered the

neuromuscular junction. Therefore, the antitoxin

RECOMMENDED READING

will not reverse paralysis that has occurred but will

prevent progression of the weakness and may

Cherington M. Clinical spectrum of botulism.

shorten hospitalization. Each 10-mL vial sufficiently

Muscle Nerve 1998;21:701-710. (Good review of

neutralizes circulating toxin found in all forms of

the clinical types of botulism.)

botulism. Because the antitoxin is produced in

Drachman DB. Myasthenia gravis. N Engl J Med

horses, there is a 3% incidence of allergic reactions,

1994;330:1797-1810. (Excellent overall review.)

including anaphylaxis. In infant botulism, human

Simpson LL. Botulism toxin: potent poison, potent

botulinum antitoxin—human Botulinum Immune

medicine. Hosp Pract 1999;34:87-91. (Excellent

Globulin-IV

(BIG)—is available; it has similar

recent review of the mechanism of action of botu-

effects, but eliminates the administration of a for-

linum toxin.)

DISORDERS OF PERIPHERAL NERVES

muscles. Each spinal cord root innervates a defined

Overview

area of skin sensation (dermatome) (see Chapter

2, Figure

4) and a defined group of muscles

The peripheral nervous system (PNS) involves all

(myotome) that differs from the innervation of a

nerves lying outside the spinal cord and brainstem

specific nerve. Knowledge of the differences helps

except the olfactory and optic nerves, which are

determine the location of a lesion (root, plexus, or

extensions of the CNS itself. All peripheral nerve

peripheral nerve).

axons are invested either with a wrapping of

Peripheral nerve diseases are traditionally clas-

myelin made by Schwann cells (myelinated nerves)

sified in different ways such as motor, sensory, or

or by cytoplasm of Schwann cells (unmyelinated

mixed nerve diseases; polyneuropathy (multiple

nerves). This chapter will focus on motor and sen-

nerve involvement that is usually distal) versus

sory nerves and excludes the sympathetic and

mononeuropathy (single nerve involvement); and

parasympathetic nerves.

demyelinating versus axonal diseases. Demyelinat-

The entire peripheral nerve divides into three

ing peripheral nerve disease is also discussed in

compartments. Between each spinal cord level and

Chapter 10, “Disorders of Myelin.”

the corresponding dorsal root ganglion

(DRG),

motor and sensory fibers separate into dorsal or

ventral roots. Distal to the dorsal root ganglion, sen-

sory and motor fibers combine. Those nerves inner-

Pathophysiology

vating limbs travel to the brachial or lumbar plexus.

In the plexus, sensory and motor nerve axons sepa-

Peripheral nerve damage occurs by 6 basic mecha-

rate and recombine to form specific peripheral

nisms: (1) axon transection, (2) axon compression

nerves. Peripheral nerves carry motor, sensory, or

(compression neuropathy), (3) neuron death, (4)

autonomic fibers, often in a mixture with a 2:3 ratio

metabolically sick neurons unable to support the

of myelinated to unmyelinated fibers.

distal axon

(“dying-back” neuropathy),

(5)

Although a few peripheral nerves contain only

demyelination, and (6) synapse dysfunction.

sensory fibers (e.g., sural nerve) or motor fibers

Following transection or severe compression,

(vagus nerve to diaphragm), most peripheral

the axon distal to the injury degenerates (waller-

nerves have their own territory of skin and specific

ian degeneration) over a period of a few weeks.

FUNDAMENTALS OF NEUROLOGIC DISEASE

However, the axon segment proximal to the lesion

to weeks. Following nerve transection or severe

does not. The sensory territory of the nerve is lost

crush injury, the proximal axons grow outward,

and the muscles innervated by the peripheral

provided the nerve sheath remains intact, at about

nerve become weakened or paralyzed.

1 mm/day, so months are required before the

A motor unit, defined as the lower motor neu-

return of strength or sensation occurs. Following

ron and all of its muscle fibers, may contain 10 to

death of the motor neuron, the now “orphaned”

1,000 muscle fibers. Each muscle fiber receives

muscle fibers generate an unknown trophic factor

innervation from only one motor neuron. Follow-

that triggers adjacent motor axons to undergo seg-

ing loss of motor neurons, muscle fibers become

mental demyelination. This segment sprouts a

paralyzed. After about 10 days the muscle fiber

branch axon that reinnervates the muscle fiber,

undergoes biochemical changes as the neuromus-

making it part of a new motor unit.

cular junction degenerates. The muscle then

acquires AchRs diffusely instead of only at the

synapse. These new AchRs make the muscle super-

Clinical Features

sensitive, and spontaneous depolarization can be

detected when a needle electrode passes into the

Clinical features indicative of peripheral nerve dis-

involved fiber

(fibrillations and positive sharp

ease are listed in Table 6-1.

waves). The muscle fiber undergoes atrophy and

may involute to ¹/₃ of the original size.

If the neuron becomes metabolically sick, the

Diabetic Distal Symmetrical

nerve can no longer maintain the most distal part

of its axon. The distal motor and sensory axons

Polyneuropathy

slowly degenerate (dying-back neuropathy). The

longer the axon length, the more susceptible the

Introduction

nerve to metabolic damage. As a consequence,

Peripheral neuropathy is common, with a preva-

symptoms (often sensory loss) develop first in the

lence of about 2.5% in adults, rising in the elderly

toes (the longest axon).

to almost 8%. The myriad causes include meta-

Peripheral nerve myelin damage occurs from

bolic disturbances (diabetes mellitus and uremia),

death of the attached Schwann cell and from

toxins

(alcohol, cisplatin, and arsenic), vitamin

immune attack or degeneration of the myelin

deficiencies (B12 and B2), genetic (hereditary sen-

sheath. The loss of myelin, usually in segments (seg-

sorimotor neuropathy and porphyria), immune-

mental demyelination), interrupts transmission of

mediated illness

(Guillain-Barré syndrome and

sensory or motor signals, producing symptoms. The

chronic inflammatory demyelinating polyneu-

cause of the myelin damage may be genetic (hered-

ropathy), vasculitis

(rheumatoid arthritis, Sjö-

itary sensorimotor neuropathy or Charcot-Marie-

gren’s syndrome, and polyarteritis nodosa), and

Tooth disease), autoimmune

(Guillain-Barré

neoplastic disorders

(lymphoma, multiple

syndrome), toxic (lead), or infectious (leprosy).

myeloma, and paraneoplastic neuropathy). Dia-

Synapse dysfunction interrupts the ability of

betic neuropathy accounts for over ¹/₂ of all causes.

the peripheral nerve to communicate with its tar-

Diabetes mellitus affects more than 100 million

get muscle or autonomic organ (see Chapter 5,

“Disorders of the Neuromuscular Junction”). The

people worldwide. Diabetic neuropathy, present in

result is weakness (myasthenia gravis) or paralysis

about 10% of patients at the time of diagnosis,

(botulism) plus a variety of autonomic dysfunc-

rises to over 50% when the diabetes has been pres-

tions (hypotension, trophic skin changes, loss of

ent for years. While diabetes causes several types of

sweating, etc.).

peripheral nerve disease, distal peripheral poly-

Unlike the CNS, the PNS recovers following

neuropathy accounts for over 90% of cases.

damage. Mechanisms of recovery include

(1)

spontaneous recovery of axons, (2) regeneration of

Pathophysiology

nerve axons, (3) axonal sprouting of intact adja-

cent axons, and (4) remyelination. If the entrap-

The pathogenesis of diabetic neuropathy, while

ment or crush injury is not severe and the cause

multifactorial, likely stems from persistent hyper-

corrected, the existing axons recover over minutes

glycemia. At the nerve cell body located in the dor-

CHAPTER 6—Disorders of Peripheral Nerves

Table 6-1

Clinical Features that Suggest Peripheral Nerve Diseases

Specific Peripheral Nerve Damage

• Both sensory loss and muscle weakness are present.

• Sensory loss and muscle weakness occur in the territory of the peripheral nerve.

• Involved muscles atrophy after a month down to 1/3 of their former size.

• Sensory changes cause loss of pain, touch, temperature, vibration, and position sense if the lesion is destruc-

tive or produce pain or paresthesias if the lesion is irritative.

• Diminished or loss of tendon reflex corresponds to the involved nerve.

• Secondary trophic skin changes may slowly develop from the lack of autonomic nerve innervation.

• Onset may be acute or gradual depending on etiology.

• Involvement is unilateral and seldom bilaterally symmetrical, although multiple nerves may be involved

(mononeuritis multiplex).

Distal Symmetrical Polyneuropathy or “Dying-Back” Neuropathy

• Maximum loss of sensation should be in toes and feet.

• Sensory and motor loss should be symmetrical.

• Onset is gradual and not acute.

• Loss of sensation is usually greater than loss of strength.

• Painful dysesthesias may occur mainly in the feet.

• Fingers lose sensation when the leg neuropathy advances to about the knee.

• Muscle loss in the feet usually begins as “hammer toes” or pulling back of toes dorsally due to weakness of

flexor intrinsic foot muscles without corresponding weakness of extensor muscles located in the leg.

• Trophic changes in the foot and nails are common from loss of autonomic nerves.

Demyelination of Peripheral Nerves

• Major finding is weakness, with minimal loss of myelinated sensory fibers for vibration and position sense.

• Weakness is usually bilateral and symmetrical.

• Pain, touch, and temperature sensations are preserved.

• Onset may be abrupt (Guillain-Barré syndrome), subacute (lead), or gradual (hereditary sensorimotor

neuropathy).

sal root ganglion there is cellular injury, leading to

impaired detoxification of reactive oxygen species

impaired protein and lipid synthesis and impaired

that then mediate nerve damage.

axonal transport. At the distal end of the nerve,

Diabetic nerves examined from biopsies or

due to the impaired transport, there is nerve

autopsies demonstrate damage to both myelinated

degeneration. The degeneration is exacerbated by

and unmyelinated axons that is more pronounced

the loss of skin trophic support. So the nerve ini-

distally than proximally. In addition, local vascular

tially (over a period of many years) becomes dys-

disease within the perineurium includes basement

functional in a distal-to-proximal fashion but in

membrane thickening, endothelial cell prolifera-

severe cases there is total nerve loss. Other proposed

tion, and vessel occlusions.

pathogenic mechanisms include (1) hyperglycemia-

induced increases in polyol pathway activity, with

Major Clinical Features

accumulation of sorbitol and fructose in nerves and

secondary axonal damage, (2) microvascular disease

This insidious syndrome initially affects the toes

of peripheral nerves, leading to nerve ischemia and

bilaterally and symmetrically. Here the loss of

hypoxia, (3) increased glycosylation of proteins crit-

small unmyelinated axons diminishes appreciation

ical to neuronal function, (4) reduction in expres-

of pain and temperature. As axon loss progresses

sion or binding of neurotrophic factors, and (5)

to involve the foot and then the lower leg, the

FUNDAMENTALS OF NEUROLOGIC DISEASE

numbness ascends with it. Because of the inability

asymmetrical pupils that poorly accommodate to

to appreciate pain, injuries of the foot and ankle

darkness, erectile dysfunction, loss of ejaculation,

can lead to secondary foot ulcers and traumatic

constipation and/or diarrhea, and orthostatic

arthritis of joints

(Charcot joints). Often the

hypotension.

patient remains unaware of the loss of sensation in

the feet until secondary foot or ankle problems

Major Laboratory Findings

develop. When the neuropathy has marched to the

knees, the patient usually notes loss of sensation in

Since the neuropathy begins distally in the feet and

the fingertips (Figure 6-1).

involves unmyelinated axons, nerve conduction

In 10% of patients with diabetic polyneuropa-

studies of sensory and motor nerves of the leg may

thy, damage to small axons leads to persistent foot

initially show mild changes, as electrophysiologic

pain. The pain, typically described as burning,

studies seldom detect abnormalities in unmyeli-

constant, prickling, and painful to light touch

nated axons. As the neuropathy progresses, the

(allodynia), may be so uncomfortable that the

findings of axonal degeneration predominate, with

patient seeks medical attention.

diminished amplitude of compound muscle action

Large, sensory, myelinated axon damage with

potentials and sensory nerve action potentials.

subsequent loss of vibration and position sense in

Needle electromyography of intrinsic foot muscles

toes and feet produces gait and balance problems.

shows denervation potentials. There is relative

Motor nerve axons may be involved with weakness

preservation of proximal conduction velocities.

of intrinsic foot muscles.

A nerve biopsy, while seldom performed, shows

Autonomic nerve axons are also impaired, lead-

nonspecific axonal damage to both myelinated and

ing to loss of sweating, thinning of involved skin,

unmyelinated axons. A nerve biopsy should come

Hand involvement is

usually not apparent

until disease is quite

advanced and numb-

ness is up to knees.

Knee jerks are lost

as deficits progress.

Variable distal motor

deficit usually lags

behind sensory loss.

Ankle jerk reflexes are

diminished and lost early.

Figure 6-1

Peripheral polyneuropathy distribution.

CHAPTER 6—Disorders of Peripheral Nerves

from a sensory nerve (like the sural nerve) that has a

electrophysiologically confirmed, symptomatic

small area of sensory innervation. Biopsy of a mixed

carpal tunnel syndrome is 3% in women and 2%

nerve will lead to paralysis of innervated muscles

in men, with peak prevalence in older women.

and thus is performed only on an intercostal nerve.

Fortunately, few individuals develop sufficient

Skin-punch biopsy

(3-4 mm full-thickness

signs and symptoms to require surgical treatment.

biopsy) with immunohistochemical staining for

peripheral nerve axons is becoming more popular.

Pathophysiology

The histologic sections demonstrate marked

reduction in the density of epidermal nerve fibers

Elevated pressure in the carpal tunnel produces

that is helpful, but not diagnostic, for diabetic neu-

CTS (Figure 6-2a). The increased pressure causes

ropathy. Thus the diagnosis relies mainly on the

ischemia of the distal median nerve, resulting in

clinical history and neurologic examination of the

impaired nerve conduction with paresthesias and

feet and lower legs.

pain along the nerve distribution. Early in the clin-

ical course there are no morphologic changes in

Principles of Management and Prognosis

the median nerve and the symptoms are reversible.

However, as compression progresses with pro-

The management of diabetic neuropathy can be

longed ischemia, axonal injury and nerve dysfunc-

divided into preventing progression of the neu-

tion become permanent.

ropathy, minimizing problems from anesthesia of

About 1/3 of patients have associated condi-

feet and hands, and reducing burning foot pain.

tions such as pregnancy, inflammatory arthritis,

Numerous studies demonstrate that good con-

Colles’ fracture, amyloidosis, hypothyroidism, dia-

trol of blood glucose can slow, halt, or reverse pro-

betes mellitus, and use of corticosteroids or estro-

gression of the neuropathy. Glucose control

gens. The remaining 2/3 have their CTS associated

involves weight loss, exercise, and use of hypo-

glycemic agents.

with repetitive, often forceful, activities of the

Foot anesthesia predisposes this limb to ulcera-

hand and wrist.

tion and infection. Proper footwear minimizes

foot and ankle trauma. The individual should be

Major Clinical Features

instructed to inspect their feet regularly for signs

of infection or ulceration and to place their hand

The symptoms and signs of CTS correspond to the

in shoes to detect objects in the soles. If loss of

distribution of the distal median nerve (Figure 6-

position sense in the feet declines, the patient

2b). Patients usually complain of pain, tingling,

should use night-lights and caution when walking

burning, and numbness that involve the palmar

on uneven surfaces or in the dark.

aspect of the thumb, index finger, middle finger,

Treating the patient with a painful peripheral

and often the radial half of the ring finger. The

neuropathy is a challenge. For many patients, the

fifth digit is only occasionally involved. The symp-

pain is reduced with tricyclic antidepressants

toms, often worse at night, may awaken the indi-

(amitriptyline and nortriptyline) in low doses.

vidual with hand discomfort extending into the

Anticonvulsants, such as gabapentin or carba-

lower arm that causes the individual to shake their

mazepine, may be slowly added if the pain relief is

hand (“flick sign”). Symptoms tend to be worse

insufficient. In some patients, foot pain sponta-

following a day of increased repetitive activity and

neously subsides when the sensory neuropathy

often increase with driving.

progresses to anesthesia.

Early, clinical exam shows normal sensation in

the hand and no weakness or atrophy of median

nerve-innervated muscles. As the disease

Carpal Tunnel Syndrome

advances, two-point discrimination in median

nerve distribution

(finger tips) diminishes and

Introduction

atrophy occurs in the thenar muscles (oppones

Carpal tunnel syndrome (CTS) is an example of

pollicis and abductor pollicis brevis).

compression mononeuropathy. Up to 15% of indi-

Helpful, but not diagnostic, bedside tests

viduals experience occasional symptoms sugges-

include Phalen and Tinel signs. In Phalen’s maneu-

tive of CTS. However, the prevalence of

ver, the patient reports that flexion of the wrist for

CHAPTER 6—Disorders of Peripheral Nerves

60 seconds elicits pain or paresthesias in the

ceral efferent) that innervate muscles of the face.

median nerve distribution. Tinel’s sign occurs

The remaining fibers include general visceral effer-

when lightly tapping the volar surface of the wrist

ent nerves that are parasympathetic nerves to the

causes radiating paresthesias in the first 4 digits.

lacrimal and submandibular glands—special vis-

For both tests, the sensitivity is about 50% but the

ceral afferent nerves that represent taste from the

specificity is slightly higher.

anterior 2/3 of the ipsilateral tongue, and general

somatic afferent nerves that transmit sensation

from the skin of the ear pinna and external audi-

Major Laboratory Findings

tory canal. The facial nerve travels with the audi-

Abnormal delay of median nerve sensory latency

tory nerve in the internal auditory canal and enters

across the wrist is the major laboratory test that

the facial canal, where it soon reaches the genicu-

confirms the clinical diagnosis. If median nerve

late ganglion containing the neuronal cell bodies

axonal loss occurs, the electromyogram of thenar

for taste and ear sensation. The greater petrosal

muscles may show evidence of denervation.

nerve, the first branch, travels to the lacrimal

gland. The second branch runs to the stapedius

muscle, and the third branch—the chorda tym-

Principles of Management and Prognosis

pani nerve—travels to the tongue. The nerve exits

When CTS arises from other medical conditions,

the facial canal at the stylomastoid foramina,

treatment of the underlying condition often

where it passes through the parotid gland and

improves the symptoms. Thus, administration of

spreads out to innervate 23 facial muscles (but not

thyroid in the patient with hypothyroidism, use of

the masseter and lateral and medial pterygoid

antiinflammatory drugs for wrist arthritis, and

muscles innervated by the trigeminal nerve).

delivery of a pregnancy will improve symptoms.

Numerous diseases cause facial palsy in adults,

Similarly, reduction of the triggering repetitive

including trauma (facial trauma and basal skull

wrist movement may improve symptoms.

fracture), infections (Lyme disease, otitis media,

Use of a wrist splint that holds the wrist in the

syphilis, meningitis, and mumps), tumors (parotid

neutral position helps symptoms in many patients.

tumors, sarcoma, and facial nerve meningioma),

Wearing the splint at night may improve symptoms

and brainstem disorders (multiple sclerosis and

within a week. Nonsteroidal antiinflammatory

strokes). However, almost 60% of cases are consid-

drugs often prove to be of little benefit. Local injec-

ered idiopathic and due to Bell’s palsy.

tions with lidocaine and long-acting corticosteroids

Bell’s palsy occurs over 65,000 times a year, with

into the carpal tunnel can give striking relief, but

an equal racial and sex distribution. Cases occur in

symptoms return after weeks or months in 60% of

all ages, but the incidence increases with age. It is

the cases. Injections can be repeated a total of 3 to 4

rare for Bell’s palsy to be bilateral or to recur.

times. Surgery is usually recommended to patients

developing objective sensory or motor axonal loss

of the median nerve. The surgeon usually releases

Pathophysiology

the transverse carpal ligament (roof of the carpal

The pathogenesis of Bell’s palsy remains poorly

tunnel) (Figures 6-2a and 6-2b) under direct visual-

understood. MRI and pathologic studies show the

ization or through an endoscope. Over

3/4 of

facial canal, especially in the tympanic and

patients experience pain relief within days after sur-

labyrinthine segments, as the site of pathology.

gery, but full use of the hand may take several weeks.

The nerve becomes edematous and may develop

mild-to-moderate wallerian degeneration, with

varying amounts of surrounding lymphocytic

Bell’s Palsy

inflammation. The geniculate ganglion may

appear normal or have inflammation. Early theo-

Introduction

ries suggested ischemia to the facial nerve led to

Bell’s palsy or idiopathic peripheral facial nerve

nerve edema and nerve compression from the

palsy is the most common cause of CN VII dys-

walls of the facial canal. Later, the ischemia con-

function. The facial nerve contains around 10,000

cept was dropped and the nerve edema was con-

axons, of which 70% are motor nerves (special vis-

sidered idiopathic. Recently, viral infection

FUNDAMENTALS OF NEUROLOGIC DISEASE

theories have focused on varicella-zoster and her-

erythrocyte sedimentation rate, and serum elec-

pes simplex viruses as potential viruses that reacti-

trolytes. The CSF is normal. If the CSF has a pleo-

vate in the facial nerve or geniculate ganglion to

cytosis, the facial palsy etiology is likely due to an

cause nerve damage, edema, and inflammation.

inflammatory or infectious process, such as vari-

While varying degrees of wallerian degeneration

cella-zoster virus, Lyme disease, neurosyphillis, or

develop, all axons are rarely destroyed. As such,

sarcoidosis. Cranial MRI with gadolinium may

spontaneous recovery usually occurs.

show enhancement of the facial nerve within the

facial canal. The EMG, normal for the first 3 days,

shows a steady decline in activity and after 10 days,

Major Clinical Features

denervation potentials begin to appear. At autopsy

The hallmark of Bell’s palsy is the abrupt onset of

of individuals without a history of Bell’s palsy, her-

painless unilateral complete or incomplete facial

pes simplex viral DNA can frequently be detected

weakness (Figure 6-3). Since damage of the facial

by polymerase chain reaction in the geniculate

nerve occurs in the facial canal, other nerve

ganglia. This suggests that the virus may become

branches are dysfunctional, with variable inci-

latent in that ganglion, but whether exacerbation

dences. In 10% to 15% of patients, vesicles appear

of the latent virus produces Bell’s palsy remains

on the skin of the ipsilateral ear pinna, external

controversial.

auditory canal, or skin below the pinna. Varicella-

zoster virus can be isolated from the vesicle, which

establishes the diagnosis of herpes-zoster oticus or

Principles of Management and Prognosis

Ramsay Hunt syndrome. In this case, the varicella-

Management of the patient with Bell’s palsy is

zoster virus became latent in the geniculate gan-

divided into treating the acute facial palsy and pre-

glion during childhood chickenpox and

venting complications. If there is incomplete

reactivated many years later.

paralysis of facial muscles, there is an excellent

prognosis for full to satisfactory recovery that

Major Laboratory Findings

spontaneously occurs within 2 months. Should the

Remarkably few laboratory abnormalities exist in

facial paralysis be complete, full to satisfactory

Bell’s palsy. The patient has a normal hemogram,

recovery spontaneously occurs in about 80% of

patients over

1 to

3 months. In an effort to

improve outcome, patients are often given corti-

Right Bell's Palsy

costeroids for several days, with the hypothesis

that the corticosteroids will lessen facial nerve

edema, reduce nerve pressure, and prevent nerve

ischemia. If one believes herpes simplex virus may

be the etiology, the antiviral drug acyclovir is given

for a week. Observing vesicles on the ear pinna

suggests another antiviral drug (famciclovir, pen-

cyclovir, or high-dose acyclovir) should be given to

treat the varicella-zoster viral infection.

Frequently the patient will have facial weakness

such that he or she cannot fully close the eyelid,

exposing the cornea to abrasions and drying. After

applying ointment, these patients should tape

their eyelid closed while sleeping. Some patients

have diminished tearing in the involved eye and

require frequent application of liquid tears. A few

patients will have aberrant regeneration of the

Right Peripheral

facial nerve during recovery, leading to synkineses

7th Nerve Paralysis

(unintentional facial movements accompanying

Figure 6-3

Bell’s palsy.

volitional facial movements).

CHAPTER 6—Disorders of Peripheral Nerves

RECOMMENDED READING

and workup for all patients with peripheral

neuropathy.)

British Medical Research Council. Aids to the

Katz JN, Simmons SP. Carpal tunnel syndrome. N

Examination of the Peripheral Nervous System.

Engl J Med

2002;346:1807-1812.

(Excellent

4th ed. Philadelphia: W. B. Saunders;

2000.

review.)

(Superb booklet that outlines how to test each

Marenda SA, Olsson JE. The evaluation of facial

muscle, describes areas of sensation for all periph-

paralysis. Otolaryngol Clin N Amer

1997;30:

eral nerves, and easily can be kept in the physi-

669-682. (Reviews causes of facial paralysis,

cian’s bag.)

including Bell’s palsy, clinical findings, laboratory

Green DA, Stevens MJ, Feldman EL. Diabetic neu-

tests, and natural history.)

ropathy: scope of the syndrome. Am J Med

Sweeney CJ, Gilden DH. Ramsay Hunt Syndrome.

1999;107(suppl):2S-7S.

(This journal supple-

J Neurol Neurosurg Psychiatry 2001;71:149-154.

ment has a series of useful articles on diabetic

(Reviews facial paralysis due to reactivation of

neuropathy.)

varicella-zoster virus.)

Hughes RAC. Peripheral neuropathy. BMJ

2002;324:466-469. (General review of causes

DISORDERS OF THE SPINAL

CORD AND VERTEBRAL BODIES

Spinal cord dysfunction results from traumatic,

Overview

ischemic, nutritional, malignant, or degenerative

conditions. Diseases affecting the spinal cord usu-

For many years, the spinal cord was conceived as a

ally cause three clinical pictures. Two involve

conduit that carried impulses from the brain to the

spinal cord parenchyma and one involves spinal

trunk and limbs and vice versa. We now know that

cord roots. The first is degenerative with loss of

spinal cord functions are not solely passive, but

specific spinal cord elements, as seen in amy-

rather modulate or generate many afferent and

otrophic lateral sclerosis (ALS) and subacute com-

efferent pathways. For example, endorphin-con-

bined degeneration (vitamin B12 deficiency). The

taining neurons in the dorsal horn actively modu-

second is from a lesion at one level of the spinal

late afferent peripheral pain fiber impulses,

cord as seen in back or neck trauma, cervical

resulting in diminishment or enhancement of per-

myelopathy from a central protruding interverte-

ceived pain. Important aspects of normal walking

bral disk, or acute transverse myelitis. The third is

appear to be generated from clusters of motor

from compression of exiting spinal cord nerve

neurons located in the lower thoracic and upper

roots, producing a radiculopathy

(sensory and

lumbar spinal cord. Rapid limb withdrawal from a

motor dysfunction of a single dermatome/

painful stimulus and deep tendon reflexes do not

myotome) due to focal lesions such as posterolat-

involve the cortex but result from local circuitry in

eral prolapse of a vertebral disk or a neurofibroma

the cord.

compressing a spinal cord root.

The spinal cord, which is about the diameter of

Clinical signs depend on the level of the spinal

a thumb, extends caudally from the medulla to the

cord damage and whether the damage involves

first or second lumbar vertebra in adults and

part or all of the cord. Thus to understand the clin-

slightly lower in infants (Figure 7-1). From L2 to

ical signs produced by lesions in spinal cord

S2 the central vertebral canal is composed of nerve

parenchyma, one must know the differences

roots, ending in the cauda equina. The absence of

between upper motor neuron and lower motor

spinal cord below L2 is the reason why a lumbar

neuron dysfunction (Figure 7-2) and anatomic

puncture can be safely performed in the lower

location and function of key spinal cord tracts

lumbar area.

(Figure 7-3 and Tables 1 and 2).

CHAPTER 7—Disorders of the Spinal Cord and Vertebral Bodies

Autoimmune hypotheses are based on observa-

tions that activated T lymphocytes and deposit of

immunoglobulin are found in the spinal cord gray

matter and motor cortex of patients. However, tri-

als of several immunosuppressant drugs have not

improved patient survival. Lack of critical neu-

rotrophic factors for motor neurons has been sug-

gested as the etiology, but specific motor neuron

growth factors have yet to be identified. Abnormal

free-radical formation with accumulation of

superoxide in the spinal cord has been proposed

based on the finding that 20% of hereditary ALS

stems from a missense mutation in the Cu/Zn

superoxide dismutase (SOD1) gene on chromo-

some

21. However, studies suggest that the

mutated SOD1 protein acts through an unknown

“gain of function” and not “loss of function,” as

knockout mice lacking this gene do not develop

signs of ALS. Whatever the abnormal mechanism,

the final common pathway appears to trigger

Figure 7-2

Characteristics of upper and lower motor

apoptosis of motor neurons.

neuron disease.

Motor neurons of the spinal cord and brain-

stem show simple atrophy and intracytoplasmic

lipofuscin accumulation, leading to cell death and

secondary astrocytic gliosis. There is significant

The incidence of ALS is

1/100,000, with a

reduction in the number of large motor neurons

prevalence of 4/100,000. The peak age of onset

in the anterior horns of the cervical and lumbar

ranges between 55 and 75 years of age. The male-

spinal cord, with a corresponding loss of large

to-female ratio is 1.5:1. Most cases are sporadic but

myelinated axons in the ventral roots and periph-

5% are hereditary.

eral nerves innervating the limbs. Interestingly,

In the typical case, the diagnosis is straight-

there is little anterior horn cell loss in the thoracic

forward. For atypical-onset cases, the differential

and sacral spinal cord, accounting for relative

diagnosis includes cervical spondylotic myelora-

preservation of autonomic function and bladder

diculopathy, multifocal motor neuropathy, X-

and bowel function. The lower cranial nerves lead-

linked spinobulbar muscular atrophy (Kennedy’s

ing to facial muscles (especially CNs VII, IX, and X

disease), thyrotoxicosis, and elongated spinal

to XII) are more affected than cranial nerves sup-

cord tumors.

plying oculomotor muscles (CNs III, IV, and VI).

In patients with prominent upper motor neuron

signs, there is severe depletion of Betz cells and

Pathophysiology

pyramidal neurons of the fifth layer of the motor

The cause of sporadic ALS is unknown, but several

cortex, with secondary degeneration of the corti-

hypotheses exist. The first is excessive extracellular

cospinal tracts.

glutamate in the spinal cord resulting from a

Loss of lower motor neurons leads to muscle

defect in glutamate reuptake. Excessive glutamate

fiber denervation and weakness. Studies show that

could stimulate calcium-permeable N-Methyl-D-

weakness progresses at a relatively constant rate

aspartate

(NMDA)-receptor channels, allowing

throughout most of the disease. In early stages of

excessive entry of extracellular calcium into motor

the illness, a compensatory mechanism enables

neurons. Evidence for this hypothesis is that ALS

denervated muscles to become reinnervated and

patients have elevated levels of glutamate in the

regain function. Following death of a motor neu-

blood and CSF. In addition, riluzole, a glutamate

ron, a denervated muscle fiber produces an

antagonist, slightly improves survival in ALS.

unknown trophic factor that signals adjacent motor

CHAPTER 7—Disorders of the Spinal Cord and Vertebral Bodies

Vibration & Position Sense

Primary

Somatosensory

Cortex

Cerebral

Cortex

Thalamus

3rd

Order

Neuron

Gracilis Nucleus

Cuniate Nucleus

Medial Leminiscus

Medullary-Cervical

Junction

2nd

Gracilis Fascicule

Order

Neuron

Cuniate Fascicule

Spinal Cord C5

Spinal Cord T5

1st

Order

Dorsal (Posterior) Column

Neuron

in Dorsal

Root Ganglion

Spinal Cord L5

Figure 7-3

(b) Vibration and position sense. (Continued)

leads to (1) limb spasticity, (2) hyperactive reflexes,

Loss of anterior horn neurons (lower motor

(3) Babinski signs, (4) variable limb paresis, and (5)

neurons) causes (1) arm and leg muscle weakness

pseudobulbar palsy

(dysarthria, dysphagia, and

that is symmetrical or slightly asymmetrical, (2)

pseudobulbar affect with emotional reactions that

muscle atrophy, (3) widespread muscle fascicula-

are labile, exaggerated, and often inappropriate).

tions, (4) eventual loss of reflexes, and (5) respira-

FUNDAMENTALS OF NEUROLOGIC DISEASE

Table 7-1

Major Spinal Cord Tracts and Their Function

Location in Point of Tract Crossing to Opposite

Tract

Direction

Function

Spinal Cord

Side of Spinal Cord or Medulla

Corticospinal

From brain Motor

Lateral

Medulla

Spinothalamic

To brain

Pain and

Lateral

Near site of spinal cord entry

temperature

Dorsal column To brain

Vibration and

Posterior

Medulla

position sense

tory weakness from loss of phrenic nerve neurons

is usually normal but may have a slightly elevated

to the diaphragm and neurons to accessory respi-

protein level.

ratory muscles.

The EMG shows evidence of widespread den-

Loss of bulbar lower motor neurons produces (1)

ervation involving muscles of multiple

atrophy of the tongue (small tongue with serrated

myotomes. Common findings include (1) fibril-

edges), (2) fasciculations of tongue, (3) atrophy of

lations and positive sharp waves,

(2) reduced

masseter muscle and muscles involved in swallow-

motor unit firing rates, and (3) neurogenic motor

ing, producing dysphagia that can cause choking

units of long duration, multiple phases, and

and malnutrition, (4) dysarthria, making speech

increased amplitude (large polyphasic motor unit

slow and difficult to understand, and (5) mild-to-

potentials). Early motor nerve conduction veloc-

moderate lower facial muscle weakness and atrophy.

ity is normal, but slows later in the illness due to

Of note, muscles involved in eye movements

loss of the large myelinated axons that have the

and bladder and bowel function are seldom

fastest conduction.

involved. Sensation, autonomic nerve function,

A muscle biopsy is occasionally done when the

and cognition are preserved.

diagnosis is uncertain. Involved skeletal muscle

The weakness usually begins distally in the

fibers show changes typical for denervation, which

limbs and progresses to involve bulbar muscles,

include pyknotic nuclear clumps involving sar-

but in 20% of cases the process begins in bulbar

colemmal nuclei and atrophy of fibers leading to

muscles. Upper motor neuron signs may predom-

small angulated fibers with concave borders that

inate early, but subside as the lower motor neuron

are all the same fiber type. Early on, the atrophic

disease progresses and masks them.

fibers are scattered, but later they occur in clusters

called “group atrophy.” The cluster has all the same

fiber-type staining. Normally, a cross section of

Major Laboratory Findings

skeletal muscle stained for fiber type presents a

No specific diagnostic test for ALS exists. The

checkerboard appearance of types I and II fibers.

hemogram, electrolytes, and liver and renal func-

Group atrophy is seen when muscle fibers lose

tion studies are normal. Serum CK is mildly ele-

their original motor unit, then gain a new motor

vated, especially in rapidly progressive disease. CSF

unit from sprouting of an adjacent motor nerve

Table 7-2

Major Spinal Cord Neuronal Groups

Name

Function

Location in Spinal Cord

Anterior Horn

Lower motor neurons

Ventrolateral gray matter

Dorsal Horn

Modulation of afferent sensory impulses

Dorsolateral gray matter

Intermediolateral Horn

Sympathetic neurons

Intermediolateral gray matter of thoracic

spinal cord

Lateral Horn

Parasympathetic neurons

Lateral gray matter of sacral spinal cord

CHAPTER 7—Disorders of the Spinal Cord and Vertebral Bodies

that in turn dies, leaving a group of muscle fibers

entire width of the spinal cord. Transverse myelitis

all of the same type.

implies involvement of a large portion of the

cross-sectional area of the spinal cord, although

such lesions often extend vertically in the spinal

Principles of Management and Prognosis

cord to varying extents. It is often clinically diffi-

No drug has been found that stops the progressive

cult to be certain that inflammation is actually at

loss of motor neurons. However, riluzole increases

the lesion site and not from a myelopathic process

survival of ALS patients by 3 to 6 months. The goal

such as ischemia. Therefore, the diagnosis of trans-

of management is to make the patient as functional

verse myelitis is usually based on characteristic

and comfortable as long as possible. Family and

signs and symptoms plus neuroimaging that iden-

friends are valuable in supporting the patient and

tifies a specific spinal cord level of involvement.

minimizing the reactive depression that commonly

Acute transverse myelitis characteristically has

develops. Usually a multidisciplinary team

signs and symptoms that progress rapidly and are

approach is taken for the medical care. As patients

monophasic. Causes of acute transverse myelitis

weaken, crutches and wheelchairs are needed.

and myelopathy include:

(1) acute infections

When dysarthria becomes severe, assistive commu-

(viruses, bacteria, tuberculosis, and parasites), (2)

nication devices allow patients to continue express-

postinfectious

(following a nonspecific

“viral”

ing themselves. Managing dysphagia presents a

infection such as an upper respiratory infection),

challenge. Patients can swallow semisolid foods

(3) autoimmune diseases (systemic lupus erythe-

(pureed or blenderized table foods) better than

matosus and sarcoidosis), (4) complications of

solid foods or liquids. To prevent malnutrition and

vaccinations (rabies vaccine derived from infected

cachexia, a feeding gastrostomy or jejunostomy

animal spinal cord and vaccinia), (5) spinal artery

may be required. Inability to swallow leads to pool-

ischemia, and (6) multiple sclerosis.

ing of saliva in the posterior pharynx, causing

Transverse myelitis is uncommon, with an inci-

choking, drooling, and aspiration. Home suction

dence ranging from 1.5 to 4 cases 1 million people

equipment may be needed to minimize choking.

per year. Both children and adults are involved;

Respiratory weakness and failure become seri-

there is no sex preference. Statistically, cases in

ous problems and usually trigger the terminal

children are commonly postinfectious, cases in

event of aspiration pneumonia. Early in the illness,

young adults are often the first manifestation of

a compassionate but frank interview with the

multiple sclerosis or postinfectious, and cases in

patient and often family should focus on the

older adults are predominately a spinal cord mass,

patient’s terminal wishes, and these should be

varicella-zoster virus infection, or ischemia.

placed in a living will. Some patients desire assisted

ventilation terminally, while many others do not

Pathophysiology

wish to undergo a tracheostomy and be mechani-

Damage to the spinal cord occurs by several mech-

cally ventilated for the rest of their life as they

anisms. One mechanism is from an expanding

become progressively immobile. A vital capacity of

mass locally destroying that part of the spinal cord

less than 50% of that predicted increases the likeli-

(such as a tuberculoma, ependymoma, bacterial

hood of development of respiratory failure.

abscess, or schistosoma in the spinal cord). The

For sporadic ALS, the mean illness duration is

second mechanism is damage to the white matter

2.5 years, but 10% to 15% of patients live 5 years

from diseases that attack myelin (as seen in postin-

or more. Younger patients live somewhat longer, as

fectious transverse myelitis and multiple sclerosis).

do patients presenting with limb weakness com-

The third mechanism is local ischemic damage

pared with those presenting with bulbar signs.

such as from angiitis in systemic lupus erythe-

matosus and syphilitic tabes dorsalis or occlusion

of spinal cord/radicular arteries from cardiac

Transverse Myelitis and Myelopathy

emboli or air emboli in decompression sickness.

The fourth mechanism is direct infection of spinal

Introduction

cord oligodendrocytes or neurons, as seen in viral

Myelitis implies inflammation within the spinal

infections such as varicella-zoster virus following

cord that may be focal or diffusely involve the

shingles or poliovirus.

FUNDAMENTALS OF NEUROLOGIC DISEASE

Pathology in acute transverse myelitis demon-

lesions in the white matter of the brain. Spinal

strates focal areas of segmental demyelination,

cord tumors and abscesses are well circumscribed

with perivenous inflammation and variable

and strongly enhance with gadolinium.

amounts of necrosis.

Principles of Management and Prognosis

Major Clinical Features

Patients should be hospitalized, usually in an

Acute transverse myelitis is preceded by an upper

intensive care unit, during the acute stage.

respiratory infection in about 1/3 of patients. The

Catheterization of the bladder may be necessary.

illness is characterized by rapidly progressive

Corticosteroids are often given, but their efficacy is

(hours to a few days) signs that include (1) para-

unproven. Physical therapy is required during

paresis or quadraparesis, (2) sphincteric distur-

rehabilitation. About 1/3 of patients make a good

bance, (3) bilateral Babinski signs, (4) variable

recovery, 1/3 a moderate recovery (able to walk)

back pain, and (5) sensory level most often at the

and 1/3 a poor recovery (need a wheelchair).

thoracic level. If the sensory level is in the thoracic

area, paraparesis develops while lesions involving

the high cervical spinal cord often produce

Low Back Pain with Radiculopathy

quadraparesis and impaired respiration. Lesions in

the lumbar spinal cord produce varying degrees of

Introduction

leg weakness. Initially spinal shock may be present,

One or more episodes of low back pain are experi-

with flaccid limb weakness and absent reflexes.

enced by 2/3 of adults. Although most do not seek

Over weeks the spinal shock resolves and upper

medical attention, low back pain is a common rea-

motor symptoms

(leg spasticity, hyperactive

son patients see a physician. About 1% of U.S.

reflexes, and Babinski signs) develop. The

anatomic location of the lesion may not be lower

adults are chronically disabled from low back pain

than the identified sensory level. However, as affer-

and another 1% are temporarily disabled such that

ent sensory fibers often climb several segments

they seek worker’s compensation. The estimated

before synapsing with dorsal horn neurons, the

annual U.S. cost for back pain is $40 billion. Low

lesion location may actually be several spinal cord

back pain affects men and women equally. The

segments higher. Headache and neck stiffness are

peak age of onset ranges between 30 and 50 years

uncommon unless the lesion is in the cervical

of age.

spinal cord.

Low back pain is a symptom and not a disease.

Studies have found that low back pain can develop

from many spinal structures, including facet

Major Laboratory Findings

joints, ligaments, vertebral periosteum, paraverte-

The CSF usually shows a pleocytosis (10-150 lym-

bral muscles, adjacent blood vessels, annulus fibro-

phocytes/mm³), moderately elevated protein level

sus, and spinal nerve roots. In addition, back pain

(80-500 mg/dL), and normal glucose level. CSF

may be a referred symptom from abdominal struc-

oligoclonal bands are unusual except when the

tures such as the abdominal aorta, GI tract, kidney,

lesion is due to multiple sclerosis. Infectious agents

bladder, uterus, ovaries, and pancreas. This chapter

are rarely recovered from CSF but may be identi-

will focus primarily on low back pain from a later-

fied by PCR. In postinfectious transverse myelitis,

ally protruding lumbar disk that creates sufficient

no infectious agents are identified.

stenosis (narrowing) at the lumbar spine neural

In postinfectious transverse myelitis, the T2-

foramina to cause a radiculopathy

(signs and

weighted MRI images usually demonstrate a spinal

symptoms belonging to one nerve root).

cord lesion that widens the spinal cord. The lesion,

In the evaluation of a patient with low back

maximal in the central spinal cord area, often

pain, the clinician should first determine whether

extends vertically over 1 to 3 spinal cord segments.

the back pain could be referred from the abdomen

Multiple sclerosis lesions extend over fewer seg-

or is coming directly from a vertebral structure. A

ments than postinfectious lesions, may be present

history of fever, recent weight loss, cancer, infec-

at several spinal cord sites, and often have similar

tion of the urinary or GI tract, drug abuse, human

CHAPTER 7—Disorders of the Spinal Cord and Vertebral Bodies

immunodeficiency virus

(HIV) infection, or

Cauda Equina

Dorsal

immunosuppression from drugs such as corticos-

Root

teroids should prompt a careful physical exam

Ganglion

with attention to the abdomen and the ordering of

laboratory tests based on the history and exam.

Attention should be paid to determine whether the

low back pain is most likely infectious

(e.g.,

Spinal

epidural abscess), neoplastic (e.g., prostate cancer

Nerve

metastasis), arthritic (e.g., ankylosing spondylitis),

Annulus

or traumatic. Finally, the history and exam should

Fibrosus

determine whether a radiculopathy or cauda

Disc

equina syndrome is present.

Nucleus

Pulposus

Pathophysiology

Figure 7-4

Lateral protrusion of disc, top view. The

disc compresses the nerve root as it exits the neural

The stability of the spine results from the integrity

foramen.

of four structures: vertebral bodies, intervertebral

disks, ligaments between the vertebral bodies, and

paraspinous and other muscles. The voluntary and

Over 90% of clinically significant problems stem

reflex contractions of the paraspinous, gluteus

from an L4-to-L5 or L5-to-S1 disk herniation,

maximus, hamstrings, and iliopsoas muscles are

with compression of the L5 or S1 nerve root.

very important in preventing vertebral injury, as

Upper-extremity radiculopathies develop mainly

ligaments are not sufficiently strong to resist the

from compression of C5, C6, and C7 nerve roots.

enormous forces that affect the lower back. In the

healthy disk, the center contains the gelatinous,

Major Clinical Features

spongy nucleus pulposus, which is surrounded by

Patients with back disease may complain of pain,

an envelope of fibrous tissue called the annulus

stiffness, limitation of movement, and spine defor-

fibrosus. These give the disk the ability to act as a

mity. Four types of pain are described. Local pain

shock absorber to the everyday trauma of walking

comes from irritation of pain fibers in the lower

and jumping. After the second decade, deposition

back and is often described as a steady and aching

of collagen, elastin, and altered glycosaminogly-

pain that is not well circumscribed and occasion-

cans in the nucleus pulposus causes it to loss water

ally becomes sharp. Patients usually complain of

progressively. The cartilaginous end plate becomes

back pain worsened by bending, twisting, or lifting

less vascular. The resulting disk becomes thinner

and may often use involuntary splinting or tight-

and more fragile; it bulges, and with injury

ening of back muscles to prevent vertebral move-

extrudes. Studies show disk bulging to be present

ment affecting the painful area. Referred pain may

in ³/₄ of asymptomatic adults over the age of 50

occur, with patients describing a diffuse and deep

years. However, the extrusion of the nucleus pul-

ache in the buttocks, pelvis, flank, lateral hip,

posus may produce local back pain from an

groin, and anterior thigh. Muscle spasm pain is

inflammatory response and the extrusion frag-

usually paraspinous in nature and associated with

ment may compress or stretch nerve roots before

paraspinous muscles that prevent motion of the

they exit the neural foramina.

involved vertebrae. Radicular or “root” pain from

Since back pain also develops from other spinal

stretching, irritation, or compression of a spinal

structures, the cause of isolated low back pain is

root is described as sharp, intense pain (sciatica)

seldom determined, forcing the use of imprecise

that radiates from the back down a leg in varying

terms such as back strain or back sprain.

patterns depending on the root involved (Figure 7-

When the disk protrudes somewhat laterally,

5). Coughing, sneezing, and straining at stool (val-

the protrusion may compress a nerve root (Figure

salva maneuvers) may aggravate the pain.

7-4). Lower extremity radiculopathy mainly comes

As noted above, the patient should not have an

from compression of L4, L5, and S1 nerve roots.

abdominal mass or bruit that would suggest

FUNDAMENTALS OF NEUROLOGIC DISEASE

Nerve Root

Pain

Numbness

Weakness

Quadriceps

Anterior Tibialis

Gastrocnemius

Lost Reflex

None

Figure 7-5

Lumbar radiculopathy. KJ, knee injury; AJ, ankle jerk.

referred abdominal pain to the back. An enlarged

The straight-leg-raising test can often help in

prostate should not be present that would suggest

determining the presence of radicular pain. The

possible metastasis to vertebrae.

patient may be sitting or lying supine. The leg is

Examination of the back should include inspec-

elevated slowly to about 70° and then the foot is

tion of the lower back to determine if local muscle

dorsiflexed (Figure 7-6). Patients with radicular

spasms are present and if the pain increases by body

pain describe sciatica pain that radiates below

movements such as bending forward or backward.

the knee and not merely in the back or ham-

The vertebral bodies should be gently palpated and

string and is particularly intense in the buttock

percussed to determine whether focal tenderness is

just lateral and below the sacroiliac joint. A

present. The presence of localized pain to a specific

radiculopathy may also produce relative numb-

tender vertebra should raise concerns of a possible

ness in a particular dermatome, leg paresthesias,

localized process such as epidural abscess, vertebral

weakness of muscles in the involved myotomes,

metastasis, or vertebral fracture. Neuroimaging is

and loss of the ankle or knee reflex (Figure 7-5).

indicated in these patients. With the onset of acute

In the patient with chronic radiculopathy, the

radicular pain, the patient may prefer lying supine

involved muscles may be hypotonic and

with the legs flexed at the knees and hips.

atrophic.

CHAPTER 7—Disorders of the Spinal Cord and Vertebral Bodies

(a)

toes. There may be weakness of plantar flexion of

the big toe and foot, making walking on the toes

difficult. Occasional hamstring weakness is noted

and the ankle jerk is diminished or lost.

≤70°

Major Laboratory Findings

The CSF is normal or has slightly elevated protein.

The EMG in a patient with radiculopathy shows

Positive Test: Pain at ≤70° elevation,

aggravated by ankle dorsiflexion

no changes for 3 weeks. After 3 weeks, the radicu-

lopathy produces sufficient root compression to

Dorsiflexion

produce denervation changes in innervated mus-

cles that include fibrillations and positive sharp

waves. A MRI is the most sensitive neuroimaging

technique used, but CT myelography can detect

≤70°

abnormalities as well. Epidural infections, tumors,

and vertebral dislocations are easily detected. Her-

niated disks and whether the herniation impinges

on a spinal root or neural foramina can be seen. It

is important to note that disk abnormalities are

commonly seen on neuroimaging, especially after

(b)

middle age, and are often incidental and noncon-

tributory to the patient’s symptoms. Since anatomy

is not function, neuroimaging must always be cor-

related with the history and neurologic exam.

Principles of Management of Lumbar Disk

Herniation and Prognosis

Back pain is usually divided into acute (<3 months

duration) and chronic (>3 months). Patients with

Figure 7-6

(a) Straight-leg-raising test. (b) Sitting

acute back pain have a high probability of natural

straight-leg test.

improvement in both back pain, disability, and

radicular signs. It has been estimated that less than

5% of patients will require surgical intervention,

L5 radiculopathy is common and usually due to

but many patients will progress to chronic back

an L4-to-L5 disk protrusion. Patients complain of

pain.

pain in the hip, posteriolateral thigh, lateral calf,

Patient care for both acute and chronic low back

and dorsal surface of the foot and first or second

pain consists of (1) alleviating the back and leg

toes. Paresthesias may be felt in the entire territory

pains, (2) activity changes, and (3) alteration in

or distal portion. Numbness may occur over the

patient’s lifestyle. For most patients, acetamino-

lateral calf and medial aspect of the dorsum of the

phen or nonsteroidal antiinflammatory drugs

foot, including the first two toes. Weakness, if pres-

(NSAIDS) will improve discomfort to tolerable lev-

ent, involves extensors of the big toe and foot with

els. Tricyclic antidepressants may be helpful if the

difficulty walking on heels. The ankle jerk may or

pain is distressing. Use of opioids may be required

may not be diminished.

for brief periods if radicular pain is severe, but pro-

The patient with an S1 radiculopathy typically

longed opioid usage is not beneficial. Muscle relax-

complains of pain in the midgluteal region, poste-

ants are similar to NSAIDS in benefit. Patients

rior part of the thigh, posterior calf and heel, and

should be encouraged to return quickly to normal

lateral foot to the 4^th and 5^th toes. Paresthesias and

activities, but not strenuous activities requiring lift-

sensory loss occur mainly in the lateral foot and

ing and bending. Prolonged bed rest leads to

FUNDAMENTALS OF NEUROLOGIC DISEASE

deconditioning and does not accelerate recovery.

logic deficits related to a specific lumbar or sacral

Spinal manipulation may offer temporary relief

nerve root involvement that persists longer than 4

when administered, but should wait until one

to 6 weeks and with neuroimaging that demon-

month after onset as spontaneous recovery often

strates a herniated disk. Patients with only back

occurs by then. Traction, massage, diathermy,

pain are the least likely to benefit from surgery.

ultrasound, biofeedback, acupuncture, and tran-

Injections of anesthetics or steroids in the lower

scutaneous electrical stimulation may offer tempo-

back area

(nerve blocks, facet injections, and

rary relief but have no proven long-term efficacy.

epidural injections) are occasionally helpful for

Lifestyle changes shown to be helpful in pre-

temporary pain relief, which may enable the indi-

venting recurrences as well as preventing chronic

vidual to exercise.

back pain include (1) weight reduction to ideal

body weight, (2) cessation of smoking, (3) avoiding

lifting heavy objects, and (4) regular aerobic exer-

RECOMMENDED READING

cise. Excess weight places awkward stresses on the

back when lifting and twisting. The nicotine from

Deyo RA, Weinstein JN. Low back pain. N Engl J

smoking is thought to constrict vascular beds in the

Med 2001;344:363-370. (Good review of causes

back, delaying natural recovery. Exercise programs

and conservative management of back pain.)

strengthen paraspinous and abdominal muscles,

Frank A. Low back pain. BMJ 1993;306:901-909.

helping to properly distribute loads on the spine

(Good review of British approach to back pain.)

when bending or twisting. Most exercise programs

Jeffery DR, Mandler RN, Davis LE. Transverse

begin with walking short distances and simple back

myelitis: Retrospective analysis of 33 cases, with

exercises, which slowly progress in duration and

differentiation of cases associated with multiple

intensity. Regular exercises and swimming have

sclerosis and parainfectious events. Arch Neurol

been shown to increase range of motion, relieve

1993;50:532-535.

(Recent review that distin-

back pain, and prevent recurrences.

guishes 4 types of transverse myelitis by clinical

Patients with fracture and instability, infection,

and laboratory features.)

tumor, severe motor weakness from nerve root

Ropper AH, Poskanzer DC. The prognosis of acute

impingement, or cauda equina syndrome (bladder

and subacute transverse myelopathy based on

or bowel dysfunction, “saddle” numbness in the

early signs and symptoms. Ann Neurol

perineum and medial thighs, and bilateral leg pain

1978;4:51-59. (Excellent older review of 52 cases.)

and weakness) often require immediate back sur-

Rowland LP, Shneider NA. Amyotrophic lateral

gery. Only 5% of patients with chronic low back

sclerosis. N Engl J Med 2001;344:1688-1700.

pain will benefit from spinal surgery. Patients most

(Excellent review of current theories of pathogen-

likely to benefit are those with considerable neuro-

esis and end-of-life issues.)

DISORDERS OF THE BRAINSTEM

AND CEREBELLUM

auditory canal, and spreads along the cerebello-

Overview

pontine angle, trapping CN V and eventually com-

pressing the pons.

The brainstem lies at the caudal end of the spinal

In assessing the location of intraaxial brainstem

cord and extend upward to the basal ganglia. No

lesions, it is useful to delineate structures along

other part of the CNS is packed with so many criti-

two planes: longitudinal and cross section. The

cal axon tracts and nuclei. Important axon tracts

include the corticospinal tract, conducting motor

longitudinal plane is usually divided into the mid-

impulses from the cortex to the spinal cord, and long

brain, pons, and medulla and the cross-sectional

sensory tracts, conducting information from the

divisions are usually medial and lateral. Review of

spinal cord to the thalamus, cerebellum, and cortex.

a neuroanatomy textbook is helpful in localizing

The nuclei for CNs II to XII lie in the brainstem. In

important tracts and cranial nerve nuclei within

addition, the brainstem contains the reticular for-

this pattern of division.

mation, with centers that mediate sleep, arousal, and

Blood supply to the brainstem and cerebellum

wakefulness, plus autonomic centers that control

comes from both vertebral arteries and the basilar

respiration, blood pressure, and GI functions.

artery (Figure 8-1). There are many small penetrat-

In determining the location of lesions involving

ing arterioles that enter the brainstem from these

the brainstem, it is useful first to determine

major vessels. The arterioles generally supply one

whether the lesion is within the brainstem

side of the medial brainstem (paramedian arteriole)

(intraaxial) or lies outside the brainstem along the

or one lateral side (circumferential arteriole). Three

cerebellopontine angle

(extraaxial). Extraaxial

arteries (superior cerebellar artery, anterior inferior

lesions initially affect cranial nerves through

cerebellar artery, and posterior inferior cerebellar

entrapment or compression, with later signs devel-

artery) supply the cerebellum with blood and may

oping from compressing brainstem structures or

have branches also going to the brainstem.

from compressing the aqueduct of Sylvius, pro-

A variety of diseases affect the brainstem, but

ducing obstructive hydrocephalus. A typical

with a lower frequency than the same diseases

extraaxial lesion would be an untreated acoustic

affecting other brain regions. Brainstem tumors

neuroma that begins in the Schwann cells of CN

are most often astrocytic and slower growing than

VIII, slowly extends medially out of the internal

astrocytic tumors in the cortex. Bacterial abscesses

FUNDAMENTALS OF NEUROLOGIC DISEASE

Posterior Communicating Artery

Midbrain

Posterior Cerebral Artery

Superior Cerebellar Artery

Pons

Basilar Artery

Pontine Arteries

Anterior Inferior

Cerebellar Artery

Medulla

Posterior Inferior

Cerebellar Artery

Cerebellum

Vertebral Artery

Anterior Spinal Artery

Figure 8-1

Anatomy of vertebral and basilar arteries.

are rare, and most viruses causing encephalitis

Most input to the highly organized and redundant

involve the brainstem less intensely. Hemorrhages

cerebellar cortex comes from many brainstem

involving the brainstem are uncommon. Ischemic

nuclei via excitatory mossy fibers that terminate

strokes of the brainstem occur as lacunes or occlu-

on myriads of granule cells. These granule cell

sions of penetrating brainstem arteries and are less

neurons then send inhibitory impulses to Purkinje

common than cortical or basal ganglia strokes.

cells. The inferior olive also sends excitatory input

The cerebellum occupies about 10% of the

directly to Purkinje cells. Purkinje cells, the only

brain volume but contains more neurons than the

output of the cerebellar cortex, send inhibitory

entire rest of the brain. The following is a brief

impulses via a GABA neurotransmitter to neurons

review of cerebellar anatomy and function to help

in the deep cerebellar nuclei that then send output

understand clinical abnormalities that develop

to the brainstem and cerebral cortex.

from cerebellar diseases. The cerebellum is divided

Cerebellar neurons do not directly produce

into the 3 functional divisions of the spinocerebel-

motor movements, but act more as a comparator

lum, cerebrocerebellum, and flocculonodular lobe

that compensates for errors in movement by com-

(Figure 8-2). Each division in the cerebellar cortex

paring intention with performance and making sub-

sends Purkinje cell axons to specific deep cerebel-

tle adjustments. As such, patients with cerebellar

lar nuclei and has different functions (Table 8-1).

diseases do not have weakness or sensory loss. Cere-

CHAPTER 8—Disorders of the Brainstem and Cerebellum

Vermis

Intermediate Zone

(Vestibulocerebellum)

(Spinocerebellum)

Lateral Zone

Anterior Lobe

(Cerebrocerebellum)

of Vermis

Lobe

Primary Fissure

Corpus

Cerebelli

Hemisphere

Flocculus

Posterior Lobe

Tonsil

Nodulus

of Vermis

Flocculonodular

Horizontal

Lobe

Nodulus

Fissure

Figure 8-2

Anatomy of cerebellum.

bellar clinical problems are expressed as impaired

This chapter will focus on spinocerebellar ataxia

coordination, imbalance, and even vertigo (Table 8-

due to a class of genetic diseases called triplet repeat

2). Dysfunction of midline cerebellar structures

nucleotide disorders; it expresses most of the clini-

(vermis of spinocerebellum) produces imbalance

cal cerebellar problems. Chapter 19, “Neurologic

problems of midline body structures such as gait and

Complications of Alcoholism,” discusses alcoholic

truncal ataxia, while cerebellar hemisphere dysfunc-

cerebellar degeneration.

tion produces ataxia of limbs. Unlike the cerebral

cortex, damage to one cerebellar hemisphere pro-

duces ipsilateral but not contralateral dysfunction.

Lateral Medullary Infarction

A variety of diseases affect the cerebellum and

(Wallenberg Syndrome)

include vascular events (ischemic and hemorrhagic

strokes), tumors (meduloblastoma and childhood

Introduction

astrocytoma), toxins

(alcohol and phenytoin),

infections (chickenpox ataxia), and genetic disease

Lateral medullary infarction (LMI) is the classical

(spinocerebellar ataxias and Freidreich’s ataxia).

stroke involving the lateral medulla (Figure 8-3)

Table 8-1

Cerebellar Functions by Location

Cerebellar

Deep Cerebellar

Cerebellar Efferent

Function

Origin

Nucleus

Connections

Adjust Ongoing Movements of

Spinocerebellum

Fastigial nucleus

Brainstem reticular

Axial and Proximal Limb

formation, vestibular

Muscles

nuclei, and motor cortex

Adjust Ongoing Movements of

Intermediate

Interposed deep

Red nucleus and motor

Distal Limb Muscles

spinocerebellum

nuclei

cortex

Initiation, Planning, and Timing of

Cerebrocerebellum

Dentate nucleus

Red nucleus and

Motor Movements

premotor cortex

Axial Control and Vestibular

Flocculonodular

Direct connection to

Brainstem vestibular

Reflexes

lobe

brainstem

nuclei

FUNDAMENTALS OF NEUROLOGIC DISEASE

Table 8-2

Signs Suggestive of Cerebellar Dysfunction and Likely

Cerebellar Localization

Vermis (Midline Cerebellum)

• Gait ataxia

Clumsy, uncertain, irregular, staggering steps in walking, with wide-based stance like “being drunk.”

Tendency to fall to involved side.

• Truncal ataxia

Inability to balance in sitting position at edge of table.

• Saccadic eye-movement abnormalities

Conjugate eye movement rapidly to a target results in overshooting of eyes followed by overcorrections until

target is reached.

Cerebellar Hemisphere

Signs are ipsilateral to side of cerebellar lesion and more abnormal with fast limb movements than with slow

movements.

• Hypotonia

Diminished arm and leg muscle tone give a loose feeling when passively moving the limb.

• Dysdiadochokinesis

Irregular, uncoordinated rapid movements of hands or fingers. Often tested by asking patient to pat one

palm alternately with the palm and dorsum of the opposite hand as rapidly as possible.

• Dysmetria

Inaccuracies in judging distance and target when moving limb to a target with eyes closed.

• Cerebellar tremor

Intention tremor develops when moving arm or leg that is perpendicular to the direction of the movement

and often amplifies as the target is reached. Usually tested by asking patient to touch a target and then

quickly touch the nose or to lift one heel and place it on the opposite knee and then move the heel down

the shin.

• Ataxic dysarthria

Poor coordination of articulation, resulting in slow, explosive speech.

Flocculonodular Lobe

• Nystagmus

• Transient vertigo

Triggered by head or body movements from abnormal vestibuloocular reflex (reflex maintains eyes steady

in space while head moves).

• Postural and gait dysfunction

• Vertigo, nausea, and vomiting

Seen only in acute lesions.

and dramatically demonstrates the multiple clini-

cerebellar artery (PICA) is a large named artery

cal signs that develop when there is damage to

that supplies blood both to the lateral medulla and

many important tracts and nuclei.

to the posterior inferior aspect of the cerebellum.

An LMI can result from stenosis, thrombosis,

embolus, or dissection in the vertebral artery, or

Pathophysiology

occlusion of the PICA or other small, unnamed,

The medulla receives its arterial blood supply from

medullary arteries. Major risk factors include

the vertebral artery via small branches that have

hypertension, diabetes mellitus, neck trauma, and

considerable variability. The posterior inferior

atrial fibrillation.

CHAPTER 8—Disorders of the Brainstem and Cerebellum

Medial

Dorsal Nuceus

Vestibular

Inferior

Cavity of

of Vagus

Nucleus

Vestibular

Fourth Ventricle

Nucleus

Inferior

Cerebellar

Peduncle

Infarct in

Spinal Tract &

Area Supplied by

Nucleus of

Posterior Inferior

Trigeminal Nerve

Cerebellar Artery

Vagus Nerve

Spinothalamic

Tract

Inferior

Lateral

Olivary

Spinothalamic

Nucleus

Tract

Hypoglossal

Corticospinal Tract

Nerve

Figure 8-3

Lateral medullary infarction.

Major Clinical Features

mon and implies ventral medullary corticospinal

tract involvement from a large medullary infarc-

Of these patients,

3/4 develop acute onset of

tion or hemorrhage.

symptoms and 1/4 have symptoms that progress

over hours to a day. The symptoms will vary

depending on how medial the infarction extends

Major Laboratory Findings

and whether the caudal or distal medulla is maxi-

An MRI, which is more sensitive than CT, demon-

mally affected. More than 1/2 of patients experi-

strates ischemic infarction in the lateral aspect of

ence multiple signs and symptoms. Dizziness,

the dorsal medulla. Magnetic resonance angiogra-

vertigo, nausea, vomiting, nystagmus, skewed

phy (MRA) and vertebral arteriography may

vision

(diplopia with targets diagonal to each

demonstrate stenosis or absence of blood flow in

other and not improved in any field of gaze), gait

the PICA, vertebral, or basilar artery.

ataxia, and ipsilateral limb ataxia are prominent

and are due to involvement of vestibular nuclei,

inferior cerebellar peduncle, and/or vestibular

Principles of Management and Prognosis

nuclei-flocculonodular connections. Patients

commonly complain of numbness and shooting

Patients require hospitalization with attention to

pains on the ipsilateral side of the face and loss of

their inability to swallow (50% will require an

pain and temperature sensation on the contralat-

enterofeeding tube for several weeks). If marked

eral side of the body caused by damage to the

vertigo, nausea, and vomiting are present, vestibu-

descending trigeminal nerve and spinothalamic

lar sedative drugs may transiently be required.

tracts. Dysphagia and dysarthria from paralysis of

Dysphagia, dysarthria, and vertigo usually

the ipsilateral palate, pharynx, and larynx muscles

improve over several weeks. Rehabilitation is

are due to damage to the nucleus ambiguous of

needed to improve balance, coordination, and gait.

CN X. Horner’s syndrome, with ipsilateral ptosis,

Most patients will regain the ability to walk and

miosis (small reactive pupil), and loss of facial

function independently. To prevent subsequent

sweating occurs from damage to ascending sym-

strokes, patients benefit from controlling their vas-

pathetic tracts. Marked limb weakness is uncom-

cular risk factors and using antiplatelet therapy.

FUNDAMENTALS OF NEUROLOGIC DISEASE

Spinocerebellar Ataxia (SCA 1)

(CAG). The nucleotide CAG encodes the amino

acid glutamine. The SCA1 gene codes for a novel

Introduction

87-kd protein called ataxin-1. In normal SCA1

genes, CAG may be repeated 6 to 44 times, pro-

Spinocerebellar ataxias

(SCAs) are a group of

ducing an ataxin-1 protein that has

6 to

genetic diseases characterized by progressive loss

repeated glutamine amino acids that are stabilized

of coordination and balance. The incidence of

by histidine repeats. However, in SCA 1 disease, the

SCA 1 is 1 to 2 cases per 100,000 population. In

mutant gene develops an expansion of CAG

recent years, enormous gains have been made in

repeats from 39 to over 80 uninterrupted repeats

understanding this heterogeneous group of dis-

and the mutant ataxin-1 protein has 40 to 81

eases; over 17 different genetic diseases have now

repeat glutamine amino acids. The length of the

been characterized and are called SCA 1 to SCA 17.

trinucleotide repeat increases in the next genera-

Most SCAs are autosomal-dominantly inherited.

tion due to gene instability, especially if the father

Three pathologic mechanisms of SCA have been

transmits the disease. The longer the repeat length,

identified. The most common type (over 60% of

the more severe and earlier the disease (anticipa-

cases) is a polyglutamine disorder resulting from

tion). The function of ataxin-1 protein is unknown.

proteins with toxic stretches of polyglutamine.

The normal protein, found in all tissues, is located

Other types are gene-expression disorders result-

in the nucleus and cytoplasm of Purkinje cells and

ing from repeat expansions outside of coding

other brainstem and spinal cord neurons at 2 to 4

regions or channelopathies resulting from disrup-

times the usual concentration.

tion of calcium or potassium channel function

Mutant proteins may cause disease by loss of

(see Chapter 4, “Disorders of Muscle”).

function (loss of the mutant protein’s ability to con-

Common features of many polyglutamine SCA

duct some critical function), gain of function

diseases include: (1) onset in adulthood, (2) slow

(acquisition of abnormal function by the mutant

progression, (3) neuronal loss in the cerebellum,

protein), or abnormal aggregation and sequestering

brainstem, and spinal cord, (4) instability and

of other critical proteins. For the mutant ataxin-1

expansion of a trinucleotide repeat tract,

(5)

protein, evidence suggests the neuronal pathology is

mutant protein aggregation or clumping in the

due to a gain of function or abnormal aggregation.

nucleus of involved neurons, and (6) occurrence of

Genetic mice lacking the mouse homologue of

anticipation or the tendency for disease onset to be

SCA1 genes do not develop ataxia. Genetic mice

more severe and occur at a younger age in the next

that carry the normal human gene and express

generation. Trinucleotide repeat genetic diseases

ataxin-1 protein remain entirely normal through-

are recognized to cause a wide variety of diseases

out life. However, genetic mice carrying a mutant

that involve the basal ganglia (Huntington’s dis-

gene expressing mutant ataxin-1 develop gait, coor-

ease), muscle

(myotonic muscular dystrophy),

dination, and balance problems and have CNS

mental retardation (fragile X syndrome), motor

pathology similar to the human disease.

neuron loss (spinobulbar muscular atrophy), and

Neuropathologic changes in SCAs 1 to 3 are

ataxia (Freidreich’s ataxia, and SCAs). The expan-

fairly similar. Gross examination reveals atrophy of

sion of the trinucleotide repeat part of the mutant

the cerebellum and pons, loss of the bulge of the

gene may occur in noncoding regions (fragile X

inferior olive, and mild-to-moderate widening of

syndrome, Freidreich’s ataxia, and myotonic mus-

sulci in the frontotemporal cortex region. Micro-

cular dystrophy) or in coding regions (SCA and

scopically, there is severe loss of (1) Purkinje cells,

Huntington’s disease) where the protein contains

maximally in the vermis, (2) dentate neurons, and

an expanded repeated amino acid.

(3) neurons in the inferior olive, pontine nuclei,

and nuclei basis pontis. There is moderate loss of

neurons in the anterior horns, cranial nuclei III, X,

Pathophysiology

and XII, and cholinergic system of the forebrain.

SCA 1 results from mutation of the SCA1 gene in

Mild neuronal loss occurs in the cerebral cortex.

chromosome 6p consisting of a highly polymor-

Extensive atrophy of the superior, middle, and

phic, unstable repeat expansion of DNA

inferior cerebellar peduncles, spinal cord posterior

nucleotide bases cytosine, adenine, and guanine

columns and spinocerebellar tracts, and corti-

CHAPTER 8—Disorders of the Brainstem and Cerebellum

cospinal tract is present. Neurons in the brainstem,

6p23. Affected individuals have alleles with 39 to

but not the cerebellum, have one intranuclear

81 CAG trinucleotide repeats. The genetic test is

inclusion containing ataxin-1 protein plus ubiqui-

100% sensitive and specific and available in many

tin, a small molecule that attaches to abnormal

clinical laboratories.

proteins headed for degradation by a proteosome

into reusable amino acids. Secondary gliosis devel-

Principles of Management and Prognosis

ops in the cerebellar molecular layer, brainstem,

and cerebral cortex.

To date, no therapy is successful in delaying or

halting disease progression. Therefore, manage-

ment is supportive. Canes and walkers help pre-

Major Clinical Features

vent patients from falling, and grab bars, raised

The key clinical features are progressive gait ataxia,

toilet seats, and ramps aid in safer ambulation.

incoordination, dysarthria, and eventual bulbar

Wheelchairs are necessary when the gait ataxia and

dysfunction. In the third or fourth decade, patients

imbalance become severe. Speech therapy and

begin to develop a slowly progressive gait ataxia,

computer-based communication devices help

dysarthria, hypermetric saccades, nystagmus on

patients with marked dysarthria. Weight control is

lateral gaze, and deterioration of handwriting.

important because obesity worsens balance and

With disease progression, spasticity develops, with

ambulation. Genetic counseling is helpful regard-

hyperreflexia and Babinski signs, ataxia worsens,

ing decisions to have children, particularly since

saccadic eye movements deteriorate, bradykinesia

anticipation may occur in the offspring. Prenatal

emerges, and dysmetria appears. In the late stage

genetic testing is possible, but should be carefully

of the disease, muscle atrophy, hypoactive deep

weighed, as this is a late-onset disease.

tendon reflexes, loss of position sense, and variable

degrees of oculomotor paralysis develop. There is

atrophy of the tongue, with severe dysphagia and

RECOMMENDED READING

dysarthria. Neuropsychiatric dysfunction and loss

of complex executive functioning are common,

Kandel ER, Schwartz JH, Jessell JM. Principles of

but dementia is rare. Dystonia or chorea occasion-

Neural Science. 4th ed. New York: McGraw-Hill;

ally is seen. Disease progression lasts 10 to 15 years,

2000 (Good review of brainstem and cerebellar

with death resulting from aspiration and respira-

anatomy and physiology.)

tory complications. Currently, the polyglutamine

Kim JS. Pure lateral medullary infarction: clinical-

SCAs (SCAs 1 to 3, 7, and 17) are clinically indis-

radiological correlation of 130 acute, consecu-

tinguishable.

tive patients. Brain

2003;126:1864-1872.

(Discusses clinical features and correlations with

MRI findings.)

Major Laboratory Findings

Margolis RL. The spinocerebellar ataxias: order

The diagnosis of SCA 1 is based on DNA testing to

emerges from chaos. Curr Neurol Neurosci Rep

detect an abnormal CAG trinucleotide repeat

2002;2:447-456.

(Excellent review of clinical,

expansion of the SCA1

gene on chromosome

pathologic, and genetic features of major SCAs.)

DISORDERS OF THE

CEREBROVASCULAR SYSTEM

Overview

Stroke is a general term that implies damage to cere-

Table 9-1

Major Stroke Types*

bral tissue from abnormalities of the blood supply.

Percentage

In simple terms, there may be insufficient blood to

(% of Each

the brain (ischemic stroke or infarction), abnormal

Stroke Type

Category)

excess blood (hemorrhagic stroke or cerebral hem-

Ischemic

85%

orrhage), or inadequate venous drainage of cerebral

• Carotid artery circulation

(55%)

blood (venous stroke). Ischemic strokes represent

85% of all strokes, hemorrhagic strokes 14%, and

• Vertebral/basilar artery circulation

(12%)

venous strokes 1% (Table 9-1).

• Lacune

(31%)

Stroke is the third-leading cause of death in the

• Other (vasculopathy, coagulo-

(2%)

United States. Each year 500,000 people in this

pathy, sickle cell, hyperviscosity,

and vasculitis)

country develop a stroke and 150,000 die. Fortu-

nately, since 1960 the incidence of strokes in the

Hemorrhagic

14%

United States has significantly fallen, primarily due

• Hypertensive hemorrhage

(50%)

to better control of hypertension and diabetes

• Amyloid angiopathy hemorrhage

(15%)

mellitus, but there are still 4 million adults with

• Saccular aneurysm

(30%)

stroke, with an overall prevalence of 750/100,000.

• Arteriovenous malformation

(3%)

• Other (infective aneurysm,

(2%)

cocaine, and anticoagulants)

Ischemic Strokes (Embolic and

Venous

Lacunar)

• Thrombosis of cortical veins, deep cerebral

veins, or dural sinuses

Introduction

* Excludes stroke due to head trauma and subdural

Ischemic stroke occurs from lack of sufficient arte-

hematomas (see Chapter 18 on traumatic brain injury

rial blood flow in the territory of a specific cerebral

and subdural hematoma)

FUNDAMENTALS OF NEUROLOGIC DISEASE

artery to maintain neuronal viability. The stroke

Table 9-2

Risk Factors for Stroke

can be due to (1) intrinsic vascular occlusion

Increase in

(thrombus) that occurs in the neck portion of the

Risk Over Normal

internal carotid artery, vertebral artery, or a cere-

Age-Matched

bral artery or (2) vascular occlusion with material

Risk Factor

Population

originating elsewhere

(embolism) such as a

Modifiable

stenotic site of the internal carotid artery or verte-

Hypertension

300%-600%

bral artery or from the heart. The large majority of

Diabetes mellitus

200%-400%

emboli are blood clots, but occasionally they can

be air, fat, or tissue fragments. Of the total number

Smoking

150%-300%

of ischemic strokes, 80% involve the carotid artery

Cocaine/crack

200%-500%

territory or anterior circulation and 20% involve

Atrial fibrillation

the vertebrobasilar artery or posterior circulation.

Untreated

300%-500%

Table

9-2 lists the major modifiable and

On warfarin

50%

unmodifiable risk factors for stroke.

Other heart abnormalities

200%-600%

(mural thrombus,

cardiomyopathy, acute

Pathophysiology

myocardial infarction,

mechanical heart valve,

Cerebral ischemia occurs from inadequate cerebral

and infective

blood flow to a brain area. Total lack of oxygen and

endocarditis)

glucose to all brain neurons, as in a 12-to-15 sec-

Obesity

200%

ond cardiac arrest, suppresses electrical activity

Serum lipid abnormalities

50%

and causes loss of consciousness. Normally cere-

Asymptomatic carotid

(Five-year increase)

bral arterial blood flow is 50 mL/100 g of brain per

artery stenosis

minute. When cerebral blood flow falls below 18

60%-74% stenosis

10%

mL/100 g of brain per minute, cerebral function

75%-94% stenosis

14%

falters but neurons may remain alive. Thus, electri-

>95% stenosis

10%

cal activity ceases and sodium/potassium pumps

Total occlusion

begin to fail, but the neurons are viable and can

recover function if blood flow improves. In a

Unmodifiable

stroke, this area of potential recovery is called an

Advancing age

Relative rates double

ischemic penumbra. Blood flow below 8 mL/100 g

every decade after

age 55 years

of brain per minute results in neuronal death as

Male gender

25%

early as 15 minutes after flow disruption. Neurons

in the hippocampus and cerebellum are the most

Prior transient ischemic

400%

attack

sensitive to ischemia, while neurons in the brain-

Heredity (first degree

100%-400%

stem and spinal cord are the most resistant. Brain

relative with stroke)

depending on cause

ischemia results in impaired energy metabolism,

with accumulation of calcium ions in the intracel-

lular space, elevated lactate levels, acidosis, and

production of free radicals. Cellular homeostasis is

cerebral arteries (parietal lobe) and between the

disrupted, leading to neuronal death.

middle and anterior cerebral arteries

(anterior

Stroke from occlusion of a specific cerebral

frontal lobe). If there is rapid reperfusion of the

artery causes a wedge-shaped infarction (Figure 9-

ischemic territory from lysis of the embolic clot,

1). If a large artery occludes, such as the middle

blood may leak from damaged small arterioles,

cerebral artery, the stroke may involve that entire

capillaries, and venules, producing hemorrhagic

vascular territory, or portions may be spared

transformation of the ischemic stroke.

depending on the degree of collateral circulation.

Lacunar strokes are small strokes rarely greater

With global hypotension, anoxia, or hypo-

in size than 10 mm in diameter and are highly

glycemia, the stroke maximally involves the water-

associated with chronic hypertension. The lesions

shed territory between the middle and posterior

are caused by arteriole microvascular occlusions

CHAPTER 9—Disorders of the Cerebrovascular System

Figure 9-1

Ischemic infarction; wedge-shaped pathologic specimen. (Courtesy of Mark Becher, MD)

due to arteriolosclerotic or lipohyalinosis changes

cospinal tracts or the ipsilateral corticospinal tract,

of deep perforating arteries less than 200 µm in

(5) movement of the functional motor cortex

diameter. The occluded vessel wall is disorganized,

within the existing domain, and (6) neuroplasticity

and replaced by connective tissue and occasionally

of the motor cortex to a new brain area. There is

macrophages. Lacunes are primarily located in the

increasing evidence that the motor cortex is not

basal ganglia, brainstem, and occasionally centrum

fixed, but plastic and can expand or shrink within

semiovale. The rate of developing subsequent

the existing site based on clinical demand and can

lacunes is 5% per year, which is more than twice

even move motor function to remote sites.

that for large-territory strokes.

Microscopically, a large vessel ischemic stroke

Major Clinical Features

shows little visible changes until about 6 hours later,

when swelling of neurons, astrocytes, and endothe-

Onset is sudden or the patient awakens from sleep

lial cells begins. Neurons first swell, then shrink,

with the completed stroke, but only rarely do

develop chromatolysis

(nuclei become eccentric,

stroke signs progress over 1 to 2 days. Table 9-3

with hyperchromasia), and then die. Neutrophils are

lists the common clinical features of lacunar, ante-

abundant after the first day. By day 2, microglia pro-

rior circulation, and posterior circulation strokes

liferate and become macrophages, engulfing myelin-

while Figures 9-2a and 9-2b show the location and

breakdown products. Astrocytes proliferate, become

distribution of the major arteries. Two-thirds of

reactive, and lay down glial fibers to produce gliosis.

lacunes are asymptomatic, while most cortical

Neovascularity slowly develops and renourishes the

strokes are symptomatic. Overall, the hemiparesis

damaged brain. Gradually over months the infarcted

is severe in 60% of cases, moderate in 20%, and

brain products are reabsorbed, producing a glial-

mild in 20%. Broca’s aphasia is more common than

lined cavity of variable size.

Wernicke’s aphasia, but severe left middle cerebral

The mechanism of natural stroke recovery is

artery strokes will have global aphasia (see Chapter

incompletely understood. Possible mechanisms for

11, “Disorders of Higher Cognitive Function”).

motor recovery include (1) recovery of motor neu-

ronal excitability as blood flow increases, (2) activa-

Major Laboratory Findings

tion of partially spared corticospinal tract pathways,

(3) alternate behavioral strategies to use limbs, (4)

Tests are performed to diagnose a stroke, identify its

parallel motor pathway activation via noncorti-

location, and determine the cause and source. Com-

FUNDAMENTALS OF NEUROLOGIC DISEASE

Table 9-3

Clinical Features of Common Strokes

Arterial Territory of Stroke

Clinical Presentation*

Left Middle Cerebral Artery

Aphasia, contralateral hemiparesis, contralateral

(Mid-Frontal and Parietal Lobes)

hemisensory loss, homonymous hemianopia, and dysphagia

Right Middle Cerebral Artery

Contralateral hemiparesis, contralateral hemisensory loss,

(Mid-frontal and Parietal Lobes)

homonymous hemianopia, dysphagia, and apraxia

Anterior Cerebral Artery (Frontal Pole and

Contralateral leg weakness and sensory loss

Medial Aspect of Frontal and Parietal Lobes)

Vertebral/Basilar Artery

Wallenberg Syndrome from Posterior

Vertigo, nystagmus, dysphagia, and dysarthria with ipsilateral

Inferior Cerebellar Artery (Medulla

Horner’s sign (miosis, ptosis, and diminished sweating on

and Cerebellum)

face), diminished facial pain and temperature perception,

limb ataxia, and contralateral loss of trunk and limp pain

and temperature

Mid Basilar Artery (Pons and Cerebellum)

Often involves bilateral branches, producing signs that include

facial weakness, quadraparesis, dysarthria, dysphagia,

vertical and horizontal nystagmus, ptosis, skew deviation of

vision, limb ataxia, and diminished level of consciousness.

Locked-in syndrome occasionally develops, with complete

loss of voluntary limb and face movement, retained con-

sciousness, and voluntary vertical eye movements.

Top of Basilar Artery (Midbrain, Occipital

Involves midbrain and posterior cerebral arteries, producing

Lobes, and Temporal Lobes)

disruption of voluntary vertical gaze, CN III palsies, ataxia,

somnolence, homonymous hemianopia or quadrantopia,

and occasionally loss of recent memory

Lacunar stroke territory

Internal Capsule

Contralateral hemiparesis and hemisensory loss without

aphasia or visual loss

Upper-Half Brainstem/Cerebellum

Combinations of ataxia, vertigo, diplopia, dysarthria, Horner’s

sign, contralateral sensory loss, ipsilateral facial weakness,

and ipsilateral facial sensory loss

Lower-Half Brainstem

Contralateral hemiparesis without sensory loss (pure motor

stroke)

* Clinical features may be less than described due to the arterial occlusion being only a branch and not the entire

artery or the existence of good collateral circulation minimizing the size of the infarction.

puted tomography (CT) scans are excellent for

the territory of the infarct within 4 hours. Diffusion-

detecting a hemorrhagic stroke but often appear

weighted MRI scans are helpful for distinguishing an

normal for 6 to 24 hours following an acute ischemic

acute stroke from older strokes that are not hyperin-

stroke. Subtle effacement (loss of boundaries) of

tense. Within 8 hours, edema from the infarction

sulci is the earliest sign, followed by development of

appears hyperintense on T2-weighted images and

a hypodense region due to development of cytotoxic

hypointense on T1-weighted images. MRI is sensi-

and vasogenic edema (see Chapter 3, “Common

tive for small lacunes and infarctions in the brain-

Neurologic Tests”). In general, the larger the stroke

stem and cerebellum that may be missed by CT. In a

the earlier it becomes visible on neuroimaging. MRI

patient with a lacunar stroke it is common to iden-

is the most sensitive neuroimaging method used to

tify other older lacunes that were clinically silent.

detect an ischemic stroke. While conventional MRI

Several tests are used to determine the cause of

may appear normal for several hours, diffusion-

the stroke. Cerebral arteriography and MRA or CT

weighted MRI will show an area of hyperintensity in

angiography can identify medium-to-large-diam-

CHAPTER 9—Disorders of the Cerebrovascular System

Lt. Anterior

Cerebral Artery

Lt. Middle

Cerebral Artery

Lt. Posterior

Communicating Artery

Lt. Posterior

Lt. Ophthalmic

Cerebral Artery

Artery (OA)

Lt. Basilar Artery

Rt. Vertebral Artery

Lt. Internal

Carotid Artery

Lt. Vertebral Artery

Lt. External

Lt. Carotid Sinus

Carotid Artery

Lt. Common Carotid Artery

Rt. Common Carotid Artery

Rt. Vertebral Artery

Lt. Subclavian Artery

Rt. Subclavian Artery

Brachiocephalic Artery

(Innominate Artery)

Figure 9-2

Arterial supply of the brain. (a) Major vessels. (Continues)

eter stenotic or occluded arteries in the neck and

the extent of functional recovery, and (3) mini-

head. Extracranial Doppler ultrasonography

mize the risk of subsequent strokes.

examination of the carotid artery in the neck also

Patients with moderate-to-severe strokes

detects narrow or occluded vessels. Transthoracic

require hospitalization and monitors. Electrocar-

or transesophageal echocardiogram can detect

diogram tests detect accompanying myocardial

clots or masses within the heart, vegetations on

infarction or cardiac arrhythmias and blood pres-

heart valves, immobile heart segments, and car-

sure checks monitor for hypotension or severe

diomegaly, which point to a cardioembolic source.

hypertension. Pulmonary monitoring with pulse

Cerebrospinal fluid examination can indicate vas-

oximetry is important, as hypoxia can worsen

culitis and CSF culture may determine an infec-

symptoms. Fevers and hyperglycemia worsen

tious etiology. A variety of blood tests can look for

stroke outcomes.

coagulopathy or vasculopathy.

Only one drug, intravenous recombinant tissue

plasminogen activator (rt-PA), has been shown to

improve the outcome of acute ischemic strokes. rt-

Principles of Management and Prognosis

PA administration offers no immediate benefit,

Treatment goals of the acute ischemic stroke are to

but produces better outcome at 3 months post-

(1) minimize the size of the stroke, (2) maximize

stroke. Disadvantages of this drug are considerable,

FUNDAMENTALS OF NEUROLOGIC DISEASE

Frontal Lobe

Parietal Lobe

Motor Cortex

Somatosensory Cortex

(Precentral Gyrus)

Leg

(Postcentral Gyrus)

Foot

Cerebral Artery

Trunk

Arm

Hand

Face

Receptive

Speech

Tongue

Broca's

Area

Expressive

Speech

Middle

Posterior

Cerebral Artery

Figure 9-2

(Continued) (b) Vascular territories.

as patients must meet strict entry criteria, includ-

or gastrostomy is needed to maintain adequate

ing (1) absence of blood on a CT scan, (2) a clini-

nutrition until spontaneous recovery of swallow-

cally small-to-moderate-sized stroke,

(3) no

ing occurs up to 2 months later. Patients lacking a

history of recent myocardial infarction, gastroin-

good cough reflex are at risk for aspiration pneu-

testinal bleeding, surgery, or anticoagulation, and

monia.

(4) reliable onset of stroke symptoms within 3

Natural recovery from stroke occurs over 3 to 6

hours of rt-PA dose. Thus, many patients do not

months. In general, 70% of motor recovery occurs

meet criteria; rt-PA carries a significant risk of

in the first month and 90% occurs by 3 months.

intracerebral or systemic bleeding if the criteria are

Recovery of speech is slower, with 90% recovery by

not followed.

6 months. In hemiparetic patients, 80% walk again

Patients should begin rehabilitation as soon as

but only 10% regain full use of the paretic hand.

they are physically and mentally able to partici-

Factors associated with a good recovery include

pate. Patients with Broca’s aphasia benefit from

young age, mild stroke severity, high level of con-

speech therapy first to improve communication by

sciousness, previous independence, living with a

gesturing and later by speaking. Patients with

partner, high frequency of social contacts, and

motor weakness need training in transferring,

positive mood. The latter factors suggest patient

dressing, standing, and eventually walking. Since

motivation is important in recovery.

20% of patients develop venous thrombosis in the

Prevention of subsequent strokes aims at iden-

paretic leg, subcutaneous heparin should be

tifying and treating the cause of the stroke, lower-

administered until the patient begins ambulating.

ing modifiable risk factors, and taking oral platelet

Most major strokes cause dysphasia of both liquids

aggregation inhibitors such as daily aspirin, clopi-

and solids. Frequently a nasogastric feeding tube

dogrel, or dipyridamole. Warfarin has not been

CHAPTER 9—Disorders of the Cerebrovascular System

shown to be better than aspirin in preventing

sion of the ophthalmic artery. This produces a

strokes unless the patient has a cardiac cause for

painless, brief

(minutes) sudden loss of sight

the stroke, such as atrial fibrillation, mechanical

involving all or part of the visual field of one eye.

valve failure, mural thrombus or severe cardiomy-

The visual loss is commonly described as a curtain

opathy. Such cardiac patients should be placed on

drawn upwards or downwards over one eye that

chronic warfarin therapy and maintained at an in

persists for minutes and then slowly reverses itself

International Normalized Ratio (INR) of 2 to 3.

to restore vision. Permanent loss of vision is rare.

Patients with anterior circulation strokes and a

Fundoscopic exam of the retina is usually normal.

corresponding high-grade

(70%-99%) carotid

Patients should not have bilateral visual loss or see

artery stenosis may be considered for carotid

lights flickering in the eye when it is closed. The

endarterectomy by a surgeon who has a low com-

latter suggests a migraine aura.

plication rate (morbidity and mortality <3%).

TIAs involving the middle cerebral artery com-

monly present with sudden, painless onset of con-

tralateral limb weakness

(hemiparesis or

Transient Ischemic Attacks

monoparesis) and partial loss of touch and tem-

perature sensation in the involved limbs. If the

Introduction

middle cerebral artery in the dominant hemi-

sphere is affected, patients often become aphasic.

A transient ischemic attack (TIA) is the sudden

TIAs involving the vertebrobasilar system most

onset of monocular visual loss or focal neurologic

commonly produce vertigo, ataxia, diplopia,

symptoms that stem from one vascular territory

dysarthria, and blurred vision in both eyes but rarely

and completely clear within 24 hours. The annual

cause isolated vertigo or loss of consciousness. By

incidence in adults is 200 to 800 per 100,000. It is

definition, a TIA must last less than 24 hours and

uncommon for a medical professional to witness a

leave no residual deficit. However, most TIAs resolve

TIA, and the diagnosis usually is made from the

within 6 hours, and often by 20 minutes.

patient’s history. However, studies in which physi-

cians examined patients during a potential TIA

report that only 2/3 of the events represented a

Major Laboratory Findings

true TIA. The significance of a TIA lies not in the

Workup of a patient with a TIA to establish the

event but in the fact that a TIA portends a future

cause should be performed as rapidly as possible.

stroke. Five-year follow up studies find there is a

The plan follows the outline presented for an

30% risk of developing a stroke.

ischemic stroke, with attention drawn to the

carotid artery and heart. The most common lesion

Pathophysiology

is ipsilateral stenosis (70%-99%) of the internal

carotid artery at the bifurcation from the common

Although incompletely understood, a TIA likely

carotid artery. However, for many TIAs the cause is

results from brief occlusion of a cerebral or central

not found.

retinal artery as a platelet embolus lodges in the

artery and rapidly breaks up, or by transiently

altering circulation dynamics and perfusion

Principles of Management and Prognosis

through a tightly stenotic artery. By definition, dif-

fusion-weighted MRI scans are normal and no evi-

Treatment for most patients involves administra-

dence of an infarction is found at autopsy.

tion of platelet aggregation inhibitors beginning

with daily aspirin and advancing to clopidogrel or

dipyridamole if the patient does not tolerate aspirin

Major Clinical Features

or continues to have TIAs. Use of daily aspirin has

TIAs symptomatically fall into 3 large groupings

been shown to reduce the risk of stroke by 13-20%

based on involvement of the

(1) ophthalmic

in high-risk patients and 5% in the general popula-

artery, (2) middle cerebral artery, or (3) verte-

tion. For patients with a tight internal carotid steno-

brobasilar artery. Transient monocular blindness,

sis, carotid endarterectomy by a surgeon who has a

or amaurosis fugax, results from transient occlu-

low complication rate should be considered.

FUNDAMENTALS OF NEUROLOGIC DISEASE

Hemorrhagic Strokes

noid space. In the United States each year an esti-

mated 45,000 people experience an intracerebral

Overview

hemorrhage, with an annual incidence of

20/100,000. Intracerebral hemorrhage is more

Intracranial hemorrhages occur in three intracra-

common in men, African Americans, and Japan-

nial spaces: intraparenchymal/ventricular, sub-

ese. Spontaneous intracerebral hemorrhages

arachnoid, and subdural/epidural. Subdural

account for only 10% of all strokes, but have the

hematomas are discussed in Chapter 18, “Trau-

highest mortality rate.

matic Brain Injury and Subdural Hematoma.” The

Primary intracerebral hemorrhage represents

significance of blood in the subarachnoid space is

85% of cases and results from spontaneous rupture

not that it causes immediate clinical symptoms

of small arteries damaged by hypertension or amy-

(headache, stiff neck, etc.) but that it often comes

loid angiopathy. Secondary intracerebral hemor-

from a ruptured aneurysm that causes life-threat-

rhages occur from arteriovenous malformations,

ening parenchymal damage.

bleeding tumors, or impaired anticoagulation.

Spontaneous Intracranial

Pathophysiology

Hemorrhage

Intracerebral hemorrhages

(hematomas) most

commonly occur in the cerebral lobes, basal gan-

Introduction

glia, thalamus, pons, and cerebellum (Figure 9-3).

Nontraumatic intracerebral hemorrhage is bleed-

The bleeding results from the rupture of small

ing into the brain parenchyma that may extend

penetrating arteries originating from the basilar

into the ventricles and rarely into the subarach-

artery or the anterior, middle, or posterior cerebral

Cerebral Cortex

(Lobar)

Basal

Cerebral Artery

Ganglia

Middle

Cerebral Artery

Thalamus

Posterior

Cerebral Artery

Superior

Pons

Cerebellar Artery

Basilar Artery

Pontine Arteries

Anterior Inferior

Cerebellum

Cerebellar Artery

Posterior Inferior

Cerebellar Artery

Figure 9-3

Common sites of intracerebral hemorrhages.

CHAPTER 9—Disorders of the Cerebrovascular System

artery. Degenerative changes in the vessel wall

Major Laboratory Findings

media and adventitia develop from the chronic

The CT scan establishes the diagnosis by the pres-

hypertension or from deposition of β-amyloid

ence of an acute intracerebral hemorrhage (Figure 9-

protein in amyloid angiopathy, particularly at or

4). Secondary findings include surrounding cerebral

near bifurcations of affected arteries.

edema, intraventricular hemorrhage, and findings of

Following vessel rupture, blood under arterial

brain herniation (see Chapter 18, “Traumatic Brain

pressure rapidly flows into adjacent brain areas. In

Injury and Subdural Hematoma,” for details).

the basal ganglia the blood disrupts the gray mat-

ter and spreads into the ventricles and into the

adjacent cerebral white matter. When the rupture

Principles of Management and Prognosis

develops in a cerebral lobe, it spreads between

The goals of management are to improve survival

planes of white matter, leaving areas of relatively

from the acute hemorrhage, identify the etiology,

intact neural tissue. The bleeding stops by tam-

and prevent future bleeds. The acute management

ponade within 30 minutes in most patients but in

of an intracerebral hemorrhage is particularly

20% the hematoma continues to expand for sev-

challenging. Patients often require early intubation

eral hours.

and placement on a ventilator to control the air-

The surrounding compressed brain develops

way, ensure sufficient oxygenation, and prevent

vasogenic edema from release and accumulation

tracheal aspiration. Frequent monitoring of vital

of osmotically active clot proteins and cytotoxic

signs and cardiac status are needed as patients

edema from compression of surrounding blood

often deteriorate in the first

24 hours. Cardiac

vessels, producing secondary tissue ischemia.

arrhythmias may develop that require treatment.

Within days macrophages and neutrophils accu-

Seizures can occur in the first 24 hours and should

mulate in the surrounding brain to slowly invade

be treated vigorously with anticonvulsants. A

the clot and remove blood products over several

seizure raises intracranial pressure

and increases

months. In survivors, months later there is only a

the risk of brain herniation.

small cavity whose orange-stained walls contain

hemosiderin-laden macrophages.

Unfortunately, in over 25% of patients the mass

from the blood clot and surrounding cerebral

edema produces immensely increased intracranial

pressure, leading to secondary brain herniation

and death with hours to a few days.

Major Clinical Features

The most common hemorrhage locations are the

putamen, thalamus, and caudate (60% of total).

These patients may suddenly become aware of

“something wrong” followed minutes later by pro-

gressive depression of consciousness, vomiting,

headache, contralateral hemiparesis, and abnor-

mal eye movements. Signs of a lobar hemorrhage

depend upon the lobe involved. A cerebellar hem-

orrhage usually begins in the dentate nucleus, with

blood expansion into one cerebellar hemisphere

producing headache, ipsilateral limb ataxia, ver-

tigo, and vomiting without limb weakness.

Patients with amyloid angiopathy are usually

over age 70 years and 30% have an associated pro-

Figure

9-4

Computed tomography

scan

acute

gressive dementia. Most patients experience a

intracerebral hemorrhage in the left thalamus. (Cour-

lobar hemorrhage.

tesy of Blaine Hart, MD)

FUNDAMENTALS OF NEUROLOGIC DISEASE

If the patient develops signs of brain hernia-

aneurysms are little outpouchings at bifurcations

tion, repeat CT scans can determine whether new

of mid-sized cerebral blood vessels, while fusiform

bleeding has occurred or there is obstructive

aneurysms are dilated elongated segments of the

hydrocephalus. Attempts to surgically remove the

vessel. Saccular aneurysms rupture much more

blood clot are controversial, except in a cerebellar

often than fusiform aneurysms. The remaining

hemorrhage. Little evidence exists that surgery

causes include superficial arteriovenous malfor-

improves quality or duration of survival. However,

mations of the brain and spinal cord and SAH in

a moderate to large cerebellar hematoma is a sur-

which no etiology is identified.

gical emergency, as removal of the hematoma car-

Major risk factors for rupture of an aneurysm

ries a significant improvement in mortality and

include hypertension, smoking, heavy alcohol con-

morbidity.

sumption, and a positive family history. Of

Patients who survive that acute phase should be

patients with SAH, 10% have a positive family his-

evaluated for the etiology of the bleed. This may

tory, and first-degree relatives have a 5-fold risk.

require a cerebral arteriogram to diagnose an

aneurysm or arteriovenous malformation and

Pathophysiology

MRI with gadolinium to identify a hemorrhagic

tumor. Surgical removal of an arteriovenous mal-

Autopsy studies estimate the prevalence of unrup-

formation may be indicated.

tured saccular aneurysms at 1%-2%, with 30% of

Rehabilitation of surviving patients aims at

these patients having multiple aneurysms. The

improving limb strength, gait, and speech. Control

location of saccular aneurysms is mainly at the

of the hypertension is essential. However, patients

bifurcation of larger vessels or at sites where dis-

with a hypertensive hemorrhage seldom experience

turbances of blood flow are generated, such as the

a second hemorrhage. Prevention of rebleeding in

anterior and posterior communicating arteries

patients with amyloid angiopathy is presently

(Figure 9-5). The most common locations are the

impossible and patients have a recurrence rate of

posterior communicating artery (40%), anterior

10% per year. Rebleeding from arteriovenous mal-

communicating artery (20%), and bifurcation of

formations ranges up to 18% per year.

the middle cerebral artery (15%). Except for a few

The overall 1-year survival rate from an intrac-

hereditary diseases, patients with cerebral

erebral hemorrhage is 40%. Neurologic sequelae

aneurysms do not have systemic aneurysms.

are typically less severe and infrequent compared

The pathophysiology by which saccular

with a similar-sized ischemic stroke because neu-

aneurysms develop is incompletely understood.

ronal tissue was compressed by the hemorrhage

Evidence points to development of the aneurysm

and less destroyed.

in adulthood, as children seldom experience a rup-

tured aneurysm and autopsy studies of infants and

children rarely find aneurysms. The origin of the

Saccular Aneurysms

aneurysm is just distal to a bifurcation where there

are high shear forces. The aneurysm wall is charac-

Introduction

terized by (1) reduction of collagenous fibers, (2)

atrophy of tunica media, and (3) loss of internal

Subarachnoid hemorrhage (SAH) is the presence

elastic lamina in addition to the expected absence

of blood in the meninges and CSF. Head trauma,

the leading cause of SAH, is discussed in Chapter

of external elastic lamina. The sac of a small

18. Excluding trauma, the annual incidence of

aneurysm is reduced to a single layer of endothe-

spontaneous SAH is 10/100,000 and accounts for

lial cells and a thin fibrous layer. The histologic

3% of all strokes. Spontaneous SAH is uncommon

appearance of the artery wall before and after the

in infants and children, has a mean age of onset in

aneurysm is normal. The role of genetic factors in

the sixth decade, and is rare in elderly adults over

the pathogenesis is unclear.

age of 75 years. Women outnumber men 3:2, and

The risk of bleeding from an aneurysm

African Americans outnumber caucasians 2:1.

increases considerably in those larger than 5-mm

At least 85% of SAH is due to rupture of a sac-

diameter. Patients with multiple aneurysms also

cular

(berry) or fusiform aneurysm. Saccular

are at higher risk of rupture.

CHAPTER 9—Disorders of the Cerebrovascular System

Anterior Cerebral Artery

Frontal Lobe

of Cerebrum

Temporal Lobe of

Anterior Communicating Artery

Cerebrum

Pituitary

Gland

Middle Cerebral Artery

Anterior Choroidal Artery

Grey Circle Size

Posterior Communicating Artery

Reflects

Aneurysm Frequency

Posterior Cerebral Artery

Superior Cerebellar Artery

Pons

Basilar Artery

Anterior Inferior

Cerebellar Artery

Posterior Inferior

Cerebellar Artery

Cerebellum

Vertebral Artery

Anterior Spinal Artery

Figure 9-5

Distribution of saccular aneurysms.

Major Clinical Features

intracranial pressure is commonly seen on fundo-

scopic exam after 12 hours.

Sudden, explosive headache, the cardinal feature,

Occasional giant and fusiform aneurysms

develops within seconds of a rupture. However, in

produce neurologic deficits by mass effect and

patients presenting to an emergency room with

may cause a CN III palsy or other cranial nerve

this description, only 10% prove to have an SAH.

deficits.

The others are due to a “thunderclap” headache or

migraine headache. Vomiting occurs in 70%. A

Major Laboratory Findings

period of unresponsiveness occurs in over half the

patients and focal neurologic signs occur in 1/3 of

The diagnosis of SAH is best made by CT, which

patients. Common neurologic signs are cranial

is widely available, rapidly performed even in a

nerve palsies, including dilated pupils, disconju-

restless patient, and identifies blood in the sub-

gate gaze, facial weakness, dysphagia, and

arachnoid space over 80% of the time. The charac-

dysarthria and hemiparesis. Seizures occur in 5%

teristic hyperdense appearance of extravasated

of patients. Neck stiffness usually develops hours

blood in the basal cisterns is the most common

after the bleed. Papilledema from increased

finding (Figure 9-6). Collections of extravasated

FUNDAMENTALS OF NEUROLOGIC DISEASE

Principles of Management and Prognosis

The goal is to maximize the quality of survival

from the acute SAH and to eliminate the

aneurysm, thus preventing rebleeding.

Patients are often classified as to severity and

prognosis based on the Glasgow coma scale and

other scales (Table 9-4). Patients should be placed

in an intensive care unit as they often deteriorate

during the first day. If mental status and breathing

deteriorate, intubation and mechanical ventilation

is required. Blood pressure should be carefully con-

trolled. Pain should be controlled with narcotics.

Secondary cerebral ischemia develops in 1/3 of

patients, often after several days and continuing

into the second week. This ischemia can lead to

secondary infarction. Arterial vasospasm

(reversible narrowing of a cerebral vessel) often

occurs 4 to 21 days after the bleed but does not

always produce recognizable cerebral ischemia

symptoms and infarctions may develop without

corresponding arterial vasospasm. Nevertheless,

daily administration of a calcium-channel blocker,

Figure 9-6

Computed tomography scan of subarach-

nimodipine, from bleeding onset is associated with

noid hemorrhage. The arrow denotes the hyperdense

a modest, but significant, reduction in secondary

blood outlining the basilar cisterns. (Courtesy of Blaine

Hart, MD)

ischemia and improvement in outcome.

Rebleeding from the aneurysm is a serious

problem. Rebleeding within 24 hours of initial

blood elsewhere may suggest the site of the bleed-

bleed occurs in 15% of patients. After survival of 1

ing aneurysm. In 30% of patients, there is also an

day, 1/3 of patients will rebleed over the next 4

intraparenchymal hematoma due to rupture of

weeks, with the daily risk of bleeding being about

the aneurysm upward into the brain. CT only

detects bloody CSF when there is an RBC concen-

Table 9-4

General Grading Systems

tration of greater than 0.5%. After 8 hours, CSF

exam demonstrates blood in all tubes and xan-

for Ruptured Saccular

thochromia (yellow color) of the supernate, estab-

Aneurysms*

lishing the diagnosis in the few patients missed by

Grade

Clinical Characteristics

CT. MRI helps to detect an SAH more than several

Alert, minimal headache, slight neck stiff-

days old.

ness, and no neurologic deficit

Several methods exist to identify the location

Alert, moderate-to-severe headache, stiff

of the aneurysm and whether other aneurysms

neck, and no neurologic deficit other than

coexist. The gold standard is four-vessel catheter

cranial nerve palsy

angiography, but this method is time consum-

Drowsiness and mild confusion with mild

ing, difficult to perform on a sick patient, and

neurologic deficit

carries a complication rate of rebleeding in

Semicoma, moderate-to-severe hemipare-

2%-5%. CT angiography using contrast media is

sis, and possible early decerebrate rigidity

becoming popular because it is faster, safer, and

Deep coma, decerebrate rigidity, and

has a sensitivity of 90% compared with arteriog-

moribund

raphy. Because MRA is slower and difficult to

perform in a patient on a ventilator, it is less

* Includes Hunt Hess and Botterell and Lougheed

helpful.

scales.

CHAPTER 9—Disorders of the Cerebrovascular System

equal. Surgical obliteration of the aneurysm has

the Glasgow coma scale, presence of intracerebral

been the mainstay of treatment for decades. The

hematoma, development of hydrocephalus, and

surgeon is often faced with a dilemma. Operating

rebleeding.

on a comatose patient with brain edema is techni-

cally difficult and carries a considerable surgical

risk of death. However, waiting 1 to 2 weeks for the

RECOMMENDED READING

brain swelling to reduce and the patient to clinically

improve carries the increased risk of the aneurysm

Brott T, Bogousslavsky J. Treatment of acute

rebleeding. Studies have not identified an ideal

ischemic stroke. N Engl J Med 2000;343:710-722.

time for surgery, but many surgeons wait until the

(Reviews how ischemia damages neurons and the

patient’s level of consciousness improves. In recent

treatment options in an acute stroke.)

years, endovascular techniques enable placement of

Johnston SC. Transient ischemic attack. N Engl J

a detachable spring coil into the aneurysm via an

Med 2002;347:1687-1692. (Good review, with

arterial catheter, which triggers aneurysm clotting.

focus on treatment.)

While this technique has promise for select

Qureshi AI, Tuhrim S, Broderick JP, et al. Sponta-

patients, the overall outcomes have been similar to

neous intracerebral hemorrhage. N Engl J Med

surgical clipping. After

1 month, the risk of

2001;344:1450-1460. (Current review of causes

rebleeding from an unclipped aneurysm is 1% per

and management options.)

year for 4 years and then falls much lower.

Staph C, Mohr JP. Ischemic stroke therapy. Annu

The prognosis of a ruptured saccular aneurysm

Rev Med 2002;53:453-475. (Current review of

is poor. Overall, 1/3 of patients die from the acute

clinical picture, workup, and treatment options.)

bleed and 2/3 of survivors are left with consider-

van Gijn J, Rinkel GJE. Subarachnoid haemor-

able neurologic sequelae and a diminished quality

rhage: diagnosis, causes and management.

of life. Poor prognostic signs include grades 4 or 5

Brain 2001;124:249-278. (Excellent review of all

on the aneurysm grading scales, scores of 3 to 6 on

causes, with attention to saccular aneurysms.)

DISORDERS OF MYELIN

strength to the axon. It also serves to insulate the

Myelin

axon from environmental toxins and prevents

ephaptic transmission (direct axon-to-axon elec-

Overview

trical transmission without a synapse). In addi-

Myelin is produced in the PNS by Schwann cells

tion, myelin allows saltatory conduction

(the

and in the CNS by oligodendrocytes. Both cells are

action potential moves down a myelinated nerve

embryologically derived from the neural crest.

by jumping from node of Ranvier to node of Ran-

Each Schwann cell myelinates a single 1-mm seg-

vier), increasing nerve conduction velocity as

ment of a PNS axon while each oligodendrocyte

much as 100-fold. An unmyelinated peripheral

myelinates as many as 60 CNS axon segments. At

sensory nerve has a conduction velocity of 0.5 to

birth, PNS myelination is almost complete, but

1.0 m/s. A myelinated peripheral motor nerve con-

CNS myelination continues after birth for a

ducts at 60 to 80 m/s. Myelination allows more

decade. In the PNS, loss of Schwann cells triggers

efficient impulse propagation, requiring less

regeneration of new Schwann cells, which then

energy. As such, myelinated axons can conduct at

remyelinate the demyelinated axon. PNS remyeli-

much faster frequencies for longer periods of time

nation is characterized by shorter-length intervals

than unmyelinated axons.

of myelin that have fewer whorls of compact

Myelin contains about 70% lipid and 30% pro-

myelin. Nevertheless, remyelination often results

tein compared with normal cell membranes,

in return of normal nerve function. Remyelination

which have only about 40% lipid. Some myelin

can occur in the CNS but does so to a far lesser

proteins, such as myelin basic protein, myelin-

extent.

associated glycoprotein, and myelin oligodendro-

Myelin serves several important functions. A

cyte glycoprotein, are specific to myelin, can

key function is to house axons and to provide for

become immunogenetic, and may be the target of

the axons’ hollow tubular channels of extracellular

immune-mediated myelin damage.

matrix. In the PNS, unmyelinated axons are sur-

Demyelinating diseases occur when the disease

rounded by Schwann cell cytoplasm, but in the

process primarily involves myelin sheaths,

CNS oligodendrocytes do not wrap around

Schwann cells, or oligodendrocytes. Thus there is

unmyelinated axons. Myelin provides physical

damage to myelin sheaths with relative sparing of

101

102

FUNDAMENTALS OF NEUROLOGIC DISEASE

the underlying axon. Diseases such as strokes that

5/100,000 to 30/100,000 adults around the world,

destroy both myelin and axons are not considered

with higher prevalences occurring the further

demyelinating diseases. The disease process may

north or south one lives from the equator.

involve CNS myelin, PNS myelin, or both. Causes

of demyelinating disease include genetic (Charcot-

Pathophysiology

Marie-Tooth neuropathy), toxic

(diphtheric

polyneuropathy), infectious (progressive multifo-

The pathologic hallmark of MS, the demyelinated

cal leukoencephalopathy), immune-mediated

plaque, consists of a well-demarcated hypocellular

(Guillain-Barré syndrome), and unknown (multi-

area characterized by the loss of myelin, relative

ple sclerosis).

preservation of axons, and the formation of astro-

There are four major mechanisms of demyeli-

cytic, glial scars (Figure 10-1). The lesions are usu-

nation: (1) death of oligodendrocytes or Schwann

ally oval and have a small- or medium-sized blood

cells,

(2) interference with myelin synthesis, (3)

vessel near the center. Inflammatory cells (mainly

interference with myelin turnover, and

(4)

lymphocytes and macrophages) are typically

immune-mediated destruction of myelin.

perivascular in location, but may infiltrate the

Signs and symptoms of demyelination are due

lesion diffusely. Some plaques demonstrate partial

to dysfunction of the underlying axon. In general,

remyelination while others do not. Plaques may

the longer the myelinated nerve tract, the greater

occur anywhere in the CNS but not in the PNS.

the probability that a demyelinating disease will

Common locations for plaques include the white

disrupt its function. In the CNS, tracts commonly

matter of optic nerves, surrounding lateral ventri-

involved include the corticospinal tract (weakness

cles, corpus callosum, brainstem, cerebellum, and

and spasticity), spinothalamic tract (sensory loss),

spinal cord. Lesions involve both hemispheres and

visual pathway

(visual disturbance), and spin-

distribute asymmetrically. Recent studies suggest

ocerebellar pathways (ataxia). Of note, demyeli-

that there are 4 pathologic forms of MS. The 2

nating diseases seldom produce the signs of gray

most-common forms appear to display primary

matter disease, such as early dementia and aphasia,

basal ganglia deficits (parkinsonism or chorea), or

seizures. In the PNS, motor and sensory (vibration

sense) myelinated nerves are often mildly involved.

Similarly, the sensations of pain and temperature

(unmyelinated axons) are seldom impaired. In

general, genetic and toxic causes of demyelination

usually produce symmetrical signs, while

immune-mediated and infectious causes of

demyelination are often asymmetrical.

Multiple Sclerosis

Introduction

Multiple sclerosis (MS) is an enigmatic, relapsing,

and often eventually a progressive disorder of CNS

myelin. The classical definition of MS requires dis-

semination of CNS white matter lesions in time

(multiple attacks) and space (involving different

areas of CNS white matter). There is a female pre-

dominance of about 2:1. The disease usually

begins in the third decade of life. Over 300,000

adults in the United States have the disorder. How-

Figure

10-1

Pathologic specimen showing multiple

ever, the prevalence varies from less than

sclerosis plaques. (Courtesy of Mario Kornfeld, MD)

CHAPTER 10—Disorders of Myelin

103

damage to CNS myelin (the first form mediated by

cord). Patients often complain of worsening of their

antibody, complement, and immune cells and the

symptoms in hot weather or when they are febrile.

second mediated only by immune cells), while the

Spontaneous clinical return of function usually

other two forms appear to incur primary damage

occurs within a month. In the relapsing-remitting

to the oligodendrocytes. Whether the 4 forms have

form of MS (80% of patients), full return of func-

different etiologies is unknown, but in the future

tion prevails but over time, attacks may leave some

may direct patient treatment.

permanent dysfunction (Figure 10-2). Return of

The cause of MS remains mysterious. Extensive

clinical function occurs when the demyelinated

searches for an infectious agent or genetic cause

portion of the axon converts from permitting only

have yet to identify a likely etiology. While there is

saltatory conduction requiring myelin to an axon

mounting evidence that damage to CNS white

segment that has continuous conduction, like

matter develops from an immune-mediated

unmyelinated axons (Figure 10-3). Thus the con-

process, the initial inciting antigen and how the

duction velocity slows but function returns. When

immune process is maintained at irregular inter-

brain temperature rises, some continuous-con-

vals for years remains unclear. Nevertheless, our

ducting axons develop temporary conduction

most-successful treatments have been directed

blocks, which explain the worsening of a patient’s

against modifying the immune process.

symptoms in hot weather. Remyelination of

demyelinated axons in a plaque is so limited that it

probably does not result in significant clinical

Major Clinical Features

improvement. Permanent loss of function is asso-

The clinical features and rate of MS progression

ciated with loss of the underlying axons.

vary considerably from patient to patient. Neu-

After 5 to 10 years, relapsing-remitting patients

roimaging has shown that plaques often appear in

often develop a slowly progressive illness called

“silent” brain areas without producing clinical signs.

secondary progressive MS (Figure 10-2). A few

In the early phase of MS, clinically apparent attacks

percent of patients slowly progress without acute

develop about once or twice a year. The onset occurs

attacks (primary progressive MS). Over 30 years,

over 1 to 2 days and does not have an identifiable

about 1/2 of MS patients will develop sufficient

trigger. Common clinical signs occur from damage

ataxia or spasticity to require a wheelchair. Life

to long CNS myelinated tracts. Thus, MS patients

expectancy shortens only slightly.

often develop hemiparesis or monoparesis (corti-

cospinal tract), unilateral visual loss (optic nerve),

Major Laboratory Findings

sensory loss (posterior columns or spinothalamic

tracts), ataxia (cerebellum or cerebellar pathways),

There is no diagnostic test for MS. However, there

and neurogenic bladder or paraparesis

(spinal

are characteristic cerebrospinal fluid (CSF) changes

Figure 10-2

Natural history of multiple sclerosis.

104

FUNDAMENTALS OF NEUROLOGIC DISEASE

Normal

Myelinated

Axon

Action Potential

Presynaptic

Axon Sodium

Myelin

Postsynaptic

Neuron

Channels

Sheath

Neuron

Demyelination

Acutely

Demyelinated

Axon

Conduction restored by

increased density

of sodium channels

Chronically

Demyelinated

Axon

Action Potential

Figure 10-3

Axonal changes in acute and chronic demyelination.

that occur in most patients. The CSF usually shows

autopsy and are commonly seen as perpendicular

an increased IgG synthesis rate (IgG index) and

ovals in the white matter around the lateral ventri-

several oligoclonal bands. This indicates migration

cles, corpus callosum, cerebellum, and spinal cord.

of B lymphocytes and plasmacytes from blood to

MS is a clinical diagnosis with laboratory sup-

brain plaques with subsequent local homogenous

port. Patients should be young adults, have at least

antibody production that then leaks into CSF. It is

one definite clinical attack characteristic for MS,

not known what antigen the MS antibody is

and have definite signs or MRI lesions distributed

directed against. The CSF may contain a small

in several areas of the white matter of the brain

number of lymphocytes but should have a normal

and the spinal cord. The clinical diagnosis is sup-

glucose level. Routine blood tests are normal.

ported by the presence of CSF oligoclonal bands

MRI scans are sensitive, but not specific, indica-

and increased IgG synthesis. No other diagnosis

tors for myelin plaques. FLAIR and T2-weighted

for the clinical signs should be apparent.

MRI lesions reflect inflammation, edema, demyeli-

nation, and gliosis

(Figure

10-4). T1-weighted

Principles of Management and Prognosis

lesions (“black holes”) often reflect marked axonal

loss in the plaque

(Figure

10-4). Gadolinium-

Treatment of MS is divided into treatment of acute

enhancing lesions on T1-weighted images suggest

lesions, rehabilitation of the patient with chronic

disruption in the blood-brain barrier from active

disease, and prevention of future plaques. Acute

inflammation and demyelination. Neuroimaging

relapses are often treated with short courses of

lesions occur in the same locations found at

high-dose corticosteroids. While spontaneous

CHAPTER 10—Disorders of Myelin

105

Figure 10-4

FLAIR magnetic resonance imaging scan of multiple sclerosis plaques. (Courtesy of Coley Ford, MD)

clinical recovery takes about

4 weeks, steroids

drugs affect the immune-mediated attack to white

appear to shorten the time to recovery by 1 to 2

matter. Both the interferons and glatiramer acetate

weeks. However, steroids do not improve the

require daily or weekly administration injections,

extent of recovery or change the course of the dis-

have a moderate number of local and systemic side

ease. Chronic treatment with steroids has not been

effects, and are expensive (about $10,000/yr). It is

shown to prevent subsequent relapses.

currently unknown how long these drugs should

Rehabilitation aims at maximizing patient func-

be taken. Mixantrone, a chemotherapeutic drug,

tioning. Patients commonly become depressed,

remains the only medication indicated for primary

requiring counseling and antidepressant medica-

or secondarily progressive MS.

tion. Fatigue becomes a problem and is difficult to

treat. Bladder spasticity with urinary incontinence

may develop, requiring treatment. Ataxia and

Guillain-Barré Syndrome

spasticity affect gait, balance, and coordination,

interfering with activities of daily living.

Introduction

Several drugs have been found effective in

reducing the frequency of new lesions in relaps-

Guillain-Barré syndrome (GBS) is a monophasic

ing-remitting MS. Interferon β-1b, interferon

disease involving only myelinated nerves in the

β-1a, and glatiramer acetate all reduce the fre-

PNS. The most common form (>80% in the

quency of relapses by about

30%. Serial neu-

United States), called acute inflammatory demyeli-

roimaging studies show these drugs reduce new

nating polyneuropathy (AIDP), appears to be due

T2-weighted lesions by about 60%. While these

to an immune-mediated attack of peripheral

drugs in short-term studies have shown a trend

myelin. Acute motor axonal neuropathy (AMAN)

toward delaying progression of disability, they

clinically is more severe than AIDP. The immune

have not reached statistical significance. The

attack in AMAN appears directed against the PNS

mechanisms by which interferon and glatiramer

myelinated axon exposed at the node of Ranvier.

acetate work are uncertain, but studies suggest the

The annual incidence of GBS in the United States

106

FUNDAMENTALS OF NEUROLOGIC DISEASE

is about 1 to 2 cases per 100,000 persons. The inci-

chronic disease of myelinated peripheral nerves

dence increases with age, and males slightly pre-

that shares many similarities with GBS and

dominate. Patients with partial immunosuppression

responds to plasmaphoresis, corticosteroids, and

are at an increased risk for GBS.

immunosuppressive agents.

Pathophysiology

Major Clinical Features

GBS occurs in the setting of an antecedent illness

Flaccid weakness is the hallmark of GBS. Leg

in about 60% of patients. Upper respiratory and

weakness is often the earliest sign but usually the

gastroenterologic infections are frequent, with the

weakness involves all extremities. The weakness is

most common being viruses (cytomegalovirus and

both proximal and distal and may also involve

Epstein-Barr) and bacteria

(Campylobacter

motor cranial nerves, producing facial weakness

jejuni). It is proposed that via molecular mimicry

and trouble swallowing and chewing. About 50%

the patient develops an immune response against

of patients experience a reduced vital capacity

the infecting agent that cross-reacts with antigens

and about 25% require ventilator assistance. The

on the patient’s peripheral nerve myelin or axons.

weakness progresses over 1 to 3 weeks and then

In AIDP, nerve damage results from lymphocytic

plateaus. Clinical involvement of the myelinated

immune responses against peripheral nerve myelin,

autonomic nerve system is common and may be

with antibodies playing an unclear role. The pathol-

life threatening. Complex supraventricular tachy-

ogy shows patchy lymphocytic infiltrates, particu-

cardias, abrupt bradycardia, and bouts of hyper-

larly around venules and capillaries within the

tension or hypotension may occur spontaneously,

endoneurium, and macrophages around the myeli-

follow minor adjustments in posture, or occur

nated nerves. Hematogenous macrophages adhere

during painful stimuli. Most patients become are-

to nerve fibers, where they penetrate the Schwann

flexic during the first week even if weakness is

cell basal lamina, extending processes that amputate

minor. Diminished vibration sense in the feet is

myelin lamellae and “strip” myelin away from the

common, but loss of touch, pain, and temperature

axon. This process produces segmental demyelina-

rarely occurs. Loss of bladder or bowel control is

tion. The most heavily affected part of the nerve is

uncommon. Mentation remains normal.

the proximal root. Multiple peripheral nerves are

In most cases the diagnosis is based on typical

involved in a uniform and generally symmetrical

clinical signs. For atypical cases, the differential

fashion. Central nervous myelin is not affected.

diagnosis includes acute intermittent porphyria,

Clinical recovery occurs over weeks when the

lead poisoning, tick paralysis, diphtheric polyneu-

demyelination stimulates abundant Schwann cell

ropathy, and critical illness neuropathy.

proliferation with subsequent remyelination of the

The weakness progresses over the first 1 to 3

naked axonal segment. Remyelination produces

weeks, with subsequent stabilization and recovery.

short-length myelin segments that are thinner than

In mild cases of AIDP, motor recovery can occur

the original myelin.

over a few weeks. For AIDP patients who cannot

In AMAN, antibodies (especially those associ-

walk, ambulation often takes 4 to 6 months. In

ated with Campylobacter jejuni) appear to attack

severe cases, recovery may continue for up to 2

axon antigens located at the internodal axolemma.

years. In AIDP, about 85% of patients fully recov-

In a variant of AMAN called Miller Fisher syn-

ery and 15% are left with minor sequelae such as

drome (ataxia, areflexia, and internal and external

loss of reflexes. In AMAN, up to 1/2 of patients are

ophthalmoparesis), the responsible antigen

left with neurologic sequelae. Death following car-

appears to be a GQ1b-like epitope that is shared by

diac arrhythmias or infectious complications still

some bacteria and axons. The nerve pathology is

occurs in 2% to 3% of patients with GBS.

largely noninflammatory and dominated by wal-

lerian-like degeneration of nerve fibers, which

Major Laboratory Findings

accounts for the poorer prognosis of AMAN.

Another uncommon variant called chronic

Major blood tests are normal. The CSF becomes

inflammatory demyelinating polyneuropathy

abnormal during the first week. CSF protein ele-

(CIDP) appears to be an antibody-mediated

vates to levels of 100 to 400 mg/dL but CSF IgG

CHAPTER 10—Disorders of Myelin

107

synthesis does not increase and oligoclonal

Principles of Management and Prognosis

bands do not develop. The CSF has a normal glu-

The key to successful management is excellent

cose level and normal WBC count. If a CSF pleo-

nursing care. Patients usually require hospitaliza-

cytosis exists, other diagnoses such as HIV

tion and placement in a critical care setting. About

infection, poliomyelitis, West Nile viral myelitis,

1/4 of patients require a ventilator. Cardiac moni-

or meningeal carcinomatosis should be consid-

toring is recommended because patients may be

ered. Neuroimaging of the spinal cord should be

prone to severe arrhythmias that may require elec-

normal.

trical cardioversion and medication.

Nerve-conduction study results become

Plasmaphoresis or human immune globulin is

abnormal in AIDP by the end of the first week.

beneficial if given early in the course of AIDP. Both

Mean values for compound motor action poten-

equally shorten the time to recovery and likely pre-

tial (CMAP) amplitude following nerve stimula-

vent progression of disease to more severe stages.

tion reduces to about 25% to 50% of normal,

In contrast, use of corticosteroids is not beneficial.

implying conduction blockage in the majority of

Presently, it is unclear which treatments for

motor axons. The motor nerve conduction

AMAN may be beneficial. During recovery, physi-

velocity reduces to 50% to 70% of normal after

cal therapy often improves function.

several weeks, reflecting the segmental demyeli-

nation. Variable evidence of muscle denervation

may be found on electromyography beginning

RECOMMENDED READING

after 2 to 3 weeks. In AMAN, the motor nerve

conduction velocity does not fall markedly, but

Noseworthy JH, Lucchinetti C, Rodriguez M,

the amplitude of the CMAP does, as there is

Weinshenker BG. Multiple sclerosis. N Engl J

widespread evidence of muscle denervation,

Med 2000;343:938-952. (Excellent recent review

reflecting that pathologic damage primarily

of genetic and pathologic features, immunology,

occurs in axons.

and treatment of MS.)

DISORDERS OF HIGHER

CORTICAL FUNCTION

ity. Visual, auditory, and somatosensory informa-

Overview

tion goes to the primary sensory cortex. The uni-

modal association cortex refines single sensory

Higher cortical functions process raw sensory sig-

information. The multimodal association cortex

nals into complex concepts that can be remembered

receives input from all sensory modalities and

and used to create new ideas that can be formulated

handles complex intellectual functions, such as

into action. It is the part of the brain which, for

logic, judgment, language, emotion, ambition, and

example, converts a sound (sensation) into a word,

imagination (Figure 11-1). Multimodal associa-

then into a sentence. This is then combined with

tion cortices are located in the prefrontal, limbic,

higher-level processes such as semantic memory,

and parietal lobes. The prefrontal lobe is responsi-

which the brain integrates into an idea or thought

ble for problem solving, self-monitoring, plan-

(conception) that can be remembered, compared

ning, mental tracking, and abstract thinking. The

with other ideas, and used to create new ideas that

limbic association cortex participates in memory

in turn can be remembered or acted upon.

and emotion. The parietal association cortex is the

The physiology involved in higher cortical

setting for language, space orientation, complex

function is poorly understood, but definitely

movement, and recognition of self and the world.

involves interaction among many cortical and sub-

Until recently, much of our understanding of

cortical regions, and often between both hemi-

higher cortical function has come from the inves-

spheres. The two hemispheres are not equal in

tigation of patients with defined cortical lesions.

function, but the precise differences are not under-

Based on these studies, we have some understand-

stood. The dominant hemisphere is the one most

ing of the functions of specific areas. Recent stud-

responsible for language and fine motor control

ies of normal individuals using PET, fMRI, and

functions such as writing. The left hemisphere is

intracortical electrical recordings are providing

dominant in over 95% of right-handed individuals

ideas of the normal functions of cortical areas. To

and in 70% of left-handed individuals.

the clinician, recognition of specific higher cortical

In simple conceptualization, the cerebral cortex

function syndromes has proven helpful in

can be divided into 3 regions that deal with sen-

anatomic cerebral localization. Below are brief

sory information in increasing levels of complex-

descriptions of what is known about the anterior

109

110

FUNDAMENTALS OF NEUROLOGIC DISEASE

Parietal Lobe

Multimodal

Association

Cortex

Prefrontal

Limbic System

Prefrontal

Multimodal

Association

Cortex

Figure 11-1

Higher cortical function multimodal association cortices.

prefrontal lobe, limbic/temporal lobe, and parietal

causing the mouth to pucker involuntarily. The

lobe. In addition, there is a discussion of the clini-

suck reflex is said to be positive when the patient’s

cal deficits patients may experience when lesions

mouth opens involuntarily in response to an

occur in a specific multimodal association cortex.

object moving toward it. The rooting reflex is posi-

tive when lightly stroking the side of the face pro-

duces an involuntary head turning toward the

Prefrontal Lobe

stimulation.

Table 11-1 lists the clinical features seen in

The prefrontal association cortex, located anterior

patients with prefrontal cortical damage. These

to the motor and premotor frontal cortex, is sup-

patients often demonstrate high impulsivity with-

plied by branches of the anterior and middle cere-

out forethought to the consequences, inability to

bral arteries. Table

11-1 lists the recognized

perform several tasks simultaneously (multitask-

functions of the prefrontal lobe. Clinical dysfunc-

ing), lack of drive to work or complete tasks, and a

tion usually occurs when the damage is fairly large

tendency to appear disheveled or half-dressed.

and involves both prefrontal cortices. Thus surgical

removal of a considerable area of one prefrontal

cortex leaves subtle deficits generally only detected

Limbic System

with detailed neuropsychologic evaluation. In con-

trast, head trauma causing bilateral prefrontal lobe

The limbic system includes the limbic lobe (sub-

damage can produce considerable signs and symp-

callosal area, cingulated gyrus, parahippocampus,

toms. This occurs in part because of bilateral dam-

uncus, and hippocampal formation), many nuclei

age to fiber pathways that communicate between

of the nucleus accumbens, the hypothalamus,

the frontal cortex and subcortical sites.

mamillary bodies, and the amygdala (Figure 11-2).

Damage to prefrontal cortices can produce such

The major arterial supply comes from the anterior

reflexes as grasp, snout, suck, and rooting. These

and posterior cerebral arteries and anterior

reflexes are normal in the newborn, but disappear

choroidal artery. The two major concerns of the

by about 4 months of age, presumably due to

limbic system are memory and emotion.

myelination of inhibitory pathways from the pre-

Consolidation of long-term memories from

frontal cortices. The grasp reflex is revealed in the

immediate memory (lasting seconds) and short-

inability to release a grasp when an object, such as

term memory (lasting minutes) is the basic func-

the examiner’s finger, stimulates the palm. The

tion of the hippocampal formation. Long-term

snout reflex is elicited by touching the patient’s lips,

memory can be recalled days to years later. While

CHAPTER 11—Disorders of Higher Cortical Function

111

Table 11-1

Major Higher Cortical Brain Areas, Normal Functions, and Syndromes

Clinical Syndromes Seen

Cortical Area

Major Functions

When Area Damaged

Prefrontal Lobe

Judgment

High distractibility

Insight

Lack of foresight or insight

Foresight

Inability to switch from one task to another

Ambition

Lack of ambition

Sense of purpose

Lack of sense of personal responsibility

Lack of social propriety and self-monitoring

Limbic System

Short-term memory

Amnesia

Consolidation of long-term memory

Akinetic mutism

Emotional response

Flat emotional affect

Parietal Lobe

Perception of somatosensory input

Cortical sensory deficits

Astereognosis

Agraphesthesia

Poor double simultaneous sensory stimulation

Integration of all sensory data

Visual neglect and Anton’s syndrome

Awareness of body and its relationship

Apraxias

to external space

Construction apraxia

Ideomotor apraxia

Ideational apraxia

Language

Aphasias

Global aphasia

Broca’s aphasia

Wernicke’s aphasia

the hippocampal formation is responsible for

The limbic system also participates in emotional

establishing long-term memories, no single brain

responses. Electrical stimulation of various sites in

location appears responsible for the repository of

the limbic system may produce fear or sorrow (aver-

long-term memories, although it is likely cortical.

sion centers) or pleasure

(gratification enters).

Thus no single brain lesion can eradicate well-

Damage to the limbic system can produce varied

formed long-term memories. However, extensive

emotional changes. Large limbic lesions often pro-

damage to the brain in dementia patients can be

duce a flattening of emotions, presumably due to

associated with impaired long-term as well as

loss of both aversion and gratification centers. Bilat-

short-term memory.

eral damage to the anterior cingulate gyri or sup-

Lesions that cause memory impairment are usu-

plementary motor area may dramatically diminish

ally bilateral and may involve the hippocampal for-

emotional responses and produce an awake-appear-

mations, dorsomedial nuclei of the thalami, or

ing patient who is immobile, mute, and unrespon-

mamillary bodies. However, damage to the left tem-

sive to his or her environment (akinetic mutism).

poral lobe can produce verbal memory deficits,

while damage to the right temporal lobe can pro-

duce nonverbal memory deficits. The most com-

Parietal Lobe

mon diseases that produce devastating memory loss

are Wernicke-Korsakoff syndrome, bilateral tempo-

The parietal lobe begins behind the central sulcus

ral lobe contusions from head trauma, anoxia due

and extends backward and inferiorly to merge with

to cardiac arrest, and advanced Alzheimer’s disease.

the occipital and temporal lobes at poorly defined

112

FUNDAMENTALS OF NEUROLOGIC DISEASE

Cingulate

Corpus

Gyrus

Callosum

Fornix

Mamillary

Body

Amygdala

Hippocampus

Figure 11-2

Limbic system anatomy.

boundaries. The inferior division of the middle cere-

which side was touched, the patient will only

bral artery principally supplies blood to the parietal

report feeling the touch on the ipsilesional side.

lobe. The parietal lobe is a higher-order integration

Neglect syndromes cause lack of attention to the

center whose functions are listed in Table 11-1. Elec-

contralateral side of the body (spatial neglect) or to

trical stimulation of most parietal lobe neurons does

the contralateral visual space

(visual neglect).

not evoke specific sensory or motor effects, but

Patients with hemiparesis due to a lesion of the

lesions do produce specific clinical deficits.

motor cortex or corticospinal tract and a parietal

Patients with a lesion involving the postcentral

lobe lesion may be unaware of their arm and leg

gyrus, especially in the hand primary sensory area,

paralysis (anosgnosia). Similarly, bilateral occipital

usually have relatively intact perception of pain,

lobe lesions that involve the parietal lobe may pro-

touch, pressure, temperature, and vibration but

duce blindness that is denied by the patient (Anton’s

often have “cortical” sensory deficits. Astereognosis

syndrome). Lesions involving only the parietal lobe

is the inability to distinguish and recognize small

may produce apraxia on one side of the body in

objects based on size, shape, and texture when

dressing and grooming (dressing apraxia). Lipstick

placed in a hand that has normal primary tactile

may be applied to only one side of the lips and

sensory input. Agraphesthesia is the inability to

patients may not be able to put on a shirt or pants.

recognize numbers or letters written on the palm.

Lesions of the nondominant superior parietal

Loss of double simultaneous sensory stimulation is

lobe may give rise to disturbances of perception of

the inability to detect and localize two identical

two- or three-dimensional space. These patients

stimuli applied simultaneously and bilaterally to

have difficulty with route finding and reproducing

comparable areas on the face or limbs. For exam-

geometric figures, and disturbances in organizing

ple, if the examiner touches the backs of the

parts of a complex object (constructional apraxia)

patient’s hands and asks him or her to identify

(Figure 11-3). A good bedside test is to ask a patient

CHAPTER 11—Disorders of Higher Cortical Function

113

to draw a clock with numbers and the hands show-

mal speech. Traditionally, language disorders have

ing a specific time. Patients with constructional

been divided into specific categories that originally

apraxia often crowd the numbers on one side

were thought to be due to damage to focal brain

(visual neglect), may draw numbers incorrectly (6

regions, usually different areas of the left hemi-

for 9) or on the wrong side of the clock, and cannot

sphere in right-handed patients. With current neu-

draw the hands correctly (Figure 11-3).

roimaging, brain regions giving rise to specific

Apraxia is the inability to execute complex and

types of language disorders have been found to be

previously learned skills and gestures in a person

much larger than previously thought and show

who is alert and has no weakness or ataxia that pre-

considerable overlap (Figure 11-4). Thus fine sub-

vents the movements. Lesions of bilateral parietal

divisions of language currently are of limited clini-

lobes may produce ideational apraxia or impaired

cal usefulness. Nevertheless, dividing language

knowledge of what action is associated with a par-

disorders into 3 major categories does have clinical

ticular object. Often they use the wrong object for

usefulness (Table 11-2).

a particular function and display spatial or tempo-

Global aphasia implies loss of all speech and

ral errors. Lesions of the dominant parietal lobe

language function. There is loss of comprehension

most frequently produce ideomotor apraxia or spa-

of verbal and written language plus inability to

tiotemporal deficits imitating movements without

communicate in speech or writing. These patients

objects. For example, the patient might use jerky

do not obey verbal commands, and cannot repeat

vertical movement rather than smooth horizontal

phrases or produce meaningful speech or writing.

movements when imitating a carving movement.

However, some patients may express stereotypic

Apraxias involve both sides of the body, but they

utterances such as “OK” , “fine” , “sure”, and “no,”

are tested in the ipsilesional limb to be sure that

or express simple profanity, none of which are

they are not due to a motor deficit.

appropriate to the question. Most cases of global

aphasia are due to large infarctions involving the

central regions surrounding the Sylvain fissure and

Aphasias

almost always produce an accompanying hemi-

paresis, hemisensory loss, and often a homony-

Theories of speech and language continue to evolve

mous hemianopia. In general, prognosis for

as no current hypothesis satisfactorily explains nor-

recovery is poor.

Contralateral Neglect

Constructional Apraxia

Figure 11-3

Parietal lobe lesions causing neglect and apraxia.

114

FUNDAMENTALS OF NEUROLOGIC DISEASE

Global

Aphasia

Wernicke's

Heschl's Gyrus

Aphasia

(In Sylvain Fissure)

Angular

Gyrus

Broca's

Aphasia

Wernicke's

Broca's

Area

Figure 11-4

Location of brain lesions causing aphasias (left cortex).

Broca’s aphasia (expressive/motor/anterior/non-

by using nonverbal responses (miming). Lesions

fluent aphasia) implies disproportionate difficulty

that produce Broca’s aphasia were originally

with formulating sentences and speaking them

thought to be from a focal lesion in the inferior

aloud, compared with comprehending verbal and

frontal area (Broca’s area), but it is now recognized

written communication. Acutely, some patients

that larger lesions in that area can produce Broca’s

cannot speak at all. Over time, patients express

aphasia (Figure 11-4). Patients with Broca’s aphasia

short telegraphic speech that emphasizes informa-

from a stroke usually have an accompanying hemi-

tional nouns and verbs and tends to be devoid of

paresis. Prognosis depends on the cause (worse for

noncritical adjectives and adverbs. The speech

tumors than infarct) and lesion size. For infarction,

melody is distorted, sounds more guttural, and is

many patients regain reasonable-to-good func-

often explosive. Use of stereotypic utterances may

tional telegraphic speech over 6 months.

occur but may not be correct responses to the ques-

Wernicke’s aphasia (receptive/sensory/posterior/

tion. Repetition of phrases is impaired. Because

fluent aphasia) implies severe impairment in com-

patients understand simple spoken language, they

prehension of verbal and written communications,

may respond appropriately or express their needs

with the maintenance of fluent speech. Patients are

Table 11-2

Major Aphasia Types and Their Clinical Features

Type

Verbal Expression

Ability to Repeat Ability to Comprehend

Broca’s aphasia

Nonfluent but content, understandable

Impaired

Good for simple one-step

with truncated phrases containing

commands but impaired

mainly informational words

for complex commands

Wernicke’s aphasia Fluent but noncomprehensible with

Impaired

Poor to absent

excess noninformation words and

paraphasias

Global aphasia

Mute or nonfluent

Impaired

Poor to absent

CHAPTER 11—Disorders of Higher Cortical Function

115

usually unaware of their comprehension difficulties

monly used tests are the Wechsler Adult Intelli-

and may appear attentive and cooperative. The

gence Scale-III and Wechsler Intelligence Scale for

speech usually has normal melody or prosody, is

Children-III. In general, mental retardation or

pronounced clearly without effort, and is of normal

dementia can be defined as IQ scores 2 standard

to prolonged length. However, the speech content

deviations or more below the norm. In mental

does not make sense, lacks informational words

retardation, the patient has never had an IQ score

(nouns), contains excessive adverbs and adjectives,

within the norm. In dementia, it is loss of previously

contains nonwords (neologisms), and is mispro-

acquired intellect. A commonly used rapid office-

nounced or has inappropriately substituted words

screening test is called the Folstein Mini Mental Sta-

(paraphasias). Semantic paraphasias are errors

tus Exam (MMSE; see Chapter 2, “Neurologic

based on the meanings of words (aunt for uncle)

Examination”). Test scores range from 0 to 30 and

and literal paraphasias are errors based on sounds

scores below 24 are an indication of moderate-to-

(hook for took). A patient with psychosis usually

severe dementia, depending on patient age and edu-

has an abnormal frame of reference. Thus in

cation level. The test has good sensitivity (90%) but

response to the question, “What is your name?” the

poor specificity (60%) for dementia because it is

schizophrenic may answer, “Jesus Christ” (implying

relatively insensitive to mild cognitive dysfunction,

he understood the question and answered it relative

especially in higher-functioning patients.

to his world), while the patient with Wernicke’s

aphasia may reply, “It is a lovely, beautiful, warm,

rainy day on this weekend (implying he never

Neurologic Changes of

understood the question).

Normal Aging

Wernicke’s aphasia patients cannot repeat

phrases. Lesions commonly involve the posterior

Introduction

end of the Sylvain fissure and spread varying dis-

tances across the posterior half of the brain (Figure

In order to understand dementia that usually

11-4). Vascular occlusions of the posterior tempo-

occurs in the elderly, one must first understand the

ral branch and the angular branch of the middle

changes that occur with normal aging. In the past

cerebral artery in the dominant hemisphere can

decade, studies have identified neurologic changes

cause Wernicke’s aphasia without producing

that occur in normal aging separate from those that

hemiparesis. The prognosis of Wernicke’s aphasia

develop from disease. Overall, there is a slow loss of

varies. Many recover reasonable verbal compre-

many neurologic functions with normal aging, but

hension and usable appropriate speech, but the

the loss is subtle, allowing the individual to con-

speech may continue to contain paraphasias and

tinue to function normally past age 100 years.

word-finding difficulties (dysnomia).

COGNITION

There is an age-related decline in the (1) speed of

Intelligence

central processing,

(2) performance on timed

tasks, (3) recent memory retrieval, and (4) learn-

Intelligence is a general mental capability that

ing. However, verbal intelligence remains well pre-

includes reasoning, planning, solving problems,

served at least through age 80 years. The elderly

thinking abstractly, comprehending complex

require more time to process a question centrally,

ideas, learning quickly, and learning from experi-

although the answer usually is correct. Memory

ence. Low intelligence does not come from dys-

studies find that, compared with young adults, the

function of a single brain region but from

elderly have a 10% decline in the time of their

dysfunction or damage of many bilateral areas of

immediate recall from working memory. In

higher cortical function. Although imperfect,

“benign senescent forgetfulness,” the elderly often

intellectual reasoning is usually represented by an

describe increased forgetfulness and vague recol-

intelligence quotient (IQ) obtained from appro-

lections, but studies suggest that this is more from

priate testing instruments. An IQ score is perform-

decreased new learning than actual forgetfulness.

ance on a standardized test adjusted to the

New learning in the elderly continues throughout

individual’s chronological age. The most com-

life, but the period of time the elderly can concen-

116

FUNDAMENTALS OF NEUROLOGIC DISEASE

trate diminishes. Some aspects of cognition

Pathologic reflexes, such as clonus, Babinski signs,

remain quite stable in the elderly, such as recogni-

or grasp reflexes, are not normal aging phenomena.

tion memory and tasks involving well-learned

knowledge. While the actual IQ score does not

decrease with age because it is corrected for age,

Dementia

the raw score necessary to obtain an IQ of 100

decreases for performance IQ, but not verbal IQ.

Dementia is an acquired loss of intellect (IQ) that

is sufficient to impair the individual’s reasoning,

VISION AND HEARING

planning, and problem-solving skills, as well as the

The cranial nerves most affected by aging are those

ability to think abstractly, comprehend complex

for vision and hearing. Visual loss diminishes due

ideas, learn quickly, and learn from experience.

to (1) the pupils becoming progressively smaller

Dementia is the fourth most-common cause of

and less reactive to light and accommodation, (2)

death in the United States. The exact prevalence is

increasing opacity of the lens and vitreous, and (3)

unknown, but 4 million Americans have dementia

subtle retinal changes. Thus presbyopia occurs,

and another 3 million have mild cognitive impair-

with the admittance of less light that is poorly

ment. In most patients, the dementia is progressive

focused on an impaired retina. The range of verti-

(as in Alzheimer’s disease), but can be static (as

cal eye movements diminishes with advanced

from hypoxia due to cardiac arrest). Unfortunately,

aging.

the vast majority of causes are not reversible.

Presbycusis is a progressive elevation of the

There is no single pathophysiologic mechanism

auditory threshold, especially for higher frequen-

that produces all types of dementia, but the final

cies. Changes of aging, more prominent in men

common pathway is loss of neurons in one or

than women, often include loss of cochlear hair

more of the multimodal association cortex regions

cells, degeneration of spiral ganglion neurons, and

(prefrontal cortex, limbic system, and parietal

atrophy of the cochlear stria vascularis. The nor-

lobe). The neuronal loss can occur abruptly by (1)

mal speech range is from 500 to 3000 Hz. When

loss of cerebral arterial blood flow from cardiac

cochlear damage progresses to impair these fre-

arrest, (2) cerebral arterial occlusion from throm-

quencies, functional hearing loss develops.

bosis or emboli, (3) loss of critical brain nutrients

from hypoxemia or hypoglycemia, (4) neuronal

STRENGTH, GAIT, AND COORDINATION

toxins, (5) head trauma, and (6) CNS infections.

With normal aging there is a progressive decline in

Progressive neuronal loss results from (1) neu-

muscle bulk and strength, speed, and coordination

rodegenerative disease, (2) chronic exposure to

of movement. Muscle wasting is most noticeable

neurotoxins,

(3) vitamin deficiencies,

(4) CNS

in intrinsic hand muscle. Grip strength declines in

infections,

(5) accumulation of cerebral infarc-

85% of normal individuals over age 60, which is

tions, and

(6) chronic systemic or metabolic

out of proportion to loss of muscle bulk. Activities

encephalopathies (Table 11-3).

of daily living require 1/3 more time in the elderly,

Not all patients experience similar clinical

and there is less precise coordination. However,

deficits. Most patients develop loss of IQ along

finger-to-nose testing remains normal. Changes of

with additional problems of higher cortical func-

gait in advancing age include a wider-based walk-

tion. For example, patients often forget easily, have

ing stance, shorter steps, mild loss of accompany-

difficulty learning new information, and express

ing arm swing, and slightly stooped posture.

subtle aphasias and apraxias. Table 11-4 lists the

major tests that should be obtained in patients

SENSATION

with dementia. In the early stages of dementia,

The elderly have a mild progressive loss of vibra-

objective neuropsychologic testing

(especially

tion and position sense, mainly in the feet, from a

memory tests) is abnormal. As the dementia pro-

progressive loss of distal peripheral nerve sensory

gresses, cerebral atrophy especially is commonly

nerve axons. The result is poorer balance, especially

seen on neuroimaging. These images may demon-

with the eyes closed. There is an accompanying

strate additional abnormalities depending on the

diminishment of the ankle jerk, but not loss of it.

disease.

CHAPTER 11—Disorders of Higher Cortical Function

117

Mild cognitive impairment (MCI) is the term

Table 11-3

Major Causes of Dementia

used to describe the earliest signs and symptoms of

in the United States

a dementia. This is the transitional zone between

Neurodegenerative and

normal aging and dementia. These individuals

Neurogenetic Diseases*

complain of memory impairment but still lead rel-

Alzheimer’s disease (60%)

atively independent lives. MCI is defined as occur-

Alzheimer’s disease plus other causes

ring in patients who have adequate general

(especially multiinfarct dementia) (15%)

cognitive functioning and perform normally in

Dementia with Lewy bodies (10%)

activities of daily living but show subjective mem-

Down’s syndrome

ory impairment that is corroborated by a spouse

Tauopathies (such as progressive supranuclear

or friend and have objective memory impairment

palsy and corticobasal degeneration)

on standardized memory tests that is at least 1.5

Huntington’s disease

SD below the normal for age and education status.

Hepatolenticular degeneration (Wilson’s disease)^†

Long-term studies of individuals with MCI find

12% per year develop frank dementia compared

Cerebrovascular Disease

with

1% for age-matched controls. Limited

Multiinfarct dementia

autopsy studies find that 90% of patients who

Subacute arteriosclerotic encephalopathy

progress to dementia have Alzheimer’s disease.

(Binswanger’s disease)

Central nervous system vasculitis

Alzheimer’s Disease

Infectious Disease

Creutzfeldt-Jakob disease

Introduction

Sequelae of viral encephalitis (such as herpes

simplex encephalitis)

Alzheimer’s disease

(AD) accounts for 60% of

Neurosyphilis

dementia in the elderly. Of the elderly, 4 million

currently suffer from this disease, and the preva-

Human immunodeficiency virus infection

(acquired immunodeficiency syndrome

lence is expected to climb to 14 million by 2050.

dementia)

About 1,000 elderly adults are diagnosed daily

with AD. The prevalence rate is 1% for individuals

Systemic Metabolic Encephalopathies

ages 60 to 64 years and doubles every 5 years to

Hypothyroidism

reach 40% by the age of 85 years.

Hepatic encephalopathy

Vitamin deficiencies (B₁ and B₁₂)

Pathophysiology

Hypoxic disorders (such as cardiac arrest and

chronic obstructive pulmonary disease)

The hallmark pathology of AD is an excess of neu-

ritic plaques and neurofibrillary tangles in the

Toxic Encephalopathies

cerebral cortex compared with healthy age-

Heavy metals (such as lead, arsenic, and mercury)

matched controls. Neuritic plaques consist of a

Alcoholism

central core of β-amyloid protein surrounded by a

Carbon monoxide

ring of astrocytes, microglia, and dystrophic neu-

Immune Disorders

rites. The dystrophic neurites often contain abnor-

mal paired helical filaments. Neurofibrillary

Systemic lupus erythematosus

tangles are abnormal accumulations in the neu-

Paraneoplastic syndromes

ronal cell body and dendrites of paired helical fila-

Psychiatric disorders

ments of abnormally hyperphosphorylated tau

proteins that can be seen by electron microscopy

Depression

or by light microscopy after silver staining. Neu-

ritic plaques and neurofibrillary tangles are maxi-

* Bold type represents common causes, with “( )” being

their approximate incidence.

mally seen in the hippocampus, limbic system, and

^† Type in italics represents causes that may be reversible.

frontal lobes (Figure 11-5).

118

FUNDAMENTALS OF NEUROLOGIC DISEASE

Table 11-4

Laboratory Workup of Patient with Dementia

Blood Tests

Hemogram

Electrolytes

Glucose

Calcium

Creatinine

Liver function studies

Thyroid-stimulating hormone

Syphilis serology (rapid plasma reagin) [RPR] test and fluorescent

treponemal antibody absorption test (FTA-ABS) if RPR is positive)

Vitamin B₁₂ level

Special tests (such as ceruloplasm level for suspected Wilson’s disease)

Neuroimaging

Magnetic resonance imaging to evaluate for central nervous system (CNS)

masses, hydrocephalus, multiple infarctions, and infection)

Computed tomography if patient is poorly cooperative

Neuropsychologic Tests

These tests provide a precise quantitation of various cognitive functions.

Tests are available to evaluate IQ, memory, apraxias, aphasias, and

behavior. They are indicated for (1) diagnosing whether dementia is

present, (2) characterizing the cognitive deficits of an atypical dementia,

(3) determining whether the dementia is static or progressive, and

(4) following response to treatment.

Lumbar Puncture with Cerebrospinal Fluid (CSF) Exam

CSF exam is indicated for patients with cancer, CNS infection, systemic

infection, reactive syphilis serology, immunosuppression, vasculitis,

rapidly progressive course, atypical course, or age younger than 60 years.

Cell count

Glucose level

Total protein and immunoglobulin G levels

Oligoclonal bands

Bacterial and fungal cultures

Venereal Disease Research Laboratory slide test-CSF (CSF-VDRL)

Optional tests based on clinical presentation and family history

Genetic tests (such as for Huntington’s disease)

Urinary heavy metals (such as for lead, mercury, or arsenic)

Toxicology screen (for recreational drugs and medications containing

anticholinergics, bromine, sedatives, barbiturates, or tranquilizers)

Serological tests (such as for human immunodeficiency virus)

Antinuclear antibodies

Electroencephalogram

Single photon/positron emission computed tomography imaging studies

Additional histological features of AD include

cortical synapses, and granulovascular degenera-

the loss of cortical neurons, producing cerebral

tion in hippocampal neurons. Neuronal loss in the

atrophy with enlarged ventricles (hydrocephalus

nucleus basalis accounts for the loss of cholinergic

ex vacuo), marked reductions in the density of

neurons and their cortical axons.

CHAPTER 11—Disorders of Higher Cortical Function

119

The pathogenic mechanisms that produce these

Table 11-5

Common Features of

histologic changes are incompletely understood.

Alzheimer’s Disease

Current evidence points to the accumulation of an

abnormal amyloid protein as being central to the

Early Disease

Later Disease

cerebral damage. The β-amyloid gene encodes a

Progressive decline in Loss of insight

large protein, amyloid precursor protein, which is

recent memory

normally inserted into neuronal membranes with

Progressive decline in Loss of judgment

a β-amyloid fragment of 40 to 42 amino acids

executive functioning

located outside the cell. In AD the β-amyloid frag-

Normal speech and

Behavioral changes with

ment is abnormally cleaved, producing a β-amyloid

gait

marked mood swings

peptide that is poorly catabolized, accumulates

and depression

locally, and is toxic to neurons.

Mild to moderate

Global dementia including

The most potent risk factor for developing AD

frontal-temporal

apraxias and severe

brain atrophy on

memory loss

is the presence of the apolipoprotein (apo) E4

neuroimaging

allele. Of the three forms, E2, E3, and E4, only E4

increases the likelihood of AD. The lifetime risk for

Normal Cerebrospinal Terminal apathy and

fluid

withdrawal from social

individuals carrying an E4 allele is 29% compared

situations, leading to

with 9% for individuals carrying the other alleles.

virtual mutism

How the E4 protein increases the risk is unclear.

Marked brain atrophy on

Other risk factors for developing AD are increasing

neuroimaging with

age, head trauma, low folate and vitamin B₁₂ levels,

hydrocephalus ex vacuo

and elevated homocysteine levels. Some risk fac-

tors such as fewer years of formal education, low

income, and lower occupational status appear to

work by decreasing the amount of “cognitive

yet cannot discuss current events. As the disease

reserve” the patient can lose before dementia

progresses, patients lose the ability to recognize

becomes evident.

close friends, carry out meaningful conversations,

and keep track of time and place.

Nearly 10% of AD occurs in association with

Major Clinical Features

vascular dementia. Vascular dementia is character-

Table 11-5 lists common early and late clinical fea-

ized pathologically by widespread white matter

tures of AD. Patients usually are apathetic and have

changes presumably from ischemic brain injury,

impairment of recent memory and some preserva-

and multiple infarcts. Clinically, vascular dementia

tion of remote recall memory. Patients lose the

is identified by a tendency for a stepwise progres-

ability to perform previously learned complex

sion of dementia.

tasks such as balancing a checkbook, handling

The clinical or presumptive diagnosis of AD is

money, and reading street maps. They also lose the

based on an insidiously progressive decline in

ability to reason, plan activities, hold complex con-

intellect, especially recent memory and executive

versations, and play games such as bridge or chess.

functioning, beginning after age 50 years. This

Except in the very early stage, patients lose insight

progresses over several years to a global dementia,

into their cognitive problems and deny or ignore

including loss of insight and judgment as well as

their presence. Thus patients may get lost driving

behavioral changes. No other medical causes of

their car or walking about in their own town.

dementia should be present.

Some patients experience unexpected periods of

agitation, anger, and abnormal sexual activity. As

Major Laboratory Findings

the disease progresses, apraxias become more evi-

dent with the inability to dress, prepare a meal, or

No laboratory test establishes the diagnosis of AD.

groom. Meals are often forgotten and patients may

A definite diagnosis is based on characteristic neu-

become malnourished. Surprisingly, language

ritic plaques and neurofibrillary tangles seen on

function is maintained until late, so patients often

brain biopsy or autopsy. Routine blood and CSF

can carry out simple “cocktail party” conversations

tests are normal. Neuroimaging usually demon-

120

FUNDAMENTALS OF NEUROLOGIC DISEASE

Figure 11-5

Schematic brain of patient with Alzheimer’s disease showing locations of neuritic plaques and neu-

rofibrillary tangles.

strates symmetrical brain atrophy that is out of pro-

ers (shopping, bill paying, and keeping doctor’s

portion for age, with an accompanying hydro-

appointments). Sudden worsening of confusion

cephalous ex vacuo of the third and lateral

occurs when the patient is moved to new sur-

ventricles. An EEG shows a diffuse slowing of back-

roundings such as a hospital or nursing home. The

ground activity that is nonspecific. PET/SPECT

family caregiver is at risk of becoming exhausted,

scans demonstrate hypometabolism and reduced

depressed, and feeling guilty as the disease relent-

blood flow to the temporal and parietal lobes.

lessly worsens. Use of other family members or

professional attendants to allow caregivers time for

themselves, or even brief respites where the patient

Principles of Management and Prognosis

is placed in a nursing home setting, may be

There is no method to stop or reverse the progres-

needed. It is strongly recommended that the

sion of AD. However, cholinesterase inhibitors

spouse have scheduled time away and respite care.

produce modest transient improvements in mem-

The duration of AD, once diagnosed, is about 3

ory and cognition and may reduce behavioral out-

to 5 years and death usually comes from pneumo-

bursts. Low doses of psychoactive medications

nia and other systemic illnesses.

may be required to treat patients who have fre-

quent outbursts of anger or agitation. Studies are

underway to determine if reducing amyloid pro-

Mental Retardation

duction and aggregation or enhancing amyloid

removal may offer clinical benefit.

Mental retardation is a disability characterized by

The heart of management lies in a quality care-

significant limitations both in intellectual func-

giver. Family caregivers provide most of the daily

tioning and in adaptive behavior as expressed in

care, which can be a 24-hour-a-day undertaking

conceptual, social, and practical adaptive skills.

since patients require almost constant supervision.

The disability usually begins in early life and

Ideally, patients should be able to safely wander

before age 18. This definition must be considered

without becoming lost, have meals provided and

within the context of community environments

supervised, and have domestic needs done by oth-

typical of the individual’s age peers and culture as

CHAPTER 11—Disorders of Higher Cortical Function

121

Table 11-6

Major Risk Factors for Mental Retardation

Time

Period

Biomedical

Social

Behavioral

Educational

Prenatal

Chromosomal disorders Maternal malnutrition

Maternal drug use

Parental cognitive

Single-gene disorders

No access to prenatal

Maternal alcohol use

disability without

Metabolic disorders

care

supports

Cerebral dysgenesis

Maternal age and illness

Perinatal

Prematurity

Lack of access to

Parental rejection

Lack of medical

Birth injury

birth care

of child or

services

Neonatal disorders

caretaking

Postnatal Traumatic brain injury

Impaired child caregiver Child abuse

Delay in medical care

Malnutrition

Lack of infant stimulation Inadequate safety

or diagnosis

Meningitis

Placement in institution

measures

Inadequate education

Degenerative disorders

Social deprivation

services

Impaired parenting

well as disabilities in communication, sensorimo-

natal birth injury) and do not progress as the child

tor function, and behavior. Disability is the expres-

grows. However, the manifestations of the mental

sion of limitations in individual function in a

retardation may evolve as the child fails to gain

social context and represents a substantial disad-

expected childhood developmental skills. Appro-

vantage to the individual.

Limitation in adaptive behavior affects both

daily life and the ability to respond to life changes

Table 11-7

Common Causes of

and environmental demands. Examples of concep-

Mental Retardation

tual adaptive skills include language, reading,

Prenatal

money concepts, and self-direction. Examples of

social adaptive skills include interpersonal con-

Fetal alcohol syndrome

duct, responsibility, self-esteem, gullibility, naiveté,

Down’s syndrome

and following rules and laws. Examples of practi-

Fragile-X syndrome

cal adaptive skills include activities of daily living

Cerebral dysgenesis

(eating, dressing, and toileting), functional aspects

Autism (not all cases)

of daily life (transportation, housekeeping, money

Perinatal

management, and taking medication) and occupa-

tional skills.

Birth injury

Mental retardation is often classified with

Marked prematurity and very low birth weight,

respect to severity. Mental retardation that is mild

especially with periventricular hemorrhage

presents with an IQ between 50 and 70; moderate

Infant illnesses such as severe sepsis, bacterial

is between 35 and 49, severe between 20 and 34,

meningitis, and undiagnosed hypothyroidism

and profound below 20.

Postnatal

Mental retardation may occur from a wide vari-

Head trauma from child abuse (shaken baby

ety of biomedical, social, behavioral, and educa-

syndrome), sports injury, or automobile accident

tion problems that occur in the prenatal, perinatal,

Severe malnutrition such as marasmus or

or postnatal periods. Table 11-6 lists risk factors

kwashiorkor

for each time period. Table 11-7 lists the major

Toxic metabolic disorders such as lead intoxication

causes of mental retardation. It is important to

Severe epilepsy

understand that some causes of mental retardation

Childhood degenerative diseases

are due to progressive degenerative illnesses result-

Infections such as bacterial meningitis, whooping

ing in steady worsening of the IQ and mental

cough, and encephalitis

retardation. Other causes are static (such as peri-

122

FUNDAMENTALS OF NEUROLOGIC DISEASE

priate treatment of the child with mental retarda-

Cummings JL, Cole G. Alzheimer’s disease. JAMA

tion requires establishing the etiology and treating

2002;287;2335-2338. (Current review of patho-

the cause, if possible, as well as maximizing the

physiology and treatment.)

personal support the child requires. Mental retar-

Luckasson R, Borthwick-Duffy S, Buntinx WHE,

dation is often accompanied by physical disabili-

et al. Mental Retardation: Definition, Classifica-

ties that also require skilled attention. In children

tion, and Systems of Support, 10th ed. Washing-

with static mental retardation the IQ may not

ton DC: American Association of Mental

improve over time, but the function in adaptive

Retardation; 2002. (Current overview of mental

skills can and this would be significant in the indi-

retardation and available support systems.)

vidual’s quality of life.

Petersen RC. Aging, mild cognitive impairment,

and Alzheimer’s disease. Neurol Clin 2000;18:

789-805. (Nice review of mild cognitive impair-

RECOMMENDED READING

ment and the workup of patients with suspected

dementia.)

Albert ML, Knoefel JE, eds. Clinical Neurology of

Aging. New York: Oxford University Press; 1994.

(Covers many neurologic aspects of normal aging.)

DISORDERS OF THE

EXTRAPYRAMIDAL SYSTEM

movement disorder while diseases that express

Overview

chorea, tremor, myoclonus, and tics represent

hyperkinetic movement disorders. Below are

The pyramidal system is the motor/premotor cor-

common types of dyskinesias seen in many

tex and corticospinal tract that governs voluntary

patients.

movements. The extrapyramidal system refers to

several systems whose neurons are largely located

in the basal ganglia that oversee nonvoluntary,

Chorea

competing aspects of the motor system. Thus one

Choreas are sudden, brief, nonrepetitive, nonperi-

can conceptualize the basal ganglia and substantia

odic, involuntary jerking movements involving

nigra as being organized to facilitate voluntary

shifting muscles or muscle groups of the arms,

movements and to inhibit competing movements

hands, legs, tongue, or trunk that cannot be volun-

that interfere with the desired movement. This is

tarily suppressed.

accomplished by enabling the brain to produce

the desired motor pattern while creating a sur-

Dystonia

round inhibition of competing motor movements

(Figure 12-1). Constant loss of surround inhibi-

Dystonias are strong, sustained, and slow contrac-

tion would result in hypokinetic movements

tions of muscle groups that cause twisting of a

while intermittent or fluctuating changes of sur-

limb or the entire body. The contractions are often

round inhibition could result in abnormal hyper-

painful and may appear disfiguring. The dystonia

kinetic movements.

lasts many seconds to minutes and occasionally

Extrapyramidal disorders refer to movement

hours, producing a dystonic posture.

disorders that result from damage or presumed

dysfunction of the basal ganglia and their brain-

Athetosis

stem and cerebellar connections. Movement dis-

orders are characterized by either excessive

Athetosis consists of sinuous, writhing, alternating

(hyperkinetic) or reduced (bradykinetic) activity.

contractions of the arms or legs that can blend

Parkinson’s disease is the classic hypokinetic

with dystonia and chorea.

123

124

FUNDAMENTALS OF NEUROLOGIC DISEASE

Inhibitory Neuron

Excitatory Neuron

Motor

Cortex

Thalamus

Putamen

Globus

Pallidus

Subthalamic

Nucleus

Substantia

Nigra

Normal

Untreated Parkinson's Disease

Figure 12-1

Parkinson’s disease pathology.

Ballismus

fee. Current evidence suggests that all tremors come

from alterations in a complex central oscillatory

Ballismus comprises uncontrollable, often vigor-

cycle that involves neurons in the basal ganglia,

ous, flinging movements of an entire limb that are

brainstem, and sometimes the cerebellum. Tremors

often due to a lesion in the subthalamic nucleus.

are classified both by frequency of oscillation (low:

<4 Hz; medium: 4 to 7 Hz; high: >7 Hz) and when

Tics

the tremor occurs (Table 12-1). Tremors involving

distal limbs (hands) are usually medium to high fre-

Tics are abrupt, brief, repetitive, stereotypical

quency while tremors involving proximal limbs

movements of the face, tongue, and limbs or vocal-

(upper arms) are usually low frequency.

izations that may be briefly voluntarily suppressed

but are often then followed by a burst of tics when

the suppression is removed.

Essential Tremor

Myoclonus

Introduction

In myoclonus, the patient experiences rapid, brief

The most common nonphysiologic tremor is

muscle jerks involving specific muscles or the

essential tremor. It is 10 times more prevalent than

entire body that do not blend together and are of

the tremor of Parkinson’s disease. About 5 million

shorter duration than chorea. Nocturnal myoclonus

Americans have essential tremor, which affects

is comprised of the normal abrupt body jerks that

both sexes equally and begins around age 45 years.

occur while an individual is falling asleep. The

By age 65 years, the prevalence is 2% to 5%. Only a

EEG may or may not have spikes correlating with

small percentage of patients with essential tremor

the myoclonus.

seek medical attention. If the patient is under age

40 years, other causes of tremor should be consid-

ered, such as Wilson’s disease and hyperthyroidism.

Tremor

A tremor is an oscillatory movement of a limb or

Pathophysiology

the head or face. All humans have physiologic

tremor or small rhythmic oscillations of their hands

In 60% of cases, there is a positive family history.

that amplify with anxiety or stimulants such as cof-

Genetic studies have identified several genes suggest-

CHAPTER 12—Disorders of the Extrapyramidal System

125

Table 12-1

Tremor Type by Clinical Presentation

Tremor Type

(Other Common Names)

Characteristics (Examples)

Rest Tremor

Present involuntarily at rest when body part is supported against gravity

and muscles are not purposefully contracting (Parkinson’s disease

tremor)

Action Tremor (Postural Tremor,

Present when voluntarily maintaining a limb still against gravity, such as

Static Tremor)

holding arms outstretched.

Usually bilateral but may be asymmetric

Low-to-medium amplitude and medium-to-high frequency

Present during some voluntary movements such as writing or pouring,

but does not interfere with general coordination (essential tremor,

physiologic tremor)

Intention Tremor (Kinetic Tremor,

Present during voluntary movement and often perpendicular to direction

Cerebellar Tremor)

of movement

Medium amplitude and low frequency

Often amplifies when limb approaches the target

Interferes with coordination (cerebellar-type tremor as seen in

finger-to-nose movements)

ing that multiple etiologies may account for essential

Several drugs that may worsen essential tremor

tremor. At present, the actual pathophysiology of

or exaggerate a physiologic tremor include

how sporadic or genetic cases develop the tremor is

lithium, levothyroxine, β-adrenergic bronchodila-

unknown, as structural lesions have not been recog-

tors, valproate, prednisone, caffeine, and selective

nized. PET studies have shown increased blood-flow

serotonin-reuptake inhibitors (SSRIs).

activity in the cerebellum, red nucleus, and inferior

olivary nucleus, implying that the oscillatory cir-

Major Laboratory Findings

cuitry involves those nuclei. There is debate as to

whether essential tremor represents a pathologic

No laboratory test is diagnostic; diagnosis rests on

exaggeration of a normal physiologic tremor.

the history and exam. Routine blood tests are nor-

mal and neuroimaging of the spinal cord and

brain are normal.

Major Clinical Features

The characteristic history is one of slowly progres-

Principles of Management and Prognosis

sive or stable bilateral tremors of the hands that

began about age

45 years. The tremor is of

Patients with mild symptoms usually do not

medium to high frequency, of fine amplitude, sus-

require treatment once they are reassured that

tained, present immediately with arms out-

they do not have Parkinson’s disease and that the

stretched (action tremor), and absent at rest. The

tremor rarely becomes incapacitating. Many

tremor seldom interferes with activities of daily

patients find that a small amount of alcohol

living, but patients often complain of problems in

(glass of wine or beer) suppresses the tremor for

writing or spilling when drinking their coffee.

hours and is useful when entertaining friends.

Occasionally the tremor also may involve the head,

For patients with severe essential tremor or

legs, or voice. Patients relate that the tremor wors-

whose occupation is impaired by the tremor,

ens with anxiety, coffee, and some medications but

propanolol and primidone have been successful

diminishes when drinking alcohol. Weakness, sen-

in reducing the tremor severity. In rare cases of

sory loss, or changes in deep tendon reflexes do

severe tremor, surgical implantation of electrical

not occur with the tremor. Patients should not

stimulators in the thalamus or stereotactic thala-

have features of Parkinson’s disease.

motomy may be indicated.

126

FUNDAMENTALS OF NEUROLOGIC DISEASE

Parkinson’s disease

Grossly, there is loss of pigmentation in the

substantia nigra and other dopaminergic nuclei

Introduction

such as the locus ceruleus (Figure 12-2). Micro-

scopically, there is loss of small pigmented neurons

Parkinson’s disease affects more than 1 million

in the substantia nigra and eosinophilic, cytoplas-

Americans and has a prevalence rate of 1% in indi-

mic inclusion bodies surrounded by a clear halo

viduals over age 55 years. The direct annual cost in

(Lewy bodies) in remaining neurons, which con-

the United States is over $10 million. Both sexes

tain aggregations of neurofilaments and α-synu-

are equally involved, and the incidence climbs

clein protein attached to ubiquitin.

exponentially with increasing age to 7% above age

Substantia nigra dopaminergic neurons project

70 years. Idiopathic Parkinson’s disease usually

to the ipsilateral striatum (caudate nucleus and

begins above age 55, while patients with genetic

putamen). Dopamine release from substantia

causes of Parkinson’s disease starting as early as

nigra neurons stimulates D1 receptors and inhibits

age 30 to 45 years. Parkinson’s disease has a dra-

D2 receptors, resulting in the striatum sending

matic impact on quality of life and produces a

impulses to the motor cortex (called the basal gan-

marked reduction in life expectancy.

glia-thalamocortical motor circuit) in a direct

The hallmarks of Parkinson’s disease and

excitatory pathway via thalamic nuclei. Concomi-

parkinsonism are bradykinesia (diminished speed

tant inhibitory impulses to the motor cortex in a

and spontaneity of voluntary movements), resting

polysynaptic indirect pathway via globus pallidus

tremor, cogwheel rigidity, gait changes, and late

externa, subthalamic nucleus, and thalamic nuclei

postural instability, all due to reduced levels of

are also sent. Loss of dopaminergic nigral cells

dopaminergic transmission from structural or

leads to striatal dopamine depletion and overall

functional disruption of nigrostriatal pathways.

decreased motor cortex excitation. The loss of

Parkinson’s disease refers to the primary idio-

excitatory stimulation decreases excitatory activity

pathic form and represents 2/3 of all parkinson-

of the direct pathway to the motor cortex and

ism. Parkinsonism is the secondary form and

increases inhibitory activity of the indirect path-

refers to the above clinical and biochemical fea-

way to the motor cortex. Not yet completely

tures that develop from specific causes such as

understood, the increased inhibitory input to the

repeated head trauma (boxing), infections of the

motor cortex causes bradykinesia.

upper midbrain, medications that affect dopamine

Using the surround inhibition model of the

transmission, or CNS diseases that damage the

nigrostriatal pathway and other brain areas.

basal ganglia, the loss of substantia nigra input to

the striatum would cause loss of inhibition of com-

peting motor movements (Figure 12-1). For exam-

Pathophysiology

ple, when a normal individual flexes an arm, the

Idiopathic Parkinson’s disease results from the

bicep fires (desired movement) and the tricep is

slowly progressive death of CNS dopaminergic

inhibited (surround inhibition). In the patient with

neurons and some adrenergic and serotonergic

Parkinson’s disease, flexion of the arm fires both

neurons. Death of the melanin-containing pig-

the bicep (desired movement) and tricep (loss of

mented dopaminergic neurons in the pars com-

surround inhibition), resulting in bradykinesia.

pacta of the substantia nigra is responsible for the

The tremor of Parkinson’s disease is felt to be sec-

motor signs of this disease. Evidence suggests that

ondary to interruption of the CNS oscillatory

the death of dopaminergic neurons begins a

pathway in the globus pallidus and thalamus.

decade before symptom onset. When the neuronal

Five percent of Parkinson’s disease is due to

loss reaches about 70% of total neurons, symp-

autosomal dominant mutation in the parkin gene

toms begin. The cause of dopaminergic neuronal

and occasionally in the α-synuclein gene. The role

death is unknown, but current theories include

of α-synuclein in the pathogenesis of Parkinson’s

exposure to environment neurotoxins, abnormal

disease is receiving attention since α-synuclein is

mitochondrial function, abnormal oxidative

normally abundant in neurons and presynaptic

metabolism, and generation of misfolded α-synu-

terminals, as well as in Lewy bodies. The parkin

clein protein, which is toxic.

gene product appears to be involved in identifying

CHAPTER 12—Disorders of the Extrapyramidal System

127

Figure 12-2

Gross brain specimen in patient with Parkinson’s disease, showing loss of pigmentation in the sub-

stantia nigra (arrows) and locus ceruleus.

proteins such as α-synuclein for degradation via

patients spend enormous amounts of energy per-

the ubiquitin pathway.

forming routine activities of daily living.

In a simplistic fashion, everything “slows down”

in the patient with Parkinson’s disease. Limb and

Major Clinical Features

chewing movements are slow; gait is slow, shuf-

The diagnosis of Parkinson’s disease is usually

fling, difficult to initiate, and often with a stooped

made by the presence of asymmetrical bradykine-

posture; standing balance is impaired from slow

sia, cogwheel rigidity, resting tremor, and good

corrective steps to maintain balance, so falling is

response to levodopa. Rigidity consists of a con-

common; spontaneous facial expression is mini-

stant resistance to passive muscle stretching in

mal (masked facies); gut peristalsis is slow so con-

both flexors and extensors throughout range of

stipation is common; and mental activities are

motion due to stretching force induction of some

slower than normal so there are both less sponta-

antagonistic motor units to fire. In Parkinson’s dis-

neous speech and delayed answers to questions

ease, rapid flexion and extension or rotation of the

spoken in a soft, dysarthric voice. In 40% a demen-

wrist or elbow often elicits a ratchetlike feeling

tia develops in the later disease stages.

(cogwheel rigidity).

Table 12-2 lists the common clinical features of

Major Laboratory Findings

Parkinson’s disease in the early, middle, and

advanced stages. The disabling feature is bradyki-

Routine blood and CSF studies are normal. Neu-

nesia. One patient described early bradykinesia as

roimaging is seldom helpful in diagnosing Parkin-

walking in a swimming pool with water up to the

son’s disease or distinguishing it from other causes

neck and advanced bradykinesia as walking in a

of parkinsonism. In Parkinson’s disease, PET stud-

swimming pool filled with molasses. Thus,

ies with radioactive fluorodopa demonstrate

128

FUNDAMENTALS OF NEUROLOGIC DISEASE

Table 12-2

Clinical Features of Parkinson’s disease

Disease

Clinical Feature

Description

Stage

Bradykinesia

Paucity or slowness in movements

E, I, L

Cogwheel Rigidity

Ratchet sensation upon moving elbow or wrist

E, I, L

Resting Tremor

“Pill-rolling” tremor of hands; often asymmetrical

E, I, L

Masked Facies

Diminished spontaneous facial expressions

E, I, L

Gait Difficulties

Start hesitancy, shuffling short steps, stooped posture, and trouble

I, L

stopping and turning

Hypokinetic Dysarthria

Low volume, monotone, and garbled speech without aphasia

I, L

Balance Problems

Tendency to fall while walking or standing, especially with eyes closed

I, L

Constipation

Slow peristalsis made worse from some drugs

I, L

Orthostatic Hypotension

Fall in blood pressure upon arising that causes dizziness and syncope

Sleep Disturbances

Insomnia, restless legs, and daytime drowsiness

I, L

Cognitive Disorders

Hallucinations, depression, and dementia in 40%

I, L

Decreased Arm Swing

Lack of associated arm swing on walking; often asymmetrical

E, I, L

* Stages: E = early (1 to 5 years after diagnosis), I = intermediate (5 to 10 years), L = late (>10 years)

reduced uptake greater in the putamen than in the

dopamine at the distant presynaptic nerve termi-

caudate.

nal, where it is taken up and stored by the nerve ter-

minal. Dopamine agonists, such as bromocriptine

and pramipexole, cross the blood-brain barrier to

Principles of Management and Prognosis

act directly upon D1 or D2 postsynaptic terminals

Since no treatments can halt disease progression of

in the striatum (Figure 12-3).

Parkinson’s disease, management aims at mini-

Levodopa is the most potent of all drugs and is

mizing the symptoms and maximizing patient

particularly helpful in reducing bradykinesia.

functioning and safety. Presently there is contro-

Controversy exists as to whether its early usage

versy whether drugs such as monoamine oxidase

may accelerate the time to developing levodopa

inhibitors (e.g., selegiline) can slow the rate of

complications, but the weight of evidence suggests

early disease progression.

the neurotoxic effect is minimal, if any.

The mainstay of early treatment is providing

In early Parkinson’s disease, complete relief of

additional dopamine or dopamine agonists to the

the bradykinesia is achieved with levodopa and

striatum. Dopamine cannot cross the blood-brain

carbidopa in low doses three times a day (tid) or

barrier and causes considerable systemic nausea

from a slow release formulation given once (qd) to

and hypotension by stimulating peripheral

twice (bid) daily. Anticholinergic drugs may help

dopamine pathways. Levodopa was found to cross

the tremor but have considerable side effects in the

the blood-brain barrier and to be converted in the

elderly, including constipation, urinary retention,

brain to dopamine by the enzyme dopa-decarboxy-

confusion, memory loss, and hallucinations.

lase. To minimize systemic conversion of levodopa

After 5 years’ duration, it becomes increasingly

to dopamine, the DOPA-decarboxylase inhibitor

difficult to achieve and maintain ideal CNS levels of

carbidopa is added to levodopa. Carbidopa does

dopamine. Patients often develop dyskinesias or

not cross the blood-brain barrier, so CNS conver-

“on” phenomena 1 to 2 hours after taking levodopa

sion of levodopa is unaffected. Levodopa is con-

medication; this is felt to represent excessively ele-

verted to dopamine within the dopamine neuron

vated CNS drug levels, which stimulate nonessen-

cell body and transported via axoplasmic flow to

tial dopamine pathways. Patients experience

the nerve terminal. Levodopa is also converted to

involuntary movements of their arms, legs, and

CHAPTER 12—Disorders of the Extrapyramidal System

129

Figure 12-3

Dopaminergic therapy for Parkinson’s disease.

face in an irregular fashion during a time when

if done bilaterally. Deep-brain stimulation uses

their bradykinesia is minimal. The levodopa level

electrodes placed stereotactically in the globus pal-

then rapidly falls below optimal CNS levels, pro-

lidus interna or subthalamic nucleus to enable

ducing freezing spells or “off ” periods where the

high-frequency stimulation of specific brain

patient can hardly move. It is felt that “on-off ” phe-

regions. Deep-brain stimulation is reversible but

nomena represent disease-related loss of dopamine

carries the infectious risk of long-term implanta-

buffering capacity and storage capacity by striatal

tion of foreign material in the brain. Both tech-

dopamine nerve terminals. It is common for

niques are more effective for tremor rather than

patients to experience hallucinations that are often

bradykinesia, do not completely relieve symptoms,

visual, occur in the evening, and may or may not be

and require continued use of some antiparkinson-

frightening to the patient. About 40% of patients

ism medications. At present, the achieved response

also develop dementia that may be from dementia

from deep-brain stimulation is similar to the best

with Lewy bodies or the coexistence of two com-

clinical improvement of the patient on an optimal

mon diseases of the elderly, Alzheimer’s disease and

dosage of levodopa but without accompanying

Parkinson’s disease. Dopamine agonists are often

dyskinesias.

given to smooth out the “on-off ” phenomena in

The goal of transplantation is to replace neu-

the intermediate stage. Unfortunately in the

ronal circuitry lost by the death of substantia nigra

advanced stage, dopamine agonists are less success-

neurons with dopamine neurons from fetal mes-

ful and have a similar side effect profile.

encephalon or adult adrenal medulla. Studies of

To treat the advanced stage of Parkinson’s dis-

patients receiving transplantation of fetal mesen-

ease, experimental surgical therapies are being

cephalon into the striatum have demonstrated

explored using ablation, deep-brain stimulation, or

survival of the dopamine neurons and even the

transplantation. Ablative surgery

(thalamotomy,

formation of some synapses to striatal neurons.

pallidotomy, and subthalamic nucleotomy) use

However, clinical benefit to the patient has been

stereotactic approaches to lesion critical basal gan-

minimal presumably because the transplanted

glia regions in an attempt to restore more normal

dopamine neurons do not spontaneously fire and

circuitry. Ablative therapy is irreversible, carries

release dopamine into synapses to stimulate the

surgical risks, and has considerable complications

striatal neurons.

130

FUNDAMENTALS OF NEUROLOGIC DISEASE

Education of both the patient and family about

with repeat lengths of greater than 50 to 60 units

Parkinson’s disease is important, as this is a slowly

develop juvenile HD with onset before age 20

progressive illness. Patients should be taught to

years. Men with HD often have sperm containing

avoid sofalike seats since arising from a chair is

an HD gene with many more CAG repeats than in

easier; to use bars in the bathroom to minimize

their own somatic cell HD gene. Thus the next

falls; and eventually to use walkers to improve bal-

generation displays the phenomenon of increasing

ance while walking. A hip fracture in a patient with

trinucleotide repeat length and gives rise to antici-

Parkinson’s disease is serious. There is a slow

pation, where the disease develops at an earlier age.

recovery and a 25% mortality risk.

Huntingtin protein is a large protein (>3,000

amino acids) that is expressed widely in neural and

nonneural tissues and whose normal function is

Huntington’s Disease

currently unknown. The amino acid sequence is

not related to other proteins, but shows a high

Introduction

degree of evolutionary conservation. Studies in

animals and man show the gene is essential in fetal

Huntington’s disease (HD) is an autosomal dom-

development as loss of both gene copies leads to

inant neurodegenerative disease characterized by

fetal death. However, fetuses containing HD pro-

progressive chorea, cognitive decline, and behav-

tein molecules with abnormal polyglutamine

ioral disturbances that usually begin in mid-life.

length have normal fetal and childhood develop-

The original description came from Dr. George

ment. Thus current evidence suggests the patho-

Huntington, a family physician, who in

1872

genesis of HD is mediated by a “gain of function”

accurately described the clinical and genetic fea-

of the Huntingtin protein. In this construct, the

tures of HD from his observations of three gener-

normal Huntingtin protein functions remain

ations of illness in a family living on Long Island,

New York.

intact, but a new function is detrimental to the

HD is found around the world, with the highest

neuron. In the end, the abnormal Huntingtin pro-

prevalence (5/100,000) in populations of western

tein somehow causes premature death of selected

European ancestry. In the United States, about

neuronal populations.

25,000 individuals have HD and another 60,000

The striking pathology in HD is atrophy of the

carry the abnormal gene but are too young to

caudate nucleus and putamen (together called the

express the disease. As an autosomal-dominant

striatum). This is easily visible on gross inspection

disorder, men and women are equally affected, and

of the brain (Figure 12-4) and can be seen on neu-

there is a high degree of penetrance in individuals

roimaging. The neuronal cell loss is primarily from

who live to middle age. Women who carry the

death of medium-sized spiny neurons, which

abnormal gene may give birth to affected offspring

account for 80% of striatal neurons. There is a rel-

before manifesting any signs of the disease.

ative preservation of large spiny neurons. Micro-

scopically, intranuclear inclusions that contain

fragments of Huntingtin protein are commonly

Pathophysiology

seen in the striatum and there is a secondary glio-

All cases of HD develop from an abnormal

sis that accompanies the neuronal loss. Medium

extended length of CAG triplet repeats in the HD

spiny neurons are inhibitory, releasing GABA as

gene. The normal length of the trinucleotide

their main neurotransmitter. Medium spiny neu-

repeats is polymorphic and ranges from 10 to 26

rons that have D2 receptors and project to the

units, producing a string of 10 to 26 polyglutamine

globus pallidus externa die earlier than those with

amino acids in the normal Huntingtin protein.

D1 receptors that project to the substantia nigra

The length of the CAG trinucleotide repeats is not

and globus pallidus interna. This unequal pattern

constant, and healthy offspring normally gain or

of neuronal death is thought to be responsible for

lose up to 6 repeats. However, CAG repeat lengths

adult HD patients experiencing chorea rather than

longer than 39 units give rise to HD. There is an

parkinsonism. In juvenile HD, both neuronal pop-

inverse correlation between the length of the CAG

ulations die early, and these patients express more

repeats and the age of disease onset. Individuals

signs of parkinsonism. PET studies demonstrate

CHAPTER 12—Disorders of the Extrapyramidal System

131

Figure 12-4

Pathology of caudate atrophy in a patient with Huntington’s disease.

that hypometabolism in the striatum begins prior

rating the involuntary jerk into a semipurposeful

to observable atrophy and before the onset of clin-

movement. Voluntary rapid eye movements from

ical symptoms. In addition to striatal neuronal

one target to another (saccadic eye movements)

loss, there is a moderate loss (10%-50%) of neu-

become slowed and uncoordinated. The inability

rons in many basal ganglia nuclei and the pre-

to sustain a constant voluntary muscle contraction

frontal cerebral cortex.

manifests as trouble extending their tongues for

any period of time and maintaining a tight hand-

shake (milkmaid’s grip). In the early stage of the

Major Clinical Features

disease, patients often have normal activities of

The mean age of onset of HD is 40 years but some

daily living and may continue to be employed. As

patients do not develop signs until past age 60

the disease worsens, dystonia and parkinsonism

years. The clinical features are progressive disor-

appears. Dysarthria develops, with hypophonic

ders of movement, cognition, and behavior. Sud-

irregular speech that becomes unintelligible. At

den nonrepetitive, nonperiodic, involuntary

this stage the patient depends on others for help.

jerking movements involving random shifting

Dysphagia appears late and often contributes to

muscles or muscle groups characterize chorea, the

the death of the patient.

principle movement disorder. Chorea soon

A global decline in cognitive capabilities begins

becomes very frequent during waking hours,

before or after the onset of chorea; only a few

involving the arms, hands, legs, tongue, or trunk.

patients develop mild cognitive loss. The cognitive

These movements can be voluntarily suppressed

decline is characterized by loss of executive func-

only briefly and are made worse by stress. Early in

tions, with the inability to plan, sequence, and exe-

the disease, patients frequently appear fidgety and

cute complex tasks; forgetfulness from loss of

mask the involuntary limb movement by incorpo-

recent memory; slow response times; and poor

132

FUNDAMENTALS OF NEUROLOGIC DISEASE

concentration. IQ score falls and dementia is pres-

risk for the illness, and prenatal screening. For pre-

ent in most patients. Aphasia, apraxia, and agnosia

dictive testing to be performed, there should be (1)

are uncommon, but impaired visuospatial abilities

multidisciplinary supportive counseling before

develop in the late stage.

and after testing, (2) clear informed consent, and

Behavioral problems often begin with personal-

(3) confidential reporting. In general, predictive

ity changes manifesting as irritability, compulsiv-

tests should not be done on minors. Although the

ity, apathy, and anxiety that may appear years

number of CAG repeats is correlated with age of

before the chorea. Depression develops in 1/3 of

disease onset, the range of onset for each CAG

patients and may lead to suicide. Psychosis is

length is so broad as not to be useful for individual

uncommon (5%).

tests and hence the length is seldom reported to

Juvenile HD has an onset of less than 20 years

the patient.

and is characterized by more prominent parkin-

sonism, especially bradykinesia. Patients have

Principles of Management and Prognosis

marked rigidity, severe mental deterioration,

prominent motor and cerebellar signs, dysarthria,

Since no treatment is available to cure or slow dis-

myoclonus, tics, and dysphagia. Juvenile HD pro-

ease progression, management aims at maximizing

gresses faster than adult HD.

the quality of life for as long as possible. Depres-

sion should be diagnosed early and actively treated

with antidepressants. Attempts to treat the chorea

Major Laboratory Findings

seldom are beneficial to the patient. Psychosis and

Routine blood and CSF tests are unremarkable.

severe agitation can be treated with low doses of

Neuroimaging studies demonstrate atrophy of the

neuroleptic medications. There is no treatment for

caudate and may show atrophy of the putamen.

the cognitive decline.

The progressive caudate atrophy parallels loss of

The mean duration from diagnosis to death is

cognitive function and putaminal atrophy with

20 years, with a range of 10 to 25 years. Mean age

motor decline. Neuropsychiatric tests demonstrate

of death is 55 years. Individuals with juvenile HD

many abnormalities, but none are diagnostic.

have a shorter life span.

The clinical diagnosis is usually made based on

(1) onset in mid-life with typical chorea, cognitive

loss, and behavioral changes, (2) positive family

RECOMMENDED READING

history, and (3) neuroimaging demonstrating cau-

date atrophy. The definite diagnosis is made by

Lang AE, Lozano AM. Parkinson’s disease (parts 1

demonstrating abnormally long CAG trinu-

and 2). N Engl J Med 1998;339:1044-1053 and

cleotide repeat lengths

(>40) in the HD gene

1130-1143. (Thorough review of clinical and

(chromosomal locus 4p16) on genetic testing. This

pathologic issues and treatment.)

commercial test is useful in establishing the diag-

Louis ED. Essential tremor. N Engl J Med

nosis in atypical cases, symptomatic individuals

2001;345:887-891.

(Reviews clinical features

without a positive family history, individuals at

and treatment options.)

CENTRAL NERVOUS

SYSTEM INFECTIONS

key element of the blood-brain barrier is tight

Overview

junctions between endothelial cells, which prevent

microorganisms or even small molecules from

Viruses, bacteria, fungi, and parasites cause CNS

passing between endothelial cells to enter the brain

infections, but bacteria and viruses are the most

or meninges. Endothelial cells in most of the body

common agents. After entering the body via the GI

tract or respiratory tract or following skin inocula-

have gap junctions that are large enough to allow

tion (animal or insect bite), the infectious organ-

lymphocytes to pass from blood vessels into the

ism sets up the initial site of replication in the GI

lymphatic system. Molecules that reach the brain

tract, respiratory tract, or subcutaneous muscle, or

do so by passing through normal cerebral

vascular tissue. Most organisms reach the CNS by

endothelial cells via specific transport systems that

way of the bloodstream, but occasional organisms

may require energy (amino acid transporters) or

reach the brain via peripheral nerves or by direct

not require energy

(glucose transporter), or

entry through adjacent bone from skull fractures

because the molecule is lipid soluble. In addition,

or infected mastoid and air sinuses.

CNS endothelial cells have transporters that

In spite of the many infections we develop dur-

remove molecules, such as amino acids that are

ing our lifetimes, organisms rarely reach the CNS.

neurotransmitters, from the CNS. Larger mole-

Important protective systems include the reticu-

cules enter the CSF from blood via the choroid

loendothelial system (which nonspecifically and

plexus, which acts as an ultrafilter of plasma.

efficiently removes microorganisms from the

When intact, the blood-brain barrier not only pre-

blood), cellular and humoral immune responses

vents entry of infectious organisms but also main-

(which destroy specific microorganisms in the

tains, under tight limits, the type and concentration

blood and at sites of infection), and the

of molecules free in the CNS.

blood-brain barrier. The CNS evolved separately

However, if an infectious organism successfully

from other systemic organs and did not develop a

enters the CNS, there are limited defenses to fight

sensitive immune surveillance system. The brain

the infection. CSF has 1/1,000 the amount of anti-

lacks lymphatic channels or lymph nodes. Instead,

bodies and complement as blood. Since the brain

a blood-brain barrier has developed to prevent

lacks a lymphatic system, there are few WBCs and

infectious organisms from entering the CNS. The

limited microglia (resident CNS macrophages) to

133

134

FUNDAMENTALS OF NEUROLOGIC DISEASE

detect and combat an infection. Nevertheless, the

most common CNS infections that develop at

CNS exhibits an inflammatory response, the hall-

these sites plus a rare infection that breaks conven-

mark of CNS infections. Neutrophils and mononu-

tional rules for infectious diseases.

clear cells from blood cross areas of activated

endothelial cells and open blood-brain barriers to

appear in the meninges, brain parenchyma, and

Bacterial Meningitis

perivascular spaces. The lymphocytes usually show

specific immune activity against the infectious

Introduction

agent. Unfortunately, the brain inflammatory

Meningitis is due to inflammation of the meninges

response is ineffective against bacteria and fungi

and is the most common CNS infection. This

and patients usually die unless treated with appro-

infection commonly is due to bacteria or viruses

priate antimicrobial drugs.

but can be caused by fungi, parasites, chemicals,

The signs and symptoms of a CNS infection

and neoplasms. Viral meningitis occurs mainly in

depend on the site of the infection and not the infec-

the spring and summer, while bacterial meningitis

tious organism. The organism determines the time

occurs year around. Bacterial meningitis has the

course and severity of the infection.

highest incidence in infants, the elderly, and the

Table 13-1 gives the keys to suspecting a CNS

immunosuppressed of any age.

infection. The patient’s signs and symptoms sug-

gest the likely location of the infection but not the

infectious organism. The time course of the infec-

Pathophysiology

tion may help determine the type of infectious

Aerobic bacteria, both gram-positive and gram-

organism. In general, viruses produce CNS signs in

negative, are the major causes of acute bacterial

hours to 1 day; aerobic bacteria in hours to a few

meningitis. Other bacteria such as Borrelia

days; anaerobic bacteria, tuberculosis, and fungi in

burgdorferi, Mycobacterium tuberculosis, and T.

days to weeks; and spirochetes such as Treponema

pallidum commonly cause chronic meningitis. The

pallidum (syphilis) in weeks to decades.

usual route of entry is via the upper respiratory

There are three major sites where infections

tract, where the bacteria establish an often-asymp-

occur in the CNS: diffusely in the meninges

tomatic infection. Special characteristics of the

(meningitis), diffusely in the brain (encephalitis),

bacterial strain allow it to invade though the respi-

and focally in the brain (abscess) (Figure 13-1).

ratory epithelial cells and reach capillaries, veins,

Table 13-2 lists the major signs and symptoms for

and lymphatic channels. In the bloodstream the

infections at these sites. Although there are many

characteristics of these bacteria

(such as large

different infectious organisms that can infect the

mucopolysaccharide coats) avoid the reticuloen-

meninges and brain, this chapter will discuss the

dothelial system, allowing them to replicate to high

titers. The exact location of penetration of the

blood-CSF barrier is unknown. Once within the

Table 13-1

Keys to Suspecting a

CSF, the bacteria again replicate and release endo-

toxin

(gram-negative bacteria) or teichoic acid

Central Nervous

(gram-positive bacteria) from their cell walls.

System Infection

These molecules stimulate resident macrophages

• Fever

and microglia to release cytokines

(especially

• Acute or subacute onset

interleukin-1

[IL-1] and tumor necrosis factor

[TNF]) that in turn recruit neutrophils and

• Headache

mononuclear cells into the CSF from the blood. In

• Focal or diffuse symptoms and signs dependent

bacterial meningitis, bacteria are confined in the

on location of infections (see Table 13-2)

meninges until just before the patient’s death.

• Elevated white blood cell count and erythrocyte

As the inflammation increases, however, the

sedimentation rate

brain does become irritated and damaged. Endo-

• Increased frequency in immunosuppressed

toxin released from the cell walls of dying bacte-

individuals

ria and molecules released from inflammatory

CHAPTER 13—Central Nervous System Infections

135

Encephalitis

Abcess

Dura

Arachnoid

Meningitis

Pia

Skull

Figure 13-1

Major sites of infection in the CNS.

cells (such as TNF and neutrophil granule mole-

passing in the meninges to reach the brain.

cules) can pass through the pial lining of the

Occlusion of these vessels leads to cerebral

brain to invade and kill neurons located in the

infarctions of the corresponding vascular terri-

surface of the cerebral cortex and cerebellum. In

tory. Thus while bacteria do not invade the

addition, the meningeal inflammation can cause

brain, severe brain damage can result from

vasospasm or thrombosis of arteries and veins

intense meningitis.

Table 13-2

Clinical Features of Major Central Nervous System Infections

Meningitis

Brain Abscess

Encephalitis

Common

Fever

Headache

Fever

Headache

Mental status changes:

Headaches, nausea, and vomiting

Stiff neck

confusion, stupor, and coma Mental status changes: confusion,

Confusion

Seizures: generalized or focal

delirium, stupor, or coma

CN VI palsy

Seizures: generalized or focal

Hemiparesis

Hyperreflexia, Babinski signs, or spasticity

Papilledema

Mild stiff neck

Less Common Seizures

Stiff neck

Tremors and dystonia

Stupor or coma

Papilledema

136

FUNDAMENTALS OF NEUROLOGIC DISEASE

Major Clinical Features

are elevated, and there are elevated numbers of

immature cells or a “shift to the left.” The blood

The clinical hallmark of any meningitis is fever,

erythrocyte sedimentation rate (ESR) and C- reac-

headache, stiff neck, and a relatively preserved

tive protein are also elevated.

mental status (Table 13-2). The headache comes

Neuroimaging does not diagnose bacterial

from inflammation, irritating pain fibers along the

meningitis. Cranial CT scans might be indicated

base of the brain and second and third spinal

before the LP if intracranial masses or acute

nerves. The fever may be due to direct irritation of

hydrocephalus are suspected (see section on CSF

the hypothalamus or CSF IL-1 released into the

in Chapter

“Common Neurologic Tests”).

CSF by the inflammatory cells. Patients with bac-

Enhancement of the meninges, especially in the

terial meningitis seldom present with focal neuro-

basal cistern area, is commonly seen with a

logic signs, but hemiparesis, aphasia, ataxia, and

gadolinium-enhanced MRI. If neurologic compli-

visual loss may develop later in the clinical course.

cations develop in the patient, neuroimaging may

Papilledema is rarely present at onset. Patients

demonstrate communicating or obstructive

with bacterial meningitis develop these symptoms

hydrocephalus, brain infarctions, or focal areas of

and signs within hours to 1 day.

brain necrosis across the cortical surface.

Major Laboratory Findings

Principles of Management and Prognosis

The definite diagnosis of meningitis and then bac-

terial meningitis is made from analysis of CSF.

The key to etiologic treatment is the prompt

When meningitis is suspected, the lumbar punc-

administration of appropriate antibiotics. Without

ture (LP) becomes an emergency procedure. Table

antibiotics, over 95% of patients die. General prin-

13-3 demonstrates the CSF findings in bacterial

ciples involved in the use of antibiotics are the fol-

meningitis and distinguishes them from other

lowing: (1) the antibiotic should be given as early

CNS infections. Figure 13-2 illustrates the com-

in the clinical course as possible; (2) the bacteria

mon bacteria that cause meningitis in the United

must be sensitive to the antibiotic administered;

States. In countries that do not give children the

and (3) the antibiotic must cross the blood-CSF

Haemophilus influenzae vaccine, H. influenzae

barrier and achieve sufficient concentration to kill

meningitis is the most common type for children

the bacteria. Once the clinical diagnosis of bacter-

younger than 5 years.

ial meningitis is made, immediate treatment with

Almost all patients have an elevated WBC

broad-spectrum antibiotics begins. Based on the

count that may be over 20,000/mm³. Neutrophils

patient’s age, predisposing medical condition,

Table 13-3

Cerebrospinal Fluid Findings in Major Central Nervous System

(CNS) Infections*

White

Bacterial

Opening

Blood Cells Predominate Protein Glucose or Fungal

Pressure

(WBCs)/mm³

WBC Type

(mg/dL)

(mg/dL) Culture

Meningitis

Viral

20-1,000

Mononuclear

Sl ↑

Normal

Negative

Bacterial

N or ↑

50-5,000

Neutrophils

↑

Low

Bacteria

Tuberculosis or fungal

↑

50-10,000

Neutrophils and

↑

Low

Sometimes

lymphocytes

positive

CNS syphilis

10-1,000

Lymphocytes

↑

Normal

Negative

Brain Abscess

↑

0-20

Lymphocytes

Normal Normal

Negative

Viral Encephalitis

Sl ↑

10-200

Lymphocytes

Sl ↑

Normal

Negative

* Exceptions to these rules often occur.

N = normal; Sl = slight; ↑ = increase.

CHAPTER 13—Central Nervous System Infections

137

Figure 13-2

Common bacteria that cause meningitis in the United States.

immune status, CSF Gram stain or bacterial anti-

Brain Abscess

gen tests, and knowledge of types of drug-resistant

bacteria in the community, antibiotics are chosen

Introduction

that likely will kill the CSF bacteria. When the bac-

A brain abscess is a localized mass infection within

terium is grown in the laboratory and antibacter-

the brain parenchyma. If the abscess develops out-

ial susceptibilities are determined, the antibiotic

side the brain and around the dura, it is called

regiment can be appropriately modified.

either a subdural empyema or epidural abscess.

The optimal initial antibiotics to be given con-

Brain abscesses most commonly occur from a bac-

stantly change; one should consult the latest

terial infection, but fungi, M. tuberculosis, and pro-

antibiotic recommendations. Currently, many

patients are initially treated with a third- or fourth-

tozoa can also cause the focal brain infection.

generation cephalosporin and vancomycin since

Brain abscesses are uncommon, with an incidence

the incidence of Streptococcus pneumoniae resist-

of about 1/100,000 persons per year, and develop

ance to third-generation cephalosporins is now

in both sexes and all ages.

>15% in most communities. In general, the antibi-

otics should be administered intravenously for 10

Pathophysiology

to 14 days. Early administration of corticosteroids

for 2 to 4 days has been shown to reduce the death

The brain has no normal flora of bacteria or fungi.

rate and long-term neurologic sequelae in children

Microorganisms that cause an abscess reach the

and adults.

brain primarily through the bloodstream or

Symptomatic treatment of seizures includes

directly from adjacent infected sinuses or mastoid

administration of phenytoin until the patient is

air cells. Less-common routes of entry include

discharged. If severe obstructive hydrocephalus

depressed skull fractures or following surgical pro-

develops, a ventriculoperitoneal shunt is required.

cedures involving the sinuses, calvarium, or brain.

Meningitis from Neisseria meningitidis and H.

Common sources of bloodstream infection

influenzae require chemoprophylaxis of immedi-

include infections of the lungs

(bronchiectasis,

ate family members and close contacts with

empyema, and lung abscess), GI tract, urinary sys-

rifampin or ciprofloxacin (adults only), as they are

tem, mouth (dental abscess), heart (acute bacterial

at increased risk of developing meningitis.

endocarditis and cyanotic congenital heart dis-

Mortality ranges from 5% to 25%, depending

ease), and intravenous drug abuse. In about 15%

on the infecting bacteria, age of patient, and pre-

of patients, no initial source for the brain abscess

disposing illnesses. In surviving children,

15%

can be identified.

have language disorders, 10% mental retardation,

The location of the abscess depends on the

10% hearing loss, 5% weakness or spasticity, and

source. Brain abscesses from sinusitis occur in the

3% epilepsy. Adults have a similar pattern.

frontal lobe adjacent to the infected sinus.

138

FUNDAMENTALS OF NEUROLOGIC DISEASE

Abscesses from mastoiditis develop in the tempo-

ing a larger mass. Without treatment, the expand-

ral lobe (from upward extension) or occasionally

ing abscess causes ruptures into the ventricle or

in the cerebellum (from medial extension). The

produces brain herniation.

locations of abscesses from a hematogenous route

are generally distributed proportional to cerebral

Major Laboratory Findings

blood flow. About 3/4 of brain abscesses are soli-

tary. Multiplicity of abscesses at different locations

The WBC count is elevated in 60%, of patients but

implies a hematogenous origin.

the total count is elevated above 20,000 cells/mm³

The brain abscess begins as a small area of brain

in only 10%. The ESR and serum C-reactive pro-

infection

(cerebritis), often located at the

tein are often elevated, indicating the presence of a

gray-white matter junction of the cerebral cortex.

systemic infection. In about 1/2 of patients, the

Growth of the organism soon results in expansion

primary source of the abscess can be identified.

of the cerebritis, with increasing numbers of neu-

Biopsy or aspiration material from the distant site

trophils and mononuclear cells entering the

can be studied in a manner similar to studying the

infected site. Necrosis with liquefaction of the cen-

abscess pus. The most important laboratory tests

ter of the abscess then occurs. A variable amount

involve the pus surgically removed from the

of surrounding cerebral edema contributes to the

abscess. The following tests should immediately be

mass of the abscess. A fibrotic and gliotic response

performed:

(1) stain of abscess material with

surrounds the abscess, forming a capsule, but the

Gram, Giemsa, and fungal stains, (2) culture of

capsule wall is inadequate to control medial

abscess material for anaerobic and aerobic bacteria

expansion of the abscess. If untreated, the abscess

and fungi, (3) culture of abscess material for M.

expansion continues until the mass is large enough

tuberculosis or protozoa if clinical history war-

to cause transtentorial herniation (cerebral hemi-

rants, and (4) processing of tissue for histologic

sphere abscess), foramen magnum herniation

examination if solid material is present to identify

(cerebellar abscess), or rupture of the abscess con-

neoplasm, bacteria, fungi, protozoa, etc.

tents into the ventricles (ventriculitis).

The clinical diagnosis is made by neuroimaging

with cranial CT with and without contrast or MRI

with and without gadolinium (Figure 13-3). The

Major Clinical Features

neuroimaging differential diagnosis includes

The signs and symptoms of a brain abscess are

necrotic or cystic primary and metastatic brain

those of an expanding brain mass that develops

neoplasms, granulomas, subdural empyema, and

over 1 to 2 weeks (Table 13-2). Common symp-

atypical cerebral infarctions and hematomas. MRI

toms at presentation are those of increased

is slightly more sensitive in establishing the diag-

intracranial pressure (ICP) and focal neurologic

nosis since it is especially good for identifying early

signs. Signs of ICP include headache

(75%),

cerebritis, multiple abscesses, abscesses located

lethargy and confusion (50%), nausea and vomit-

adjacent to bone, and distinguishing abscess from

ing (50%), and CN palsies (30%). Less-common

tumor or other mass.

signs of ICP include papilledema (10%-25%) and

stiff neck

(25%). Focal neurologic signs (40%)

Principles of Management and Prognosis

depend upon the abscess location, but hemipare-

sis, aphasia, homonymous hemianopsia, and

Optimal management of the patient involves (1)

ataxia are common. Focal or generalized seizures

prompt reduction of the size of the life-threaten-

occur in

33%. Systemic signs are uncommon.

ing mass

(abscess and surrounding cerebral

Fever is present in less than 1/2 of patients and is

edema), (2) collection of appropriate culture spec-

usually below 39°C. Depending on the location,

imens, (3) definitive treatment of the brain abscess

the focal neurologic signs may present first, fol-

with antibiotics and usually neurosurgical

lowed by increasing signs of ICP. If the abscess

drainage or evacuation of the abscess, (4) identifi-

begins in a clinically silent area such as the anterior

cation and elimination of the source of the brain

frontal lobe, the reverse order of symptoms may

abscess, (5) prevention of seizures, and (6) neu-

develop. The abscess continues to expand, produc-

rorehabilitation.

CHAPTER 13—Central Nervous System Infections

139

edema

pus

capsule

pus

Figure 13-3

Brain abscess (computed tomography and magnetic resonance imaging scans).

Reduction of the mass size is best accomplished

indications include cerebritis without encapsula-

by stereotactic surgical aspiration of the abscess

tion, multiple small abscesses in whom the likely

once it has reached the liquefaction and cavitation

bacteria can be isolated from the site of the initial

stage. Stereotactic surgery using CT or MRI guid-

infection source, and abscesses located deep in the

ance is minimally invasive and provides pinpoint

brainstem or basal ganglia. In these patients, fre-

accuracy for aspiration of selected sites. Corticos-

quent repeat neuroimaging should be used to

teroids may be administered briefly to reduce the

monitor for abscess expansion that might then

surrounding cerebral edema but should be

alter the treatment plan.

stopped as soon as possible since steroids may

Administration of phenytoin is given to prevent

interfere with the host cellular immune response

seizures, which dramatically further elevate the

to the abscess.

ICP. Rehabilitation after treatment helps minimize

The initial antibiotic treatment should be tar-

neurologic sequelae.

geted against a wide variety of anaerobic and aero-

The mortality of a brain abscess remains 10%

bic gram-positive and gram-negative bacteria. If

to 20%. In survivors, 20% to 60% are left with

the patient is immunocompromised or has existing

neurologic sequelae that include hemiparesis,

chronic sinusitis or mastoiditis in which a fungal

aphasia, ataxia, and visual loss. Chronic seizures

infection is suspected, the addition of antifungal

are common, may be focal or generalized, and may

drugs should be considered. Chosen antibiotics

be difficult to suppress with anticonvulsants.

should penetrate the blood-brain barrier and

abscess wall and not become inactivated by abscess

pus. The most common initial therapy is a third- or

Herpes Simplex Virus Encephalitis

fourth-generation cephalosporin plus metronida-

zole for anaerobic bacterial coverage. The duration

Introduction

of antibiotic treatment ranges from 4 to 8 weeks.

Under some circumstances, patients can be

Encephalitis is a diffuse infection of the brain

treated with antibiotics and without surgery. These

parenchyma. Viruses are the most common infec-

140

FUNDAMENTALS OF NEUROLOGIC DISEASE

tious agents, but bacteria

(e.g., general paresis

viral proteins appear on the neuronal membranes,

from T. pallidum), and protozoa (e.g., toxoplasmo-

so the host immune system cannot detect and

sis) also cause diffuse brain infections. There are

eliminate the virus. From time to time, viral

numerous viruses that cause encephalitis, but her-

latency breaks and new virus produced in the neu-

pes simplex virus

(HSV) and a group of

ron cell body travels down the axon-releasing virus

arboviruses (for arthropod-borne viruses) are the

at the skin, ending where a localized infectious

most common. Arboviruses are transmitted by

vesicle (fever blister) develops.

mosquitoes or ticks. As such, human infections

How HSV reaches the brain is poorly under-

occur in clusters or epidemics in late spring, sum-

stood. Since HSE usually develops in healthy indi-

mer, and early fall, when the vectors are present.

viduals who have been previously infected with

The natural cycle of many arboviruses involves

HSV, activated latent virus appears to reach the

birds and mosquitoes; humans are not part of this

brain. One hypothesis proposes that a latently

life cycle. When a new arbovirus is introduced into

infected neuron in the trigeminal ganglion inner-

an area that has mosquitoes and birds that can

vates the base of the brain rather than the face.

become infected by the virus, an epidemic may

Should that neuron break latency, the resulting

develop (e.g., West Nile virus in North America).

viral infection would develop in the ipsilateral

Humans become infected when bitten by virus-

temporal lobe.

infected mosquitoes. Herpes simplex encephalitis

Most cases of HSE start in the temporal lobe.

(HSE) occurs sporadically year round since the

The viral infection rapidly produces encephalitis

virus is usually latent in the host. In the United

in the medial temporal lobe, then spreads to the

States, HSV is the most common cause of sporadic

opposite temporal lobe and throughout the brain.

encephalitis and West Nile virus the cause of clus-

The pathologic hallmark of all encephalitides is

tered or epidemic encephalitis.

widespread brain inflammation usually character-

The severity of the encephalitis depends mainly

ized by perivascular cuffing (lymphocytes adjacent

on the infectious organism. Thus HSV, eastern

to cerebral blood vessels) and focal areas of necro-

equine encephalitis, and Japanese B virus cause

sis with secondary gliosis (glial nodules). Com-

severe encephalitis while Venezuelan equine

monly HSE is severe enough to produce areas of

encephalitis and California viruses produce mild

necrosis and hemorrhage. Viral-infected neurons

disease. Most viruses that cause encephalitis infect

and glia often develop an intranuclear inclusion

both neurons and glia. An exception to this rule is

body (Cowdry type A inclusion) that can be seen

poliomyelitis, where the poliovirus selectively

by light microscopy. Intranuclear inclusions are

infects only neurons involved in the motor system.

not specific for HSE and can be seen in cells

HSV type 1 is most often responsible for

infected with other herpes viruses (varicella-zoster

acquired encephalitis in children and adults. In

and cytomegalovirus) and rubeola (measles) virus.

contrast, type 2 virus is associated with genital her-

petic lesions and most often causes acute and

Major Clinical Features

recurrent meningitis in children and adults. It also

causes encephalitis and disseminated infection in

HSE develops equally in both sexes and in all ages

newborn infants who acquire the viral infection

without a prodromal illness. Acute encephalitis is

during delivery.

characterized by the abrupt onset of fever,

headache, and mental obtundation. Table 13-2 lists

the most common signs and symptoms for all

Pathophysiology

forms of encephalitis, including HSE. Although

HSV type 1 is most often acquired during early

HSE begins in the temporal lobe, there are no clin-

childhood as a self-limited stomatitis that is sel-

ical features that allow its distinction from other

dom diagnosed. During that infection, the virus

viral causes of encephalitis. For example, the pres-

travels up the sensory axons of the trigeminal

ence of a labial fever blister or isolation of HSV

nerve from the mouth to the trigeminal ganglia. In

from the blister or throat is of no diagnostic value

the corresponding ganglion neuron, the virus

since HSV oral lesions often develop in any ill

becomes latent in the nucleus. During latency, no

patient with encephalitis from any cause.

CHAPTER 13—Central Nervous System Infections

141

Encephalitis differs from meningitis in that

sooner the acyclovir is given, the better the out-

patients present with prominent mental changes

come. Patients who are lethargic at the start of

and minimal or absent stiff neck.

therapy do better than those who are comatose.

Acyclovir is given in high dosage intravenously

usually for 14 days.

Major Laboratory Findings

In the presence of HSV thymidine kinase, acy-

The peripheral WBC count is often mildly ele-

clovir is monophosphorylated within a cell. Host

vated, with a shift to the left. The CSF may be

cell thymidine kinases then phosphorylates the

under increased pressure and usually shows a

drug to its active triphosphate state, which then

mononuclear pleocytosis ranging from 10 to 200

inhibits DNA synthesis. Of note, acyclovir is rela-

WBC/mm³. Frequently, the CSF contains elevated

tively nontoxic to normal cells and has few side

RBCs that can range over 1,000/mm³. The CSF

effects, but its administration requires good hydra-

protein level is mildly to moderately elevated, but

tion to prevent renal failure from the drug precip-

the glucose level remains normal. Gram stain is

itating in the kidney.

negative. CSF viral cultures rarely grow HSV. IgG

Unfortunately there are no satisfactory drugs for

antibodies to HSV type 1 are present in most older

the common RNA viruses (arboviruses, measles,

children and adults and HSE does not result in

and rabies). Thus treatment for encephalitis from

production of immunoglobulin (IgM) antibody.

these viruses remains symptomatic.

Therefore, the presence of antibody to HSV rarely

In the absence of acyclovir treatment, HSE has

helps make the diagnosis.

a mortality rate of 70%. Mortality from encephali-

A definitive diagnosis is usually made by detec-

tis from arboviruses ranges as high as 50% for

tion of HSV DNA in CSF by a PCR test (see Chap-

eastern equine encephalitis and Japanese B virus to

ter 3, “Common Neurologic Tests”). The CSF PCR

10% to 15% for West Nile virus and other

assay for HSV is positive in over 95% of HSE

arboviruses. Currently about 70% of patients with

patients during the first week of the encephalitis.

HSE treated with acyclovir survive and 30% of

The EEG is abnormal in all cases of encephali-

survivors make a good recovery.

tis and helps distinguish viral encephalitis from

viral meningitis, which usually has a normal EEG.

In some patients with HSE, the EEG demonstrates

Prion Diseases

high-voltage complexes that originate from the

temporal lobes in a semiperiodic nature that are

Introduction

suggestive but not diagnostic.

The MRI scan is very helpful in HSE. Early MRI

Prion diseases are uncommon and occur as

images often demonstrate T2- weighted abnor-

Creutzfeldt-Jakob disease (CJD), the juvenile vari-

malities in the medial aspect of a temporal lobe,

ant of CJD (vCJD), Gerstmann-Sträussler syn-

with extension into the subfrontal and insular cor-

drome, fatal familial insomnia, and kuru in

tex. Cingulate gyrus involvement is also common.

humans, scrapie in sheep, and bovine spongiform

When MRI changes are seen in the medial tempo-

encephalopathy (mad cow disease) in cattle. These

ral lobe in a patient with encephalitis, the likeli-

prion diseases are discussed because the infectious

hood of HSE is greatly increased, as arbovirus

agent (prion) breaks the conventional rules for

encephalitis seldom begins in the temporal lobe.

infectious agents and may represent a new class of

CT is less helpful since abnormalities appear a few

misfolding diseases. First, the infectious particle is

days later than in an MRI. CT abnormalities

a single unique protein molecule (prion) of 27 to

include low-density lesions in one or both tempo-

30 kd whose DNA resides in host chromosome 20.

ral lobes and areas of hemorrhagic necrosis.

No nucleic acid has been identified that is attached

to the protein. Second, the infectious particle is not

killed by formalin, ethanol, or boiling but can be

Principles of Management and Prognosis

destroyed by autoclaving. Third, patients with the

Treatment with the antiviral drug acyclovir dra-

illness do not present with typical signs of an

matically improves morbidity and mortality. The

infection. They lack fever or elevated WBC counts

142

FUNDAMENTALS OF NEUROLOGIC DISEASE

and have normal-appearing CSF. Fourth, the host

in the recipient has been shown to occur following

makes no immune response to the infectious pro-

transplantation of corneas, pituitary extracts, and

tein, so the brain lacks inflammatory cells typical

dural grafts. There is considerable evidence that

of encephalitis.

the vCJD seen in the United Kingdom can develop,

though rarely, from oral consumption of the meat

of infected cattle. Finally, CJD as well as other

Pathophysiology

human prion diseases can be autosomal dominant

Prion diseases occur by three different routes: spo-

hereditary diseases occurring in families with spe-

radic, infectious, and hereditary, and all share an

cific single-site mutations in the PRNP gene.

abnormal brain protein called a prion. The PRNP

Again, these patients are infectious should the

gene on human chromosome 20 produces a nor-

above tissues be donated to others.

mal cellular protein (PrP^c) that has a specific 3-

The pathologic hallmarks of CJD are generalized

dimensional (3-D) configuration that is found in

brain atrophy, spongiform degeneration

(

“tiny

membranes of neurons and other cells. The nor-

holes” in the cortex), and widespread gliosis without

mal function of the PrP^c protein is poorly under-

inflammation. Amyloid plaques are seen in the

stood. In prion diseases, the normal cellular

juvenile variant of CJD and Gerstmann-Sträussler

protein somehow alters its 3-D configuration to

syndrome. Antibody to prions specifically stains

become a family of abnormal prion proteins, com-

amyloid plaques, brain cortex, cerebellum, and ton-

monly called PrP^sc, that all contain the same

sils from vCJD patients. Systemic organs are histo-

amino acid sequence. The normal PrP^c protein has

logically normal.

a high α-helical structure content while abnormal

Prion diseases may represent the first of a new

prions have in common a high β-sheet content,

class of misfolding diseases. It is known that yeasts

but each has a different 3-D configuration. Each

and fungi, when environmental conditions war-

different 3-D configuration causes a human dis-

rant, have some proteins that can alter their 3-D

ease that has a different clinical picture (pheno-

configuration normally to acquire unique proper-

type). The probability of the protein misfolding

ties for the new environment. If vertebrate pro-

increases if genetic mutations are present at spe-

teins also can change their

3-D structures

cific DNA sites. The abnormal protein not only

normally, then misfolding can occur and lead to

causes neurologic disease but also is infectious.

disease that would not necessarily be infectious.

When the abnormal prion enters a normal cell

Currently, Huntington’s, Alzheimer’s, and Parkin-

containing only normal PrP^c proteins, the prion

son’s disease are potential candidates for this new

causes PrP^c proteins to reconfigure their

3-D

disease mechanism.

structure to become identical to the 3-D structure

of the abnormal prion. Prions are poorly catabo-

Major Clinical Features

lized by the host cell, accumulate, and eventually

kill the cell. While systemic cells dying from prions

CJD is the most common prion disease, with an

can be replaced, neurons cannot divide, leading to

incidence of 1/1 million adults. The majority of cases

neurologic disease from a progressive loss of neu-

are sporadic, developing in previously healthy adults

rons. The abnormal prion is structurally so close

with a mean age of 65 years (CJD from a genetic or

to the normal cell protein that the host does not

infectious cause has an earlier age of onset). The

recognize prions as foreign and hence produces no

onset is insidious but then patients develop a rapidly

immune response. As such, prion diseases appear

progressive dementia. Myoclonus appears in over

like a degenerative disease without inflammatory

1/2 of patients as the dementia progresses. Occa-

cells or the production of a specific antibody.

sionally patients also develop ataxia, visual loss (cor-

The most common form of CJD is sporadic, in

tical blindness or homonymous hemianopia), and

which many neurons have prions. How the body

extrapyramidal or pyramidal signs. Patients lack sys-

first developed prions remains unclear, but it could

temic symptoms of fever, aches, and myalgia. Within

begin following spontaneous transformation of a

4 to 6 months, patients are severely demented, rigid,

normal PrP^c protein into a prion. Once CJD devel-

mute, and unresponsive.

ops from any cause, the nervous system becomes

vCJD appears in children and young adults who

infectious. Infectious transmission producing CJD

have eaten beef of British origin years earlier.

CHAPTER 13—Central Nervous System Infections

143

These patients often present with psychiatric

for vCJD and other genetic prion diseases. Since

symptoms (anxiety, withdrawal, behavior changes,

the infectious agent is present in tissues, patients

and depression) shortly before dementia and

suspected of a prion disease should not donate

myoclonus develop.

blood or autopsy organs.

Major Laboratory Findings

RECOMMENDED READING

Routine blood tests are normal. Cerebrospinal

fluid is under normal pressure and contains no

Davis LE, Kennedy PGE. Infectious Diseases of the

cells and normal glucose and protein. Oligoclonal

Nervous System. Oxford, England: Butterworth-

bands are not seen. The CSF contains a nonprion,

Heinemann; 2000. (Comprehensive review of

chaperone protein called 14-3-3. When seen on

many different CNS infections.)

electrophoresis, it is characteristic, but not diag-

Mathisen GE, Johnson JP. Brain abscess. Clin Infect

nostic, for CJD. An EEG may show characteristic

Dis 1997;25:763-781. (Good overall review that

abnormalities, particularly later in the illness. MRI

includes pathophysiology, clinical features, and

shows progressive brain atrophy and often demon-

treatment.)

strates increased signal in the basal ganglia and

Peterson LR, Marfin AA. West Nile virus: a primer

cortex on a diffusion-weighted image. The later

for the clinician. Ann Intern Med

2002;137:

finding is diagnostically helpful.

173-179. (Nice review of the clinical features of

The prion infectious agent is complicated to

West Nile encephalitis.)

isolate and requires incubation in small laboratory

Saez-Llorens X, McCracken GH. Bacterial menin-

animals for months. However, CSF, brain, pitu-

gitis in children. Lancet 2003;361:2139-2148.

itary, and peripheral nerves that innervate cornea

(Reviews pathogenesis, diagnosis, and treatment

and dura contain infectious prions. Tonsils are

of bacterial meningitis in children and, by exten-

infectious in vCJD. The infectious agent does not

sion, adults.)

appear to be present in saliva, urine, sweat, or

Sy MS, Gambetti P, Wong BS. Human prion dis-

stool, so isolation of the patient is not necessary.

eases. Med Clin North Am 2002;86:551-571.

Blood should be considered infectious, but no

(Good review of prions and the human diseases

documented human cases have occurred from

they cause.)

blood transfusions.

Whitley RJ, Lakeman F. Herpes simplex virus

infections of the central nervous system: thera-

peutic and diagnostic considerations. Clin

Principles of Management and Prognosis

Infect Dis 1995, 20:414-420. (Excellent review of

Currently, there is no available treatment to stop

clinical features, pathogenesis theories, diagnosis,

disease progression. Death in CJD usually occurs

and treatment.)

within 6 months of diagnosis and within 2 years

BRAIN TUMORS

space. In addition, many tumors release unknown

Overview

substances that affect the surrounding blood-brain

barrier, allowing vasogenic edema to develop. As

The term “brain tumor” refers to a collection of

such, tumors and their surrounding cerebral edema

neoplasms of differing cell types, biology, progno-

soon produce gradually increasing intracranial

sis, and treatment arising as a primary tumor or

pressure (ICP). Increased ICP causes headaches,

metastasis. Each year over 17,000 new primary

psychomotor retardation (slowing in amount and

brain tumors are diagnosed in the United States

speed of cognitive functions coupled with a slowing

and about 13,000 people die from their disease. Pri-

of motor activities), nausea, vomiting, and

mary brain tumors mainly occur in adults, with a

papilledema (blurring of optic discs, retinal edema,

peak incidence in the elderly. Most of these adult

and flame hemorrhages without loss of vision). The

neoplasms occur above the tentorium in the hemi-

headache is ill defined, intermittent, and may be lat-

spheres. Primary tumors develop in infants and

eralizing. As the tumor expands, the headache

children, mainly in the posterior fossa (especially

becomes more intense, constant, and increases with

cerebellum), and have different histologic types

coughing or straining at stool. The papilledema

from those in adults. Most CNS tumors are of glial

results from increased pressure on both optic nerves

(astrocytoma more often than oligodendroglioma)

that impedes axonal flow and venous return from

origin (>90%) and rarely of neuronal origin (1%).

the retina.

Brain tumors produce signs and symptoms by 3

Third, as the mass expands, the resulting

mechanisms. The first of these is the tumor loca-

increased ICP may shift intracranial structures

tion. Since the hemispheres are most commonly

downward enough to produce brain herniation.

affected, common signs include hemiparesis,

hemisensory loss, aphasia, and visual field deficits.

When the cerebral gray matter is involved, seizures

are common and may be either focal or secondar-

Brain Herniation Syndromes

ily generalized. As the tumor spreads, cognitive

dysfunction is common.

Brain herniation may occur as a result of down-

Second, the mass of the tumor can produce signs

ward herniation of the brain through the tento-

and symptoms as it expands in a closed intracranial

rium (central and uncal herniation), cingulate

145

146

FUNDAMENTALS OF NEUROLOGIC DISEASE

gyrus herniation under the falx (subfalcial hernia-

compression of the CN III, followed by ipsilateral

tion), or cerebellar tonsillar herniation into the

hemiparesis from compression of the cerebral

foramen magnum and against the medulla (tonsil-

peduncle against the tentorial edge. Compression of

lar herniation) (Figure 14-1). Death from central

the posterior cerebral artery may occur, with

brain herniation results from progressive bilateral

ischemia/infarction of the ipsilateral occipital lobe,

parenchymal impairment of the diencephalons,

producing a contralateral homonymous hemi-

leading to ischemia and necrosis of the mid-brain

anopia. Events then are similar to central herniation.

and pons (Duret hemorrhages). Signs and symp-

Tonsillar herniation is due to compression of

toms of progressive central brain herniation

the cerebellar tonsils against the medulla, produc-

include

(1) impairment of alertness that pro-

ing early nuchal rigidity and head tilt followed by

gresses to stupor and coma, (2) sighs and yawns

coma and respiratory arrest.

that progress to Cheyne-Stokes breathing, then to

Depending on the tumor’s rate of growth, death

fixed hyperventilation, and finally to apnea, (3)

can occur when the tumor reaches the size of

small pupils (1 to 3 mm) that barely react to light

about 100 grams (~1 × 10¹¹ cells) or about the size

that progress to midposition (3 to 5 mm) pupils

of a golf ball. This is compared with systemic

that do not react to light, and (4) vestibuloocular

tumor, where death occurs when the tumor

reflex (“doll’s eyes” reflex) and ice water caloric test

reaches about 1,000 grams.

(ice water placed in the external auditory canal)

that progress from normal to being nonresponsive

(see Chapter 16, “Coma and Cerebral Death”).

Cerebral Edema

Uncal herniation occurs when a lateral hemi-

sphere mass displaces the medial edge of the uncus

Cerebral edema, excess fluid present either locally or

and hippocampal gyrus through the tentorium. Ini-

diffusely in the brain, develops as a result of many

tially there is dilation of the ipsilateral pupil due to

pathologic processes, including brain tumors, head

Subfalcine

Falx

Herniation

Skull

Dura

Pia

Tumor

Cerebrum

Uncal

Herniation

Tumor

Cerebellum

Tonsillar

Herniation

Central

Herniation

Figure 14-1

Brain herniations secondary to tumors.

CHAPTER 14—Brain Tumors

147

trauma, brain abscess and meningitis, anoxia, and

of all primary brain tumors and cause over 7,500

some metabolic disorders. Cerebral edema has been

deaths per year in the United States. This tumor

divided into three types: vasogenic, cytotoxic, and

tends to occur in older adults (mean age 55 years).

interstitial. Interstitial edema is uncommon and

results in obstructive hydrocephalus with CSF back-

Pathophysiology

ing into the white matter around the ventricles.

Vasogenic edema is the most common form of

Astrocytomas arise from cerebral astrocytes (glial

cerebral edema and frequently surrounds brain

cells) that abnormally proliferate. Grade 1 astrocy-

tumors. The edema results from localized dysfunc-

tomas are very slow growing, have a normal cellu-

tion of the blood-brain barrier, with increased per-

lar morphology, and do not induce abnormal

meability of capillary endothelial cells. Vasogenic

vascularity. The most benign astrocytomas typi-

edema reduces following administration of corti-

cally arise in the optic nerve or brainstem, and

costeroids. Cytotoxic edema develops from a

patients often survive decades from diagnosis.

swelling of neurons, glia, and endothelial cells, usu-

Malignant (high-grade) astrocytoma or glioblas-

ally following hypoxia. Hypoxia causes failure of the

toma multiforme usually arises in the cerebral hemi-

adenosine triphosphate (ATP) dependent sodium

spheres and appears grossly as a soft, relatively

pump within cells with subsequent accumulation of

circumscribed mass that may contain cysts or necro-

intracellular sodium and water. Cytotoxic edema is

sis (Figure 14-2). The tumor extends many centime-

difficult to reduce and does not respond to corticos-

ters beyond the apparent gross or neuroimaging

teroids. Characteristics of vasogenic and cytotoxic

margin. Microscopically, the tumor is highly cellular,

edema are listed in Table 14-1. Both types of edema

containing either a uniform cell type or extremely

produce a mass effect that can contribute to shifting

pleomorphic cell types. Multinucleated giant cells

of brain structures and brain herniation.

are frequently seen. There is extensive neovascular-

ization, with marked proliferation of endothelium of

small capillaries feeding the tumor. Astrocytomas

Glioblastoma Multiforme—

rarely metastasize outside the brain.

Tumor cell chromosomes often have extra ele-

Malignant Astrocytoma

ments or copies of chromosome 7, resulting in

overexpression of the epidermal growth factor

Introduction

receptor (EGFR) gene. Alternately, tumor cells can

Glioblastoma multiforme

(high-grade astrocy-

have deletions in chromosomes 9 or 10 or have

toma) is the most common primary brain tumor

mutations in the tumor-suppressor gene P53.

in adults, with an annual incidence of 3/100,000

These abnormalities are felt to be responsible for

population. Glioblastomas account for over 40%

the malignant growth.

Table 14-1

Features of Vasogenic and Cytotoxic Brain Edema

Feature

Vasogenic

Cytotoxic

Pathogenesis

Opening of blood-brain barrier

Cellular swelling of glia, neurons, and

with increased capillary permeability

endothelial cells

Edema Location

Chiefly white matter

Gray and white matter

Edema Fluid Composition

Plasma filtrate

Increased intracellular water and sodium

Common Causes

Brain tumor, abscess, infarction,

Brain hypoxia/ischemia

trauma, lead encephalopathy,

hemorrhages, and bacterial

meningitis

Corticosteroid Effect

Reduces edema

No edema reduction

Osmotic Agents

Acutely reduces water in normal

Acutely reduces water in edematous

brain

148

FUNDAMENTALS OF NEUROLOGIC DISEASE

Figure 14-2

Pathology of glioblastoma multiforme, with cysts and necrosis. (Courtesy of Blaine Hart, MD)

Major Clinical Features

The EEG shows focal or extensive slowing (δ

waves) in the region of the tumor, with varying

Early signs and symptoms include headaches in 50%

degrees of spikes at the tumor edge and surround-

of patients, altered mental status in 50%, hemipare-

ing edematous brain.

sis in 40%, aphasia in 15%, visual field loss in 5%,

and seizures in 20%. (See “Overview” for details)

The seizures may be either focal seizures (usually

Principles of Management and Prognosis

motor) or secondarily generalized tonic-clonic

Glioblastoma multiforme is always fatal. Thus

seizures. Papilledema may be seen on fundoscopy. In

management aims at slightly prolonging survival

the absence of treatment, symptoms of glioblastoma

and controlling symptoms. Corticosteroids usu-

progress relatively rapidly over weeks.

ally reduce the surrounding edema and temporar-

ily improve symptoms and prolong survival for 1

to 3 months. Following steroids, headache lessens,

Major Laboratory Findings

mental status perks up, and focal neurologic signs

MRI with gadolinium is the test of choice. On MRI

(such as hemiparesis) improve. Since steroids do

the tumor characteristically has low signal inten-

not affect tumor growth, the signs and symptoms

sity on T1-weighted and high signal intensity on

eventually return. Neurologic side effects of high-

T2-weighted images (Figure 14-3). The appear-

dose corticosteroids include psychosis, hyperac-

ance of gadolinium-enhanced T1-weighted images

tivity, irritability, insomnia, and myopathy.

is that of a central low signal outlined by high-

Surgical removal of the main tumor mass

intensity enhancement. Surrounding the high-

(debulking) improves the length of survival and

intensity areas are hypointense signals, representing

often improves neurologic signs by reducing ICP.

cerebral edema and tumor infiltration. The extent

Since fingers of the tumor have already spread far

of cerebral edema varies from tumor to tumor. A

beyond the main tumor margins, debulking is

CT scan shows variably hypodense or isodense

never curative. Brain biopsy and minor tumor

lesions surrounded by hypodense cerebral edema.

removal have no effect on survival.

CHAPTER 14—Brain Tumors

149

Figure 14-3

Magnetic resonance image (with gadolinium) of glioblastoma multiforme. (A) T1 with gadolinium; (B)

T2 weighted image showing tumor, edema, and midline shift. (Courtesy of Blaine Hart, MD)

Radiotherapy after surgery slightly improves

Meningioma

survival compared with surgery alone. Side effects

of radiotherapy commonly include anorexia, nau-

Introduction

sea, hair loss, and fatigue and may include late

Meningiomas belong to a group of brain tumors

radiation necrosis of normal brain.

that are often called “benign” since they are slow

The value of chemotherapy for glioblastoma is

growing, do not invade surrounding structures,

controversial. The choice of agent is difficult, as

and are not histologically malignant. Other com-

many antineoplastic agents do not cross the

mon benign tumors include pituitary adenomas,

blood-brain barrier and thus poorly penetrate the

acoustic neuromas, and epidermoid cysts. Menin-

tumor. Antineoplastic agents used alone or in

giomas account for 15% of all intracranial tumors

combination have been of limited benefit in

and have an incidence of about 3/100,000 popula-

improving mean survival time.

tion. The peak incidence is in older adults. Menin-

In summary, if the glioblastoma is untreated,

giomas are located outside the brain, occur twice

the mean survival from diagnosis is less than 6

as often in women as men, and may be incidental

months; adult patients rarely survive longer than

findings at autopsy. Table 14-2 lists their most

18 months. In adult patients receiving corticos-

common locations.

teroids and surgical tumor debulking followed by

radiotherapy with or without chemotherapy, 40%

to 50% survive 1 year, 10% to 15% survive 2 years,

Pathophysiology

and <1% survive 5 years.

Palliative care minimizes the patient’s discom-

The cause of meningiomas is unknown, but 3/4

fort and disability. Headaches can be controlled

have loss of genetic material from chromosome 22

with surgical debulking, corticosteroids, and anal-

that likely contains a poorly defined tumor-sup-

gesics. Anticonvulsants should be given to patients

pressor factor. In addition, 3/4 of meningiomas

who experience seizures. Cognitive dysfunction can

contain high-affinity, robustly expressed proges-

arise from tumor progression, effects of radiother-

terone receptors that may account for the tumor’s

apy and chemotherapy, corticosteroids, metabolic

higher predilection in women. Various androgen

disturbances, and depression. Treatment efforts

and dopamine receptors of unknown clinical sig-

should be aimed at the appropriate causes.

nificance occur in 1/2 of these tumors.

150

FUNDAMENTALS OF NEUROLOGIC DISEASE

hypointense and on T2-weighted images it is

Table 14-2

Location of Meningiomas

isointense or hyperintense. With gadolinium, T1-

Location

Percent

weighted images show intense and homogenous

Falx/parasagittal

25%

enhancement. Some meningiomas show edema in

the adjacent brain but rarely do they appear to

Cerebral convexity

20%

invade the brain.

Sphenoid wing

20%

Olfactory groove

10%

Principles of Management and Prognosis

Suprasellar

10%

Posterior fossa

10%

Since meningiomas are slow growing, many small

asymptomatic tumors can be followed safely with

Other

periodic neuroimaging. However, when the tumor

becomes symptomatic, surgical removal is indi-

cated. Depending on the location, the tumor can be

totally excised or partially removed. Total removal

Meningiomas are felt to arise from arachnoid

has a 10-year recurrence rate of about 10%. For par-

cap cells and thus may develop at any dural site

tial resection, about 40% of patients develop major

and receive their blood supply from the external

symptoms in the following 10 years. Both radio-

carotid artery. Grossly, the tumor is firm, round,

therapy and chemotherapy show little to no benefit.

and flat, and has a smooth edge. Histologically the

classical tumor is characterized either by a sheet-

like syncytial pattern in which the nuclei appear to

Pituitary Adenoma

be lying in an undivided expanse and/or a fibrob-

lastic pattern with fascicles of spindle cells bundled

Introduction

in sweeping, parallel, and gentle curves and whorls

throughout the tumor. The whorls may form a

The pituitary lays in the sella turcica, surrounded

nidus for calcifications.

by the sphenoid bone and covered by the sellar

Meningiomas are very slow growing tumors

diaphragm. The hypothalamus and optic chiasm

and may be present for more than a decade before

lie nearby. The pituitary weighs about 0.6 gm and

they cause symptoms. Their slow growth often

physiologically enlarges during pregnancy and lac-

tation. It divides into the adenohypophysis (80%)

allows physicians to simply follow small menin-

and neurohypophysis (20%). Blood supply mainly

giomas discovered in the elderly.

comes from portal circulation and lacks a

blood-brain barrier.

Major Clinical Features

Tumors of the pituitary can be divided into

microadenomas (<10 mm diameter) and macroade-

As with other brain tumors, meningiomas may

nomas (>10 mm diameter) or divided into the cell

present with seizures, headaches, and focal neuro-

types that secrete different hormones. Macroadeno-

logic deficits. Because some meningiomas arise

mas expand above the sella turcica, often affecting

from the base of the skull, cranial neuropathies

the optic chiasm, and may enlarge laterally into the

may occur. Meningiomas in the falx cerebri may

cavernous sinus to entrap cranial nerves. Microade-

present with paraparesis due to bilateral compres-

nomas are usually suspected based on hormonal

sion of the leg areas of the motor cortex.

changes in the patient or are incidentally identified

on MRI scans performed for other reasons.

Major Laboratory Findings

Pathophysiology

CT demonstrates the typical meningioma to be a

smooth, lobulated, isodense tumor that is adjacent

Pituitary adenomas account for 10% of all intracra-

to dura and enhances uniformly with contrast.

nial tumors. The cause of this tumor formation is

Multiple small calcifications are sometimes seen in

unknown. Overall, these tumors rarely appear

some tumors. MRI is often less characteristic. On

malignant, seldom metastasize, grow slowly, and

T1-weighted images, the tumor is isointense or

remain stable in size for years. Some tumors, such as

CHAPTER 14—Brain Tumors

151

Table 14-3

Common Hormone-Secreting Pituitary Adenomas

Prolactinoma

Acromegaly

Cushing’s Disease

Hormone Secreted

Prolactin

Growth hormone

ACTH

Cell Type

Lactotroph, mammotroph

Somatotroph

Corticotroph

Percent of Cell Type in

20%

50%

20%

Normal Pituitary

Tumor as a Percentage

50%-75%

10%-15%

1%-4%

of All Adenomas

Major Signs Due to

Women

Recent extremity growth

Weight gain

Hormone Secretion

Glactorrhea

Arthralgias

Centripetal obesity

in Adults

Abnormal menstruation

Excessive sweating

Moon facies

Infertility

Myopathy

Skin striae

Men

Jaw malocclusion

Myopathy

Hypogonadism with

Carpal tunnel syndrome

Depression and

decreased libido

Hypertension

occasional psychosis

and impotence

Gynecomastia

Common Tumor Type

Macroadenoma

Microadenoma

Hormone Tests

Elevated serum prolactin

Elevated plasma

Elevated 24-h urinary

level

insulinlike growth

glucocorticoid level

factor 1

Abnormal glucose

Dexamethasone-

tolerance test

suppression test fails

Random growth hormone

to suppress urinary

levels not helpful

glucocorticoids

ACTH level in petrosal

sinus vs. systemic

blood has ratio of

>2:1

Main Therapy

Bromocriptine

Transphenoidal excision

Other Causes

Pregnancy, breast feeding,

Exogenous corticos-

medications

teroids, adrenal

hyperplasia, and

ACTH-secreting

tumors elsewhere

ACTH = Adrenocorticotropic hormone.

prolactin-secreting adenomas, are responsive to

sign from damage to the optic chiasm is bitempo-

hormones or drugs and can expand or shrink in size

ral hemianopsia (loss of temporal vision in each

in response to these compounds. A number of pitu-

eye, which may not be apparent to the patient with

itary tumors do not secrete any hormones.

both eyes open). There may be optic disk atrophy

Table 14-3 lists the most common types of hor-

seen on fundoscopy, but papilledema is rare.

mone-secreting pituitary adenomas and their hor-

Headaches are common (75%) and are likely due

monal features, diagnostic tests, and treatments.

to traction on the diphragma sellae or surround-

ing dural structures. The character and location of

the headache is nondiagnostic. If the adenoma

Major Clinical Features

expands laterally into the cavernous sinus, the

Macroadenomas with upward growth put pressure

tumor may entrap CNs III, IV, and VI and the first

on the optic nerves and chiasm, causing visual loss

and second division of CN V, producing diplopia

in 50% of patients. The most characteristic visual

and unilateral upper and mid-facial numbness or

152

FUNDAMENTALS OF NEUROLOGIC DISEASE

pain. Rarely an adenoma may hemorrhage or

cirrhosis, and dopamine receptor antagonists

infarct, producing pituitary apoplexy with

(chlorpromazine, haldoperidol), estrogens, and

headache, ophthalmoplegia, bilateral visual loss,

opiates. Thus a patient with a prolactinoma should

and drowsiness, leading to coma. Corticosteroid

have both an elevated serum prolactin level and an

replacement becomes an emergency.

adenoma found on neuroimaging.

Major Laboratory Findings

Principles of Management and Prognosis

A pituitary tumor (both macro- and microade-

Goals for treatment are to reduce hormone hyper-

noma) has characteristic abnormalities on high-

secretion to normal, shrink tumor size, correct any

resolution imaging of the sella turica with MRI

visual or cranial nerve abnormalities, and restore

and gadolinium or CT with contrast. Common

any abnormal pituitary function. Except for pro-

findings include upward convexity of the gland,

lactinomas, surgical removal of the macroadenoma

increased size of the gland, stalk deviation, floor

is commonly required to preserve vision. About

erosion, gland asymmetry, and focal hypodensity

75% of patients with surgery are cured (total tumor

or hypointensity in the gland (Figure 14-4). The

removal observed on MRI and return of involved

normal pituitary gland rapidly enhances with

pituitary hormones to normal blood levels).

gadolinium but the adenoma does not thus

Prolactinomas dramatically respond to dopa-

enabling its identification.

mine agonists (bromocriptine), with a prompt

Specific hormone levels are often elevated.

reduction in serum prolactin levels, shrinkage of

Depending on the tumor type, hormone levels may

the tumor, and disappearance of the signs and

be difficult to detect in routine blood samples.

symptoms. The effect of bromocriptine adminis-

Thus elevated levels of growth hormone (GH) in

tration persists for years to decades. Thus admin-

acromegaly are best identified by sampling petrosal

istration of bromocriptine usually precludes the

sinus GH levels via catherization, which should be

need for surgery even when the tumor is a

twice simultaneous systemic blood GH levels.

macroadenoma affecting the visual system. How-

Serum prolactin levels are elevated in prolactin-

ever, if the drug is stopped, prolactin levels again

omas, but prolactin levels also may be elevated by

elevate and the tumor again grows.

pregnancy, breast-feeding, marked renal failure,

Radiotherapy may reduce growth of the

macroadenoma but usually does not stop hormone

secretion. Chemotherapy has not been beneficial.

Cerebral Metastases

Introduction

Brain metastases are neoplasms that originate in

tissues outside the brain and spread secondarily to

involve the brain. Of cancer patients, 25% develop

brain metastases. As such, cerebral metastases are

the most common type of brain tumor in adults.

There are more than 100,000 brain metastases

annually in the United States. Of these metastases,

80% are supratentorial, 15% are cerebellar, and 5%

are located in the brainstem or spinal cord. In

addition, 25% of metastases are discovered before

or at the time of diagnosis of primary tumor; 60%

develop in the next 1 to 6 months, and 10% in

months 7 to 12. About 5% develop more than 1

Figure 14-4

Magnetic resonance imaging scan of pitu-

itary adenoma. (Courtesy of Blaine Hart, MD)

year after the primary tumor is diagnosed.

CHAPTER 14—Brain Tumors

153

The most common sources of intracranial

Table 14-4

Presenting Signs of Brain

metastases are the lung, breast, GI or genitourinary

Metastases

tracts, skin

(melanoma), and leukemia. For

unknown reasons, a few cancers, such as prostate,

Sign

Percent

uterine, and ovarian, seldom metastasize to the

Impaired Cognition

60%

brain. At the time of diagnosis, 1/3 of metastases

Hemiparesis

60%

are single and 2/3 are multiple. However, only 1%

Headache

50%

of cerebral metastases that are solitary have not

metastasized elsewhere in the body. In addition, it

Aphasia

20%

is common for a patient with an initial single

Hemisensory Loss

20%

metastasis subsequently to develop other cerebral

Seizures

20%

metastases.

Papilledema

20%

Visual Field Cut

10%

Pathophysiology

Stupor or Coma

Most metastases arrive via the blood stream and

commonly lodge at the gray-white matter junction,

particularly in watershed areas of the cerebral hemi-

Major Clinical Features

spheres. A few metastases reach the spinal cord via

retrograde flow via the veins in Batson’s plexus or by

Cerebral metastases are usually symptomatic, but a

extension into the brain from dural or skull metas-

few are discovered at autopsy. Over 2/3 of patients

tases. The tumor embolus begins to grow and pro-

have neurologic signs and symptoms that are sim-

duces angiogenesis factors that stimulate new vessel

ilar to other mass lesions (Table 14-4). Seizures are

formation to supply blood to the tumor bed. These

usually focal motor, some of which become sec-

new blood vessels lack a blood-brain barrier. Brain

ondarily generalized. As metastases expand and

metastases cause considerable vasogenic edema sur-

produce increased ICP, deterioration of mental

rounding the tumor that may exceed the size of the

status develops and brain herniation may occur.

tumor. Thus the mass effect of even small metas-

tases may be considerable.

Major Laboratory Findings

Metastases produce clinical symptoms through

several mechanisms. The most common is dis-

MRI with gadolinium enhancement is the best

placement of brain tissue by the rapidly growing

diagnostic test. A negative test essentially rules out

tumor and the adjacent cerebral edema. The dis-

cerebral metastases. T1-weighted images may not

placement causes vessel compression and

show a small lesion unless there is hemorrhage,

ischemia, alterations in normal anatomy, and dis-

but areas of low intensity from the edema may be

ruption of extracellular fluid spaces. If the tumor is

seen. T2-weighted images show areas of increased

located in the eloquent cortex, the tumor itself

intensity that encompass both the tumor and sur-

may destroy critical neurons and cause symptoms.

rounding edema. T1-weighted images with

A metastasis may suddenly become necrotic, hem-

gadolinium show a heterogenous or ring-enhanc-

orrhage, rapidly expand in size, and produce an

ing lesion, usually with surrounding edema. Shift-

abrupt increase of symptoms. The tumor may

ing of brain structures from the tumor mass effect

“irritate” adjacent cerebral cortex neurons, trigger-

commonly are seen on all images. A careful search

ing focal seizures. Finally, the mass effect of the

for other metastases should be made, as all lesions

tumor and cerebral edema may trigger brain her-

are not the same size.

niation (see “Overview”).

Cerebral metastases must be distinguished

from other brain lesions such as a primary brain

Principles of Management and Prognosis

tumor, cerebral hemorrhage, cerebral infarction,

and brain abscess. In autopsy series, 5% to 10% of

Surgical removal of the metastasis only occasion-

lesions thought to be a solitary metastasis had

ally is helpful in markedly prolonging life. Surgery

another etiology.

should be considered when the diagnosis is in

154

FUNDAMENTALS OF NEUROLOGIC DISEASE

doubt or when the patient is in good overall

Black PM. Benign brain tumors: meningiomas,

health, the primary tumor is small and responding

pituitary tumors and acoustic neuromas. Neu-

to treatment, and there are no other critical sys-

rol Clin 1995;13:927-952. (Review of clinical,

temic metastases.

neuroimaging, and treatments of these tumors).

Dexamethasone reduces the cerebral edema

Ciric I. Long-term management and outcome for

and often dramatically improves the patient’s

pituitary tumors. Neurosurg Clin N Am

symptoms for 1 to 2 months. The addition of

2003;14:167-171. (Entire issue is devoted to clin-

whole-brain or localized radiation therapy to the

ical, pathologic, and medical/surgical manage-

metastases adds a few more months of survival,

ment of pituitary tumors).

but the patient must undergo the complications of

DeAngelis LM. Brain tumors. N Engl J Med

radiation and a month of therapy. Chemotherapy

2001;344:114-123. (Excellent overall review).

appears to add little to survival, but the patient

Fishman RA. Brain edema. N Engl J Med 1975;293:

706-711. (Classic review of types of cerebral

often receives systemic chemotherapy for the pri-

edema and their treatments).

mary tumor.

Posner JB. Neurologic Complications of Cancer.

In summary, the median survival without any

Philadelphia: FA Davis; 1995. (Excellent com-

treatment is 1 to 2 months from the discovery of

prehensive review of all types of CNS cancer com-

the brain tumor. With corticosteroids, the survival

plications, including metastases to the brain and

extends to 2 to 4 months. The median survival

leptomeninges, CNS infections, paraneoplastic

with steroids plus radiostherapy is between 3 and

syndromes, and side effects of chemotherapy and

6 months, with 10% surviving 1 year.

radiation).

RECOMMENDED READING

Arnold SM, Patchell RA. Diagnosis and manage-

ment of brain metastases. Hematol Oncol Clin

N Amer 2001;6:1985-1107. (Good brief review

of brain metastases and treatment options).

SEIZURES AND STATUS

EPILEPTICUS

els of epilepsy, the event is thought to involve a

Overview

reduction in cortical inhibition mediated by

GABA, combined with divergent excitation, proba-

Single seizures occur in about 5% of the popula-

bly mediated by glutamate. In a focal seizure, the

tion. Nearly 2 million individuals in the United

synchronously depolarizing neurons remain local-

States (~1%) have epilepsy; 100,000 new cases of

epilepsy are diagnosed annually. An epileptic

ized, while in a generalized seizure, the synchro-

seizure is the behavioral manifestation of abnormal

nous depolarizations are present throughout both

brain neuronal activity. Recurrent seizures second-

hemispheres. Why a seizure terminates also is

ary to brain disease or dysfunction define epilepsy,

unknown but it likely is not due to exhaustion of

which is characterized by recurrent, usually tran-

neuronal energy-producing substrates.

sient, abrupt episodes of disturbed brain function

with combinations of loss of consciousness, altered

psychic function, and convulsive movements.

Etiologies of Seizures

It is important to remember that a seizure is a

Pathophysiology of Seizures

symptom and not a disease. Any individual can

experience a seizure under certain conditions, such

The genesis of a seizure remains poorly under-

as marked hypoxia, severe hypoglycemia, very high

stood. Normal brain function, awake or asleep,

fever, or if given an electrical shock to the head

produces an organized, yet nonsynchronous, EEG

(electroconvulsive therapy). It is likely that

pattern. A seizure, however, results from a paroxys-

unknown genes determine some people’s suscepti-

mal high-frequency or synchronous low-frequency

bility to developing a seizure. In addition, numer-

electrical discharge that can arise from almost any

ous other disorders that affect the brain can cause

part of the cerebral cortex (i.e., not the cerebellum,

seizures. The most common causes of seizures

brainstem, or spinal cord). A seizure begins as a

vary by age (Table 15-1) and include brain tumors,

spike discharge seen on the EEG and results from

strokes, metabolic diseases, drug reactions, drug

thousands of localized pyramidal neurons depolar-

withdrawal, and infections. In some patients, no

izing synchronously. Based on experimental mod-

cause is found (idiopathic epilepsy).

155

156

FUNDAMENTALS OF NEUROLOGIC DISEASE

The most common types of partial seizures are

Table 15-1

Common Causes of

simple partial seizures, complex partial seizures,

Seizures by Age

and partial seizures that become secondarily gen-

Age Range

Major Causes

eralized. Table 15-2 outlines the clinical features of

Infant

Birth injury, hypoxia/ischemia,

these seizure types. Properly classifying the type of

congenital malformations, and

epilepsy and determining the cause of the seizures

congenital infection

allows a better prognosis and enables selection of

Childhood

Febrile seizures, central nervous

the best anticonvulsant medication to control the

system infection, head trauma,

seizures.

birth injury, and idiopathic origin

Young adult Head trauma, drugs, withdrawal

from alcohol or sedatives, and

Primarily Generalized

idiopathic origin

Tonic-Clonic Seizures and

Elderly

Strokes, brain tumor, cardiac arrest

with hypoxia, and metabolic origin

Secondarily Generalized Partial

Seizures (Grand Mal Seizure)

Introduction

Electroencephalogram

These seizure types are common and occur in both

An EEG commonly helps classify the individual’s

sexes and at all ages past the newborn period. To

type of epilepsy (see Chapter 3,“Common Neuro-

the patient, a primarily generalized seizure and a

logic Tests”). Patients rarely experience a seizure

secondarily generalized partial seizure often

during a routine EEG. However, it can provide

appear the same (grand mal seizure). However, the

confirmation of the presence of abnormal electri-

presence of a warning or aura suggests the seizure

cal activity, information about the type of seizure

began focally and secondarily generalized. An aura

disorder, and the location of the seizure focus. On

identifies the part of the brain that malfunctioned

a single routine wake-and-sleep EEG, only 50% of

first and is in fact a partial seizure. Generalized

epilepsy patients will have an abnormal tracing.

seizures may be idiopathic (particularly primarily

The spike is the EEG sign of hypersynchronous

generalized seizures) or due to many brain diseases

activation of a population of neurons that could

(particularly secondarily generalized partial

develop into a seizure. Unfortunately, at least 10%

seizures)

(Table

15-1). Primary generalized

of epilepsy patients never have an abnormal EEG

seizures usually begin in adolescence while sec-

and 2% of normal individuals who never experi-

ondarily generalized seizures may begin at any age

ence a seizure will have epileptiform abnormalities

but especially in adulthood.

on their EEG. Therefore, the routine EEG cannot

rule in or rule out epilepsy, thus the diagnosis of

Major Clinical Features

epilepsy remains a clinical function.

Nearly 50% of patients experience an aura that is

identical in characteristics from seizure to seizure.

Seizure Classification

The aura lasts seconds and commonly is described

as a sinking, rising, gripping, or unnatural sensa-

There are several classifications for types of

tion that may be accompanied by movements such

epilepsy, which are based on clinical seizure types

as head and eye turning. Occasionally, patients will

and/or EEG findings. Seizures are classified as par-

experience an aura without generalizing, especially

tial or generalized. Generalized seizures involve the

if taking anticonvulsants. The patient often

both hemispheres early in the seizure. The most

remembers the aura after the seizure is over.

common types of generalized seizures are prima-

When the generalized seizure begins, con-

rily generalized tonic-clonic (grand mal) seizures

sciousness is always lost and there is no memory of

and absence (petit mal) seizures. Partial seizures

the seizure event. In the tonic phase, the body and

involve only a portion of the brain at their onset.

limbs stiffen for 20 to 30 seconds. If the patient is

CHAPTER 15—Seizures and Status Epilepticus

157

Table 15-2

Principal Seizure Types and Their Clinical Features

Type of Seizure

Clinical Features

Generalized seizure

Primarily generalized seizure

Loss of consciousness occurs without warning, marked increase in all muscle

(tonic-clonic or grand mal)

tone (tonic) for about 20-30 seconds followed by rhythmic (clonic) jerks

with a gradual slowing or rate and abrupt stopping after 20-60 seconds.

Patient is unconscious during and immediately after seizure and slowly

recovers over minutes to 1 hour. Tongue biting and urinary incontinence

are common. Patient has no recall of actual seizure event.

Absence seizure (petit mal)

Rapid onset of unresponsiveness that lasts an average of 10 seconds. There

often is staring that may be associated automatisms (eye blinking or lip

movements), an increase or decrease in muscle tone, and mild jerks.

Recovery is immediate but there is no recall of event. Hyperventilation

often precipitates seizure. Patients are 3-20 years of age.

Partial seizure

Simple partial seizure (focal)

Signs and symptoms may be motor (twitching of hand, arm, face, legs, or

trunk) sensory, autonomic, or rarely psychic and depend on the location of

the seizure focus. Consciousness is not impaired. Focal seizures recur at

the same location and should not move about. Seizures may last seconds

to many hours.

Complex partial seizure

Seizure may begin with or without a warning or aura, or with stereotyped

(temporal lobe or

motor, sensory, autonomic, or psychic signs or symptoms. Consciousness

psychomotor)

is impaired and patient does not recall actual seizure. During seizure that

usually lasts 1-3 minutes, patient may sit, walk, mumble, and often exhibit

autonomic acts such as lip smacking and repetitive hand jesters. Seizure is

usually followed by a period of confusion of 5-20 minutes.

Secondarily generalized

Seizure begins as a complex partial seizure (above) and then is followed soon

complex partial seizure

by a generalized seizure. Thus the patient usually has a warning (aura) that

(tonic-clonic or grand mal)

culminates in a tonic-clonic seizure.

standing, he or she will fall like a log, often result-

often sleeps following the seizure, which can cause

ing in traumatic injuries. If air forces out the

witnesses to describe the seizure as lasting an hour

closed glottis, a grunting sound may occur.

or more.

Patients may also bite their tongue, lip, or cheek

Seldom does a physician witness a seizure, so

and become incontinent of urine. Occasionally in

the diagnosis must be made by the history

the elderly, the tonic phase may be severe enough

obtained from a witness and the patient. Disorders

to cause a compression fracture, usually involving

that must be distinguished from a seizure include

a thoracic vertebra. Since breathing does not occur

syncope, migraine, transient ischemic attack,

during the tonic phase of the seizure, blood may

nonepileptic seizure

(psychogenic nonepileptic

become sufficiently oxygen desaturated to make

seizure), rage attacks, Meniere’s disease attack, and

the patient temporarily cyanotic (blue).

severe movement disorders. In children, breath-

In the clonic phase, rhythmic jerking of the

holding spells, night terrors, and pallid infantile

limbs begins in rapid synchrony that slows in

syncope must also be considered.

intensity and frequency over 20 to 40 seconds.

Syncope is suggested by the onset always occur-

Usually the jerking then abruptly ceases and the

ring when the patient is erect (seizures occur in

seizure ends.

any position). Before fainting, the patient usually

The postictal period lasts for minutes to over an

has a feeling of being “light-headed” or of impend-

hour but may be longer following a prolonged

ing faint that may be accompanied by loss or dark-

seizure or multiple closely spaced seizures. The

ening of vision. Syncope is brief (10-20 seconds)

patient is unconscious initially and then is difficult

and results in loss of muscle tone so patients col-

to arouse and confused for a time. The patient

lapse with less chance of hurting themselves. Syn-

158

FUNDAMENTALS OF NEUROLOGIC DISEASE

cope seldom causes muscle twitching, which, if

common toxicities are listed. For generalized

present, should always be very brief (a few sec-

seizures, the first-line anticonvulsants are val-

onds). Syncope does not cause postictal confusion.

proate, phenytoin, and lamotrigine. About 2/3 of

Nonepileptic seizures should be considered

patients can be well controlled with anticonvul-

when the patient has (1) complex, prolonged, and

sants. If seizure control is not achieved with the

variable warnings,

(2) nonsymmetrical limb

first drug, a second drug should be substituted. If

movements, (3) nonrhythmic or semipurposeful

the patient is compliant in taking the medication,

limb movements, (4) prolonged limb movements

success with anticonvulsants is seldom achieved if

that subside and then amplify, (5) no postictal

the third drug trial fails. Some of these patients

confusion, and (6) memory of the event.

benefit from 2-drug regiments or from alternate

Following a first seizure, the physical examina-

methods such as vagal nerve stimulators or surgi-

tion should search for other findings suggestive of

cal removal of a seizure focus.

the cause. There should be a search for signs of

All states require individuals with a driver’s

head trauma, infections of ear, sinuses, brain or

license to notify the motor vehicles department

meninges, congenital abnormalities (like tuberous

following a seizure and most prohibit driving for 6

sclerosis), focal or diffuse neurologic abnormali-

to 12 months after the last seizure.

ties, alcohol or drug abuse and cancer.

The decision when to stop anticonvulsants is

complex; most patients should continue their anti-

convulsant for at least

2 years after their last

Major Laboratory Findings

seizure. Reasons to discontinue anticonvulsants

In general the following tests are usually performed

are to prevent drug interactions, side effects, risk of

on a new seizure patient with a normal neurologic

teratogenicity if pregnancy is desired, and cost of

examination: serum electrolyte and liver function

medication. Factors to consider anticonvulsant

tests, hemogram, neuroimaging, and an EEG done

continuation include the social stigma of a seizure

at least 48 hours after the seizure. MRI is preferred

and the risk of another seizure, which would result

over CT because it can detect small masses and

in loss of driving privileges for 6-12 months.

mesial temporal sclerosis. Seldom are major blood

or CSF abnormalities found. Elderly patients are

Absence Seizure (Petit Mal Seizure)

more likely to have abnormalities on neuroimaging

to account for the seizure etiology.

Introduction

Primarily generalized absence seizures or petit mal

Principles of Management and Prognosis

epilepsy has an onset between the ages of 3 and 12

Management of epilepsy should be directed toward

years. This type of seizure disorder has been con-

preventing future seizures and eliminating or con-

sidered “benign” as it produces brief seizures that

trolling the cause. If this is the first seizure, a deci-

do not cause loss of muscle tone (falling) and often

sion whether to administer anticonvulsants must

spontaneously subside in adulthood.

be made based on the neurologic exam and EEG.

Several studies suggest the risk of developing sub-

Pathophysiology

sequent seizures is 25% to 50%. The risk becomes

higher if there is a history of brain contusion or

The etiology of absence seizures is unknown. Since

familial epilepsy and if neuroimaging identifies a

the EEG shows the onset to be simultaneous, with

brain mass or the EEG is very abnormal.

synchronous 3-Hz spike and wave discharges dif-

Anticonvulsants all inhibit excessive neuronal

fusely in both hemispheres, the origin is thought to

activity by (1) blockade of voltage-gated sodium

be in deep diencephalic structures with early spread

channels, (2) indirect or direct enhancement of

of the seizure throughout both hemispheres.

inhibitory GABA neurotransmission, and (3) inhi-

bition of excitatory glutamatergic neurotransmis-

Major Clinical Features

sion. In Table 15-3, the major anticonvulsants,

first-line seizure indications (most effective drugs

The typical seizure begins with arrest of speech

with least toxicity), mechanisms of action, and

and the abrupt onset of loss of consciousness but

CHAPTER 15—Seizures and Status Epilepticus

159

Table 15-3

Major Anticonvulsants

Main Seizure

Likely

Major

Anticonvulsant

Indications

Mechanisms of Action

Side Effects*

Phenytoin

Generalized and

Inhibits voltage-dependent

Nystagmus, ataxia, gum

status epilepticus

sodium channels in a voltage-

hyperplasia, and hirsutism

and use-dependent manner

Valproate

Generalized,

Inhibits voltage-dependent sodium

Gastrointestinal (GI) distress,

complex partial,

channels in a voltage- and use-

ataxia, weight gain, and

and absence

dependent manner plus other

hepatic dysfunction

mechanisms

Carbamazepine

Complex partial

Inhibits voltage-dependent sodium

Ataxia, dizziness, diplopia,

and oxcarbazepine

channels in a voltage- and

and blood dyscrasia

use-dependent manner

Lamotrigine

Generalized

Inhibits voltage-dependent sodium

Abnormal thinking, ataxia,

channels in a voltage- and

dizziness, and nausea

use-dependent manner

Ethosuximide

Absence

Blocks voltage-dependent calcium

Headache, GI distress, ataxia,

channels that affect T currents

and blood dyscrasia

Lorazepam and

Status epilepticus

Increases GABA-mediated

Hypotension, respiratory

diazepam

inhibition by affecting the

depression, and secondary

GABA_A-receptor complex and

cardiac arrhythmias when

increasing open-time GABA-

given intravenously

activated chloride channels plus

increases the frequency of

opening of GABA-activated

chloride channels

Vigabatrin

Infantile spasms

Inhibits GABA transaminase,

Headache, irritability,

resulting in increased brain

depression, and confusion

GABA levels

* Most anticonvulsants are metabolized by the liver, cause sedation to varying extent, cause idiosyncratic rashes, and

are teratogenic.

GABA = γ-aminobutyric acid.

does not cause loss of muscle tone and falling. The

Principles of Management and Prognosis

individual often stares and has eye blinking and

First-line treatment choices are valproate and

minor body jerks for 10 to 30 seconds. The indi-

ethosuximide for typical absence seizures and val-

vidual then becomes alert but does not recall the

proate for atypical absence seizures. In young

episode. The seizures may occur in clusters and are

adulthood, absence seizures stop in about 2/3 of

often precipitated by hyperventilation. In school,

patients. In the remaining patients, absence

teachers may think the child is daydreaming or

seizures may progress to primarily generalized

deliberately not paying attention.

seizures or atypical absence seizures.

Major Laboratory Findings

Infantile Spasms (West’s Syndrome)

The EEG is diagnostic and usually shows general-

ized 3-Hz spike and wave discharges that can be

Introduction

induced with hyperventilation. Atypical absence

seizures can occur with EEG discharges slightly

A triad of infantile spasms, hypsarrhythmia on

faster or slower than 3 Hz; these may coexist with

EEG, and mental retardation characterize West’s

other seizure types. Neuroimaging is normal.

syndrome. Infantile spasms affect 1 in 3,000 live

160

FUNDAMENTALS OF NEUROLOGIC DISEASE

births. The seizures begin in the first year of life,

Infantile spasms disappear at

1 at

5 years

with a peak onset between 2 and 8 months.

whether or not the child received treatment. How-

ever, the outcome for most children with West’s

syndrome is poor. About 1/3 die before the age of

Pathophysiology

3 years and ³/₄ have moderate-to-severe mental

The pathophysiology of infantile spasms and hyp-

retardation. Of these children,

1/2 progress to

sarrhythmia is unknown, but most cases are associ-

experiencing tonic-clonic, atonic, and simple par-

ated with nonprogressive single or multiple prenatal

tial seizures and many of these children have EEG

and postnatal cortical lesions that include cerebral

patterns suggestive of the Lennox-Gastaut syn-

malformations, congenital infections, vascular mal-

drome—a difficult-to-treat form of childhood

formations, metabolic disorders, asphyxia, leuko-

epilepsy. Good prognostic factors include normal

malacia

(abnormal softening of white matter),

development until seizure onset, cryptogenic

kernicterus (deposition of bile pigment in deep

cause, and mild hypsarrhythmia.

brain nuclei with degeneration from neonatal jaun-

dice), head trauma, and intracranial hemorrhage.

Complex Partial Seizure

Major Clinical Features

(Localization-Related,

Infantile spasms or salaam seizures are character-

Temporal Lobe, or

ized by brief, symmetric contractions of neck,

Psychomotor Seizure)

trunk, and limb muscles. The spasm may involve

groups of muscles

(usually both extensor and

Introduction

flexor muscles) or an isolated muscle. Eye devia-

tion, nystagmus, and interrupted respiration are

About 450,000 individuals have complex partial

common during the spasm. The spasm is usually

seizures. They are particularly common in young

followed by a brief tonic phase. The spasms occur

adults. In about 80% of cases, the onset is in the

in clusters of up to 100 and are most common dur-

temporal lobe, with about

20% developing

ing sleep or upon arousal. Cognitive disorders may

seizures in the frontal lobe. Nearly 30% of patients

include mental retardation, speech delay, visuo-

may have a mass (tumor, arteriovenous malforma-

motor apraxia, and autism.

tion, hamartoma, etc.) identified in either the tem-

poral or frontal lobe. However, the most common

etiology is mesial temporal sclerosis.

Major Laboratory Findings

Mesial temporal sclerosis usually develops in

The EEG classically shows hypsarrhythmia—ran-

older children and adolescents and is characterized

dom, high-voltage slow waves and spikes that vary

by progressive loss of neurons and gliosis in one

from moment to moment in location and dura-

hippocampus. It can be identified as a hyperinten-

tion. During sleep the EEG may show a burst-sup-

sity of the hippocampus on T2-weighted MRI

pression pattern. The more severe the EEG

images, which over years proceeds to atrophy. The

pattern, the more frequent and severe are the

pathogenesis remains unclear but may follow subtle

infantile spasms.

brain damage

(head trauma, meningitis, and

hypoxia) that occurred in infancy or earlier in child-

hood. Patients with mesial temporal sclerosis often

Principles of Management and Prognosis

experience frequent complex partial seizures that do

Empirically, adrenocorticotropic hormone

not respond to anticonvulsant medication. How-

(ACTH) and vigabatrin (not available in the

ever, anterior temporal lobectomy may be curative

United States) have been found to reduce the fre-

in 75% of patients with mesial temporal sclerosis.

quency of infantile spasms. Both drugs are most

effective when given as soon as the infantile

Pathophysiology

spasms begin, but neither drug has been proven

to improve the long-term outcome of affected

The seizure genesis is felt to be similar to that of

children.

generalized seizures. The striking behavioral

CHAPTER 15—Seizures and Status Epilepticus

161

abnormalities are felt to occur because the seizure

oxcarbazepine, and phenytoin. Anticonvulsants

rapidly spreads in the temporal lobe to affect the

adequately control about 50% of patients, which is

limbic system. It is recognized that complex partial

less than that for primarily generalized seizures.

seizures are often more difficult to control ade-

Patients with mesial temporal sclerosis who fail

quately than are other seizure types, but the expla-

to respond to anticonvulsants are candidates for

nation is unknown.

anterior temporal lobectomy if the seizures are

coming from only one temporal lobe. Following

surgical removal of the anterior 2/3 of the involved

Major Clinical Features

temporal lobe, over 80% of patients have a marked

The majority of patients experience an aura, often

reduction in seizure frequency and 60% are cured.

recalled as a rising or falling sensation in their

abdomen, disgusting smell, or limb jerks immedi-

ately prior to the seizure. The seizure often begins

Status Epilepticus

with cessation of verbal activity associated with a

motionless stare. Patients do not normally respond

Introduction

to verbal or visual stimuli. Automatisms may occur

A widely accepted definition of status epilepticus is

that are gestural

(picking at objects, repetitive

more than 30 minutes of continuous seizure activ-

hand-washing movements) or oral (lip smacking),

ity or 2 or more sequential seizures without full

and the patient may wander aimlessly. These

recovery of consciousness between seizures. The

movements tend to be stereotyped for each patient

incidence in the United States is about 125,000

and occur with most seizures. Purposeful move-

cases annually. Each year 55,000 deaths occur that

ments or violence is unusual. Planned activities,

are associated with status epilepticus, which has

such as finding a gun, loading it with bullets and

the highest incidence in the first year of life and in

shooting someone, have never been felt to be due

the elderly, though the elderly have the highest

to a complex partial seizure. The ictal event

mortality rate. Over 10% of adults with their first

(seizure) lasts only 1 to 3 minutes, followed by a

seizures present in status epilepticus. Table 15-4

period of postictal confusion that usually lasts 5 to

lists the etiologies for status epilepticus.

20 minutes. The patient does not recall events dur-

ing the seizure.

Pathophysiology

Major Laboratory Findings

Presumably the seizures are initiated by the same

mechanism as with all seizures. However, status

The EEG is often helpful in establishing the diag-

epilepticus involves a failure to terminate the

nosis, particularly when interictal spikes are iden-

tified as coming from the temporal or frontal lobe.

Because the temporal lobe and underside of the

Table 15-4

Etiologies of Status

frontal lobe are distant from EEG electrodes, it is

Epilepticus

difficult to find spikes in some patients. Use of

sleep deprivation and special nasopharyngeal and

Etiology

Frequency

sphenoidal electrodes may improve diagnostic

Low Anticonvulsant Level

34%

yield.

The MRI scan is often performed with special

Cerebrovascular Accident

22%

views of the hippocampus to demonstrate mesial

Hypoxia/Anoxia

18%

temporal sclerosis. In 30% the cause for complex

Metabolic Cause

15%

partial seizures is found.

Drug Overdose

13%

Alcohol Related

13%

Principles of Management and Prognosis

Central Nervous System Infection

10%

Management is aimed at controlling the complex

Brain Tumor

partial seizures and removing the etiology of the

Other

seizures. First-line drugs are carbamazepine,

162

FUNDAMENTALS OF NEUROLOGIC DISEASE

seizure. Experimental studies find this failure can

(complex partial status epilepticus). In these

arise from abnormally persistent, excessive excita-

patients, a persistently and specifically abnormal

tion or ineffective recruitment of inhibition. Stan-

EEG establishes the diagnosis.

dard drugs used for status epilepticus are more

effective if given in the first hour of status.

Major Laboratory Findings

Status epilepticus can cause cerebral injury,

especially in limbic structures such as the hip-

A marked leukocytosis (WBC count >20,000/mm³)

pocampus. During the first 30 minutes of seizures,

without an increase in bands occurs due to loss of

the brain is able to maintain homeostasis through

margination of WBCs rather than production

increases in blood flow, blood glucose, and oxygen

from bone marrow as seen in an infection. As a

utilization. After 30 minutes, homeostatic failure

consequence of prolonged seizures, the patient

begins and may contribute to brain damage.

develops elevated serum potassium, metabolic aci-

Hyperthermia, rhabdomyolysis, hyperkalemia,

dosis (pH <7.0), and varying degrees of hypoxia. A

and lactic acidosis develop from constant wide-

screen of toxins and anticonvulsant levels that are

spread muscle firing. After 30 minutes, other signs

low or absent also may establish the cause.

of decompensation may develop, including

The EEG is always severely abnormal, showing

hypoxia, hypoglycemia, hypotension, leukocytosis,

continuous or nearly continuous spike and wave

and poor cardiac output: However, seizure activity

complexes. The findings on neuroimaging depend

itself appears sufficient to cause brain damage.

on the etiology of the status epilepticus, as status

One mechanism of damage is glutamate-mediated

epilepticus of unknown cause may have initially

excitotoxicity, particularly in the hippocampus.

normal neuroimaging.

The normal concentration of calcium outside of

neurons is at least 1,000 times greater than that

Principles of Management and Prognosis

inside of neurons. During seizures, the receptor-

gated calcium channel is opened following stimu-

The goal is to stop the seizures from status epilep-

lation of the N-methyl-D-aspartate

(NMDA)

ticus, identify and treat the cause, and prevent

receptor by glutamine. This enables intracellular

complications. The initial priority is to establish an

calcium levels to rise potentially to cytotoxic levels.

airway and maintain circulation (“ABCs”). This is

accomplished by administering oxygen by mask or

cannula; monitoring heart rate, temperature, and

Major Clinical Features

blood pressure; following oxygen saturation by

Initially patients are unresponsive and have clini-

pulse oximetry; and establishing intravenous

cally obvious seizures with tonic, clonic, or tonic-

access with administration of thiamine and a bolus

clonic limb movements. With time the seizure

of 50% glucose (glucose will terminate seizures

activity is less obvious. Patients may show only

due to hypoglycemia).

small-amplitude twitching movements of the face,

The initial anticonvulsant given is usually

hands, and feet and nystagmoid jerking of the eyes.

lorazepam delivered intravenously as soon as pos-

If the seizure-induced movements stop, the patient

sible. This is soon followed by a full intravenous

remains unresponsive or very confused and the

loading dose of fosphenytoin or phenytoin to

next seizure begins.

maintain cessation of the seizures. Fosphenytoin is

On neurologic exam the patient will not

a water-soluble analogue of phenytoin that is con-

respond to verbal commands. He or she will have

verted to phenytoin in the body. Fosphenytoin can

increased or decreased muscle tone, no purposeful

be given at a faster rate and is somewhat safer than

limb movements, and will frequently demonstrate

phenytoin but is more expensive.

Babinski signs. In general, the neurologic signs will

If fosphenytoin and lorazepam fail to control

be symmetrical.

the seizures, the patient should be intubated and

There are occasional patients who present with

placed on a ventilator. Iatrogenic anesthetic coma is

constant confusion, impaired awareness, and able

then induced with pentobarbital or occasionally

to move limbs and walk that have a type of status

midazolam until there is cessation of seizure activ-

epilepticus called nonconvulsive status epilepticus

ity both clinically and on the EEG. Attempts should

CHAPTER 15—Seizures and Status Epilepticus

163

be made to wean these drugs slowly under EEG

Cascino GD. Complex partial seizures: clinical fea-

control to ensure that the seizures do not return.

tures and differential diagnosis. Psych Clin N

Patients, especially children, with epilepsy who

Amer 1992;15:373-382. (Reviews clinical fea-

experience repeated bouts of status epilepticus can

tures, EEG findings, and anticonvulsants.)

begin early treatment at home by rectal adminis-

Lowenstein DH, Alldredge BK. Status epilepticus.

tration of a special gel formulation of diazepam. In

N Engl J Med 1998;338:970-976. (Reviews cur-

children, this rectal delivery often stops seizures

rent management options in detail.)

within 15 minutes.

Mikati MA, Lepejian GA, Holmes GL. Medical

treatment of patients with infantile spasms.

Clin Neuropharmacol

2002;25:61-70.

(Good

RECOMMENDED READING

review of syndrome and challenges to treatment.)

Browne TR, Holmes GL. Epilepsy. N Eng J Med

2001;344:1145-1151. (Excellent review aimed at

the primary care physician.)

COMA AND CEREBRAL DEATH

aroused by verbal stimuli but respond poorly to

Coma

questions, with a prolonged delay in their verbal or

motor responses. In stupor or semicoma, individu-

Overview

als require constant strong verbal or physical stim-

Consciousness has 3 attributes: arousal, wakeful-

uli to remain aroused. Their responses are simple

ness, and awareness of self and environment.

and often inaccurate. When the stimulus stops,

Arousal is the ability to awaken from sleep. This

they return to unconsciousness.

normal state is characterized by specific stages,

Coma is the pathologic state of the inability to

characteristic EEG patterns, and the ability of ver-

arouse from any stimuli to produce appropriate

bal or physical stimuli to terminate sleep to wake-

responses. The majority of patients have impair-

fulness. Wakefulness and awareness are states of

ment of reticular function. Occasionally, coma

alertness (usually with eyes open) and character-

results from extensive damage to both cerebral

ized by appropriately creating and responding to

hemispheres, but hemispheric lesions usually pro-

sensation, emotion, volition, and thought. Wake-

duce coma via transtentorial compression of the

fulness and awareness require the interaction of a

reticular formation.

relatively intact cerebral cortex and normally func-

tioning reticular-activating system in the upper

Pathophysiology

brainstem extending from the mid-brain to the

hypothalamus and thalamus.

Etiologies causing coma can be divided into 3

Loss of consciousness has several stages. Confu-

major categories: supratentorial mass lesions,

sion and delirium are characterized by impaired

infratentorial destructive lesions, and metabolic

capacity to think clearly and respond appropri-

causes. Specific causes of coma in each category

ately. In addition, delirious patients are agitated

are listed in Table 16-1. In the emergency room

and easily distractable. These states involve a gen-

setting, the etiologies are divided about equally

eralized disturbance of cortical function, often

into drug overdoses, supratentorial or infratentor-

with EEG abnormalities. Obtundation is a disorder

ial mass lesions, and other metabolic causes.

of alertness associated with slow reaction times

Supratentorial structurally caused coma usu-

(psychomotor retardation). Individuals can be

ally begins as a unilateral hemispheric mass that

165

166

FUNDAMENTALS OF NEUROLOGIC DISEASE

Table 16-1

Major Causes of Coma

Supratentorial Structural

Infratentorial Structural

Metabolic

(18% of Total)

(14% of Total)

(68% of Total)

Head Trauma

Brainstem/cerebellar

Drugs

Contusion with brain swelling*

ischemic or

Sedatives

Subdural/epidural hematoma

hemorrhagic stroke

Opioids

Intracerebral hemorrhage

Tranquilizers

Salicylates

Brain Tumor

Brainstem/cerebellar

Hypoxia

tumor

Cardiac or respiratory arrest

Severe anemia

Toxins (carbon monoxide)

Massive Stroke

Blood-glucose abnormalities

Ischemic stroke

Hypoglycemia coma from excess

insulin

Cerebral hemorrhage

Hyperglycemic coma from

diabetes mellitus

Encephalitis

Abnormal ionic central nervous system

environment

Hypo/hyper blood sodium, potas-

sium, calcium, and magnesium

Brain abscess

Organ diseases

Liver (hepatic coma)

Kidney (uremic coma)

Lungs (CO₂ narcosis and respiratory

failure)

Thyroid (myxedema coma)

Brain cofactor deficiency

Thiamine (B₁), cyanocobalamine

(B₁₂), and pyridoxine (B₆) deficiency

Poor cerebral perfusion

Hypertensive encephalopathy

Obstructive hydrocephalus

Bleeding with low blood volume

Decreased cardiac output

(myocardial infarction and cardiac

arrhythmia)

Toxins

Ethanol

Methanol and ethylene glycol

* Bold type refers to the most-common causes within a category.

progressively expands to produce brain hernia-

penetrating brainstem veins

(Duret hemor-

tion (see Chapter 14,“Brain Tumors”).As the her-

rhages), producing fatal brainstem hemorrhages

niation progresses across the tentorium, the upper

and ischemia. Coma from infratentorial destruc-

brainstem pushes downward, often rupturing

tion can be from ischemic brainstem stroke or a

CHAPTER 16—Coma and Cerebral Death

167

mass (hemorrhage or tumor) involving the brain-

to determine the cause within the category.

stem or cerebellum, directly damaging or compress-

Obtaining a history, including drug use, from a

ing the reticular formation. Metabolic-caused coma

friend or relative is extremely helpful in placing the

primarily affects reticular formation neurons.

patient into a category.

Table 16-2 gives the major clinical features found

in each coma category (also refer to Figures 16-1

Major Clinical and Laboratory Features

and 16-2). An elevated temperature and WBC

There are three critical questions to be answered

count usually implies an infection (sepsis, pneu-

about a comatose patient: where is the lesion? what

monia, or CNS), while a low temperature usually

is the cause? and is the coma stable, improving, or

implies the patient has been comatose in a cold

worsening? Generally, the physician first deter-

environment for some period of time. Rapid regu-

mines whether the etiologic category is supraten-

lar breathing often denotes a metabolic acidosis

torial, infratentorial, or metabolic. The next step is

from a metabolic cause. During the physical exam-

Table 16-2

Coma Characteristics Excluding Those Caused by Head Trauma

Supratentorial

Infratentorial

Characteristic

Structural

Metabolic

Early History

Signs suggesting dysfunction

Signs of cranial nerve

Rapid onset (anoxia) or sub-

of the hemisphere (hemi-

dysfunction. Headaches and

acute progression (drugs,

paresis, hemisensory defect,

stiff neck may be present.

uremia, etc). Patient looks

aphasia, and visual defect).

asleep. Headaches are

Headaches common.

uncommon. Fever may be

present if sepsis or pneu-

monia present.

Breathing

Normal or Cheyne-Stokes

Apneustic (deep inspiration,

Normal or rapid due to

sign (periodic cycles of

long pause, and prolonged

metabolic acidosis.

rapid breathing followed

exhalation at a rate of ~ 5/s)

by period of apnea).

or ataxic (irregular, ineffective

breathing that is often shallow).

Early Eye

Pupillary light reflexes are

Pupil size often unequal and

Normal size and reaction to

Findings (see

present but pupil size may

may be unresponsive to light

light, normal

Figure 16-2)

be small or unilaterally

(fixed). Eyes may not be

vestibuloocular reflexes,

dilated. Papilledema may

parallel and vestibuloocular

and no papilledema.

be seen. Vestibuloocular

reflex is sluggish or absent.

reflexes may be present

Papilledema is absent.

or impaired.

Motor (see

Asymmetric spontaneous or

Bilateral limb weakness or

Symmetric spontaneous or

Figure 16-3)

pain-induced limb

quadraparesis may be

pain-induced limb

movements. Decorticate

present. Decerebrate

movements.

posturing (flexion of the

posturing (unilateral or

arm and extension of the

bilateral extension of arms

leg on the involved side) to

and legs) to pain seen in

pain may occur.

mid-brain lesions.

Reflexes

Often hyperactive with

Often normal or hyperactive.

Normal or depressed. No

Babinski sign on

Babinski signs may appear.

Babinski signs.

contralateral side.

Neuroimaging

Hemispheric mass (tumor,

Mass in brainstem or

Normal.

hemorrhage, abscess, and

cerebellum and occasional

stroke), shift of midline

cerebellar tonsillar herniation

structures, and brain

through foramen magnum.

herniation. Occasional

obstructive hydrocephalus.

168

FUNDAMENTALS OF NEUROLOGIC DISEASE

Normal Response

Abnormal Response

Head Rotation or

Doll's Eye Maneuver

Head to Left:

Eyes Hold Original Position

Eyes Move With Head

Ice Water

Caloric Test

4∞

A Normal Tonic Response

A Negative Response

Eyes Move Toward the Ear

Eyes Do Not Move

With Ice Water

Figure 16-1

Assessment of vestibuloocular reflex in coma.

ination, attention should be paid to find signs of

unilateral hemispheric signs or a unilateral fixed

trauma (especially head or neck trauma), bleeding

dilated pupil. The late stages of a supratentorial

(external or internal), organ dysfunction (especially

coma are due to brainstem dysfunction and often

lungs, heart, kidney, and thyroid), and sepsis. Since

appear similar to infratentorially caused coma.

mentation, fine sensation, and coordination cannot

Infratentorial structural coma usually has a rapid

be tested in a comatose patient, the neurologic exam

onset, involves multiple cranial nerves, and pro-

focuses on spontaneous or pain-induced limb

duces brainstem findings before or accompanying

movements, breathing patterns, ocular findings and

coma. Table 16-3 lists the brainstem reflexes that

cranial nerve function (Tables 16-2 and 16-3).

can be evaluated in a comatose patient and the

Important clues to a supratentorial location for

clues each give regarding brainstem localization.

the coma include an early history of progressive

Weakness may be unilateral if the brainstem lesion

CHAPTER 16—Coma and Cerebral Death

169

Decorticate Posturing

Decerebrate Posturing

Figure 16-2

Decorticate and decerebrate posturing reflexes. Supraorbital pressure induces posturing.

is unilateral (brainstem stroke) or bilateral if the

Principles of Management and Prognosis

lesion involves both halves of the brainstem (brain-

In the emergency management of a comatose

stem hemorrhage or tumor). Metabolic coma may

patient, the first step is control of the ABCs (air-

have a rapid or subacute onset, usually produces

way, breathing, and circulation) (Figure 16-3).

mental changes before motor signs, has preserved

pupillary reactions, rarely produces asymmetric

Steps include ensuring the airway is open, deliv-

motor, sensory, or reflex findings, and is often asso-

ering oxygen either nasally or via intubation if

ciated with systemic disease (abnormal blood find-

needed, and establishing intravenous access.

ings and signs of other organ failure). Occasional

Commonly ordered tests include the following: a

patients have psychogenic coma characterized by

toxicology screen, a hemogram, electrolytes,

normal muscle tone and reflexes, unpredictable

liver-function studies, creatinine, glucose, cal-

vestibuloocular reflexes with the fast phase pre-

cium, and a “save-serum” specimen for possible

served on ice water caloric testing, atypical irregu-

future tests. Depending on the history and initial

lar breathing patterns, and nonphysiologic

evaluation of the patient, the following drugs

responses to cranial nerve testing.

may be intravenously administered: thiamine, an

170

FUNDAMENTALS OF NEUROLOGIC DISEASE

Table 16-3

Bedside Examination of Cranial Nerves in a Comatose Patient

Cranial

Brainstem

Nerves

Location

Test

Tested

Testing Method

Tested

Papillary

II, III

Normal: bright light shined into 1 eye causes both pupils promptly Mid-brain

Light Reflex

to reduce in size. Large pupil that is fixed to ipsilateral and

bilateral light implies damage to CN III.

Corneal

V, VII

Normal: touching cornea with cotton causes both eyelids to

Pons

Reflex

promptly close or blink. Failure of both eyelids to blink when

stimulating 1 cornea implies dysfunction of ipsilateral CN V.

Failure of 1 eyelid to blink with direct and consensual corneal

stimulation implies dysfunction of ipsilateral CN VII.

Symmetrical

VII

Normal: in light coma, ipsilateral or contralateral pain to face or

Pons

Face Movement

body causes grimace of lower face. Unilateral grimace to

to Pain

stimuli implies dysfunction of CN VII.

Vestibuloocular

III, VI, VIII

Normal: when rotating head laterally, the eyes remain fixed at

Lower pons

Reflex or

original target. Abnormal test result occurs when eyes move

to mid-

“Doll’s Eyes”

with head on lateral rotation.

brain

Maneuver

Ice-Water

III, VI, VIII

Normal: irrigation with 25-50 mL of cold or ice water in 1 ear

Lower pons

Caloric Test

causes both eyes to move to side with water and stay fixed.

to mid-

If 1 side is absent but the opposite side normal, damage to

brain

ipsilateral CN VIII is implied. If both sides are abnormal, this

implies brainstem lesion in pathways of vestibular nuclei to

CN III and VI.

Gag Reflex

IX, X

Normal: suctioning of mouth or stimulation of posterior pharynx

Medulla

triggers gag reflex. Absent gag implies dysfunction to medullary

gag center.

Cough Reflex

IX, X

Normal: spontaneous cough or cough upon stimulating trachea. Medulla

Absent cough implies dysfunction to cough center.

Yawn or Sneeze

V, IX, X

Presence of these long loop reflexes implies brainstem function

Medulla to

Reflexes

reasonably intact.

upper brain

Deep Tendon

Spinal cord

Normal: limb movement in response to percussion of joint tendon. Spinal cord

Reflexes

Presence implies lack of spinal shock and intact spinal cord

level

level but does not imply brainstem or cortical function.

opioids antagonist, and a bolus of 50% glucose

needed. Neuroimaging can identify the cause, but

solution.

surgical intervention is seldom indicated. If the

If a supratentorial cause is suspected, the situa-

cause of metabolic coma is due to insufficient cir-

tion becomes emergent and immediate cranial CT is

culation, oxygen, or glucose to the brain, rapid

indicated. If impending brain herniation is present,

correction of the etiology may reverse the situa-

lowering of ICP is accomplished by intubation and

tion. For many other causes, including organ dys-

hyperventilation

(to cause cerebral vasoconstric-

function and drug overdose, the patient should be

tion), administration of intravenous mannitol (to

stabilized, appropriate blood tests ordered to iden-

reduce cerebral fluid volume), and prompt surgical

tify the etiology, and treatment focused on correct-

intervention (to remove a hemispheric mass or to

ing the underlying metabolic cause.

remove CSF if obstructive hydrocephalus is present).

The outcome of a comatose patient varies with

With infratentorial causes of coma, vital signs

the etiology but in those with a structural brain

may rapidly worsen so intubation with mechanical

lesion the mortality is high, with severe neurologic

ventilation and blood pressure drugs may be

sequelae in survivors. The following generaliza-

CHAPTER 16—Coma and Cerebral Death

171

1. Provide a free and open airway,

inserting an oral or endotracheal airway,

if necessary.

2. Determine that the patient is

breathing adequately.

3. Check heart function.

4. Assess blood pressure.

5. Make certain there is no internal or

external blood loss.

Figure 16-3

Assessment of ABCs (airway, breathing, and circulation) in coma.

tions help predict outcomes from coma in patients

important to know when the brain is dead. A series

without head trauma. Head trauma has a better

of rules have been developed to diagnose brain

prognosis

(see Chapter

18,

“Traumatic Brain

death. Although the legal definition of brain death

Injury and Subdural Hematoma”):

varies from state to state and by country, all use

similar general guidelines. If the coma etiology is

• Coma seldom persists longer than 2 weeks.

known and irreversible, the decision is straightfor-

The patient dies, develops a persistent vegeta-

ward. When the etiology is unknown, the patient

tive state (a chronic condition in which he or

must not be hypothermic (core body temperature

she appears awake but has no evidence of

below 30°C) or intoxicated with sedating drugs

cognition), or improves, opens the eyes, and

(such as barbiturates), as these conditions suppress

regains consciousness.

brainstem reflex function, giving the false impres-

• Less than 1% of patients regain independent

sion of death. In patients with body temperatures

function if they still have absent corneal,

below 30°C or with high levels of barbiturates,

pupillary light, or vestibuloocular reflexes

brainstem reflexes may disappear. The coma should

after 1 day of coma.

have persisted for at least 6 to 12 hours. In children,

• Only 15% of patients comatose for over 6

an initial exam usually is followed by a confirma-

hours and 7% of patients comatose for 3 days

tory exam up to 24 hours later. In adults the confir-

recover with independent functioning.

matory exam is often optional. Table 16-4 lists the

• In metabolic coma, prognosis is best for

neurologic criteria that must be met. The presence

patients with drug or endocrine causes and

of deep tendon reflexes implies only spinal cord

worst for anoxia or inadequate cerebral per-

segmental function, which will soon disappear and

fusion from any cause.

does not negate a diagnosis of brain death.

A series of confirmatory tests are available to

Cerebral Death

establish brain death. These tests are optional in

adults and seldom performed when the etiology is

In spite of medical advances, many comatose

known. In infants, however, confirmatory tests are

patients progress to death. Since these patients are

recommended. The most common test is an EEG,

often mechanically and chemically supported, it is

which demonstrates isoelectric silence (no detec-

172

FUNDAMENTALS OF NEUROLOGIC DISEASE

When the legal criteria for brain death are met,

Table 16-4

Common Clinical Criteria

life support can be discontinued and if other crite-

for Brain Death

ria are met, organs can be harvested for donation

• Coma, usually for ≥ 6 hours

to others.

• Absence of marked hypothermia (<30°C) or

sedative intoxication

• Absence of motor responses

RECOMMENDED READING

• Absence of brainstem reflexes (see Table 16-3)

Plum F, Posner JB. The Diagnosis of Stupor and

• Absence of respiratory drive (at a PaCO₂ that is

Coma. 3rd ed. Oxford: Oxford University Press;

60 mm Hg or 20 mm Hg above baseline values)

1982. (Comprehensive review of coma and its

causes.)

Wujdicks EFM. The diagnosis of brain death. N

tion of cerebral electrical activity when the EEG

Engl J Med 2001;344:1215-1221. (Reviews cri-

machine is at maximum sensitivity). When neu-

teria and problems with definitions of brain

rons and glia die, the cells swell (cytotoxic edema),

death.)

increasing ICP and preventing cerebral arterial

Young GB, Ropper AH, Bolton CF. Coma and

blood flow. Tests such as a cerebral arteriogram,

Impaired Consciousness: A Clinical Perspective.

transcranial Doppler ultrasonography, or SPECT

New York: McGraw-Hill, 1998.

blood flow study can be done to prove absence of

cerebral blood flow.

DISORDERS OF THE DEVELOPING

NERVOUS SYSTEM

causing a variety of defects. In addition, multiple

Overview

abnormalities may occur from a single primary

deficit in early morphogenesis, causing a cascading

Amazing events in growth and development occur

process of secondary and tertiary errors in mor-

before birth as one cell develops into an infant. In

phogenesis. Insults that affect the CNS from weeks

spite of the immense complexity, most infants are

3 to 6 usually produce major morphologic abnor-

born with a normal nervous system containing 50

to 100 billion functioning nerve cells. Unfortu-

malities while insults occurring later may produce

nately, 1% to 2% of infants are born with neu-

more subtle or localized dysfunction. Thus it is

rodevelopmental defects. About 40% of deaths in

possible to determine the latest time in gestation a

the first year of life are related to malformations of

malformation could occur but not the earliest.

the CNS and an unknown percent of spontaneous

Table 17-2 presents the gestational timing of some

deaths in utero result from CNS maldevelopment.

neurodevelopmental milestones.

Although the cause of neurodevelopmental defects

Based on a limited number of fetuses studied by

is unknown in 60%, defects can occur from several

anatomists and experimental studies of vertebrates

causes, including genetic mutations, exposure to

and invertebrates, we are gaining a glimpse of the

toxins or teratogens, CNS infections, metabolic

incredibly complex sequence of events that must

deficiencies, and trauma. Table 17-1 lists some of

occur at precise times for normal brain develop-

the more commonly recognized causes.

ment. The basic steps of development are neurula-

Equally important as the cause of the CNS

tion, neuronal and glial proliferation, migration,

insult is the timing. By 3 weeks’ gestation, the prim-

differentiation of neurons with axonal, dendritic,

itive neural tube has begun to develop and CNS

and synaptic development, programmed cell

growth and maturation continue throughout the

death, and myelination.

embryonic period (0-8 weeks), the fetal period

In neurulation, primitive cells destined to

(9-38 weeks), infancy, and well into late childhood.

become neurons originate close to the neuroep-

The characteristics of the malformation depend on

ithelium of the neural tube. These cells begin rap-

the timing of the CNS developmental disruption,

idly replicating by the fourth week, producing cells

although some insults, such as genetic mutations,

that differentiate into bipolar neuroblasts. Some

may disrupt development over extended periods,

radial glia appear early and serve as scaffolding for

173

174

FUNDAMENTALS OF NEUROLOGIC DISEASE

that are subsequently pruned to the appropriate

Table 17-1

Major Recognized Causes

number by a process of programmed cell death

of Neurodevelopmental

called apoptosis. Somehow neurons that do not

Defects of the Nervous

establish correct neuronal connections by late

System

pregnancy are triggered to die. Apoptosis does not

Genetic Mutations

elicit inflammation or gliosis, so there is no histo-

logic evidence of their premature death.

Mutations primarily affecting gray matter (neurons)

Few fetal genes that control this intricate

Tay-Sachs disease

process have been characterized. Homeobox genes

Mutations primarily affecting white matter (myelin

comprise a family of genes that encode DNA-bind-

and their cells of origin)

ing proteins that regulate gene expression and con-

Adrenoleukodystrophy

trol various aspects of morphogenesis and cell

Krabbe disease

differentiation. Mutations in homeobox genes

Unbalanced chromosomes (from duplications or

often produce malformations in the brain and

deletions)

other organs.

Down syndrome

Many terms describe abnormal brain tissue.

Fragile X syndrome

The term dysplasia refers to abnormal cellular

Toxins

organization resulting in structural and functional

consequences. Dysplasias may be localized (such as

Alcohol

a hemangioma) or generalized, affecting a variety

Organic mercury

of structures from widespread distribution of the

Lead

tissue defect. Heterotopias are portions of an

Teratogenic Drugs

organ displaced to an abnormal site within the

same organ of origin, such as nodules of gray mat-

Anticonvulsants (phenytoin, carbamazepine, and

valproic acid)

ter located in deep white matter due to incomplete

Thalidomide

neuronal migration. A hamartoma is a portion of

tissue at the proper site but is architecturally disor-

Congenital Infections

ganized, such as a focus of abnormal cortical lam-

Rubella

ination due to disorganization of pyramidal

Cytomegalovirus

neurons. Malformation refers to a structural defect

Toxoplasmosis

arising from a localized error in morphogenesis

and may contain one or more of the features

Syphilis

described above. Deformation occurs when nor-

Metabolic Diseases

mally formed tissue is secondarily damaged.

Phenylketonuria

Ionizing Radiation

Anencephaly

Defects uncommon unless radiation exposure is

very high, which causes fetal death

Introduction

Anencephaly is an abnormality of neurulation that

occurs because of failure of closure of the anterior

end of the neural tube. The timing of the insult

neurons to migrate to the marginal layer, which

therefore occurs around week 4 of gestation.

will become the gray matter of the cerebral cortex.

Ultimately the radial glia divide and become astro-

Pathophysiology

cytes. The migration of these postmitotic neurons

occurs in a precise orderly manner that is largely

The causes are unknown. The incidence of anen-

completed by the end of the fifth month but does

cephaly in the United States is 1/1,000 live births.

continue at a slow rate until birth. This process

Failure of anterior neuropore closure results in fail-

appears to produce an excess number of neurons

ure of development of the forebrain and calvarium.

CHAPTER 17—Disorders of the Developing Nervous System

175

Table 17-2

Milestones in Pre- and Perinatal Development

Time

Period of Gestation

Major Developmental Event

Week(s)

Neural tube invaginates

Anterior, then posterior ends of neural tube close

Brain and head represent 50% of total body length

Rapid neuronal division into bipolar neuroblasts at rates up to 250,000 divisions/min

Radial glia appear and migration begins

Lens placodes of eye develop

Forebrain, midbrain, and hindbrain become evident

Neuronal migration largely complete

Dorsal and ventral horns of spinal cord appear

Peripheral nerves appear

6-8

Migration of neurons

Ears develop

Limbs develop

All major organs under development

9-12

Gross brain structure established

Glial development and migration appears

Very rapid growth of axons and synapses

Muscle contractions begin

13-20

Rapid brain growth

Central nervous system (CNS) myelination begins

α-fetoprotein elevates in amniotic fluid and maternal serum if there is failure of proper neural tube closure

21-40

Primary cerebral fissures appear followed by secondary cerebral sulci

Myelination continues

Synaptic development continues

Neuronal pruning of excess neurons by programmed apoptosis

Birth

Head is 25% of total body length

Peripheral nerve myelination almost complete but CNS myelination continues through age 2 years

Cry vigorous, sucks and swallows liquids, yawns

Suck, root, grasp, and Moro reflex present

Head control present

Visual and auditory responses elicitable

Months

2-5

Rapid brain growth continues with head circumference growing at 2 cm/month in first 3 mo and

1 cm/mo during months 4-6

Neurons develop more complex dendrites and synapses

Oligodendrocytes and astrocytes in matrix zones continue to divide and migrate to about 6 months

Voluntary or social smile appears

Head control improves

Eye contact increases

Turns to sounds

6-11

Rolls over, crawls, begins sitting

Babbles, recognizes parents, says “Ma Ma”

Head circumference grows at ¹/₂ cm/mo

Moro response and grasp reflex disappear

Neuronal dendrites continue growth but head circumference growth slows to ¹/₄ cm/mo

Walks with hand held

Uses pincer grip of thumb and forefinger

Single words appear

Babinski sign disappears

(Table continues)

176

FUNDAMENTALS OF NEUROLOGIC DISEASE

Table 17-2

(Continued)

Time

Period

Major Developmental Event

Months

Walks independently

Follows simple commands

Runs stiffly

Knows about 10 words, identifies pictures

Feeds self

Runs well, climbs stairs one step at time, opens doors

Puts 3 words together (subject, verb, object)

Tells of immediate experiences

Major Clinical Features

movements demonstrating that lower brainstem,

spinal cord, and motor neurons are functioning.

The most common phenotype has a lack of the

cerebral cortex and variable loss of the basal gan-

glia and upper midbrain, leaving in its place a

Chiari Type I and II

small hemorrhagic, fibrotic mass of degenerating

Malformations

glia and neurons. The frontal, parietal, and occipi-

tal bones are absent, leaving an open calvarium

Introduction

above the eyes.

Chiari type I and II malformations are dysplasias

of the brainstem, cerebellum, and spinal cord. The

Major Laboratory Findings

etiology is unknown, but there is suspicion of a

Polyhydramnios (excess amniotic fluid) is a fre-

homeobox gene abnormality. Patients with Chiari

quent feature. Sonograms are abnormal and

type I malformation often have a variable amount

demonstrate the malformed head. There is marked

of downward displacement of the cerebellar ton-

elevation of serum and amniotic α-fetoprotein,

sils, which is often found incidentally by neu-

which is synthesized by the fetal liver, circulates in

roimaging. Some individuals develop clinical signs

fetal blood, and is excreted in fetal urine into the

at adolescence when they develop headaches from

amniotic fluid. It is then swallowed and digested by

progressing hydrocephalus, limb spasticity, cere-

the fetal GI tract. Thus, amniotic fluid and mater-

bellar ataxia, and lower cranial nerve dysfunction.

nal blood normally contain little α-fetoprotein.

The protein is elevated in fetal conditions such as

open neural tube malformations, abnormalities in

Pathophysiology

the upper GI tract, multiple fetuses, and fetal death.

The key anatomic features of Chiari II malforma-

The optimal time to test amniotic fluid for α-feto-

tion consist of (1) downward displacement and

protein is during weeks 14 to 16 gestation, while

extension of the cerebellar vermis through the

maternal serum testing occurs at 16 to 18 weeks;

foramen magnum and into the cervical canal and

both are nearly 100% elevated in anencephaly.

(2) downward displacement of the ventral medulla

and the inferior fourth ventricle into the cervical

canal (Figure 17-1a). In addition, the following

Principles of Management and Prognosis

associated features frequently occur: (1) elonga-

About three-quarters of affected infants are dead

tion of the upper medulla and pons, (2) narrowing

at delivery and the others die in the neonatal

of the aqueduct of Sylvius, (3) fibrosis of the cere-

period. However, living infants often make sucking

bellar CSF exits of the fourth ventricle (foramens

and chewing movements and have simple limb

of Luschka and Magendie), and (4) hydrocephalus

178

FUNDAMENTALS OF NEUROLOGIC DISEASE

secondary to features 2 and 3, and (5) an associ-

productive lives. Most children with Chiari I mal-

ated meningomyelocoele in the lumbosacral area.

formation have normal intelligence.

In a meningomyelocoele, failure of the lower ver-

The incidence of both neural tube defects such

tebral arches to close causes extrusion of the dura,

as anencephaly and Chiari malformations have

arachnoid and cauda equina, or spinal cord into a

been greatly reduced by the use of supplemental

cystic swelling that protrudes the skin above the

folate, best administered before conception.

lower back (Figure 17-1b).

Phenylketonuria (PKU;

Major Clinical Features

Phenylalanine Hydroxylase [PAH]

The typical child with Chiari type II malformation

Deficiency)

has progressive hydrocephalus, variable cerebellar

ataxia, and lower CN VI though XII dysfunction,

Introduction

with horizontal diplopia, facial weakness, deafness,

sternomastoid muscle weakness and head lag,

Metabolic disorders include derangements in

laryngeal stridor, and tongue atrophy. There is

metabolism of amino and organic acids. This

variable spastic paraparesis in the arms from sec-

includes storage diseases, mitochondrial enzyme

ondary cervical stenosis and cervical myelopathy.

defects, and leukodystrophies. These infants usu-

The meningomyelocoele causes variable paralysis

ally appear normal at birth but subsequently

and atrophy of lower-leg and buttock muscles, loss

develop cerebral abnormalities. PKU is the most-

of bowel and bladder control, and lumbar kypho-

common disorder of amino acid metabolism and

has an incidence in the United States of 1/14,000

sis. Cysts may develop in the cervical spinal cord,

births. PAH deficiency is an autosomal recessive

producing syringomyelia with variable loss of sen-

disorder that results in intolerance to the dietary

sation (especially pain and temperature) and atro-

intake of the essential amino acid phenylalanine

phy of arm muscles.

and produces PKU children with profound and

irreversible mental retardation when not treated.

Major Laboratory Findings

PKU is caused by mutations in the PAH gene on

chromosome 12q23.2. Some mutations allow for

The diagnosis of Chiari II is confirmed in infants

partial PAH enzyme function and produce milder

born with a meningomyelocoele by MRI, demon-

forms of the disease.

strating the anatomic abnormalities, including

protrusion of the cerebellar vermis below the fora-

Pathophysiology

men magnum.

Phenylalanine is metabolized primarily in the liver

by hydroxylation via PAH to tyrosine. Mutations

Principles of Management and Prognosis

of the PAH enzyme cause abnormal elevations in

Treatment of infants with type II defects usually

plasma phenylalanine and low tyrosine levels.

involves placement of a ventriculoperitoneal shunt

Normal plasma phenylalanine levels are

<120

to relieve the increased ventricular CSF pressure

µmol/L; affected infants are born with normal lev-

from obstructive hydrocephalus and creating a new

els unless the mother has PKU not controlled by

pathway for exit of ventricular CSF. Depending

diet. After birth, dietary exposure occurs with con-

upon the extent of the lumbosacral nerve damage

sumption of either mother’s or cow’s milk that is

as the child grows older, bracing may be needed for

rich in phenylalanine and cannot be metabolized

walking and surgical placement of rods along the

to tyrosine. When plasma phenylalanine levels rise

lower vertebral bodies for stability to correct the

above 1,000 µmol/L, damage to the developing

secondary kyphosis that develops. Urinary tract

CNS occurs. Up to 1 g/d of excess phenylalanine

infections are common and secondary kidney

and phenylpyruvic acid is then excreted in urine.

problems may develop. While many children with

Studies suggest that elevated brain-free pheny-

Chiari II malformation have mental retardation,

lalanine and decreased levels of large neutral

many do not and grow to adults who live normal

amino acids

(tyrosine and methionine) cause

CHAPTER 17—Disorders of the Developing Nervous System

179

decreased protein synthesis, increased myelin

include hypomyelination or demyelination of

turnover, and abnormalities in dopamine and nor-

white matter, gliosis, and widespread neuronal loss

epinephrine neurotransmitter systems. The cere-

with gross microcephaly.

bral cortex that was histologically normal at birth

develops abnormalities of myelination, dendritic

Principles of Management and Prognosis

growth, and synaptic development—i.e., systems

that normally continue to mature after birth are

The goal of treatment is normalization of plasma

affected. In occasional untreated infants, degener-

concentrations of phenylalanine and tyrosine and

ation of established white matter may develop.

the prevention of cognitive disorders. A diet

restricted in phenylalanine should be instituted as

soon as possible and continued at least into adoles-

Major Clinical Features

cence, and in severe cases for life. A phenylalanine-

Clinically, infants are normal at birth. Over the

free medical formula with supplemental

first year of life, they develop eczematous skin

tetrahydrobiopterine is needed along with protein

rashes, progressive mental retardation, micro-

restriction, as protein restriction only is insufficient

cephaly, seizures, and behavioral problems.

to provide sufficient nutrition and maintain plasma

Hypopigmentation of hair, skin, and iris occurs

phenylalanine levels <300 µmol/L (5 mg/dL). How

due to inhibition of tyrosinase and lack of melanin

high plasma phenylalanine levels can rise in adult-

production. Excretion of excessive phenylalanine

hood before cognitive impairment occurs is unclear.

and its metabolites creates a musty body odor. If

However, noncompliance with dietary restrictions

PKU is not treated early, the mental retardation is

and markedly elevated plasma phenylalanine levels

irreversible. Untreated older children may develop

can result in decreased cognitive functioning and

spasticity, hyperactive reflexes, and paraplegia.

white matter abnormalities detectable on MRI.

There is increasing evidence that affected infants

Plasma phenylalanine levels must be monitored

treated with careful phenylalanine-deficient diets

closely and maintained below 300 µmol/L during

grow to adulthood with an IQ in the broad range

pregnancy, as high maternal phenylalanine levels

of normal. However, subtle cognitive deficits are

can produce fetal abnormalities.

present. Children experience delayed acquisition

of speech, have more behavioral problems, and

have some impairment of executive function on

Tay-Sachs Disease

neuropsychologic tests. Affected siblings have a

(Hexosaminidase A Deficiency)

lower IQ than those unaffected. Adults who go on

a regular diet also may develop mild spasticity and

Introduction

subtle cognitive deficits.

Tay-Sachs disease is the classic example of a lipid-

storage disease and of a genetic disease that prima-

Major Laboratory Findings

rily affects gray matter (neurons of the brain and

The diagnosis is made by newborn screening in

retina). Clinicians often divide degenerative dis-

virtually 100% of cases, based upon the detection

eases in infants and children into those primarily

of hyperphenylalaninemia (levels >1,000 µmol/L)

affecting gray or white matter (Table 17-3).

using the Guthrie (microbial assay) test on a blood

Tay-Sachs disease is a fatal autosomal recessive

spot obtain from a heel prick obtained several days

infantile disease due to severe deficiency of β-hex-

after feeding begins. The Guthrie screening test

osaminidase A enzyme, resulting in abnormal

usually is confirmed by more specific methods

accumulation of glycosphingolipid GM2 ganglio-

such tandem mass spectrometry. Molecular

sides within neurons, leading ultimately to neu-

genetic testing of the PAH gene exists but is diffi-

ronal death. Although cases have been reported in

cult and expensive since many possible mutation

all ethnic groups, the incidence is markedly higher

sites exist.

in Jewish communities of Central and Eastern

Neuroimaging is normal at birth and later

European descent (Ashkenazi Jews). Before cur-

detects irreversible abnormalities mainly in white

rent genetic testing, the incidence of Tay-Sachs dis-

matter. Histologic changes in untreated cases

ease in this population was 1/3,600 births. The

180

FUNDAMENTALS OF NEUROLOGIC DISEASE

jerks, and startle responses to sudden noises. By 9

Table 17-3

Clinical Features of

months, the infant fails to achieve milestones and

Diseases Affecting

is losing those already acquired. Weakness is more

Primarily Gray and

pronounced. There is diminished visual attentive-

White Matter

ness from loss of acuity, and a “cherry red spot” is

Gray Matter

seen in the retina on fundoscopy. By 12 months,

(Neurons of

White Matter

voluntary limb movements are minimal, vision is

Brain and Retina)

(Myelin and Axons)

lost, and partial complex and absence seizures

Loss of previously

Spasticity

develop. By year 2, the infant has decerebrate pos-

attained intellectual

turing, marked seizures, swallowing difficulties,

skills

and becomes almost vegetative. Death from bron-

Sensory abnormalities

chopneumonia occurs between ages 2 and 4 years.

Seizures

Ataxia and incoordination

Aphasia

Visual field defects

Major Laboratory Findings

Loss of visual acuity

Visual loss

The diagnosis is established by demonstration of

Memory loss

deficient hexosaminidase A enzymatic activity in

Variable muscle atrophy

the serum or WBCs of a symptomatic individual

from loss of anterior

in the presence of normal activity of the hex-

horn neurons

osaminidase B isoenzyme. Mutation analysis of the

HEXA gene on chromosome 15q23-q24 can be

done, but is less sensitive than the enzymatic assay

incidence in other populations is at least 10-fold

because current assays do not detect all 90 known

lower.

mutations.

Neuroimaging shows an enlarged head from

gliosis and not hydrocephalus. The EEG is abnor-

Pathophysiology

mal early and shows paroxysmal slow waves and

Hexosaminidase A and B are two catabolic enzymes

spikes.

that hydrolyze gangliosides with terminal β-N-

acetylgalactosamine residues. In Tay-Sachs disease,

Principles of Management and Prognosis

there is a mutation in the hexosaminidase-α subunit

such that the enzymatic activity of hexosaminidase B

No treatment currently exists to replace the miss-

is normal but is nearly absent in hexosaminidase A.

ing hexosaminidase A enzyme, and the disease

As a consequence, the ganglioside GM2 cannot be

relentlessly progresses to death. The goal of man-

catabolized and accumulates within the cytoplasm

agement is to provide supportive care, give ade-

of neurons, eventually causing the neuron’s death. In

quate nutrition and hydration, minimize

the retina, the fovea lacks ganglion cell bodies. Thus

respiratory infections, and control seizures with

accumulation of whitish GM2 gangliosides in gan-

anticonvulsants.

glion neurons surrounding the fovea is seen with an

Since asymptomatic, heterozygote carriers

ophthalmoscope as a “cherry red spot.”

can be detected by a simple, inexpensive, and

Pathologically, there is a large brain containing

sensitive serum hexosaminidase A enzyme assay,

excessive neuronal glycolipids (up to 12% of the

genetic screening as well as prenatal genetic tests

brain dry weight contains GM2 gangliosides).

are frequently done. Currently, Jews of Ashke-

There is widespread loss of neurons, with reactive

nazi extractions are often tested when reaching

gliosis. All remaining neurons are distended with

adulthood. Prenatal testing is available when

glycolipid.

both parents are heterozygous or the mother is

heterozygous and the father is unknown. The

hexosaminidase A assay can be performed upon

Major Clinical Features

a chorionic villus sample at 10 to 12 weeks’ ges-

Affected infants appear normal at birth. By

tation or by amniocentesis at 16 to 18 weeks’

months, infants develop mild weakness, myoclonic

gestation.

CHAPTER 17—Disorders of the Developing Nervous System

181

Down Syndrome

rowing of the superior temporal gyrus. The pri-

mary gyri are wider than normal and secondary

Introduction

gyri are narrower. The cerebellum and brainstem

are smaller than normal. Reduced numbers of

Chromosomal abnormalities occur when there are

neurons in the cortex and hypomyelination are

too many copies, too few copies, or abnormal

present and continue in subsequent growth. As the

arrangements (duplications or deletions) of normal

child grows older, there is significant reduction in

genes. At least 0.5% of all live births and 50% of

linear growth and brain growth. Most adults have

spontaneously aborted fetuses in the first trimester

short stature and mild microcephaly.

are the consequence of chromosomal imbalances.

Adults demonstrate basal ganglia calcifications

The human genome contains approximately 6 × 10⁹

and after the age of 30 years develop senile plaques

base pairs of DNA, and is 2 m long if uncoiled. Each

and neurofibrillary tangles similar to those seen in

somatic cell has 22 pairs of homologous chromo-

Alzheimer’s disease. By age 50 years, there is consid-

somes that are identical in morphology and con-

erable loss of cortical neurons and brain atrophy.

stituent gene loci plus 1 pair of sex chromosomes.

Malformations are likely to develop if this genetic

Major Clinical Features

arrangement is significantly altered.

Most chromosomal disorders involving autoso-

Newborns have hypotonia, hyperextensible joints,

mal chromosomes are associated with multiple con-

excess skin on the back of the neck, flat facial pro-

genital abnormalities. Many of these individuals

files, slanted palpebral fissures, overfolded helices,

have in common some degree of intrauterine and

protruding tongues, short fifth fingers, and single

postnatal microcephaly, mental retardation,

palmar creases (Figure 17-2). Congenital heart dis-

seizures, and assorted ocular, gastrointestinal, and

ease is present in 50%. Moderate mental retarda-

skin abnormalities. Only 3 autosomal trisomies (13,

tion becomes apparent as the child grows. In

18, and 21) survive to term and only trisomy 21 or

addition, the child may develop strabismus, nys-

Down syndrome survives past one year. Some

tagmus, small genitalia, and pectus excavatum.

patients with various chromosome deletions

Some children have immunoglobulin imbalance

express only mild signs.

and a susceptibility to respiratory infections while

Down syndrome occurs around the world and

some, especially older children, develop hypothy-

has a prevalence of

90/100,000 live births and

roidism. Most males are infertile. In adulthood

increases dramatically with maternal age >35 years.

after the age of 30 years, a progressive dementia

that has features of Alzheimer’s disease often wors-

Pathophysiology

ens the existing mental retardation.

About 95% of individuals with Down syndrome

Major Laboratory Findings

have trisomy 21 or three copies of chromosome 21

from nondisjunction mainly during gamete for-

Neuroimaging in childhood may demonstrate

mation in the mother. The risk of this maternal

hypomyelination for age. In adults, basal ganglia

abnormality increases with age. Of these cases 5%

calcifications are seen in 50% of cases; brain atro-

have translocations where all or part of chromo-

phy is seen in older adults.

some 21 is attached to another chromosome, usu-

Karyotyping performed on blood lymphocytes

ally 14. It is still unknown how the presence of

or skin fibroblasts establishes the diagnosis and

additional chromosome 21 genes causes this com-

determines whether the cause is trisomy 21 or

plex but easily recognized syndrome. Chromo-

translocation. Finding a translocation means that

some 21 is the shortest chromosome, and genetic

subsequent children of the mother or affected indi-

mapping of the human chromosome suggests it

vidual carry a 50% risk of having Down syndrome.

contains only 225 genes. Clinical features are iden-

tical in children with trisomy or translocation.

Principles of Management and Prognosis

Brain size and weight are normal at birth, but

there is foreshortening of the anterior-posterior

The goal of management is to prevent or minimize

head diameter, flattening of the occiput, and nar-

recognized malformations of the heart, thyroid,

182

FUNDAMENTALS OF NEUROLOGIC DISEASE

Broad,

Flattened Face

Overfolded Helices

Slanted Palpebral Fissures

Protruding

Tongue

Abundant

Neck Skin

Down Hand

Normal Hand

Broad

Normal

Shortened

Fifth finger

Single Palmar

Normal Palmar

Transverse

(Simian) Crease

Creases

Figure 17-2

Down syndrome (Trisomy 21) features.

and GI tract and maximize the potential of the

RECOMMENDED READING

individual. Infants should have careful cardiac,

hearing, and thyroid evaluations. Respiratory and

Fenichel GM. Clinical Pediatric Neurology: A Sign

ear infections should be treated aggressively. Older

and Symptom Approach. 4th ed. Philadelphia:

children may require special school supports but

W.B. Saunders Company; 2001. (This and other

should attend regular elementary and high schools.

pediatric neurology textbooks cover the many dis-

Repeat testing in children and adults for problems

orders of the developing nervous system in detail.)

of thyroid function, vision, hearing, and cardiac

Hoffman HJ, Hendrick EB, Humphreys RP. Mani-

problems should be done. The mean age of sur-

festations and management of Arnold-Chiari

vival at birth is 50 years.

malformations in patients with myelomeningo-

TRAUMATIC BRAIN INJURY AND

SUBDURAL HEMATOMA

Young adult males are at highest risk for TBI,

Traumatic Brain Injury

but the syndrome occurs at all ages, including

babies (shaken baby syndrome). In young adults,

Overview

motor vehicle accidents are the leading cause while

Traumatic brain injury (TBI) is the most com-

in older adults, falls prevail.

mon cause of death and disability in young

TBI is graded as mild, moderate, and severe

adults. Each year in the United States, almost 2

based on the Glasgow coma scale (GCS) after

million people sustain TBI,

1 million receive

resuscitation

(Table

18-1). The GCS is easily

emergency room or outpatient care, and 270,000

administered and helps in acute management

require hospitalization. The incidence of TBI is

and prognosis of the patient. The scale is based

200/1,000,000 individuals. Nearly 50,000 people

on responses to eye opening, limb movements,

die each year and 80,000 have severe neurologic

and verbalization, with a score of 15 being nor-

disabilities from TBI.

mal. GCS scores rank the degree of injury as

Table 18-1

Glasgow Coma Scale

Eye Opening

Motor Response

Verbal Response

Response

Score

Response

Score

Response

Score

Spontaneous

Obeys

Oriented

To speech

Localizes

Confused

To pain

Withdraws

Inappropriate

None

Abnormal flexion

Incomprehensible

(decorticate rigidity)

Extension response

None

(decerebrate rigidity)

None

185

186

FUNDAMENTALS OF NEUROLOGIC DISEASE

mild

(13-15), moderate

(9-12), and severe

present clinically until later. Brain swelling, the

(3-8).

most important cause of secondary injury, begins

shortly after the TBI. Local edema can be found at

areas of brain necrosis as a result of contusion,

Pathophysiology

expanding intracerebral hematomas, or pockets of

Brain damage from TBI in nonmissle head injury

subarachnoid blood. Diffuse brain swelling results

is divided into 2 mechanisms: primary and sec-

from brain hypoxia and ischemia that open the

ondary brain injury. Primary injury occurs at the

blood-brain barrier and allow egress of plasma

moment of head trauma, with several factors con-

into the brain (cerebral edema). As the ICP ele-

tributing to the brain damage. Skull fractures por-

vates, further brain ischemia may develop if the

tend considerable brain injury and are found in

cerebral blood flow falls to critical levels and no

3% of head trauma patients seen in emergency

longer perfuses brain tissue. Subdural or epidural

rooms but are present in over 50% of patients hos-

hematomas may also contribute to increasing ICP.

pitalized and 80% of those who die. Over 1/2 of

Once ICP reaches a critical level (above 20-25 mm

patients have a linear fracture of the skull vault;

Hg), ischemic brain damage develops. One study

4% of these fractures are depressed from their nor-

found ischemic brain damage present in 90% of

mal location.

TBI patients (severe in 27%, moderate in 43%, and

The piaarachoid membrane remains intact over

mild in 30%). The most-common locations of

a contusion, but in a brain laceration, it tears, pro-

ischemic damage were the hippocampus, basal

ducing bleeding. Contusions and lacerations char-

ganglia, and cerebral hemispheres in the watershed

acteristically occur on the inferior surfaces of the

territories (boundary zones between the anterior

frontal and temporal lobe poles where the brain

and middle cerebral arteries and middle and pos-

comes in contact with bony protuberances of the

terior cerebral arteries). Neuronal death, particu-

skull base. The crests of the gyri incur the greatest

larly in the hippocampus, may be mediated by the

injury, but the damage may penetrate to varying

release of glutamate. This activates adjacent

depths. Contusions may develop at the site of

NMDA receptors in calcium channels. Calcium

injury (coup) or to the brain diametrically oppo-

influx then leads to cell death.

site the site of injury (countercoup).

Diffuse axonal injury may be seen in over 1/2 of

Major Clinical Features

TBI patients when unconsciousness lasts as short as

5 minutes. The majority of axonal injury occurs

Many patients with TBI also have severe injuries to

from tearing the axon in the white matter at the

other body parts; these will need to be identified

moment of impact, but some axonal destruction

and treated. This section discusses only the brain

develops later when excess calcium entry and

signs and symptoms seen in TBI.

swelling further damage axon segments (Figure 18-

Information about the cause of head trauma,

1). Common sites of axonal injury include cerebral

location of head impact, and duration of uncon-

gray and white matter, corpus callosum, cerebellum,

sciousness should be obtained from witnesses.

and brainstem. Initially, an axon bulb (retraction

Focal blows from blunt trauma are more likely to

bulb) develops, followed in a few weeks by accumu-

cause skull fractures and contusions while high-

lation of microglia at the injury site. Months later,

velocity accidents and falls often produce more

wallerian degeneration of the axon tract occurs.

diffuse axonal injury. The head should be exam-

Diffuse vascular injury is commonly seen in

ined for signs of penetrating injuries. Signs sugges-

severe TBI. Petechial hemorrhages are seen through-

tive of a basal skull fracture include periorbital

out the hemispheres, basal ganglia, and brainstem

ecchymoses or “raccoon eyes,” CSF drainage from

from shearing damage to small blood vessels.

the nose (rhinorrhea), bleeding from the external

Intracerebral hematomas develop in 10% to 15%

auditory canal, or ecchymoses over the mastoid

of patients, may be single or multiple, and are

bone (Battle’s sign). Pupils should be examined for

often located in the frontal and temporal lobes.

symmetry in size and function. A unilateral fixed

Secondary injury is a multifactorial process that

dilated pupil suggests brain uncal herniation,

initiates at the moment of injury but does not

unless there has been direct eye trauma.

CHAPTER 18—Traumatic Brain Injury and Subdural Hematoma

187

Figure 18-1

(A) MRI of diffuse brain injury 5 days after a high-speed bicycle accident. Arrows indicate several

small areas of subcortical hemorrhage (dark areas in the right hemishpere). (B) FLAIR MRI image of the same

patient showing edema and blood in the posterior body of the corpus callosum. (Courtesy of Blaine Hart, MD)

Mild TBI (GCS scores 13-15) is the most com-

plain of headaches, poor recent memory, inability

mon. These patients often do not lose conscious-

to concentrate, unsteadiness, or vertigo for varying

ness but are stunned (“see stars”) or experience a

lengths of time.

simple concussion

(brief loss of consciousness

In severe TBI (GCS scores 3-8) the patient is

without permanent brain damage). They may not

comatose and unable to open his or her eyes and

recall the event. Such patients may experience

follow verbal commands. The presence of trauma

short-term memory and concentration difficulties

elsewhere in the body is common. These patients

that persist for days to months. Some complain of

may have severe bleeding, hypotension, and

posttraumatic symptoms such as headaches, giddi-

hypoxia that require emergency management. It is

ness, fatigability, insomnia, and nervousness that

common for these patients to worsen over hours as

appear within a few days of the head trauma. Mild

secondary injury events develop. Once comatose,

head trauma patients normally make a full recov-

patients may remain unresponsive for hours, days,

ery, but the process may take months if diffuse

or weeks. A few patients never regain conscious-

axonal injury occurred.

ness and evolve into a persistent vegetative state

In moderate TBI (GCS scores 9-12), the patient

(permanent coma with return of spontaneous

often is stuporous, poorly verbalizes, and opens

breathing and other brainstem reflexes).

the eyes to pain. Other signs of trauma (skin lacer-

A few patients will have initial loss of con-

ations, fractures, etc.) are common. These patients

sciousness followed by a lucid interval, followed

require immediate care, with special attention to

by deterioration of consciousness. The initial loss

possible neck injuries and should be taken to an

of consciousness is due to the impact of the head

emergency room for further observation and neu-

trauma and the second is due to an epidural

roimaging. Recovering patients frequently com-

hematoma. This scenario develops in about 1/2 of

188

FUNDAMENTALS OF NEUROLOGIC DISEASE

patients with epidural hematoma; the others do

gitis, or brain abscess). The risk of a subdural or

not regain full consciousness before deteriora-

epidural hematoma is low (1/1,000) if no frac-

tion. An epidural hematoma develops most fre-

ture is identified but rises to 1/30 if a fracture is

quently from a linear skull fracture that causes

seen. Since secondary brain injury may be

laceration of a branch of the middle meningeal

delayed, repeat CT scans are often required as

artery (Figure 18-2).

new signs develop.

The EEG immediately after injury shows sup-

pression of electrical activity over the injured brain

Major Laboratory Findings

that returns as generalized, large-amplitude, slow

Neuroimaging in the emergency room is usually

waves (δ). Depending on the severity of the TBI,

done to evaluate for neck fractures, skull fractures,

the EEG can return to normal.

and intracranial hematomas. Most often this

involves initial cervical spine x-rays followed by a

Principles of Management and Prognosis

cranial noncontrasted CT. If a depressed skull

fracture

(bone completely beneath the skull

Optimal treatment of the TBI patient has yet to be

vault and often penetrating into the brain) is

established. The amount of primary brain injury is

detected, surgery is required. Open fractures

determined at the time of trauma. However, the

where there is a connection from the skin surface

outcome can be improved by minimizing second-

to the brain increase the risk of intracranial

ary brain injury. One important way is by control-

infection (subdural infection [empyema], menin-

ling increased ICP and preventing cerebral

Dura

Epidural

Subdural

Hematoma

Skull

Middle

Meningeal

Arteries

Figure 18-2

Diagram of epidural and subdural hematomas.

CHAPTER 18—Traumatic Brain Injury and Subdural Hematoma

189

ischemia. Diffuse cerebral ischemia occurs when

serum osmolality reaches 320 mmol/L. At >320

the cerebral perfusion pressure is inadequate. This

mmol/L, mannitol loses its effect and serum

is particularly important, since TBI often results in

electrolytes become deranged. Hyperventilation

loss of cerebral autoregulation of blood pressure,

will reduce ICP, but its use is controversial since

making brain perfusion dependent on cerebral

it does so by lowering arterial PCO₂ and con-

perfusion pressure. Cerebral perfusion pressure is

stricting cerebral blood vessels. Long-term use of

defined as “(mean arterial pressure) - (intracranial

hyperventilation is thought to worsen diffuse

pressure).” Thus a fall in systemic blood pressure

cerebral ischemia and hence prognosis. Drainage

or a rise in ICP decreases cerebral perfusion pres-

of CSF through a ventricular pressure monitor

sure. Brain ischemia occurs when the cerebral per-

catheter will also reduce ICP. If the ICP cannot

fusion pressure is <70 mm Hg, which corresponds

be controlled by standard medical management

to a cerebral blood flow of <40 mL/100 g of brain

or by surgical removal of any hematomas, iatro-

per minute. Studies have shown that hypotension

genic anesthetic coma with barbiturates can be

(systolic blood pressure <90 mm Hg), elevated

considered since barbiturate coma can some-

ICP (above 20-25 mm Hg), and hypoxia (arterial

what protect neurons from ischemia. Corticos-

PaO₂ <65 mm Hg, with digital pulse oximetery

teroids and hypothermia have not been shown to

oxygen saturation of <90%) are the major causes

be beneficial.

of diffuse brain ischemia. Elevated ICP comes

The arterial blood pressure should be main-

from intracerebral hemorrhages, extracerebral

tained >90 mm Hg and treated aggressively if

hematomas, and cerebral edema. Normal ICP is 0

hypotension develops. Patients with prolonged

to 10 mm Hg; >20 mm Hg is considered suffi-

coma will require nasogastric feeding to maintain

ciently abnormal to treat.

nutrition. Since subdural and epidural hematomas

Prevention of secondary injury begins at the

may develop late, repeat CT scans may be neces-

scene of the accident. Studies have shown that up to

sary if the ICP rises or if the patient deteriorates.

1/3 of patients with severe TBI experience hypoten-

About 5% of TBI patients will experience a gen-

sion or hypoxia before reaching a hospital; the

eralized seizure during their hospitalization, but

hypotension doubles the morbidity and mortality.

prophylactic use of anticonvulsants has limited

Thus management of the ABCs is essential (see

benefit. Following hospitalization, 5% of patients

Chapter 16, “Coma and Cerebral Death”). All mod-

subsequently develop posttraumatic epilepsy

erate-to-severe TBI patients should receive nasal

(focal or primarily generalized seizures) that

oxygen, and the systolic blood pressure should be

requires anticonvulsants.

maintained >90 mm Hg. In the case of cervical

The prognosis of TBI depends on its severity. In

spine fractures, intubation should occur without

severe TBI (GCS scores 3-8), there is a linear corre-

neck extension. If signs of impending herniation

lation between admission GCS and poor outcome

are present (dilated and fixed pupil or decerebrate

(death, vegetative state, and neurologic disability).

posturing), emergency hyperventilation is started.

Other poor early prognostic indicators include age

In the emergency room following stabilization

>60 years, hypotension on admission, and a fixed

of the patient, a noncontrast CT is performed. If

dilated pupil. The duration of coma, severity of

surgical lesions are identified

(subdural or

ICP, and development of hypotension correlate

epidural hematoma, large intracerebral hematoma,

with poor patient outcomes. Of hospitalized

or depressed skull fracture), the patient usually

patients with severe TBI, 20% die and many sur-

goes to the operating room. Since measurement of

vivors have residual neurologic deficits. Rehabilita-

ICP plays a key role in the management of severe

tion of these patients is slow and difficult. Patients

TBI, many neurosurgeons place an ICP monitor to

may complain of headaches, poor concentration,

follow changes.

cognitive deficits, and impulsivity. In adults with

The goal is to maintain ICP <20 mm Hg, but

severe TBI, unemployment at 5 years is about 70%

most medical management methods reduce ICP

compared with a 14% preinjury unemployment

only temporarily. Elevation of the head to 30°

rate. In children who survive severe TBI, behavioral

may help. Mannitol given in intravenous boluses

and learning problems may be a consequence of

will lower ICP and can be continued until the

loss of cognitive skills and poor concentration.

190

FUNDAMENTALS OF NEUROLOGIC DISEASE

However, under federal special education laws, a

In adults, there is a slowly progressive, age-

child who has a TBI is eligible for free and appro-

dependent, atrophy of the brain. From age 50 to 80

priate public school education and related services.

years the normal brain shrinks by 200-g weight

and the space between the brain and skull

increases by 10% of total intracranial space. In

Chronic Subdural Hematoma

addition, many degenerative brain diseases accel-

erate brain atrophy. Since the skull does not invo-

Introduction

lute, the smaller brain enables independent

movement of the two during head trauma that can

A subdural hematoma (SDH) may be acute, suba-

lead to a shearing or tearing of small arachnoid

cute (signs appear within 1 to 3 weeks of head

venules. The existence of anticoagulation pro-

trauma), or chronic (signs appear more than 3

motes a prolonged oozing of blood into the sub-

weeks after trauma). Acute SDHs develop within 1

dural space.

week following moderate-to-severe TBI or in

Once present, the subdural blood may expand

patients with bleeding diatheses and are discussed

rather than shrink, as a bruise would do elsewhere

earlier in this chapter. This section will discuss

in the body. Within days, fibroblasts from adjacent

those patients who develop chronic SDHs follow-

blood vessels begin forming a capsule around the

ing mild or inapparent head trauma.

hematoma. New vessels that nourish the capsule

The incidence of SDH is rare in small children,

and enter the hematoma lack a blood-brain bar-

lowest in young adults (1/100,000 and usually fol-

rier. This neovascularization is “leaky,” allowing

lows moderate-to-severe TBI), and highest in the

RBCs and protein to enter the hematoma. Sec-

elderly (7/100,000). In young adults the male-to-

ondary clotting changes from increased tissue

female ratio is 3:1 while in the elderly it is 1:1.

plasminogen activator and diminished plasmino-

Chronic SDH mainly develops from head trauma

gen activator inhibitor also contribute to

(motor vehicle accidents; falls from syncope,

hematoma expansion in a poorly understood

ataxia, weakness, or seizures; or child abuse), but

manner. Hence, the hematoma expansion appears

can occur in patients with bleeding problems

to be due to recurrent small hemorrhages into the

(anticoagulation, thrombocytopenia, liver failure,

hematoma (20%) and/or from leaky neovascular-

and alcoholism), dural lesions (sarcomas, arteri-

ization of the hematoma (80%).

ovenous malformations, and metastatic cancer),

Over weeks to months many hematomas con-

and low CSF volume (CSF shunts, renal dialysis,

tinue to expand until they eventually displace suf-

and excess diuretics).

ficient underlying brain tissue to cause signs and

symptoms. Untreated, the SDH will continue to

Pathophysiology

shift intracranial structures until coma and brain

An SDH begins in the subdural space between the

herniation occur. In others, there is stabilization of

dura mater and arachnoid mater of the meninges.

the clot with slow clot resolution unless subse-

The dura intimately adheres to the inner table of

quent head trauma causes a new hemorrhage into

the skull and consists of a thick layer of fibroblasts

the subdural hematoma.

and extracellular collagen. Inner border cells con-

The majority of SDHs develop over the lateral

nect directly with the outer layer of the arachnoid

aspect of the cerebral convexities but they rarely

membrane. The arachnoid is more vascular and

occur in the posterior fossa.

contains blood vessels with tight junctions that

arise from meningeal vessels in the internal carotid

Major Clinical Features

and vertebral artery system. Blood leakage from

tears of arachnoid venules initiates the hematoma.

In a chronic SDH, signs and symptoms slowly

In infants and small children whose brain is

develop over weeks. Headache occurs in >90% of

growing, the cerebral cortex abuts tightly against

patients and may be lateralizing, constant, and rel-

the dura, preventing movement of the brain apart

atively mild. As ICP increases, they often note a

from the skull. As such, a stretching of these blood

deterioration of mental status, with confusion,

vessels does not occur, making SDHs rare.

lethargy, and memory disturbances. This is partic-

CHAPTER 18—Traumatic Brain Injury and Subdural Hematoma

191

ularly common in the elderly. A progressive hemi-

paresis develops in about 1/2 of patients and apha-

sia is found in 20%. Focal or generalized seizures

occur in

10%. The signs and symptoms of a

chronic SDH are not specific; 40% are initially

misdiagnosed as other diseases such as Alzheimer’s

disease, vascular dementia, stroke, depression, or

brain neoplasm. In general, SDH should be con-

sidered in the elderly who have progressive deteri-

oration of mental status, hemiparesis, and

new-onset headache.

Major Laboratory Findings

Neuroimaging is the key to the diagnosis. The CT

scan demonstrates an oval hematoma between the

dura and brain and, depending on the age of the

hematoma, has differing densities (Figure 18-3).

Acute SDH looks hyperdense relative to brain tis-

sue. Subacute SDH appears isodense (same density

Figure 18-3

Computed tomography scan of chronic

as adjacent brain) and is recognized by lateral ven-

subdural hematoma with mixed densities. (Courtesy of

tricle compression and shifting, medial displace-

Blaine Hart, MD)

ment of the gray-white junction, and loss of sulcal

spaces that normally are seen against the skull

table. Chronic SDHs are hypodense (75%) or have

the outcome of surgery for symptomatic SDH

mixed densities (25%), suggesting recurrent bleed-

was good in 86% of patients, with moderate dis-

ing into the hematoma. SDHs on T1-weighted

ability in 10%, severe disability in 2%, and death

MRI images are hyperintense. On T2-weighted

in 2%. The time to maximum recovery can be

images, the hematoma acutely is hypointense,

within days in younger patients and months in

becoming hyperintense after 2 weeks.

the elderly.

The EEG typically shows nondiagnostic sup-

As a consequence of frequent hematoma recur-

pression of activity and slow waves in the area of

rence in the very old or in patients with disease-

the hematoma.

induced brain atrophy, a decision must be made

whether to operate and remove all the SDH. Indi-

Principles of Management and Prognosis

cations for observation include no major shift of

mid-line structures, no marked new neurologic

Typical management of a symptomatic SDH is

signs from the baseline, and incidental discovery

drainage of the hematoma by craniotomy; this

by neuroimaging.

usually is performed when the hematoma has

solid clots or is associated with recurrent bleed-

ing, tumor, or possible infection. Surgical com-

RECOMMENDED READING

plications include recurrent hematoma, infections,

and air under pressure in the meninges or ven-

Chen JC, Levy ML. Causes, epidemiology, and risk

tricles (tension pneumocephalus) from incorrect

factors of chronic subdural hematoma. Neuro-

placement of the drain. Recurrent hematoma

surg Clin N Am 2000;11:399-406. (Entire issue

often occurs when marked brain atrophy pre-

devoted to chronic subdural hematoma.)

vents the brain from reexpanding to the inner

Ghajar J. Traumatic brain injury. Lancet 2000;356:

table of the skull. In an emergency, twist drill

923-929. (Good review of current management

burr holes can be made to relieve ICP. In 1 study

of TBI.)

NEUROLOGIC COMPLICATIONS

OF ALCOHOLISM

rates leads to increasing alcohol levels in the blood

Overview

and brain.

Alcoholism, the addiction to alcohol, is character-

The effects of ethanol on the nervous system

ized by a craving of alcohol and a tolerance to its

are numerous and complex. Which brain interac-

intoxicating effects. Worldwide, alcoholism has an

tions are responsible for specific ethanol syn-

enormous impact on society, as it is the number

dromes remains unclear. Ethanol enters to cell

one abused drug in the world. In the United States,

membranes, increasing membrane fluidity and

there an estimated 8 million people are alcoholics.

possibly interfering with signal transduction. Sig-

About 20% of hospital admissions involve medical

nificant components of the withdrawal syndrome

complications of excessive drinking. The cause of

after chronic alcohol use reflect reduced neuro-

alcoholism remains poorly understood but genetic

transmission in the inhibitory type A GABA path-

factors appear to play a role, as alcoholism is 7

ways and enhanced neurotransmission in

times more frequent in first-degree relatives of

glutamate (NMDA) pathways. Alcohol withdrawal

alcoholics than in the general population. Adop-

causes complex decreases in GABA receptor bind-

tion studies in Sweden found that alcoholism in a

ing, resulting in loss of presynaptic inhibitory con-

biologic parent was more important than growing

trol. During alcohol withdrawal, increased

up in an environment with alcoholism in the

dopaminergic transmission may cause hallucina-

adoptive parents. Identical twins have a higher

tions and increased autonomic activity. Hypomag-

concordance for alcoholism than fraternal twins.

nesia and hypocalcemia frequently occur during

Ethanol enters the circulation within minutes

alcohol withdrawal and likely contribute to CNS

of consumption and rapidly distributes through-

hyperexcitability by altering neuronal action

out the body. The liver metabolizes over 95% of

potentials.

alcohol via alcohol dehydrogenase, which converts

Complications of alcoholism involve many

ethanol into acetaldehyde, which is in turn metab-

organs, but damage to the CNS and PNS is partic-

olized by aldehyde dehydrogenase into acetate. In

ularly common. This chapter will review the major

the average adult, alcohol metabolizes at a rate of 8

neurologic complications from alcohol intoxica-

g/h (~8 oz beer/h). Alcohol consumption at faster

tion and withdrawal (Figure 19-1).

193

194

FUNDAMENTALS OF NEUROLOGIC DISEASE

•Tremulousness and hallucinosis

•Withdrawal seizures

•Delirium tremens

Early

Late

Days after abstinence

Figure 19-1

Time course of alcohol withdrawal.

Drunkenness and Alcoholic Coma

Alcoholic Tremulousness and

Hallucinosis

Ethanol readily crosses the blood-brain barrier,

enabling brain alterations to begin soon after

When alcohol is abruptly reduced, a hyperex-

drinking. Signs of intoxication in nonalcoholic

citable withdrawal syndrome develops. The symp-

persons begin at blood levels of approximately 60

toms of alcohol withdrawal can be divided roughly

mg/dL; gross intoxication occurs at levels of 120 to

into those from autonomic hyperactivity (tremu-

150 mg/dL. In alcoholics, intoxication may not

lousness, sweating, nausea, vomiting, and anxiety)

occur until blood levels are as high as 150 mg/dL.

and from neuronal excitation (confusion, agita-

Signs of intoxication consist of varying degrees of

tion, delusions, hallucination, and seizures).

euphoria, exhilaration, excitement, loss of

Tremor (“shakes” or “jitters”) develops in over

restraint, irregular behavior, slurred speech, inco-

50% of individuals in withdrawal. The tremors

ordination of movement, gait ataxia, irritability,

begin about 6 hours after the last drink and worsen

and combativeness. While the biochemical effects

over the next 2 to 3 days (Figure 19-1). The tremor

are incompletely understood, the net result

occurs at rest and with action, and is coarse, irreg-

appears to be excitation of brain activity. Con-

ular, and increases with stress. Patients may also

sumption of large volumes of beer (beer is hypo-

have an increased startle response. The mental sta-

tonic and ethanol inhibits antidiuretic hormone)

tus remains relatively clear, but the patient feels

may produce a sufficient degree of hyponatremia

uncomfortable. The tremor abates with consump-

to cause a generalized seizure.

tion of more ethanol or use of benzodiazepines.

At higher blood levels, brain functions deterio-

Alcoholic hallucinosis occurs in 10% of patients

rate, with the development of lethargy, stupor, and

in alcohol withdrawal and typically begins from 24

coma, suggesting ethanol now produces inhibition

to 36 hours after drinking cessation. Disordered

of brain activity. Alcoholic coma is seen at blood

perceptions of vision or sound develop that may

levels around 300 mg/dL and respiratory failure

frighten or amuse the patient. Occasionally, frank

develops at levels of

>400 mg/dL. Comatose

hallucinations occur. Patients feel “shaky” inside,

patients often require intubation and mechanical

develop tachycardia, and complain of general

ventilation until the alcohol level lowers.

weakness and insomnia but do not become agi-

CHAPTER 19—Neurologic Complications of Alcoholism

195

tated. This clinical picture persists for several days

alcohol-withdrawal seizures. Since patients often

to weeks. Use of benzodiazepines again relieves

stop their anticonvulsants during drinking spells,

most symptoms.

the combination of alcohol and anticonvulsant

withdrawal may actually increase their risk of

future seizures.

Alcohol-Withdrawal Seizures

Alcohol-withdrawal seizures occur in nearly 5% of

Delirium Tremens

individuals who have been drinking steadily for

years and then abruptly stop. For example, undiag-

Delirium tremens (DTs) is a serious but uncom-

nosed alcoholics who are hospitalized may experi-

mon complication of alcohol withdrawal (less than

ence a seizure the day after admission. The

5% of hospital admissions for alcoholism) and

primarily generalized seizure occurs 7 to 72 hours

presents with profound delirium and autonomic

after alcohol cessation, with a peak at 12 to 48 hours

nervous system overactivity. Patients have marked

(Figure 19-1). Patients tend to have 1 to 4 seizures

confusion, agitation, hallucinations, tremors, and

over several hours. Status epilepticus is rare.

sleeplessness. Signs of increased autonomic nerv-

Alcohol-withdrawal seizures are partly a diagno-

ous system activity include fever, tachycardia,

sis of exclusion. The mechanism for withdrawal

dilated pupils, and profuse sweating. Clinical signs

seizures is unknown but thought to result from a

begin 2 to 5 days after alcohol withdrawal and may

hyperactive brain

(due to alcohol withdrawal),

be preceded by withdrawal seizures (Figure 19-1).

accompanying low serum magnesium, and elevated

Life-threatening events include high fever, dehy-

arterial pH from respiratory alkalosis. In keeping

dration, hypotension, cardiac arrhythmias, and

with this,¹/₂ of patients withdrawing from ethanol

secondary complications of trauma (from the agi-

have an abnormal EEG manifesting myoclonic or

tation) or alcohol-associated medical conditions

convulsive responses to flashing lights.

(liver failure, GI bleeding, systemic infection, or

Of patients brought to the emergency room with

pancreatitis).

possible alcohol-withdrawal seizures,

50% have

Treatment aims at reducing agitation and main-

another identifiable etiology. These patients often

taining fluid and electrolyte balance. Lorazepam

have a seizure aura (implying a focal origin for the

given repeatedly intravenously or intramuscularly

seizure), history of serious head trauma while intox-

is required for sedation. Patients require fluid

icated, atypical seizures, abnormal neurologic exam,

replacement of up to 4 to 10 L/24 h to prevent

or signs of systemic infection. Neuroimaging stud-

dehydration and circulatory collapse. Serum

ies can identify subdural hematomas, hemispheric

potassium and magnesium levels are usually low

contusions or infarctions, intracerebral masses

and require correction.

(brain abscess, neurocysticercosis, tumors, and vas-

The duration of DTs lasts 2 to 7 days, with most

cular malformations), or meningitis. In patients

cases ending by day 3. Recovering patients regain

with known epilepsy, some seizures are actually

alertness and the ability to cooperate but seldom

triggered by drinking alcohol and stopping their

have any memory of the acute illness. The mortal-

anticonvulsant medications. Neurologic exam

ity rate is 10%.

should not show acute signs that cannot be attrib-

uted to chronic alcohol usage. The blood alcohol

level should be 0 or very low and the CSF exam, if

Wernicke’s Encephalopathy and

done, is normal.

Korsakoff ’s Psychosis Syndrome

Administration of benzodiazepines (lorazepam

or diazepam) to patients during alcohol with-

Introduction

drawal usually prevents further seizures during the

critical withdrawal period. Phenytoin administra-

Wernicke’s encephalopathy and Korsakoff ’s psy-

tion does not prevent seizures. Patients who per-

chosis are linked to abnormally low levels of thi-

manently stop drinking do not have future

amine (vitamin B₁) in the CNS. Chronic alcoholic

seizures. Controversy exists as to whether adminis-

patients tend toward malnourishment. People with

tration of anticonvulsants prevents subsequent

alcoholism may obtain as much as 1/2 their daily

196

FUNDAMENTALS OF NEUROLOGIC DISEASE

caloric intake from ethanol, resulting in serious

indifference to surroundings. Speech is minimal.

nutritional deficiencies, including thiamine,

Drowsiness is common and may progress to stu-

niacin, folate, and protein. Hence, these two disor-

por if untreated. Mild disorders of perception or

ders are not linked to the direct toxic effects of

hallucinations are experienced by 20% of patients.

alcohol or alcohol withdrawal. Thiamine is

Korsakoff ’s psychosis is a unique mental state in

required for all tissues and is found in high con-

which retentive memory is impaired out of propor-

centration in the brain, heart, skeletal muscle, liver,

tion to other cognitive functions in an otherwise

and kidney. Thiamine is absorbed in the small

alert, fluent, and responsive patient. A selective dis-

intestine and transported to the brain by an

order of memory, Korsakoff ’s psychosis typically

energy-dependent transport system. A series of

follows ≥1 episodes of Wernicke’s encephalopathy.

phosphorylation reactions produces thiamine

Impaired memory for previously established recent

diphosphate, a required cofactor in carbohydrate

events (retrograde amnesia) and the inability to

incorporate new memories (anterograde amnesia)

and amino acid metabolism. Thiamine-dependent

appears, but immediate recall stays preserved.

enzymes are involved in the biosynthesis of neuro-

Patients, while disoriented to place and time and

transmitters and for the production of reducing

unaware of their memory deficits, confabulate or

equivalents used in oxidant stress defenses.

invent material to fill in memory gaps.

Manifestations of thiamine deficiency can

involve the brain

(Wernicke-Korsakoff syn-

drome), peripheral nerves (dry beriberi), or the

Major Laboratory Findings

cardiovascular system (wet beriberi).

MRI abnormalities vary in acute patients and

include T2-weighted abnormalities in the peri-

Pathophysiology

aqueductal region, medial thalamus, and mamil-

Neuropathologic findings in Wernicke’s encephalo-

lary bodies. Later, the T2-weighted abnormalities

pathy include demyelination, glial and vascular

disappear and atrophic changes occur in the

proliferation, hemorrhage, and necrosis. These

mamillary bodies and cerebellar vermis, with

principally affect gray-matter regions of the medial

enlargement of the third ventricle.

thalamus, hypothalamus, tegmentum of the pons

and medulla, and cerebellum

(particularly the

Principles of Management and Prognosis

Purkinje and granule cells of the anterior-superior

Early diagnosis of Wernicke’s encephalopathy is

vermis). Korsakoff ’s psychosis shows pathologic

critical, as administration of intravenous thiamine

brain changes, including hemorrhages and necro-

can correct the acute neurologic problem. In fact, it

sis in the dorsomedial nucleus of the thalamus

and/or the mamillary bodies.

is prudent to administer parenteral thiamine to

every alcoholic patient seen in the emergency room

or hospitalized, since administration of glucose can

Major Clinical Features

precipitate the onset of Wernicke’s encephalopathy.

Wernicke’s encephalopathy is a disease of acute or

It is less clear whether thiamine can reverse the

subacute onset and is characterized by nystagmus,

memory deficit seen in Korsakoff ’s psychosis. Poor

abducens and conjugate gaze palsies, gait ataxia,

prognostic factors include severe clinical features,

and a confusional state. The ocular signs consist of

delayed thiamine administration, T2-weighted

nystagmus that is both horizontal and vertical,

abnormalities on MRI, and cerebellar or mamillary

paralysis of external recti, and paralysis of conju-

body atrophy. In countries using thiamine-enriched

gate gaze. Nystagmus and weakness of the lateral

flour in bread, the incidence of Wernicke-Korsakoff

rectus muscles are the most common; total oph-

syndrome has fallen but not disappeared.

thalmoplegia is rare. The ataxia of stance and gait

typically produces a wide-based, unsteady, short-

stepped, lurching gait. Ataxia of limbs remains less

Alcoholic Cerebellar Degeneration

pronounced, and many patients have normal fin-

ger-to-nose and heel to shin tests.

Chronic alcoholism often leads to slowly progres-

Most patients experience a quiet confusional

sive gait ataxia similar to that seen in Wernicke’s

state characterized by apathy, inattentiveness, and

encephalopathy. This is a wide-based, unsteady,

198

FUNDAMENTALS OF NEUROLOGIC DISEASE

develops, no treatment has been shown to reverse

brain weight and numbers of neurons, and (4)

it.

peak blood alcohol concentrations are more criti-

cal than the same dose of alcohol at a lower peak

level. The threshold amount of alcohol consump-

Alcoholic Polyneuropathy

tion needed to produce fetal toxicity remains

unknown. As such, total abstinence from drinking

A distal symmetrical sensorimotor polyneuropathy

alcohol is currently recommended for pregnant

is common in chronic alcoholism. The etiology of

women and women planning pregnancy.

the neuropathy remains unclear, although direct

How alcohol damages the developing fetal

effects of alcohol on the peripheral nerve and nutri-

brain is poorly understood, but it can kill develop-

tional/vitamin deficiencies have been proposed.

ing neurons. In early development, excessive cell

The majority of patients have slowly progres-

sive symptoms of paresthesias, burning dysesthe-

sias, numbness, and muscle cramps in their feet

Table 19-1

Characteristic Features of

and lower legs. On exam, there is a loss of ankle

Fetal Alcohol Syndrome

jerks, diminished vibratory sensation in the feet,

and varying degrees of foot numbness and weak-

Facial Abnormalities

ness. Loss of pain sensation appears less com-

Short palpebral fissures

monly. As the disease advances, leg weakness and

Ptosis (droopy eyelids)

gait apraxia occur from loss of position sense in

Flat mid-face

the feet and possibly concomitant alcoholic cere-

Smooth philtrum

bellar degeneration. Axonal degeneration, the

Thin upper lip

principal pathologic process, occurs although seg-

mental demyelination can occur. If alcohol con-

Growth Retardation

sumption stops, the neuropathy may improve. Use

Low relative birthweight

of simple analgesics and tricyclic antidepressant

Growth retardation despite adequate nutrition

medications may alleviate the burning dysesthe-

Low weight relative to height

sias.

Central Nervous System

Neurodevelopmental Abnormalities

Fetal Alcohol Syndrome (FAS)

Microcephaly

Agenesis of corpus callosum

Introduction

Cerebellar hypoplasia

Neurologic signs that may include poor fine-motor

Alcohol is the most common human teratogen. Of

coordination, hearing loss, and clumsy gait

the 60% of women who drink alcohol, 16% report

Behavioral Abnormalities

drinking during their pregnancy and 4% report

drinking more than 7 times per week. An esti-

Learning disabilities (poor abstract reasoning, math

mated 0.5% (500/100,000) of all live births have

skills, judgment, concentration, and memory)

some prenatal alcohol damage.

Poor school performance

Poor impulse control

Hyperactivity

Pathophysiology

Poor social interactions

The pathophysiology of FAS, while incompletely

Birth Defects

understood, has several generalizations. Human

and animal studies have found that (1) consump-

Congenital heart defects

tion of ≥1 alcoholic drinks per day is highly asso-

Skeletal and limb abnormalities

ciated with FAS, (2) alcohol exposure in the first

Ophthalmologic abnormalities

trimester of pregnancy leads to the characteristic

Sensorineural hearing loss

congenital malformations of the face and midline

Cleft lip or palate

brain, (3) third-trimester alcohol exposure decreases

CHAPTER 19—Neurologic Complications of Alcoholism

199

Low Nasal Bridge

Microcephaly

Epicanthal Folds

Short Palpebral

Flat Midface

Fissures with

Wide-spaced Eyes

Short, Upturned Nose

Indistinct Philtum

Low Set Ears

Thin Upper Lip

with Minor

Abnormalities

Micrognathia

(Small Chin)

Figure 19-3

Fetal alcohol syndrome.

death in the mid-line of the developing embryo

Major Laboratory Findings

may account for mid-line brain defects (agenesis

Clinicians have created categories such as alcohol-

of corpus callosum) and craniofacial abnormali-

related birth defects and fetal alcohol effects or

ties. In late fetal development, the loss of neurons

alcohol-related neurodevelopmental disorder for

is more widespread, producing a low brain weight.

infants damaged by ethanol who do not meet all

Hypotheses of the mechanism by which ethanol

the criteria for FAS. Presently there is no labora-

kills neurons includes formation of toxic acetalde-

tory test that establishes the diagnosis.

hyde by alcohol dehydrogenase metabolism of

ethanol; free-radical formation, which causes cel-

lular damage in the developing brain; and disrup-

Principles of Management and

tion of the L1 cell adhesion molecule (CAM),

Prognosis

which is important in the developing brain.

Patient management begins with an early diagno-

sis that enables medical intervention, psychologic

Major Clinical Features

help, educational evaluation, and access to special

Infants with FAS demonstrate several characteris-

education and related services such as speech and

tic abnormalities that involve growth retardation,

language programs and community resource pro-

craniofacial structure, neurodevelopmental abnor-

grams. Helping the mother and other family mem-

malities, behavioral problems, and occasional

bers enables family preservation and helps prevent

birth defects (Table 19-1 and Figure 19-3). The

drinking during subsequent pregnancies.

average IQ score in FAS is 66, with a range of 16 to

105. These IQ scores are higher than those seen in

Down syndrome (25-65) and fragile-X syndrome

RECOMMENDED READING

(30-55). Nearly 60% of FAS children develop sig-

nificant behavioral problems compared with 25%

Earnest MP. Seizures. Neurol Clin 1993;11:563-575.

for Down syndrome children. The cognitive,

(Good review of alcohol-withdrawal seizures.)

behavioral, and psychosocial problems persist into

Erwin WE, Williams DB, Speir WA. Delirium

adulthood.

tremens. South Med J

1998;91:425-432.

200

FUNDAMENTALS OF NEUROLOGIC DISEASE

(Reviews pathophysiology and current therapeu-

348:1786-1795. (Nice review of the many prob-

tic approaches.)

lems and treatment approaches for patients dur-

Foy A, Kay J, Taylor A. The course of alcohol with-

ing alcohol withdrawal.)

drawal in a general hospital. Q J Med

Thackray HM, Tifft C. Fetal alcohol syndrome.

1997;90:253-261. (Observational study of 539

Pediatr Rev 2001;22:47-55. (Excellent review of

hospitalizations for alcohol withdrawal in an

clinical and laboratory features of FAS.)

Australian general hospital.)

Victor M. Persistent altered mentation due to

Hall W, Zador D. The alcohol withdrawal syn-

ethanol. Neurol Clin 1993;3:639-661. (Reviews

drome. Lancet 1997;349:1897-1900. (Reviews

Wernicke-Korsakoff syndrome, acquired hepato-

the clinical features, proposed pathogenesis, and

cerebral degeneration, and alcoholic dementia.)

management of patients in alcohol withdrawal.)

Zubaran C, Fernandes JG, Rodnight R. Wernicke-

Kosten TR, O’Connor PG. Management of drug

Korsakoff syndrome. Postgrad Med J 1997;73:

and alcohol withdrawal. N Engl J Med 2003;

27-31. (Overall review of subject.)

DISORDERS OF PAIN

AND HEADACHE

pain. C fibers travel to the dorsal root ganglion and

Pain

terminate in the outer layers of the dorsal horn of

several adjacent segments of the spinal cord. They

Pain and headache are symptoms and not diseases.

release glutamate and substance P as their excita-

Like weakness and dizziness, pain has many causes

tory neurotransmitters. In the periphery, pain

that must be sorted out by careful history and

fibers also may release a variety of peptides,

exam.

including substance P, bradykinin, serotonin, and

prostaglandin, which induce local inflammation.

Overview

These, in turn, trigger firing of adjacent pain noci-

Pain, a highly complex perception, is more than a

ceptors, thus amplifying the intensity of the pain

sensory experience warning of danger. The percep-

signal and expanding the skin area involved.

tion of pain is influenced by environment and by

In the dorsal horn, interneurons modulate

emotion as well as by complex and incompletely

propagation of the upward pain signals. The signal

understood pathways that have multiple regula-

may be diminished or inhibited by interactions

tory controls. The following simplification of the

from endorphin interneurons (endogenous opi-

immensely complicated pain system is useful in

oids) or by concomitant signals coming from

understanding the types of pain patients may

peripheral Aδ pain fibers. The pain signal may also

experience.

be amplified by a less-understood mechanism

Pain pathways appeared at different times in

called central sensitization. Many pain drugs, such

evolution for potentially different purposes. The

as opioids, tricyclic antidepressants, and capsaicin,

most primitive system uses polymodal nociceptors

act, in part, at the dorsal horn.

activated by a variety of high-intensity mechani-

There are 2 major pathways for the central

cal, chemical, and thermal stimuli. These nerve

transmission of pain signals. The first uses the

fibers are small-diameter, unmyelinated C fibers

spinomesencephalic pathway, where pain fibers

that conduct slowly at 0.5 to 2.0 m/s. They fire

project from the dorsal horn to the mesencephalic

continuously without decay if the noxious stimu-

reticular formation and periaqueductal gray

lus is maintained. Activation of C fibers is appreci-

region of the mid-brain. Signals may also travel via

ated as a burning, uncomfortable, poorly localized

the second spinoreticular (contralateral and ipsi-

201

202

FUNDAMENTALS OF NEUROLOGIC DISEASE

lateral) pathway from the dorsal horn to reach the

to it. Proximal nerve damage may be from

reticular formation of the medulla and pons. Some

demyelination or local pressure damage, while dis-

of these impulses eventually reach the thalamus

tal damage may be secondary to infection, etc. If

and somatosensory cortex. Both pain pathways

only Aδ fibers fire ectopically, the result is painless

interact with interneurons, where again pain mod-

paresthesias, like hitting the ulnar nerve at the

ulation occurs. The periaqueductal gray region is

elbow. If C fibers or both fiber types ectopically

rich in endorphin-containing interneurons that

fire, the individual may experience dysesthesias,

can inhibit pain signals. This brain area is also a

which are spontaneous uncomfortable sensations,

target for pain medications. Morphine activates

or allodynia, which is discomfort from gently rub-

opioid receptors and affects descending pathways

bing the skin. Hyperalgesia develops when the

that control nocioceptive inputs. Both central

nociceptor input is amplified peripherally or cen-

pathways are thought to be responsible for slower,

trally, yielding more pain than would otherwise be

more diffuse, burning types of pain sensation. It is

expected.

dysfunction of this complex pain pathway that

commonly produces the chronic disagreeable pain

so disruptive to the lives of many patients.

Headache Pain

The most recent evolutionarily pain pathway

conducts nocioceptive pain signals generated by

Overview

mechanical, thermal, or chemical noxious stimuli

For most types of head pain, the first and second

all the way to the cerebral cortex and thus into

divisions of the trigeminal nerve bring noxious

consciousness. This pathway system, more rapid

signals to the brain and to awareness. Only certain

than the primitive pathway, gives more precise

parts of the CNS are innervated by pain fibers.

localization of the pain source. Stimulation gener-

These include all blood vessels (arteries, veins, and

ates signals that are felt as sharp, pricking, localiz-

sinuses), meninges, bone, and several cranial

able pain. Peripheral pain fibers are small-diameter,

nerves (CNs V, VII, IX, and X). In addition, the

thinly myelinated Aδ fibers that conduct at 5-30

scalp, skull muscles, sinus mucosa, and teeth con-

m/s. These axons usually have dynamic firing rates

vey pain signals. However, the brain parenchyma is

that decline with time even if the stimulus is main-

insensitive to pain. Somatic pain usually localizes

tained (accommodation). These fibers travel to the

to the exact area of injury (e.g., scalp laceration),

dorsal root ganglion, terminate in the outer layers

while the pain from headache is more diffuse and

of the dorsal horn of the adjacent segments of

localizes only to large regions of the head.

spinal cord, and release glutamate as the excitatory

There are over 250 causes of headache. In gen-

neurotransmitter. Again, complex interneurons

eral, a simple classification divides headaches into

modulate further transmission of the pain signal.

primary and secondary. Primary headaches (like

Second-order axons in the spinothalamic pain

tension type, migraine, and cluster) are those

pathway cross the spinal cord mid-line and travel

headaches in which pain is the primary symptom

up the contralateral spinothalamic tract to termi-

and no structural damage occurs to the brain. Sec-

nate at the thalamus (ventral posterior lateral and

ondary headaches (from tumor, infection, sub-

central lateral nuclei). Third-order axons then

dural hematoma, etc.) develop from structural

travel to the somatosensory cortex and somatosen-

damage to the skull or CNS masses that generate

sory association cortex. What happens after pain

increased ICP. Secondary headaches may be due to

signals reach conscious perception is poorly

serious conditions and often produce other neuro-

understood. Pathology in this system may give rise

logic signs and symptoms.

to lancinating pains (brief, sharp, intense pains) as

The evaluation of a patient with headache usu-

seen in trigeminal neuralgia and shingles neuritis.

ally requires a careful history with attention to its

Spontaneous firing of a sensory nerve may

characteristics (Table 20-1). The exam should be

occur from degeneration of a distal sensory nerve,

thorough, with attention for the presence of

also called dying back neuropathy. This ectopic fir-

papilledema, neck stiffness, cranial nerve signs

ing can also occur from nerves adjacent to tissue

(especially the trigeminal nerve), signs of sinus or

damage occurring at the nerve ending or proximal

tooth or mouth infection, etc. For the headache to

CHAPTER 20—Disorders of Pain and Headache

203

Pathophysiology

Table 20-1

Important Considerations

in Headache Evaluation

Remarkably little is understood about TTH. We

currently do not know the etiology of the

• Headache warning (aura)

headache, the exact structure(s) that generate the

• Antecedent event (head trauma or dental/facial

pain (myofacial tissues or central brain mecha-

infection)

nisms), or whether TTH is part of the migraine

• Headache location

spectrum. Currently, there is general agreement

• Headache intensity (mild, moderate, or severe or

that scalp and neck muscles (frontalis, temporalis,

a Likert scale score of 0 to 10)

pterygoids, masseter, and trapezius) have increased

• Headache frequency

tenderness and possibly thicken during a TTH.

• Pain character (constant pressure or throbbing;

However, resting EMG studies of these muscles

sharp or dull)

have not shown increased muscle firing rates com-

• Headache duration (minutes, hours, days, or

pared with nonheadache controls; nonheadache

constant)

individuals may have tender muscle areas to palpa-

• Headache triggers (coughing, sneezing, eating

tion similar to individuals with TTH. Stress and

cold food, alcohol consumption, etc.)

poor sleep habits may trigger headaches, but the

• Age of onset of headaches

mechanism remains unknown. Elderly individuals

with cervical arthritis may experience TTH.

• Presence of family history of similar headaches

• Presence of other neurologic symptoms, including

nausea, vomiting, weakness, loss of facial

Major Clinical Features

sensation, hearing changes, vertigo, etc.

The typical patient with TTH complains of con-

stant, nonpulsating (75%), bilateral pain (90%),

which is localized over the frontal, temporal, and

be considered primary, the neurologic exam should

posterior neck muscles (Table 20-2). Usually the

be normal. If the neurologic exam is abnormal, the

headache is not aggravated by physical activity,

headache may be secondary and the result of struc-

light, or sound. Nausea and vomiting are uncom-

tural damage of the face, skull, meninges, or brain.

mon. The headache begins as a dull pain, often in

If structural damage is suspected, neuroimaging

the neck, that slowly progresses in intensity and

should be considered, especially if the neurologic

cranial area over several hours. If the headache

abnormalities are of recent origin.

becomes intense, it may become unilateral and

throbbing in nature. The headache may last from a

few hours to all day. Scalp and neck muscles may

Tension-Type Headache

be tender. Specific headache triggers are seldom

identified except for stress, lack or excess of sleep,

Introduction

and missed meals. The neurologic exam during

Tension-type headaches

(TTHs) are the most-

and between headaches should be normal.

common type of headache, with a lifetime preva-

lence of

78% and a yearly prevalence of 38%.

Major Laboratory Findings

About 1/3 of patients with TTH experience 14 or

more headaches a year. While the majority of indi-

Patients with TTH have normal neuroimaging

viduals do not seek medical attention and treat the

exams, routine blood tests, and normal EEGs.

headache with over-the-counter analgesics, about

3% experience severe incapacitating pain or

Principles of Management and Prognosis

headaches that occur multiple times a week

(chronic daily headache). There is seldom a

Management of TTH patients is divided into acute

genetic predisposition. The peak prevalence rates

treatment and prophylaxis. Most patients treat

occur in young adults. Simple TTHs occur about

mild-to-moderate TTH with simple over-the-

equally in men and women, but women have twice

counter analgesics, such as aspirin, acetaminophen,

the rate of chronic daily headaches.

and nonsteroidal analgesics. Studies generally have

204

FUNDAMENTALS OF NEUROLOGIC DISEASE

Table 20-2

Clinical Differences Between Tension-Type and Migraine Headache*

Symptom

Tension Type

Migraine

Onset

Slow over hours

More rapid

Visual Aura

20%

Pain Character

Constant pressure

Throbbing

Location

Bilateral, often in neck and frontalis and

Unilateral

temporalis muscles

Nausea and Vomiting

Uncommon

Common

Photophobia

Uncommon

Common

Duration

Hours to years

Hours to 2 to 3 days

Neurologic Signs

Only if complicated migraine

Relief from Sleep

Seldom

Frequent

* Not all headaches demonstrate all properties. Some migraines are bilateral and nonthrobbing and some tension-type

headaches will develop migraine-like symptoms if the headache becomes intense or prolonged. It is also common for

migraine patients to develop tension-type headaches.

found that all 3 types are about equally effective,

Therefore, reduction of chronic analgesic use is

especially if taken early in the headache. Muscle

warranted. Avoiding caffeine may decrease

relaxants (such as benzodiazepines) and migraine-

headache frequency, although caffeine-withdrawal

specific drugs are seldom effective. Narcotics may

headaches can occur.

give temporary pain relief but often do not termi-

It is important for patients to understand the

nate the headache.

nature of their TTH headache. They should expect

Nonpharmacologic treatments are often effec-

recurring headaches that continue for years and

tive and include hot and cold packs to the head or

the need to develop their own patterns of coping

neck and hot baths or showers. Acupuncture and

with them.

spinal manipulation therapy has not been shown

to be effective.

If the headache becomes severe, treatment is

Migraine Headache

often difficult as simple analgesics are seldom

effective. Stronger analgesics and medications

Introduction

aimed at inducing sleep are often needed.

Migraine headache is a common and often-debili-

If headaches become frequent (>15 d/mo), pro-

tating disorder that is treatable. The syndrome is

phylactic treatment is indicated. This may include

characterized by recurrent attacks of headache that

regular aerobic physical exercise (walking, jogging,

vary widely in intensity, duration, and frequency. It

or swimming for 20 to 30 min 5 times per week),

is associated with varying amounts of nausea,

neck-stretching exercises, and pharmacologic pro-

vomiting, and photophobia. About

28 million

phylaxis. Tricyclic antidepressants (amitriptyline

Americans suffer from migraine, with a prevalence

and nortriptyline) in low doses taken daily are

widely used and often successful in reducing fre-

rate of 18% for adult women and 6% for adult

quency and intensity of the headache. Once the

men. Migraine usually begins during adolescence

headache frequency reduces (usually over weeks to

or young adulthood. After the age of 50 years,

several months), the drugs are then slowly discon-

migraines begin to subside spontaneously. Occa-

tinued. A few patients take analgesics in high doses

sionally children from ages 5 to 10 years also may

many times daily to control the pain. These indi-

experience migraines. There is a dominant genetic

viduals are prone to developing a rebound

predisposition to migraines, but specific genes

headache when they do not take the analgesic.

have not been identified.

CHAPTER 20—Disorders of Pain and Headache

205

Pathophysiology

Migraine headaches are divided into 4 phases:

prodrome, aura, headache, and postheadache.

The etiology of migraine is unknown and the

Occasionally patients have a prodrome and are

pathophysiology is incompletely understood. Early

aware a migraine attack is coming hours before the

theories focused on intracranial blood vessels that

headache begins. These vague symptoms are often

were thought to vasoconstrict during the migraine

described as irritability, mood changes, fluid reten-

aura and dilate during the headache. There is now

tion, polyuria, photophobia, or unusual drowsiness.

considerable evidence that active vasoconstriction

About 20% of patients experience an aura that

does not cause the aura.

begins 5 to 20 minutes before the headache phase.

More-recent theories have focused on the roles

The aura of most patients is visual, but a few

of the trigeminal nerve, meningeal blood vessels,

patients have sensory, motor, or aphasic auras. The

and brain in producing a migraine. These hypothe-

visual aura usually begins as a vague diminishing

ses are labeled the

“trigeminovascular theory.”

or blurriness (not total loss) of vision (like looking

Nerves going to meningeal blood vessels are

through water), with varying amounts of flicker-

unmyelinated and contain vasoactive peptides such

ing dots of bright white or colored lights that often

as substance P, neurokinin A, nitric oxide, and calci-

expand and move into the periphery of one visual

tonin gene-related peptide. These are released when

field and then disappear (Figure 20-1). A key iden-

the trigeminal nerve is stimulated. In addition, sero-

tifier of an aura is that the lights do not disappear

tonin (5-hydroxytryptamine or 5-HT) receptors are

when the eyes are closed. In contrast, most ocular

present in meningeal blood vessels and in the

causes of visual disturbance disappear with closure

trigeminal nerve endings. The trigger for trigeminal

of the eyes.

nerve stimulation is unknown, but release of these

The headache is usually unilateral

(in the

vasoactive peptides triggers a sterile inflammatory

response that secondarily stimulates the trigeminal

frontal or temporal area), pounding, and severe

nerve pain fibers. Central brain connections of the

(Table 20-2). The time from headache onset to

trigeminal nerve travel to the brainstem and are

severe headache is usually less than 1 hour. About

thought to activate autonomic responses such as

1/4 of patients will describe their severe headache

nausea and vomiting. Trigeminal nerve axons trav-

as bilateral or nonthrobbing. Nausea and vomiting

eling to the reticular activating system and cortex

are common and may occur early in the headache

are thought to activate the pain responses.

phase. Patients commonly note photophobia

The aura of a migraine is felt to represent a

(increased pain from bright light) or phonophobia

direct cortical event. Abnormal depolarization

(increased pain from loud noises). During the

occurs mainly in the occipital cortex, with neuro-

headache phase, many find concentration and

transmitter release to adjacent neurons producing

higher cortical functioning difficult, even if the

a wave of depolarization spreading at

2 to

pain is controlled with medication. Patients often

mm/min and producing the typical visual aura. In

avoid further stimulation of the CNS and fre-

addition, persistent hyperpolarization of the

quently seek a dark, quiet room to rest, as sleep

involved brain area results in reduction of local

often relieves the headache. The headache typically

blood flow to the hyperpolarized brain cells. The

lasts 4 to 24 hours, with occasional headaches last-

term spreading depression refers to this phenome-

ing up to 3 days. As the headache subsides, some

non. The trigger for the aura is unknown.

patients experience lingering symptoms of fatigue,

difficulty in concentrating, and residual nausea for

up to 1 day.

Major Clinical Features

Migraine attacks usually occur 1 to 2 times per

Major Laboratory Findings

month. In most there is no recognized trigger. How-

ever, triggers noted by patients include consump-

The diagnosis of migraine in an adult patient is usu-

tion of alcohol, excessive salt intake, menstrual

ally based on a typical history and a normal neuro-

periods, use of birth control pills or conjugated

logic exam. There is no diagnostic test for the

estrogen tablets, sleep irregularities, certain foods,

disease. Routine blood and CSF exams are normal.

and stress or even the resolution of stress.

PET and fMRI scans may demonstrate focal areas of

206

FUNDAMENTALS OF NEUROLOGIC DISEASE

Area of Blurred Vision

Scotoma

Onset

3 Minutes

7 Minutes

10 Minutes

Figure 20-1

Classical migraine visual aura as it progresses over 10 minutes.

mildly reduced blood flow that are not diagnostic.

peptide mediators from the trigeminal nerve. Side

The migraine of patients who experience auras is

effects, mainly nausea and vomiting, are common.

classified as migraine with aura or classical migraine.

These drugs work best if given early in the

Patients without auras are classified as migraine

headache phase or during the aura. In some

without aura or common migraine. Patients who

patients, vomiting, nausea, and gastroparesis may

develop prolonged auras or headaches with neuro-

prevent systemic absorption of oral medications,

logic signs that persist are classified as migraine with

making oral treatment ineffective.

prolonged aura or complicated migraine. Occasional

In 1990, treatment of headache pain dramati-

patients will experience a visual aura without the

cally improved with the introduction of triptan

headache (migraine equivalent).

medications that could be delivered by the subcu-

taneous, nasal, sublingual, and oral routes. Trip-

tans are receptor agonists that act at the 5-HT_1B

Principles of Management and Prognosis

receptor located on meningeal blood vessels and

Management of patients with migraine headaches

appear to inhibit the aseptic perivascular inflamma-

is divided into treatment of the acute headache

tion induced by stimulation of the trigeminal nerve.

and prevention of frequent headaches.

Triptans may also inhibit transmission through sec-

In many patients, migraine responds well to

ond-order neurons of the trigeminocervical com-

simple treatment at the time of an attack. Drugs

plex. Triptan medication can be given at any time

such as aspirin, acetaminophen, ibuprofen, or

during the headache. Subcutaneous formulations

naproxen should be taken as soon as the headache

deliver pain relief within 1 to 2 hours in about 3/4

component of the attack is recognized. A variety of

of patients while oral tablets deliver pain relief in 2

other drugs are aimed at inducing sleep, a potent

to 4 hours in slightly fewer patients. Triptans may

terminator of migraine. Ergotamine and dihy-

cause mild constriction of coronary arteries and

droergotamine (DHE), 2 ergot alkaloids, are sero-

thus are contraindicated in patients with ischemic

tonin antagonists and have a high affinity for the

heart disease, Prinzmetal’s angina, or the presence

5-HT_1A and 5-HT_1D trigeminal nerve receptors.

of a complicated migraine.

These drugs constrict cerebral and systemic blood

Attempts to reduce the frequency of migraines

vessels and also prevent release of inflammatory

are usually directed toward patients with

≥4

CHAPTER 20—Disorders of Pain and Headache

207

headaches per month. Nonpharmacologic therapy

McGraw-Hill; 2000:472-491. (Excellent review

is beneficial and aims at encouraging regular aero-

of central and peripheral pain systems.)

bic exercise, keeping regular sleeping hours, and

Goadsby PJ, Lipton RB, Ferrari MD. Migraine—

avoiding alcohol, caffeine, and other known trig-

current understanding and treatment. N Engl J

gers. The U.S. Headache Consortium identified 4

Med. 2002;346:257-270. (Good review of patho-

medications shown to significantly reduce the

genesis theories and tryptan medications.)

frequency of migraines on multiple double-blind

Purdy RA. Clinical evaluation of a patient present-

placebo-controlled trials: amitriptyline, dival-

ing with headache. Med Clin North Am 2001;85:

proex sodium, propanolol, and timolol. These

847-864. (Nice review of workup of new patient

drugs must be taken daily, have a variety of mild-

with headache.)

to-moderate side effects, and often reduce

Silberstein SD. Tension-type and chronic daily

migraine frequency by about 50%. Many other

headache. Neurology. 1993;43:1644-1649. (Good

medications have been shown to have some ben-

review of diagnosis and management of these

efit in preventing migraines, but the evidence is

headaches.)

less certain and/or side effects are more common

Silberstein SD, Lipton RB, Dalessio DJ. Wolff ’s

or serious.

Headache and Other Head Pain. 7th ed. Oxford:

Oxford University Press; 2001. (Reviews most

primary and secondary headache types.)

RECOMMENDED READING

Solomon S, Newman LC. Episodic tension-type

headaches. In: Silberstein SD, Lipton RB,

Basbaum AI, Jessell TM. The perception of pain.

Dalessio DJ, eds. Wolff ’s Headache and Other

In: Kandel ER, Schwartz JH, Jessell TM, eds.

Head Pain. 7th ed. Oxford: Oxford University

Principles of Neural Science. 4th ed. New York:

Press; 2001:239-246. (Good review of TTH.)

DISORDERS OF THE

VESTIBULAR SYSTEM

response to changes in gravity. Changes in gravity

Overview

are detected by the bending of hair cells in the

macula of the utricle and saccule when there is

Dizziness and vertigo are especially common in the

movement of otoconia (tiny calcium carbonate

elderly, but symptoms occur at any age. Dizziness, a

crystals embedded in a gelatinous matrix).

nonspecific term, implies a sense of disturbed rela-

Impulses sent via the vestibular nerve to vestibular

tionship to the space outside oneself. Patients fre-

nuclei are processed and then transmitted to ante-

quently use such words as imbalance, off-balance,

rior horn cells of antigravity muscles to maintain

swaying, floating, light-headed, impending faint,

stable body posture. Changes in posture usually

giddiness, fuzzyheaded, reeling, and anxiety. Ver-

occur without an individual’s awareness.

tigo is an illusion of rotation or body movement

through space and implies dysfunction of the

Second, the vestibuloocular system maintains

vestibular system. Table 21-1 lists the major causes

steady eye position in space during head move-

of dizziness and vertigo. In the elderly, multiple

ment. Angular acceleration is detected by one or

causes are often present (multifactorial).

more pairs of the semicircular canals, which are

Normal balance comes from appropriate brain-

located at right angles to each other. Head rotation

stem and cerebellar integration of 3 sensory sys-

bends SCC hair cells in the endolymph, sending a

tems: vestibular, visual, and proprioceptive (Table

change in baseline frequency of nerve signals to

21-2). Incorrect sensory signals or inappropriate

brainstem vestibular nuclei. The signals are inte-

integration of sensory signals gives rise to dizziness

grated, resulting in appropriate signals transmitted

and vertigo.

via CN III, IV, and VI to move the eyes equally in

The vestibular system comprises end organs

the opposite direction of head rotation. Thus dur-

adjacent to each cochlea (3 semicircular canals

ing head movement, the world does not appear to

[SCCs], utricle, and saccule), vestibular nerves,

move. Individuals with vestibuloocular reflex

and vestibular nuclei located in the dorsal medulla

(VOR) dysfunction complain of vertigo when they

at the floor of the fourth ventricle and mid-line

move their head.

cerebellum (Figure 21-1). The vestibular system

The visual system locates the horizon and

divides into

2 major components. First, the

detects head movement from the horizon. It also

vestibulospinal system alters body position in

sends feedback (retinal slip) information to the

209

210

FUNDAMENTALS OF NEUROLOGIC DISEASE

Table 21-1

Major Causes of Dizziness and Vertigo

Vestibular System (25%)*

Benign paroxysmal positional vertigo

Meniere’s disease

Vestibular neuritis

Chronic labyrinthine imbalance

Proprioceptive System (15%)

Distal sensory peripheral neuropathy (diabetes, alcohol, and toxic compounds)

Pernicious anemia (Vitamin B₁₂ deficiency)

Spinocerebellar ataxia

Human immunodeficiency virus myelopathy

Visual System (<1%)

Recent unrecognized diplopia or cataracts

Brainstem or Cerebellum (25%)

Structural (1%)

Infarction (lateral medulla or mid-line cerebellum)

Tumor (glioma, ependymoma, etc)

Degenerative (multisystem atrophy)

Congenital (Arnold-Chiari malformation)

Metabolic (24%)

Cardiovascular (orthostatic hypotension, vasovagal syncope, cardiac arrhythmia, heart failure, and severe

anemia)

Endocrine (hypo- or hyperglycemia, hypothyroidism)

Psychophysiologic (5%)

Anxiety with hyperventilation

Adverse Drug Effects (30%)

Over 150 drugs have >3% incidence of dizziness and vertigo, but those listed below are the major drug types.

Vestibulotoxic drugs that cause permanent vestibular hair cell damage

Aminoglycoside antibiotics (gentamycin and kanamycin)

Cancer chemotherapeutics (cisplatin and chlorambucil)

Central nervous system drugs

Sedatives (benzodiazepines and sleeping pills)

Psychoactive (phenothiazines, lithium, and tricyclics)

Anticonvulsants (phenytoin and carbamazepine)

Circulatory drugs

Antihypertensives (prazosin, ganglionic blockers, and β-blockers)

Vasodilators (isosorbide and nitroglycerin)

Antiarrhythmics (mexiletine, flecainide, and amiodarone)

Loop diuretics (furosemide and ethacrinic acid)

Herbal medicines

Dizziness is a side effect of many herbs

*(%) refers to the approximate distribution of causes. Bold type refers to the most common cause in each category.

CHAPTER 21—Disorders of the Vestibular System

211

vestibular nuclei regarding the integrity of the

Table 21-2

Components of Normal

vestibuloocular reflex. The visual system is com-

Balance

prised of eyes, optic nerves, lateral geniculate

Vestibular System

nuclei, optic radiations, visual cortexes, and path-

Detects changes in gravity and adjusts body posture

ways from the lateral geniculate bodies and occip-

ital cortex to vestibular nuclei. The visual system

Maintains eye steadiness during head movement

seldom causes primary dizziness. However, it is the

Proprioceptive System

major compensating system when other sensory

Knowledge of position of feet

systems are impaired. As such, patients commonly

Detection of leg and foot movement (sway)

have good balance during the day but feel off bal-

ance and dizzy and fall at night when they have

Visual System

diminished vision.

Detection of head movement from horizon

The proprioceptive system delivers knowledge

Feedback (“retinal slip”) information on integrity of

of foot position, detecting and compensating for

vestibuloocular reflex

leg and foot movement (sway). Joint position sen-

Vestibular Nuclei in Brainstem and

sors located in the feet transmit changes in foot

Cerebellum

position via small myelinated peripheral nerves to

Integrates signals from vestibular, visual, and

the spinal cord. Information then rises to the

proprioceptive systems, sending information to

vestibular nuclei via the posterior columns. Nerve

the semicircular canals, eye muscles, and

impulses sent from joint position sensors in the

cerebral cortex to make appropriate changes

feet are important for maintaining balance while

in posture and eye movements.

standing and walking. Dysfunction of this system

Semicircular Canals

Horiz. Post.

Ant.

Middle Ear Ossicles

Anvil

Hammer

Stirrup

Vestibular Nerve

(Stapes)

Acoustic Nerve

Auditory

(Cochlear) Nerve

Cochlea

Eustachian

Tube

Tympanic Membrane

(Eardrum)

External Acoustic Meatus

Auditory Canal

Oval (Vestibular) Round (Cochlear)

Window

Figure 21-1

Anatomy of the inner ear.

212

FUNDAMENTALS OF NEUROLOGIC DISEASE

does not lead to vertigo, but rather to a feeling of

neuritis, Meniere’s disease, and temporal bone

dizziness and being off balance (dysequilibrium)

destruction. Examination of CSF is seldom helpful

when standing and walking, which improves with

unless a meningeal tumor or infection is suspected.

lying down or sitting.

In summary, vestibular nuclei integrate signals

from the vestibular, visual, and proprioceptive

Principles of Vertigo Management

systems to trigger appropriate changes in posture

to maintain balance and to alter eye position in

Vertigo is a frightening experience often associated

order to keep the world steady during head move-

with marked nausea and vomiting. Reassurance and

ment. Paired vestibular nuclei in dorsal lateral

simple explanations often relieve much of the anxi-

medulla, as well as the flocculus and nodulus of

ety. The intensity of vertigo can be lessened with

the cerebellum, receive and integrate afferent sen-

several medications. Diazepam administered intra-

sory signals. Efferent signals travel via the medial

venously usually stops severe symptoms. Promet-

and lateral vestibulospinal tracts to anterior horn

hazine given intravenously, rectally, or orally is

neurons of antigravity muscles and to the sensori-

effective in reducing the vertigo and nausea but is

motor cortex for conscious knowledge of body

sedating. Meclizine offers minimal benefit.

position and balance.

Symptomatic treatment should be given for

Dizziness and vertigo are symptoms, not diseases.

acute severe vertigo until the severe symptoms

The key to diagnosis is to determine which sys-

subside. Chronic administration of these drugs for

tem(s) is responsible for the symptoms. The history,

mild vertigo may actually delay natural recovery

associated symptoms, and physical exam lead to the

and is especially sedating in the elderly. Patients

involved system (Table 21-3). If the vestibular sys-

with brief recurrent vertigo episodes seldom bene-

tem is involved, additional localization questions

fit from drugs. Patients with dizziness from pro-

include: does the problem lie in the vestibuloocular

prioceptive, visual, or metabolic brainstem causes

reflex or vestibulospinal system, and is the dysfunc-

are not helped by antivertigo medications. Simply

tion peripheral in the end organs (common) or cen-

treating the vertigo symptom is insufficient; spe-

tral in the brainstem or cerebellum (uncommon)?

cific treatment should also be directed toward the

Frequently the history and exam are sufficient

etiology of the dizziness.

to establish the cause of the vestibular dysfunction.

However, laboratory tests and neuroimaging may

be helpful in some circumstances. Neuroimaging

Benign Paroxysmal

is not capable of demonstrating inner-ear mem-

Positional Vertigo

branous structures such as cristae or macula and is

of little value for many primary vestibular diseases.

Introduction

However, thin CT sections through the temporal

bones can identify a temporal bone fracture,

Benign paroxysmal positional vertigo (BPPV) or

tumor, or infection that damaged the inner ear.

benign positional vertigo is the most common type

MRI can identify middle-ear infections, tumors

of vertigo. Overall the incidence is 60/100,000 indi-

including an acoustic neuroma, masses involving

viduals per year, but the incidence rises to

the cerebellopontine angle, and structural damage

120/100,000 per year in individuals over age 50

to the brainstem or cerebellum. Electronystag-

years. Most cases develop from peripheral SCC dys-

mography (ENG) records eye movements and nys-

function, but a few are of central brainstem origin.

tagmus in response to a variety of maneuvers

similar to those done in the office (Table 21-3).

Pathophysiology

ENG also determines the integrity of the horizon-

tal semicircular canal (but not other canals, utricle,

The signs and symptoms of BPPV are due to

or saccule) following irrigation of the external

abnormal movements of endolymphatic fluid in a

auditory canal with cool and warm water. ENG

SCC due to the presence of agglomerated debris.

helps when one wants to determine if the vestibu-

In most cases, the debris is otoconia breaking loose

lar dysfunction is bilateral, as in drug toxicity and

from the macula of the utricle. Gravity causes

hereditary diseases, or unilateral, as in vestibular

loose otoconia to fall downward into the posterior

Table 21-3

Key Elements of the Office Evaluation of Dizziness or Vertigo

History

Dizziness or vertigo

Constant or intermittent

Duration of dizziness (seconds, minutes, hours, days, weeks)

Circumstances of onset (e.g., head trauma, infection, new drug usage, etc.)

Triggers or exacerbating factors (head movement in particular direction, diabetic missing meals, getting out of

bed, etc.)

Course of vertigo improving, stable, or worsening

Syncope (if yes, problem is not dizziness or vertigo)

Associated Diseases, Signs, and Symptoms

New hearing loss or tinnitus—vestibular

Diplopia, new glasses, or cataracts—ocular

Pain, numbness or paresthesias in feet, or bilateral leg weakness—proprioceptive

Facial weakness, numbness, stiff neck, unequal pupils, or diplopia—brainstem or structural

Diabetes mellitus, hypothyroidism, or cardiovascular disease—brainstem or metabolic

Exam

Vestibuloocular system

Vestibuloocular reflex test: subject looks at distant target while slowly rotating the head horizontally or

vertically. Abnormal result is when target moves and examiner sees late saccades to catch up with target.

Head shaking test: subject rapidly rotates head horizontally (like saying “no”) for 10 cycles and then looks

forward. Abnormal result is horizontal nystagmus present after stopping head shaking, and dizziness.

Hallpike maneuver: Sit patient on exam table with back toward the end. Turn head 45° laterally and rapidly lay

patient down with head hanging below the table for 30 seconds. Abnormal result is presence of directional-

rotary nystagmus often after a short delay, with subject reproducing dizziness symptoms (Figure 21-3).

Vestibulospinal system

Tandem gait test: subject walks a straight line with feet in front of each other. Abnormal result is when patient

sways and side steps. Normal test suggests system is intact, but abnormal test has many causes, including

orthopedic leg problems or proprioceptive or cerebellar dysfunction.

Romberg test: subject asked to stand with feet together with eyes open and closed. Abnormal result is when

patient can stand with eyes open but not closed, and implies dysfunction in proprioceptive or vestibular system.

Nystagmus (described in direction of the fast phase)

Slow phase derives from vestibular activity and fast phase from cerebral cortex action to correct slow phase

Nystagmus from vestibular end organ dysfunction is horizontal or direction-rotary, occurring in mid-position or

45° off center that is worsened by removal of fixation (such as by Frenzel +30 lenses).

Nystagmus from central vestibular cause is purely rotary or purely vertical, long lasting, and independent of

fixation.

Gaze-evoked nystagmus is symmetrical, high-frequency, and low-amplitude horizontal nystagmus seen at

end of far lateral gaze in both directions and is usually due to drugs such as alcohol, benzodiazepine,

phenytoin, and sedatives.

Hearing tests

Inspection of the external auditory canal with otoscope

Ability to hear whispers or finger rubs in each ear and hear low frequencies such as 128-Hz tuning fork

If hearing loss, determine if sensorineural (air conduction greater than bone conduction) or middle-ear

conductive (bone conduction greater than air conduction)

Proprioceptive system

Position and vibration sensitivity in feet

Romberg test and tandem gait

Visual system

Extraocular muscle exam for diplopia

Simple visual acuity

Fundoscopic exam for cataracts

Brainstem and cerebellum

Cranial nerve exam (especially CNs V, VII, and IX)

Cardiovascular

Heart rate and rhythm and presence of murmurs

Lying and standing blood pressure

Pulmonary

Respiratory rate resting and with exercise

Auscultation of lungs

214

FUNDAMENTALS OF NEUROLOGIC DISEASE

SCC (Figure 21-2). With rotation of the head in a

or Dix-Hallpike maneuver, performed in the office,

vertical plane, the debris in one SCC briefly alters the

can often trigger a patient’s vertigo (Figure 21-3,

dynamics of the vestibulocular in 1 SCC compared

Table 21-3). The maneuver should reproduce the

with the opposite side, causing transient vertigo.

patient’s vertigo symptoms. The examiner looks for

directional-rotary nystagmus to appear 1 to 5 sec-

onds after the patient’s head is hanging below the

Major Clinical Features

table. The diagnosis is made based on a characteris-

Most patients experience transient vertigo lasting

tic history and a positive Hallpike maneuver.

less than

15 seconds when rotating their head

upward (e.g., to place an object on a shelf) or down-

Major Laboratory Findings

ward (e.g., to tie their shoes). The sensation is unex-

pected and often disconcerting to the patient. There

Neuroimaging and ENG tests are not helpful and

is no associated nausea, vomiting, hearing loss, tin-

are normal.

nitus, or other neurologic signs. Attacks occur 1 to 5

times per day. If the maneuver that precipitated the

Principles of Management and Prognosis

episode is repeated several times, the vertigo

fatigues, becoming less intense and shorter in dura-

Most episodes of BPPV spontaneous resolve within

tion, and then enters a refractory period for hours

1-2 months but a few can persist for prolonged

when the maneuver does not trigger dizziness.

periods. In over two-thirds of patients, BPPV can be

About 20% of cases follow minor head trauma, but

terminated or greatly improved by the Epley

most have no recognized precipitating factor.

maneuver (Figure 21-4) or otoconia-repositioning

Between attacks, the patient is asymptomatic and

maneuver. In this maneuver, the posterior SCC

has normal balance and coordination. The Hallpike

canal debris moves by gravity around the SCC to

Membranous Labyrinth

Posterior View

Ampulla

Cochlear

Utricle

Duct

(Superior)

Common

Saccule

SCC

Canal

Horizontal

SCC

Posterior

SCC

Cupula

(Crista

Ampullaris)

Otoconia

(Otoliths)

Endolymphatic

Duct

Figure 21-2

Benign paroxysmal positional vertigo.

CHAPTER 21—Disorders of the Vestibular System

215

Figure 21-3

Hallpike maneuver.

deposit back in the utricle where it is then absorbed.

sion of endolymphatic fluid at the expense of the

This is accomplished by repeating the maneuver

perilymphatic system. Secondary endolymphatic

with the ear side down that triggered the vertigo.

membrane ballooning and distortions develop in

Over a period of 2 minutes, the head is held in this

the cochlea, utricle, and saccule. Evidence of rup-

position, then slowly rotated to midline, then

ture with healing of endolymphatic membranes is

rotated to the opposite side, and finally the patient

common. There is variable damage either to

is rotated to a sitting position. The patient sleeps on

cochlear or vestibular hair cells depending of the

several pillows that night to prevent debris from

duration of the disease.

falling back into the canal. The Epley maneuver

Acute attacks are thought to occur when an

eliminates or reduces BPPV over 75% of the time.

endolymphatic membrane rupture occurs tran-

siently, allowing potassium-rich endolymph and

potassium-depleted perilymph to mix. The result-

Meniere’s Disease

ing abnormal stimulation of vestibular and

cochlear axons leads to permanent hearing and

Introduction

vestibular function loss over time.

Meniere’s disease, or endolymphatic hydrops, is

The etiology is unknown in over 90%. The

less common than BPPV but more incapacitating.

remaining cases appear as delayed consequences of

The yearly incidence varies from 10 to 150 cases

otitic syphilis, mumps labyrinthitis, head trauma,

per 100,000 individuals depending on the defini-

or meningitis. Of these patients, 10% have a fam-

tion used. The illness affects both sexes and most

ily history of Meniere’s disease.

ages, with peak age from 40 to 60 years.

Major Clinical Features

Pathophysiology

Abrupt attacks of vertigo develop without warning

Temporal bone studies demonstrate characteristic

or are preceded by an aura of increasing tinnitus,

endolymphatic hydrops with pathologic expan-

fullness in the ear, and diminished hearing on that

CHAPTER 21—Disorders of the Vestibular System

217

attacks is 1 per month, with a range of 2 per week

endolymph and include low salt diets and daily

to 2 per year. The patient slowly and progressively

diuretics (hydrochlorothiazide or acetazolamide).

loses hearing in the involved ear.

In patients with frequent severe attacks who fail

medical treatment, gentamycin locally instilled in

the middle or inner ear has been successful in

Major Laboratory Findings

destroying vestibular hair cells, with reduction of

The progressive hearing loss begins with low fre-

attack severity, but at the price of variable loss of

quencies

(peak loss at

250-500 Hz) such that

hearing in that ear. Surgical approaches to shunt

speech discrimination is affected early. As the dis-

endolymph or destroy vestibular nerves are

ease progresses, all frequencies are lost. Finding

unproven.

low-frequency hearing loss is helpful, as most cases

Spontaneous vertigo attacks usually subside

of acquired sensorineural hearing loss, such as

over 5 to 10 years, when the disease progresses to

hearing loss in the elderly (presbycusis), involve

the point where the patient is deaf and has no

high frequencies. In over 50% of patients, caloric

caloric response. Unfortunately, 15% of patients

testing demonstrates a diminished or absent

develop Meniere’s disease in the opposite ear.

caloric response in the involved ear. Neuroimaging

and CSF are normal in idiopathic cases.

RECOMMENDED READING

Principles of Management and Prognosis

Baloh R. Dizziness, Hearing Loss, and Tinnitus.

There is no cure for the disease. Acute vertiginous

Philadelphia: FA Davis;

1998.

(Excellent

attacks are difficult to symptomatically treat, as

straightforward book on causes of vertigo.)

nausea and vomiting prevent use of oral medica-

Furman JM, Cass SP. Benign Paroxysmal Posi-

tions and the vertigo often ends in ¹/₂ to 2 hours.

tional Vertigo. N Engl J Med 1999;341:1590-

Rectal medications, such as promethazine suppos-

1596. (Excellent review of this syndrome and the

itories, lessen the vertigo and nausea. Since the

Epley maneuver.)

clinical course and frequency of attacks are vari-

Paparella MM, Djalilian HR. Etiology, pathophysi-

able, determination of effective drugs to reduce the

ology of symptoms, and pathogenesis of

frequency of attacks has been difficult. The most

Meniere’s disease. Otolaryngol Clin North Am

commonly administered treatments are aimed at

2002;35:529-545. (Entire issue devoted to reviews

reducing production or enhancing absorption of

of Meniere’s disease.)

Glossary of Common

Neurologic Terms

Accommodation Sensory nerves having dynamic

Anal reflex Reflexive contraction of anal sphinc-

firing rates that decline with time even though

ter upon perianal sensory stimulation.

the stimulus is maintained. Changes in the eye

Aneurysm Abnormal dilatation or bulging of an

that enable clear vision at various distances.

intracranial artery wall, usually at bifurcations

Afferent pathway Axons leading to the brain or

of the Circle of Willis.

spinal cord.

Anisocoria Unequal pupil size.

Agnosia Lack of knowledge and is synonymous

Ankle jerk Deep tendon reflex (Achilles reflex)

with an impairment of recognition. An exam-

elicited by striking the Achilles tendon at the

ple is visual agnosia in which patient cannot

ankle resulting in foot plantar flexion.

arrive at the meaning of previously known

Anterior horn Gray matter in the ventral spinal

nonverbal visual stimuli despite normal visual

perception and alertness.

cord that contains neurons including anterior

horn cells (lower motor neurons).

Agraphia Inability to recognize numbers/letters

written on the palm or fingertips.

Anterior root Segment of motor nerves com-

posed of anterior horn neurons exiting the ven-

Alexia Acquired reading impairment that may

tral spinal cord to where they join the mixed

be accompanied with writing deficits (alexia

peripheral nerve.

with agraphia) or without writing deficits

(alexia without agraphia).

Anton’s syndrome Lesions involving the occipi-

tal and parietal lobes that produce blindness or

Allodynia Non-painful cutaneous stimuli caus-

a homonymous hemianopia that is denied by

ing pain.

the patient.

Amaurosis fugax Transient monocular blind-

ness. This usually comes from an internal

Aphasia Disorder of expression or comprehen-

carotid artery embolus temporarily occluding

sion of spoken language due to dysfunction of

the ophthalmic artery.

language centers in dominant cerebral cortex or

thalamus.

Amnesia Partial or complete loss of the ability to

learn new information or to retrieve previously

Apoptosis Genetically programmed neuronal

acquired knowledge.

cell death that may be normal or abnormal.

Amyotrophy Wasting of muscles usually from

Apraxia Inability to perform a learned act,

denervation.

despite demonstrated ability to perform com-

219

220

GLOSSARY OF COMMON NEUROLOGIC TERMS

ponents of the act usually due to dysfunction

Bruit Sound due to turbulence of blood passing

of a parietal lobe.

a narrow artery segment, often heard from the

internal carotid artery in the neck.

Arteriovenous malformation (AVM) Abnormal

blood vessel complex consisting of arteries,

Bulbar Refers to the medulla and pons of the

veins, and capillaries located in the brain or

lower brainstem.

spinal cord that often hemorrhage.

Calcarine cortex Primary visual cortex located

in the medial occipital lobe.

Arteritis Inflammation of walls of arteries.

Caloric test Placement of warm or cool water in

Astereognosis The inability to distinguish and

the external canal to evaluate eye movements

recognize small objects based on size, shape,

from stimulation of the vestibulo-ocular reflex.

and texture when placed in the hand that has

Cauda equina Lumbosacral nerve roots in the

normal primary tactile sensory input.

lumbar and sacral vertebral canal before the

Ataxia Incoordination of limb or body move-

exit via neural foramina.

ments, particularly gait, often due to impair-

Caudal Lower in the neural axis compared with

ment of cerebellar function.

other structures of the same kind nearer the

Athetosis Involuntary movements characterized

head.

by slow, sinuous, twisting of arms, legs, or body.

Charcot-Marie-Tooth disease Dominant auto-

Atrophy Wasting of muscle/s from disuse or

somal genetic disease affecting distal myeli-

denervation.

nated axons of limbs, especially legs producing

Autism Childhood illness affecting language and

distally symmetrical polyneuropathy.

interpersonal relationships.

Cheyne-Stokes respirations Regular cyclic oscil-

lations of breathing between hyperpnea or over

Babinski sign Extensor response of the great toe

breathing and apnea.

with fanning of the other toes in response to

stimulus on sole of foot. The extensor plantar

Chorea Abnormal involuntary movements

response is normal in infants to about

characterized by rapid flicks or jerks of limb,

face, or trunk muscles.

months, thereafter reflects damage to the corti-

cospinal tract (upper motor neuron sign).

Chromatolysis Disintegration of chromophilic

substance or Nissl body from neuron when the

Basal ganglia Deep gray matter nuclei of the

axon is divided.

cerebral hemispheres comprising putamen,

caudate, globus pallidus, subthalamic nucleus,

Cogwheel rigidity Ratchet-like increased resist-

ance to passive movement (hypertonia) usually

substantial nigra, and often thalamus.

found at the wrists of patients with Parkinson’s

Biceps reflex Deep tendon reflex elicited by hit-

disease.

ting the biceps tendon resulting in brief con-

Computerized tomography (CT) Neuroimag-

traction of the biceps muscle.

ing technique based on computer processing of

Brachioradialis reflex Deep tendon reflex

data from differential attenuation of x-ray

elicited by hitting the distal radius resulting in

beam passing through tissue (often the skull &

brief contraction of the brachioradialis muscle.

brain) that produces a series of slices through

Bradykinesia or Akinesia Difficulty in moving

the tissue.

despite intact motor nerves and normal mus-

Constructional apraxia Disturbances in organ-

cles as seen in Parkinson’s disease.

izing parts of a complex object.

Broca’s aphasia Motor speech disorder (expres-

Corticobulbar tract Descending cortical motor

sive aphasia, nonfluent or anterior aphasia) due

tract traveling to a brainstem motor nucleus.

to dysfunction located in the dominant frontal

Corticospinal tract Descending cortical motor

lobe and characterized by effortful, sparse,

tract primarily from motor cortex that

agrammatic, halting, truncated speech with loss

descends down the spinal cord to synapse at

of normal language melody.

anterior horn cells or adjacent interneurons.

GLOSSARY OF COMMON NEUROLOGIC TERMS

221

Countercoup Injury to brain on opposite side as

Dressing apraxia Lesions only involving the

head trauma.

non-dominant parietal lobe that produce neg-

lect on one side of the body in dressing and

Coup Injury occurring to brain on same side as

head trauma.

grooming.

Decerebrate posture Both arms and legs are

Dysarthria Impaired articulation of speech that

extended, especially when painful stimuli are

sounds like

“speaking with rocks in your

administered usually due to a lesion that sepa-

mouth.”

rates upper from lower brainstem.

Dyskinesia Several involuntary movements of

Decorticate posture Flexion of one or both

limbs or face that include chorea, athetosis, tics,

arms and extension of ipsilateral or both legs

and dystonia.

due to lesion that isolates brainstem from con-

Dysmetria Limb ataxia in directed movement

tralateral or bilateral cortical influences.

that misses the target.

Deep tendon reflexes

(DTR) Term used to

Dysphagia Impairment of swallowing.

describe a monosynaptic stretch reflex elicited

Dysphonia Difficulty in speaking, often with a

by tapping a tendon with resulting muscle con-

low speech volume.

traction.

Dystonia Strong, sustained, and slow contrac-

Demyelination Primarily loss of the axon nerve

tions of muscle groups that cause twisting or

sheath in the peripheral or central nervous sys-

writhing of a limb or the entire body. The con-

tem with relative sparing of the underlying

tractions are often painful and may appear dis-

axon. Segmental demyelination implies that

figuring. The dystonia lasts seconds to minutes

the myelin loss is patchy along the nerve leaving

and occasionally hours producing a dystonic

part of the axon with intact myelin.

posture.

Dizziness General term to describe sensation of

Edema Excess water in the brain from swelling

light-headedness or feeling off balance.

of cell bodies (cytotoxic) or increased fluid in

Doll’s eyes maneuver Vestibulo-ocular reflex

extracellular spaces (vasogenic).

that is performed usually in comatose patient

where the head is rotated laterally but the eyes

Efferent pathway Axons leading away from the

remain stationary and do not move with head.

brain or spinal cord.

Dominance Term that refers to cerebral hemi-

Electroencephalograph Instrument for record-

sphere that controls language and principle

ing minute electrical currents developed in the

limb involved in writing, eating, and throwing.

brain by means of electrodes attached to the

scalp.

Dorsal column nuclei Nucleus gracilis and

cuneatus in the caudal medulla that contain 2^nd

Electronystagmograph Instrument for record-

order neuronal cell bodies for the dorsal

ing electrical signals generated by eye move-

columns in the spinal cord and usually conduct

ments or nystagmus during tests to evaluate

position sense, vibration, and touch sensations.

patients with vertigo.

Dorsal horn Dorsal (posterior) aspect of the

Epilepsy Illness resulting from repetitive

spinal cord gray matter that contains neurons

seizures due to abnormal brain electrical activ-

associated with peripheral afferent sensory

ity that is often subdivided into specific seizure

fibers.

types (e.g., generalized tonic-clonic).

Dorsal root Part of the peripheral afferent sen-

Epley maneuver In patients with benign parox-

sory nerve between the dorsal root ganglia and

ysmal positional vertigo, a variation of the

the dorsal horn of the spinal cord.

Hallpike maneuver is performed to roll loose

Dorsal root ganglia Cluster of 1^st order periph-

otoconia around the posterior semicircular

eral afferent sensory neuron cell bodies located

canal eliminating the recurrent brief vertigo

at each segmental level near vertebral bodies.

spells.

222

GLOSSARY OF COMMON NEUROLOGIC TERMS

Extraocular movements Eye movements due to

muscles places his hands on the knees and

contraction of extraocular eye muscles rather

climbs up his thighs to stand.

than muscles that govern the iris and lens.

Grasp reflex Involuntary grasping of the hand

Falx cerebri Rigid dural fold in midsagittal

when the palm is stimulated. This is normal in

plane that separates the two hemispheres.

babies but abnormal in older children and

adults and is often associated with diffuse

Fasciculation Contraction of fascicle (group) of

frontal lobe damage.

muscle fibers innervated by single nerve from

Gray matter Term that refers to gray color of

one anterior horn neuron that produces visible

part of CNS that contains neurons rather than

intermittent spontaneous twitching of part of a

white matter that contains mainly axons and

muscle but does not move the body part.

myelin sheaths.

Fibrillation Spontaneous contraction (invisible

Hallpike maneuver A test to detect positional

to the eye but detected by EMG) of individual

nystagmus performed by laying a patient down

denervated muscle fibers no longer under the

with their head hanging below the table.

control of a motor nerve.

Hammer toes Cocking up of toes like gun ham-

Flaccid Limp muscle that has no muscle tone.

mers often due to a distal sensorimotor

Foramen magnum Large opening at base of

polyneuropathy causing atrophy and weakness

skull where spinal cord and brainstem join.

of intrinsic flexor toe muscles with overriding

Fovea Central part of macula of retina related to

pull of more proximal extensor toe muscles.

sharpest vision for reading.

Hemianopia Refers to loss of vision in half the

visual field in the vertical plane. If both eyes are

Frenzel glasses Strong positive lenses that

equally involved, it is called homonymous

inhibit patients from seeing clearly enough to

hemianopia.

fixate but allow the examiner to see the eye.

Glasses used to detect nystagmus.

Hemiparesis Incomplete weakness involving

one side of body.

Gadolinium Rare earth compound given intra-

venously before MRI to detect brain areas that

Horner’s syndrome Miosis, ptosis, and dimin-

ished sweating on the ipsilateral face due to

have a broken blood-brain barrier (such as at

lesion in the 3rd neuron pathway starting in

tumors).

hypothalamus and traveling to the brainstem,

Ganglia Clusters of neurons all having similar

thoracic spinal cord, cervical sympathetic gan-

function, such as dorsal root ganglia.

glion, and sympathetic nerves along the carotid

Gerstmann’s syndrome The inability to desig-

and ophthalmic arteries.

nate or name the different fingers of the two

Hydrocephalus Abnormal enlargement of one

hands, confusion of the right and left sides of

or more ventricles of the brain. Obstructive

the body and inability to calculate or to write.

hydrocephalus is when there is obstruction of

Glasgow coma scale Simple scoring system of

CSF flow in ventricular system or subarachnoid

unconscious patients based on eye opening,

space. Hydrocephalus ex vacuo refers to passive

motor response, and verbal response that is

ventricular enlargement from loss of surround-

useful for prognosis.

ing white matter and neurons. Communicating

hydrocephalus refers to nonobstructed pathway

Glia Term for supporting cells of CNS that

from spinal subarachnoid space to lateral ven-

includes astrocytes and oligodendroglia.

tricles.

Glioma Term used for CNS tumors of astrocyte

Hypertonia Increased muscle tone or resistance

or oligodendrocyte lineage.

produced by passive movement of a limb on a

Global aphasia Acquired loss of ability to com-

joint.

prehend or produce verbal messages.

Hypotonia Decreased muscle tone or resistance

Gower’s maneuver Seen in muscular dystrophy

produced by passive movement of a limb on a

where an individual with weak proximal leg

joint.

GLOSSARY OF COMMON NEUROLOGIC TERMS

223

Hypsarrhythmia Random, high-voltage slow

Lordosis Curvature of the spinal column with a

waves and spikes seen on EEG that vary from in

forward convexity.

time and location.

Lower motor neuron Motor neurons in the

Ice water caloric Test used in comatose patients

anterior horn of the spinal cord or brainstem

to determine whether the pathway from the

that directly innervate muscles.

vestibular inner ear to the 3rd and 6th cranial

Lumbar puncture Placement of a hollow needle

nerves is intact. When pathway is intact, ice

with a stylet into the spinal canal in the lower

water irrigated in one ear produces bilateral eye

lumbar space to withdraw cerebrospinal fluid

movement to the ipsilateral side.

or instill medications.

Infantile spasms Brief, symmetric contractions

Magnetic resonance imaging (MRI) Use of

of neck, trunk, and limb muscles seen in infants

changing magnetic fields to create brain images

(also called salaam seizures).

as brain slices in any plane.

Ischemic penumbra Area of brain around an

Meralgia paresthica Sensory impairment and

acute stroke that immediately has insufficient

dysthesias in the skin distribution of the lateral

blood flow to function but sufficient to prevent

femoral cutaneous nerve of the thigh.

cell death and may or may not subsequently

Mesial temporal sclerosis Progressive loss of

die.

neurons and gliosis in one hippocampus that

Jaw jerk Corticobulbar reflex produced by tap-

often causes complex partial seizures.

ping downward on the chin with resulting con-

Miosis Abnormal constriction of a pupil.

traction of masseter muscles and upward jaw

movement. When unusually brisk, the jaw jerk

Mononeuropathy Lesion involving a single

implies an upper motor neuron abnormality in

peripheral nerve.

corticobulbar tract to 5th cranial nerve nuclei.

Mononeuropathy multiplex Lesions involving

Kernicterus Deposition of bile pigment in deep

more than one peripheral nerve.

brain nuclei with neuronal degeneration from

Myalgia Muscle aches and pains that are not

neonatal jaundice.

cramps.

Knee jerk (KJ) The patellar reflex is a deep ten-

Myelin Lipid-protein sheath that wraps some

don reflex in which the patellar tendon is

peripheral nerves that is made by Schwann cells

tapped causing a brief extension of the leg.

and some central nerves that is made by oligo-

Korsakoff ’s syndrome or psychosis Loss of

dendroglia.

the ability to learn new memories with a ten-

Myeloradiculopathy Disease process affecting

dency to fabricate answers. It is usually part of

the spinal cord, adjacent peripheral nerve roots,

Wernicke-Korsakoff ’s encephalopathy from

and nerves.

alcoholism.

Myoclonus Rapid, brief muscle jerks involving

Lateral geniculate body (nucleus) Thalamic

specific muscles or the entire body that do not

nucleus that receives input from optic nerves

blend together and are shorter duration than

and sends outward optic radiations to the

chorea. Nocturnal myoclonus is the normal

occipital cortex and upper brainstem.

abrupt body jerks that occur when an individ-

Lateral medullary syndrome Infarction of dor-

ual is falling asleep. The electroencephalogram

solateral medulla and inferior cerebellum due

may or may not have spikes correlating with the

to occlusion of posterior inferior cerebellar

myoclonus.

artery, a branch of the vertebral artery.

Myopathy General term implying disease of

Lenticular (lentiform) nucleus Combination of

muscle from any cause.

the putamen and the globus pallidus.

Myotonia Abnormal sustained muscle contrac-

Leukomalacia Abnormal softening of white

tions with slow relaxation that have a character-

matter areas.

istic pattern on electromyogram.

224

GLOSSARY OF COMMON NEUROLOGIC TERMS

Neglect Inability to attend normally to a portion

Paroxysmal Sudden event, as in spikes on elec-

of extrapersonal or intrapersonal space or both

troencephalogram.

that cannot be explained by altered perception.

Past pointing Repeated missing a target by

In visual neglect, the patient ignores objects,

going too far or off to one side when using a

persons, or movement in the left or right of the

finger or toe with closed eyes that is due to dys-

environment.

function of the vestibular system or cerebellum.

Neuraxis Longitudinal axis of the central nerv-

Patellar reflex Knee jerk reflex is a deep tendon

ous system that runs from the rostral forebrain

reflex in which the patellar tendon is tapped

to the caudal spinal cord.

causing a brief extension of the leg.

Neuronophagia Destruction of neurons by

Peripheral nervous system

(PNS) All neural

phagocytic cells.

structures that lie outside the spinal cord and

Neuropathy Term that describes disorders of

brainstem and includes motor, sensory, and

peripheral nerves.

autonomic nerves and their ganglia.

Nocioceptive Sensory receptors that respond to

PERRLA Abbreviation for pupils equal, round,

painful stimuli.

and reactive to light and accommodation.

Non-convulsive status epilepticus Complex

Phlebitis Inflammation of veins.

partial status epilepticus where the patient has

Phonophobia Discomfort from noises that nor-

constant confusion and impaired awareness but

can move his limbs.

mally do not cause discomfort.

Nystagmus Oscillatory eye movements that may

Photophobia Abnormal eye pain from bright

be physiologic (following spinning in a circle)

lights.

or abnormal (from inner ear, brainstem, and

Polyneuropathy Diffuse and symmetrical distal

cerebellar dysfunction).

dysfunction of sensory, motor, and autonomic

OD Right eye.

nerve axons that usually begins in the feet.

Ophthalmoplegia Paralysis of eye movements.

Positron emission tomography (PET) Imaging

Oriented x 3

Oriented to person, place, and time

technique that detects emissions from injected

in mental status testing.

radiolabeled compounds to create a quantifi-

able image of blood flow, glucose utilization, or

Orthostatic hypotension Fall in blood pressure

location of specific ligands that attach to brain

upon standing causing dizziness or even syn-

receptors, etc.

cope.

Prefrontal lobe Part of brain anterior to the

OS Left eye.

motor and premotor cortex that is a multisen-

Otoconia Tiny calcium carbonate crystals

sory association cortex.

embedded in a gelatinous matrix above the

macula of the utricle and saccule that move

Prion Abnormal protein configuration of a nor-

with gravity changes bending attached hair cells

mal host protein that causes transmissible

allowing detection of gravity.

spongiform encephalopathies, like Creutzfeldt-

Jakob disease.

Otorrhea CSF drainage from ear.

Proprioception Sense of position of body part

Papilledema Swelling of optic nerve disc from

relative to fixed object like a floor that is both

elevated intracranial pressure.

unconscious and conscious.

Paraphasias Mispronounced or inappropriately

substituted words with sematic paraphasias

Prosopagnosia Inability to recognize familiar

being errors based on meanings of words (aunt

faces (facial agnosia).

for uncle) and literal paraphasias being errors

Pseudobulbar palsy Syndrome that affects

based on sounds (hook for took).

speech articulation, phonation, swallowing,

Paresthesias Spontaneous firing of peripheral

and emotional lability due to bilateral dysfunc-

nerve fibers causing a tingling sensation.

tion of corticobulbar tracts in the brainstem.

GLOSSARY OF COMMON NEUROLOGIC TERMS

225

Psychomotor retardation Abnormal slowing of

Salaam seizures Brief, symmetric contractions

mental behavior and limb movements that is

of neck, trunk, and limb muscles seen in infants

not due to mental retardation.

(also called infantile spasms).

Ptosis Abnormal drooping of one or both eye-

Saltatory conduction Nerve action potential

lids.

that moves down a myelinated nerve by jump-

Putamen Part of basal ganglia. The caudate and

ing from node of Ranvier to node of Ranvier,

putamen form the striatum and putamen and

increasing conduction velocity to as fast as 80

globus pallidus from the lentiform or lenticular

meters/second.

nucleus.

Sciatica Term for radiating pain down a leg from

Quadrantanopia Loss of vision in one quadrant

damage to one or more lumbosacral nerve

of vision.

roots that form the sciatic nerve.

Radiculopathy Damage to a nerve root leaving

Semicircular canals Three canals at right angles

the spinal cord that causes weakness, sensory

to each other and located in the temporal bone

loss or dysesthesias, and diminished reflex in

detect angular acceleration and serve to keep

corresponding myotome and dermatome.

eyes steady during head movement.

Ramsay Hunt syndrome Acute facial weakness

Shunt Tubing used to move cerebrospinal fluid

due to herpes-zoster virus reactivation from the

that is blocked along its pathway (usually a ven-

geniculate ganglion.

tricle) to the abdomen or jugular vein where it

can be absorbed.

Rigidity Constant resistance to muscle stretch-

ing in both flexors and extensors throughout

Single photon emission computed tomography

range of motion due to the stretching force

(SPECT) Imaging system that is similar but

inducing some motor units to fire. In Parkin-

cheaper than positron emission tomography

son’s disease, rapid flexion and extension of

that qualitatively determines regional blood

wrist or elbow often elicits a ratchet-like feeling

flow or brain metabolism relative to other brain

(cogwheel rigidity).

areas.

Rinne test Comparison of bone conduction

Skew deviation of vision Vertical and slightly

(placing a vibrating tuning fork on the mastoid

horizontal (diagonal) double vision that is the

process) to air conduction in which air conduc-

same in all fields of gaze due to a brainstem

tion normally is heard better.

lesion.

Rolandic fissure Fissure that separates the

Snout reflex Pouting of lips following tapping

motor cortex in the frontal lobe from the sen-

the lips.

sory cortex in the parietal lobe.

Spasticity Condition resulting from damage to

Romberg sign Ability to stand with feet together

the corticospinal tract in which at-rest muscles

and eyes open and the inability to maintain

are in midposition and limbs held in a charac-

posture with the eyes closed.

teristic flexed posture. Rapid passive limb

Rooting reflex Normal turning of infant’s face

movement initially produces little resistance

and lips toward a nipple touching the cheek but

but then quickly has increasing muscular resist-

abnormal “frontal release reflex” when seen in

ance to a point when the resistance suddenly

adults upon touching the cheek.

disappears (“clasp-knife” phenomena).

Rostral Direction or position of neuroaxis

Stenosis Narrowing of lumen of artery or spinal

towards the forebrain and away from the caudal

canal.

spinal cord.

Strabismus Lack of eye alignment such that the

Saccadic eye movement Fast eye movement,

two visual axes assume positions relative to

voluntary or reflex, usually accomplishing

each other different from that required by the

foveal fixation.

physiologic task.

226

GLOSSARY OF COMMON NEUROLOGIC TERMS

Straight leg raise test Test for lumbar radicu-

Uncal herniation Movement of the uncal gyrus of

lopathy in which passive elevation of a straight-

the medial temporal lobe under the tentorial

ened leg produces pain in the lower back.

notch in response to mass in the temporal-frontal

lobes producing increased intracranial pressure.

Striate cortex Primary visual cortex.

Upper motor neuron Neurons in the upper

Striatum Combination of the caudate nucleus

brain that synapse with lower motor neurons in

and the putamen.

the brainstem or spinal cord.

Subfalcial space Space beneath the falx in which

Utricle Part of the inner ear that detects gravity.

the cingulate gyrus can herniate from increased

intracranial pressure.

Valsalva maneuver Increase in intrapulmonic

pressure by forcible expiration against a closed

Suck reflex Normal sucking response of infants

glottis.

when touching the lips but abnormal “frontal-

release” reflex in adults when touching the lips

Ventricles Four cerebrospinal fluid-filled cavities

elicits a sucking response.

in the brain (lateral ventricles, third ventricle

and fourth ventricle) along the cerebrospinal

Sylvian fissure Major horizontal fissure that

fluid pathway.

separates the temporal lobe from adjacent parts

of the frontal and parietal lobes.

Vermis Midline part of the cerebellum that par-

ticipates in truncal balance and gait.

Tandem gait Walking heel to toe in a straight

line.

Vertigo Illusion of abnormal spinning move-

ment by the individual or his environment.

Tics Abrupt, transient, repetitive, stereotypical

movements of face and limbs or vocalizations

Watershed brain territory Cerebral cortex

that may be briefly voluntarily suppressed but is

located between the distal ends of the middle

often then followed by a burst of tics when the

and posterior cerebral arteries (parietal lobe)

suppression is removed.

and middle and anterior cerebral arteries (ante-

rior frontal lobe) that are damaged when

Tonsillar herniation Downward movement of

hypoperfusion of the brain occurs.

cerebellar tonsils into the foramen magnum in

response to increased intracranial pressure

Wernicke’s aphasia Language disorder in which

from localized mass in the posterior fossa.

there is loss of ability to comprehend verbal or

written communications and ability to speak in

Tonsils Most inferior part of the midline cere-

fluid sentences with normal melody that make

bellum.

no sense.

Transient ischemic attack Focal neurologic

White matter Central nervous tissue that con-

signs from transient occlusion of a cerebral

tains mainly myelinated

(white appearing)

artery that usually last less than an hour but

nerve fibers, but not their neuronal cell bodies.

always less than 24 hours.

Xanthochromia Yellow color of CSF super-

Triceps jerk Deep tendon reflex elicited by tap-

natant that comes from lysed RBCs, bilirubin,

ping the triceps tendon above the back of the

or very elevated CSF protein concentration.

elbow.

Index

cerebellar degeneration, 196-198

management and prognosis, 176

Abducens nerve examination,

complications of, 193-194

pathophysiology, 174

11-12

delirium tremens, 195

Anticonvulsants, major, 159

Abscess, brain, in coma, 166

effects of, 193

Aphasias, 113-115

Absence seizure

fetal alcohol syndrome, 198-199

Broca’s aphasia, 114

major clinical features, 158-159

Korsakoff ’s psychosis syndrome,

global aphasia, 113

major laboratory findings, 159

195-196

Wernicke’s aphasia, 114-115

management and prognosis, 159

polyneuropathy, 198

Apoptosis, 174

pathophysiology, 158

time course of withdrawal, 194

Apraxia, 112-113

Accessory nerve examination, 13

tremulousness and hallucinosis,

Arboviruses, 140

Acetylcholine receptor, in

194-195

Arterial supply, brain, 91-92

myasthenia gravis, 50, 52

Wernicke’s encephalopathy,

Aspirin, for stroke prevention,

Acromegaly, 151

195-196

92-93

Action tremor, 125

withdrawal seizures, 195

Astereognosis, 112

Acute inflammatory demyelinating

Alzheimer’s disease, 117-120

Astrocytomas. See Malignant

polyneuropathy (AIDP),

common features of, 119

astrocytoma

105-107

computed tomography, 120

Ataxic dysarthria, 82

Acute motor axonal neuropathy

major clinical features, 119

Athetosis, 123

(AMAN), 105-107

major laboratory findings,

Auditory nerve examination, 13

Acyclovir, 141

119-120

Aura, in migraine headaches, 205-

Adenomas. See Pituitary adenoma

management and prognosis, 120

206

Adrenocorticotropic hormone

pathophysiology, 117-119

Automated fluorescent sequencing,

(ACTH), 160

vascular dementia and, 119

Aerobic bacteria, 136

Amytrophic lateral sclerosis, 68-73

Axonal injury, in traumatic brain

Agraphesthesia, 112

characteristics, 68-69

injury, 186

Airway, breathing, and circulation

major clinical features, 70-72

(ABC’s), in trauma, 169-

major laboratory findings, 72-73

171

management and prognosis, 73

Babinski sign, 18-19

Alcoholic cerbellar degeneration,

pathophysiology, 69-70

Bacterial meningitis, 136-137

196-198

Anatomic localizaton, 2-3

cerebrospinal fluid findings in,

Alcoholic polyneuropathy, 198

Anencephaly

136

Alcoholism, 193-199

major clinical features, 176

common bacteria causing, 137

alcoholic coma, 194

major laboratory findings, 176

major clinical features, 135, 136

227

228

INDEX

Bacterial meningitis (continued)

Brain herniation

keys to suspecting, 134

major laboratory findings, 136

lumbar puncture and, 34

major clinical features, 135

management and prognosis,

syndromes, 145-146

major sites of infection, 135

136-137

Brain swelling, in coma, 166

prion diseases, 141-143

Balance, components of normal,

Brain tumors

Central nervous system

211

brain herniation syndromes,

maldevelopment. See

Ballismus, 124

145-146

Developing nervous system

Basilar artery anatomy, 80

cerebral edema, 146-147

Cerebellar degeneration. See

Bell’s palsy, 63-64

cerebral metastases, 152-154

Alcoholic cerebellar

characteristics, 63

coma, 165

degeneration

major clinical features, 64

cytotoxic brain edema, 147

Cerebellar dysfunction

major laboratory findings, 64

glioblastoma multiforme,

likely localization, 82

management and prognosis, 64

147-149

signs suggesting, 82

pathophysiology, 63-64

malignant astrocytoma, 147-149

Cerebellar tremor, 82, 125

Benign paroxysmal positional

meningioma, 149-150

Cerebellum

vertigo, 212-216

nature of, 145

anatomy of, 81

Epley maneuver in, 215, 216

pituitary adenoma, 150-152

disorders of (See also Brainstem

Hallpike maneuver in, 214, 215

vasogenic brain edema, 147

and cerebellum disorders)

major clinical features, 214

Brainstem and cerebellum

functions by location, 81

major laboratory findings, 214

disorders, 79-85

Cerebral death, 171-172

management and prognosis,

anatomy, 80-81

Cerebral edema, 146-147

214-215

cerebellar functions by location,

Cerebral hemorrhage, in coma,

pathophysiology, 212, 214

166

Benign senescent forgetfulness,

characteristics, 79-81

Cerebral metastases, 152-154

115

lateral medullary infarction,

characteristics, 152-153

Benton Figure Copying Tests, 24

81-83

major clinical features, 153

Birth defects, in fetal alcohol

lesions, 79

major laboratory findings, 153

syndrome, 198

signs and localization, 82

management and prognosis,

Borrelia burgdorferi, 134

spinocerebellar ataxia, 84-85

153-154

Botulinum toxin, 53-56

British Medical Research Council

pathophysiology, 153

Botulism, 53-56

method of scoring muscle

presenting sings, 153

characteristics, 53

strength, 14

Cerebral perfusion pressure, 189

food-borne, 54-55

Broca’s aphasia, 114

Cerebrospinal fluid (CSF)

infant, 55

examination, 29-34. See

major clinical features, 54-55

also Lumbar puncture

major laboratory findings, 55

Carbamazepine, 159

management and prognosis,

Carpal tunnel syndrome, 61-63

bloody fluid, 33

55-56

characteristics, 61

in central nervous system

pathophysiology, 53-54

major clinical features, 61-63

infections, 136

types of, 53

major laboratory findings, 63

normal values, 32-33

Bradykinesia, 128-129

management and prognosis, 63

Cerebrovascular system disorders,

Brain abscess, 135-139

median nerve in, 62

87-99

cerebrospinal fluid findings in,

pathophysiology, 61

arterial supply to brain, 91-92

136

sensory distribution, 62

characteristics, 87

in coma, 166

Central nervous system

clinical features of common

computer tomography of, 139

abnormalities, in fetal

strokes, 90

magnetic resonance imaging of,

alcohol syndrome, 198

ischemic infarction pathologic

139

Central nervous system infections,

specimen, 89

major clinical features, 135, 138

133-143

ischemic strokes, 87-93

major laboratory findings, 138

bacterial meningitis, 134-137

major stroke types, 87

management and prognosis,

brain abscess, 137-139

risk factors for stroke, 88

138-139

cerebrospinal fluid findings, 136

saccular aneurysms, 96-99

pathophysiology, 137-138

characteristics, 133-134

spontaneous intracranial

Brain biopsy, 36

herpes simplex virus

hemorrhage, 94-96

Brain death, 171-172

encephalitis, 139-141

transient ischemic attacks, 93

INDEX

229

Channelopathies. See Primary

in Guillain-Barré syndrome, 106

major causes of, 166

hyperkalemic periodic

in herpes simplex virus

major clinical features, 167-169

paralysis

encephalitis, 140-141

management and prognosis,

Chiari type I and II

in Huntington’s disease, 131-132

169-171

malformations, 176-178

in infantile spasms, 160

metabolic, 167, 169

major clinical features, 178

in ischemic strokes, 89

pathophysiology, 165-167

major laboratory findings, 178

in Korsakoff ’s psychosis

supratentorial location in,

management and prognosis, 178

syndrome, 196

167-169

pathophysiology, 176-178

in lateral medullary infarction,

temperature level and, 167-168

Childhood seizures, 156

vestibuloocular reflex

Chorea, 123

in low back pain with

assessment, 168

Chromosomal disorders, 181

radiculopathy, 75-77

Communicating hydrocephalus, 31

Chronic demyelinating

in Meniere’s disease, 215-217

Complex partial seizure, 160-161

polyneuropathy, 105

in meningiomas, 150

major clinical features, 161

Chronic low back pain. See Low

in migraine headache, 205

major laboratory findings, 161

back pain with

in multiple sclerosis, 103

management and prognosis, 161

radiculopathy

in myasthenia gravis, 50-52

mesial temporal sclerosis and,

Chronic subdural hematoma, 190-

in Parkinson disease, 127

160

192

in phenylketonuria, 179

pathophysiology, 160-161

characteristics, 190

in pituitary adenoma, 151-152

Computed tomography (CT),

major clinical features, 191

in primary generalized tonic-

34-37. See also Laboratory

major laboratory findings, 191

clonic seizures, 156-158

findings

management and prognosis,

in primary hyperkalemic

Confusion, loss of consciousness

191-192

periodic paralysis, 46-47

and, 165, 166

pathophysiology, 190-191

in prion diseases, 142-143

Congenital infections, in

Clinical features

in saccular aneurysms, 97

neurodevelopmental

in absence seizures, 158-159

in secondary generalized partial

defects of nervous system,

in Alzheimer’s disease, 119

seizures, 156-158

174

in amyotrophic lateral sclerosis,

in spinocerebellar ataxia, 85

Constructional apraxia, 112-113

70-72

in Tay-Sachs disease, 180

Coordination

in anencephaly, 176

in tension-type headache, 203

evaluation, 16

in bacterial meningitis, 136

in transient ischemic attacks, 93

in normal aging, 116

in Bell’s palsy, 64

in transverse myelitis and

Corticospinal tract, anatomy of, 15

in benign paroxysmal positional

myelopathy, 74

Cranial nerve examination, 10-13

vertigo, 214

in traumatic brain injury,

CN 1, 10-11

in botulism, 54-55

186-188

CN II, 11

in brain abscess, 138

in Wernicke’s encephalopathy,

CN III, IV, VI, 11-12

in carpal tunnel syndrome,

196

CN IX, 13

61-63

Clostridium botulinum, 53-54

CN V, 12

in cerebral metastases, 153

Cognition

CN VII, 12-13

in Chiari type I and II

examination for difficulties, 9

CN VIII, 13

malformations, 178

in normal aging, 115-116

CN X, 13

in chronic subdural hematoma,

Coma, 166-172

CN XI, 13

191

airway, breathing, and

CN XII, 13

in coma, 167-169

circulation assessment,

in coma, 170

common, 4

169-171

Creutzfeldt-Jakob disease, 141-143

in complex partial seizure, 161

alcoholic, 194

Cushing’s disease, 151

in dermatomyositis, 44

cerebral death, 171-172

Cytotoxic edema, 147

in diabetic distal symmetrical

characteristics excluding head

polyneuropathy, 59-60

trauma, 167

in Duchenne muscular

cranial nerve examination, 170

Decerebrate posturing reflexes, in

dystrophy, 40-44

decorticate and decerebrate

coma, 169

in essential tumor, 125

posturing reflexes, 169

Decorticate posturing reflexes, in

in fetal alcohol syndrome, 199

infratentorial location in, 167

coma, 169

in glioblastoma multiforme, 148

laboratory findings, 167-169

Deep-brain stimulation, 129

230

INDEX

Deep tendon reflexes, 16-18, 19

neurorehabilitation, 7

management and prognosis, 125

Delirium, loss of consciousness

symptom time course, 3

pathophysiology, 124-125

and, 165

Diagnosis, establishing, 6

Ethosuximide, 159

Delirium tremens (DTs), 195

Diazepam, 159

Exercise programs, for back pain,

Dementia, 116-118

Differential diagnosis, 3

Denervated muscle

Disease etiology, 3

Extensor plantar reflex, 18-19

electromyogram, 26

Dizziness. See also Vertigo;

Extrapyramidal system, 123-132

Depression, 10

Vestibular system disorders

athetosis, 123

Dermatomes distribution, 17-18

key evaluation elements, 213

ballismus, 124

Dermatomyositis, 44-45

major causes of, 210

chorea, 123

characteristics, 44

Double simultaneous sensory

dystonia, 123

major clinical features, 44

stimulation, 112

essential tumor, 124-125

major laboratory findings, 44-45

Down syndrome, 181-182

Huntington’s disease, 130-132

management and prognosis, 45

features of, 182

myoclonus, 124

muscle biopsy in, 45

major clinical features, 181

Parkinson disease, 126-130

pathophysiology, 44

major laboratory findings, 181

tics, 124

Developing nervous system, 174-

management and prognosis,

tremor, 124

182

181-182

Eye examination, pediatric, 20

anencephaly, 174-176

pathophysiology, 181

apoptosis, 174

Drunkenness, alcoholic coma and,

Chiari type I malformations,

194

Facial abnormalities, in fetal

176-178

Duchenne muscular dystrophy,

alcohol syndrome, 198

Chiari type II malformations,

40-44

Facial nerve examination, 12-13

176-178

characteristics, 40

Fatal familial insomnia, 141-143

CNS maldevelopment, 173

major clinical features, 42-43

Fencer posture, 20

Down syndrome, 181-182

major laboratory findings, 43

Fetal alcohol syndrome, 198-199

homeobox genes and, 174

management and prognosis,

characteristic features, 198

neurodevelopmental defect

43-44

IQ scores in, 199

causes, 174

pathophysiology, 40-42

major clinical features, 199

phenylketonuria, 178-179

Dysdiadochokinesis, 82

major laboratory findings, 199

pre- and perinatal development

Dystonia, 123

management and prognosis,

milestones, 175-176

Dystrophin, in Duchenne

199

Tay-Sachs disease, 179-180

muscular dystrophy, 41-42

pathophysiology, 198

Developmental events, major, 175

Finger-nose-finger test, 16

Diabetic distal symmetrical

Fluorescence in situ hybridization,

polyneuropathy, 58-61

Edema. See Cerebral edema

characteristics, 58

Elderly, seizures in, 156

Folstein Mini Mental Status Exam,

distribution, 60

Electroencephalography (EEG),

9-10, 115

major clinical features, 59-60

24-25, 156. See also

Food-borne botulism, 54-55

major laboratory findings, 60-61

Laboratory findings

Fractures. See Traumatic brain

management and prognosis, 61

Electromyogram (EMG), 25-26

injury

pathophysiology, 58-59

Electronystagmography, in

Frontal lobe release signs, 19

Diagnosing neurologic conditions,

vestibular system disorders,

Function neurologic tests, 23-29

2-7

212

Functional magnetic resonance

anatomic localization, 2-3

Embolic strokes. See Ischemic

imaging (fMRI), 36

clinical or differential diagnosis,

strokes

Encephalitis. See also Herpes

determining nervous system

simplex virus encephalitis

Gait, in normal aging, 116

condition, 2

in coma, 166

Gait ataxia, 82

disease etiology, 3

major clinical features, 135

Gait evaluation, 14

establish definite diagnosis, 6

Epidural hematoma, in coma, 166

General pediatric exam, 20

etiologic and symptomatic

Epley maneuver, 215, 216

Genetic mutations, in

treatment, 6-7

Essential tumor, 124-125

neurodevelopmental

laboratory and neuroimaging

major clinical features, 125

defects of nervous system,

tests, 3-6

major laboratory findings, 125

174

INDEX

231

Gerstmann-Sträussler syndrome,

saccular aneurysms, 96-99

Intracerebral pressure, 189

141-143

spontaneous intracranial

Involuntary movements

Glasgow coma scale, 185

hemorrhage, 94-96

evaluation, 16

Glioblastoma multiforme, 147-149

Herniation. See Brain herniation

Ionizing radiation, 174

magnetic resonance images, 149

syndromes

Ischemic infarction, pathology, 89

major clinical features, 148

Herpes simplex virus encephalitis,

Ischemic penumbra, 88

major laboratory findings, 148

139-141

Ischemic strokes, 87-93

management and prognosis, 148

characteristics, 139-140

characteristics, 87-88

pathology of, 148

major clinical features, 140-141

in coma, 166

pathophysiology, 147-148

major laboratory findings, 141

major clinical features, 89

Glioblastomas. See Glioblastoma

management and prognosis, 141

major laboratory findings, 89-91

multiforme

pathophysiology, 140

management and prognosis,

Global aphasia, 113

Hexosaminidase A deficiency. See

91-93

Gowers maneuver, 43

Tay-Sachs disease

pathophysiology, 88-89

Grading systems, for ruptured

Higher cortical function disorders,

risk factors, 88

saccular aneurysms, 98

110-122

Grand mal seizure. See Secondarily

Alzheimer’s disease, 117-120

generalized partial seizures

aphasias, 113-115

Kinetic tremor, 125

Grasp reflex, 21, 110

changes of normal aging and,

Korsakoff ’s psychosis syndrome,

Growth retardation, in fetal

115-116

196

alcohol syndrome, 198

characteristics, 109-110

Kuru, 141-143

Guillain-Barré syndrome, 105-107

dementia, 116-117

major clinical features, 106

intelligence, 115

major laboratory findings, 107

limbic system, 110-111

Laboratory findings

management and prognosis, 107

mental retardation, 120-122

in absence seizures, 159

pathophysiology, 106

multimodal association cortices,

in Alzheimer’s disease, 119-120

Guthrie screening test, 179

110

in amyotrophic lateral sclerosis,

parietal lobe, 111-113

72-73

prefrontal lobe, 110

in anencephaly, 176

Haemophilus influenzae meningitis,

Homeobox genes, in developing

in bacterial meningitis, 136

136, 137

nervous system, 174

in Bell’s palsy, 64

Hallpike maneuver, 214

Human Genome Project, 36-37

in benign paroxysmal positional

Hallucinosis, alcoholic, 194-195

Huntington’s disease, 131-132

vertigo, 214

Halstead-Reitan Battery, 24

major clinical features, 131-132

in botulism, 55

Head examination, pediatric, 20

major laboratory findings, 132

in brain abscess, 138

Head trauma, in coma, 166

management and prognosis, 132

in carpal tunnel syndrome, 63

Headache pain, 202-207. See also

pathophysiology, 130-131

in cerebral metastases, 153

Migraine headache;

Hypertonia, 20

in Chiari I and II

Tension-type headache

Hypoglossal nerve examination, 13

malformations, 178

causes of, 202

Hypotonia, 82

in chronic subdural hematoma,

characteristics, 202-203

191

evaluation of, 202-203

in coma, 167-169

important considerations in, 203

Ideational apraxia, 113

in complex partial seizure, 161

lumbar puncture and, 34

Ideomotor apraxia, 113

in dermatomyositis, 44

migraine headache, 204-207

Infant botulism, 55

in diabetic distal symmetrical

tension-type, 203-204

Infants, seizures in, 156

polyneuropathy, 60-61

Hearing, in normal aging, 116

Inflammatory myopathy. See

in Duchenne muscular

Heel-to-shin test, 16

Dermatomyositis

dystrophy, 43

Hematoma

Infratentorial location, for coma,

in essential tumor, 125

in coma, 166

167

in fetal alcohol syndrome, 199

subdural (See Chronic subdural

Inner ear anatomy, 211

in gioblastoma multiforme, 148

hematoma)

Intelligence, 115

in Guillain-Barré syndrome, 107

Hemorrhage, cerebral, in coma,

Intention tremor, 125

in herpes simplex virus

166

Interferon, 105

encephalitis, 141

Hemorrhagic strokes, 94-99

Interstitial edema, 147

in infantile spasms, 160

232

INDEX

Laboratory findings (continued)

characteristics, 74-75

Migraine headache, 205-207. See

in ischemic strokes, 89-91

lateral protrusion of disc, 75

also Headache pain

in Korsakoff ’s psychosis

lumbar radiculopathy, 76

aura in, 205- 206

syndrome, 196

major clinical features, 75-77

characteristics, 204

in lateral medullary infarction,

major laboratory findings, 77

major clinical features, 205

management and prognosis,

major laboratory findings,

in low back pain with

77-78

205-206

radiculopathy, 77

pathophysiology, 75

management and prognosis,

in Meniere’s disease, 217

straight-leg-raising test, 77

206-207

in meningiomas, 150

Lumbar puncture, 29-34

pathophysiology, 205

in migraine headache, 205-206

algorithm, 32

phases of, 205

in multiple sclerosis, 103-104

anatomy and physiology and,

spreading depression in, 205

in myasthenia gravis, 2

29-31

trigeminal nerves in, 205

in Parkinson’s disease, 127-128

brain herniation and, 34

visual aura, 206

in phenylketonuria, 179

complications of, 33-34

Mild cognitive impairment (MCI),

in pituitary adenoma, 152

contraindications for, 29

117

in primarily generalized tonic-

for dementia, 118

Milner’s Maze Learning Task, 24

clonic seizures, 158

headaches and, 34

Minnesota Multiphasic Personality

in primary hyperkalemic

normal CSF values and, 32-33

Inventory, 24

periodic paralysis, 47-48

positioning, 31

Mixantrone, 105

in prion diseases, 143

technique of, 31-32

Molecular tests, 36-38

in saccular aneurysms, 97-98

Lumbar radiculopathy, 76

Moro reflex examination, 21

in secondary generalized partial

Motor examination, 13-16

seizures, 158

Motor nerve function, conduction

in spinocerebellar ataxia, 85

Magnetic resonance imaging

tests, 28

in Tay-Sachs disease, 180

(MRI), 34-37. See also

Motor units electromyogram, 27

in tension-type headache, 203

Laboratory findings

Mouth examination, pediatric, 20

in transient ischemic attacks, 93

Malignant astrocytoma, 147-148

Multiple sclerosis, 102-105

in transverse myelitis and

major clinical features, 148

axonal changes, 104

myelopathy, 74

major laboratory findings, 148

magnetic resonance imaging, 105

in traumatic brain injury,

management and prognosis, 148

major clinical features, 103

188-189

pathophysiology, 147-148

major laboratory findings,

in Wernicke’s encephalopathy,

Memory impairment, 9, 110-111.

103-104

196