Acknowledgements

Nitamar Abdala

Peter J. Goadsby, MD

Federal University of Sao Paulo

Institute of Neurology

Rua Napoleao de Barros, 800

National Hospital for Neurology &

Vila Clementino

Neurosurgery

Sao Paulo, SP, CEP 04024-002

Queen Square

Brazil

London WC1N 3BG

United Kingdom

David J. Capobianco, MD

Mayo Clinic, Jacksonville

Richard Hargreaves, PhD

4500 San Pablo Road

Pharmacology and Imaging

Jacksonville, FL 32224

Merck Research Laboratories

Merck & Co, Inc

Gary Carpenter, MD

WP 42-300

Jefferson Medical College

770 Sumneytown Pike

1025 Walnut Street

P.O. Box 4

Philadelphia, PA 19107

West Point, PA 19486

Henrique Carrete Jr, MD

Bernadette Jaeger, DDS

Department of Radiology

Section of Oral Medicine and Orofacial Pain

Universidade Federal de S~o Paulo

School of Dentistry

S~o Paulo

University of California, Los Angeles

Brazil

Los Angeles, CA 90064-1782

John Edmeads, MD

Marco A. Lana-Peixoto, MD

Sunnybrook Medical Center

Federal University of Minas Gerais

University of Toronto

Medical School

2075 Bayview Avenue

Rua Psdre Rolim 769-13 Andar

Toronto, Ontario M4N 3M5

Belo Horizonte - MG 30130-090

Canada

Brazil

Richard B. Lipton, MD

Luiz Paulo de Queiroz, MD, MSc

Innovative Medical Research

Clinica do Cerebro

1200 High Ridge Road

Rua Presidente Coutinho, 464

Stamford, CT 06905

88015-231 Florianopolis, SC

Brazil

Suzana M.F. Malheiros, MD

Department of Neurology

Margarita Sanchez del Rio, MD

Universidade Federal de S~o Paulo

Neurology Department

S~o Paulo

Fundacion Hospital Alcorcon

Brazil

Juan Carlos I University

Alcorcon, Madrid,

Pericles de Andrade Maranhao-Filho,

Spain

MD, MSc, PhD

Federal University of Rio de Janeiro

Clementino Fraga Filho Hospital

Germany Goncalves Veloso, MD

National Institute of Cancer

Department of Neurology

Rio de Janeiro

Federal University of Sao Paulo

Brazil

Sao Paulo

Brazil

Andrew A. Parsons, PhD

Head Migraine & Stroke Research

Paul Winner, DO, FAAN

GlaxoSmithKline

Palm Beach Headache Center

Neurology Centre of Excellence

Nova Southeastern University

for Drug Discovery

5205 Greenwood Avenue

New Frontiers Science Park

West Palm Beach, FL 33407

Harlow, Essex

United Kingdom

Vera Lucia Faria Xavier, MD

Julio Pascual, MD

Headache Center

University Hospital ‘Marqués de Valdecilla’

Santo Amaro University

39008 Santander

Sao Paulo

Spain

Brazil

Foreword

In medieval maps, the periphery of the world was

illustrations - some scientific, some historical and

shrouded in mystery with vivid images of hypo-

some artistic. This display makes for a relaxed

thetical dragons lurking at the edges. One might

approach to a complex subject like ambling

suspect that an ‘Atlas of Headache’ would be rife

through an art gallery to view an exhibition that

with such dragons as not all of the headache world

conveys a message. It is a pathway well worth

has been completely charted. How does one see a

taking for pleasure as well as enlightenment.

headache? How does one map a headache?

The present authors are to be commended for

presenting an ‘Illustrated Headache News’ for our

James W. Lance

information and enjoyment. The common head-

Emeritus Professor of Neurology

ache entities of migraine, cluster and tension-type

University of New South Wales

headaches as well as the more sinister structural

Sydney, Australia

causes of headache are outlined in the text to

President of the International

provide a framework on which to hang the

Headache Society, 1987-9

Preface

Physicians need to learn to diagnose and manage

challenge. We include the history of headache, its

headaches. Despite this need, it is rare for medical

epidemiology, diagnosis and treatment. We address

students to have more than one lecture on head-

migraine, tension-type and cluster headache, in

ache management during their education, and

addition to the rare or more unusual primary and

residents in training, even in neurology, rarely get

secondary headache disorders. We have tried to

any more formal training. Educating caregivers to

include classic images from other texts, as well as

recognize head pain complaints will provide better

new images that illustrate the disorders and reflect

care for patients.

the most current thinking. This compilation of

Our Atlas approaches the problem of headache

images has been contributed by physicians from all

from a visual perspective; it visualizes the subjec-

over the world. Our goal in presenting an overview

tive complaint of headache and makes it easier to

of the numerous disorders that cause head pain is

understand. For some, this type of visual learning

to provide a better understanding for those treat-

may be the best approach; for others, it will

ing these disorders and, ultimately, better care for

reinforce other learning strategies. Anything that

headache sufferers.

leads to a better understanding of headaches will

lead to better diagnosis and management.

There are many causes of headache. Some are

Stephen D. Silberstein, Alan Stiles,

secondary to other conditions; others are disorders

William B. Young and Todd D. Rozen

in themselves. Diagnosis and treatment is often a

April 2002

CHAPTER 1

Historical aspects of headache

HEADACHE IN THE ANCIENT WORLD

and that vomiting could partially relieve the pain

of headache5,6. Celsus

(215-300 AD) believed

Headache has troubled mankind from the dawn

‘drinking wine, or crudity [dyspepsia] or cold, or

of civilization. Signs of trepanation, a procedure

heat of a fire or the sun’ could trigger migraine.

wherein the skull was perforated with an instru-

Because of his classic descriptions, Aretaeus of

ment, are evident on neolithic human skulls dating

Cappodocia

(second century AD) is credited

from 7000-3000 BC¹ (Figures 1.1 and 1.2). Origi-

with discovering migraine headache. The term

nally, it was thought that the procedure had been

‘migraine’ itself is derived from the Greek word

performed to release demons and evil spirits, but

‘hemicrania’, introduced by Galen in approxi-

recent evidence suggests that it was carried out

mately 200 AD. He mistakenly believed it was

for medical reasons². Trepanation continues to be

caused by the ascent of vapors, either excessive,

practiced today, without anesthesia, by some

too hot or too cold. Clearly, migraine was well

African tribes. It is primarily performed for relief

known in the ancient world⁴.

of headache or removal of a fracture line after head

injury³.

HEADACHE OVER THE CENTURIES

Headache prescriptions written on papyrus

(Figure 1.3) were already known in ancient Egypt.

In the twelfth century, Abbess Hildegarde of

The Ebers Papyrus, dated circa 1200 BC and said

Bingen described her visions (Figure 1.6), later

to be based on medical documents from 2500 BC,

attributed to her migraine aura, in terms that are

describes migraine, neuralgia and shooting head

both mystical and apocalyptic⁷:

pains⁴. It was practice at the time to firmly bind a

clay crocodile holding grain in its mouth to the

‘I saw a great star, most splendid and beauti-

patient’s head using a strip of linen that bore the

ful, and with it an exceeding multitude of

names of the gods^5,6 (Figure 1.4). This technique

falling sparks with which the star followed

may have produced headache relief by compress-

southward … and suddenly they were all

ing and cooling the scalp⁵.

annihilated, being turned into black coals …

Hippocrates

(470-410 BC, Figure

1.5)

and cast into the abyss so that I could see them

described a shining light, usually in the right eye,

no more’.

followed by violent pain that began in the temples

and eventually reached the entire head and neck

1683 Thomas Willis

(Figures

1.7 and

1.8)

area⁵. He believed that headache could be triggered

brilliantly described a woman with severe, periodic,

by exercise or intercourse⁶, that migraine resulted

migrainous headache preceded by a prodrome and

from vapors rising from the stomach to the head

associated with vomiting⁴:

‘… beautiful and young woman, imbued with

Glass, depicting instances of central scotoma,

a slender habit of body, and an hot blood,

tunnel vision, phonophobia, vertigo, distortions in

was wont to be afflicted with frequent and

body image, dementia and visual hallucinations

wandering fits of headache … On the day

(Figures 1.11 and 1.12).

before the coming of the spontaneous fit of this

Greek and Roman ancient writings include ref-

disease, growing very hungry in the evening,

erences to ‘blighted grains’ and ‘blackened bread’,

she eat a most plentiful supper, with an hungry,

and to the use of concoctions of powdered barley

I may say a greedy appetite; presaging by this

flower to hasten childbirth. During the Middle

sign, that the pain of the head would most

Ages, written accounts of ergot poisoning first

certainly follow the next morning; and the event

appeared. Epidemics were described in which the

never failed this augury … she was troubled

characteristic symptom was gangrene of the feet,

also with vomiting’.

legs, hands and arms, often associated with burning

sensations in the extremities. The disease was

Migraine was distinguished from common

known as ‘Ignis Sacer’ or ‘Holy Fire’ and, later, as

headache by Tissot in 1783⁸, who ascribed it to

‘St. Anthony’s Fire’, in honor of the saint at whose

a supraorbital neuralgia ‘… provoked by reflexes

shrine relief was obtained. This relief probably

from the stomach, gallbladder or uterus’. Over

resulted from the use of a diet free of contamina-

the next century, DuBois Reymond, Mollendorf

ted grain during the pilgrimage to the shrine

and, later, Eulenburg proposed different vascular

(Figure 1.13)¹¹. The term ‘ergot’ is derived from

theories for migraine. In the late eighteenth

the French word ‘argot’ meaning ‘rooster’s spur’. It

century, Erasmus Darwin (Figure 1.9), grandfather

describes the small, banana-shaped sclerotium of

of Charles Darwin, suggested treating headache by

the fungus. Louis René Tulasne of Paris in 1853

centrifugation. He believed headaches were caused

established that ergot was not a hypertrophied

by vasodilation, and suggested placing the patient

rye seed, but a fungus having three stages in one

in a centrifuge to force the blood from the head to

life cycle, and he named it Claviceps purpurea

the feet^5,6. Fothergill in 1778 introduced the term

(Figure 1.14). Once infected by the fungus, the rye

‘fortification spectra’ to describe the typical visual

seed was transformed into a spur-shaped mass of

aura or disturbance of migraine. Fothergill used the

fungal pseudotissue, purple-brown in colour: the

term ‘fortification’⁶ because the visual aura resem-

resting stage of the fungus, known as the ‘scle-

bled a fortified town surrounded with bastions^9,10.

rotium’ (derived from the Greek ‘skleros’ meaning

In 1873, Liveing (Figure 1.10) wrote the first

‘hard’)¹¹. In 1831, Heinrich Wiggers (Figure 1.15),

monograph on migraine, entitled On Megrim, Sick-

a pharmacist of Göttingen, Germany tested ergot

headache, and Some Allied Disorders: A Contribution

extracts in animals. Among his models was the

to the Pathology of Nerve-storms, and originated the

‘rooster comb test’: a rooster, when fed ergotin,

neural theory of migraine. He ascribed the prob-

became ataxic and nauseous, acquired a blanched

lem to ‘… disturbances of the autonomic nervous

comb and suffered from severe convulsions, dying

system’, which he called ‘nerve storms’⁹. William

days later. The ‘rooster comb test’ continued to be

Gowers, in 1888, published an influential neurol-

used into the following century by investigators

ogy textbook, A Manual of Disease of the Nervous

studying the physiologic properties of ergot¹¹.

System¹⁰. Gowers emphasized the importance of

Later Woakes, in 1868, reported the use of ergot of

a healthy lifestyle and advocated using a solution

rye in the treatment of neuralgia¹². The earliest

of nitroglycerin (1% in alcohol), combined with

reports in the medical literature on the use of

other agents, to treat headaches. The remedy later

ergot in the treatment of migraine were those of

became known as the ‘Gowers mixture’. Gowers

Eulenberg in Germany in 1883, Thomson in the

was also famous for recommending Indian hemp

United States in 1894 and Campbell in England

(marijuana) for headache relief^5,6.

in 1894. Stevens’ Modern Materia Medica men-

Lewis Carroll described migrainous phenomena

tioned the use of ergot for the treatment of

in Alice in Wonderland and Through the Looking

migraine in 1907¹³.

The first pure ergot alkaloid, ergotamine, was

for migraine. Concomitant with the development

isolated by Stoll (Figure 1.16) in 1918 and used

of new treatments is the development of the basic

primarily in obstetrics and gynecology until 1925,

sciences of headache and the renewed dedication

when Rothlin successfully treated a case of severe

of clinicians to headache treatment and teaching.

and intractable migraine with a subcutaneous injec-

tion of ergotamine tartrate. This indication was

REFERENCES

pursued vigorously by various researchers over the

following decades and was reinforced by the belief

Lyons A, Petrucelli RJ. Medicine: An Illustrated

in a vascular origin of migraine and the concept

History. New York: Harry N. Abrams, Inc, 1978:113-5

that ergotamine tartrate acted as a vasoconstrictor.

Venzmer G. Five Thousand Years of Medicine.

In 1938, John Graham and Harold Wolff¹⁴ demon-

New York: Taplinger Publishing Co, 1972:19

strated that ergotamine worked by constricting

Rawlings CE, Rossitch E. The history of trepanation

blood vessels and used this as proof of the vascular

in Africa with a discussion of its current status and

continuing practice. Surg Neurol 1994;41:507-13

theory of migraine (Figures 1.17 and 1.18).

Critchley M. Migraine: From Cappadocia to Queen

For further milestones in the history of

Square. In: Smith R, ed. Background to Migraine,

headache, see Figures 1.19-1.30.

Volume 1. London: Heinemann, 1967

Edmeads J. The treatment of headache: a historical

perspective. In: Gallagher RM, ed. Therapy for Head-

MODERN HEADACHE TREATMENTS

ache. New York: Marcel Dekker Inc, 1990:1-8

The modern approach to treating migraine began

Lance JW. Mechanisms and Management of Headache,

4th edn. London: Butterworth Scientific, 1982:1-6

with the development of sumatriptan by Pat

Singer C. The visions of Hildegarde of Bingen. In:

Humphrey and his colleagues¹⁵. Based on the

Anonymous. From Magic to Science. New York: Dover,

concept that serotonin can relieve headache, they

1958

designed a chemical entity that was similar to

Sacks O. Migraine: Understanding a Common Disorder.

serotonin, although more stable and with fewer

Berkeley: University of California Press, 1985:158-9

side-effects. This development led to the modern

Patterson SM, Silberstein SD. Sometimes Jello

clinical trials for acute migraine treatment and to

helps: perceptions of headache etiology, triggers and

the elucidation of the mechanism of action of what

treatment in literature. Headache 1993;33:76-81

are now called the triptans.

10.

Raskin NH. Migraine: clinical aspects. In: Headache,

We are at the threshold of an explosion in the

2nd edn. New York: Churchill-Livingstone,

1988:

understanding, diagnosis and treatment of

35-98

migraine and other headaches. Many new triptans

11.

Bové FJ. The Story of Ergot. New York: Karger, 1970

have been developed and many more will soon be,

12.

Woakes E. On ergot of rye in the treatment of

neuralgia. Br Med J 1868;2:360-1

or are already, available, including zolmitriptan,

13.

Silberstein SD. The pharmacology of ergotamine

naratriptan, eletriptan, frovatriptan, rizatriptan and

and dihydroergotamine. Headache 1997;37:S15-S25

almotriptan. Modern preventive treatment began

14.

Graham JR, Wolff HG. Mechanisms of migraine

with the belief that migraine was due to excess

headache and action of ergotamine tartrate. Arch

serotonin. Sicuteri¹⁶ helped develop methysergide,

Neurol Psychiatry 1938;39:737-63

a serotonin antagonist, for the prophylactic treat-

15.

Humphrey PP, Feniuk W, Marriott AS, et al. Preclini-

ment of migraine and cluster headache. After a

cal studies on the anti-migraine drug, sumatriptan.

long hiatus, new drugs are being tested and devel-

Eur Neurol 1991;31:282-90

oped for the preventive treatment of migraine. The

16.

Sicuteri F. Prophylactic and therapeutic properties

anti-epileptic drugs have been investigated and

of 1-methylsergic acid butanole in migraine. Int Arch

some have already been proven to be effective

Allergy 1959;15:300-7

CHAPTER 2

Headache classification

Headache, like any other disease entity, requires

known, have since received broad international

a classification system. Diagnosis of the various

support and have been endorsed by the World

headache disorders will be more accurate and

Health Organization (WHO) and its principles

universal when it has as its basis a consistent clas-

incorporated into the International Classification

sification system and a set of scientifically derived

of Diseases

(ICD-10)³. In it, headaches are

diagnostic criteria. The ideal classification table

subtyped using the principles of classification

should be sensitive, specific, exhaustive, generaliz-

developed by the American Psychiatric Association

able, reliable and valid. Sensitivity occurs when

and assigned into 12 major categories (Figure 2.1).

patients with a particular form of headache are all

These can be divided into two broad groups, the

diagnosed as such; specificity is when patients who

primary headache disorders (categories 1-4) and

do not have a particular disorder are invariably

the secondary headache disorders

(categories

excluded. A classification table is exhaustive when

5-12). The primary headache disorders are classi-

its usage enables all headaches to be classified. It

fied based on symptom profiles, while the

is generalizable when it can be used in diverse

secondary headache disorders are classified based

settings by both headache specialist and non-

on their causes, e.g. metabolic, structural or vascu-

specialist alike. Reliability occurs when the system

lar causes. The IHS system is currently undergoing

has high inter-obsever repeatability with low vari-

revision.

ability. High correlation of diagnosis with the

underlying biological disorder underlines validity.

The precusor to the modern classification was

REFERENCES

created in the early 1960s by an ad hoc committee

1. Ad Hoc Committee on Classification of Headache.

of the United States National Institutes of Health¹.

Classification of headache. JAMA 1962;179:717-8

The classification table it devised was an advance-

2. Headache Classification Committee of the Inter-

ment to the scientific study of headache but at the

national Headache Society. Classification and diagnos-

same time was criticized by many as being too

tic criteria for headache disorders, cranial neuralgias

vague in its definitions. In 1985, the International

and facial pain. Cephalalgia 1988;8 (Suppl 7):1-96

Headache Society (IHS) formed a headache classi-

3. World Health Organisation. The International Statis-

fication committee that published, in

1988, a

tical Classification of Diseases and Related Health Prob-

classification system that has become the standard

lems; 10th rev. Geneva: World Health Organisation,

for headache diagnosis, particularly for clinical

1992-1994

research². The IHS criteria, as it soon became

CHAPTER 3

Epidemiology of migraine

INTRODUCTION

within one year. Incidence is the onset of new cases

of a disease in a defined population over a given

Headaches are one of the most common complaints

period of time.

encountered by the practicing physician. Despite

the amount of suffering and disability they cause,

headaches are still underdiagnosed and under-

EPIDEMIOLOGY OF PRIMARY

treated.

AND SECONDARY HEADACHES

Epidemiology has important implications for

Using the IHS criteria, Rasmussen et al.¹ examined

the diagnosis and treatment of headache dis-

the population distribution of all headache disor-

orders. Examination of sociodemographic, distri-

ders via in-person clinical assessment in a large,

bution, impact, familial and environmental risk

representative community sample in the greater

factors may provide clues to preventive strategies

Copenhagen area. The lifetime prevalence of

and disease mechanisms. In this chapter, epidemi-

tension-type headache was

78% and that of

ologic terms, prevalence rates, impact, costs and

migraine 16%. The most common secondary cause

comorbitity of migraine are reviewed.

was fasting, which was the case in 19% of patients,

followed by nose/sinus disease in 15% of patients

and head trauma in 4%. Non-vascular intracranial

DEFINITIONS OF EPIDEMIOLOGIC

TERMS

disease, including brain tumor, accounted for 0.5%.

Rasmussen and Olesen² studied the epidemiology

For clinical practice and epidemiologic research, it

of other headache disorders. Lifetime prevalence

is important to have precise definitions to enable

of idiopathic stabbing headache was 2%, external

reliable and valid diagnosis

(Figure

3.1). Since

compression headache was 4% and cold stimulus

there is no true diagnostic gold standard for the

headache was 15%. Benign cough headache, benign

primary headache disorders, it is difficult to study

exertional headache and headache associated

validity and to define diagnostic boundaries for

with sexual activity were each 1%. Lifetime preva-

symptom-based conditions.

lence of hangover headache was 72%, of fever

Epidemiologic studies often focus on preva-

headache 63% and of headache associated with

lence or incidence. Prevalence is the proportion of

disorders of the nose or sinuses 15%. Headaches

a given population that has a disorder over a

associated with severe structural lesions were

defined period of time. Lifetime prevalence is the

rare. Most headaches showed a significant female

proportion of individuals who have ever had the

predominance. Symptomatic headaches were more

condition, and one-year prevalence is the propor-

prevalent among migraineurs. In subjects with

tion of individuals who have had at least one attack

tension-type headache, only hangover headache

was over-represented. There was no association

prevalence is inversely proportional to income,

between the headache disorders and abnormal

with the low income groups having the highest

routine blood chemistries or arterial hypertension.

prevalence (Figure 3.7). Ethnicity and geographic

In women with migraine, however, diastolic blood

region also influence migraine prevalence⁴. It is

pressure was significantly higher than in women

highest in North America and Western Europe,

without migraine.

and more prevalent among Caucasians than

African- or Asian-Americans. Migraine is influ-

enced by environmental and genetic factors.

MIGRAINE

Migraine with aura has a stronger genetic influence

than migraine without aura and is influenced more

Migraine is a very common condition worldwide.

by environmental factors. Behavioral, emotional

Estimates of its prevalence have varied widely,

and climatologic changes may trigger migraine,

ranging from 3% to about 22% (Figure 3.2). The

modify the vulnerability to migraine or impact on

differences can be accounted for by the differing

its prevalence.

definitions and methodologies employed. A reason-

Evidence suggests that the incidence of migraine

able estimate of one-year prevalence of migraine in

may be increasing. Stang et al.⁷, in a population-

adults is 10 to 12% (6% in men and 15-18% in

based survey of migraine conducted from

women). In a Danish epidemiologic study³, life-

1979-1981 in Olmsted County, found that there

time prevalence of migraine was 16% (8% in men

was a striking increase in the age-adjusted inci-

and 25% in women) and one-year prevalence was

dence of migraine in those under 45 years of age.

10% (6% in men and 15% in women). Prevalence

Migraine incidence increased by 34% for women

of migraine without aura was

6% and that of

and by 100% for men. In this study, the overall

migraine with aura was 4%.

age-adjusted incidence was 137 per 100 000 indi-

In the US population, the one-year prevalence

viduals per year for men and 294 per 100 000

of migraine was 12% (6% in men and 18% in

individuals per year for women.

women)⁴. The same rates were found in France⁵.

In contrast, the American Migraine Study II, a

Migraine has been estimated to affect 1.5% of

follow-up to the original American Migraine

people in Hong Kong, 2.6% in Saudi Arabia, and

Study, showed that the prevalence of migraine in

3% in Ethiopia. In Japan and Malaysia, prevalence

the United States is 18.2% for women and 6.5%

rates were similar to those found in Western coun-

for men. This is essentially unchanged from the

tries

(8.4 and 9.0%, respectively; Figure 3.3). A

original study

(prevalence

17.6% and

5.7%,

recent epidemiologic study in South America⁶

respectively). The distribution of disease by

showed one-year prevalence of migraine in women

sociodemographic factors has remained stable

(men) of 17% (8) in Brazil, 6% (4) in Argentina,

over the last decade, and migraine continues to be

14% (5) in Colombia, 12% (4) in Mexico and 12%

more prevalent in Caucasians than in other ethnic

(5) in Venezuela.

groups and in the lower income groups.

Migraine prevalence is age- and gender-

dependent. Before puberty, migraine is slightly

more common in boys, with the highest incidence

Impact and costs

between 6-10 years of age. In women, the inci-

dence is highest between 14-19 years of age. In

Migraine is a public health problem of enormous

general, women are more commonly affected than

scope that has an impact on both the individual

men (Figure 3.4), with a lifetime prevalence of

sufferer and on society. Migraine is a lifelong,

12-17% and 4-6%, respectively. In the American

common disorder that affects people during their

Migraine Study, the one-year prevalence of

most productive years. The individual burden

migraine increased with age among women and

accounts for the impact of attacks on quality of life,

men, reaching the maximum at ages 35-45 and

and reduction of family, social and recreational

declining thereafter (Figures 3.5 and 3.6). Migraine

activities. The societal burden refers to direct costs,

primarily the cost of medical care, and indirect

Both epilepsy and migraine can cause headache

costs, which are due to the impact on work (absen-

and transient alterations of consciousness. Stroke

teeism and reduced effectiveness; Figure 3.8). The

and migraine can both cause transient neurologic

American Migraine Study estimates that 23 million

signs and headaches. Prodromal migraine symp-

US residents have severe migraine headaches.

toms, such as fatigue and irritability, may be part

Twenty-five percent of women experience four or

of comorbid depression. Migraine is also a risk

more severe attacks a month; 35% experience one

factor for a number of comorbid disorders. Comor-

to three severe attacks a month; and 40% experi-

bidity has important therapeutic implications.

ence one, or less than one, severe attack a month.

Comorbid conditions may impose therapeutic

Similar frequency patterns were observed for men⁴.

limitations, but therapeutic opportunities may

In the American Migraine Study, more than

arise as well. For example, anti-depressants would

85% of women and more than 82% of men with

be the first option when migraine and depression

severe migraine had some headache-related dis-

are concomitant.

ability. About one-third were severely disabled or

In addition to the diagnostic and therapeutic

needed bed rest (Figure 3.9). As headache pain

implications, the presence of comorbidity may

intensity increases, more migraineurs report

provide clues to the pathophysiology of migraine.

disability

(Figure 3.10). It is estimated that the

When two conditions occur in the same person,

typical male migraineur has 3.8 and the typical

the apparent associations may arise by coinci-

woman sufferer 5.6 days of bed rest each year,

dence, one condition may cause the other or

resulting in a total of 112 million bedridden days

shared environmental or genetic risk factors might

per year in the US⁸. In addition to the attack-

account for the co-occurrence of two disorders. For

related disability, many migraineurs live in fear,

example, head injury is a risk factor for both

knowing that at any time an attack could disrupt

migraine and epilepsy and may account for part of

their ability to work, care for their families or meet

the relationship between the disorders. Shared

social obligations. In a prospective diary study, 17%

genetic risk factors may also account for the asso-

of social and family activities had to be cancelled

ciation between comorbid disorders. Finally, inde-

because of headaches⁹.

pendent genetic or environmental risk factors may

Migraine has an enormous impact on society. In

produce a brain state that gives rise to both migraine

the US, annual lost productivity due to migraine

and a comorbid condition.

costs

13 billion dollars³, while direct costs are

estimated to be

2.5 billion dollars per year.

Migraine’s impact on health care utilization is

Migraine and stroke

marked as well. The National Ambulatory Medical

Both migraine and stroke are neurologic disorders

Care Survey, conducted from 1976-1977, found

that are associated with focal, neurologic signs,

that 4% of all visits to physicians’ offices (over

alterations in blood flow or headache. The rela-

10 million visits a year) were for headache.

tionship between stroke and migraine could be

Migraine also results in major utilization of emer-

better understood by the following proposed clas-

gency rooms and urgent care centers¹⁰.

sification system: (i) coexisting stroke and migraine;

(ii) stroke with clinical features of migraine (symp-

Comorbidity

tomatic migraine, migraine mimic); (iii) migraine-

Comorbidity refers to the coexistence of one dis-

induced stroke (with and without risk factors);

order with another that occurs more commonly

(iv) uncertain¹¹. The proportion of strokes attri-

than by chance. Stroke, epilepsy, depression,

buted to migraine varies from 1-17% in clinical

mania, anxiety and panic disorders are comorbid

series. Migraine is a risk factor for stroke. The risk

with migraine. Comorbidity has implications for

of stroke among women under 45 years of age with

headache diagnosis. Migraine has substantial

migraine was three-fold higher than that of

overlap of symptoms with its comorbid conditions.

controls, and six-fold higher than that of controls

for women suffering migraine with aura. Young

ratios were 4.5 for major depression, 6.0 for manic

women with migraine who smoked increased their

episode, 3.2 for any anxiety disorder and 6.6 for

stroke risk to approximately ten-fold that of

panic disorder. Migraine with aura was more

controls, and to 14-fold that of controls if they

strongly associated with the various psychiatric

were on oral contraceptives¹².

disorders than was migraine without aura.

Personality disorders have been linked to mig-

raine. Brandt et al.¹⁷ used the Eysenck Personality

Migraine and epilepsy

Questionnaire (EPQ) in the Washington County

Migraine Prevalence Study sample. The EPQ is a

The prevalence of epilepsy in migraine patients is

well-standardized measure that includes four

5.9%, greatly exceeding the population prevalence

scales: psychoticism (P), extroversion (E), neuroti-

of 0.5%. There is a two-fold increase in migraine

cism

(N) and lie

(L). Migraineurs had higher

among both epileptic probands and their rela-

scores than controls on the EPQ N scale, indicat-

tives¹³(Figure 3.11). The comorbidity of migraine

ing that they were more tense, anxious and

and epilepsy can be explained by a state of

depressed than the control group. Women with

neuronal excitability that increases the risk of

migraine scored significantly higher than controls

both disorders. Treatment strategies for patients

on the P scale, indicating that they were more

with comorbid migraine and epilepsy may have

hostile, less interpersonally sensitive and out of

limitations, such as drugs that lower seizure

step with their peers.

threshold (tricyclic antidepressants, neuroleptics),

Chronic daily headache, particularly chronic

but anticonvulsants (topiramate, divalproex) are

migraine, is highly comorbid with depression,

drugs of choice for this association.

anxiety and insomnia¹⁸. Fibromyalgia is present in

35% of chronic migraine patients, and it is associ-

Migraine and psychiatric disorders

ated with depression and insomnia¹⁹.

Several population-based studies have examined

REFERENCES

the comorbidity of migraine, major depression,

panic disorder and other psychiatric disorders.

1. Rasmussen BK, Jensen R, Schroll M, Olesen J.

Stewart et al.¹⁴

found that 15% of women and

Epidemiology of headache in a general population - a

12.8% of men with headache between the ages of

prevalence study. J Clin Epidemiol 1991;44:1147-57

24-29 years had panic disorder. Migraine headache

2. Rasmussen BK, Olesen J. Symptomatic and non-

was higher in individuals with a history of panic

symptomatic headaches in a general population.

disorder. The relative risk was 7.0 for men and

Neurology 1992;42:1225-31

3.7 in women.

3. Russell MB, Rasmussen BK, Thorvaldsen P, Olesen J.

Merikangas et al.¹⁵ found that anxiety and affec-

Prevalence and sex-ratio of the subtypes of migraine.

tive disorders were more common in migraineurs.

Int J Epidemiol 1995;24:612-8

The odds ratio was 2.2 for depression, 2.9 for bipolar

4. Stewart WF, Lipton RB, Celentano DD, Reed ML.

Prevalence of migraine headache in the United States.

spectrum disorders, 2.7 for generalized anxiety dis-

JAMA 1992;267:64-9

order, 3.3 for panic disorder, 2.4 for simple phobia

5. Henry P, Michel P, Brochet B, et al. A nationwide survey

and 3.4 for social phobia. Major depression and

of migraine in France: prevalence and clinical features

anxiety disorders were commonly found together.

in adults. GRIM. Cephalalgia 1992;12:229-37

In individuals with all three disorders, the onset of

6. Morillo LE, Sanin LC, Takeuchi Y, et al. Headache

anxiety generally precedes the onset of migraine,

in Latin America: A multination population-based

whereas the onset of major depression usually

survey. Neurology 2001;56:A544 (abstract)

follows the onset of migraine.

7. Stang PE, Yanagihara PA, Swanson JW, et al.

Breslau et al.¹⁶

found that lifetime rates of

Incidence of migraine headache: a population-based

affective and anxiety disorders were elevated in

study in Olmsted County, Minnesota. Neurology 1992;

migraineurs. After adjusting for sex, the odds

42:1657-62

8. Hu XH, Markson LE, Lipton RB, et al. Burden

14. Stewart WF, Shechter A, Liberman J. Physician

of migraine in the United States: disability and

consultation for headache pain and history of panic:

economic costs. Arch Intern Med 1999;159:813-8

results from a population-based study. Am J Med

9. Edmeads J, Findlay H, Tugwell P, et al. Impact of

1992;92:35S-40S

migraine and tension-type headache on life-style,

15. Merikangas KR, Angst J, Isler H. Migraine and

consulting behavior, and medication use: a Canadian

psychopathology. Results of the Zurich cohort study

population survey. Can J Neurol Sci 1993;20:131-7

of young adults. Arch Gen Psychiatry 1990;47:849-53

10. Celentano DD, Stewart WF, Lipton RB, Reed ML.

16. Breslau N, Davis GC. Migraine, major depression and

Medication use and disability among migraineurs: a

panic disorder: a prospective epidemiologic study of

national probability sample. Headache 1992;32:223-8

young adults. Cephalalgia 1992;12:85-9

11. Welch KM. Relationship of stroke and migraine.

17. Brandt J, Celentano D, Stewart WF, et al. Personality

Neurology 1994;44:S33-6

and emotional disorder in a community sample of

12. Carolei A, Marini C, De Matteis G. History of migraine

migraine headache sufferers. Am J Psychiatry 1990;

and risk of cerebral ischaemia in young adults. The

147:303-8

Italian National Research Council Study Group on

18. Mathew NT. Transformed migraine. Cephalalgia

Stroke in the Young. Lancet 1996;347:1503-6

1993;13:78-83

13. Ottman R, Lipton RB. Is the comorbidity of epilepsy

19. Peres MFP, Young WB, Zukerman E, et al. Fibro-

and migraine due to a shared genetic susceptibility?

myalgia is common in patients with transformed

Neurology 1996;47:918-24

migraine. Neurology 2001;57:1326-8

CHAPTER 4

Pathophysiology of migraine

There are two main competing theories for migraine

predicts that alterations in blood flow develop as a

pathogenesis: the vasogenic theory and the neuro-

consequence of neuronal events. During a migraine

genic theory. At first these two theories appear to be

attack there is an initial brief hyperperfusion phase

at odds, but novel ways of looking at brain function

followed by a relatively sustained phase of hypo-

indicate that they may complement each other.

perfusion that corresponds to cortical spreading

depression¹ (Figure 4.2). This probably reflects a

wave of neuronal and glial depolarization followed

THE VASOGENIC THEORY OF MIGRAINE

by longer-lasting suppression of neural activity.

Credence has been lent to this theory by recent

The premise of the vasogenic theory is that focal

magnetic resonance imaging studies using blood

ischemia is the root cause of the migraine aura.

oxygenation level-dependent and perfusion-

Auras are due to hypoperfusion secondary to

weighted imaging techniques during migraine with

vasoconstriction of the blood vessel that supplies

aura attacks, revealing signal changes characteristic

the cortical lobe corresponding to the aura symp-

of cortical spreading depression within the human

tom, be it visual, sensory or motor. Reactive vasodi-

brain². These studies revealed an initial vasodilation

lation would explain the genesis of pain through

occurring with the onset of visual aura that pro-

stimulation of the perivascular pain-sensitive

gressed contiguously over the occipital cortex at a

fibers. This theory would be in agreement with the

rate of 3.5 ± 1.1 mm/min. This initial vasodilation

throbbing quality of pain, its varied location and

was followed by hypoperfusion. The fact that the

the pain relief caused by vasoconstrictive agents

blood oxygenation level-dependent signal changes

such as ergotamine. Patients undergoing the aura

during aura abort at major sulci, that the light-

phase of their attacks were studied using ¹³³Xe

evoked visual responses were suppressed during

blood flow techniques and these studies revealed a

migraine with aura attacks and took 15 min to return

17-35% reduction in cerebral blood flow in the

to 80% of baseline, and that those areas first affected

posterior regions of the brain. More recent

were the first to recover provides strong evidence

positron emission tomographic scan studies during

consistent with the theory that an electrophysiologic

the aura phase of migraine confirm these results

event, such as cortical spreading depression

and reveal slowly spreading hypoperfusion.

(Figures 4.3 and 4.4), generates the migraine aura in

Neither study showed evidence of ischemia.

the human visual cortex² (Figures 4.5-4.8).

THE NEUROGENIC THEORY OF

MIGRAINE

THE TRIGEMINOVASCULAR SYSTEM

The neurogenic theory has as its basis the cortical

The brain is an insensate organ that lacks innerva-

spreading depression of Leao

(Figure

4.1). It

tion by pain fibers. However, the dura mater and

meningeal blood vessels are richly innervated by

stem do not seem to be activated as a response to

sensory nerve fibers that originate from the

head pain

(Figure

4.12). Noradrenergic and

ophthalmic division of the trigeminal nerve.

serotoninergic nuclei participate in stress responses,

Together with the trigeminal nucleus they con-

anxiety and depressive states. Migraineurs may

stitute the trigeminovascular system³. During a

exhibit central hypersensitivity to dopaminergic

migraine attack these sensory fibers release vaso-

stimulation, which has been linked to behaviors

dilating and permeability-promoting peptides

observed during migraine, such as yawning, irri-

from perivascular nerve endings, e.g. substance P,

tability, hyperactivity, gastroparesis, nausea and

calcitonin gene-related peptide and neurokinin A.

vomiting. Molecular genetic studies have provided

These peptides promote a sterile inflammatory

further evidence for the involvement of the

response within the dura mater and cause the

dopaminergic system. Migraine is associated with

sensitization of sensory nerve fibers to previously

the dopaminergic hypersensitivity phenotype and

innocuous stimuli (e.g. blood vessel pulsations or

genes encoding the DRD₂ receptor⁶.

venous pressure changes) and manifest themselves

The possibility of a ‘migraine generator’ in the

as increased intracranial mechanosensitivity and

rostral brainstem was raised by a positron emission

hyperalgesia worsened by coughing or sudden

tomography blood flow study performed during

head movement⁴. Calcitonin gene-related peptide

spontaneous unilateral headache in nine patients

levels have been found to be elevated in jugular

without aura⁵. Increased regional cerebral blood

venous blood during migraine attacks, returning to

flow was found in medial brainstem predomi-

normal after administration of sumatriptan and

nantly contralateral to the headache, which

amelioration of the headache. This is consistent

persisted after relief of migraine pain with suma-

with neuropeptide release from activated sensory

triptan

(Figure 4.13). Whether these brainstem

nerves during the migraine attack and blockade

nuclei serve as migraine generators or participate

of peptide release by sumatriptan, mediated via

in modifying the threshold for neuronal activation

5-HT_1B/1D prejunctional receptors (Figure 4.9) on

or are part of the neuronal system that terminates

sensory terminals (Figure 4.10). A recent single

an attack remains to be clarified (Figure 4.14).

photon emission computed tomography study

provided the first direct evidence for the presence

REFERENCES

of plasma protein extravasation localized to extra-

parenchymal regions ipsilateral to the side of pain

1. Cutrer FM, O’Donnell A, Sanchez DR. Functional

during a spontaneous migraine attack.

neuroimaging: enhanced understanding of migraine

Trigeminovascular activation occurs secondary

pathophysiology. Neurology 2000;55:S36-45

to an initiation factor for migraine attacks. What

2. Sanchez DR, Bakker D, Wu O, et al. Perfusion

initiates this is still unclear. Brainstem, cortical

weighted imaging during migraine: spontaneous visual

structures or neurochemical dysfunction may play

aura and headache. Cephalalgia 1999;19:701-7

an important role in either the genesis or modula-

3. Sanchez del Rio M, Moskowitz MA. The trigeminal

tion of migraines, or both. It now appears that the

system. In: Olesen J, Tfelt-Hansen P, Welch KM, eds.

The Headaches. Philadelphia: Lippincott Williams &

migraine brain is inherently more hyperexcitable

Wilkins, 2000:141-9

either due to genetic factors (e.g. point mutations

4. Moskowitz MA. The neurobiology of vascular head

in genes encoding calcium channels, mitochondrial

pain. Ann Neurol 1984;16:157-68

energy impairment and magnesium deficiency) or

5. Weiller C, May A, Limmroth V, et al. Brain stem

external factors

(such as stress and hormonal

activation in spontaneous human migraine attacks. Nat

changes).

Med 1995;1:658-60

Brainstem nuclei, including the periaqueductal

6. Peroutka SJ, Price SC, Wilhoit TL, Jones KW.

gray matter, locus coeruleus and dorsal raphe nuclei

Comorbid migraine with aura, anxiety, and depression

(Figure 4.11), have been shown to either generate

is associated with dopamine D2 receptor (DRD2)

or suppress pain symptoms resembling migraine in

NcoI alleles. Mol Med 1998;4:14-21

animals and humans⁵. These locations in the brain

CHAPTER 5

Migraine

Migraine is a common primary episodic headache

changes (depression, anger, euphoria), stiff neck,

disorder. In the United States, more than 17% of

fatigue, yawning, food cravings, fluid retention and

women and 6% of men had at least one migraine

increase in urination.

attack in the past year. Although the term migraine

The aura is composed of focal, neurologic

derives from the Greek word ‘hemicrania’, which

symptoms that usually precede the headache,

means ‘half of the head’, it is not always a strictly

lasting in general less than 60 min. Visual symp-

unilateral headache; it can be bilateral and it is

toms are the most common, such as zigzag or

characterized by various combinations of neuro-

scintilating figures (fortification spectrum), scoto-

logic, gastrointestinal and autonomic symptoms.

mata and distortions in shape and size. Motor,

There are many migraine subtypes, including

sensory or brainstem disturbances can also occur

migraine without aura, migraine with aura, basilar

(Figures 5.1-5.9).

migraine, familial hemiplegic migraine, status

The headache phase is typically characterized

migrainosus and chronic (previously transformed)

by unilateral pain that is throbbing, moderate to

migraine.

marked in severity and aggravated by physical

According to the International Headache

activity. The pain of migraine is invariably accom-

Society (IHS)’s classification and diagnostic criteria

panied by other features. Nausea occurs in almost

for primary headaches, certain clinical features

90% of patients, while vomiting occurs in about

must be present and organic disease must be

one-third of migraineurs. Many patients experi-

excluded for headaches to qualify as migraine.

ence sensory hyperexcitability manifested by

To diagnose migraine without aura, five attacks

photophobia, phonophobia and osmophobia, and

are needed, each lasting 4 to 72 h and having two

seek a dark, quiet room. Other systemic symp-

of the following four characteristics: unilateral

toms, including anorexia, blurry vision, diarrhea,

location, pulsating quality, moderate-to-severe

abdominal cramps, polyuria, pallor of the face,

intensity and aggravation by routine physical

stiffness and tenderness of the neck and sweating,

activity. In addition, the attacks must have at least

may also be noted during the headache phase.

one of the following: nausea (and/or vomiting) or

Impairment of concentration is common; less often

photophobia and phonophobia.

there is memory impairment. Depression, fatigue,

Four phases of migraine

(prodrome, aura,

anxiety, nervousness and irritability are also

headache and postdrome) are recognized and may

frequent. Lightheadedness, rather than true vertigo,

occur alone or in combination with any other

and a feeling of faintness may occur.

phase. The prodrome consists of premonitory

In the postdrome phase, the pain wanes.

phenomena generally occurring hours to days

Following the headache, the patient may feel tired,

before the headache and include mental and mood

washed out, irritable and listless and may have

impaired concentration, scalp tenderness or mood

migraine and to optimize the patient’s ability to

changes. Some people feel unusually refreshed

function normally. To achieve these goals patients

or euphoric after an attack, while others note

must learn to identify and avoid headache triggers.

depression and malaise.

Pharmacologic treatment of migraine may be acute

A number of mechanisms and theories have

(abortive, symptomatic) or preventive (prophylac-

been proposed to explain the causes of migraine.

tic). Patients experiencing frequent, severe head-

The strong familial association and the early onset

aches often require both approaches. The choice of

of the disorder suggest that there is an important

treatment should be guided by the presence of

genetic component, and migraine has been con-

comorbid conditions. A concurrent illness should

sidered to be a chanellopathy.

be treated with a single agent when possible and

The pain distribution suggests involvement of

agents that might aggravate a comorbid illness

the trigeminal nerve, trigeminal activation resulting

should be avoided. Biofeedback, relaxation techni-

in the release of neuropeptides, producing neuro-

ques and other behavioral interventions can also be

genic inflammation with increased vascular per-

used as adjunctive therapy.

meability, and dilation of blood vessels. This is the

Many medications have been used for acute

trigeminal vascular model proposed by Moskowitz¹

migraine treatment, including analgesics, anti-

(Figures 5.10-5.14).

emetics, anxiolytics, nonsteroidal anti-inflammatory

Muscle contraction and tenderness might be

drugs, ergots (Figure 5.15), steroids, major tranquili-

another important component in migraine patients.

zers and narcotics. Recently, triptans

(selective

Neurotransmitters including serotonin, dopamine,

5-HT_lB/D(serotonin) agonists; Figure

5.16) have

norepinephrine, glutamate, nitric oxide, GABA

been used with success (e.g. sumatriptan, rizatrip-

and other substances such as magnesium and

tan, zolmitriptan and naratriptan).

melatonin have also been considered in migraine

Preventive treatments include a broad range of

pathophysiology.

medications, most notably antidepressants, anti-

The goals of migraine treatment are to relieve

convulsants, serotonin antagonists, β-blockers and

or prevent the pain and associated symptoms of

calcium channel blockers.

CHAPTER 6

Trigeminal-autonomic cephalgias

INTRODUCTION

migraine and tension-type headache is the extreme

intensity of the headache and the unique associ-

This chapter will discuss the distinct headache

ated symptoms representing both parasympathetic

disorders known as the trigeminal-autonomic

nervous system activation (eye lacrimation, con-

cephalgias (TACs). This group of primary head-

junctival injection, nasal congestion or rhinorrhea)

aches is characterized by short-duration unilateral

and sympathetic nervous system dysfunction

head pains and associated ipsilateral autonomic

(miosis, ptosis, partial Horner’s syndrome). What

symptoms. Recognized TACs include cluster

distinguishes each of the TACs from each other is

headaches, chronic paroxysmal hemicrania (CPH),

the duration of the headache attacks. SUNCT has

episodic paroxysmal hemicrania (EPH) and the

the shortest attacks lasting 5 to 250 s (Figure 6.1),

syndrome of short-lasting unilateral neuralgiform

with CPH lasting 2 to 45 min (Figure 6.2) and

headache with conjunctival injection and tearing

cluster headaches lasting 15 to 180 min (Figure

(SUNCT); see Table 6.1. Cluster headaches are a

6.3). What ties the syndromes together is a linkage

fairly common condition while CPH and SUNCT

between headache and autonomic symptoms.

may never be seen by physicians in their entire

This clinical phenotype can be explained by an

practice lifetime. What sets these headaches apart

underlying trigeminal-autonomic reflex pathway

from the other primary headache disorders such as

which consists of a brainstem connection between

Table 6.1

The differential diagnosis for cluster headache involves the other known trigeminal-

autonomic cephalgias: SUNCT, CPH, EPH, idiopathic stabbing headache and trigeminal neuralgia.

Based on individual attack duration, attack frequency and associated symptoms, a correct diag-

nosis of cluster can be made. In the United States it takes an average of 6 years before a cluster

patient is correctly diagnosed. It should not be difficult to make a diagnosis of cluster if a good

headache history is taken. PPT, precipitant. Reproduced with permission from reference 1

Feature

Cluster

CPH

EPH

SUNCT

Stabbing

Trigeminal

headache

neuralgia

Gender (M:F)

4:1

1:3

1:1

2.3:1

F>M

Attack

15-18 min

2-45 min

1-30 min

5-250 s

<1 s

duration

Attack

1-8/day

1-40/day

3-30/day

1/day-30/h Few-many Few-many

frequency

Autonomic

−

features

Alcohol PPT

−

Indomethacin

+/−

−

effect

the trigeminal nerve and the facial nerve (the site

Table 6.2

Cluster headache has been recognized in the

literature by many names, some of which are still used today

of the cranial parasympathetic outflow system). It

is very important for the clinician to recognize

Hemicrania angioparalytica (Eulenberg, 1878)

Sluder’s sphenopalatine neuralgia (Sluder, 1908)

the TACs as distinct headache disorders outside of

Ciliary neuralgia, migrainous neuralgia (Harris, 1926)

migraine and tension-type headache, because treat-

Autonomic faciocephalalgia (Brickner and Riley, 1935)

ment strategies are different for each headache.

Erythromelalgia of the head, histaminic cephalalgia

For example, CPH is an indomethacin-responsive

(Horton, 1939, 1941; Figure 6.10)

headache syndrome, while cluster headaches and

SUNCT do not respond to this non-steroidal anti-

Table 6.3

International Headache Society’s classification of

inflammatory agent. In the following paragraphs

cluster headache. Adapted with permission from reference 3

short descriptions of the distinct TACs will be

(1) At least five attacks fulfilling (2)-(4)

given, following which a pictorial presentation of

(2) Severe unilateral, orbital, supraorbital and/or temporal

the TACs will be made including images on

pain lasting 15 to 180 min untreated

epidemiology, pathogenesis, clinical characteristics

(3) Headache is associated with at least one of the following

signs that have to be present on the pain side:

and treatment strategies (Figures 6.1-6.35).

(a) conjunctival injection

(b) lacrimation

CLUSTER HEADACHES

(d) rhinorrhea

(e) forehead and facial sweating

There is no more severe pain than that sustained

(f)

miosis

(g)

ptosis

by a cluster headache sufferer. Cluster headache is

(h)

eyelid edema

known as the ‘suicide headache’ (for other names

(4) Frequency of attacks: from one every other day to

of this condition, see Table 6.2), and if not for

eight a day

the rather short duration of attacks most cluster

sufferers would choose death rather than continue

Table 6.4

Distribution of associated symptoms with cluster

suffering. Cluster headache is a primary headache

headaches. Lacrimation is the most common symptom. Cluster

syndrome (Figure 6.4). It is very stereotyped in its

patients do get

‘migrainous associated symptoms’. If a

presentation and fairly easy to diagnose with an

cluster patient has typical cluster symptoms but also has nausea

in-depth headache history. Fortunately cluster

and vomiting, the diagnosis is still cluster and not migraine

headaches are easy to treat in most individuals if

Autonomic symptoms

the correct medications are used and the correct

Lacrimation (73%)

Conjunctival injection (60%)

dosages are given. Our understanding of the patho-

Nasal congestion (42%)

genesis of cluster headaches is increasing and with

Rhinorrhea (22%)

this there should arise better and more specific

Partial Horner’s syndrome (16-84%)

cluster therapies. Recently Klapper et al.² deter-

General symptoms

mined that the average time it takes for a cluster

Nausea (10-54%; 29%)

Vomiting (1-15%; 9%)

sufferer to be diagnosed correctly by the medical

Photophobia (5-72%)

profession is 6.6 years. This statistic is unacceptable

Phonophobia (12-39%)

based on the pain and suffering cluster patients

must endure when they are not treated correctly

or not treated at all. In many instances cluster head-

from

15 to

180 min untreated. The headache

ache is misdiagnosed as migraine or sinus headache,

needs to be associated with at least one of the

so an inappropriate therapy regime is prescribed.

following signs or symptoms: lacrimation, conjunc-

The International Headache Society (IHS) in 1988

tival injection, rhinorrhea, nasal congestion, fore-

composed diagnostic criteria for cluster headache³

head and facial sweating, miosis, ptosis or eyelid

(Table 6.3). Patients with cluster headache should

edema (Table 6.4). Cluster headaches are typically

experience at least 5 attacks of severe unilateral,

side-fixed and will remain on the same side of the

orbital, supraorbital and/or temporal pain that lasts

head for a patient’s entire lifetime. Only 15% of

Table 6.5

Comparison chart looking at percentage of patients with migrainous symptoms

(photophobia, phonophobia, nausea, vomiting) from three cluster investigations and the

average percentage of these symptoms from seven migraine studies. Cluster patients have just

as much photophobia and phonophobia as migraine patients but less nausea and vomiting.

Photophobia and phonophobia should not be considered good differentiating symptoms

between cluster and migraine. Data derived from Rozen TD, Niknam RM, Shechter AL, et al.

J Neurol Neurosurg Psychiatr 2001;70:613-7; Nappi G, Micieli G, Cavallini A, et al. Cephalalgia

1992;12:165-8; Vingen JV, Pareja JA, Sovner LJ. Cephalalgia 1998;18:250-6. n/a, data not available

Symptom

Rozen, 2001

Nappi, 1992

Vingen, 1998

Migraine

(n = seven studies)

Photophobia

80%

56%

91%

79%

Phonophobia

50%

15%

89%

80%

Nausea

53%

41%

n/a

87%

Vomiting

32%

24%

n/a

56%

patients will have a shift of sides between cluster

one age peak of cluster onset in their twenties

periods. The pain of cluster headaches is described

(Figure 6.11a), while women have one peak in

as sharp or boring and usually localizes behind the

their late teens and twenties and a second in their

eye. During a cluster attack, cluster patients cannot

fifties or sixties (Figure 6.11b). In most instances

and do not want to remain still. They typically pace

cluster headaches should be easy to distinguish

the floors or even bang their heads against the wall

from migraine based upon the duration of indivi-

to try and alleviate their pain. Cluster headaches

dual attacks

(cluster headaches last

15 min to

are short in duration compared to some of the

3 h versus migraines which last > 4 h) and the

other primary headaches, usually with an average

number of attacks experienced per day (cluster:

duration of 45 min to 1 h (Figure 6.3). Cluster

one or more; migraine: none or one). In addition,

patients will frequently have between one and

only about 3% of cluster patients can remain still

three attacks per day. The headaches have a

during a headache, while almost all migraineurs

predilection for the first REM sleep phase, so the

want to lie down with a migraine. It used to be

cluster patient will awaken with a severe headache

thought that cluster patients did not experience

60 to 90 min after falling asleep (Figure 6.5).

‘migrainous symptoms’ (nausea, vomiting, photo-

Cluster headaches can be of an episodic (greater

phobia, phonophobia) and that these were good

than 14 headache-free days per year) or chronic

distinguishing characteristics between the two

(occuring for more than 1 year without remission

disorders, but this may not be true. Photophobia

or with < 14 headache-free days per year) subtype.

and phonophobia occur almost as frequently in

Between 80-90% of cluster patients have the

cluster headaches as they do in migraine. Nausea

episodic variety (Figure 6.6). Cluster periods, or

and vomiting also occur in cluster patients, specifi-

the time when patients are experiencing daily

cally females, but not nearly as frequently as in

cluster attacks, usually last between

2 and 12

migraine (Table 6.5). With regard to the autonomic

weeks and patients can have 1-2 cluster periods

symptoms which are hallmarks of cluster attacks,

per year (Figure 6.7). It is not uncommon for a

only about

20% of migraineurs have associated

patient to experience a cluster period at the same

ptosis, unilateral lacrimation or nasal congestion/

time each year. This circadian periodicity suggests

rhinorrhea with their headaches. In addition, aura,

a hypothalamic generator for cluster headaches

which was supposed to be a migraine-only event,

(Figures 6.8-6.9). In regard to age of onset, cluster

has now been shown to occur with cluster head-

headaches are a disorder of young people but the

aches, so the presence of aura cannot define a

headaches do not start as young as they do in

primary headache syndrome. Finally, migraine is

migraine. Typically cluster headaches will begin in

a disorder of women and cluster headache is

the twenties or thirties, although they can start

supposed to be a disorder of men (Figure 6.12). It

in the teens or even younger. Men appear to have

is not uncommon for physicians to give a woman a

Table 6.6

Data illustrating how the male:female cluster

Table 6.9

Sumatriptan injectable is the fastest and most

headache gender ratio is decreasing over time.The cause of this

effective therapy for cluster headache at the present time. It is

is unknown but may reflect a true increase in cluster incidence

contraindicated in cluster patients with cardiovascular risk

or better diagnoses by physicians. In total,

482 patients

factors. Reproduced with permission from reference 1

(374 males, 108 females) were evaluated. Reproduced with

Effective in 90% of patients for 90% of their attacks for both

permission from reference 4

episodic and chronic cluster headache

Male to female ratios

Efficacy within 15 min in 50-75%

Before 1960 6.2:1

No tachyphylaxis

1960-1969 5.6:1

Attack frequency not increased with prolonged use

1970-1979 4.3:1

Not effective for cluster prophylaxis

1980-1989 3.0:1

1990-1995 2.1:1

Table 6.10

Surgical procedures for cluster headache are

Is this due to a decrease in male cluster patients or an

directed towards the sensory trigeminal nerve or cranial

increase in females, or better diagnosis?

parasympathetic system (Figure 6.14). Surgery should only be

considered once a patient is deemed refractory to medical

Table 6.7

Abortive treatment of cluster headache. Sumatriptan

treatment. Cluster patients who have only had one side of the

injectable can provide relief within 5 min (Figure 6.13, Table 6.9).

head affected can get surgery in contrast to those who have

Oxygen is safe in all cluster patients, even those with cardio-

had side-switching, as the latter are at great risk of having the

vascular risk factors

(see also Table

6.8). Reproduced with

headache switch sides after surgery

permission from reference 1

Procedures directed towards the sensory trigeminal nerve

High efficacy

Alcohol injection into supraorbital and infraorbital nerves

O₂

Alcohol injection into Gasserian ganglion

sumatriptan subcutaneous (6 mg)

Avulsion of infraorbital/supraorbital/supratrochlear nerves

IV/IM/SQ dihydroergotamine mesylate 0.5-1.0 mg

Retrogasserian glycerol injection (less corneal anesthesia)

Limited efficacy

Radiofrequency trigeminal gangliorhyzolysis (75% effective,

zolmitriptan 5-10 mg oral

20% recurrence)

ergotamine 1-2 mg oral or suppository

Trigeminal root section

intranasal lidocaine

Procedures directed at autonomic pathways

Section of greater superficial petrosal nerve

Section of nervus intermedius

Table 6.8

Oxygen is effective in up to

70% of cluster

patients. A non-rebreather face mask should be used as delivery

system. Reproduced with permission from reference 1

SUNCT

100% O₂ 7-10 liters/min for 15 min

Efficacy 70% at 15 min

The syndrome of short-lasting unilateral neuralgi-

Most effective when headache is at maximum intensity

form headache attacks with conjunctival injection

May delay rather than completely abort attack

and tearing, or SUNCT, was first described by

Main limitation is accessibility

Sjaastad et al. in

1978 in an article entitled

‘Multiple neuralgiform unilateral headache attacks

diagnosis of migraine even though she has typical

associated with conjunctival injection and appear-

cluster features just because she is a woman,

ing in clusters’. The description of the complete

falsely believing that women do not get cluster

syndrome came in 1989⁵. SUNCT is the rarest

headaches. Cluster headaches undoubtedly occur

of the primary headache disorders with less than

in women, and there is a recent epidemiologic

30 documented cases. Many headache specialists

study from Italy suggesting that more women are

have stated that they have never seen SUNCT and

developing or being diagnosed with cluster

some still question the validity of the syndrome.

headaches (Table 6.6). The previous male:female

SUNCT is comprised of brief attacks of moderate

cluster ratio of 6-7:1 has decreased to 2:1 in the

to severe head pain with associated autonomic

1990s. Female cluster headaches can appear

disturbances of conjunctival injection, tearing,

exactly like male cluster headaches except that

rhinorrhea or nasal obstruction ( Table 6.11). The

female cluster patients develop more nausea and

typical age of onset is between 40 and 70 years

vomiting with cluster attacks and have less miosis

(Figure 6.15). SUNCT pain is normally localized

and ptosis than their male counterparts.

to an orbital or periorbital distribution, although

Table

6.11

Proposed criteria for SUNCT syndrome.

Table 6.12

SUNCT attacks are marked by associated symp-

Reproduced from reference

6, with permission of Oxford

toms of parasympathetic activation (lacrimation, conjunctival

University Press

injection) and much less common sympathetic dysfunction

(ptosis); *symptomatic side; * *symptomatic cases;^†one patient

Diagnostic criteria

reported bilateral nasal stenosis during attacks;^††reported as

(1)

At least 30 attacks fulfilling (2)-(5)

being bilateral by one patient. Reproduced with permission

(2)

Attacks of unilateral, moderately severe, orbital or

from reference 7

temporal stabbing or throbbing pain lasting from

15-120 s

(3)

Attack frequency from 3 to 100/day

(4)

Pain is associated with at least one of the following signs

Lacrimation*

21 (2* *)

or symptoms of the affected side with feature (a) being

Conjunctival injection*

20 (2* *)

most often present and very prominent:

Rhinorrhea*

14 (1* *)

(a) conjunctival injection

Nasal obstruction*^†

14 (1* *)

(b) lacrimation

Eyelid edema*

8 (1* *)

Decreased palpebral fissure*

5 (1* *)

(d) rhinorrhea

Facial redness*

4 (1* *)

(e) ptosis

Tachypnea, clinically observable

(f)

eyelid edema

Photophobia*

(5)

At least one of the following:

Blepharospasm^††

(a) There is no suggestion of one of the disorders

Miosis*

listed in groups 5-11 (see Figure 2.1).

Feeling of facial sweating

(b) Such a disorder is suggested but excluded by appro-

Nausea

priate investigations.

Ptosis

Feeling of foreign body in the eye*

attacks do not occur in close temporal relation to

Polyuria

the disorder.

Unpleasant feeling, nose

Clinical note: The literature suggests that the most common

Dilated vessels, eyelids*

secondary cause of SUNCT would be a lesion in the

posterior fossa.

80 episodes a day. Individuals can experience

the forehead and temple can be the main site

fewer than one attack an hour to more than 30.

of pain (Figure 6.16). Head pain can radiate to

Mean attack frequency is

28 attacks per day.

the temple, nose, cheek, ear and palate. The pain

SUNCT is an episodic disorder that presents in

is normally side-locked and remains unilateral

a relapsing/remitting pattern. Each symptomatic

throughout an entire attack. In rare instances

period can last from several days to several months,

SUNCT pain can be bilateral. Pain severity is

and a person with SUNCT will typically have 1 to

normally moderate to severe, unlike cluster head-

2 symptomatic periods a year. The longest docu-

ache pain which is always severe. The pain is

mented symptomatic period is 5 years, and the

described most often as a stabbing, burning, prick-

highest number of reported SUNCT episodes in

ing or electric shock-like sensation. Pain duration

one year is 22. Remissions typically last months but

is extremely short, lasting between 5 and 250 s,

can last years. Symptomatic periods appear to

with an average duration of 10 to 60 s (Figure 6.1).

increase in frequency and duration over time.

It is this extremely brief pain duration that sets

All documented SUNCT patients experience

SUNCT apart from other primary headache

conjunctival injection and lacrimation (ipsilateral

syndromes; SUNCT pain normally plateaus at a

to the side of the head pain) with each attack.

maximum intensity for several seconds and then

Ipsilateral rhinorrhea and/or nasal obstruction

quickly abates. SUNCT can occur at any time of

occur in 67% of individuals. Less frequent associ-

the day, and does not show a tendency towards

ated symptoms include eyelid edema, a decreased

nocturnal attacks; only 1.2% of reported sufferers

palpebral fissure, facial redness, photophobia and

have night-time episodes

(Figure

6.17). Attack

blepharospasm (Table 6.12). Typically, conjunctival

frequency varies greatly between sufferers and

injection and eye tearing will start within 1 to 2 s

within an individual sufferer. The usual attack

of pain onset and remain until the head pain

frequency ranges anywhere from 1 to more than

ceases, sometimes outlasting the pain by up to

Table 6.13

All patients with SUNCT must have an MRI to rule out secondary causes, espe-

cially vascular malformation in the cerebellopontine region. MRI (n = 12), CT (n = 11), angio-

graphy (n = 6); * symptomatic side, * * symptomatic cases. Reproduced with permission from

reference 7

Patient

Procedure

Results

Some enlarged sulci in frontal area

CT, MRI

Cholesteatoma*

MRI

Bilateral lacunar infarcts

Head x-ray

Osteoma in anterior part of scalp

20 * *

MRI, angiography

Vascular malformation in cerebellopontine region*

21* *

Table 6.14

Until recently multiple medications had been tried in SUNCT, all without

success. Recently several case reports have documented the efficacy of lamotrigine, gabapentin

and topiramate for SUNCT; -, treatment had no effect; x, treatment worsened condition;

SC, subcutaneous; IV, intravenous; * one patient with slight improvement. Reproduced from

reference 6, with permission of Oxford University Press

Treatment

Dosage (max/day)

Response

Pharmacologic

Aspirin

1800 mg

Paracetamol

Indomethacin

200 mg

Naproxen

Ibuprofen

1200 mg

Ergotamine (oral)

3 mg

Dihydroergotamine (IV)

3 mg

Sumatriptan (oral)

300 mg

Sumatriptan (SC)

6 mg

Prednisone (oral)

100 mg

Methysergide

8 mg

Verapamil

480 mg

Valproate

1500 mg

Lithium

900 mg

Propranolol

160 mg

Amitriptyline

100 mg

Carbamazepine

1200 mg

Procedures or infusions

Lignocaine (IV)

4 mg/min

Greater occipital nerve

block

s. Rhinorrhea, on the other hand, starts in the

the ending phase of a previous attack, a new one

mid-to-late phase of an attack. Nausea, vomiting,

can begin immediately. This is unlike the refrac-

photophobia and phonophobia are not normally

tory period of trigeminal neuralgia. The true

associated with SUNCT. SUNCT can arise spon-

epidemiology of SUNCT is not known, and there

taneously, but many sufferers have identified

is no prevalence or incidence data available. The

triggering maneuvers, including mastication, nose

extremely low number of reported cases suggests

blowing, coughing, forehead touching, eyelid

it is a very rare syndrome. All patients with

squeezing, neck movements (rotation, extension

SUNCT must have an MRI to rule out secondary

and flexion) and ice cream eating. In SUNCT

causes (Table 6.13). SUNCT does appear to have

there is no refractory period between pain attacks,

a clear male predominance, with a male:female

so that if a trigger zone is stimulated during

ratio of 4.25:1⁶. SUNCT is a disease of middle-aged

Table

6.15

Chronic paroxysmal hemicrania

(CPH) is a

Table 6.16 Proposed criteria for chronic paroxysmal hemi-

relatively rare condition even in headache specialty clinics. By

crania and episodic paroxysmal hemicrania. Reproduced from

1989, 84 cases had been described in the literature. CPH case

reference 6, with permission of Oxford University Press

reports are no longer published because this syndrome is now

Chronic paroxysmal hemicrania

recognized as a true primary headache disorder. Reproduced

Diagnostic criteria

with permission from reference 9

(1) At least 30 attacks fulfilling (2)-(5)

Published case reports

Year

(2) Attacks of severe unilateral, orbital, supraorbital and/or

temporal pain always on the same side lasting

Sjaastad & Dale

1974

2-45 min

Sjaastad & Dale

1976

(3) Attack frequency above five a day for more than half the

Kayed et al.

1978

time (periods with lower frequency may occur)

Price & Posner

1978

(4) Pain is associated with at least one of the following

Christoffersen

1979

signs/symptoms on the pain side:

Manzoni & Terzano

1979

Leblanc et al.

1980

(a) conjunctival injection

Sjaastad et al.

1980

(b) lacrimation

Stein & Rogado

1980

Guerra

1981

(d) rhinorrhea

Hochman

1981

(e) ptosis

Manzoni et al.

1981

(f)

eyelid edema

Rapoport et al.

1981

(5) At least one of the following:

Jensen et al.

1982

Kilpatrick & King

1982

(a) There is no suggestion of one of the disorders

Pelz & Meskey

1982

listed in groups 5-11 (see Figure 2.1).

Geaney

1983

(b) Such a disorder is suggested but excluded by

Peatty & Clifford Rose

1983

appropriate investigations.

Thevenet et al.

1983

Bogucki et al.

1984

attacks do not occur in close temporal relation to

Boulliat

1984

the disorder.

Dutta

1984

Note: Most cases respond rapidly and absolutely to

Pfaffenrath et al.

1984

indomethacin (usually in doses of 150 mg/day or less)

Pradalier & Dry

1984

Episodic paroxysmal hemicrania

Sjaastad et al.

1984

Diagnostic criteria

Drummond

1985

Granella et al.

1985

(1) At least 30 attacks fulfilling (2)-(6)

Heckl

1986

(2) Attacks of severe unilateral, orbital or temporal pain,

Pollman & Pfaffenrath

1986

or both, that is always unilateral and lasts from

Bogucki & Kozubski

1987

1-30 min

Centonze et al.

1987

(3) An attack frequency of three or more a day

Durko & Klimek

1987

(4) Clear intervals between bouts of attacks that may last

Hannerz et al.

1987

from months to years

Joubert et al.

1987

(5) Pain is associated with at least one of the following signs

Kudrow et al.

1987

or symptoms on the painful side:

Nebudova

1987

(a) conjunctival injection

Rasmussen

1987

(b) lacrimation

Pearce et al.

1987

Sum:

(d) rhinorrhea

Unpublished case reports

(e) ptosis

Bousser

(f)

eyelid edema

Davalos

(6) At least one of the following:

Graham

Greene

1. There is no suggestion of one of the disorders

Jaeger

listed in groups 5-11 (see Figure 2.1).

Manzoni

2. Such a disorder is suggested but excluded by

Mathew

appropriate investigations.

Nappi

3. Such a disorder is present, but the first headache

Sjaastad

attacks do not occur in close temporal relation

Wall

to the disorder.

Sum:

Note: In most cases responds rapidly and absolutely to

Total:

indomethacin (usually 150 mg/day or less)

Table 6.17

Autonomic symptoms mark the chronic paroxys-

and older individuals with no reported cases below

mal hemicrania syndrome, specifically those suggesting cranial

age 23. Up until recently there have been no

parasympathetic activation. Reproduced with permission from

reported therapies for SUNCT

(Table

6.14),

reference 9

although several case reports documenting relief

Symptoms and signs

with lamotrigine and topiramate have come into

the literature.

Lacrimation

Nasal stenosis

Conjunctival injection

CHRONIC PAROXYSMAL HEMICRANIA

Rhinorrhea

Ptosis

Photophobia

Chronic paroxysmal hemicrania is a very rare

Miosis

headache syndrome first described by Sjaastad

Nausea

and Dale in

1974⁸

(Table

6.15; for proposed

Generalized sweating

V1 hypersensitivity

criteria of this condition see Table 6.16). Unlike

Phonophobia

cluster headaches and SUNCT, CPH has a female

Temporal artery pulsation

predominance, with a female:male ratio of 3:1.

Visual phenomena

CPH normally develops in the second or third

Temporal artery dilatation

Tinnitus

decade of life but it can occur at any age

Vomiting

(Figures 6.19 and 6.20). The natural history of

V2 hypersensitivity

this disorder is unknown (Figure 6.21). Clinically

Exophthalmus

CPH patients have strictly unilateral headaches

and the same side of the head is always affected.

The pain location is normally orbital, temporal and

Table 6.18

Chronic paroxysmal hemicrania (CPH) is one of

above or behind the ear. The pain is very severe and

the indomethacin-responsive headache syndromes. When a

is described as boring or claw-like (Figure 6.22).

CPH patient cannot tolerate indomethacin or has contraindi-

Attacks are short-lasting, between 2 and 45 min

cations to this drug, there are very few, if any other, medications

(Figure 6.2). Individuals can have between 1 and

that work in this disorder. Reproduced with permission from

40 attacks in a day; median frequency is 5 to 10

reference 9

attacks per day. Unlike cluster headache there is

Drug

Partial efficacy

Total number

no predilection for nocturnal attacks, although

reports

of reports

CPH attacks can certainly awaken patients from

Salicylates

sleep (Figure 6.23). In regard to associated symp-

Ergotamine

toms, most CPH patients exhibit lacrimation

Prednisone

β-Receptor blocking agents

(62%), followed by nasal congestion

(42%),

Pizotifen

conjunctival injection and rhinorrhea (36%) and

Carbamazepine

ptosis (33%) (Table 6.17). Neck movements and

Lithium

Amitriptyline

external pressure to the transverse processes of

Ketoprofen

C4 to C5 or the C2 nerve root can trigger CPH

Methysergide

attacks. In phenotype, CPH is characterized by

Butazolidin

short-duration and more frequent cluster attacks.

Naproxen

Phenobarbital

Unlike cluster patients, CPH patients typically

Oxygen

remain still during an attack and by definition CPH

Tiapride

responds to indomethacin treatment (Table 6.16).

Ibuprofen

It does not matter how many years a patient has

Diclofenac

Valproate

suffered from CPH and how many therapies they

Verapamil

have tried, once indomethacin is administered

Clonazepam

the headaches will be gone within

48 h and

Nimodipine

Histamine

remain alleviated as long as the patient remains

Placebo

on indomethacin (Figure 6.33). Very few other

medications have ever worked for patients with

Klapper JA, Klapper A, Voss T. The misdiagnosis of

CPH (Table 6.18). Secondary causes of CPH

cluster headache: a nonclinic, population-based Internet

survey. Headache 2000;40:730-5

reported in the literature include: gangliocytoma

Headache Classification Committee of the Interna-

of the sella turcica, pancoast tumor, frontal lobe

tional Headache Society. Classification and diagnostic

tumor and cavernous sinus menigioma.

criteria for headache disorders, cranial neuralgias and

Episodic paroxysmal hemicrania

(EPH) is

facial pain. Cephalalgia 1988;8 (Suppl 7):1-96

characterized by frequent daily attacks of unila-

Manzoni GC. Male preponderance of cluster head-

teral short-duration headaches with associated

ache progressively decreasing over the years. Headache

autonomic symptoms. EPH is really CPH, except

1997;35:588-9

EPH has periods of headache remission lasting

Sjaastad O, Saunte C, Salvesen R, et al. Shortlasting

weeks or months (Table 6.16 and Figure 6.21).

unilateral neuralgiform headache attacks with conjunc-

There is debate if EPH is just an episodic variant

tival injection, tearing, sweating, and rhinorrhea.

of CPH or its own entity. Attack duration in EPH

Cephalalgia 1989;9:147-56

varies from 1 to 30 min with attack frequency

Goadsby PJ, Lipton RB. A review of paroxysmal hemi-

between 6 and 30 individual headaches per day.

cranias, SUNCT syndrome and other short-lasting

headaches with automatic feature, including new

EPH unlike CPH may not have a gender predomi-

cases. Brain 1997;120:193-209

nance. EPH like CPH invariably responds to

Pareja JA, Sjaastad O. SUNCT syndrome. A clinical

indomethacin. There are reports in the literature

review. Headache 1997;37:195-202

of transformation from EPH to CPH suggesting

Sjaastad O, Dale I. Evidence for a new, treatable

these two conditions are ends of a spectrum.

headache entity. Headache 1997;14:105-8

Antonaci F, Sjaastad O. Chronic paroxysmal hemi-

REFERENCES

crania (CPH): A review of the clinical manifestations.

Headache 1989;29:648-56

1. American Headache Society. Neurology Ambassador

Program. http://www.ahsnet.org/ambass/ 3/27/2002

CHAPTER 7

Tension-type headaches

INTRODUCTION

Table 7.1

IHS criteria for migraine and tension-type headache

Migraine

The most controversial and difficult boundary

≥ 5 attacks lasting 4-72 h

among primary headaches is the one between

Two of the following four:

unilateral

migraine and tension-type headache. While some

pulsating

view these disorders as distinct entities, others

moderate to severe intensity

favor the ‘spectrum’ or ‘continuum’ concept, the

aggravation by routine physical activity

idea that migraine and tension-type headache exist

One of the following:

nausea and/or vomiting

as polar ends on a continuum of severity, varying

photophobia and phonophobia

more in degree than in kind (Figure 7.1). Lipton

No evidence on history or examination of disease that

et al.¹ in the ‘spectrum’ study found that migrainous

might cause headaches

and tension-type headaches in migraine patients

Tension-type headache

responded to sumatriptan, supporting the spectrum

10 attacks lasting 30 min-7 days

theory. In the early phase of a migraine headache,

Two of the following four:

bilateral

the patient may have mild, non-pulsating pain

not pulsating

and a lack of nausea, vomiting, photophobia and

mild or moderate intensity

phonophobia, in which case the headache resembles

no aggravation by routine physical activity

a tension-type headache. Individuals often report

One of the following:

no nausea/vomiting

only the symptoms of tension-type headache, yet

either photophobia or phonophobia or neither

have headaches that respond to migraine-specific

No evidence on history or examination of disease that

treatment on prospective diary studies.

might cause headaches

The International Headache Society

(IHS)

Adapted with permission from reference 2

classification of headache, published in

1988,

defined diagnostic criteria for primary headaches,

including migraine and tension-type headaches (see

EPIDEMIOLOGY

Table 7.1). These criteria were more complete,

explicit, and rigorous than criteria used in past

Tension-type headache is the most common

studies, and led to an important advance in the

headache type. Estimates of its prevalence have

research of headache disorders. However, tension-

varied widely. In Western countries, one-year

type headache was defined as recurrent head-

prevalence ranges from 28-63% in men and from

ache without the features of migraine, perhaps

34-86% in women, depending, in part, on method-

artificially dividing a single disorder.

ologic differences between studies. A lifetime

prevalence of 69% in men and 88% in women, and

prominent disability, nearly 50% of migraineurs

a one-year prevalence of 63% in men and 86% in

and more than 80% of tension-type headache

women, was found in Denmark³. Interestingly, in

patients had never consulted their general practi-

mainland China there was a very low prevalence of

tioner because of headache⁷. Patients with daily

tension-type headache⁴.

headaches may have even more disability than

The prevalence of chronic tension-type head-

episodic migraine and tension-type headache

ache has varied from

2-3% in three Western

sufferers, although there are no data to confirm

studies^3,5.

this assumption.

CONCLUSIONS

PATHOPHYSIOLOGY

The pathophysiology of tension-type headache is

The term tension-type headache represents a

not clearly understood. Raskin introduced the

compromise between those who believed this

headache ‘continuum’ in 1988. In the last decade

entity to be due to psychologic tension and

the pathogenesis of tension-type headache has

those who felt muscle tension to be paramount.

again been called into question

(Figure

7.2).

Ultimately, very little is known about the

Patients with migraine often suffer from milder

pathophysiology of tension-type headache. The

headaches which meet the IHS criteria for tension-

IHS recognizes tension-type headache with and

type headache^8,9. These milder tension-type

without a pericranial muscle disorder. Muscle

headaches seen in migraineurs often have a few

tenderness may be seen in migraine, and findings

associated migrainous features such as phono-

in EMG and pressure algometry studies are incon-

phobia or photophobia¹⁰. Cady et al.¹¹ observed

sistent, even in the pericranial muscle abnormality

that non-IHS migraine and tension-type headaches

group of tension-type headache patients.

in patients with migraine respond to triptans,

supporting theories of a common pathophysiology.

IMPACT AND COSTS

Lipton et al.¹ demonstrated that in patients with

migraine, sumatriptan was effective for their

Tension-type headaches often interfere with acti-

tension-type headaches (Figure 7.3). Tension-type

vities of daily living⁶. Eighteen percent of

headaches in patients with no migraine history

tension-type headache sufferers had to discon-

seemingly lack migrainous features and do not

tinue normal activity, while

44% experienced

respond to triptans^12,13. To clarify these issues a

some limitation of function. Like migraine,

prospective trial is needed testing triptans in

tension-type headache is a disorder of middle life,

migraineurs and non-migraineurs¹⁴.

striking individuals early in life and continuing

to affect them through their peak productive

years. All migraineurs, and 60% of tension-type

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work or other activities during an attack. In a

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12% of employed tension-type headache suffer-

Headache 2000;40:783-91

ers missed one or more days of work because of

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headache. Migraine caused at least one day of

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missed work for 5% of sufferers, while tension-

criteria for headache disorders, cranial neuralgias and

type headache caused a day of missed work for

facial pain. Cephalalgia 1988;8 (Suppl 7):1-96

9%. Annually, per 1000 employed individuals,

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270 lost work days were due to migraine and

Epidemiology of headache in a general population - a

820 were due to tension-type headache. Despite

prevalence study. J Clin Epidemiol 1991;44:1147-57

4. Wong TW, Wong KS, Yu TS, Kay R. Prevalence of

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migraine and other headaches in Hong Kong. Neuro-

Clinical characteristics of migraine and episodic

epidemiology 1995;14:82-91

tension-type headache in relation to old and new

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Headache 1999;39:190-6

Responsiveness of non-IHS migraine and tension-

6. Rasmussen BK. Epidemiology and socio-economic

type headache to sumatriptan. Cephalalgia 1997;17:

impact of headache. Cephalalgia 1999;19:20-3

588-90

7. Rasmussen BK, Olesen J. Symptomatic and

12. Brennum J, Kjeldsen M, Olesen J. The 5-HT₁-like

nonsymptomatic headaches in a general population.

agonist sumatriptan has a significant effect in chronic

Neurology 1992;42:1225-31

tension-type headache. Cephalalgia 1992;12:375-9

8. Rasmussen BK, Jensen R, Schroll M, Olesen J.

13. Brennum J, Brinck T, Schriver L, et al. Sumatriptan

Interrelations between migraine and tension-type

has no clinically relevant effect in the treatment of

headache in the general population. Arch Neurol

episodic tension-type headache. Eur J Neurol 1996;

1992;49:914-8

3:23-8

9. Ulrich V, Russell MB, Jensen R, Olesen J. A compari-

14. Olesen J. Responsiveness of non-IHS migraine and

son of tension-type headache in migraineurs and

tension-type headache to sumatriptan. Cephalalgia

in non-migraineurs: a population-based study. Pain

1997;17:559

1996;67:501-6

CHAPTER 8

Secondary headaches

The International Headache Society

(IHS) has

should be considered ‘red flags’ and will warrant

classified the secondary headaches into eight distinct

further diagnostic evaluation.

categories based upon their causes

(Figure

2.1).

‘Red flags’ include: (i) a new sudden-onset head-

Secondary headaches can often have the same char-

ache in patients without previous headache or in

acteristics as primary headache disorders such as

patients who have cancer or test positive for HIV;

migraine and tension-type headache. Some of the

(ii) the presence of new neurologic symptoms

secondary headaches can have serious and at times

such as changes in vision, cognition or personality;

life-threatening causes. Fortunately, the vast major-

(iii) precipitation of headache by strain or exertion;

ity of headache complaints are due to primary

(iv) a change in headache pattern in a patient with

headache disorders such as migraine or tension-

a known headache disorder; (v) any new-onset

type headache. Many different diseases may present

headache after the age of 50; and (vi) headache

with the symptom of headache, and physicians

accompanied by systemic symptoms such as fever,

must determine which cases need to be investi-

nuchal rigidity, jaw claudication and weight loss.

gated further for possible secondary causes.

Symptomatic or secondary headaches have

Not all headache patients need to be imaged; in

not been well described clinically, and studying

fact the ‘gold standard’ in headache diagnosis is

secondary causes in a prospective manner offers

a complete and thorough history backed by a gen-

many challenges. Analyzing secondary causes for

eral physical and a neurologic examination. The

headache will be important to elucidate potential

primary purpose of radiographic investigation in

mechanisms and locations involved in the primary

headache patients is to exclude secondary causes

disorders.

in patients with unusual histories or abnormal

This chapter includes images of some of the

physical exams. Certain clinical or historical features

secondary causes for headache (Figures 8.1-8.41).

Figure 1.9

Erasmus Darwin, Charles’ grandfather, a physician,

lived in the eighteenth century. He postulated that since

migraine, as Willis suggested, was due to too much blood in the

head, ideal treatment would be to construct a giant centrifuge,

put the patient in it and spin him. As the blood left the head,

the headache should disappear. Fortunately, the technology was

not available to mount the experiment. Courtesy of the

National Library of Medicine, Bethesda, USA

Figure 1.11

Illustration by John Tenniel from Alice in Wonder-

land.Was Lewis Carroll writing his migraine auras into his book?

Figure 1.10

Edward Liveing, the author of an influential book

Figure 1.12

Illustration by John Tenniel from Alice in Wonder-

on migraine from 1873, which argued that ‘megrim’ was a

land. The image depicts the sense of being too large for one’s

‘nerve-storm’ or epileptic manifestation

surroundings

Figure 1.15

As the botanists argued over the nature of

ergot, the chemists were attempting to unravel the mystery of

its composition. Heinrich Wiggers, a pharmacist of Göttingen,

Germany was probably the first to analyze ergot with the

set purpose of trying to isolate the active principle or princi-

ples. In 1831 he tested his ergot extracts in animals. Among

the models was the ‘rooster comb test’ - when fed ergotin the

rooster became ataxic, nauseous, acquired a blanched comb

and suffered from severe convulsions, dying days later. The

Figure 1.13

Saint Anthony. Note the patient who has lost

rooster comb test continued to be used into the following

limbs as a result of gangrene due to ergotism (eating bread

century by investigators studying the physiologic properties of

made from rye contaminated with ergot fungus). Limbs turned

ergot

black, as though charred by fire, then fell off. Hence the term

‘St. Anthony’s Fire’. If you prayed to Saint Anthony, your

symptoms might improve. Note Anthony’s pet pig. Courtesy of

the National Library of Medicine, Bethesda, USA

Figure 1.16

In 1918, Arthur Stroll, a young chemist working

in Basel, Switzerland announced the isolation of the first pure

crystalline substance, ergotamine. Professor Stroll made many

Figure 1.14

A stalk of grain upon which are growing two

additional contributions to our understanding of ergot, and

purple excrescences - Claviceps purpurea, or ‘ergot fungus’.

1917 became the founder of the Sandoz ‘Department of

Reproduced with kind permission of John Edmeads

Pharmaceutical Specialities’

Figure 1.21

On July 30, 1609, Samuel de Champlain, a French explorer of New France (North America), was taken along by his

Huron Indian hosts on a raid against the Mohawks, who lived on the shores of a large lake (Lake Champlain) in what is now upper

New York State.There is a drawing by Champlain himself of the battle, in which he and his fellow Frenchmen won the day with their

muskets.Towards the end of the battle, Champlain developed a severe migraine. See Figure 1.22

Figure 1.22

The victorious Hurons caught a gar pike in the

Figure 1.23

Dutch engraving, seventeenth century. The

lake, stripped its head of the flesh and instructed Champlain

migraine sufferer has had puncture wounds put into his sore

to rake his painful head with the sharp teeth,sufficient to draw

temples. Then heated glass globes are placed with their open

blood. He did so, and his headache disappeared. Champlain

mouths over the puncture wounds. As the globes cooled, a

took the head back to France with him, and gave it to the King

vacuum was set up, sucking the blood from the temples into the

of France, who also had migraine.We do not know if he ever

globes and relieving the headache. In this way, several patients

used it

could be treated at once (the first migraine clinic?)

CLASSIFICATION OF HEADACHE

4.5

BENIGN EXERTIONAL HEADACHE

DISORDERS, CRANIAL NEURALGIAS

4.6

HEADACHES ASSOCIATED WITH SEXUAL ACTIVITY

AND FACIAL PAIN

Dull type

Explosive type

Migraine

Postural type

1.1

MIGRAINE WITHOUT AURA

1.2

MIGRAINE WITH AURA

Headache associated with head trauma

Migraine with typical aura

5.1

ACUTE POST-TRAUMATIC HEADACHE

Migraine with prolonged aura

With significant head trauma and/or

Familial hemiplegic migraine

confirmatory signs

Basilar migraine

With minor head trauma and no

Migraine aura without headache

confirmatory signs

Migraine with acute onset aura

5.2

CHRONIC POST-TRAUMATIC HEADACHE

1.3

OPHTHALMOPLEGIC MIGRAINE

With significant head trauma and/or

1.4

RETINAL MIGRAINE

confirmatory signs

1.5

CHILDHOOD PERIODIC SYNDROMES THAT MAY BE

With minor head trauma and no

PRECURSORS TO OR ASSOCIATED WITH MIGRAINE

confirmatory signs

Benign paroxysmal vertigo of childhood

Headache associated with vascular disorders

Alternating hemiplegia of childhood

6.1

ACUTE ISCHEMIC CEREBROVASCULAR DISEASE

1.6

COMPLICATIONS OF MIGRAINE

Transient ischemic attack (TIA)

Status migrainosus

Thromboembolic stroke

Migrainous infarction

6.2

INTRACRANIAL HEMATOMA

1.7

MIGRAINOUS DISORDER NOT FULFILLING ABOVE

Intracerebral hematoma

CRITERIA

Subdural hematoma

Tension-type headache

Epidural hematoma

2.1

EPISODIC TENSION-TYPE HEADACHE

6.3

SUBARACHNOID HEMORRHAGE

Episodic tension-type headache associated

6.4

UNRUPTURED VASCULAR MALFORMATION

with disorder of pericranial muscles

Arteriovenous malformation

Episodic tension-type headache unassoci-

Saccular aneurysm

ated with disorder of pericranial muscles

6.5

ARTERITIS

2.2

CHRONIC TENSION-TYPE HEADACHE

Giant-cell arteritis

Chronic tension-type headache associated

Other systemic arteritides

with disorder of pericranial muscles

Primary intracranial arteritis

Chronic tension-type headache unassoci-

6.6

CAROTID OR VERTEBRAL ARTERY PAIN

ated with disorder of pericranial muscles

Carotid or vertebral dissection

2.3

HEADACHE OF THE TENSION-TYPE NOT

Carotidynia (idiopathic)

FULFILLING ABOVE CRITERIA

Post-endarterectomy headache

6.7

VENOUS THROMBOSIS

Cluster headache and chronic paroxysmal hemicrania

6.8

ARTERIAL HYPERTENSION

3.1

CLUSTER HEADACHE

Acute pressor response to exogenous agent

Cluster headache periodicity undetermined

Pheochromocytoma

Episodic cluster headache

Malignant (accelerated) hypertension

Chronic cluster headache

Pre-eclampsia and eclampsia

Unremitting from onset

6.9

HEADACHE ASSOCIATED WITH OTHER VASCULAR

Evolved from episodic

DISORDER

3.2

CHRONIC PAROXYSMAL HEMICRANIA

3.3

CLUSTER HEADACHE-LIKE DISORDER NOT

Headache associated with non-vascular intracranial

FULFILLING ABOVE CRITERIA

disorder

7.1

HIGH CEREBROSPINAL FLUID PRESSURE

Miscellaneous headaches unassociated with struc-

Benign intracranial hypertension

tural lesion

High pressure hydrocephalus

4.1

IDIOPATHIC STABBING HEADACHE

7.2

LOW CEREBROSPINAL FLUID PRESSURE

4.2

EXTERNAL COMPRESSION HEADACHE

Post-lumbar puncture headache

4.3

COLD STIMULUS HEADACHE

Cerebrospinal fluid fistula headache

External application of a cold stimulus

7.3

INTRACRANIAL INFECTION

Ingestion of a cold stimulus

7.4

INTRACRANIAL SARCOIDOSIS AND OTHER NON-

4.4

BENIGN COUGH HEADACHE

INFECTIOUS INFLAMMATORY DISEASES

Figure 2.1

Classification of headache disorders, cranial neuralgias and facial pain published by the International Headache

Society. Purple, primary headache disorders; blue, secondary headache disorders. Reproduced with permission from Headache

7.5

HEADACHE RELATED TO INTRATHECAL

11.

Headache or facial pain associated with disorder

INJECTIONS

of cranium, neck, eyes, ears, nose, sinuses, teeth,

Direct effect

mouth or other facial or cranial structures

Due to chemical meningitis

11.1

CRANIAL BONE

7.6

INTRACRANIAL NEOPLASM

11.2

NECK

7.7

HEADACHE ASSOCIATED WITH OTHER

Cervical spine

INTRACRANIAL DISORDER

Retropharyngeal tendinitis

11.3

EYES

Headache associated with substances or their

Acute glaucoma

withdrawal

Refractive errors

8.1

HEADACHE INDUCED BY ACUTE SUBSTANCE USE

Heterophoria or heterotropia

OR EXPOSURE

11.4

EARS

Nitrate/nitrite-induced headache

11.5

NOSE AND SINUSES

Monosodium glutamate-induced headache

Acute sinus headache

Carbon monoxide-induced headache

Other diseases of nose or sinuses

Alcohol-induced headache

11.6

TEETH, JAWS AND RELATED STRUCTURES

Other substances

11.7

TEMPOROMANDIBULAR JOINT DISEASE

8.2

HEADACHE INDUCED BY CHRONIC SUBSTANCE

(FUNCTIONAL DISORDERS ARE CODED TO

USE OR EXPOSURE

GROUP 2)

Ergotamine-induced headache

Analgesics abuse headache

12.

Cranial neuralgias, nerve trunk pain and

Other substances

deafferentation pain

8.3

HEADACHE FROM SUBSTANCE WITHDRAWAL

12.1

PERSISTENT (IN CONTRAST TO TIC-LIKE) PAIN

(ACUTE USE)

OF CRANIAL NERVE ORIGIN

Alcohol withdrawal headache (hangover)

Compression or distortion of cranial

Other substances

nerves and second or third cervical roots

8.4

HEADACHE FROM SUBSTANCE WITHDRAWAL

Demyelination of cranial nerves

(CHRONIC USE)

Optic neuritis (retro-bulbar neuritis)

Ergotamine withdrawal headache

Infarction of cranial nerves

Caffeine withdrawal headache

Diabetic neuritis

Narcotics abstinence headache

Inflammation of cranial nerves

Other substances

Herpes zoster

8.5

HEADACHE ASSOCIATED WITH SUBSTANCES BUT

Chronic post-herpetic neuralgia

WITH UNCERTAIN MECHANISM

Tolosa-Hunt syndrome

Birth control pills or estrogens

Neck-tongue syndrome

Other substances

Other causes of persistent pain of cranial

nerve origin

Headache associated with non-cephalic infection

12.2

TRIGEMINAL NEURALGIA

9.1

VIRAL INFECTION

Idiopathic trigeminal neuralgia

Focal non-cephalic

Symptomatic trigeminal neuralgia

Systemic

Compression of trigeminal root or

9.2

BACTERIAL INFECTION

ganglion

Focal non-cephalic

Central lesions

Systemic (septicemia)

12.3

GLOSSOPHARYNGEAL NEURALGIA

9.3

HEADACHE RELATED TO OTHER INFECTION

Idiopathic glossopharyngeal neuralgia

Symptomatic glossopharyngeal neuralgia

10.

Headache associated with metabolic disorder

12.4

NERVUS INTERMEDIUS NEURALGIA

10.1

HYPOXIA

12.5

SUPERIOR LARYNGEAL NEURALGIA

High altitude headache

12.6

OCCIPITAL NEURALGIA

Hypoxic headache (low pressure environ-

12.7

CENTRAL CAUSES OF HEAD AND FACIAL PAIN

ment, pulmonary disease causing hypoxia)

OTHER THAN TIC DOULOUREUX

Sleep apnea headache

Anesthesia dolorosa

10.2

HYPERCAPNIA

Thalamic pain

10.3

MIXED HYPOXIA AND HYPERCAPNIA

12.8

Facial pain not fulfilling criteria in groups

10.4

HYPOGLYCEMIA

11 and 12

10.5

DIALYSIS

10.6

HEADACHE RELATED TO OTHER METABOLIC

ABNORMALITY

13.

Headache not classifiable

Figure 2.1

Continued Classification Committee of the International Headache Society. Classification and diagnostic criteria for

headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8(Suppl 7):1-96

a) Migraine symptoms

b) Frequency of attacks

Type of headache

Pulsating

Aggravated by activity

Moderate or severe

One-sided

Associated symptoms

Photophobia

Phonophobia

Nausea

Aura

≥ 1/month

1/month

Vomiting

2-4/month

>1/month

100

Percentage of sufferers

d) Severity of headache pain during

c) Duration of attacks

attacks

2-4 h

4-6 h

6-12 h About

2-3

Mild Moderate Severe

Very

1 day days

severe

Figure 3.1

Migraine characteristics from population studies of migraine epidemiology using the diagnostic criteria of the Interna-

tional Headache Society (IHS). (a) Adapted with permission from Micieli G. Suffering in silence. In: Edmeads J, ed. Migraine: A Brighter

Future, 1993:1-7, with permission of Cambridge Medical Publications; (b) to (d) data derived from Henry P, Michel P, Brochet B, et al.

A nationwide survey of migraine in France: prevalence and clinical features in adults. Cephalalgia 1992;12:229-37

Female

Male

Africa

Asia

Europe

S/C America

N America

Figure 3.2

Adjusted prevalence of migraine by geographic area. Adapted with permission from Stewart WF, Lipton RB, Celentano

DD, Reed ML. Prevalence of migraine headache in the United States. Relation to age, income, race, and other sociodemographic

factors. JAMA 1992;267:64-9

Netherlands

Denmark

Norway

Male

8-12%

Female

11%

Female

12%

Female

14%

Female

24-25%

Both sexes

Both sexes 12%

Both sexes 16-18%

Canada

Male

7-10%

Female

22-23%

Both sexes 15-17%

France

Male

Japan

Female

18%

Male

USA

Both sexes

12%

Female

13%

Male

6-7%

Both sexes

8.4%

Female

16-18%

Germany

Both sexes

11-13%

Male

22%

Hong Kong

Female

32%

Both sexes

28%

Both sexes

1.5%

Saudi Arabia

Peru

Both sexes

Male

32%

Ethiopia

Both sexes

International

(Canada, Belgium,

Malaysia

Italy, Sweden, UK)

Male

Female

11%

Female

15%

Both sexes

12%

Figure 3.3

Estimates of migraine prevalence in studies using the diagnostic criteria of the International Headache Society (IHS).

Adapted with kind permission of Richard B. Lipton

4.0

3.5

3.0

2.5

Figure

3.4

Women are more

commonly affected by headache than

2.0

men. This graph shows the prevalence

ratio of migraine headache (females to

1.5

males) over a lifetime. Adapted with

permission from Lipton RB, Stewart

19 23 27

31 35

39 43

55 59

67 71 75 79

WF. Migraine in the United States: a

Age (years)

review of epidemiology and health care

use. Neurology 1993;43(Suppl 3):S6-10

Female

Male

Figure 3.5

Age-specific prevalence of

migraine among women and men in a

US study. Adapted with permission

from Stewart WF, Lipton RB, Celentano

DD, Reed ML. Prevalence of migraine

Age (years)

headache in the United States. JAMA

1992;267:64-9

Female

Male

Figure 3.6

Age- and sex-specific

prevalence of migraine based on a

meta-analytic summary of 18 popula-

tion-based studies. Adapted with per-

mission from Scher AI, Stewart WF,

Lipton RB. Migraine and headache: A

meta-analytic approach. In: Crombie I,

Age (years)

ed. Epidemiology of Pain. Seattle: IASP

Press, 1999:159-70

1.00

Females

Males

0.80

0.60

0.40

0.20

< $10 000

$10

000- $20 000- $30 000-

≥ $45 000

< $10 000

$10

000- $20 000- $30 000-

≥ $45 000

$19 999

$29 999

$44 999

$19 999

$29 999

$44 999

Household income

Figure 3.7

Migraine prevalence is inversely proportional to income, with the low income groups having the highest prevalence.

Adapted with permission from Lipton RB, Stewart WF, Celentano DD, Reed ML. Undiagnosed migraine headaches. A comparison of

symptom-based and reported physician diagnosis. Arch Intern Med 1992;152:1273-8

a Females

b Males

100

Sufferers (%)

Figure 3.8

Fifty percent of female migraineurs and almost 40% of male migraineurs

accounted for approximately 90% of lost working day equivalents. Adapted with per-

mission from Stewart WF, Lipton RB, Simon D. Work-related disability: Results from the

American Migraine Study. Cephalalgia 1996;16:231-8

Figure 3.9

Degree of disability due

to migraine in a US study. Adapted

with permission from Stewart WF,

None

Mild/

Severe/

Don’t know

moderate

bed rest

Lipton RB, Celentano DD, Reed ML.

Prevalence of migraine headache in the

Degree of disability

United States. JAMA 1992;267:64-9

Figure 3.10

Relationship between

disability and headache pain intensity in

a group of migraine sufferers. Adapted

with permission from Stewart WF,

Shechter A, Lipton RB. Migraine hetero-

geneity. Disability, pain intensity and

attack

frequency and duration.

Pain intensity

Neurology 1994;44:24-39

Probands with epilepsy

Relatives with epilepsy

Relatives without epilepsy

Figure 3.11

Cumulative incidence of

migraine headache, by age, in probands

with epilepsy

(red), relatives with

epilepsy (yellow) and relatives without

epilepsy (green). Adapted with permis-

sion from Ottman R, Lipton RB.

Comorbidity of migraine and epilepsy.

Age (years)

Neurology 1994;44:2105-10

Figure 4.1

Leao found that noxious stimulation of the exposed cortex of a rabbit produced a spreading decrease in electrical

activity that moved at a rate of 2-3 mm/min. Reading from the rabbit cortex illustrating spreading depression of EEG activity.

Reproduced with permission from Leao AAP. Spreading depression of activity in cerebral cortex. J Neurophysiol 1944;7:359-90

Hyperperfusion

Normal

CBF

Hypoper-

fusion

Aura

Headache

Hours after angiography

Figure 4.2

Line drawing (panel a) of the spreading oligemia

observed with studies of cerebral blood flow (CBF) during aura

after Lauritzen. Adapted with permission from Lauritzen M.

Cortical spreading depression as a putative migraine mechanism.

Trends Neurosci 1987;10:8-13, with permission from Elsevier

Science. Panel b illustrates the variable time course and rela-

tionship of the changes in cerebral blood flow and the sympto-

matology of migraine. Adapted with permission from Olesen J,

Friberg L, Skyhoj-Olesen T, et al.Timing and topography of cere-

bral blood flow, aura and headache during migraine attacks. Ann

Neurol 1990;28:791-8

Figure 4.3

Propagation of cortical spreading depression (CSD) across the surface of the cat brain in vivo. Top left, control,

horizontal, gradient-echo anatomic image depicting the suprasylvian and marginal gyri. Remaining images (b−x): coloured overlays,

shown at 10 s intervals starting about 50 s after KCI application, represent elliptical regions of reduced diffusion travelling away from

the KCI application site with a velocity of 3.2 ± 0.1 mm/min (mean ± SEM of 5 measurements). Over the first eleven frames (b−1)

the wave travels both rostrally and caudally along the suprasylvian gyrus; when it reaches the caudal junction of the two gyri (m−s),

it appears to pass into the marginal gyrus (t−x); likewise, rostrally, the wave passes first (r−x) into the ectosylvian gyrus where it

dissipates (v-x) and then into the marginal gyrus (t-x). Waves were never detected in the contralateral hemisphere. A, anterior;

P, posterior; R, right; L, left; overlays were obtained by subtracting a baseline image from the high-b images obtained in the DWEP

sequence and transforming the signal difference into a percentage change (blue 5%, red 30%). Scale bar, 15 mm.This image represents

the first reported detection of CSD with magnetic resonance imaging (MRI) in a species which shares with man a complex, gyren-

cephalic brain structure. Reproduced with permission from James MF, Smith MI, Bockhorst KH, et al. Cortical spreading depression

in the gyrencephalic feline brain studied by magnetic resonance imaging. J Physiol 1999;519:415-25

Figure 4.4

Spreading depression: A model of migraine. Colored overlays of changes in blood oxygenation in an experimental model

of cortical spreading depression. Overlays a-d represent the points 0.5, 1.0, 1.4 and 5.1 min post-induction. Reproduced with permis-

sion from James MF, Smith MI, Bockhorst KH, et al. Cortical spreading depression in the gyrencephalic feline brain studied by magnetic

resonance imaging. J Physiol 1999;519:415-25

Figure

4.5

Blood oxygenation level-dependent

(BOLD) changes during an exercise-

triggered migraine visual aura. Time-dependent BOLD activity changes from a single region of

interest in the primary visual cortex (Vl), aquired before and during episodes of induced visual

aura.The upper panel shows a series of anatomic images, including BOLD activity on ‘inflated’

cortical hemispheres showing the medial bank (similar to a conventional mid-sagittal view).

Images were sampled at 32 s intervals, showing the same region of interest (circle) in VI. The

lower panel shows the MR signal perturbation over time from the circled region of interest.

Variations in time are color-coded (deep red to magenta) and the four-colored circles match

corresponding times within the VI region of interest. Prior to the onset of the aura, the BOLD

response to visual stimulation shows a normal, oscillating activation pattern. Following the

onset of aura (red arrow), the BOLD response shows a marked increase in mean level and a

marked suppression to light modulation followed by a partial recovery of the response to light

modulation at a decreased mean level. Reproduced with kind permission of Margarita Sanchez

del Rio

Figure 4.6

Spreading suppression of cortical activation during

migraine visual aura. Data from the same patient as in Figure 4.5.

The posterior medial aspect of the occipital lobe is shown in an

‘inflated cortex’ format. The cortical sulci and gyri appear in

darker and lighter gray respectively, on a computationally inflated

surface. MR signal changes over time are shown on the right.

Each time course was recorded from one in a sequence of

voxels which were sampled along the calcarine sulcus in V1, from

the posterior pole to the more anterior location, as indicated by

the arrow. A similar BOLD response was found within all the

extrastriate areas, differing only in the time of onset of the MR

perturbation. The MR perturbations developed earlier in the

foveal representation, compared to the more eccentric repre-

sentation of the retinotropic visual cortex. This was consistent

with the progression of the aura from central to peripheral eccen-

tricities in the corresponding visual field. Reproduced with kind

permission of Margarita Sanchez del Rio

Figure

4.7

BOLD changes

during spontaneous migraine

visual aura. Data from a sponta-

neous attack captured approxi-

mately 18 min after the onset of

the visual symptoms affecting the

right hemifield.The data represent

the time course in the left visual

area V1, at an eccentricity of

approximately 20º of visual angle.

BOLD signal changes resemble

the changes observed at a similar

time point in Figure 4.5. Repro-

duced with kind permission of

Margarita Sanchez del Rio

Figure 4.8

Perfusion weighted

imaging

(PWI) during migraine

with aura attacks. PWI maps

obtained at different time points

during migraine with aura attacks

during the presence of the

stereotypical visual aura (patient I,

approximately 20 min after onset

of visual symptoms) and after

resolution of the aura and into

the headache phase (patients

and 3). In all cases a perfusion

defect

(decreased rCBF and

rCBV, the latter not shown, and

increased MTT) was observed in

the occipital cortex contralateral

to the visual field defect. rCBF,

reduced cerebral blood flow;

rCBV, regional cerebral blood

volume; MTT, mean transit time.

Reproduced with kind permission

of Margarita Sanchez del Rio

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L L N

S A L

V S M L

I V

I P

L I

I N I M

V F V W

L T T V

V M P

S M P

P V A

F P I

V I I

L G F L

S T A S

S V G I

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E A D E Q S N K K Q G

RAK

L A

SMVTLGKQQSE

S I

DD C

COOH

Figure 4.9

Schematic representation of the primary sequence of the 5-HT₂ receptor. Reproduced from Hartig PR. Molecular

biology of 5-HT receptor. Trends Pharmacol Sci 1989;10:64-9, with permission from Elsevier Science

Figure 4.10

Trigeminal stimulation in the rat produces plasma protein extravasation. 5-Hydroxytryptamine receptor agonists for

the abortive treatment of vascular headaches block this effect. (a) control; (b) stimulated. Reproduced from Buzzi MG, Dimitriadou V,

Theoharides TC, Moskowitz MA. 5-Hydroxytryptamine receptor agonists for the abortive treatment of vascular headaches block

mast cell, endothelial and platelet activation within the rat dura mater after trigeminal stimulation. Brain Res 1992;583:137-49, with

permission from Elsevier Science

Capsaicin

z = −32mm

z = −30mm

z = −28mm

Sinus

No brain stem/hypothalamic activation

Figure 4.12

An experimental pain study was conducted in healthy volunteers to further test whether brain stem neuronal activa-

tion during migraine is specific to the generation of migraine symptoms. In this study, capsaicin was injected subcutaneously into the

right forehead to evoke a painful burning sensation in the first division of the trigeminal nerve.The monoaminergic brain stem regions

(raphe nucleus and the locus coeruleus) and the periaqueductal gray were not activated in the acute pain state compared to the pain-

free state.Thus, brain stem activation during a migraine attack is probably not a generalized response to head pain but instead repre-

sents sites in the nervous system that may give rise to migraine symptomatology. Adapted with permission from May A, Kaube H,

Buchel C, et al. Experimental cranial pain elicited by capsaicin: a PET study. Pain 1998;74:61-6

Dysfunction of brain stem pain and

vascular control centers

Pain perception*

Anterior cingulate cortex

‘Migraine generator’*

Raphe nuclei

Locus coeruleus

Periaqueductal gray

*Areas of red indicate cerebral blood flow increases (p < 0.001)

Figure 4.13

The development of migraine, e.g. episodes in patients undergoing surgery to implant electrodes in the periaqueductal

gray and raphe nuclei for the treatment of chronic pain, generated the hypothesis that CNS dysfunction early in the migraine attack

could provoke changes in these brain stem nuclei.Weiller et al. used positron emission tomography (PET) to examine the changes in

regional cerebral blood flow, an index of neuronal activity, during spontaneous migraine attacks. The left panel above is a PET scan

from an individual during a migraine attack treated acutely with sumatriptan. The scan depicts neuronal activity in a section through

the brain stem. The authors of this study reported that monoaminergic brain stem regions (raphe nucleus comprising serotonergic

neurons and the locus coeruleus comprising noradrenergic neurons) and the periaqueductal gray are selectively activated during a

migraine attack. When this patient used subcutaneous sumatriptan to acutely relieve his headache pain, the brain stem centers contin-

ued to appear active on the follow-up PET scans. By contrast, the anterior cingulate cortex, a region thought to be involved in

processing affective components of pain, was also activated during spontaneous migraine attacks, and this activation was reduced

concomitantly with headache pain relief after administration of sumatriptan. Taken together, these observations suggest that the

raphe nucleus, locus coeruleus and the periaqueductal gray are regions that may be involved in the generation of headache pain and

associated symptoms during a migraine attack. Adapted with permission from Weiller C, May A, Limmroth V, et al. Brain stem

activation in spontaneous human migraine attacks. Nat Med 1995;1:658-60

Cerebral

cortex

POm

VPM

CGRP

Thalamus

NKA

VPL

Ach

VIP

PHI

Midbrain

Sensory

NPY

PYY

TNC

Pons

STN

SPG

VII

Otic

Parasympathetic

SSN

Medulla

SCG

Spinal

Sympathetic

cord

T2-3

Figure 4.14

Brainstem nuclei and their transmitters. Ach, acetylcholine; C2, second cervical segment of the spinal cord; CGRP,

calcitonin gene-related peptide; CL, centrolateral nucleus of thalamus; CM, centromedial nucleus of thalamus; NA, noradrenaline;

NKA, neurokinin A; NPY, neuropeptide Y; Otic, otic ganglion; PHI, peptide histidine isoleucine (methionine in man); POm, medial

nucleus of the posterior complex; PYY, peptide YY; SCG, superior cervical ganglion; SP, substance P; SPG, sphenopalatine ganglion;

SSN, superior salivatory nucleus; STN, spinal trigeminal nucleus; T2-3, second and third thoracic segments of the spinal cord; TNC,

trigeminal nucleus caudalis; VII, seventh cranial nerve (parasympathetic outflow); VIP, vasoactive intestinal polypeptide; VPL, ventro-

posterolateral nucleus of thalamus; VPM, ventroposteromedial nucleus of thalamus; Vg, trigeminal ganglion; VI-3, first, second and third

divisions of the trigeminal nerve. Reproduced with permission from Goadsby PJ, Zagami AS, Lambert GA. Neural processing of cranio-

vascular pain: a synthesis of the central structures involved in migraine. Headache 1991;31:365-71

Figure 5.1

Fortification spectra seen in migraine visual auras

Figure

5.2

Migraine visual auras are very similar to

have been compared to the aerial view of the fortified, walled

epileptic visual hallucinations seen here. Reproduced from

city of Palmanova, Italy. Reproduced with permission from

Panayiotopoulos CP. Elementary visual hallucinations in

Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical

migraine and epilepsy. J Neurol Neurosurg Psychiatr

1994;57:

Practice. Oxford, UK: Isis Medical Media, 1998:64

1371-4, with permission from the BMJ Publishing Group

Figure 5.5

Fortification spectra as depicted by Lashley. An

arch of scintillating lights, usually but not always beginning near

the point of fixation, may form into a herring bone-like pattern

that expands to encompass an increasing portion of the visual

hemifield. It migrates across the visual field with a scintillating

edge of often zigzag, flashing or occasionally colored pheno-

mena. Reproduced with permission from Lashley K. Patterns of

cerebral integration indicated by the scotomas of migraine.

Arch Neurol Psychiatr 1941;46:331-9

Figure

5.6

Migraine aura.

1-4, Early stages of sinistral

teichopsia beginning close to the sight point, as seen in the

dark. The letter O marks the sight point in every figure; 5-8, a

similar series of the early stages of sinistral teichopsia beginn-

ing a few degrees below and to the left of the sight point;

9, sinistral teichopsia fully developed. Beginning of a secondary

attack, which never attains full development, until it arises on

the opposite side

Figure 5.9

Motorist’s right-sided hemianopic loss of vision, the scotomatous area being surrounded by a crescentic area of brighter

lights. Reproduced with permission from Wilkinson M, Robinson D. Migraine art. Cephalalgia 1985;5:151-7

Trigger

Pain

Antidromic

conduction

Orthodromic

Cortex

conduction

Trigeminal

Thalamus

neuron

Autonomic

Endothelium

activation

Nausea

5-HT

emesis

Inhibitory

site

Mast

cell

C-fos

Vasodilation

Plasma extravasation

Brainstem

(TNC)

Figure 5.10

Pathophysiologic mechanism and postulated anti-nociceptive site for sumatriptan and ergot alkaloids in vascular

headaches.The triggers for headache activate perivascular trigeminal axons, which release vasoactive neuropeptides to promote neuro-

genic inflammation (vasodilation, plasma extravasation, mast cell degranulation). Ortho- and antidromic conduction along trigeminovas-

cular fibers spreads the inflammatory response to adjacent tissues and transmits nociceptive information towards the trigeminal nucleus

caudalis and higher brain centers for the registration of pain. TNC, trigeminal nucleus caudalis. Adapted from Moskowitz MA. Neurogenic

versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. Trends Pharmacol Sci 1992;13:307-11, with permission from

Elsevier Science

Neuropeptides

Neurokinin A

2 Neuropeptide release

Substance P

- vasodilation

CGRP

- neurogenic inflammation

Cortex

Pain

5 HT

Trigeminal

ganglion

B receptors

Thalamus

1 Vasodilation

5-HT1D receptors

4 Central pain

transmission

3 Pain signal

transmission

Figure 5.11

A primary dysfunction of brain stem pain and vascular control centers elicits a cascade of secondary changes in vascular

regulation within pain-producing intracranial structures that ultimately manifests in headache pain and associated symptoms. A

synthesis of these views and observations forms the neurovascular hypothesis of migraine. It is critical to understand the anatomy of

the trigeminal vascular system and the pathophysiologic events that arise during a migraine attack before considering the proposed

mechanisms of action of acute therapies. Current theories suggest that there are several key steps in the generation of migraine pain:

(1) Intracranial meningeal blood vessel dilation which activates perivascular sensory trigeminal nerves. (2) Vasoactive neuropeptide

release from activated trigeminal sensory nerves. These peptides can worsen and perpetuate any existing vasodilation, setting up a

vicious cycle that increases sensory nerve activation and intensifies headache pain.The peptides include substance P (increased vascular

permeability), neurokinin A (dilation and permeability changes) and calcitonin gene-related peptide (CGRP; long-lasting vasodilation).

(3) Pain impulses from activated peripheral sensory nerves are relayed to second-order sensory neurons within the trigeminal

nucleus caudalis in the brain stem and upper cervical spinal cord (C1 and C2, trigeminocervical complex). (4) Headache pain signals

ascend to the thalamus, via the quintothalamic tract which decussates in the brain stem, and on to higher cortical centers where

migraine pain is registered and perceived.Adapted with permission from Hargreaves RJ, Shepheard SL. Pathophysiology of migraine -

new insights. Can J Neurol Sci 1999;26(Suppl 3):S12-19

Neuropeptides

Neurokinin A

Substance P

CGRP

4 Neuropeptide

release

Cortex

Pain

Trigeminal

ganglion

1 Activation of

5 HT_1B

Thalamus

receptors

Direct

vasoconstriction

5-HT1D receptors

4 Inhibition of

trigeminal inhibition

2 Presynaptic 5-HT_1D

central pain

activation

transmission

3 Decreased pain

transmission

Inhibits neuropeptide release

- blocks vasodilation

- inhibits neurogenic

inflammation

Figure 5.12

Increased knowledge of 5-HT receptor distribution within the trigeminovascular system has led to the introduction

of highly effective serotonergic anti-migraine drug therapies. Detailed molecular biology mapping of mRNA (RT-PCR and in situ

hybridization) and immunohistochemical studies of recepter proteins have revealed populations of vasoconstrictor 5-HT_1B receptors

on the smooth muscle of human meningeal blood vessels.Thus, agonists of 5-HT_1B receptors, which cause vasoconstriction, are ideally

placed to reverse the dilation of meningeal vessels that is thought to occur during a migraine attack (see 1). 5-HT_1B receptors have

also been found on human coronary arteries making it important to establish the relative contribution of this subtype to the contrac-

tile response in coronary arteries compared with the target meningeal blood vessels. While 5-HT_1F mRNA has also been demon-

strated in human blood vessels, there appears to be no expression of functional receptors since 5-HT_1F agonists appear devoid of

vasoconstrictor effects. Immunohistochemical mapping studies on the localization of 5-HT_1D and 5-HT_1F receptor proteins in human

trigeminal nerves have shown that 5-HT_1D and 5-HT_1F receptors are present on trigeminal nerves projecting peripherally to the dural

vasculature and centrally to the brain stem trigeminal nuclei. Activation of such prejunctional receptors on nerve terminals can modu-

late neurotransmitter release. In this context, agonists of 5-HT_1D and 5-HT_1F receptors are ideally placed, peripherally (see 2) to

inhibit activated trigeminal nerves and promote normalization of blood vessel caliber (by preventing the release of vasoactive

neuropeptides) and centrally (see 3) to intercept pain signal transmission from the meningeal blood vessels to second-order sensory

neurons in the trigeminal nucleus caudalis of the brain stem (see 4). Adapted with permission from Hargreaves RJ, Shepheard SL.

Pathophysiology of migraine - new insights. Can J Neurol Sci 1999;26(Suppl 3):S12-19

Baseline

Dilated

Normalized

Neurogenic blood vessel vassel vasodilation: Intravital microscopy

5-HT_1B/1D agonists block release of vasoactive neuropeptides

(CGRP)

Figure 5.14

Results from a preclinical intravital microscope dural plasma protein extravasation (DPPE) assay that was used to

investigate the anti-migraine action of rizatriptan.These videoframes show a branch of the middle meningeal artery embedded within

the dura mater (running bottom left to top right of each section).The sequence shows the artery at baseline (left panel), in a dilated

state after electrically evoked vasoactive neuropeptide release from the perivascular nerves (middle panel) and when normalized by

drug treatment.

These intravital studies showed that rizatriptan blocks the electrically evoked release of peptides including CGRP from perivascu-

lar sensory nerves in the meninges but does not inhibit vessel dilation to CGRP when it is given intravenously.This suggests that riza-

triptan is not a CGRP receptor antagonist but instead inhibits the release of CGRP from trigeminal sensory nerves.This blockade of

neuropeptide release is thought to occur through stimulation of prejunctional 5-HT_1D receptors. Since all of the 5-HT_1B/1D agonists

are capable of blocking the release of vasoactive neuropeptides, it suggests that one mechanism of action of these drugs is blockade

of neurogenic inflammation. Reproduced with permission from Shepheard SL, Williamson DJ, Hargreaves RJ. Intravital microscope

studies of dural blood vessels in rats. In: Migraine and Headache Pathophysiology, 1st edn. London: Martin Dunitz, 1999:103-17

Serotonergic

Ergots

Side-effects

5-HT_1A

+++

Nausea/emesis/dysphoria

5-HT_1B

Anti-migraine

5-HT_1D

+++

5-HT_2A

5-HT_2C

Unnecessary vascular effects

Asthenia

Adrenergic

Dizziness

α₁

α₂

Dopaminergic

D₂

GI/nausea/emesis

Figure 5.15

The ergots were the first 5-HT agonists used for the treatment of migraine. They are not particularly useful when

given orally due to their unpredictable absorption and their low bioavailability. This is improved, however, by intranasal or rectal

administration. The peripheral vascular effects of the ergots were already known during the Middle Ages, when they caused the

disorder known as ‘Saint Anthony’s fire’ due to the ingestion of bread infected by Claviceps purpurea, the ergot-producing fungus (see

Chapter 1). This caused such a profound vasoconstriction of the extremities that patients felt as if their extremities were burning

with the latter eventually turning black. The victims looked as if they had been charred by fire and the epidemic got its name from

this fact. Nausea and dizziness, the common side-effects of ergots, may be explained by the actions of these compounds on multiple

monoamine receptors.

Ergots are potent agonists at the 5-HT_1B/1D receptors and this explains their anti-migraine effect. They also act on 5-HT_1A recep-

tors, an activation that is probably responsible for the production of nausea and dysphoria. The constriction of the peripheral vascula-

ture is probably through activation of α-adrenoreceptors and 5-HT_2A receptors. Agonist activity at dopamine D₂ receptors produces

gastrointestinal disturbances, nausea and emesis. Thus, based on their pharmacologic activity at monoamine receptors, it is possible

to conclude that although ergots are good anti-migraine agents, they also have many other unwanted effects. Adapted from

Goadsby PJ. Serotonin 5-HT_1B/1D receptor antagonists in migraine. CNS Drugs 1998;10:271-86

Serotonergic

Triptans

Side-effects

5-HT_1A

Nausea/emesis/dysphoria

5-HT_1B

Anti-migraine

5-HT

5-HT_2A

−

5-HT_2C

−

Unnecessary vascular effects

Asthenia

Adrenergic

Dizziness

α₁

−

α₂

−

Dopaminergic

D₂

−

GI/nausea/emesis

Figure 5.16

The triptans selectively target and activate 5-HT_1B and 5-HT_1D receptors. Like the ergots, they have potent activity at

the ‘anti-migraine’ 5-HT_1B/1D receptors but have much weaker action at 5-HT_1A receptors. The triptans lack binding activity on the

monoamine receptors of the ergots. Adapted from Goadsby PJ. Serotonin 5-HT_1B/1D receptor antagonists in migraine. CNS Drugs

1998;10:271-86

Figure 6.1

SUNCT is marked by very short lasting attacks

(5 to 250 s) of headache and associated autonomic symptoms.

90 100110 120130 140 >150

Adapted with permission from Pareja JA, Shen JM, Kruszewski P,

Duration of SUNCT attacks (s)

et al. SUNCT syndrome: duration, frequency, and temporal

distribution of attacks. Headache 1996;36:161-5

Minimum duration

Maximum duration

Figure

6.2

Duration of individual attacks of chronic

paroxysmal hemicrania (CPH) in minutes. Most attacks will be

15 to

20 min in duration. Adapted with permission from

1/5

6/10

11/15

16/20

21/25 26/30

>31

Antonaci F, Sjaastad O. Chronic paroxysmal hemicrania (CPH):

Time (min)

a review of the clinical manifestations. Headache

1989;29:

648-56

Attacks beginning

during sleep

Patient awake at

beginning of attacks

Figure 6.3

Duration of cluster attacks.Typical attack duration

¹/₄

¹/₂

³/₄

1¹/₄

1¹/₂

1³/₄

2¹/₄

2¹/₂

2³/₄

3³/₄

is 1 h or less. Adapted with permission from Russell D. Cluster

Time (h)

headache: Severity and temporal profiles of attacks and patient

activity prior to and during attacks. Cephalalgia 1981;1:209-16

Vascular

Infection

Figure

6.4

Cluster headache is considered a primary

Trauma

headache disorder, so there are no underlying secondary

Neoplasm

causes. In rare instances cluster headache has been linked to

various secondary causes including: aneurysms, head trauma,

orbital enucleation, sphenoid sinusitis, parasellar tumors, cervi-

cal cord mengiomas or infarction, subdural hematomas and

arteriovenous malformations. Adapted from the Neurology

Ambassador Program with permission from the American

Headache Society

Attacks daily (up to 8 attacks/day)

Peak time periods

Figure 6.5

Cluster headache has a distinct circadian periodi-

city to its attacks. Cluster patients will get attacks at the same

time each day and cluster periods at the same time each year.

This suggests that the hypothalamus (suprachiasmatic nucleus) or

circadian clock is playing a role in cluster genesis. A hallmark of

cluster is for the patient to awaken with a cluster headache 1.5

to 2 h after falling asleep (first REM period of the night); typically

these night-time attacks are the most painful. Adapted from the

REM sleep

Neurology Ambassador Program with permission from the

American Headache Society

Cluster headache

Episodic (90%)

Chronic (10%)

Cluster period

lasts for more than

one year without

remission or

remission lasts less

than 14 days

Related syndromes

Figure 6.6

Most cluster patients have the episodic subtype so

they will have periods of remission sometimes for years at a

Episodic

time. Adapted from the Neurology Ambassador Program with

Chronic

permission from the American Headache Society

a Male

b Female

Age of cluster onset (years)

Figure 6.11

Age of cluster onset. (a) Most men develop their first ever cluster attack in their twenties or thirties (standard

deviation = 13.47, mean = 31.3, n = 69); (b) women with cluster headaches have two age peaks of cluster onset (unlike men), one in

their late teens or twenties and a second when they are 50 or 60 years of age (standard deviation = 15.89, mean = 29.4, n = 32). Late

age of onset of female cluster headaches needs to be recognized by the treating physician. Adapted from Rozen TD, Niknam RM,

Shechter AL, et al. Cluster headache in women: clinical characteristics and comparison with cluster headache in men. J Neurol

Neurosurg Psychiatr 2001;70:613-7, with permission from the BMJ Publishing Group

100

Placebo

Sumatriptan

Prevalence

Predominantly male

(male: female ratio)

Mean age of onset

Rare before the age

of 10 years

Time (min)

Figure 6.12

Cluster predominantly occurs in men, although

Figure 6.13

Reduction in pain severity after administration

more women are being diagnosed with cluster headache. The

of sumatriptan injectable to patients with cluster headache.

prevalence of cluster headache is

0.4% of the population.

A significant response was observed by

10 and

15 min

Adapted from the Neurology Ambassador Program with

versus placebo. Adapted with permission from Olesen J,

permission from the American Headache Society

Tfelt-Hansen P, Welch KMA, eds. The Headaches, 2nd edn.

Philadelphia, PA: Lippincott Williams & Wilkins, 2000:733

Sensory trigeminal pathway

procedures

Radiofrequency or glycerol

Figure 6.14

Presently the most effective surgical

rhizotomy

therapy for cluster is radiofrequency lesioning of the

Gamma knife radiosurgery

gasserian

(trigeminal) ganglion. Under radiographic

Trigeminal root section

control a device is inserted into the cheek and directed

Other

through the foramen ovale into the area of the gasser-

Autonomic (parasympathetic)

ian ganglion where a specific denervating agent

pathway procedures

(radiofrequency, glycerol) is then used. Adapted from

the Neurology Ambassador Program with permission

from the American Headache Society

Age at onset of SUNCT

Figure 6.15

SUNCT is considered a disorder of the

elderly, although there are some reported cases

21-30

31-40

41-50

51-60

61-70

71-80

younger than age 40. Adapted with permission from

Age groups (years)

Pareja JA, Sjaastad O. SUNCT syndrome. A clinical

review. Headache 1997;37:195-202

Localization of SUNCT pain

Main areas

Areas to which

pain spreads

Figure 6.16

SUNCT pain is located in or around the eye and/or the forehead region. It can spread to extra-trigeminal innervated

areas. Adapted with permission from Pareja JA, Sjaastad O. SUNCT syndrome. A clinical review. Headache 1997;37:195-202

Pre-CPH stage

Time

Age groups (years)

Figure

6.21

The natural history of chronic paroxysmal

hemicrania (CPH) is unknown. When Sjaastad first identified

Figure 6.19

Chronic paroxysmal hemicrania (CPH) typically

CPH he noticed that some patients went through a pre-CPH

starts to occur in the teens or twenties, very similar to the

stage of CPH attacks with remission periods. In some patients

age of onset of cluster. Adapted with permission from

these patients never went on to have CPH. Most likely this pre-

Antonaci F, Sjaastad O. Chronic paroxysmal hemicrania (CPH):

CPH stage is episodic paroxysmal hemicrania (EPH). Adapted

a review of the clinical manifestations. Headache

1989;29:

with permission from Russell D, Sjaastad O. Chronic paroxysmal

648-56

hemicrania. In: Pfaffenrath V, Sjaastad O, Lundberg PO, eds. Updat-

Springer-Verlag

Female

Male

Age groups (years)

Figure 6.20

Both females and males who develop chronic

Figure 6.22

Quality of chronic paroxysmal hemicrania (CPH)

paroxysmal hemicrania (CPH) typically have their first attacks

pain. Adapted with permission from Antonaci F, Sjaastad O.

in their teens or twenties. Adapted with permission from

Chronic paroxysmal hemicrania (CPH): a review of the clinical

Antonaci F, Sjaastad O. Chronic paroxysmal hemicrania (CPH):

manifestations. Headache 1989;29:648-56

a review of the clinical manifestations. Headache

1989;29:

648-56

High alcohol/

tobacco usage

Leonine facies (heavy

facial features)

Peau d’orange skin

Hazel-colored eyes

Duodenal ulceration

Type A personality

Figure 6.25

Cluster headache has been linked to a

typical facies, eye color and certain medical conditions.

Adapted from the Neurology Ambassador Program

with permission from the American Headache Society

Trigeminovascular

Cranial

Sympathetic innervation

system

parasympathetic system

of internal carotid artery

CGRP

VIP

Trigeminovascular

Cranial parasympathetic

Internal carotid artery

activation (CGRP)

activation (VIP)

dilation (cavernous)

Figure 6.26

The true pathogenesis of cluster headache is still unknown.What must be accounted for when determining a unified

theory of cluster pathogenesis are: (a) The pain is orbital in location. This means the ipsilateral sensory trigeminal nerve system is

involved. Trigeminal afferents transmit cephalic pain via the ophthalmic division of the trigeminal nerve synapse in the trigeminal

ganglion which then relays this sensory input to the trigeminal nucleus caudalis in the brainstem. Calcitonin gene-related peptide

(CGRP) is the neurotransmitter released in this system; (b) Ipsilateral symptoms of parasympathetic activation (lacrimation, nasal

congestion). Cranial parasympathetic innervation of the intracranial vessels arise in primary order neurons in the superior salivatory

nucleus in the pons. Efferents from this system (via the seventh cranial nerve) act to stimulate the nasal and lacrimal glands.Vasoactive

intestinal peptide (VIP) is a marker of activation of the cranial parasympathetic system; (c) Ipsilateral symptoms of sympathetic

dysfunction (miosis, ptosis, partial Horner’s syndrome). As a result of activation of sensory trigeminal and cranial parasympathetic

systems there is blood vessel dilation in the internal carotid artery. If the cavernous carotid artery (level at which the parasympa-

thetic, sympathetic and trigeminal fibers converge) dilates, it can cause compression of the sympathetic system with the production

of a postganglionic Horner’s syndrome. Adapted from the Neurology Ambassador Program with permission from the American

Headache Society

140

(n=1)

Interictal

(n=1)

Interictal

(n=12)

120

CGRP

VIP

(n=12)

Headache

100

CGRP

VIP

(n=27)

Migraine

Cluster

CPH

Migraine

Cluster

CPH

Figure 6.27

Changes in calcitonin gene-related peptide (CGRP; a) and vasoactive intestinal polypeptide (VIP; b) levels during

migraine, cluster and chronic paroxysmal hemicrania (CPH) attacks. Note elevation of both CGRP and VIP levels in the trigeminal-

autonomic cephalgia (TAC) headaches but not in migraine. Adapted from Goadsby PJ, Lipton RB.A review of paroxysmal hemicranias,

SUNCT syndrome and other short-lasting headaches with autonomic feature, including new cases. Brain 1997;120:193-209, with

permission by Oxford University Press

0.5

0.4

0.3

0.2

0.1

Jan

Mar

May

Jul

Sep

Nov

Figure 6.29

Urine melatonin levels were examined for up to

14 months in episodic cluster headache patients (red line)

Figure 6.28

Dilation of the ophthalmic artery during a

and healthy controls (yellow line). The mean levels of urinary

spontaneous cluster attack.The artery normalized after cluster

melatonin were significantly lower in patients than controls in

remission. Artery dilation in cluster headache may result from

both cluster periods and during remissions. Adapted from

trigeminal nerve activation with release of calcitonin gene-

Waldenlind E, Gustafsson SA, Ekbom K,Wetterberg L. Circadian

related peptide (CGRP) or from an inflammatory process in

secretion of cortisol and melatonin in cluster headache during

the cavernous sinus and tributary veins leading to venous stasis

active cluster periods and remission. J Neurol Neurosurg Psychiatr

and resultant artery dilation. Vascular congestion within the

1987;50:207-13, with permission by the BMJ Publishing Group

cavernous sinus region can explain the pain of cluster and the

sympathetic damage seen during attacks. A venous vasculitis

theory for cluster is another possible etiology for cluster

pathogenesis. Reproduced with permission from Waldenlind E,

Ekbom K,Torhall J. MR-angiography during spontaneous attacks

of cluster headache: a case report. Headache 1993;33:291-5

Figure 6.30

Image on the left demonstrates hypothalamic activation during a cluster attack on PET. The image on the right is a

voxel-based morphometric analysis of the structural T1-weighted MRI scans from 25 right-handed cluster patients revealing a signifi-

cant difference in hypothalamic gray matter density (yellow) compared with non-cluster patients. The hypothalamus of cluster

patients appears to have an increased volume compared with controls. Adapted from the Neurology Ambassador Program with

permission from the American Headache Society

Trigger

Photoperiod stress

Sleep-wake cycle alteration

Trigger

02, nitroglycerin,

alcohol

Hypothalamus

VIP

Figure 6.31

Image showing how the hypothalamus, trigemi-

CGRP

SSN

nal sensory, cranial parasympathetic and carotid sympathetic

systems interact to produce a cluster headache.The brainstem

Trigeminal

Pterygopalatine

connection between the trigeminal and cranial sympathetic

ganglion

systems (trigeminal-autonomic reflex pathway) helps to explain

(parasympathetic)

the clinical phenotype of the trigeminal-autonomic cephalgias

Superior cervical

(TACs). CGRP, calcitonin gene-related peptide; SSN, superior

ganglion

salivatory nucleus; VIP, vasoactive intestinal polypeptide. Adap-

ted from the Neurology Ambassador Program with permission

from the American Headache Society

• Episodic

Chronic (13%)

Figure 6.32

The natural history of cluster headaches is not

well documented in the literature. About

13% of episodic

cluster patients will develop into chronic cluster, whereas one-

• Chronic

Episodic (33%)

third of chronic patients will change to episodic cluster. Being

on a preventive appears to help with the latter transition. Most

cluster patients will continue over their lifetime to have the

• Cluster-free intervals: 1.1 years

3.5 years

same number of attacks per day and the same duration for each

attack. Adapted from the Neurology Ambassador Program with

permission from the American Headache Society

Pre-test attack pattern

CPH attacks

−1

−2

−3

270

180

Time (min)

Pattern after 50 mg indomethacin

Minimal duration

Mean duration

Maximal duration

of RP

of RP * *

Time (h)

Indomethacin injection

(50 mg IM)

Pattern after 100 mg indomethacin

Minimal duration

Mean duration

Maximal duration

of RP

of RP * *

* * *

Time (h)

Indomethacin injection

(100 mg IM)

Figure 6.33

Indomethacin is the sole treatment of choice in chronic paroxysmal hemicrania (CPH). Antonaci et al. have described

the ‘indotest’ in which a 50 mg indomethacin IM test dosage can be given to patients in the office with possible CPH.When looking

at the mean interval of attack frequency pre-indomethacin and post-indomethacin, after indomethacin the attack frequency is reduced

(refractory period (RP) was initiated post-indomethacin). If a patient after indomethacin does not get their typical next attack, then

indomethacin should be effective in that patient for their headaches.^*Hatched lines indicate putative attacks that have not materialized;

^**pre-attack pattern re-established in all patients;^***the timing of the anticipated attacks is not based on exact recording of the attack

pattern prior to the 100 mg test. Adapted with permission from Antonaci F, Pareja JA, Caminero AB, Sjaastad O. Chronic paroxysmal

hemicrania and hemicrania continua. Parenteral indomethacin: the ‘indotest’. Headache 1998;38:122-8

Figure 6.34

Orbital phlebography in a 49-year-old man with SUNCT. On the side of the pain on the right (see arrow), there was

narrowing of the whole superior ophthalmic vein (1 and 2). Orbital phlebography completed when the patient was in a remission

state was normal (3). The findings suggest that SUNCT, at least in a subset of patients, may be caused by a venous vasculitis.

Reproduced with permission from Hannerz J, Greitz D, Hansson P, Ericson K. SUNCT may be another manifestation of orbital venous

vasculitis. Headache 1992;32:384-9

Figure 6.35

BOLD contrast-MRI of the brain of a 71-year-old woman with SUNCT syndrome. (a) Activation is noted in the ipsilat-

eral posterior hypothalamic gray region (yellow). Almost the same exact area of activation is noted during a cluster attack (b) suggest-

ing a similar underlying cause of these clinically disparate TACs.Adapted with permission from May A, Bahra A, Buchel C, et al. Functional

magnetic resonance imaging in spontaneous attacks of SUNCT: Short-lasting neuralgiform headache with conjunctival injection and

Common

Tension-vascular

migraine

headache

Classic

Tension

migraine

headache

Prominent vomiting

Nondescript pain

Figure 7.1

‘The continuum of

Lateralized headache

Rare vomiting

benign recurring headache’ was

Focal neurologic symptoms

Holocephalgia

introduced by Raskin. Adapted

with permission from Raskin NH.

Headache,

2nd edn. New York:

Churchill Livingstone, 1988:215-24

Initial

Final

diagnosis

Migraine

(n = 249)

Migrainous

Migraine

(n = 108)

(n = 49, 45%)

Migrainous

(n = 59, 54%)

TTH

Migraine

(n = 75)

(n = 24, 32%)

Migrainous

Figure

7.2

Reclassification of headache diagnosis based

(n = 4, 5%)

on diary review. TTH, tension-type headache. Adapted from

TTH

Lipton RB, Stewart WF, Hall C, et al. The misdiagnosis of

(n = 47, 63%)

disabling episodic headache: Results from the Spectrum Study.

Presented at the International Headache Congress, June 2001

100

OR = 3.43

OR = 0.38

OR = 1.31

Migraine

Migrainous

ETTH

(n = 81)

(n = 22)

(n = 73)

Figure 7.3

Pain-free response at 2 h by headache attack type

Headache attack type

in individuals with an initial diagnosis of tension-type headache

and a final diagnosis of migraine. ETTH, episodic tension-type

Sumatriptan

Placebo

headache; OR, odds ratio. Adapted with kind permission of

Richard B. Lipton

Figure 8.1

Vascular compression theory for trigeminal

neuralgia. One of the first surgical proponents of the vascular

theory was Walter Dandy. In 1934, Dandy wrote, ‘I believe no

less responsible for the production of trigeminal neuralgia;

these are the arteries and veins which impinge upon and

frequently distort the sensory root. In the region of the sensory

root the superior arterial branch forms a loop…as the artery

hardens from advancing age, the nerve becomes indented by

the arterial branch’. Reproduced from Dandy WE. Concerning

the cause of trigeminal neuralgia. Am J Surg 1934;24:447-55,

with permission from Excerpta Medica Inc

Figure 8.2

Overlapping pain referral patterns from myofascial

trigger points in various masticatory and cervical muscles

produce typical unilateral or bilateral migraine or tension-type

headache. Reproduced with kind permission of Bernadette

Jaeger

Figure 8.3

Referred pain from superficial masseter and upper

trapezius myofascial trigger points may produce unilateral or

bilateral tension-type and migraine headache symptoms.

Reproduced with kind permission of Bernadette Jaeger

Figure 8.4

(a), (b) and (c) belong to the same patient, a 67-year-old woman with severe, continuous left occipital pain and swallowing

difficulties during the previous two weeks.The pain became unbearable with right suboccipital palpation or on neck rotation to the left.

Neurologic examination showed a right twelfth nerve paralysis. She died suddenly several days after admission. Clinical diagnosis was

‘right occipital condyle syndrome’ secondary to a metastasis of unknown origin. (a) Posteroanterior skull radiograph with an inclination

of 30° showing an osteolytic lesion of the right occipital condyle; (b) axial skull base. CT scan with bone window setting showing erosion

of the right occipital condyle; (c) right hypoglossal paralysis. Reproduced with permission from Moris G, Roig C, Misiego M, et al. The

distinctive headache of the occipital condyle syndrome: A report of four cases. Headache 1998;38:308-11

Figure 8.6

Very severe conjunctival injection (more pronounced in the patient’s left side) and uveitis in a 63-year-old woman

presenting as bilateral periocular headache as the first sign of a confirmed Wegener’s syndrome. Headache and ocular manifestations

resolved after aggressive treatment with steroids and cyclophosphamide. Reproduced with kind permission of Julio Pascual

Figure

8.7

Cranio-cervical MRI study of a

39-year-old-

woman complaining of brief

(second-1 minute) occipital

headache when coughing and other Valsalva maneuvers showing

tonsillar descent. Sagittal MRI T1 W1 pulse sequence demon-

strates low lying tonsils, normal fourth ventricle and normal

posterior fossae anatomy indicative of Chiari I. Headache has

disappeared after suboccipital craniectomy. Reproduced with

permission from Pascual J, Iglesias F, Oterino A, et al. Cough,

exertional and sexual headache. Neurology 1996;46:1520-4

Figure 8.8

This 78-year-old man went to hospital due to constant temporal headache during the previous two months. On exami-

nation there was no pulsation in the left temporal artery, which appeared thickened and painful on palpation. The erythrocyte sedi-

mentation rate was 96 mm in the first hour, while a temporal artery biopsy showed changes diagnostic of giant-cell arteritis. Courtesy

of Jose′ Berciano, University Hospital Marques de Valdecilla, Santander, Spain

Figure 8.9

Seventy-year-old man with giant-cell arteritis. A portion of the anterior branch of the left temporal artery is visibly

swollen. It was tender and thickened on palpation. Reproduced with permission from Caselli RJ, Hunder GG. Giant cell arteritis and

polymyalgia rheumatica. In: Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolff ’s Headache and other Head Pain, 7th edn. New York: Oxford

University Press, 2001:525-35

Figure

8.10

Temporal artery biopsy specimen showing

active inflammation in all three vascular layers (intima, media,

adventitia). The lumen is partially shown, at the top of the

figure, and is narrowed. In most temporal artery biopsy speci-

mens with giant-cell arteritis, the media, especially the inner

media in the region of the internal elastic Iamina, is involved

to the greatest extent and the intimal and adventitial layers

are involved to a lesser degree than in this patient (hematoxylin

and eosin stain,

200x). Reproduced with permission from

Casselli RJ, Hunder GG. Giant cell arteritis and polymyalgia

rheumatica. In: Silberstein SD. Lipton RB, Dalessio DJ, eds.

Wolff ’s Headache and Other Head Pain, 7th edn. New York:

Oxford University Press, 2001:525-35

Figure 8.11

Lyme disease most often presents with a char-

acteristic ‘bull’s eye’ rash, erythema migrans, accompanied by

non-specific symptoms such as fever, malaise, fatigue, myalgia

and joint aches (arthralgia). Many patients complain of persis-

tent daily headaches

Figure 8.12

A 22-year-old man with a one-month history of

a left hemicranial pain and cluster-like features. An axial CT

scan post-enhancement demonstrated a multilocular lesion in

the left frontal lobe with white matter edema, displacement

of the falx to the right and enhancement of the rings measur-

ing

3.5 cm at the widest. This is a pyogenic brain abscess

approximately 14 days old. Reproduced with kind permission of

Germany Goncalves Veloso

Figure 8.13

A 53-year-old female patient with a strong pain

in the left periocular and temporal region. She presented with

autonomic signs, eyelid ptosis and conjunctival injection, ipsi-

lateral to and concurrent with the pain.The duration of the pain

was 40 min. It occurred three times per day and was worse at

night. As a result of the painful episodes she had decreased

sensitivity in the left facial region. The angiogram disclosed an

occlusion at the proximal region of the external carotid artery

on the left. Patient experienced total relief using verapamil.

Reproduced with kind permission of Vera Lucia Faria Xavier

Figure 8.14

A 34-year-old healthy farmer reported a mild occipital headache for 4 weeks. The general and neurologic examina-

tions were normal. (a) Sagittal T1 W1 MRI and (b) axial T1 W1 MRI showed a large cyst in the posterior fossa displacing the cere-

bellar hemispheres upwards; this is likely to be a congenital Dandy-Walker abnormality. Surgical approaches were contraindicated by

the neurosurgical staff. After

3 years the patient remains asymptomatic, except for transient, mild headaches associated with

emotional stress. Reproduced with kind permission of Pericles de Andrade Maranh~o-Filho

Figure 8.15

A 35-year-old man with a history of chronic daily headache and recent-onset partial motor seizures. (a) Axial CT scan

shows multiloculated cysts in the left sylvian fissure; (b) axial CT scan at the same level. The subarachnoid lesion is not enhanced.

The diagnosis is cysticercosis. Reproduced with kind permission of Suzana M.F. Malheiros

Figure 8.16

A 34-year-old woman with a history of thunderclap headache during sport activity associated with blurred vision.

(a) Axial CT scan shows multifocal high-density intraparenchymal lesions; (b) CT scan shows an irregularly enhancing rim of the three

lesions each located bilaterally in the parietal lobes with surrounding edema. Note a fluid-fluid level within the right periventricular

lesion.The lesions were confirmed as metastatic melanoma. Reproduced with kind permission of Suzana M.F. Malheiros

Figure 8.17

A 60-year-old man with a six-month history of

pressing/tightening headache that antedated the development

of mild right hemiparesis. Axial post-contrast T1-weighted MR

scan shows a large, enhancing, ill-delineated left basal ganglia

mass.The diagnosis is anaplastic astrocytoma. Reproduced with

kind permission of Suzana M.F. Malheiros

Figure 8.21

Two axial T1 W1 MRI non-enhancing images

Figure 8.23

A patient who presented with headache with

reveal a large hypointense, scallop-bordered mass with exten-

papilledema. These are images demonstrating a filling defect or

sion to the foramen of Luschka, compressing the brainstem and

lack of filling of the superior sagittal sinus consistent with

fourth ventricle which demonstrates hyperintensity on the

thrombosis

T2-weighted image (b) so that it becomes iso-intense with the

cerebral spinal fluid (CSF)

Figure 8.22

A 40-year-old male with continued headache

Figure

8.24

Carotid arteriogram showing an aneurysm

following head trauma from a motorcycle accident. An axial T1

which comes to a point consistent with this being the area of

non-enhanced image shows bilateral, concave, hyperintense

pathology. No areas of spasm are noted. Reproduced with kind

collections that are 3 days to 3 weeks old. The diagnosis is

permission of Nitamar Abdala

subacute subdural hematoma

Figure 8.31

Three-year-old boy with two prior episodes of spontaneously resolving oculomotor nerve palsy. (a) and (b), sagittal

T1-weighted MR images before (a) and after (b) contrast administration show diffuse thickening and enhancement of the oculomotor

nerve. The symptoms resolved spontaneously in 6 weeks. Reproduced with permission from Mark AS, Casselman J, Brown D, et al.

Ophthalmoplegic migraine: Reversible enhancement and thickening of the cisternal segment of the oculomotor nerve on contrast-

Figure 8.32

Twenty-seven-year old woman with two prior episodes of headache and oculomotor nerve palsy. (a) and (b), axial

non-contrast (a) and contrast-enhanced (b) T1-weighted images show focal nodular enhancement of the exit zone of the oculomotor

nerve (see arrows). Follow-up study showed virtually complete resolution of the enhancement. Reproduced with permission from

Mark AS, Casselman J, Brown D, et al. Ophthalmoplegic migraine: Reversible enhancement and thickening of the cisternal segment of

Neuroradiology (www.ajnr.org)

Figure 8.33

Twelve-year-old boy with two prior episodes of ophthalmoplegic migraine. (a) and (b), axial T1-weighted MR images

before (a) and after (b) contrast administration show enhancement of the oculomotor nerve (arrow in panel b) and thickening of its

root entry zone. Follow-up studies showed virtually complete resolution of the enhancement. Reproduced with permission from

Mark AS, Casselman J, Brown D, et al. Ophthalmoplegic migraine: Reversible enhancement and thickening of the cisternal segment of

Neuroradiology (www.ajnr.org)

Figure 8.34

Twenty-three-year-old woman with one prior episode of ophthalmoplegic migraine. (a) axial T1-weighted contrast-

enhanced MR image shows enhancement of the oculomotor nerve and thickening of its root entry zone; (b) follow-up study shows

virtually complete resolution of the enhancement. Reproduced with permission from Mark AS, Casselman J, Brown D, et al.

Ophthalmoplegic migraine: Reversible enhancement and thickening of the cisternal segment of the oculomotor nerve on contrast-

Figure 8.35

Eight-year-old girl with one prior episode of spontaneously resolving oculomotor nerve palsy. (a) and (b), sagittal

T1-weighted MR image before (a) and after (b) contrast administration show focal thickening and enhancement of the root exit zone

(see arrows). The symptoms resolved spontaneously within 6 weeks. Reproduced with permission from Mark AS, Casselman J,

Brown D, et al. Ophthalmoplegic migraine: Reversible enhancement and thickening of the cisternal segment of the oculomotor nerve

(www.ajnr.org)

List of Illustrations

Figure 1.1

Figure 1.14

Trepanned skull, approximately 3000 years old

A stalk of grain upon which are growing two purple excres-

cences - Claviceps purpurea, or ‘ergot fungus’

Figure 1.2

Trepanation has been done around the world

Figure 1.15

Heinrich Wiggers, a pharmacist of Göttingen, Germany

Figure 1.3

Papyrus from Thebes, Egypt (2500 BC)

Figure 1.16

In 1918, Arthur Stroll, a young chemist working in Basel,

Figure 1.4

Switzerland announced the isolation of the first pure crystalline

Cartoon, translating above papyrus

substance, ergotamine

Figure 1.5

Figure 1.17

Hippocrates described migraine circa 400 BC

Harold Wolff

Figure 1.6

Figure 1.18

‘Vision of the Heavenly City’ from a manuscript of

Illustration from Wolff’s classic paper on the effect of

Hildegard’s Scivias written at Bingen (circa 1180 AD)

ergotamine tartrate on pulsatility of cranial blood vessels and

Figure 1.7

on migraine headache

Thomas Willis, the father of neurology

Figure 1.19

Figure 1.8

Mural from wall of Roman villa, circa 300 AD

Original publication of Thomas Willis’ work, The London

Practice of Physick

Figure 1.20

Illustration from Italian medieval manuscript, by Della

Figure 1.9

Croce, dated 1583

Erasmus Darwin, Charles’ grandfather, a physician, lived in

the eighteenth century

Figure 1.21

On July 30, 1609, Samuel de Champlain, a French explorer

Figure 1.10

of New France (North America), was taken along by his Huron

Edward Liveing, the author of an influential book on

Indian hosts on a raid against the Mohawks, who lived on the

migraine from 1873, which argued that ‘megrim’ was a ‘nerve-

shores of a large lake (Lake Champlain) in what is now upper

storm’ or epileptic manifestation

New York State

Figure 1.11

Figure 1.22

Illustration by John Tenniel from Alice in Wonderland

The victorious Hurons caught a gar pike in the lake,

Figure 1.12

stripped its head of the flesh and instructed Champlain to rake

Illustration by John Tenniel from Alice in Wonderland

his painful head with the sharp teeth, sufficient to draw blood

Figure 1.13

Figure 1.23

Saint Anthony

Dutch engraving, seventeenth century

Figure 1.24

Figure 3.8

Advertisement from USA popular magazine

(Harper’s),

Fifty percent of female migraineurs and almost 40% of male

1863

migraineurs accounted for approximately 90% of lost working

day equivalents

Figure 1.25

Advertisement continued

Figure 3.9

Degree of disability due to migraine in a US study

Figure 1.26

‘Headache’. The colored etching by George Cruikshank

Figure 3.10

(English, 1792-1878) after a design by Maryatt (London, 1819)

Relationship between disability and headache pain intensity

dramatizes the impact of a headache of such intensity that one

in a group of migraine sufferers

might almost venture to diagnose it as migraine

Figure 3.11

Figure 1.27

Cumulative incidence of migraine headache, by age, in

In 1888, Isaac E. Emerson, with his background in chemistry

probands with epilepsy, relatives with epilepsy and relatives

and pharmacy, conceived the idea of a headache remedy in his

without epilepsy

drugstore in Baltimore

Figure 4.1

Figure 1.28

Leao found that noxious stimulation of the exposed cortex

Sir William Osler, Professor of Medicine at Johns Hopkins

of a rabbit produced a spreading decrease in electrical activity

University, who in his classic textbook

(first edition

1892)

that moved at a rate of 2-3 mm/min

opined that what we now call ‘tension-type headache’ was due

to ‘muscular rheumatism’ of the scalp and neck

Figure 4.2

Spreading oligemia observed with studies of cerebral blood

Figure 1.29

flow during aura

Paul Ehrlich, Nobel Prize winner in 1908, for work on

immunology and receptors

Figure 4.3

Figure 1.30

Propagation of cortical spreading depression across the

Tweedledee, drawn by John Tenniel

surface of the cat brain in vivo

Figure 2.1

Figure 4.4

Classification of headache disorders, cranial neuralgias

Spreading depression: A model of migraine

and facial pain published by the International Headache

Society

Figure 4.5

Blood oxygenation level-dependent (BOLD) changes during

Figure 3.1

an exercise-triggered migraine visual aura

Migraine characteristics from population studies of migraine

epidemiology using the diagnostic criteria of the International

Figure 4.6

Headache Society

Spreading suppression of cortical activation during migraine

visual aura

Figure 3.2

Adjusted prevalence of migraine by geographic area

Figure 4.7

BOLD changes during spontaneous migraine visual aura

Figure 3.3

Estimates of migraine prevalence in studies using the diag-

Figure 4.8

nostic criteria of the International Headache Society

Perfusion weighted imaging during migraine with aura

attacks

Figure 3.4

Women are more commonly affected by headache than men

Figure 4.9

Schematic representation of the primary sequence of the

Figure 3.5

5-HT₂ receptor

Age-specific prevalence of migraine among women and men

in a US study

Figure 4.10

Figure 3.6

Trigeminal stimulation in the rat produces plasma protein

Age- and sex-specific prevalence of migraine based on a

extravasation

meta-analytic summary of 18 population-based studies

Figure 4.11

Figure 3.7

Brainstem nuclei thought to be involved in migraine gener-

Migraine prevalence is inversely proportional to income,

ation include the periaqueductal gray matter and dorsal raphe

with the low income groups having the highest prevalence

nucleus

Figure 4.12

Figure 5.12

An experimental pain study was conducted in healthy

Increased knowledge of 5-HT receptor distribution within

volunteers to further test whether brain stem neuronal activa-

the trigeminovascular system has led to the introduction of

tion during migraine is specific to the generation of migraine

highly effective serotonergic anti-migraine drug therapies

symptoms

Figure 5.13

Figure 4.13

5-HT_1B/1D receptor immunoreactivity in human cranial and

The development of migraine, e.g. episodes in patients

coronary arteries

undergoing surgery to implant electrodes in the peri-

Figure 5.14

aqueductal gray and raphe nuclei for the treatment of chronic

Results from a preclinical intravital microscope dural

pain, generated the hypothesis that CNS dysfunction early in

plasma protein extravasation assay used to investigate the

the migraine attack could provoke changes in these brain stem

anti-migraine action of rizatriptan

nuclei

Figure 5.15

Figure 4.14

The ergots were the first 5-HT agonists used for the treat-

Brainstem nuclei and their transmitters

ment of migraine

Figure 5.1

Figure 5.16

Fortification spectra seen in migraine visual auras have been

The triptans selectively target and activate

5-HT_1B and

compared to the aerial view of the fortified, walled city of

5-HT_1D receptors

Palmonara, Italy

Figure 6.1

Figure 5.2

SUNCT is marked by very short lasting attacks (2 to 250 s)

Migraine visual auras are very similar to epileptic visual

of headache and associated autonomic symptoms

hallucinations seen here

Figure 5.3

Figure 6.2

An artist’s representation of his visual disturbance during a

Duration of individual attacks of chronic paroxysmal hemi-

migraine attack

crania (CPH) in minutes

Figure 5.4

Figure 6.3

Paresthesias are the second most common migraine aura

Duration of cluster attacks

Figure 5.5

Figure 6.4

Fortification spectra as depicted by Lashley

Cluster headache is considered a primary headache dis-

order, so there are no underlying secondary causes

Figure 5.6

Migraine aura

Figure 6.5

Cluster headache has a distinct circadian periodicity to its

Figure 5.7

attacks

Adapted from drawings by Professor Leao depicting an

expanding hemianopsia as seen by a patient experiencing

Figure 6.6

migraine visual aura

Most cluster patients have the episodic subtype, so they will

have periods of remission sometimes for years at a time

Figure 5.8

Adapted from drawings by Professor Leao depicting a

Figure 6.7

variety of visual auras described by patients

Cluster periods plotted against month of the year and

mean monthly daylight duration

Figure 5.9

Motorist’s right-sided hemianopic loss of vision

Figure 6.8

The hypothalamus or circadian clock must be involved in

Figure 5.10

cluster genesis

Pathophysiologic mechanism and postulated anti-nociceptive

site for sumatriptan and ergot alkaloids in vascular headaches

Figure 6.9

The suprachiasmatic nucleus is the human circadian clock

Figure 5.11

A primary dysfunction of brain stem pain and vascular

Figure 6.10

control centers elicits a cascade of secondary changes in

An actual cluster patient of Bayard T. Horton

vascular regulation within pain-producing intracranial structures

that ultimately manifests in headache pain and associated

Figure 6.11

symptoms

Age of cluster onset

Figure 6.12

Figure 6.26

Cluster predominantly occurs in men, although more

A comparison of trigeminovascular activation, cranial

women are being diagnosed with cluster headache

parasympathetic activation and sympathetic dysfunction

Figure 6.27

Figure 6.13

Changes in calcitonin gene-related peptide and vasoactive

Reduction in pain severity after administration of sumatrip-

intestinal polypeptide levels during migraine, cluster and chronic

tan injectable to patients with cluster headache

paroxysmal hemicrania attacks

Figure 6.14

Figure 6.28

Presently the most effective surgical therapy for cluster is

Dilation of the ophthalmic artery during a spontaneous

radiofrequency lesioning of the gasserian (trigeminal) ganglion

cluster attack

Figure 6.15

Figure 6.29

SUNCT is considered a disorder of the elderly, although

Urine melatonin levels examined for up to 14 months in

there are some reported cases younger than age 40

episodic cluster headache patients and healthy controls

Figure 6.16

Figure 6.30

SUNCT pain is located in or around the eye and/or the

Hypothalamic activation during a cluster attack on PET

forehead region

Figure 6.31

Figure 6.17

Image showing how the hypothalamus, trigeminal sensory,

SUNCT attacks tend to cluster around morning and

cranial parasympathetic and carotid sympathetic systems inter-

afternoon/evening times, although attacks can occur at any time

act to produce a cluster headache

during the day

Figure 6.32

Figure 6.18

Transition from episodic to chronic cluster and vice versa

Orbital phlebogram showing narrowing of the

superior ophthalmic vein and partial occlusion of the cavernous

Figure 6.33

sinus in an episodic cluster patient

Indomethacin is the sole treatment of choice in chronic

paroxysmal hemicrania

Figure 6.19

Figure 6.34

Chronic paroxysmal hemicrania typically starts to occur in

Orbital phlebography in a 49-year-old man with SUNCT

the teens or twenties, very similar to the age of onset of cluster

Figure 6.35

Figure 6.20

BOLD contrast-MRI of the brain of a 71-year-old woman

Both females and males who develop chronic paroxysmal

with SUNCT syndrome

hemicrania typically have their first attacks in their teens or

twenties

Figure 7.1

‘The continuum of benign recurring headache’ by Raskin

Figure 6.21

Figure 7.2

The natural history of chronic paroxysmal hemicrania is

Reclassification of headache diagnosis based on diary

unknown

review

Figure 6.22

Figure 7.3

Quality of chronic paroxysmal hemicrania pain

Pain-free response at 2 h by headache attack type in indi-

Figure 6.23

viduals with an initial diagnosis of tension-type headache and a

Chronic paroxysmal hemicrania attacks, unlike cluster

final diagnosis of migraine

attacks, occur anytime during the day and night and do not have

Figure 8.1

a predeliction for nocturnal attacks

Vascular compresssion theory for trigeminal neuralgia

Figure 6.24

Figure 8.2

Cluster is not considered to have a genetic predisposi-

Overlapping pain referral patterns from myofascial trigger

tion as is seen in migraine, but first-degree relatives have a

points in various masticatory and cervical muscles produce

14-fold increased risk of developing cluster headaches in their

typical unilateral or bilateral migraine or tension-type headache

lifetime

Figure 8.3

Figure 6.25

Referred pain from superficial masseter and upper trapez-

Cluster headache has been linked to a typical facies, eye

ius myofascial trigger points may produce unilateral or bilateral

color and certain medical conditions

tension-type and migraine headache symptoms

Figure 8.4

Figure 8.18

A 67-year-old woman with severe, continuous left occipital

A 29-year-old man with a history of sudden onset headache

pain and swallowing difficulties during the previous two weeks

associated with exertional worsening

Figure 8.5

Figure 8.19

A 37-year-old with a Wallenberg’s syndrome accompanied

Sagittal T1 W1 MRI post-enhancement venous angioma

by retro-ocular headache with autonomic features resembling

‘continuous’ cluster headache

Figure 8.20

Sagittal T1 W1 non-enhanced MRI demonstrating a Chiari II

Figure 8.6

malformation

Very severe conjunctival injection (more pronounced in the

patient’s left side) and uveitis in a 63-year-old woman present-

Figure 8.21

ing as bilateral periocular headache as the first sign of a

Two axial T1 W1 MRI non-enhancing images reveal a large

confirmed Wegener’s syndrome

hypointense, scallop-bordered mass with extension to the

foramen of Luschka

Figure 8.7

Cranio-cervical MRI study of a

39-year-old woman

Figure 8.22

complaining of brief (second-I minute) occipital headache when

A 40-year-old male with continued headache following

coughing and other Valsalva maneuvers showing tonsilar

head trauma from a motorcycle accident

descent

Figure 8.23

Figure 8.8

A patient who presented with headache with papilledema

Seventy-eight-year-old man with giant-cell arteritis

Figure 8.24

Figure 8.9

Carotid arteriogram showing an aneurysm which comes to

Seventy-year-old man with giant-cell arteritis

a point consistent with this being the area of pathology

Figure 8.10

Temporal artery biopsy specimen showing active inflamma-

Figure 8.25

tion in all three vascular layers (intima, media, adventitia)

Two axial CT scans showing diffuse blood-filled CSF and

cisternal spaces

Figure 8.11

Lyme disease most often presents with a characteristic

Figure 8.26

‘bull’s eye’ rash, erythema migrans, accompanied by non-specific

A middle-aged male with left-sided head pain and hearing

symptoms such as fever, malaise, fatigue, myalgia and joint aches

loss

(arthralgia)

Figure 8.27

Figure 8.12

Tolosa-Hunt syndrome is an idiopathic inflammatory condi-

A 22-year-old man with a one-month history of a left hemi-

tion that usually presents with painful ophthalmoplegia

cranial pain and cluster-like features

Figure 8.28

Figure 8.13

A 32-year-old woman with a four-month history of a new-

A 53-year-old female patient with a strong pain in the left

onset throbbing headache followed by sixth nerve palsy and

periocular and temporal region

ataxia

Figure 8.14

Figure 8.29

A 34-year-old, previously healthy farmer reported a mild

A 15-year-old girl with a history of progressive severe

occipital headache for 4 weeks

headache initiating

2 weeks before, associated with nausea,

vomiting and decreased consciousness

Figure 8.15

A 35-year-old man with a history of chronic daily headache

Figure 8.30

and recent-onset partial motor seizures

A middle-aged woman presenting with headaches is found

to have an empty sella

Figure 8.16

A 34-year-old woman with a history of thunderclap

Figure 8.31

headache during sport activity associated with blurred vision

Three-year-old boy with two prior episodes of sponta-

neously resolving oculomotor nerve palsy

Figure 8.17

A 60-year-old man with a six-month history of pressing/

Figure 8.32

tightening headache that antedated the development of mild

Twenty-seven-year old woman with two prior episodes of

right hemiparesis

headache and oculomotor nerve palsy

Figure 8.33

Figure 8.38

Twelve-year-old boy with two prior episodes of ophthal-

Forty-year-old female presents with sudden-onset, right-

moplegic migraine

sided headache with nausea and vomiting, decreased right facial

sensation, dysarthria, partial pointing of right arm, ataxia,

Figure 8.34

increased deep tendon reflexes and sensory loss in left hand

Twenty-three-year-old woman with one prior episode of

ophthalmoplegic migraine

Figure 8.39

Seventy-year-old male presents with bilateral parietal

Figure 8.35

headache and unsteady gait

Eight-year-old girl with one prior episode of spontaneously

resolving oculomotor nerve palsy

Figure 8.40

Twenty-six-year-old male presents with severe headache

Figure 8.36

and pulsatile tinnitus

Sixty-three-year-old female presents with right eye pain

and ptosis

Figure 8.41

Figure 8.37

Twenty-eight-year-old female with a history of Dandy-

Elderly patient presents with complaint of recent memory

Walker syndrome diagnosed at age 16 presents with sudden

difficulties, dizziness, headache and gait disturbances

onset headache