Headache Medicine, v.3, n.1, p.5-12, Jan./Feb./Mar. 2012 5

Cluster headache: review of current understandings

Cefaleia em salvas: revisão dos conhecimentos atuais

ABSTRACTABSTRACT

ABSTRACT

Cluster headache (CH) is the trigeminal autonomic cephalalgia

whose pain is considered to be one of the most severe known

to man. Although diagnosed less frequently than migraine

and tension-type headaches, CH is nonetheless an important

clinical entity, particularly given our evolving understanding

of its actual epidemiology, pathophysiology, current diagnostic

criteria and treatment approaches. We carried out a systematic

review through the United States National Library of Medicine

(PUBMED) by using the search term "cluster headache" and

the results were narrowed to manuscripts published in the last

ten years with subsequent reference searches and verification

of source data. This article presents a review of the current

understanding of the most important aspects of CH, with

emphasis on mechanisms and treatment approaches.

Keywords: Keywords:

Keywords: Cluster; Headache; Review

RESUMORESUMO

RESUMO

A cefaleia em salvas (CS) é a cefaleia trigêmino-autonômica

cuja dor é considerada uma das mais intensas conhecidas

pelo homem. Apesar de ser diagnosticada com menor frequência

do que migrânea e cefaleia do tipo tensional, a CS é de fato

uma entidade clínica importante, principalmente pelo nosso

progresso na compreensão de sua real epidemiologia,

fisiopatologia, critérios diagnósticos atuais e abordagens

terapêuticas. Nós realizamos uma revisão sistemática através

da United States National Library of Medicine (PUBMED) usando

o termo "cluster headache" e os resultados foram reduzidos aos

manuscritos publicados nos últimos dez anos com subsequente

busca das referências e verificação das fontes de informação.

Este artigo apresenta uma revisão da compreensão atual dos

principais aspectos da CS, com ênfase nos mecanismos e

abordagens terapêuticas.

alavrasalavras

alavras

chave: chave:

chave: Cefaleia; Salvas; Revisão

VIEW AND REVIEWVIEW AND REVIEW

VIEW AND REVIEW

Reinaldo Teixeira Ribeiro

, André Leite Gonçalves

, Maria Eduarda Nobre

Deusvenir de Souza Carvalho

, Mario Fernando Prieto Peres

Universidade Federal de São Paulo – UNIFESP, São Paulo, SP, Brazil

Universidade Federal Fluminense – UFF, Niteroi, RJ, Brazil

Trabalho financiado pela Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Capes

Ribeiro RT, Gonçalves AL, Nobre ME, Carvalho DS, Peres MF

Cluster headache: review of current understandings. Headache Medicine. 2012;3(1):5-12

INTRODUCTION

Cluster headache (CH) is a debilitating condition with

recurrent unilateral attacks of excruciating pain and cranial

autonomic features.

(1)

Among the most severe pain known

to man, it has considerable impact on social functioning

and quality of life.

(2)

Effective therapies are available, but

unlikely to be prescribed as it remains underdiagnosed.

(3)

HISTORY

Some authors label Nicolaes Tulp as the first to

describe a headache resembling CH in 1641, although

lacking some of the current diagnostic criteria.

(4)

The first

historical description to fulfill the International Headache

Society (IHS) diagnostic criteria of episodic CH (ECH) was

published in 1745 by van Swieten.

(5)

The unique features of CH have been more recognized

since the nineteenth century, under various eponyms and

nicknames: in 1878, "hemicrania angioparalytica";

(6)

1913, "erythroprosopalgia";

(4)

in 1926, "periodic migrainous

neuralgia", which was changed to "ciliary neuralgia" in

1936;

(7)

"erythromelalgia of the head" in 1939, which was

renamed to "histaminic cephalalgia" and "Horton's

headache" in 1952.

(6)

IHS International Classification of

Headache Disorders (ICHD) also includes "greater

superficial petrosal neuralgia" and "hemicrania

neuralgiformis chronica".

(1)

"Sphenopalatine neuralgia"

and "vidian neuralgia" are not sufficiently validated as

distinct entities,

(1)

justifying classification as CH.

(6)

6 Headache Medicine, v.3, n.1, p.5-12, Jan./Feb./Mar. 2012

RIBEIRO RT, GONÇALVES AL, NOBRE ME, CARVALHO DS, PERES MF

The name CH was used for the first time in 1952 by

Kunkle et al. to emphasize the typical recurrence pattern

of the pain

(8)

and its clinical description was broadened in

1958, being widely accepted henceforth.

(9)

In 1962, the

IHS included the term CH among the "vascular headaches

of migraine type".

(10)

First published in 1988

(11)

and revised

in 2004,

(1)

ICHD included diagnostic criteria gleaned from

observations, studies and consensus.

EPIDEMIOLOGY

The prevalence, incidence and distribution of CH in

the general population is uncertain because most studies

taken as reference applied inconsistent diagnostic criteria

and used biased methods to investigate a very large

sample.

(4)

Prior to the ICHD era, a questionnaire was used to

find a prevalence of 92/100,000 18-year-old Swedish

men in 1977.

(12)

Past medical records of neurological,

ophthalmological and otorhinolaryngological services

were reviewed with a questionnaire to find a prevalence

of 69/100,000 in San Marino between 1970 and

1984.

(13)

The first population-based study on CH to use the

IHS diagnostic criteria revised the medical records of

patients from Olmsted County, USA, between 1979 and

1981 to find an overall incidence of 9.8/100,000/year

(men 15.6; women 4.0).

(14)

Their follow-up study looking

at years 1989-1990 showed a decrease in the overall

incidence to 2.07/100,000/year (men 4.25).

(15)

San

Marino follow-up study applied the previous methodology

with the IHS diagnostic criteria to find a prevalence of

56/100,000 between 1985 and 1999 with an estimated

incidence of 2.5/100,000/year.

(16)

These studies are

biased because less than half of patients seek medical

care.

(12,17-18)

Published in 2008, a meta-analysis pooled the data

from almost all epidemiological study on CH, despite

their biases, and obtained a lifetime prevalence of 124/

100,000 and 1-year prevalence of 53/100,000.

(19)

A retrospective chart review has shown that African-

American women develop CH more commonly than African-

American men (25% and 17.4%).

(20)

Methodological issues

have affected other studies with non-caucasian populations:

Nigeria and China were studied prior to ICHD era; lay

health care workers were used in Ethiopia; and a relatively

small sample of the Malaysian population was studied.

(19)

Published in 1997, a review of 482 patients referred

to a headache center for CH showed that the male:female

(M:F) ratio was declining with time, from a ratio of 6.2:1

prior to 1960 to 2.1:1 between 1990 and 1995.

(21)

2002, similar findings were published after observing 554

patients between 1963 and 1997.

(22)

Contradictorily, a

patient sample obtained prospectively find a constant low

ratio over the decades of 2.5:1

(23)

and a meta-analysis

showed an overall ratio of 4.3:1.

(19)

Studies have reported a mean age of onset of CH

between 29.6

(16)

and 35.7

(17)

years, some with no

statistical difference between genders,

(3)

others with lower

age of onset for women compared to men (29.2 and

40.5 years).

(17)

Women seem to have a bimodal peak of

onset of CH in the third and fifth decades, whereas men

appear to have a single peak of onset in the third

decade.

(20)

ECH is more common in both genders,

affecting at least 80% of patients, while chronic CH (CCH)

is rare, having been reported in only 4-20% of

patients.

(22,24)

A meta-analysis showed a higher M:F ratio

in CCH compared to ECH (15:1 and 3,8:1), and an

overall ECH to CCH ratio of 6:1.

(19)

The mean age of

onset of CCH for women is higher than it is for men (50.8

and 31.8 years) with M:F ratio reversal with age of onset

after 50 years (0.6:1).

(22)

CH in children is rare.

(25)

PATHOPHYSIOLOGY

The first hypotheses on CH were based on the vascular

theory that oriented studies toward the trigeminal-vascular

system (TVS). Innervation of encephalic blood vessels and

meninges is mostly provided by fibers from the trigeminal

ganglion,

(26)

containing calcitonin gene-related peptide

(CGRP),

(27)

nitric oxide

(28)

and others vasodilators.

Nociceptive stimulation activates neurons in the trigeminal

nucleus caudalis (TNC), which project to multiple

subcortical and cortical regions.

(29)

The activated trigeminal

pain pathways play a major role in the modulation and

experience of pain.

(26)

Although TVS is actually activated

in CH, with increased CGRP in jugular veins during

attacks,

(27)

it is not specific and whether it is cause or

consequence is not clear.

Later, the autonomic features of CH have oriented the

studies toward the trigeminal-autonomic reflex (TAR),

generated when a stimulation of the TVS results in a rebound

activation of the parasympathetic outflow via the facial

nerve.

(30)

TAR releases acetylcholine and vasoactive

intestinal peptide (VIP), important regulators of lacrimation

and vasodilatation.

(31)

Believed to be a normal

physiological response to pain because it occurs in

migraine

(32)

and can be elicited even in healthy volunteers

Headache Medicine, v.3, n.1, p.5-12, Jan./Feb./Mar. 2012 7

CLUSTER HEADACHE: REVIEW OF CURRENT UNDERSTANDINGS

with experimental trigeminal pain,

(33)

its intensity correlates

with the severity of pain.

(26)

Despite the activation of TAR

in CH, with increased VIP in jugular veins during attacks,

(34)

increased prevalence of autonomic features points to

further autonomic dysfunctions.

Recently, the circadian rhythmicity of CH has oriented

the studies toward the hypothalamus. The suprachiasmatic

nucleus (SCN) controls the biological clock, projecting

luminosity information to the pineal gland where melatonin

is produced in a circadian rhythm to act satisfactorily.

(26)

CH reduces the melatonin production until its nocturnal

peak disappears,

(35)

altering biological rhythms and

decreasing its additional analgesic effect related to

gabaergic reinforcement,

(36)

calcium modulation

(37)

and

prostaglandin synthesis inhibition.

(38)

Occasional hyper-

sexuality, hyperphagia

(39)

and laboratory evidence of

perturbations in the hypothalamic-pituitary axis

(35,40)

suggest

hypothalamic dysfunction beyond the SCN. Functional

neuroimaging studies have shown an activation of the

ipsilateral posterior hypothalamus during CH attacks

(41)

with neuronal loss or dysfunction,

(42)

while structural

neuroimaging studies demonstrated an increase in the gray

matter volume of the same hypothalamic area in CH

patients.

(43)

Hypothalamus receives connections from the frontal

cortex and projects them to brainstem areas that have

been implicated in the modulation of pain.

(44)

The posterior

hypothalamus contains connections to the TNC,

(45)

to the

parasympathetic

(46)

and sympathetic

(47)

systems that

modulate TVS and TAR. It produces excitatory neuropeptides

orexins A and B with orexin-A demonstrating equal affinity

for orexin receptors 1 and 2, while orexin-B has a 10-

fold higher affinity for receptor 2.

(26)

Activation of these

receptors has been shown to differentially modulate inputs

to the TNC,

(48)

where receptor 1 elicits an antinociceptive

effect and receptor 2, whose gene (HCRTR2) 1246G>A

polymorphism has been associated with increased risk of

CH,

(49)

elicits a pronociceptive effect. The orexinergic

system in the posterior hypothalamus is modulated by the

SCN,

(26)

which explains how a dysfunctional biological

pacemaker can originate periodic attacks of trigeminal

pain with prominent autonomic features and endocrine

abnormalities.

CLINICAL ASPECTS

Studies have shown that CH attacks usually lasts

between 15 minutes and 3 hours, which helps to

differentiate it from migraine. The pain is recurrent with a

frequency from one every other day to eight per day.

Usually described as a very severe unilateral orbital pain,

it may be located in other areas within the first trigeminal

branch territory.

(23,50)

The duration, frequency, severity and

localization of attacks were included in the ICHD diagnostic

criteria due to their marked constancy.

(1)

However, about

15% of patients had attacks lasting less than 15 minutes

or more than 3 hours,

(50)

the pain sometimes extends to

other trigeminal branches territories or even the occipito-

cervical region, and at least 15% of patients experience a

change of attack side during their clinical course,

(23)

which

is notably common in CCH with 50.8% of side shift.

(51)

CH pain rises and ends abruptly, often leaving

patients asymptomatic between attacks. There may be a

continuous discomfort on the affected side in severe CCH

or ECH with numerous daily attacks.

(52)

The presence of

cluster peaks around solstices

(53)

and dramatic regularity

of timed attacks on day or during sleep (circannual and

circadian rhythmicity) are not included in the ICHD

diagnostic criteria because they are not seen in all patients.

Ipsilateral autonomic signs are another distinctive feature

of CH with parasympathetic hyperactivity and sympathetic

hypoactivity

(54)

included in the ICHD diagnostic criteria. A

sense of restlessness or agitation is so typical of a CH

attack,

(55)

only approximately 3% of patients can lie still

during a bout,

(56)

that it was accepted as an alternative

criterion when the autonomic signs are subtle or even absent

in up to 7% of patients.

(50,54)

Other relevant features of CH include few recognized

triggers such as alcohol, smoking, nitrates, increase in body

heat, hypoxia and napping, which occur only during cluster

periods. Symptoms generally attributed to migraine without

aura can be observed in approximately 50% of patients,

whilst up to 14% of patients report aura symptoms, with

transient visual, motor or sensory disturbances preceding

an attack.

(23)

Nausea and vomiting are more common in

women with CH than men (46.9% and 17.4%)

(20)

and

auras have been reported in 20% of patients with CCH.

(52)

Patients with CH and visual symptoms have been reported

since 1972,

(57)

but the first four cases of hemiplegic cluster

were published only thirty years later, in 2002.

(58)

Graham

(59)

was the first to notice that some patients

have a leonine facies with broad head and reddish thick

furrowed brows and cheeks. Rare case reports have

described patients with "CH sine headache".

(60)

Increased

prevalence of obstructive sleep apnea (OSA),

(61,62)

patent

foramen ovale

(63)

and right-to-left shunt64 has been

reported in patients with CH. OSA prevalence in CH

patients has ranged between 58.562 and 80.64%

(61)

with

8 Headache Medicine, v.3, n.1, p.5-12, Jan./Feb./Mar. 2012

some reports of benefit of continuous positive airway

pressure to patients suffering from both conditions.

(62,65)

However, activation of temperature-sensitive neurons in

the preoptic/anterior hypothalamus suppress the activity

of the airway dilator muscles and diaphragmatic muscle

during non-rapid eye movement sleep,

(66)

suggesting that

OSA and CH are parallel processes generated in different

areas of the hypothalamus.

(67)

Early studies on smoking in CH were conducted on a

small number of patients with similar high prevalence until

1990, when changing habits in the population determined

a sustained decrease in the prevalence of smoking.

(68)

Italian cohort demonstrated that the increased propensity

of CH patients to smoking remained almost unaltered

through time:

(69)

the prevalence of smoking in Italy in 1975

and in 1993 was 53.2% and 35% for men, and 16.3%

and 19.2% for women; whereas the prevalence of smoking

in CH patients before 1990 and after 1990 was 89.4%

and 87.8% for men, and 56.5% and 57.1% for women.

Two small case series hypothesized that smoking may

impact the perpetuation and onset of CH.

(70,71)

When compared with a group of matched patients

with tension-type headache (TTH), ECH patients showed

a higher frequency of anxiety disorders (23.8%) during

the year preceding the onset of headaches and significantly

greater anxiety scores during the clinical episode than TTH

patients (4.8%).

(72)

Studies demonstrated that ECH patients

presented impaired neuropsychological evaluations on

verbal memory, visuospatial memory and executive

performance.

(72,73)

Those studies have shown that this

cognitive decline was not related to a mood disorder and

not statistically different from those presented by patients

with migraine

(73)

or TTH.

(72)

Further studies confirm that all

cognitive impairments in CH are transient, mild, and do

not relevantly contribute to morbidity.

(74)

DIAGNOSIS

ICHD diagnostic criteria:ICHD diagnostic criteria:

ICHD diagnostic criteria:

(1)(1)

(1)

A. At least five attacks fulfilling B through D.

B. Severe or very severe unilateral orbital, supra-

orbital and/or temporal pain lasting 15 to 180 minutes if

untreated.

C. Headache is accompanied by at least one of the

following: ipsilateral conjunctival injection and/or

lacrimation; ipsilateral nasal congestion and/or rhinorrhea;

ipsilateral eyelid edema; ipsilateral forehead and facial

sweating; ipsilateral miosis and/or ptosis; a sense of

restlessness or agitation.

D. Attacks have a frequency from one every other

day to eight per day.

E. Not attributed to another disorder.

Additional ICHD diagnostic criteria for ECH and

CCH:

(1)

A. All fulfilling criteria A through E of CH.

B. At least two cluster periods lasting from 7 to 365

days and separated by pain free remissions of > 1 month

(for ECH); Attacks recur for > 1 year without remission

periods or with remission periods lasting < 1 month (for

CCH).

A review of 56 cases of symptomatic trigeminal

autonomic cephalalgias (TACs) found a wide range of

both intracerebral and extracerebral cranial and cervical

lesions and diseases that could be associated with them,

and a abnormal neurological examination required

additional neuroimaging in almost all reports.

(75)

A first

attack suggestive of CH and all atypical cases must always

be thoroughly investigated, but when the history is so typical

with numerous periods, attacks and without interictal

neurological deficits, complimentary investigation is not

mandatory.

Differential diagnosis includes migraine, other TACs,

trigeminal neuralgia (TN) and hypnic headache (HH).

Migraine attacks are longer,

(1)

sometimes bilateral, with

female preponderance, with prostration and quietness, and

triggered by hormonal and dietary triggers other than

alcohol.

(23)

Other TACs differs from CH by the shorter length

and higher frequency of their attacks or absolute response

to at least 150 mg of indomethacin.

(1,23)

TN attacks are

briefer and more frequent, rarely affecting the first trigeminal

branch territory, with female preponderance, trigger zones

and without autonomic signs.

(1,76)

HH affects elderly patients

with exclusively sleep attacks, usually bilateral, diffuse and

without autonomic signs.

(1)

When CH symptoms are

associated or overlapped with another headache, such as

cluster-migraine

(77)

and cluster-tic,

(78)

the patient should

receive a medication efficient for both conditions. Overlap

between attack duration in TACs is expected,

(1)

but some

overlap in treatment response among the TACs has

emerged

(79)

and some clinical overlap includes coexistence

of CH and chronic or episodic paroxysmal hemicrania

(EPH),

(80)

CH and hemicrania continua,

(81)

and a case of

EPH with seasonal variation similar to CH.

(82)

TREATMENT

CH treatment can be divided in abortive, transitional

and preventive.

(56)

The goal is to suppress attacks and to

GONÇALVES AL, NOBRE ME, CARVALHO DS, PERES MF

Headache Medicine, v.3, n.1, p.5-12, Jan./Feb./Mar. 2012 9

maintain remission over the expected duration of the cluster

period.

(56,83)

First option for the abortive therapy of CH: pure

oxygen inhalation via a non-rebreathing facial mask with

a flow rate of at least 7 l/min over 15 minutes.

(83)

It is the

safest method available, supported by a Cochrane

review

(84)

and a randomized controlled trials (RCT),

(85)

which suggested that normal pressure oxygen therapy was

likely to be effective in up to 78% of the cases. Although

subcutaneous injection of sumatriptan 6 mg is the most

effective medication for the abortive therapy in up to 75%

of all patients,

(56,83,86)

should only be considered for patients

without cardiovascular risk. Alternatives include nasal

sprays of sumatriptan 20 mg or zolmitriptan 5 mg with

slower onset, but being able to treat more attacks in a day.

(83)

Subcutaneous octreotide 100 mcg and oral zolmitriptan

5-10 mg can be tried with some efficacy,

(83,86)

while

intranasal lidocaine 4-10%, ergotamine,

(86)

oral olanzapine

2.5-10 mg and suppositories of chlorpromazine or

indomethacin

(56)

lack RCTs and they should be reserved to

intractable CH attacks.

Without adequate RCTs about transitional therapy,

(83,86)

review of open studies and case series has confirmed the

clinically well known efficacy of corticosteroids given under

different short course regimens in up to 80% of all CH

patients.

(87)

Dihydroergotamine has also been considered

for a more laborious transitional therapy at daily

intramuscular injections of 1 mg for a week or intravenous

infusion of 1 mg twice or thrice a day for 3 days.

Naratriptan 2.5 mg or frovatriptan 2.5 mg have been

proposed as more tolerable with oral administration of

one tablet twice a day for a week.

(56)

Verapamil is the first choice in preventive therapy for

CH, at a daily dose of at least 240 mg.

(56,83,86)

It can be

used with other abortive and preventive medications for

CH safely,

(64)

although serial electrocardiograms are

recommended during titration

(56,83,86)

and should probably

be monitored due to eventual PR prolongation during

maintenance therapy.

(88)

Lithium 300-900 mg,

(56,83,86)

melatonin 10 mg, topiramate 50-400 mg,

(56,83)

methysergide 4-8 mg, pizotifen 3 mg,

(83)

intranasal

capsaicin, and intranasal civamide

(83,86)

are drugs of

second choice with decreasing level or recommendation.

Other third choice agents have been reported to be

effective: baclofen, valproate,

(56,83,86)

gabapentin,

transdermal clonidine, leuprolide,

(56,86)

tizanidine,

(86)

mycophenolate, clomiphene, and testosterone.

(56)

Interventional therapy includes greater occipital nerve

(GON) blockade,

(56,83,86,89)

botulinum toxin (BTX)

injections,

(83,86,89)

radiofrequency (RF) thermocoagulation,

GON stimulation,

(56,83)

and hypothalamic stimulation.

(56,83)

GON injections have recently been shown to be efficacious,

(89)

either using an anesthetic alone or associated with

steroids,

(56,89)

a good alternative to both abortive and

transitional therapies.

(56)

BTX injections in some muscles

ipsilateral to the pain have shown only limited success in

CCH patients.

(89)

RF thermocoagulation of the trigeminal

ganglion is the most commonly used surgical technique,

among the best options for pain relief with only approximately

30% of procedure failure.

(56)

GON stimulation has been

studied in 8 patients with refractory CCH and it may take up

to 5 months to show any effect, suggesting more central than

peripheral neuromodulation.

(56,90)

Stimulation of the posteri-

or inferior hypothalamus ipsilateral to the pain is now

established as a treatment for selected refractory cases of

CCH and almost every patient has had a remarkable

reduction in CH frequency.

(56,91)

As of 2009 April, 54

patients have been submitted to hypothalamic stimulation

and 50% to 75% of CCH patients eligible to improvement

evaluation, as the response may take weeks to months,

were pain free or almost pain free.

(91)

CONCLUSION

A rare disease when compared to migraine and TTH,

CH gets less attention from private initiatives and public

healthcare policies. Improvement in the management of

CH should ultimately affect the quality of life of patients

suffering from it.

REFERENCES

1. The International Classification of Headache Disorders: 2nd

edition. Cephalalgia. 2004;24 Suppl 1:9-160.

2. Jensen RM, Lyngberg A, Jensen RH. Burden of cluster headache.

Cephalalgia. 2007 Jun;27(6):535-41.

3. van Vliet JA, Eekers PJ, Haan J, Ferrari MD; Dutch RUSSH Study

Group. Features involved in the diagnostic delay of cluster

headache. J Neurol Neurosurg Psychiatry. 2003 Aug;74(8):

1123-5.

4. Broner SW, Cohen JM. Epidemiology of cluster headache. Curr

Pain Headache Rep. 2009 Apr;13(2):141-6.

5. Isler H. Episodic cluster headache from a textbook of 1745: van

Swieten's classic description. Cephalalgia. 1993 Jun;13(3):

172-4.

6. Goadsby PJ. Trigeminal autonomic cephalgias (TACs). Acta Neurol

Belg. 2001 Mar;101(1):10-9.

7. Boes CJ, Capobianco DJ, Matharu MS, Goadsby PJ. Wilfred Harris'

early description of cluster headache. Cephalalgia. 2002

May;22(4):320-6.

CLUSTER HEADACHE: REVIEW OF CURRENT UNDERSTANDINGS

10 Headache Medicine, v.3, n.1, p.5-12, Jan./Feb./Mar. 2012

8. Kunkle EC, Pfeiffer JB Jr, Wilhoit WM, Hamrick LW Jr. Recurrent

brief headache in cluster pattern. Trans Am Neurol Assoc. 1952;

56(77th Meeting):240-3.

9. Friedman AP, Mikropoulos HE. Cluster headaches. Neurology.

1958 Sep;8(9):653-63.

10. Classification of Headache. Ad Hoc Committee on Classification

of Headache. JAMA. 1962;179(9):717-8.

11. Classification and diagnostic criteria for headache disorders,

cranial neuralgias and facial pain. Headache Classification

Committee of the International Headache Society. Cephalalgia.

1988;8 Suppl 7:1-96.

12. Ekbom K, Ahlborg B, Schele R. Prevalence of migraine and

cluster headache in Swedish men of 18. Headache. 1978 Mar;

18(1):9-19.

13. D'Alessandro R, Gamberini G, Benassi G, Morganti G, Cortelli

P, Lugaresi E. Cluster headache in the Republic of San Marino.

Cephalalgia. 1986 Sep;6(3):159-62.

14. Swanson JW, Yanagihara T, Stang PE, O'Fallon WM, Beard CM,

Melton LJ 3rd, et al. Incidence of cluster headaches: a population-

based study in Olmsted County, Minnesota. Neurology. 1994

Mar;44(3 Pt 1):433-7.

15. Black DF, Swanson JW, Stang PE. Decreasing incidence of cluster

headache: a population-based study in Olmsted County,

Minnesota. Headache. 2005 Mar;45(3):220-3.

16. Tonon C, Guttmann S, Volpini M, Naccarato S, Cortelli P,

D'Alessandro R. Prevalence and incidence of cluster headache

in the Republic of San Marino. Neurology. 2002 May

14;58(9):1407-9.

17. Torelli P, Beghi E, Manzoni GC. Cluster headache prevalence in

the Italian general population. Neurology. 2005 Feb

8;64(3):469-74.

18. Sjaastad O, Bakketeig LS. Cluster headache prevalence. Vaga

study of headache epidemiology. Cephalalgia. 2003

Sep;23(7):528-33.

19. Fischera M, Marziniak M, Gralow I, Evers S. The incidence

and prevalence of cluster headache: a meta-analysis of

population-based studies. Cephalalgia. 2008 Jun;28(6):

614-8.

20. Rozen TD, Niknam RM, Shechter AL, Young WB, Silberstein SD.

Cluster headache in women: clinical characteristics and

comparison with cluster headache in men. J Neurol Neurosurg

Psychiatry. 2001 May;70(5):613-7.

21. Manzoni GC. Male preponderance of cluster headache is

progressively decreasing over the years. Headache. 1997 Oct;

37(9):588-9.

22. Ekbom K, Svensson DA, Traff H, Waldenlind E. Age at onset and

sex ratio in cluster headache: observations over three decades.

Cephalalgia. 2002 Mar;22(2):94-100.

23. Bahra A, May A, Goadsby PJ. Cluster headache: a prospective

clinical study with diagnostic implications. Neurology. 2002 Feb

12;58(3):354-61.

24. Ekbom K, Waldenlind E. Cluster headache in women: evidence

of hypofertility(?) Headaches in relation to menstruation and

pregnancy. Cephalalgia. 1981 Sep;1(3):167-74.

25. Majumdar A, Ahmed MA, Benton S. Cluster headache in children-

-experience from a specialist headache clinic. Eur J Paediatr

Neurol. 2009 Nov;13(6):524-9.

26. Holland PR, Goadsby PJ. Cluster headache, hypothalamus, and

orexin. Curr Pain Headache Rep. 2009 Apr;13(2):147-54.

27. Tfelt-Hansen P, Le H. Calcitonin gene-related peptide in blood:

is it increased in the external jugular vein during migraine and

cluster headache? A review. J Headache Pain. 2009

Jun;10(3):137-43.

28. Olesen J. The role of nitric oxide (NO) in migraine, tension-type

headache and cluster headache. Pharmacol Ther. 2008

Nov;120(2):157-71.

29. Hardebo JE. How cluster headache is explained as an

intracavernous inflammatory process lesioning sympathetic

fibers. Headache. 1994 Mar;34(3):125-31.

30. May A, Goadsby PJ. The trigeminovascular system in humans:

pathophysiologic implications for primary headache syndromes

of the neural influences on the cerebral circulation. J Cereb

Blood Flow Metab. 1999 Feb;19(2):115-27.

31. Goadsby PJ, Matharu MS, Boes CJ. SUNCT syndrome or

trigeminal neuralgia with lacrimation. Cephalalgia. 2001

Mar;21(2):82-3.

32. Obermann M, Yoon MS, Dommes P, Kuznetsova J, Maschke M,

Weimar C, et al. Prevalence of trigeminal autonomic symptoms

in migraine: a population-based study. Cephalalgia. 2007

Jun;27(6):504-9.

33. Frese A, Evers S, May A. Autonomic activation in experimental

trigeminal pain. Cephalalgia. 2003 Feb;23(1):67-8.

34. Goadsby PJ, Edvinsson L. Human in vivo evidence for

trigeminovascular activation in cluster headache. Neuropeptide

changes and effects of acute attacks therapies. Brain. 1994

Jun;117 (Pt 3):427-34.

35. Chazot G, Claustrat B, Brun J, Jordan D, Sassolas G, Schott B.

A chronobiological study of melatonin, cortisol growth hormone

and prolactin secretion in cluster headache. Cephalalgia. 1984

Dec;4(4):213-20.

36. Wu FS, Yang YC, Tsai JJ. Melatonin potentiates the GABA(A)

receptor-mediated current in cultured chick spinal cord neurons.

Neurosci Lett. 1999 Feb 5;260(3):177-80.

37. Zhang QZ, Zhang JT. Inhibitory effects of melatonin on free

intracellular calcium in mouse brain cells. Zhongguo Yao Li Xue

Bao. 1999 Mar;20(3):206-10.

38. Bettahi I, Guerrero JM, Reiter RJ, Osuna C. Physiological

concentrations of melatonin inhibit the norepinephrine-induced

activation of prostaglandin E2 and cyclic AMP production in rat

hypothalamus: a mechanism involving inhibiton of nitric oxide

synthase. J Pineal Res. 1998 Aug;25(1):34-40.

39. Dodick DW, Capobianco DJ. Treatment and management of cluster

headache. Curr Pain Headache Rep. 2001 Feb;5(1):83-91.

40. Strittmatter M, Hamann GF, Grauer M, Fischer C, Blaes F,

Hoffmann KH, et al. Altered activity of the sympathetic nervous

system and changes in the balance of hypophyseal, pituitary and

adrenal hormones in patients with cluster headache.

Neuroreport. 1996 May 17;7(7):1229-34.

41. Morelli N, Pesaresi I, Cafforio G, Maluccio MR, Gori S, Di Salle

F, et al. Functional magnetic resonance imaging in episodic cluster

headache. J Headache Pain. 2009 Feb;10(1):11-4.

42. Wang SJ, Lirng JF, Fuh JL, Chen JJ. Reduction in hypothalamic

1H-MRS metabolite ratios in patients with cluster headache. J

Neurol Neurosurg Psychiatry. 2006 May;77(5):622-5.

GONÇALVES AL, NOBRE ME, CARVALHO DS, PERES MF

Headache Medicine, v.3, n.1, p.5-12, Jan./Feb./Mar. 2012 11

43. May A, Ashburner J, Buchel C, McGonigle DJ, Friston KJ,

Frackowiak RSJ, et al. Correlation between structural and

functional changes in brain in an idiopathic headache syndrome.

Nat Med. 1999 Jul;5(7):836-8.

44. Millan MJ. Descending control of pain. Prog Neurobiol. 2002

Apr;66(6):355-474.

45. Malick A, Strassman RM, Burstein R. Trigeminohypothalamic

and reticulohypothalamic tract neurons in the upper cervical

spinal cord and caudal medulla of the rat. J Neurophysiol. 2000

Oct;84(4):2078-112.

46. Hosoya Y, Matsushita M, Sugiura Y. A direct hypothalamic

projection to the superior salivatory nucleus neurons in the rat.

A study using anterograde autoradiographic and retrograde HRP

methods. Brain Res. 1983 May 5;266(2):329-33.

47. Pyner S, Coote JH. Identification of branching paraventricular

neurons of the hypothalamus that project to the

rostroventrolateral medulla and spinal cord. Neuroscience.

2000;100(3):549-56.

48. Bartsch T, Levy MJ, Knight YE, Goadsby PJ. Differential modulation

of nociceptive dural input to [hypocretin] orexin A and B recep-

tor activation in the posterior hypothalamic area. Pain. 2004

Jun;109(3):367-78.

49. Rainero I, Gallone S, Rubino E, Ponzo P, Valfre W, Binello E, et

al. Haplotype analysis confirms the association between the

HCRTR2 gene and cluster headache. Headache. 2008

Jul;48(7):1108-14.

50. Torelli P, Cologno D, Cademartiri C, Manzoni GC. Application

of the International Headache Society classification criteria in

652 cluster headache patients. Cephalalgia. 2001

Mar;21(2):145-50.

51. Leone M, D'Amico D, Frediani F, Torri W, Sjaastad O, Bussone

G. Clinical considerations on side-locked unilaterality in long-

lasting primary headaches. Headache. 1993 Jul-

Aug;33(7):381-4.

52. Donnet A, Lanteri-Minet M, Guegan-Massardier E, Mick G,

Fabre N, Géraud G, et al. Chronic cluster headache: a French

clinical descriptive study. J Neurol Neurosurg Psychiatry. 2007

Dec;78(12):1354-8.

53. Kudrow L. The cyclic relationship of natural illumination to cluster

period frequency. Cephalalgia. 1987;7 Suppl 6:76-8.

54. Ekbom K. Evaluation of clinical criteria for cluster headache with

special reference to the classification of the International

Headache Society. Cephalalgia. 1990 Aug;10(4):195-7.

55. Torelli P, Manzoni GC. Pain and behaviour in cluster headache.

A prospective study and review of the literature. Funct Neurol.

2003 Oct-Dec;18(4):205-10.

56. Rozen TD. Trigeminal autonomic cephalalgias. Neurol Clin.

2009 May;27(2):537-56.

57. Horven I, Nornes H, Sjaastad O. Different corneal indentation

pulse pattern in cluster headache and migraine. Neurology. 1972

Jan;22(1):92-8.

58. Siow HC, Young WB, Peres MF, Rozen TD, Silberstein SD.

Hemiplegic cluster. Headache. 2002 Feb;42(2):136-9.

59. Graham JR. Cluster headache: the relation to arousal, relaxation,

and autonomic tone. Headache. 1990 Feb;30(3):145-51.

60. Russell MB. Cluster headache sine headache: two new cases in

one family. Cephalalgia. 2002 Feb;22(1):1.

61. Graff-Radford SB, Newman A. Obstructive sleep apnea and

cluster headache. Headache. 2004 Jun;44(6):607-10.

62. Nobre ME, Leal AJ, Filho PM. Investigation into sleep disturbance

of patients suffering from cluster headache. Cephalalgia. 2005

Jul;25(7):488-92.

63. Dalla Volta G, Guindani M, Zavarise P, Griffini S, Pezzini A,

Padovani A. Prevalence of patent foramen ovale in a large series

of patients with migraine with aura, migraine without aura and

cluster headache, and relationship with clinical phenotype. J

Headache Pain. 2005 Sep;6(4):328-30.

64. Morelli N, Gori S, Cafforio G, Gallerini S, Baldacci F, Orlandi

G, et al. Prevalence of right-to-left shunt in patients with cluster

headache. J Headache Pain. 2005 Sep;6(4):244-6.

65. Ludemann P, Frese A, Happe S, Evers S. Sleep disordered breathing

in patients with cluster headache. Neurology. 2001 Apr

10;56(7):984.

66. McGinty D, Metes A, Alam MN, Megirian D, Stewart D, Szymusiak

R. Preoptic hypothalamic warming suppresses laryngeal dilator

activity during sleep. Am J Physiol Regul Integr Comp Physiol.

2004 Jun;286(6):R1129-37.

67. Graff-Radford SB, Teruel A. Cluster headache and obstructive

sleep apnea: are they related disorders? Curr Pain Headache

Rep. 2009 Apr;13(2):160-3.

68. Schurks M, Diener HC. Cluster headache and lifestyle habits.

Curr Pain Headache Rep. 2008 Apr;12(2):115-21.

69. Manzoni GC. Cluster headache and lifestyle: remarks on a

population of 374 male patients. Cephalalgia. 1999 Mar;

19(2):88-94.

70. Millac P, Akhtar N. Cigarette smoking and cluster headaches.

Headache. 1985 Jun;25(4):223.

71. Rozen TD. Childhood exposure to second-hand tobacco smoke

and the development of cluster headache. Headache. 2005

Apr;45(4):393-4.

72. Jorge RE, Leston JE, Arndt S, Robinson RG. Cluster headaches:

association with anxiety disorders and memory deficits.

Neurology. 1999 Aug 11;53(3):543-7.

73. Meyer JS, Thornby J, Crawford K, Rauch GM. Reversible cognitive

decline accompanies migraine and cluster headaches. Headache.

2000 Sep;40(8):638-46.

74. Evers S. Cognitive processing in cluster headache. Curr Pain

Headache Rep. 2005 Apr;9(2):109-12.

75. Wilbrink LA, Ferrari MD, Kruit MC, Haan J. Neuroimaging in

trigeminal autonomic cephalgias: when, how, and of what? Curr

Opin Neurol. 2009 Jun;22(3):247-53.

76. Bennetto L, Patel NK, Fuller G. Trigeminal neuralgia and its

management. BMJ. 2007 Jan 27;334(7586):201-5.

77. Applebee AM, Shapiro RE. Cluster-migraine: does it exist? Curr

Pain Headache Rep. 2007 Apr;11(2):154-7.

78. Monzillo PH, Sanvito WL, Peres MF. Cluster-tic syndrome: two

case reports. Arq Neuropsiquiatr. 1996 Jun;54(2):284-7.

79. Leone M, Bussone G. Pathophysiology of trigeminal

autonomic cephalalgias. Lancet Neurol. 2009 Aug;8(8):755-

64.

80. Shah ND, Prakash S. Coexistence of cluster headache and

paroxysmal hemicrania: does it exist? A case report and literature

review. J Headache Pain. 2009 Jun;10(3):219-23.

CLUSTER HEADACHE: REVIEW OF CURRENT UNDERSTANDINGS

12 Headache Medicine, v.3, n.1, p.5-12, Jan./Feb./Mar. 2012

81. Rozen TD. Verapamil-responsive hemicrania continua in a patient

with episodic cluster headache. Cephalalgia. 2006

Mar;26(3):351-3.

82. Veloso GG, Kaup AO, Peres MF, Zukerman E. Episodic

paroxysmal hemicrania with seasonal variation: case report and

the EPH-cluster headache continuum hypothesis. Arq

Neuropsiquiatr. 2001 Dec;59(4):944-7.

83. May A, Leone M, Afra J, Linde M, Sándor PS, Evers S, et al. EFNS

guidelines on the treatment of cluster headache and other

trigeminal-autonomic cephalalgias. Eur J Neurol. 2006

Oct;13(10):1066-77.

84. Bennett MH, French C, Schnabel A, Wasiak J, Kranke P.

Normobaric and hyperbaric oxygen therapy for migraine and

cluster headache. Cochrane Database Syst Rev.

2008(3):CD005219.

85. Cohen AS, Burns B, Goadsby PJ. High-flow oxygen for treatment

of cluster headache: a randomized trial. JAMA. 2009 Dec

9;302(22):2451-7.

86. Tyagi A, Matharu M. Evidence base for the medical treatments

used in cluster headache. Curr Pain Headache Rep. 2009

Apr;13(2):168-78.

87. Ekbom K, Hardebo JE. Cluster headache: aetiology, diagnosis

and management. Drugs. 2002;62(1):61-9.

88. Cohen AS, Matharu MS, Goadsby PJ. Electrocardiographic

abnormalities in patients with cluster headache on verapamil

therapy. Neurology. 2007 Aug 14;69(7):668-75.

89. Ailani J, Young WB. The role of nerve blocks and botulinum

toxin injections in the management of cluster headaches. Curr

Pain Headache Rep. 2009 Apr;13(2):164-7.

90. Burns B, Watkins L, Goadsby PJ. Treatment of medically

intractable cluster headache by occipital nerve stimulation: long-

term follow-up of eight patients. Lancet. 2007 Mar

31;369(9567):1099-106.

91. Sillay KA, Sani S, Starr PA. Deep brain stimulation for medically

intractable cluster headache. Neurobiol Dis. 2010;38:361-

368.

GONÇALVES AL, NOBRE ME, CARVALHO DS, PERES MF

Correspondence

einaldo Teinaldo T

einaldo T

eixeira Ribeiroeixeira Ribeiro

eixeira Ribeiro

Universidade Federal de São Paulo

Rua Borges Lagoa, 71, ap.93 – Vila Clementino

04038-030, São Paulo, SP, Brazil

Telephone/Fax: +55 11 35828744.

Email:reinaldo_ribeiro@yahoo.com.br

Received: 2/5/2012

Accepted: 3/1/2012