BMJ 2012;344:e2407 doi: 10.1136/bmj.

e2407 (Published 11 April 2012) Page 1 of 9

Clinical Review

CLINICAL REVIEW

Cluster headache
12 2
Alexander D Nesbitt research fellow , Peter J Goadsby professor of clinical neurology

Surrey Sleep Research Centre, University of Surrey, Guildford GU2 7XP, UK; 2Department of Neurology, University of California, San Francisco,
1

CA 94115, USA

Few, if any, medical disorders are more painful than cluster (box 2).3 However, about 10% of patients have the chronic form
headache. Previously termed migrainous neuralgia, it was last of the disorder and have continuous attacks with no respite.
reviewed in the BMJ nearly 50 years ago.1 At that time, the A well described physiological reflex arc, the trigeminovascular
authors stressed the importance of covering the topic in a general reflex, potentiates the trigeminal pain and cranial autonomic
medical journal to aid recognition. Despite this remarkably features of cluster headache by positive feedback mechanisms
prescient view, and the extreme and stereotyped nature of its (fig 2⇓).8
presentation, cluster headache is still commonly misdiagnosed.
Functional imaging studies have detected activation ipsilateral
Without a clear diagnosis, affected patients can wait many years
to the pain in the region of the posterior hypothalamus (fig 2),
before receiving adequate help, and they often endure
which may have a pivotal role in integrating the pain, cranial
unnecessary and unhelpful attempts at treatment before gaining
autonomic features, and unique timing of cluster headache.11
any relief.2
Patients describe the pain of a single attack as being worse than
anything else they have experienced, including childbirth. Many
Who gets it?
endure repeated attacks, lasting up to three hours, every single Pooled data from epidemiological studies give cluster headache
day. The severity of the pain has earned it the sobriquet “suicide a lifetime prevalence of 0.12%, with data from a door to door
headache,” although in our experience this is a rare occurrence study in Norway showing a one year prevalence of 0.3%.12 The
in this exceptional patient group. condition has a heritable tendency in some families, and first
The management of this condition differs from that of other degree relatives of affected people have an estimated 14-48-fold
headache disorders. This article will review the clinical entity increased risk of developing it.13
of cluster headache by highlighting its unique and defining The male to female ratio varies between 2.5:1 and 3.5:1.4 14
characteristics as an aid to correct diagnosis, before critically Patients typically start to develop the attacks in their third to
appraising current treatment methods. In doing so, we outline fifth decade, although patients as young as 4 years and as old
an up to date streamlined management strategy aimed at limiting as 96 years can be affected. There seems to be an association
the considerable burden that this condition places on patients. with smoking, with around 65% of patients being active smokers
What is cluster headache? or reporting a history of smoking.14 However, a causative link
to smoking seems unlikely, because smoking cessation does
Cluster headache is a primary headache disorder classified with not seem to alter the clinical course of the disorder and cannot
similar conditions known as trigeminal autonomic cephalalgias easily account for the disorder in children.
(table⇓).3 These conditions are typified by recurrent attacks of The natural course of cluster headache can be difficult to predict,
unilateral pain, which are very severe and usually involve the with some people showing a bidirectional transition between
orbital or periorbital region innervated by the first (ophthalmic) the episodic and chronic form of the condition. Less frequent
division of the trigeminal nerve. Characteristic signs and bouts of attacks and more prolonged, and sometimes permanent,
symptoms of activation of the cranial autonomic pathways periods of remission can occur with advancing age.
accompany the pain on the same side: lacrimation, conjunctival
injection, nasal congestion or rhinorrhoea (or both), ptosis or
miosis (or both), and periorbital oedema (box 1; fig 1⇓). How is cluster headache diagnosed?
The term cluster headache originates from the tendency of The diagnosis of cluster headache is made by a careful history
attacks to cluster together into bouts that last several weeks. In that elicits the clinical features of short lasting unilateral pain
the episodic form of the disorder, the bouts can occur at certain with cranial autonomic disturbances (box 2), and the cyclical
times of year, often with a seasonal predilection.4 They are nature of the bouts in which the attacks occur. Descriptions of
separated by periods of remission, which last at least a month

Correspondence to: P J Goadsby pgoadsby@headache.ucsf.edu

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CLINICAL REVIEW

Summary points
Cluster headache is an excruciatingly painful primary headache disorder, which places an exceptional burden on those affected
Attacks are one sided, generally last 15 minutes to three hours, and have a characteristic set of cranial autonomic features, which are
accompanied by agitation
Attacks occur from once every other day to eight times daily, in bouts that last several weeks, usually with complete remission between
bouts
Treat acute attacks with high flow oxygen (12 L/min for at least 15 minutes) or parenteral triptans (or both), such as subcutaneous
sumatriptan 6 mg, unless contraindicated
High doses of verapamil are often necessary as preventive treatment; electrocardiographic monitoring is mandatory when escalating
doses

Sources and selection criteria

We based this clinical review on personal reference archives, personal experience, and extensive literature searches of the PubMed and
Cochrane databases using the search terms “cluster headache” and “trigeminal autonomic cephalalgia”. We also consulted management
guidelines from the European Federation of Neurological Sciences and the British Association for the Study of Headache.

Box 1 Cranial autonomic features of cluster headache attacks4 5*

Ipsilateral lacrimation (91%)
Ipsilateral conjunctival injection (77%)
Ipsilateral nasal congestion or rhinorrhoea (75%/72%)
Ipsilateral ptosis† (74%)
Ipsilateral oedema of the eyelid or the face (or both) (74%)
Ipsilateral sweating of the forehead or the face (or both) (38%)
Ipsilateral miosis† (29%)
*Features are ipsilateral to the side of pain; not all features need to be present
†A partial Horner’s syndrome may persist to a lesser degree between attacks.

Box 2 Diagnostic criteria for cluster headache3

A) At least five attacks fulfilling criteria B-D
B) Severe or very severe unilateral orbital, supraorbital, or temporal pain that lasts for 15-180 minutes if untreated
C) Headache accompanied by at least one of the following:
Ipsilateral conjunctival injection or lacrimation (or both)
Ipsilateral nasal congestion or rhinorrhoea (or both)
Ipsilateral eyelid oedema
Ipsilateral forehead and facial sweating
Ipsilateral miosis or ptosis (or both)
Restlessness or agitation
D) Attacks have a frequency of one every other day to eight each day
E) Not attributed to another disorder
Episodic cluster headache: Attacks occurring in periods that last seven days to one year separated by pain-free periods that last one
month or longer
Chronic cluster headache: Attacks that occur for more than one year without remission or with remissions that last less than one month

the disorder are supported by three large prospective case series How long does an attack last?
that use similar methods.4 5 14 The diagnostic criteria (box 2) state that attacks should last
between 15 and 180 minutes, although on rare occasions they
Where is the pain and what is it like? can last longer. In the British series, a mean untreated minimum
The pain of cluster headache is unilateral in at least 97% of duration of 72 minutes and maximum duration of 159 minutes
people with episodic disease and mainly focused behind the eye was reported.4
(88-92%), over the temple (69-70%), or over the maxilla The onset of pain is rapid, and the sensation increases from
(50-53%), although it may extend to other areas of the head and serious discomfort to excruciating pain over the course of a few
neck.4 5 14 Between 14% and 18% of patients report that the pain minutes. The pain usually stays at maximal intensity for the
shifts sides between bouts of attacks and less commonly during duration of the attack, although it may wax and wane slightly,
a bout, but never during the attack itself.4 14 Patients often or be punctuated by super-intense stabs of pain. The attack will
describe the pain as a sharp, piercing, burning, or pulsating often end as abruptly as it started.
sensation like “having a red hot poker forced through my eye,”
and they report that the intensity is so extreme it is unlike
anything they have ever experienced (“11 out of 10”).

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CLINICAL REVIEW

How often do individual attacks occur? Which conditions resemble cluster

The frequency of attacks is also a feature of the diagnostic headache?
criteria (box 2), and it varies from one attack every 48 hours to
eight separate attacks in 24 hours, although less frequent attacks The table highlights the main features of cluster headache and
may occur at the beginning and end of bouts. the other trigeminal autonomic cephalalgias, which although
rare are the main differential diagnoses.
The British study found the mean maximum number of attacks
each day to be 4.6, with 37% of patients reporting a predictable Secondary (or symptomatic) cluster headache may be caused
time of onset during the day and 72% reporting attacks occurring by several structural lesions, particularly pituitary tumours, in
at predictable times during the night, waking them from sleep.4 addition to carotid dissections and cavernous sinus pathology,
so magnetic resonance imaging of the brain and, potentially,
Which other symptoms occur with the attack? carotid arteries is a useful part of the diagnostic investigation.20
Attacks of migraine tend to be less severe and to last longer;
Each attack is accompanied by one or more cranial autonomic
cranial autonomic features, if present, are less prominent and
symptom or sign on the same side as the pain (box 1; figs 1 and
more likely to be bilateral.21 Nausea, vomiting, and bilateral
2). All of these signs and symptoms are transient and resolve
photophobia are common. Migraine lacks the striking timing
with the cessation of pain, although a partial Horner’s syndrome
patterns and clustering effects, and most patients prefer not to
or isolated ptosis may persist between attacks or even bouts as
move during the episode, in contrast to the agitation and
a result of local damage to oculosympathetic fibres during
restlessness experienced during a cluster attack. Alcohol
repeated attacks (fig 2).10 The persistence of these signs in the
ingestion may also precipitate migraine, typically after a time
context of the disorder need not cause undue alarm, unless they
delay of several hours.
progressively worsen, in which case secondary causes should
be considered and investigations or referral initiated. Trigeminal neuralgia tends to affect people over the age of 50
years and consists of sudden short lasting stabs of lancinating
Between 70% and 93% of patients describe a sense of
pain, usually affecting the second and third divisions of the
restlessness and agitation during an attack and will often pace,
trigeminal nerve. It is not associated with cranial autonomic
rock back and forth, and bang their heads.4 14 Most patients wish
features and is often precipitated by touch, chewing, swallowing
to isolate themselves and seek a cold environment. Between
hot or cold liquids, and cold wind.3
28% and 50% report nausea,4 5 14 and a further 23% may vomit
during an attack.4 More than half (54-64%) of patients have
photophobia, often limited to the same side as the pain, with How should patients with cluster
slightly fewer reporting an aversion to loud noise (43%) or headache be managed?
strong smells (26%) during the attack.4 14 15
Effective management relies on shared responsibility between
Aura phenomena, similar to those experienced during migraine,
primary and secondary care, and all suspected cases should be
including visual phenomena and paraesthesia, precede attacks
initially referred for specialist neurological or headache
by up to 60 minutes in 14% of patients.4
assessment. Patients should be kept under long term follow-up
Patients commonly have tenderness and cutaneous allodynia at and if possible be offered open appointments at times when
and around the site of pain between attacks, including over the bouts recur.
ipsilateral greater occipital nerve.16
Treatment of individual attacks
Does anything trigger the attacks?
Standard analgesia is ineffective, and there is no evidence to
In over half of patients (53-63%), small quantities of alcohol, support the use of non-steroidal anti-inflammatory drugs,
particularly red wine (70%), will precipitate an attack, usually paracetamol (acetaminophen), codeine, or opioids in the
within an hour of ingestion.4 14 15 However, this is only the case treatment of individual attacks. Prescription of such agents
during a bout rather than when in remission. should therefore be avoided. The mainstay of abortive treatment
In most patients (72%), attacks are related to nocturnal sleep, consists of inhaled oxygen and parenteral triptans.
with daytime naps also being triggers in some.4 Small case series
have reported a raised apnoea-hypopnoea index in some patients, Oxygen
suggesting a higher incidence of obstructive sleep apnoea, A recent double blind randomised placebo controlled crossover
although no convincing mechanistic or therapeutic insights trial found that 78% of subjects were pain free after inhalation
currently exist to explain this.17 of 100% oxygen at 12 L/min for 15 minutes (P<0.001).22 Patients
Some patients report that odours from volatile organic should continuously inhale oxygen at this rate for at least 15
compounds, such as perfume and paint, can also trigger attacks. minutes through a non-rebreathing facemask. Guidelines for
Nitrates may trigger attacks,18 and glyceryl trinitrate is used to oxygen use, including a prefilled home oxygen order form for
provoke attacks experimentally.11 Sildenafil has also been doctors of patients in the United Kingdom, are provided on the
reported to induce attacks during a bout.19 website of the Organisation for the Understanding of Cluster
Headache.
How often do bouts of attacks occur?
Most people with cluster headache experience one bout a year, Triptans
with a unimodal frequency distribution and mean bout duration Parenteral triptans have been shown to be an effective treatment
of 8.6 weeks found in the British series. However, patients may for individual attacks, whereas orally administered triptans have
go for several years without a bout (up to 20 in some cases), not. A randomised double blinded placebo controlled crossover
and others may have more frequent bouts each year.4 study of sumatriptan 6 mg subcutaneous injections showed
freedom from pain or a reduction to mild pain in 74% of attacks
15 minutes after administration (P<0.001).23 The incidence of

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CLINICAL REVIEW

rebound and tachyphylaxis is lower in patients with cluster Neuromodulation

headache than in those with migraine when sumatriptan is The small proportion of people with chronic cluster headache
injected up to twice daily on a long term basis. Good randomised who gain no meaningful benefit from preventive drugs should
placebo controlled evidence also supports the use of sumatriptan be considered for surgical intervention. Occipital nerve
nasal spray 20 mg (57% of patients reported adequate relief stimulation involves the extracranial implantation of stimulating
(P=0.002) and 47% reported freedom from pain (P=0.003) at electrodes around the greater occipital nerve, situated below the
30 minutes)24 and zolmitriptan nasal spray 10 mg (61% scalp and overlying the occipital bones.33 34 Long term follow-up
(P=0.002) and 50% (P=0.003)).25 of a small cohort showed improvement in 71%, with 64% stating
that they would recommend the procedure to others. This safe
Preventive treatment and effective technique should be considered part of routine
Preventive treatment aims to suppress the attacks for the duration care in selected patients with drug refractory chronic cluster
of the bout, or over longer periods in those with chronic cluster headache.35
headache, with the fewest possible side effects. Because functional imaging studies show activation in the region
Consensus evidence, based on observation and one small of the posterior hypothalamus during attacks,11 deep brain
randomised controlled trial,26 suggests that a tapering course of stimulation of this area is also being used to treat refractory
corticosteroids—such as 1 mg/kg prednisolone (maximum 60 cases. This technique offers good efficacy in about 60% of
mg) for five days, which is then reduced by 10 mg every three patients,36 although a small controlled trial was negative, and
days—may temporarily reduce the frequency of headaches. A death has been reported as a complication of this approach.37
preventive agent, with longer latency until onset of action, Its use should be restricted to patients who have failed peripheral
should be started at the same time.27 stimulation techniques.
The preventive drug of choice is verapamil. This is based on
consensus agreement and a small double blinded multicentre Contributors: ADN initiated and planned the manuscript. ADN and PJG
placebo controlled study.28 Baseline electrocardiography should both contributed to the manuscript and provided figures. PJG critically
be performed before starting verapamil at a dose of 80 mg three revised drafts of the article and approved the content of the final version
times a day and increasing this by 80 mg each fortnight. to be published. PJG is guarantor.
Electrocardiography should be repeated 10 days after the dose Competing interests: Both authors have completed the ICMJE uniform
change and reviewed before each dose increase, paying disclosure form at www.icmje.org/coi_disclosure.pdf (available on
particular attention to the PR interval. This is essential because request from the corresponding author) and declare: ADN had financial
of the relatively high incidence of heart block associated with support from the Patrick Berthoud Charitable Trust for the submitted
verapamil.29 For adequate control, at least 480 mg daily is work; no financial relationships with any organisations that might have
usually needed, and doses of up to 960 mg daily are sometimes an interest in the submitted work in the previous 3 years; no other
needed.28 At higher doses, other side effects of verapamil include relationships or activities that could appear to have influenced the
constipation, dizziness, and peripheral oedema. submitted work. PJG has consulted for or lectured in sessions supported
by Allergan, American Headache Society, Colucid, MAP Pharma, Merck,
Verapamil can be slowly withdrawn and stopped once the bout
eNeura, Autonomic technologies, Boston Scientific, Eli-Lilly, Medtronic,
is assumed to have ended and lower doses do not allow
Linde gases, Mennarini, BristolMyersSquibb, and Pfizer, and had grant
breakthrough attacks. The maximum efficacious dose achieved
support from GlaxoSmithKline, MAP Pharma, Merck, eNeura, and
can then be given at the beginning of subsequent bouts, as long
Amgen.
as a baseline electrocardiogram remains within normal limits.
Provenance and peer review: Commissioned; externally peer reviewed.
Although evidence from controlled trials is limited, there is
consensus that lithium may be a useful preventive treatment, Patient consent obtained.
even though it is generally of less use than verapamil and it is
1 Balla JI, Walton JN. Periodic migrainous neuralgia. BMJ 1964;1:219-21.
associated with more side effects and the need for regular plasma 2 Bahra A, Goadsby PJ. Diagnostic delays and mis-management in cluster headache. Acta
monitoring.27 Neurol Scand 2004;109:175-9.
3 Headache Classification Committee of the International Headache Society. The
Observational studies from the 1960s suggest that methysergide international classification of headache disorders (second edition). Cephalalgia
can be efficacious, particularly for short bouts, but its use is 2004;24(suppl 1):1-160.
4 Bahra A, May A, Goadsby PJ. Cluster headache: a prospective clinical study in 230
restricted by serious fibrotic side effects, and it should therefore patients with diagnostic implications. Neurology 2002;58:354-61.
be given for short periods only under specialist supervision.27 5 Donnet A, Lanteri-Minet M, Guegan-Massardier E, Mick G, Fabre N, Geraud G, et al.
Chronic cluster headache: a French clinical descriptive study. J Neurol Neurosurg
Melatonin can be useful in doses of 9-15 mg at night, and this Psychiatry 2007;78:1354-8.
is supported by a small double blind pilot study.30 6 Cittadini E, Matharu MS, Goadsby PJ. Paroxysmal hemicrania: a prospective clinical
study of thirty-one cases. Brain 2008;131:1142-55.
Other agents such as topiramate, sodium valproate, pizotifen, 7 Cohen AS, Matharu MS, Goadsby PJ. Short-lasting unilateral neuralgiform headache
and gabapentin are occasionally used with some success, attacks with conjunctival injection and tearing (SUNCT) or cranial autonomic features
(SUNA). A prospective clinical study of SUNCT and SUNA. Brain 2006;129:2746-60.
although data from clinical trials are limited.27 8 Goadsby PJ. Pathophysiology of cluster headache: a trigeminal autonomic cephalgia.
Lancet Neurol 2002;1:37-43.
9 Akerman S, Holland P, Goadsby PJ. Diencephalic and brainstem mechanisms in migraine.
Nerve blocks and infusions Nat Rev Neurosci 2011;12:570-84.
10 Drummond PD. Mechanisms of autonomic disturbance in the face during and between
Data from a recent randomised controlled trial support the attacks of cluster headache. Cephalalgia 2006;26:633-41.
injection of a mixture of local anaesthetic and corticosteroid 11 May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. Hypothalamic activation in
cluster headache attacks. Lancet 1998;352:275-8.
solution over the greater occipital nerve on the side of the pain.31 12 Fischera M, Marziniak M, Gralow I, Evers S. The incidence and prevalence of cluster
This can be used as an effective bridging technique to allow an headache: a meta-analysis of population-based studies. Cephalalgia 2008;28:614-8.

adequate dose of oral preventive drug to be achieved. Its use 13

14
Russell MB. Epidemiology and genetics of cluster headache. Lancet Neurol 2004;3:279-83.
Schurks M, Kurth T, de Jesus J, Jonjic M, Rosskopf D, Diener HC. Cluster headache:
would normally be limited to once every eight to 12 weeks. clinical presentation, lifestyle features, and medical treatment. Headache 2006;46:1246-54.
15 Irimia P, Cittadini E, Paemeleire K, Cohen AS, Goadsby PJ. Unilateral photophobia or
A repeated course of intravenous dihydroergotamine, when used phonophobia in migraine compared with trigeminal autonomic cephalalgias. Cephalalgia
according to established protocols in specialist centres only, 2008;28:626-30.
16 Marmura MJ, Pello SJ, Young WB. Interictal pain in cluster headache. Cephalalgia
was shown to break the cycle in a cohort study.32 2010;30:1531-4.

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CLINICAL REVIEW

Tips for non-specialists

Consider cluster headache in anyone who presents with a regularly occurring severe unilateral headache that lasts for three hours or
less
A marked sense of agitation and need to move about can help differentiate cluster headache from migraine, which usually compels the
patient to remain calm and still
Conventional analgesia is ineffective and not worth trying
Offer all patients short burst oxygen therapy and parenteral (injectable or nasal) triptans to treat attacks
Prefilled, cluster specific home oxygen supply order forms and guidelines on use are available to download at www.ouchuk.org

Ongoing and future research

Imaging studies using functional and high resolution anatomical approaches aim to provide more detailed information on the activating
mechanisms of attacks
Future randomised controlled trials may assess the efficacy of the calcitonin gene related peptide inhibitors or receptor antagonists, a
new class of headache abortive drugs
Further investigation of the sleep and circadian physiology of patients is providing important mechanistic information designed to help
develop new proof of concept treatments
Randomised controlled trials of different methods of oxygen delivery will provide information that can help rapidly abort individual attacks
Needleless triptan injections are currently being marketed
New modes of neurostimulation, such as sphenopalatine ganglion stimulation, are being explored
Patient databases will help enable longitudinal assessment of the natural course of the disorder

Additional educational resources

Resources for healthcare professionals
Organisation for the Understanding of Cluster Headache (OUCH UK; www.ouchuk.org/html/clusters_video5.asp)—Video of a patient
enduring an attack, which shows the characteristic psychomotor agitation that accompanies an attack
BMJ Learning (http://learning.bmj.com/learning/module-intro/.html?moduleId=5004479&searchTerm=%E2%80%9Ccluster%20headache%
E2%80%9D&page=0 )—A guide to diagnosis and management
British Association for the Study of Headache (www.bash.org.uk)—Guidelines on the diagnosis and management of a range of primary
headaches, including cluster headache; also gives details of regular meetings and teaching weekends for GPs, specialist registrars,
and consultants throughout the UK
International Headache Society (http://ihs-classification.org/en/)—Useful diagnostic criteria that cover all forms of primary and secondary
headache disorders; registered members may take advantage of an online learning resource centre and access to the journal Cephalalgia

Resources for patients

Organisation for Understanding Cluster Headache (OUCH UK; www.ouchuk.org)—A unique patient support group that offers practical
advice and information for patients and supporters plus an online support forum and regular meetings throughout the UK

A patient’s perspective
I am careful not to wake the children as I make my way downstairs. If they were to witness my nightly cluster ritual, they would never see
me the same way again. Their father, fearless protector, diligent provider, crawling about in tears, beating his head on the hard wood floor.
The pain is so intense I want to scream, but I never do. I go down three flights of stairs where I can’t be heard, and drop to my knees. I place
my hands on the back of my neck and lock my fingers together. I bind my head between my arms and squeeze as hard as I can in an attempt
to crush my skull. I begin to roll around, banging my head on the floor, pressing my left eye with the full force of my palm. I search for the
telephone that has always been my weapon of choice for creating a diversion, and I beat my left temple with the hand piece. I create a
rhythm as I strike my skull, cursing the demon with each blow.
With permission from www.clusterheadaches.com

17 Chervin RD, Zellek N, Lin X, Hall JM, Sharma N, Hedger KM. Sleep disordered breathing 27 May A, Leone M, Afra J, Linde M, Sandor PS, Evers S, et al. EFNS guidelines on the
in patients with cluster headache. Neurology 2000;54:2302-6. treatment of cluster headache and other trigeminal-autonomic cephalalgias. Eur J Neurol
18 Ekbom K. Nitroglycerin as a provocative agent in cluster headache. Arch Neurol 2006;13:1066-77.
1968;19:487-93. 28 Leone M, D’Amico D, Frediani F, Moschiano P, Grazzi L, Attanasio A, et al. Verapamil in
19 Evans RW. Sildenafil can trigger cluster headaches. Headache 2006;46:173-4. the prophylaxis of episodic cluster headache: a double-blind study versus placebo.
20 Wilbrink LA, Ferrari MD, Kruit MC, Haan J. Neuroimaging in trigeminal autonomic Neurology 2000;54:1382-5.
cephalgias: when, how, and of what? Curr Opin Neurol 2009;22:247-53. 29 Cohen AS, Matharu MS, Goadsby PJ. Electrocardiographic abnormalities in patients with
21 Lai T-H, Fuh J-L, Wang S-J. Cranial autonomic symptoms in migraine: characteristics cluster headache on verapamil therapy. Neurology 2007;69:668-75.
and comparison with cluster headache. J Neurol Neurosurg Psychiatry 2009;80:1116-9. 30 Leone M, D’Amico D, Moschiano F, Fraschini F, Bussone G. Melatonin versus placebo
22 Cohen AS, Burns B, Goadsby PJ. High flow oxygen for treatment of cluster headache. A in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups.
randomized trial. JAMA 2009;302:2451-7. Cephalalgia 1996;16:494-6.
23 Ekbom K; the Sumatriptan Cluster Headache Study Group. Treatment of acute cluster 31 Leroux E, Valade D, Taifas I, Vicaut E, Chagnon M, Roos C, et al. Suboccipital steroid
headache with sumatriptan. N Engl J Med 1991;325:322-6. injections for transitional treatment of patients with more than two cluster headache attacks
24 Van Vliet JA, Bahra A, Martin V, Aurora SK, Mathew NT, Ferrari MD, et al. Intranasal per day: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2011;10:891-7.
sumatriptan in cluster headache—randomized placebo-controlled double-blind study. 32 Nagy AJ, Gandhi S, Bhola R, Goadsby PJ. Intravenous dihydroergotamine (DHE) for
Neurology 2003;60:630-3. inpatient management of refractory primary headaches. Neurology 2011;77:1827-32.
25 Cittadini E, May A, Straube A, Evers S, Bussone G, Goadsby PJ. Effectiveness of 33 Burns B, Watkins L, Goadsby PJ. Successful treatment of medically intractable cluster
intranasal zolmitriptan in acute cluster headache. A randomized, placebo-controlled, headache using occipital nerve stimulation (ONS). Lancet 2007;369:1099-106.
double-blind crossover study. Arch Neurol 2006;63:1537-42. 34 Magis D, Allena M, Bolla M, De Pasqua V, Remacle JM, Schoenen J. Occipital nerve
26 Jammes JL. The treatment of cluster headaches with prednisone. Dis Nerv Syst stimulation for drug-resistant chronic cluster headache: a prospective pilot study. Lancet
1975;36:375-6. Neurol 2007;6:314-21.
35 Burns B, Watkins L, Goadsby PJ. Treatment of intractable chronic cluster headache by
occipital nerve stimulation in 14 patients. Neurology 2009;72:341-5.

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36 Leone M. Deep brain stimulation in headache. Lancet Neurol 2006;5:873-7. Cite this as: BMJ 2012;344:e2407
37 Schoenen J, Di Clemente L, Vandenheede M, Fumal A, De Pasqua V, Mouchamps M,
et al. Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and © BMJ Publishing Group Ltd 2012
mode of action. Brain 2005;128:940-7.

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Table

Table 1| Comparison of the trigeminal autonomic cephalalgias based on cohorts studied,4 6 7 the international classification of headache
disorders,3 and patients seen in practice*

Characteristic Cluster headache Paroxysmal hemicrania SUNCT/SUNA

Sex (M:F) 3:1 1:1 1.5:1
Pain:
Quality Sharp/stabbing/throbbing Sharp/stabbing/throbbing Sharp/stabbing/throbbing
Severity Very severe Very severe Severe
Distribution V1>C2>V2>V3 V1>C2>V2>V3 V1>C2>V2>V3
Attacks:
Frequency per day 1 every other day to 8/day 1-40 (>5/day for more than half the 3-200 (typically 100/day)
time)
Length 15-180 min 2-30 min 5-240 s
Triggers
Alcohol +++ + −
Nitroglycerin +++ + −
Cutaneous − − +++
Agitation or restlessness 90% 80% 65%
Episodic v chronic 90:10 35:65 10:90
Circadian or circannual periodicity Present Absent Absent
Treatment effects:
Oxygen 80% No effect No effect
Sumatriptan 6 mg subcutaneously 75% 20% <10%
Indomethacin No effect 100% No effect
Migrainous features with attacks:
Nausea 50% 40% 25%
Photophobia or phonophobia 65% 65% 25%

*SUNCT/SUNA=short lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing/short lasting unilateral neuralgiform headache attacks
with cranial autonomic features; C=cervical; V=trigeminal.

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CLINICAL REVIEW

Figures

Fig 1 Cranial autonomic features during a cluster headache attack. This photograph was taken during an attack and clearly
shows characteristic left periorbital oedema and left partial ptosis, with left conjunctival injection and tear formation. These
signs reverted to normal when the attack stopped

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CLINICAL REVIEW

Fig 2 The trigeminovascular reflex. Nerve endings containing pain receptors innervate structures of the face and cranial
vault, particularly the pain producing dura mater and cerebral blood vessels (the durovascular complex). This nociceptive
information is carried to the brainstem in the trigeminal nerve, via the trigeminal ganglion. Within the brainstem, trigeminal
fibres synapse in an area known as the trigeminocervical complex (TCC). From here, information ascends to the
hypothalamus, thalamus, and cortex via pain processing pathways. In addition, the afferent trigeminal signals arriving at
the TCC also stimulate the cranial parasympathetic system via the superior salivatory nucleus. This results in increased
firing of parasympathetic fibres carried from the brainstem in the facial nerve and then greater superficial petrosal nerve,
which synapse at the sphenopalatine ganglion. These fibres innervate facial structures (including the lacrimal gland and
nasal mucosa, thus causing the lacrimation and rhinorrhoea seen with attacks) and the durovascular complex.
Neurotransmitter release at these parasympathetic terminals (vasoactive intestinal polypeptide) causes further irritation of
trigeminal sensory nerve endings and release of calcitonin gene related peptide, which potentiates the trigeminovascular
reflex arc. It is this reflex that is responsible for the pain and facial parasympathetic signs of cluster headache attacks.9 The
ptosis and miosis seen with attacks arise from interruption of the oculosympathetic fibres that run with the internal carotid
artery and through the cavernous sinus, where they are thought to be affected by local vascular distension.10 The posterior
hypothalamus, which shows a strong activation signal in functional imaging studies during attacks (insert), may modulate
signalling through the TCC, perhaps providing a breaking mechanism to regulate the trigeminovascular reflex9

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