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Trigeminal Autonomic Cephalalgias (TACs) – Cluster Headache
AD Nesbitt, University of Surrey, Surrey, UK
PJ Goadsby, Wellcome-NIHR Clinical Research Facility, King’s College Hospital, London, UK; and University of California San
Francisco, San Francisco, CA, USA
r 2014 Elsevier Inc. All rights reserved.
Introduction
Cluster headache defines a specific primary headache syndrome, which manifests itself as repetitive, highly stereotyped
attacks of excruciating one-sided head pain. It is the most
prevalent form of a group of neurological disorders termed
trigeminal autonomic cephalalgias (TACs), all of which consist of consecutive attacks of similar unilateral pain, of varying
duration, with the common shared feature of aberrant tone
within cranial autonomic pathways on the same side as the
pain, which causes both visible ocular and facial signs, and
additional symptoms.
Few medical disorders are more painful, and it thus places
an exceptional burden on the sufferers.
Historical Context
Many of the features of cluster headache were first described in
two separate reports detailed during the seventeenth century. In
1641, the eminent Dutch physician and anatomist Nicholaes
Tulp described the suffering endured by one of his patients:
In the beginning of the summer season, [he] was afflicted with a very
severe headache, occurring and disappearing daily on fixed hours,
with such intensity that he often assured me that he could not bear
the pain anymore or he would succumb shortly. For rarely it lasted
longer than two hours [y] but this recurring pain lasted until the
14th day [y] and lost a great deal of fluid from the nose.
Three decades later, the Oxford physician Thomas Willis,
widely regarded as the founding father of clinical neuroscience, published De Anima Brutorum, the first textbook of
clinical neurology. The first two chapters comprise his treatise
on headache, De Cephalalgia, in which he describes the peculiar periodicity of possible cluster headache attacks:
Usually the attacks of seemingly suppressed headache recur around
the solstices and equinoxes [...] but the majority, provided with
subordinate periods, habitually molests at fixed hours within every
cycle of 24 hours.
Taken collectively, these accounts conform to many of the
current diagnostic criteria for cluster headache, although neither physician commented on the unilateral, side-locked nature of the attacks.
The disorder received wider attention from the midnineteenth century, when it was variously given the eponyms
Sluder’s syndrome, Bing’s headache, Horton’s headache; the
descriptive terms red migraine, angioparalytic hemicrania,
eythroprosopalgia, vidian neuralgia; and most commonly migrainous neuralgia, ciliary neuralgia, and histaminic cephalgia.
The use of the current term cluster headache is attributed to
Encyclopedia of the Neurological Sciences, Volume 4
Kunkle, who described a case series from the USA in 1952, and
refers to the tendency of the individual attacks to cluster together in time into bouts, during which the attacks occur daily,
usually for periods of several weeks or months at a time.
Medical historians have debated whether the disabling
headaches suffered by the US president Thomas Jefferson were
actually bouts of cluster headache rather than migraine.
Classification
The International Classification of Headache Disorders (third
edition), published by the International Headache Society,
outlines the diagnostic criteria needed to make an accurate
diagnosis of cluster headache (Table 1).
Of note, it further subdivides the disorder into two forms,
episodic and chronic cluster headache, based on the duration
of active periods (or bouts), during which the attacks cluster
together, and periods of quiescence or remission.
Episodic cluster headache can only be diagnosed if a patient has had at least 2 bouts, lasting between 7 and 365 days,
and separated by a period of remission of Z1 month. For the
diagnosis of chronic cluster headache to be fulfilled, attacks
must persist for a period 41 year, without any remission
period of Z1 month. Patients who only ever have one bout
are simply classified as having cluster headache.
Chronic cluster headache is the less common of the two
subtypes, with only approximately 10% of the sufferers
meeting the time criterion for this.
Symptomatic (or secondary) cluster headache is the term given
to a syndrome that is otherwise identical to cluster headache, but
caused by an identified lesion, often in the pituitary fossa.
Epidemiology and Genetics
Pooled data from limited epidemiological studies conducted
mainly in Europe and North America give cluster headache a
lifetime prevalence of 0.12%, with data from a door-to-door
study in Norway showing a 1-year prevalence of 0.3%.
The condition has a heritable tendency in some families,
and first-degree relatives of affected people have an estimated
14–48-fold increased risk of developing it. However, in familial cases, segregation analysis has not revealed a single
mode of inheritance, and it is likely that penetrance can be
highly variable, even within the same kindred. Two studies
have reported a polymorphism of the type 2 hypocretin receptor gene in association with cluster headache, although this
was not replicated in a third multinational study.
Males are 2.5–3.5 times more likely to be affected than
females, and patients typically start to develop the attacks in
their third to fifth decade, although patients as young as 4
doi:10.1016/B978-0-12-385157-4.01094-0
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Trigeminal Autonomic Cephalalgias (TACs) – Cluster Headache
Table 1
International Classification of Headache Disorders, 3rd edition (ICHD-III) of the International Headache Society diagnostic criteria for
cluster headache
Diagnostic Criteria for Cluster Headache
1.
2.
3.
4.
5.
At least five attacks fulfilling criteria 2–4
Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15–180 min (when untreated)a
Either, or both of the following:
a. At least one of the following symptoms or signs, ipsilateral to the headache:
i. conjunctival injection and/or lacrimation
ii. nasal congestion and/or rhinorrhea
iii. eyelid edema
iv. forehead and facial sweating
v. forehead and facial flushing
vi. sensation of fullness in the ear
vii. miosis and/or ptosis
b. A sense of restlessness or agitation
Attacks have a frequency from one every other day to 8 per day for more than half of the time when the disorder is active
Not better accounted for by another ICHD-III diagnosis
a
During part (but less than half) of the time course of cluster headache, attacks may be less severe and/or of shorter or longer duration.
Source: Reproduced with permission from the Headache Classification Subcommittee of the International Headache Society (IHS) (2013) The International Classification of Headache
Disorders, 3rd edition (beta version). Cephalalgia 33: 629–808.
years and as old as 96 years have been affected. There seems to
be an association with smoking, with approximately 65% of
patients being active smokers or reporting a history of smoking. However, a causative link to smoking has not been proven
and seems unlikely, as smoking cessation does not seem to
alter the clinical course of the disorder and cannot easily
account for the disorder in children.
The natural course of cluster headache can be difficult to
predict, with some people showing a bidirectional transition
between the episodic and chronic forms of the condition. Less
frequent bouts of attacks and more prolonged, and sometimes
permanent, periods of remission can occur with advancing age.
Clinical Features
Pain
Individual attacks of cluster headache are strictly unilateral in
at least 97% of individuals, although very rare reports of
simultaneous bilateral attacks do exist. Less than 20% of sufferers may experience attacks alternating between the right and
left sides, and the side may vary between bouts or less commonly between attacks within a bout.
The pain is typically focused in the distribution of the
ophthalmic branch of the trigeminal nerve, behind the eye, over
the temple or over the maxilla, although it may extend to other
areas of the head and the neck. Patients often describe the pain
as a sharp, piercing, burning, or pulsating 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’), including childbirth, limb fractures,
and acute abdominal pathology such as a ruptured viscera.
Cranial Autonomic Symptoms and Other Features
Each attack is accompanied by one or more cranial autonomic
symptoms or signs on the same side as the pain. The most
commonly experienced symptoms of exaggerated parasympathetic tone are lacrimation and watery rhinorrhea. Common
mixed signs are conjunctival redness and periorbital swelling.
Nasal congestion is a symptom of sympathetic interruption, of
which ptosis and miosis (postganglionic Horner’s syndrome)
are classic signs. All these signs and symptoms are transient
and resolve with the cessation of pain, although a partial
Horner’s syndrome or isolated ptosis may persist between
attacks.
The vast majority of patients describe a sense of restlessness
and agitation during an attack and will often pace, rock
back and forth, and bang their heads. Most wish to isolate
themselves and seek a cold environment. Fewer than half report
nausea, and fewer again may vomit during an attack. Photophobia may be reported, often limited to the same side as the
pain, with fewer reporting an aversion to loud noise or strong
smells during the attack.
Aura phenomena, similar to those experienced during
migraine, including visual phenomena and paresthesia, preceding the attacks by up to 60 min, have been described in a
small minority of patients.
Patients commonly have tenderness and cutaneous allodynia
at and around the site of pain between attacks, including over
the ipsilateral greater occipital nerve.
Attack Duration and Frequency
Attacks typically last between 15 and 180 min, although on
rare occasions they can last longer. In a case series of British
patients, a mean untreated minimum duration of 72 min and
maximum duration of 159 min was reported.
The onset of pain is rapid, and the sensation increases from
serious discomfort to excruciating pain over the course of a few
minutes. The pain usually stays at maximal intensity for the
duration of the attack, although it may wax and wane slightly, or
be punctuated by superintense stabs of pain. The attack will
often end as abruptly as it started.
Trigeminal Autonomic Cephalalgias (TACs) – Cluster Headache
The frequency of attacks varies from one attack every 48 h
to eight separate attacks in 24 h, although less frequent attacks
may occur at the beginning and end of bouts. Typically 1–2
attacks will occur each day, and case series have reported a
mean maximum number of attacks as 4.6 per 24 h.
Just over a third of patients report an often highly
predictable time of onset during the day, with three quarters
reporting attacks occurring at predictable times during the
night, awakening them from sleep.
Bout Duration and Frequency
Most people with episodic cluster headache experience one bout
a year, with a mean duration of approximately 8–9 weeks.
However, patients may go for several years without a bout (up to
20 years in some cases), and others may have more frequent
bouts each year. The onset of bouts can be very regular in some
individuals, with spring and autumn months being particularly
noted for bout onsets, which is potentially related to the
changes in day length.
Precipitants
Small quantities of alcohol will precipitate an attack in the
majority of sufferers, usually within an hour of ingestion.
However, this only occurs during a bout, rather than when in
remission.
In three quarters of patients, attacks are related to nocturnal
sleep, with daytime naps also being triggers in some. Small case
series have reported a raised apnea–hypopnea index in some
patients, suggesting a higher frequency of obstructive sleep
apnea, although no convincing mechanistic or therapeutic insights currently exist to explain this.
Odors from volatile organic compounds, such as perfumes
and paints, can also trigger attacks, as can nitrates and the
phosphodiesterase inhibitor sildenafil.
Pathophysiology
The pathophysiology of cluster headache, as with the other
TACs, is complex, and no single unifying mechanism has been
identified to explain the syndrome as a whole. The classic
reflex arc, which underpins much of the acute symptomatology of the TACs, is the trigeminovascular reflex. This
mechanism involves reflex activation of parasympathetic outflow via the facial nerve and sphenopalatine ganglion caused
by incoming nociceptive signals carried to the brainstem by
the trigeminal nerve, which provides afferent pain innervation
from the sensate structures of the face, orbit, cranial vault,
and vasculature. The postganglionic parasympathetic efferent
neurons colocalize with the trigeminal sensory afferent fibers
throughout this region, and release of proinflammatory
neurotransmitters by the activated parasympathetic fibers
(namely vasoactive intestinal peptide (VIP)) further stimulate
the trigeminal nerve endings, causing local release of the
potent vasodilator calcitonin gene-related peptide (CGRP) by
the trigeminal neurons, all of which further potentiates the
reflex. Increased parasympathetic tone in the sphenopalatine
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ganglion causes the lacrimation and rhinorrhea seen during
cluster headache attacks. It is thought that vasodilation and
neurogenic inflammation in and around the wall of the
internal carotid artery and cavernous sinus may compress
oculosympathetic fibers that travel with these structures
from the superior cervical ganglion, resulting in partial ptosis,
miosis, and partial Horner’s syndrome often seen during
the attacks.
It is widely accepted that a permissive state must exist within
the central nervous system to facilitate central disinhibition of
this neurovascular reflex, and that the origin of the pain does
not lie solely within the periphery or indeed is not entirely
mediated by the trigeminal nerve, as sectioning of this nerve
does not provide universal relief from attacks. The simultaneous
integration of both trigeminal pain and cranial autonomic signs
afforded by this reflex may not always be a mutual relationship,
as painless attacks of autonomic disturbance have been observed, both in trigeminally intact patients and those who have
undergone trigeminal nerve section.
The characteristic timing of the attacks, their seasonal
preponderance, and the striking autonomic features of the
attacks have led to decades of speculation that the hypothalamus might house the generator of cluster attacks. This
hypothesis gained further support from seminal neuroimaging
studies, which showed both strong activation of an area of the
posterior hypothalamus ipsilateral to the side of pain specific
to the attacks of cluster headache using positron emission
tomography, as well as anatomical derangement within this
same area during voxel-based morphometric magnetic resonance imaging (MRI) studies of patients.
However, therapeutic deep brain stimulation of this area is
only effective in approximately 60% of patients, and stimulation cannot acutely terminate an attack, which suggests that
this area may be activated as part of a pain matrix response
specific to a cluster headache attack, but that is not responsible
for triggering the attack. Indeed, it may be that it is intensely
activated as a breaking mechanism to terminate the attack,
rather than trigger it.
A small population of neurons containing the neurotransmitter orexin (or hypocretin) localize specifically to this
area of the hypothalamus. They have widespread connections
throughout the brainstem and are implicated in stabilizing
sleep–wake transitions, as well as a host of other functions
relating to appetite and autonomic control. It has been demonstrated in animals that infusion of orexin-A into the posterior hypothalamus attenuates neuronal firing within the
trigeminal nucleus caudalis, whereas orexin-B has the opposite
effect and potentiates firing, hence providing an attractive
possible mechanism by which these neurotransmitters might
also facilitate periodic pain processing at the level of the trigeminal nucleus caudalis, and thus be implicated in stabilizing the interface between the cranial autonomic system and
the central pain mechanisms.
Treatment
Treatment of cluster headache falls into four main categories:
abortive, transitional, preventive, and neuromodulatory, each
of which is considered separately below.
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Trigeminal Autonomic Cephalalgias (TACs) – Cluster Headache
Abortive Treatment
Abortive treatment is aimed at abolishing, or significantly reducing, the intensity of individual attacks. The current mainstay
of this approach is the use of high-flow inhaled oxygen and
parenteral triptan preparations. All other conventional analgesia, particularly the common oral preparations used to treat
acute pain, are believed to be ineffective in cluster headache and
not supported by any evidence base.
In support of the use of high-flow inhaled oxygen, a recent
double-blind randomized placebo controlled crossover trial
found that 78% of subjects were pain free after inhalation of
100% oxygen at 12 l/min for 15 min. Preclinical studies in rats
have identified that oxygen appears to reduce the firing of specific populations of neurons in the trigeminocervical complex,
namely those giving rise to the facial nerve parasympathetic
outflow, which not only reduces parasympathetic tone but
also reduces subsequent trigeminovascular-evoked neuronal
activation within the trigeminocervical complex, which effectively dampens the trigeminovascular reflex during an attack.
The triptans are a family of tryptamine-based analgesic
drugs with agonist action at 5-hydroxytriptamine (5-HT or
serotonin) 1B/1D receptor subtypes distributed throughout
the craniofacial vasculature. This class of drugs was specifically
developed as migraine-abortive analgesia, and two subtypes,
sumatriptan and zolmitriptan, also demonstrate efficacy in
randomized controlled trials of use in cluster headache.
However, the tablet forms of these agents show little effect,
possibly due to the speed of onset and short duration of
cluster headache attacks making the oral route of administration, and enteric absorption, less efficient within the time
frame of an attack. However, sumatriptan given subcutaneously by injection works rapidly and can be extremely effective, as are preparations of sumatriptan and zolmitriptan
delivered via the nasal route.
Transitional Treatment
Patients with episodic cluster headache often need a therapeutic bridge between the beginning of a bout and establishing definitive preventive treatment, which often has a
longer latency to be effective and requires dose escalation over
a longer time period. This approach can often be useful at
minimizing the side effects from too rapid an escalation of
preventive therapy, particularly with untried treatments.
Two approaches are widely used in this regard. A short
pulse of high-dose oral corticosteroids, which is then incrementally reduced every few days, may temporarily reduce the
frequency and intensity of headaches.
Another approach, which is supported by randomized
controlled trial data, is the injection of a mixture of local
anesthetic and corticosteroid solution over the greater occipital nerve on the side of the pain. This approach would normally be limited to use once in every 8–12 weeks.
Preventive Treatment
Preventive treatment aims to suppress the attacks for the duration of the bout, or over longer periods in those with chronic
cluster headache. High doses of preventative medications are
often required, so this approach aims to balance a good or
satisfactory response in terms of reducing the frequency, severity,
and duration of attacks against minimal drug-related side effects.
Verapamil, an L-type calcium channel blocker of the phenylalkylamine class, is the preventive drug of choice, and
this largely consensus agreement is supported by a small
double-blinded multicenter placebo controlled study. Baseline
electrocardiography must be performed before initiating verapamil, with monitoring electrocardiograms performed fortnightly before each incremental dose increase. High doses are
often needed, and electrocardiogram monitoring is essential
as conduction delays and cardiac arrhythmias are a common
side effect.
Lithium salts can also be a useful preventive treatment,
even though it is generally less effective than verapamil and it
is associated with greater side effects and the need for regular
plasma monitoring.
Observational studies have also suggested that methysergide
(no longer available in the US), a headache specific ergot derivative with mixed 5-HT receptor effects, can be efficacious,
particularly for short bouts, but its use is restricted owing to its
serious fibrotic side effects, and it should therefore be given for
short periods only under specialist supervision. Temporary relief, and sometimes termination of bouts, can also occasionally
be provided by controlled, repetitive intravenous infusions of
dihydroergotamine, another of the ergot derivatives.
Other agents such as melatonin, the anticonvulsants topiramate, gabapentin, and sodium valproate, in addition to the
benzocycloheptine-based drug pizotifen, are occasionally used
with some success, although data from clinical trials are limited.
Neuromodulation
Several neuromodulatory approaches of varying degrees of
invasiveness and risk exist, which can be effective in providing
relief to patients, especially those who are refractory to
pharmacological interventions.
Newer approaches, which are less invasive, include sphenopalatine ganglion stimulation and the noninvasive delivery of
vagus nerve stimulation using a custom-made external device.
Occipital nerve stimulation involves the extracranial implantation of stimulating electrodes around the greater occipital nerve, situated below the scalp and overlying the
occipital bones, and is generally considered to be a safe
approach providing relief to approximately 70% of chronic
sufferers who do not respond to medication.
Deep brain stimulation in the area of the posterior hypothalamus is also being used to treat refractory cases. This
technique offers good efficacy in approximately 60% of patients, although a small controlled trial was negative, and
death has been reported as a complication of this approach.
Thus, its use should be restricted to patients who have failed
peripheral stimulation techniques.
See also: Autonomic Nervous System; Overview. Headache and
Craniofacial Neuralgias. Headache, Hypnic. Horner’s Syndrome.
Horton, Bayard Taylor. Migraine; Clinical Aspects. Migraine; Genetics.
Migraine, Pathophysiology of. Neuroimaging, Headache Disorders
and. Neuromodulation Techniques, Pain and. Pain; Basic
Trigeminal Autonomic Cephalalgias (TACs) – Cluster Headache
Mechanisms. Parasympathetic System; Overview. Pituitary Tumors.
Ptosis. Pupillary Disorders, Afferent. Trigeminal Autonomic
Cephalalgias (TACs) – Hemicrania Continua. Trigeminal Autonomic
Cephalalgias (TACs) – Paroxysmal Hemicrania. Trigeminal Autonomic
Cephalalgias (TACs) – SUNCT/SUNA. Willis, Thomas
Further Reading
Akerman S, Holland PR, and Goadsby PJ (2011) Diencephalic and brainstem
mechanisms in migraine. Nature Reviews in Neuroscience 12: 570–584.
Leone M and Bussone G (2009) Pathophysiology of trigeminal autonomic
cephalalgias. Lancet Neurology 8: 755–764.
May A (2005) Cluster headache: Pathogenesis, diagnosis, and management. Lancet
366: 843–855.
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May A, Bahra A, Büchel C, Frackowiak RS, and Goadsby PJ (1998) Hypothalamic
activation in cluster headache attacks. Lancet 352: 275–278.
Nesbitt AD and Goadsby PJ (2012) Cluster headache. British Medical Journal 344:
37–42.
Relevant Websites
http://learning.bmj.com/learning/module-intro/cluster-headache-diagnosismanagement.htmlmoduleId=5004479
BMJ Learning.
http://ihs-classification.org/en/
IHS Classification.
http://www.ouchuk.org/
Organisation for the Understanding of Cluster Headache.