Pathophysiology

The underlying pathophysiology of CH is incompletely understood. [4, 5] The periodicity of the attacks
suggests the involvement of a biologic clock within the hypothalamus (which controls circadian rhythms),
with central disinhibition of the nociceptive and autonomic pathwaysspecifically, the trigeminal
nociceptive pathways. Positron emission tomography (PET) and voxel-based morphometry have identified
the posterior hypothalamic gray matter as the key area for the basic defect in CH. [1] See the images below.

Cluster headache: Functional imaging shows activation of

specific brain areas during pain. Courtesy of Wikipedia Commons.

Cluster headache (CH): Voxel-based

morphometry (VBM) structural imaging shows specific brain area of CH patients' (hypothalamus) being different to nonCH patients' brains. Courtesy of Wikipedia Commons.

Altered habituation patterns and changes have been observed within the trigeminal-facial neuronal circuitry
secondary to central sensitization, in addition to dysfunction of the serotonergic raphe nuclei-hypothalamic
pathways (though the latter is not as striking as in migraine). Functional hypothalamic dysfunction has been

confirmed by abnormal metabolism based on the N-acetylaspartate neuronal marker in magnetic

resonance spectroscopy.[6]
Substance P neurons carry sensory and motor impulses in the maxillary and ophthalmic divisions of the
trigeminal nerve. These connect with the sphenopalatine ganglion and interior carotid perivascular
sympathetic plexus. Somatostatin inhibits substance P and reduces the duration and intensity of CH.
Vascular dilatation may play a role in the pathogenesis of CH, but blood flow studies are inconsistent.
Extracranial blood flow (hyperthermia and increased temporal artery blood flow) increases, but only after
the onset of pain. Vascular change is considered secondary to primary neuronal discharge.
Although the evidence supporting a causative role for histamine is inconsistent, cluster headaches may be
precipitated with small amounts of histamine. Antihistamines do not abort cluster headaches. Increased
numbers of mast cells have been found in the skin of painful areas of some patients, but this finding is
inconsistent.

Link : http://emedicine.medscape.com/article/1142459-overview#a3

Cluster headache
Pathogenesis and pathophysiology
Article section 6 of 16. Previous Next
By Peter J Goadsby MD PhD

The 3 major aspects of the pathophysiology of cluster headache are the trigeminal distribution of
the pain, the autonomic features, and, more important, the inherent periodicity of the attacks and
bouts (Goadsby 2002a). Ekboms observation of a patient suffering an acute cluster headache
demonstrating angiographic changes in the internal carotid artery suggested a pathological focus
in the region of the cavernous sinus (Ekbom and Greitz 1970). The arguments for this locus for the
disease have been set out clearly (Moskowitz 1988; Hardebo 1994). There are no consistent
markers of inflammation when measured in the periphery (Remahl et al 2000) and signs of
cavernous sinus inflammation when studied with SPECT/MRI (Schuh-Hofer et al 2006). Three lines
of evidence suggest that the cavernous sinus is not the site of the basic biological problem. The
clinical manifestations outlined above, in particular the periodicity, the neuroendocrine changes,
and the functional neuroimaging results (Cohen and Goadsby 2006; DaSilva et al 2007), suggest
that cluster headache involves biological dysfunction in the posterior hypothalamic grey matter
pacemaker neurons.
Pain transmission in cluster headache. The pain of cluster headache is a first division of
trigeminal phenomenon. Many of the autonomic features are due to seventh nerve activation,
whereas the remaining changes are due to a transient cervical sympathetic deficiency. It is both
clinically likely and experimentally clear (Goadsby and Duckworth 1987) that a trigeminalautonomic reflex underlies the pain expression of cluster headache. There are neuropeptide
changes in the cranial circulation in both calcitonin gene-related peptide (CGRP) and vasoactive
intestinal polypeptide (Goadsby and Edvinsson 1994; Fanciullacci et al 1995) and nociceptin
(Ertsey et al 2004) release during headache that reflect the trigeminal and autonomic dimensions
of the syndrome. Human studies have shown that this process does not seem to be active in
cluster headache (May et al 1998c), at least as far as experimental plasma protein extravasation is
concerned (Moskowitz and Cutrer 1993). Interestingly, in rats with 5-HT1D immunoreactivity there
are documented primary afferents fibers that innervate postganglionic neurons in the
sphenopalatine ganglion, suggesting a site for modulation by triptans (Ivanusic et al 2011). Taken
together, the clinical and experimental evidence has suggested the term trigeminal autonomic
cephalalgias as an umbrella term for cluster headache and related conditions (Goadsby and Lipton
1997). Drummond argues for a peripheral sympathetic autonomic disturbance (Drummond 2006),

and minimal systemic autonomic disturbances are reported (van Vliet et al 2006c). For cluster
headache, a crucial aspect of the dysfunction appears to lie within the ipsilateral hypothalamic grey
(May et al 1998a), and it is clear that the carotid flow changes are driven by the ophthalmic
division of the trigeminal nerve and are not due to cluster headache as such. Further evidence of
brain mechanisms in cluster headache patients is the fact that the nociceptive flexion reflex
threshold is asymmetrically reduced (Sandrini et al 2000). More challenging is the observation of a
typical cluster headache patient whose attacks persist after trigeminal root section (Matharu and
Goadsby 2002; Jarrar et al 2003). In comparison to migraine, it is notable that there is no defect
in habituation of the nociceptive blink reflex in cluster headache (Holle et al 2012b), with
lateralized facilitation of central pain pathways (Holle et al 2012a).
Neuroendocrine changes in cluster headache. Kudrow pointed out that testosterone levels are
altered in cluster headache patients during a bout (Kudrow 1976; 1977b). Leone and colleagues
identified reduced responses to stimulation by thyrotropin-releasing hormone (Leone et al 1990),
and interesting observations have been made of disordered circadian rhythm for cortisol, growth
hormone, luteinizing hormone, and prolactin (Chazot et al 1984; Waldenlind and Gustafsson
1987). Despite suggested involvement of the hypothalamic-pituitary axis, somatostatin infusion
does not trigger acute cluster headache even with suppression of growth hormone (Levy et al
2003). One area involved in human clock systems is the suprachiasmatic nucleus in the
hypothalamic grey, which sits at the base of the third ventricle (Moore-Ede 1983; Moore 1997).
Melatonin is produced by the pineal gland and has a strong circadian rhythm, which is regulated by
the suprachiasmatic nucleus. Connections between the retina and the hypothalamus are thought to
provide light cues for the circadian rhythm (Hofman et al 1996). The characteristic nocturnal peak
of melatonin secretion is blunted during the active phase of cluster headache (Waldenlind et al
1987), whereas urinary excretion of 6-sulphatoxymelatonin, the main metabolite of melatonin, is
reduced both within and between bouts compared with controls (Leone et al 1998). This suggests
a defect with some permanent nature possibly amenable to treatment (Leone and Bussone 1998).
Involvement in some part of nitric oxide mechanisms in cluster headache is supported by the
finding of elevated levels of nitrix oxide-oxidation end products in the CSF of patients with cluster
headache (Steinberg et al 2010). Latencies of the endogenous event-related-potential components
are significantly increased during the cluster period as compared with outside the cluster period
and with healthy subjects (Evers et al 1999), further contributing to the notion of a central
nervous system dysfunction. The hypothalamic gray is, therefore, of potential interest in studies of
cluster headache.
Functional imaging and other physiological studies of cluster headache. Acute cluster
headache triggered by nitroglycerin produces brain activations on positron emission tomography
(PET) that fall into 3 categories: areas generally associated with pain, an area that seems specific
to cluster headache, and vascular structures (May et al 1998a). The anterior cingulate was
significantly activated, as would be expected, because in most human PET pain studies, activation
of the anterior cingulate is observed, perhaps as a part of the affective response. Its degree of
activation seems to track the subjective reporting of pain (May et al 2000b) and can be seen in
spontaneous attacks (Sprenger et al 2004) and when using fMRI (Morelli et al 2009). Activation
was also noted in the frontal cortex and insulae and ventroposterior thalamus contralateral to the
side of the pain. In addition, activation in the ipsilateral basal ganglia was observed. This is not the
first observation of basal ganglia changes associated with pain (Chudler and Dong 1995;
Derbyshire et al 1997). This may simply relate to movement, the wish to move that is common in
cluster patients, or even some deliberate inhibition of movement. Moreover, after occipital nerve
stimulation (see Management section), there was normalization of pain matrix areas and lower
pons but not of the posterior hypothalamic region. Remarkably, the perigenual anterior cingulate

cortex was hyperactive in occipital nerve stimulation responders compared to nonresponders

(Magis et al 2011a).
The only activated area that is particular to cluster headache is a region near the base of the third
ventricle, the posterior hypothalamic gray matter. One may speculate that orexinergic neurons
play some role at this level (Holland and Goadsby 2009), and indeed, data demonstrate reduced
orexin levels in the CSF of cluster headache patients (Barloese et al 2014b). Activation of the
hypothalamic gray matter in this region is not seen in migraine (Afridi and Goadsby 2006), nor in
experimental first (ophthalmic) division of trigeminal nerve head pain (May et al 1998b). This
region is not activated when the patient is out of a bout (May et al 2000a) but, remarkably, seems
to have some structural difference when compared to control brains, notably a subtle increase in
gray matter volume in the posterior hypothalamus (May et al 1999a). Moreover, a PET scan of a
patient with both cluster headache and migraine who had a migraine at the time of the PET scan
only showed brainstem, and not hypothalamic, activation (Bahra et al 2001). An increase of 20 Hz
in the local field potential power in the region of the posterior hypothalamus has been noted in a
patient undergoing implantation who had a spontaneous attack of cluster headache (Brittain et al
2009). These observations have led to implantation of deep brain stimulating electrodes into this
portion of the brain with excellent outcomes in otherwise intractable patients (Franzini et al 2003;
Leone 2006). Stimulation of the posterior hypothalamic region using the implanted electrodes
produces a unique pattern of activation and de-activation in the brain, suggesting that the
therapeutic effect is specific and not head pain generic (May et al 2006). Similarly, 1H-MRS studies
have reported reduced N-acetylaspartate levels, implying local neuronal loss or dysfunction in the
posterior hypothalamic region (Lodi et al 2006; Wang et al 2006) whereas resting-state network
fMRI demonstrated increased connectivity between hypothalamic and thalamic nuclei in cluster
headache (Rocca et al 2010). Supporting a brain basis for cluster headache, 11C-diprenorphine
PET studies reveal reduced pineal opiate receptor availability (Sprenger et al 2006) and triggering
of attacks from emotional trauma (Sandor et al 2006). It is to be expected that discussion remains
as to both the mechanism and effective site of stimulation. It has been noted through indirect
means that the optimal site for stimulation is located in the region just posterior to the
hypothalamus (Fontaine et al 2010), although the clear anatomical definition of the posterior
hypothalamus in humans seems unclear if one considers the basis on which the structure has been
defined. It has been shown using high-resolution T1-weighted MRI that cortical thickness in cluster
headache patients is reduced compared to controls, perhaps related to disease duration, ie, as a
consequence not cause (Seifert et al 2012).
During acute cluster headache, activation or signal on the PET studies is observed in the region of
the cavernous sinus (May et al 1998a) and has been shown, using MRA, to be due to internal
carotid artery vasodilation (May et al 1999b). The same region is activated during capsaicininduced experimental head pain (May et al 2000a; 2001), but when capsaicin is injected into the
skin innervated by the mandibular division of the trigeminal nerve or the ipsilateral leg, no carotid
dilation is observed (May et al 2001). Moreover, after trigeminal root section, attacks of tearing
without pain are well recognized (Matharu and Goadsby 2002; Lin and Dodick 2005). These data
imply that the activation of the carotid does not relate specifically to cluster headache, but that it
is a trigeminovascular autonomic reflex to first division pain. The flow changes are, therefore, an
epiphenomenon of the trigeminal activation, and not part of the disease generation process in
cluster headache.

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Cluster headache
Prognosis and complications
Article section 11 of 16. Previous Next
By Peter J Goadsby MD PhD

The prognosis of episodic cluster headache is generally good. As patients age, cluster headaches
usually disappear. Approximately 10% of patients have the chronic variety of cluster headache,
which tends to run a difficult and often intractable course. Transformation from the episodic to the
chronic form, and less commonly from the chronic to the episodic variety, is well recognized. In a
follow-up study with a range of 2 to 17 years, 27% of 60 newly diagnosed patients had only 1
attack over a mean follow-up of 8.9 years (Sjostrand et al 2000). A number of patients with
cluster headache have obstructive sleep apnea (Kudrow et al 1984; Chervin et al 2000; Nobre et al
2003; 2005; Graff-Radford and Newman 2004), and it can be clinically useful to inquire about such
symptoms and investigate appropriately.

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Cluster headache
Management
Article section 12 of 16. Previous Next
By Peter J Goadsby MD PhD

The management of cluster headache can be divided into the management of the acute attacks of
pain and preventive management to reduce the number of attacks or control the attacks during a
bout (Dodick et al 2000; Goadsby et al 2007; Nesbitt and Goadsby 2012). Some surgical options
are available, and these may afford a more permanent solution; however, they are not guaranteed
to work, nor are they without significant morbidity. An interesting development is the description
of headache caused by medication overuse in patients with cluster headache who all had
migrainous biology (Paemeleire et al 2006); the message for practitioners is to beware of this
complication in that group.
Preventive treatments. The options for preventive treatment in cluster headache are determined
by the length of the bout, not by whether the patient has the episodic or chronic variety of the
condition. Treatments may be regarded as short- or long-term preventive treatments, based on
how quickly they act and how long they can be safely used. Most experts favor verapamil as the
first-line preventive treatment, although short-term prevention with limited courses of oral
corticosteroids (Jammes 1975; Antonaci et al 2005), ergotamine (Friedman and Mikropoulos
1958), or methysergide (Curran et al 1967) can be useful strategies for some patients with short
bouts.
Verapamil has been used for cluster headache for over a decade (Gabai and Spierings 1989). It is
superior to placebo (Leone et al 2000) and compares favorably with lithium (Bussone et al 1990).
Clinical practice has shown that the verapamil dosage should be higher than that used for cardiac
indications and higher than what originally was thought necessary. Although most patients will
start on doses as low as 40 mg twice daily, doses up to 960 mg daily are now employed (Olesen
and Goadsby 1999). Side effects, such as constipation and leg swelling can be a problem
(Silberstein 1994), but more difficult is the issue of cardiovascular safety. Verapamil can cause
heart block by slowing conduction in the atrioventricular node (Singh and Nademanee 1987), as

demonstrated by prolongation of the A-H interval (Naylor 1988). Given that the PR interval on the
ECG is made up of atrial conduction and A-H and His bundle conduction, it may be difficult to
monitor subtle early effects as the verapamil dose is increased. This question needs study in this
group of patients, but for the moment it seems appropriate to do a baseline ECG and then repeat
the ECG 1 to 2 weeks after a dose change, usually in 80 mg increments, when doses exceed 240
mg daily (Cohen et al 2007; Lanteri-Minet et al 2011). We have also seen a malignant skin lesion
related to verapamil usage, lymphomatoid papulosis (Afridi et al 2004), which may prove an issue
in the future.
Because of its side effects, lithium carbonate is mainly used for the prophylactic treatment of
chronic cluster headache, but it is sometimes employed in the episodic variety (Ekbom 1977;
1981; Kudrow 1977a; Mathew 1978). The usual dose of lithium is 600 to 900 mg per day in
divided doses. Lithium levels should be obtained within the first week and periodically thereafter.
The serum level required for therapeutic response is usually 0.4 to 0.8 mEq/L. Lithium and
verapamil were shown to be similar in a comparative trial (Bussone et al 1990). The side effects of
lithium are significant, and its use needs to be carefully monitored. Neurotoxic effects such as
tremor, lethargy, slurred speech, blurred vision, confusion, nystagmus, ataxia, extrapyramidal
signs, and seizures can occur if toxic levels are reached. Concomitant use of sodium-depleting
diuretics should be avoided, as sodium depletion will result in high lithium levels and neurotoxicity.
Long-term effects such as hypothyroidism and renal complications must be monitored when
chronic cluster headache patients use lithium for extended periods of time. Polymorphonuclear
leukocytosis is a common reaction to lithium and is often mistaken for occult infection.
Concomitant use with indomethacin can increase the lithium level; an important consideration is a
trial in a relatively refractory patient in consideration of paroxysmal hemicrania.
An open study suggested that valproate is effective as a preventive treatment of cluster headache
(Hering and Kuritzky 1989), but a subsequent controlled study showed no advantage (El Amrani et
al 2002b). Melatonin may be helpful as a cluster headache preventive (Leone et al 1996; Peres
and Rozen 2001; Pringsheim et al 2002). Intranasal capsaicin application has also been used
(Marks et al 1993), and intranasal civamide has modest effects (Saper et al 2002). Induction of
nitrate tolerance is not helpful in cluster headache (Christiansen et al 2000). Gabapentin has been
reported to be useful in cluster headache in some cases (Ahmed 2000; Leandri et al 2001; Tay et
al 2001). Similarly, topiramate has proved effective in a number of cases (Wheeler and Carrazana
1999; Mathew et al 2002; Forderreuther et al 2003; Lainez et al 2003; Leone et al 2003; Rapoport
et al 2003), but a controlled trial is required. Testosterone therapy has been used with some
success for refractory cluster headache (Stillman 2006); there is a report of psilocybin and LSD
use (Sewell et al 2006) and of 2-bromo-lysergic acid diethylamide use (Karst et al 2010); each
requires more controlled investigations. Given the involvement of circadian biology in cluster
headache, the possible use of sodium oxybate as a preventive in chronic cluster headache is an
interesting new suggestion (Khatami et al 2011).
Newer triptans have been suggested to be helpful as preventives in cluster headache, although the
studies have not been easy to conduct (Gaul and Jurgens 2011). As a short-term preventive
approach, a course of intravenous dihydroergotamine can be helpful (Nagy et al 2011).
Acute attack treatment. Cluster headache attacks often peak rapidly and, thus, require a
treatment that has a quick onset. Moreover, the established placebo effect in cluster headache
(Nilsson Remahl et al 2003) makes it necessary to conduct controlled trials.
Many patients with acute cluster headache respond well to treatment with oxygen inhalation
(Kudrow 1981; Fogan 1985). A placebo-controlled study has established clearly that oxygen is

superior to air in the treatment of acute cluster headache (Cohen et al 2009). This should be given
as 100% oxygen at 10 to 12 L/min for 15 minutes. It seems important to have a high flow and
high oxygen content, whereas hyperbaric oxygen confers no prophylactic benefit above its
treatment in acute attacks (Nilsson Remahl et al 2002). Some proportion of patients who are
treated with oxygen for acute attacks have the attacks rebound quickly when it is stopped
(Geerlings et al 2011), and this can limit the utility of oxygen therapy.
Injectable sumatriptan has been a boon for many patients with cluster headache (Goadsby 1994).
It is effective and rapid in onset (Ekbom and The Sumatriptan Cluster Headache Study Group
1991), with no dose-response benefit over 6 mg and no evidence of tachyphylaxis (Ekbom et al
1993), although there has been one report of increased headache frequency (Rossi et al 2004).
Sumatriptan is not effective when given preemptively as 100 mg orally 3 times daily (Monstad et
al 1995), although longer acting triptans, such as frovatriptan (Gaul and Jurgens 2011), have been
used in open-label fashion. Both intranasal sumatriptan (20 mg) (van Vliet et al 2003a) and
intranasal zolmitriptan (5 mg) (Cittadini et al 2006; Rapoport et al 2007) have been shown to be
effective in acute cluster headache in placebo-controlled trials. Olanzapine has been reported to be
helpful for acute cluster headache (Rozen 2001); this requires a controlled trial.
Dihydroergotamine is effective in the relief of acute attacks of cluster headache (Horton 1952).
Intravenous administration gives rapid relief in less than 10 minutes, whereas intramuscular
injection takes longer to be effective. Intranasal administration of dihydroergotamine may also be
of benefit (Andersson and Jespersen 1986). Dihydroergotamine can be used repetitively to
improve some patients with more difficult cluster headache (Mather et al 1991). Clinical experience
suggests that ergotamine by inhalation may be useful, although the oral and suppository
formulations are too slow-acting.
Locally applied lidocaine nasal drops have been reported to be effective in the treatment of acute
attacks of cluster headache (Kitrelle et al 1985). Patients are told to lie supine with the head tilted
backwards toward the floor at 30 degrees and turned to the side of the headache. A nasal dropper
may be used and the dose (1 mL of 4% lidocaine) repeated once after 15 minutes. An interesting
extension of this concept is the use of cocaine in cluster headache, which works for some patients
(Penarrocha et al 2000), presumably in the same way as lidocaine (Costa et al 2000).
Procedures. Injection of certain nerves and more radical procedures has been employed in
patients with frequent or intractable attacks of cluster headache.
Injections of methylprednisolone (120 mg) with lidocaine into the greater occipital nerve ipsilateral
to the site of attack have been reported to result in remissions lasting from 5 to 73 days (Anthony
1985). This is a simple, relatively benign procedure that seems to help some patients (Ambrosini
et al 2005; Afridi et al 2006; Leroux et al 2011). Interestingly, changes in the nociception-specific
blink reflex do not predict a clinical effect (Busch et al 2006), suggesting that the mechanism is
rostral in the CNS. Blockade of the sphenopalatine ganglion using cocaine or lidocaine is a useful
temporary measure to give freedom from attacks for a few days, although an endoscopic study
reported 2 of 21 patients having a break of 12 months or more (Felisati et al 2006; Pipolo et al
2010). The recurrence rate is high, however. In one series, 40% of patients with cluster headache
reported improvement after radiofrequency lesion of the ipsilateral sphenopalatine ganglion
(Filippini-De Moor et al 1999; Narouze et al 2009). Microvascular decompression does not seem
useful (Oomen et al 2011). Initial data from a randomized controlled trial have been preliminarily
reported as positive (Schoenen et al 2011).

A small number of patients with cluster headache are intractable to treatment and require
consideration for surgical treatment (Goadsby et al 2006). Accepted favorable indications for
surgical treatment include (1) strictly unilateral headache, (2) total resistance to medical therapy
or significant contraindications to the use of effective medical therapy, and (3) a stable personality
profile without the potential for addictive behavior. The current choice is between destructive and
neuromodulatory procedures.
One destructive procedure is radiofrequency thermocoagulation of the trigeminal ganglion (Onofrio
and Campbell 1986; Mathew and Hurt 1988). The procedure is essentially the same as that done
for trigeminal neuralgia, except that both the first and second divisions of the trigeminal nerve are
made fully analgesic. The overall results have been encouraging. Almost 75% of patients become
free of cluster headache attacks. Recurrence of pain is possible, however, after a number of years.
A repeat surgical procedure is considered in such patients. Corneal analgesia with resulting
potential corneal infection or opacification and anesthesia dolorosa is an important sequelae. The
benefit from surgery generally outweighs the potential sequelae, and, therefore, it is worth
considering in patients with total resistance to medical treatment. Injections of percutaneous
retrogasserian glycerol rhizolysis have resulted in an initial 83% improvement with a 39%
recurrence (Pieper et al 2000); numbers are small and the uncontrolled nature of the injection is
unattractive.
Gamma knife radiosurgery has been suggested (Ford et al 1998), but an open study indicates that
such an approach is not useful in the long term (Donnet et al 2005) and can produce
deafferentation pain (Donnet et al 2012). A more invasive approach is trigeminal root section.
There are 2 substantial series in the literature (Kirkpatrick et al 1993; Jarrar et al 2003). Although
some patients do well, some die a drastic outcome by any standard.
Based on functional imaging studies that identified the posterior hypothalamic grey as a target
area of importance in cluster headache (May et al 1998a), deep brain stimulation has been used.
Some excellent early reports indicate that this approach is effective in some patients (Franzini et al
2003; Leone et al 2004; 2006), although again caution is required because 1 death has been
reported (Schoenen et al 2005). An alternative is occipital nerve stimulation, which is widely
regarded as being helpful (Burns et al 2007; 2009; Magis et al 2007), and is without significant
morbidity or mortality. It has a good long-term effect (Magis et al 2011b) and is to be preferred
over deep-brain stimulation procedures, although optimal use of the therapy is yet to be
determined (Mueller et al 2011).
Other treatments. There has been discussion on the use of hallucinogenic drugs to treat cluster
headache. Perhaps one quarter of patients have used such treatments (Rossi et al 2012). Much
work needs to be done to understand whether such an approach has a sustainable role or whether
it is a distraction (May 2012) given the comparable pharmacology between, for example, BOL-148,
2-bromo-lysergic acid diethylamide (Karst et al 2010), methysergide, and ergotamine (Berde and
Schild 1978).

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Cluster headache
Clinical manifestations
Article section 3 of 16. Previous Next
By Peter J Goadsby MD PhD

There are 2 major forms of cluster headache, namely, episodic cluster headache and chronic
cluster headache (Headache Classification Committee of The International Headache Society
2004). The term attack generally is used to refer to a distinct attack of pain, whereas a bout is a
series or cluster of attacks. Thus, episodic cluster headache is characterized by bouts lasting 7
days to 1 year separated by remission periods lasting 1 month or longer. Chronic cluster headache
is characterized by the absence of remission for 1 year or short remissions of less than 1 month.
Both classifications assume no preventive treatments. Patients cluster headaches may evolve from
the episodic to the chronic form with sporadic, late-onset attacks, a high frequency of cluster
periods, and short-lived duration of remission periods when the headache is still the episodic form,
all correlating with the transition to the chronic form (Torelli and Manzoni 2002). Chronic cluster
headache may be seen de novo (primary), or it may evolve from the episodic form (secondary);
differences between the 2 include earlier cluster headache onset and duration of attacks varying
more frequently between 120 and 180 minutes (Torelli et al 2000), although in practice this
distinction seems to have no clinical utility (Donnet et al 2007). Cluster headache is extremely
disabling when patients are experiencing a bout (D'Amico et al 2002). Even with chronic cluster
headache, cycling can occur (Irimia et al 2008b), which could be called micro-cycling; a similar
phenomenon is seen in SUNCT (Irimia et al 2008b).
The attack consists of the rapid onset of headache that builds to a peak in about 10 to 15 minutes
and lasts for approximately 30 to 180 minutes, although longer attacks are not infrequent (van
Vliet et al 2006a). The headache is almost always unilateral. In order of decreasing frequency,
common sites of pain are: orbital, retro-orbital, temporal, supraorbital, and infraorbital. The head
pain occasionally switches sides, and in extremely rare cases it can be bilateral. Typically, the pain
is in the trigeminal nerve distribution, but extra-trigeminal pain, especially in the suboccipital area,
is known to occur. Rarely, attacks may occur without cranial autonomic symptoms, although in
each such case we have seen, the patients have had typical agitation and restlessness. Cranial
autonomic symptoms can also occur alone (Martins et al 2005), typically in patients who have
been treated with nerve root sections (Matharu and Goadsby 2002). The number of attacks per
day varies, usually from 1 to 3, but the International Headache Society classification allows from 1
every second day to 8 per day. More frequent or treatment-resistant attacks should lead to
consideration of other trigeminal-autonomic syndromes, such as paroxysmal hemicrania.
Migrainous features, such as nausea, photophobia, and phonophobia, can be present in as many
as half of cluster headache cases (Bahra et al 2000b). Moreover, between 6% (Silberstein et al
2000) and 14% (Bahra et al 2000b) of patients report typical migraine aura with their cluster
headache. Hemiplegic aura has been reported (Siow et al 2002). This needs careful evaluation
from a diagnostic viewpoint. Cluster headache is well-recognized in children (McNabb and
Whitehouse 1999; Lampl 2002), and this author has seen a 3-year-old child with a convincing
story, although it may begin as late as 89 years of age (Fischera et al 2005).
One remarkable aspect of cluster headache is its periodicity, with attacks often occurring at almost
the same time every day (Ekbom 1970); this phenomenon has resulted in suggestions that human
circadian pacemaker physiology is involved. Nocturnal attacks occur during both REM and non-REM
sleep periods (Kudrow et al 1984). Sleep studies show reduced REM sleep in cluster headache
(Barloese et al 2014a). Attacks are characterized by excruciating pain that is regarded by
sufferers, without exception, as the worst pain that they have ever experienced. The pain is
associated with ipsilateral cranial parasympathetic overactivity, lacrimation, conjunctival injection
and nasal stuffiness or rhinorrhea, and an ipsilateral partial (third neuron) Horner syndrome
(Drummond 1988) with ptosis and miosis. These symptoms are equally likely in episodic and
chronic cluster headache (Gaul et al 2012). In exceptional cases, the cranial autonomic symptoms
can result in obvious swelling (Attanasio et al 2000) or even nose bleeds. Although less common

than in migraine, photophobia and phonophobia occur in cluster headache (Vingen et al 1998) and
when present are more often lateralized to the side of the pain (Irimia et al 2008a).
Neurologic examination may reveal mild ptosis and miosis on the side of the headache, especially
during or immediately following the attack, and from time to time impaired trigeminal sensation,
although the latter will trigger a search for a lesion. Ipsilateral tenderness of the carotid artery,
periorbital swelling, and congestion of the conjunctiva are also noted. During a bout, a subtle but
convincing, mild, partial Horner syndrome ipsilateral to the pain is often present. Alcohol,
nitroglycerin, and histamine can induce attacks during cluster periods (Horton et al 1939; Ekbom
and Kugelberg 1968). Allodynia and interictal pain is seen in cluster headache (Lance and Goadsby
2005; Marmura et al 2010) and is almost invariably found in patients who also have a personal or
family history of migraine.

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Cluster headache
Etiology
Article section 5 of 16. Previous Next
By Peter J Goadsby MD PhD

The etiology of cluster headaches is not known. It seems likely that some inherited basis for the
problem exists (Russell et al 1995; 1996; Montagna et al 1998a; 1998b; Leone et al 2001;
Svensson et al 2003; Russell 2004), although it has proved hard to study (El Amrani et al 2002a).
Cluster headache is probably not related to the familial hemiplegic migraineCACNA1A gene (Haan
et al 2001; Sjostrand et al 2001) or to nitric oxide synthase genes (Sjostrand et al 2002) or to
methylenetetrahydrofolate reductase C>T polymorphism (Schurks et al 2010). There are reports of
a polymorphism in the hypocretin receptor 2 gene (Rainero et al 2004; 2008; Schurks et al 2006),
which would be attractive because of the localization in the hypothalamus (Smart and Jerman
2002), although the finding could not be reproduced in another group (Baumber et al 2006), and
the CSF levels of hypocretin-1 are unaltered in cluster headache (Cevoli et al 2011).

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Cluster headache
Differential diagnosis
Article section 9 of 16. Previous Next
By Peter J Goadsby MD PhD

The differential diagnosis for cluster headache lies between other trigeminal autonomic cephalalgia
and the so-called secondary cluster headache syndromes, where pituitary tumour pathology is an
important consideration (Levy et al 2004; Levy et al 2005; Favier et al 2007a; Favier et al 2007b;
Schankin et al 2012). Unfortunately, cluster headache is often missed (Geweke 2002), and many
patients have unnecessary dental (Penarrocha et al 2001) and ENT procedures (Bahra and
Goadsby 2004). Reasons for missing the diagnosis include gender (ie, a female patient) (Bahra
and Goadsby 2004) and the presence of migrainous features, such as photophobia or phonophobia
(van Vliet et al 2003b). The primary headaches that arise in the differential diagnosis of cluster
headache include paroxysmal hemicrania, short-lasting neuralgiform headache attacks with

conjunctival injection and tearing (SUNCT), and hemicrania continua (Goadsby and Lipton 1997;
Silberstein et al 1998). These can be differentiated by clinical features, such as length and
frequency of attacks, and by the response to indomethacin, which is absent for cluster headache,
at least in an open-label study (Antonaci et al 2003) and in the authors placebo-controlled
experience. It is likely that cases of cluster headache labeled as indomethacin-sensitive are
misdiagnosed (Prakash et al 2010). Trigeminal neuralgia is sometimes mistaken for cluster
headache, but the attacks are much shorter, and autonomic activation does not seem to be an
important issue. Hypnic headache is a more moderate form of headache that is usually seen in the
elderly. It is characterized by attacks of moderately severe headache that come on after falling
asleep. The attacks can usually be controlled by lithium taken at night or by caffeine consumption
(Raskin 1988; Newman et al 1990; Gould and Silberstein 1997; Dodick et al 1998; Ivanez et al
1998; Morales-Asin et al 1998).
Table 1. Diagnostic Criteria for Cluster Headaches

At least 5 attacks fulfilling the following criteria:

Severe or very severe unilateral orbital, supraorbital, or temporal pain lasting 15 to 180
minutes if untreated.
Headache accompanied by one of the following:
- ipsilateral conjunctival infection or lacrimation
- ipsilateral nasal congestion or rhinorrhea
- ipsilateral eyelid edema
- ipsilateral forehead and facial sweating
- ipsilateral miosis or ptosis
- a sense of restlessness or agitation
Attacks have a frequency from one every other day to 8 per day
Attacks are not attributed to another disorder
Episodic cluster headaches also have at least 2 cluster periods lasting 7 days to 1 year and separated
by pain-free remission periods of 1 month or more.
Chronic cluster headaches also have attacks that recur for more than 1 year, without remission
periods or with remission periods lasting less than 1 month.
It could be argued that secondary cluster headache should be divided into lesions that produce
trigeminal-autonomic activation, which one might call pseudo-secondary cluster headache, where
episodicity is not a key feature, and true secondary cluster headache. The latter is likely to be due
to lesions in and around the diencephalon. A secondary cluster headache should be suspected
when the clinical features of the headache are atypical. Atypical features include lack of periodicity,
inter-attack pain (although this can be seen with frequent attacks), poor response to medications,
and neurologic signs other than a partial Horner syndrome.
Table 2. Differential Diagnosis of Trigeminal Autonomic Cephalalgias

Primary trigeminal autonomic cephalalgias

Cluster headache
Paroxysmal hemicrania
SUNCT/SUNA syndrome
Similar secondary headaches
Tolosa-Hunt syndrome
Maxillary sinusitis

 Temporal arteritis
Raeder paratrigeminal neuralgia (Goadsby 2002b)
Trigeminal neuralgia
Secondary trigeminal autonomic cephalalgias cluster-like headaches
Vascular:
- Carotid artery dissection (Rosebraugh et al 1997; Mainardi et al
2002;Razvi et al 2006; Godeiro-Junior et al 2008; Tsivgoulis et al 2013) or
aneurysm (Greve and Mai 1988)
- Vertebral artery dissection (Cremer et al 1995) or aneurysm (West and
Todman 1991)
- Pseudoaneurysm of intracavernous carotid artery (Koenigsberg et al 1994)
- Anterior communicating artery aneurysm (Sjaastad et al 1976; Greve and
Mai 1988)
- Occipital lobe AVM (Mani and Deeter 1982)
- Middle cerebral artery territory AVM (Munoz et al 1996)
- AVM in soft tissue of scalp above ear (Thomas 1975)
- Frontal lobe and corpus callosum AVM (Gawel et al 1989)
- Cervical cord infarction (de la Sayette et al 1999)
- Lateral medullary infarction (Cid et al 2000)
- Frontotemporal subdural hematoma (Formisano et al 1990)
- Trigeminal root compression (Mjaset and Russell 2010)
Tumors:
- Pituitary tumors (Tfelt-Hansen et al 1982; Greve and Mai 1988; Levy et al
2005; Negoro et al 2005; Favier et al 2007a; Favier et al 2007b; Levy et al
2012; Schankin et al 2012)
- Parasellar meningioma (Hannerz 1989)
- Sphenoidal meningioma (Lefevre et al 1984; Molins et al 1989)
- Epidermoid tumour in the prepontine (behind the dorsum sella turcica)
(Levyman et al 1991)
- Clival epidermoid (Massie et al 2006)
- Tentorial meningioma (Taub et al 1995)
- High cervical meningioma (Kuritzky 1984)
- Nasopharyngeal carcinoma (Appelbaum and Noronha 1989)
- C3 root fibrosis (Creac'h et al 2010)
Infective:
- Maxillary sinusitis (Molins et al 1989)
- Orbito-sphenoidal aspergillosis (Heidegger et al 1997)
- Herpes zoster ophthalmicus (Sacquegna et al 1982)
Posttraumatic or surgery:
- Facial trauma (Lance and Goadsby 1998)
- Following enucleation of eye (Rogado and Graham 1979; McKinney
1983; Prusinski et al 1985; Evers et al 1997)
Dental:
- Impacted wisdom tooth (Romoli and Cudia 1988)
- Following dental extraction (Soros et al 2001)
Miscellaneous:
- Cervical Syringomyelia and Chiari malformation (Seijo-Martinez et al
2004)
- Idiopathic intracranial hypertension (Volcy and Tepper 2006)

SUNCT: Short lasting Unilateral Neuralgiform headache attacks with Conjunctival injection and
Tearing/cranial autonomic features

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