Cluster headache attacks are unilateral, severe, short-lasting (15 to 180 minutes) and recurrent (1 every other day to 8 per day) 1. This special pattern is very important to recognize the cluster headaches and to differentiate them from migraine attacks. A patient describing a pain lasting less than three hours, severe and localized on one side of the head, coming back at specific times of the day or during sleep, must be asked if symptoms like tearing, eye swelling and nasal congestion are present on the other side. The fact that the attack ends after one or two hours must not be attributed to a success of standard analgesics, which are not useful in CH.

A prospective study on clinical characteristics of CH has been published by Bahra et al. 2. Pain is described mostly in the first trigeminal branch territory, on one side of the head only and almost always the same side (rarely, attacks may switch the location). Pain may be centered on the eye but may also be periorbital and temporal, sometimes extending to the maxillary, ear or even occipito-cervical region. Some patients describe the pain as radiating to the teeth, thus they may first consult a dentist. As to its severity, CH is one of the most painful conditions known to man (worse than giving birth according to female patients). It is described as excruciating and intolerable. Patients compare it to a white-hot needle or knife being pushed into the eye, the eye being crushed or ripped of the orbit. Suicidal ideations may be expressed during the attacks. The nickname of the CH among patients is "The Beast", a term suggesting an animal hiding in the shadow, attacking in a terrible and unpredictable way. Pain rises abruptly over a few minutes. It also ends rapidly. In severe chronic forms or in episodic forms with numerous daily attacks, there may be a continuous discomfort on the affected side 20, but usually CH patients are completely asymptomatic between attacks.

Parasympathetic hyperactivity signs include ipsilateral lacrimation, redness of the eye and nasal congestion. The affected side of the face may be red and sweaty. Sympathetic hypoactivity is demonstrated by the combination of ipsilateral ptosis and miosis (droopy eye and smaller pupil on the affected side) during attacks. The combination of ptosis and miosis on one side is called Claude-Bernard-Horner syndrome (CBH). Persistence of CBH signs after the end of the attack in episodic CH should alert the clinician to suspect underlying lesion in hypothalamus, brainstem, paravertebral sympathetic chain or carotid. Proper investigations should be undertaken: brain magnetic resonance imaging (MRI), chest computerized tomography and carotid ultrasound.

Autonomic signs are very prominent in certain patients, but may be subtle or even absent in 3% of patients 21. They can be unrecognized because of the pain ("I close my eye, I cry because I'm in pain"). In case of uncertainty, the patient can be asked to observe these specific signs during the attack.

Physical activity seems to partially alleviate the pain in CH. During the attacks, patients tend to be restless. They may rock from side to side, hit their heads, hit objects with the fist, or even hit their head against the wall 22. This behavior is so typical of CH that it is accepted as an official criterion in the ICHD-II 1. Indeed, it is possible to diagnose CH without any dysautonomic sign if the behavioral criterion is satisfied. This restless attitude may help to differentiate CH from migraine, where patients are quiet and avoid any movement. CH patients are cognitively alert, but may also be irritable and aggressive. There is no mental slowing or fatigue, as it may be seen in migraine patients.

CH shows circannual and circadian cyclicity. Peaks have been described around solstices, in relation to changes in daylight duration 23. Attacks can happen at a precise time during the sleeping cycle, with dramatic regularity reported by patients. This cyclicity is not observed in all CH patients and is not included in the ICHD-II criteria, though most experts find it very suggestive of CH when present.

Alcohol is recognized as the only dietary trigger of CH. Nitroglycerin has been used to trigger attacks for diagnostic purpose (therefore, e nitrates should be avoided during bouts). Strong odors (mainly solvents and cigarette smoke) and napping may trigger CH attacks. It is surprising that all triggers are effective only during bouts. In between periods, patients may smoke and drink alcohol without triggering attacks.

There is a significant delay in diagnosing CH (reported median delay of three years 16), though there is an improvement as compared to the 1960's when a diagnostic delay of more than 20 years was not infrequent 15. Up to 30% of patients have previously undergone many investigations and seen dentists, ENT (ears, nose, throat) surgeons, ophthalmologists, even neurologists, without being diagnosed. Up to 16% may have undergone dental, sinus or eye surgery 16. The periodicity of attacks makes the diagnosis difficult and sometimes suggests an infectious cause. Prednisone can be prescribed for sinusitis and have a positive effect, falsely confirming an erroneous diagnosis. Some patients do not seek medical advice once the bout has ended by itself.

Though aura is not frequent in CH 24, up to 14% of patients report aura symptoms, with transient visual, motor or sensory disturbances preceding the facial pain 2. In chronic CH, auras have been reported in 20% of patients 20. Nausea, vomiting, photophobia and phonophobia can be observed in approximately 50% of patients, and must not discard the diagnosis of CH if other criteria are fulfilled. A shift of the affected side may be observed within a bout or between two bouts in 15% of patients 2. Case reports of "CH sine headache" have described patients with episodes of unilateral facial autonomic dysfunction without pain 2526, but this is very rare.

Initially, CH was not thought to be a genetic disease. With official criteria published and the increasing recognition of the disease, a genetic aspect of CH has been identified. Cases of twin pairs affected by CH have been published 303132. Studies using large twin registries have shown that monozygotic twins present a higher concordance rate for CH (2/12 pairs) than dizygotic twins (0/25 pairs), indicating the existence of genetic factors, but monozygotic twins can also be concordant or discordant for CH, confirming a role for environmental factors 1133. Family studies of CH patients' cohorts have shown a familial aggregation in 7% to 20% of patients, and a relative risk for first-degree relatives between 14 and 39 343536. The transmission mode has still not been established. Some studies have suggested an autosomal dominant way with incomplete penetrance 37, while other described an autosomal recessive transmission 38. So far, no X-linked pedigrees have been published. No susceptibility locus has been identified. Much work has recently been done on the HCRTR2 gene (hypocretin receptor 2) polymorphism 3940, suggesting a role of this gene in CH susceptibility. Hypocretins are secreted in the hypothalamus, a structure clearly involved in CH. All these findings suggest that genetic factors do play a role in CH 4142, though, so far, the transmission mode remains to be established and the contribution of individual factors to be clearly understood. The HCRTR2 gene is a promising research area.

Features suggesting a secondary CH are: persistent or worsening pain, abnormal signs on neurological examination, and a first period after 50 years old. An underlying cause has sometimes been found in a patient with typical CH features 5556. Benign intracranial tumors like meningiomas and neurinomas, but also carcinomas and metastases, have been reported. There seems to be an overrepresentation of pituitary tumors in CH patients 44, and a role of prolactin has been suggested in these cases. Orbital tumors or infections have been reported. Sinusitis may present with symptoms typical for CH. Arteriovenous malformations and aneurysms, if strategically located, may cause CH symptoms. In a first episode, carotid dissection has to be suspected and ruled out (it also can produce Claude-Bernard-Horner syndrome, and the pain may respond to triptans) 57. Any case of refractory CH deserves a brain MRI. Some experts even recommend MRI for every CH patient, to avoid unnecessary treatments if a treatable cause is found.

Because of the excruciating character of the pain, rapid-acting treatments are preferred for acute management of attacks 59. The oral route of administration is too slow and is rarely used. Inhaled, subcutaneous and intra-nasal treatments are preferred. The pain in CH is often underestimated by the medical community. Interictally, patients appear normal. In most cases, witnessing a CH attack is convincing enough, but not possible for every practitioner. Adequate treatments must be provided, and a nihilistic, observational approach should be absolutely avoided.

The two most efficient acute treatments are subcutaneous sumatriptan and high-flow inhaled oxygen.

Sumatriptan is a serotonin 5HT1 B/D agonist, acting on blood vessels with a vasoconstricting effect, and centrally on brainstem receptors. Subcutaneous sumatriptan 6 mg (Imiject, Imitrex) has been shown to efficiently relieve the CH pain and dramatically improve the management of patients 60. After the injection, the patient may feel a rush of heat and chest tightness that disappear in a few minutes and are followed by rapid relief of the pain. Intra-nasal sumatriptan 6162 and zolmitriptan 63 may be tried if patients refuse to use injections. Absolute contra-indications to subcutaneous sumatriptan include pregnancy, lactation, coronary artery disease, stroke, and peripheral artery disease. Relative contra-indications are age (under 18 or over 65), an isolated controlled vascular risk factor, Raynaud phenomenon, allergy to sulfa medications, treatment with a serotonin recapture inhibitor (SSRI). Maximal doses for 24 h period (sumatriptan 12 mg subcutaneous or 40 mg intra-nasal, zolmitriptan 10 mg intra-nasal) have to be explained to the patient to avoid dangerous side effects, such as coronary or distal artery spasm. Surprisingly, CH patients do not develop medication-overuse headache (MOH) with triptans as often as migrainers do 64. They may use regular sumatriptan for many months without developing a different type of headache. As MOH is more frequent in CH patients with a history/diagnosis of migraine, these patients must be carefully monitored for MOH, especially if CH is chronic and refractory 65.

Inhaled oxygen with high-flow (10 to 15 l per minute) 100% normobaric oxygen breathed through a mask is efficient and useful especially when contra-indications to triptans exist 6667. The device is not easy to carry around, and not always reimbursed by health security services, depending on the country. The efficacy of oxygen has been recently re-examined and confirmed. There are no contra-indications or limitations for the use of oxygen.

Ergotamine and dihydroergotamine have been used in CH 68. They must not be combined with triptans on the same 24 hour period, have the same contra-indications as triptans (without additional efficacy), therefore are rarely useful.

Intra-nasal application of topical lidocaine may be tried in refractory CH cases or in case of contra-indications to triptans. Its efficacy is not well proven.

Topic cocaine was used in the past, but abandoned because of equivocal efficacy, side-effects and risks of dependency.

The aim of prophylactic treatment is to reduce the frequency of attacks during the bout. Continuous use of prophylactic treatments in episodic CH is not recommended, since there is no proof that it prevents the next bout. Therefore, the dose may be progressively decreased after two or three months, or after the usual known duration of the bout. The prophylactic treatment should be restarted if attacks reappear. In patients with few attacks per week responding to acute treatment, prophylactic treatment can be withheld. In chronic CH, treatments are used for a long term epriod, and a low attack rate has to be reached (always considering the potentially serious and incapacitating side effects).

The calcium-channel blocker verapamil remains the main treatment of episodic and chronic CH 6970. Doses range from 360 mg to 960 mg per day, and the maximal tolerated dose should be reached before concluding about efficacy. Side effects are weakness, fatigue, lower extremities edema, and conduction heart block. An electrocardiogram should be performed at the baseline and for every increase in the dose when it exceeds 480 mg per day 71.

Greater occipital nerve blocks are used, based on the connection between this nerve and the trigeminal circuitry 72. One randomized study showed that this technique may end a bout, or, at least, may diminish the number of attacks per day 73. More evidence is needed to recommend this procedure 74, but it is widely used by experts 7576. The block is performed with a long-acting injectable steroid, sometimes combined with a local anesthetic. Different combinations have been described. The needle is inserted midway between the mastoid and the occipital protuberance, until it touches the occipital bone (sub occipital technique).

Topiramate has shown a convincing efficacy in CH 7778. Usual dosing is 100 mg per day (range 25 mg to 200 mg). Side effects include numbness and tingling in the extremities, weight loss, and neuro-cognitive difficulties, all reversible after drug discontinuation.

Lithium is used in chronic CH 697980. Doses range from 600 to 1200 mg per day. Blood levels must not exceed 0,9 mEq per liter, and thyroid and renal function must be monitored. Side effects include tremors, insomnia, fatigue, nausea and blurred vision. Intoxication may be severe and has to be suspected quickly if nausea, confusion, rigidity and difficulty to walk appear. Because of these side effects, lithium is used sparingly, in selected cases only.

A short course of decreasing-dose prednisone (starting at 1 mg/kg) may be used to treat a bout refractory to verapamil (however, recurrence is frequent with the decrease of the dose). Long-term side effects of corticotherapy restrict the use of prednisone in chronic CH.

Methysergide acts on serotonin receptors. Doses range from 6 to 12 mg per day. Some patients do respond very well to this drug but a major limitation is that triptans and ergots cannot be used simultaneously because of the risk of serotoninergic syndrome. The main side effect is nausea, sometimes severe. Methysergide can be considered if oxygen alone is used as an acute treatment. The main complication is retroperitoneal, pulmonary or cardiac fibrosis after prolonged use. This mandates one-month drug-holiday after six months of use, then methysergide can be started again. Methysergide is not available in United States.

Valproic acid 81, pizotifen, gabapentin 8283, baclofen 84, and melatonin 8586 have shown some effect in CH prophylaxis and may be used in selected patients as a second-line therapy.

Destructive approaches like trigeminal section, thermocoagulation of gasserian ganglion, glycerol rhizotomy 8788 and radiosurgery 89909192 of the trigeminal nerve have shown variable results and irreversible complications like anesthesia dolorosa.

Hypothalamic deep-brain stimulation (hDBS) has shown a convincing benefit in some refractory patients in series totalizing a few dozens of cases 93949596, but can be completely inefficient97, and has potential serious complications. Its mechanism is not well understood98 and no controlled studies are available.

Neurostimulation of the greater occipital nerve has recently been described 7699100101. It is less invasive than DBS but costly; its long-term effects are unknown.

Non-pharmacological approaches like massotherapy, physiotherapy and acupuncture have not been adequately studied in CH.