Cluster headache

Cluster headache is said to be the most painful form of recurrent headache.[1] The severity of cluster attacks and their unique characteristics allow physicians to make a reliable diagnosis based on history alone,[1,2] in spite of the low prevalence of the condition and the rarity of observing a patient during an attack.

Cluster headache has been known by many names, causing considerable confusion. For example, descriptions by Horton, and his belief in the crucial role of histamine in the etiology, led to the terms "Horton's headache" and "histamine cephalgia."[1] Much of the confusion has been resolved by the adoption of the term "cluster headache," which emphasizes the unique clustering of individual attacks into a specific time pattern. According to the diagnostic criteria of the Headache Classification Committee of the International Headache Society (Table 1),[3] the essential characteristics of cluster headaches are unilaterality, severity and location of pain, the associated autonomic phenomena and the pattern of attacks.[3]

Clinical Characteristics

Cluster headaches occur predominately in adult men. The condition is rare, with an overall prevalence of 0.69 percent in the adult population.[4] The male-to-female ratio among patients with cluster headaches is approximately 6:1.[4-6] Attacks commonly begin around age 30, although onset has been reported in children and in adults as old as 70 years.[4-6]

A typical cluster headache starts suddenly and without warning. In half of cases, the attack awakens the patient within two hours of falling asleep.[4] The attack may begin with a sensation of pressure in the eye or temple. The pain is unilateral, constant and very severe. The excruciating pain reaches a peak within 15 minutes and typically persists for about 45 minutes. Individual attacks can last up to four hours. Towards the end of the attack, patients may experience additional paroxysms of stabbing pain superimposed on the constant severe pain.[4,5] Attacks generally end quickly without sequelae, apart from exhaustion and apprehension.[1,4,6]

The prevalence of both cigarette smoking and alcohol use is consistently reported to be higher in patients with cluster headaches than in control subjects.[5,6,7] Despite the fact that alcohol use can induce an attack during cluster periods, the prevalence of excessive alcohol use is 50 percent in patients with cluster headaches.[6] Other vasodilating agents, particularly nitroglycerin and histamine, are reported to induce attacks during vulnerable periods.

PAIN

The pain of cluster headache is always unilateral and centered on the eye, although the area of maximum pain may be in the temple, frontal or maxillary region.[1,4,6] Attacks always involve the same side during a cluster of attacks, but in about 10 to 15 percent of patients subsequent clusters involve the corresponding areas of the opposite side of the face and head.[4,6] Vivid descriptions of the severity of the pain are common, and even the most stoic patient may describe sensations of the eye being "pushed out" or the skull being "drilled"

In contrast to patients with migraine headaches, patients with cluster headaches are restless, active and even violent during attacks.[1,6] Most apply pressure or cold to the painful area, and many attempt to keep the head low but avoid lying down since this position can initiate and increase cluster headache pain.[1,8] Almost all patients try to isolate themselves during an attack because of their behavior in reaction to the pain and to avoid distressing others. Some patients lock themselves in a room, while others may attempt strenuous outdoor activity to "fight through" an attack.

AUTONOMIC SYMPTOMS

In addition to headache, cluster attacks are characterized by a variety of autonomic symptoms occurring on the same side as the pain. The most common symptoms are lacrimation, conjunctival injection and rhinorrhea or nasal stuffiness, which indicate parasympathetic overactivity.[4,6] The sympathetic system is also involved, as shown by the fact that partial Horner's syndrome of ptosis and miosis occur in up to two-thirds of patients during an attack.[4] Other symptoms may include visibly distended ipsilateral temporal artery, facial flushing or pallor, edema of the eyelid, photophobia and phonophobia.[1,3,4]

The unique feature that differentiates cluster headache from all other types of headache is the periodicity of individual attacks. The individual attacks are grouped, or clustered, into periods of weeks or months during which attacks occur regularly up to eight times per day at almost predictable intervals. The mean number of attacks per day during a cluster period is one to two; in 86 percent of patients these attacks occur at the same hour or hours each day until the cluster period is over. Nocturnal attacks are common, but the peak time for attacks is 1 p.m. to 3 p.m., followed by 1 a.m. to 3 a.m. and 9 p.m.[3] Cluster periods may last only a few days, but most last four to eight weeks. No seasonal variation has been documented.[5] About 10 percent of patients develop chronic cluster headaches that recur over several years.

Diagnosis

The diagnosis is essentially based on the history, since patients are rarely observed during an attack. The unique pattern of several attacks at the same time on consecutive days differentiates cluster headache from other severe unilateral headaches such as migraine and temporal arteritis. The associated autonomic symptoms also help differentiate cluster attacks from other types of facial pain.

Some of the most common misdiagnoses of cluster headache are migraine, sinusitis, acute glaucoma, temporal arteritis and trigeminal neuralgia (Table 2). Trigeminal neuralgia is an uncommon disorder that is characterized by attacks of less than 30 seconds that can be triggered by touching the face. Migraine headaches are throbbing in nature, with less excruciating pain and without the distinctive periodicity of cluster attacks. Sinusitis is characterized by a dull pain and a purulent nasal discharge, which may be bilateral; there is no associated Horner's syndrome. Acute glaucoma is associated with visual changes and increased intraocular pressure during an attack, while temporal arteritis is usually associated with systemic symptoms such as night sweats, anorexia and weight loss.[9] The headache of pheochromocytoma is usually bilateral and occipital. It occurs at the time of natural wakening, rather than disrupting sleep.

Etiology

Much research has focused on cerebral blood-vessel reactivity as a cause of cluster headaches. Serotonin, histamine and choline have been implicated in the etiology of cluster headaches. It now seems likely that the primary disorder in cluster attacks is neuronal, probably in the hypothalamus.[4,6,10] The clinical characteristics, timing of attacks and pathophysiology suggest that cluster headache may be due to a disorder of the "biologic clock" that controls circadian rhythm.[4,6] The circadian pacemaker is believed to be located in the suprachiasmic nuclei, which link to the midbrain and nuclei of the trigeminal nerve. Hence, the timing, autonomic features and pain distribution can be linked in terms of neuroanatomy.[4,8]

Treatment Strategies

Cluster headaches cannot be cured. Treatment goals in cluster headache include relief of the acute attack and shortening of the cluster period. Patient education underlies all treatment strategies. Most patients and their families are afraid that the severe and bizarre symptoms indicate a serious intracranial disease.[1,6,11] Providing a diagnosis, sharing the descriptions of the condition, and building the patient's confidence and interest are important since the patient and family will be responsible for the management of acute attacks and maintenance of prophylactic therapy.

Lifestyle adjustments may help patients avoid precipitating attacks during vulnerable periods. Unlike migraine, food items have not been implicated in cluster headache, with the notable exception of alcohol,[5] which almost inevitably induces an attack during a vulnerable period. Changes in normal sleep patterns, particularly afternoon naps, are known to precipitate cluster headaches. Thus, patients should be advised to maintain a regular sleep schedule.

Stress, anger, excitement, strenuous physical activity and other "high-adrenaline" situations have been implicated both in initiating cluster periods and in precipitating individual attacks.[5] During a cluster period, individual cluster headaches tend to occur during the relaxation period following stressful activities rather than during the stress itself.

Acute Therapy

Treatment of acute cluster headaches must be easily managed by the patient or family despite the restlessness and distraction of the patient during the attack. The short duration of attacks essentially rules out the use of conventional analgesics. Table 3 lists the treatment options for acute cluster headache.

OXYGEN

Inhalation of oxygen at 8 L per minute for 10 minutes by facial mask is a traditional treatment that is reported to be effective in approximately 70 percent of cases. Although safe and relatively inexpensive, oxygen therapy is cumbersome and may be technically difficult for a very restless patient to use.

ERGOTAMINES

To provide rapid and effective treatment, ergotamines can be administered by aerosol or injection. They can be used both to abort an acute attack and as prophylaxis. If properly administered, each inhalation provides 0.36 mg of ergotamine. One to three inhalations are reported to provide relief in up to 85 percent of attacks.[1,6]

Patient technique is the most frequent reason for poor response; in particular, the container must be vigorously shaken before inhalation, since the drug is in suspension. The drug must be taken early in the attack to be effective, and the total dosage must be monitored to avoid side effects such as peripheral vasoconstriction.

Dihydroergotamine (D.H.E. 45) is an injectable form of ergotamine that is effective in terminating acute cluster attacks. Patients and families can be trained to give a subcutaneous injection of 0.5 to 1.0 Mg.[1,6] Rectal, sublingual and oral forms of ergotamine are of limited usefulness except in long-lasting attacks, because of the slow onset of action and the difficulty in administering the medication during the furious activity of a cluster attack.

SUMATRIPTAN

Sumatriptan (Imitrex) is a specific agonist of 5-[HT.sub.1] receptors in cranial vessels. The drug has been demonstrated to be effective in migraine headaches, and a recent European study showed it to be highly effective in acute cluster attacks.[12] It is given as a subcutaneous injection of 6 mg at the start of an attack.

LOCAL ANESTHETICS

The use of local anesthetics intranasally on the side of the headache has been reported to give dramatic results[7] but has been studied in very few patients. Several texts describe instillation of 1 mL of either 4 percent or 2 percent lidocaine (Xylocaine) through a nasal dropper into the nostril on the side of the pain. Patients lie in a supine position with the head extended backwards 45 degrees and rotated 30 degrees towards the headache.[4,6,8] It is not known if the effect is local or through direct action on the sphenopalatine ganglion.

Prophylactic Therapy

While acute therapy may make individual attacks manageable, it does not truncate the cluster period. Prophylactic therapy to suppress the cluster period is therefore the mainstay of treatment[13] (Table 4). Several agents have been reported to be effective prophylaxis for cluster headaches, but there is limited understanding of their mechanisms of action. These prophylactic drugs may act by suppressing headaches during a cluster period rather than shortening the actual cluster period. If drugs are stopped before the natural end of the cluster period, the attacks will return.[13] Duration of treatment is based on the length of the previous cluster in individual patients. Currently, there is no treatment that will completely suppress all attacks during a cluster period,[6] but the severity, frequency and duration of attacks can be reduced.

PREDNISONE

Its rapid onset of action and efficacy make prednisone the initial drug of choice.[4,12] The usual dosage of 40 to 80 mg per day generally provides relief within two days. At this dosage, marked relief is reported in 77 percent of patients, and improvement is reported in another 12 percent.[4,6,13] Several authors state that if no improvement occurs in 48 to 72 hours, alternative therapy should be instituted. If patients respond well to prednisone, 40 to 80 mg may be continued for one to two weeks; the dosage may then be taper-ed over one week.[4,6,13] In a few patients, the response to prednisone is poor, but the response to 32 mg per day of triamcinolone (Aristocort, Kenacort) is ciramatic.[4,6]

LITHIUM

The introduction of lithium as a therapeutic agent in cluster headache was partially based on the frenetic, manic-like behavior of patients during an attack.[9] The usual dosage is 300 mg two to four times daily.[4-6] A therapeutic response occurs at serum lithium levels of 0.4 to 0.8 mEq per L, which is lower than that required for bipolar disorder.[6] Cluster headaches characterized by no remmitission between clusters and those precipitated by alcohol appear to be particularly responsive to lithium.[4] Men lithium alone is not completely effective, the addition of 2 to 4 mg per day of ergotamine appears to be synergistic.[4,6]

Lithium has significant interactions with other drugs, particularly methyldopa Aldomet, Amodopa), indomethacin (Indocin), diuretics, calcium channel blockers and tetracycline.[4,13] In addition, potentially dangerous toxicity has been reported when lithium is used concurrently with neuroactive drugs, particularly phenytoin (Dilantin) and haloperidol (Haldol).[4,13]

Side effects are common. Dose-related tremor, weakness, thirst, diarrhea, polyuria and nausea commonly occur at the onset of therapy. Because the therapeutic window for lithium is narrow, monitoring serum lithium levels does not always safeguard against toxicity.[12] The early signs of toxicity are predominately gastrointestinal; neurologic signs such as tremor, apathy and weakness indicate that serious toxicity may develop. With longterm therapy, renal and thyroid function need to be monitored, since chronic lithium use is associated with hypothyroidism and renal dysfunction.[6]

ERGOTAMINES

As previously stated, ergotamine can be given in several forms. The route and timing of ergotamine administration can be individualized to the cluster pattern of each patient. For example, 1 mg orally or 2 mg rectally may be given two hours before an anticipated attack[4] or 1 mg may be given twice a day during cluster periods.[6]

Ergotamine should not be used in any situation in which its vasoconstrictive actions are contraindicated (e.g., claudication or myocardial ischemia). Side effects of ergotamine are usually seen at high doses and include nausea, vomiting, cold extremities, myalgias, dizziness, numbness and malaise.[9]

CALCIUM CHANNEL BLOCKERS

Verapamil (Calan, Isoptin) binds more strongly to 5-[HT.sub.1] receptors than nifedipine (Adalat, Procardia) or diltiazem (Cardizem)[13] and is currently the most widely studied of the calcium channel blockers in cluster headaches. The recommended dose is 120 mg three to four times daily[6] or 240 mg of sustained-release verapamil once daily.[4,8] Verapamil may be used synergistically with lithium.

Verapamil should not be used in patients with cardiac conduction problems or low systolic blood pressure. The most common side effect is constipation, which occurs in approximately 7 percent of patients.[13] Less common side effects include nausea, dizziness and headache.

INDOMETHACIN

Indomethacin is particularly effective in rare headache syndromes such as chronic paroxysmal hemicrania. Case reports and small studies indicate that this drug is also effective in cluster headache.[4,6,8,13] Approximately 20 percent of patients discontinue indomethacin because of side effects, of which gastrointestinal side effects are the most common.

METHYSERGIDE

Methysergide (Sansert) is now rarely used because of concerns about retroperitoneal fibros is and cardiac valve damage.[6,8] However, these effects are rare (1:1,500) and associated with dosages over 8 mg per day.[4] Gastrointestinal and muscle cramps are reported in as many as 30 percent of patients.

In dosages of 4 to 10 mg per day, methysergide is reported to be effective in about 70 percent of patients with episodic cluster headaches.

Surgical Treatment

A number of surgical treatments have been used in patients who are intolerant of drug side effects or who have severe, intractable cluster headaches that do not respond to medical management. The procedures ablate components of the trigeminal nerve or of autonomic pathways.[6] These procedures have significant side effects, but have been reported to relieve attacks in carefully selected patients.

REFERENCES

[1.] Campbell JK, Caselli RJ. Headache and other craniofacial pain. In: Bradley WG, et al., eds. Neurology in clinical practice. Boston: Butterworth-Heinermann, 1991:1531-6. [2.] Adams RD, Victor M. Principles of neurology. 4th ed. New York: McGraw-Hill, 1989: 144-5. [3.] Headache Classification Committee of the Internationale Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8(Suppi 7):1-96. [4.] Raskin NH. Headache. 2d ed. New York: Churchill Livingstone, 1988:229-54. [5.] Kudrow L. Cluster headache. In: Dalessio DJ, ed. Wolff's Headache and other head pain. 5th ed. New York: Oxford University Press, 1987: 112-30. [6.] Matthew NT. Advarices in cluster headache. Neurol Clin 1990;8:867-90. [7.] Diamond S, Delassio DJ, eds. The practicing physician's approach to headache. 4th ed. Baltimore: Williams & Wilkins, 1986. [8.] Ryan RE Jr, Ryan RE Sr. Cluster headaches. Otolaryngol Clin North Am 1989;22:1131-44. [9.] Sjaastad O. Cluster headache syndrome. Philadelphia: Saunders, 1992:81-9. [10.] Hardebo JE. Activation of pain fibers to the internal carotid artery intracranially may cause the pain and local signs of reduced sympathetic and enhanced parasynipathetic activity in cluster headache. Headache 1991;31: 314-20. [11.] Taylor RB, ed. Difficult medical management. Philadelphia: Saunders, 1991:156-60. [12.] The Sumatriptan Cluster Headache Study Group. Treatment of acute cluster headache with sumatriptan. N Engl J Med 1991;325: 322-6. [13.] Solomon SS, Lipton RB, Newman LC. Prophylactic therapy of cluster headaches. Clin Neuropharmacol 1991;14:116-30.

ANNE D. WALLING, M.D. is vice-chairman of the Department of Family and Community Medicine at the University of Kansas School of Medicine-Wichita, where she is professor of family and community medicine with a joint appointment in internal medicine. Dr. Walling received her medical degree from St. Andrew's University, Dundee, Scotland, and completed internships at the Dundee Teaching Hospitals. She holds an advanced degree in community medicine from the Royal College of Physicians, London.

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