Cluster Headache: a Review MARILYN J

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• Cluster headache: A review MARILYN J. CONNORS, DO ID Cluster headache is a debilitat consists of episodes of excruciating facial pain that ing neuronal headache with secondary vas is generally unilateraP and often accompanied by cular changes and is often accompanied by ipsilateral parasympathetic phenomena including other characteristic signs and symptoms, such nasal congestion, rhinorrhea, conjunctival injec as unilateral rhinorrhea, lacrimation, and con tion, and lacrimation. Patients may also experi junctival injection. It primarily affects men, ence complete or partial Horner's syndrome (that and in many cases, patients have distinguishing is, unilateral miosis with normal direct light response facial, body, and psychologic features. Sever and mild ipsilateral ptosis, facial flushing, and al factors may precipitate cluster headaches, hyperhidrosis).4-6 These autonomic disturbances including histamine, nitroglycerin, alcohol, sometimes precede or occur early in the headache, transition from rapid eye movement (REM) adding credence to the theory that this constella to non-REM sleep, circadian periodicity, envi tion of symptoms is an integral part of an attack and ronmental alterations, and change in the level not a secondary consequence. Some investigators of physical, emotional, or mental activity. The consider cluster headache to exemplify a tempo pathophysiologic features have not been com rary and local imbalance between sympathetic and pletely elucidated, but the realms of neuro parasympathetic systems via the central nervous biology, intracranial hemodynamics, endocrinol system (CNS).! ogy, and immunology are included. Therapy The nomenclature of this form of headache in is prophylactic or abortive (or both). Treat the literature is extensive and descriptive, includ ment, possibly with combination regimens, ing such terminology as histamine cephalgia, ery should be tailored to the needs of the indi thromelalgia of the head, red migraine, atypical vidual patient. facial neuralgia, ipsilateral redness of the face, (Key words: Neuronal headache, vascular sphenopalatine neuralgia, greater superficial pet headache, parasympathetic, circadian peri rosal neuralgia, and Horton's headache.3,7-9 odicity, hemodynamics, immunology, pro phylactic therapy, abortive therapy, chronic Clinical features cluster headache, episodic cluster headache, Cluster headaches occur predominantly in white histamine, nitroglycerin, alcohol, REM sleep, men, with a male-to-female ratio of 5:1.3-5 The aver non-REM sleep, substance P, serotonin, central age age at onset is in the late 20s to 40s, but clus opiates) ter headache may afflict anyone.3,lO The incidence of cluster headache is 0.40% in males and 0.08% in Thus did I become acquainted early on with the three females.3,5 Individuals who suffer from cluster Ps of cluster headache, the pain, the pattern and the headaches are often described as ''leonine'' in appear parasympathetic phenomena that distinguish this most ance, with a particularly masculine body habitus distressing of headaches to which, now, we may be adding including tall stature, thick skin folds, coarse facial substance P .1 skin with telangiectasias, broad chin, and well Cluster headache was first documented in med chiseled lower lip.l,3,8,lO Cluster headache patients icalliterature at the turn of the 20th century.!,2 It very often have hazel eyes and smoke and drink is primarily a neuronal headache with secondary alcohol more than the average person.3,5 vascular changes and therefore involves alterations A great deal of controversy exists regarding in the caliber of cerebral blood vessels (that is, the psychologic profile of these individuals. Inves vasoconstriction/vasodilation). Cluster headache tigators have noted that these patients are ambi tious, perfectionist, hypochondriacal, and depen dent personalities who may display unhealthy Correspondence to Marilyn J . Connors, DO, Department of Family Practice, Scripps Clinic Medical Group, Inc, 3835 Avo strategies for coping with anger.!,4,5,7,8,1l-16 To date, cado Blvd, La Mesa, CA 91941. no conclusive evidence exists to support an inher-

Review article • Connors JAOA · Vol 95 • No 9 · September 1995 • 533 ent psychopathologic matrix in cluster headache 3 Table patients. A family history is rarely present. ,5 Factors Precipitating Cluster Headaches Cluster headaches occur in groups, or clusters, of attacks, with headache-free periods of remis sion. They can be episodic (remissions of 1 year or o Subcutaneous injection more), or chronic (no sustained remissions).2,9,17 of histamine Chronic cluster headaches occur at least twice a o Subcutaneous injection of nitroglycerin week for 2 years or more without remission. Between o Alcohol consumption 80% and 97% of sufferers have episodic cluster o Transition from REM to non-REM sleep headaches, and the remaining 3% to 20% have o Environmental changes chronic headaches.2,10 Chronic cluster headaches o Circadian rhythm are further differentiated into two subgroups (pri o Decrease in level of activity mary, chronic pattern de novo; and secondary, evo lution of episodic cluster pattern to a chronic pat tern).8 Cluster periods usually range from 6 to 12 ation. This theory encompasses the concept that a weeks.5,18 switch from the parasympathetic cholinergic sys The pain is typically of sudden onset and is tem (that is, the predominant neurotransmitters described as a burning, stabbing, or boring sensa of REM sleep) to a primarily sympathetic, aminer tion in the eye, temple, forehead, jaw, or teeth, gic, especially serotoninergic system (that is, the with occasional radiation to the ear or neck.4,l9 The mediators of non-REM sleep) provokes cluster duration of a cluster headache is usually 30 min headache. Many cluster headache patients are awak utes to 2 hourS.1-3 Attacks often occur in the evening ened from a sound sleep and recall a vivid dream. or within 2 hours of the patient's falling asleep, During REM sleep, many physiologic changes occur and the pain awakens the patient.1,19 Patients may affecting heart rate, lacrimation, body temperature, have 1 to 15 attacks per day.2,3 Cluster headache gastric acid secretion, miosis, sweating, dreaming, patients are rarely quiescent, but are more often pac and vasodilation, which exemplifies a heightened ing, rocking, or moving about, and they even may parasympathetic state.l This theory may parallel display bizarre behaviors (for example, violence, the increased incidence of cluster headache when suf fugues, transvestism, trancelike states, and even con ferers change from a state of activity to inactivity templation of suicide). 1,4 (for example, difference between work and home or work and vacation) and is related to a decrease Precipitating factors in overall vasomotor tone. Factors that have been reported to precipitate clus Sudden changes in environment (changes in ter headaches (Table ) include subcutaneous injec temperature, time zone, barometric pressure, tion of histamine and nitroglycerin,2,3,5,10 the use etcetera) are associated with an increased inci of alcohol during a cluster period,1,5 the transition dence of cluster headache. 1 Seasonal variations from rapid eye movement (REM) to non-REM sleep, also appear to affect cluster cycles, and it is often environmental alterations, circadian periodicity, 1-3 reported that spring and fall are particularly and change in level of physical, emotional, or intel adverse.5,10 Circadian rhythm has been implicat lectual activity. 1 ed as a factor, in that many patients have anoth Horton2 demonstrated that subcutaneous injec er episode 12 or 24 hours after their last bout on suc tion of histamine reproduces the symptoms of clus cessive days.1-3 ter headache within 5 to 45 minutes, and this was once used as a diagnostic test.2,5 Nitroglycerin sub Differential diagnosis cutaneously injected also induces cluster headache Cluster headache can be differentiated from a vari in most patients. Alcohol consumption during a ety of entities on the basis of several unique char cluster cycle precipitates attacks. 1,3,5 All three sub acteristics, including male preponderance, absence stances are cerebral vasodilators and may trigger of aura or prodrome, brevity of attacks, pattern of cluster headache by operating on a preexisting occurrence, and behavior of patient during an attack. decrease in vasomotor tone, causing excessive vasodi The differential diagnosis includes migraine lation. It has been proposed that these substances headache, chronic paroxysmal hemicrania, trigem cause a reflex vasoconstriction that mediates changes inal neuralgia, temporal arteritis, Raeder's para in blood flow, consequently causing pain.1,5 Sub trigeminal syndrome, pheochromocytoma associated stance P has been implicated in this potential path with headache, and acute scenarios such as acute way. 1,3,20,21 sinusitis and acute pathologic headache. Several investigators1,5,22 have proposed that cluster headache is related to a transition from a state Pathophysiologic features of relative arousal or activity to a state of relax- There exists a multitude of hypotheses regarding

534· JAOA · Vol 95 • No 9 · September 1995 Review article • Connors the pathophysiologic process of cluster headaches. met-enkephalin levels in patients with cluster Theories encompass the realms of neurobiology (for headache and normal or even slightly elevated l3-endor example, central opiate activity, substance P, his phin levels.24,25 Because these peptides participate tamine, serotonin, and trigeminovascular system), in the central control of pain, alterations in the intracranial hemodynamics, endocrinology, and bioavailability may have a role in the perception immunology. What follows is a synopsis of the pro of cluster headache pain. posed mechanisms of pathogenesis, from the tra The hypothalamus coordinates the homeosta ditional to the edge of the investigational frontier. tic regulation of circadian rhythm (a daily rhythm approximately 24 hours long) for many physiolog Histamine and serotonin ic processes, including REM sleep, plasma corti The fact that subcutaneous injection of histamine costeroid levels, body core temperature, calcium can reproduce the exact symptom complex of an and potassium excretion, slow-wave sleep, plasma individual's cluster headache has prompted researchers growth hormone, and skin temperature, as well as to explore the role of neurotransmitters in cluster coordinating the function of other hormonal sys headache. It has been shown that blood levels of tems. The hypothalamus also mediates autonom histamine are increased during a cluster attack, ic nervous system function. The vast array of the with an insignificant rise in serotonin levels. Con endocrine products secreted by or present in the versely, during a migraine attack, the plasma lev hypothalamus include a -endorphins, enkephalins, els of serotonin decrease, and plasma histamine and substance P. Some evidence suggests that levels rise during the postheadache period. 10 Hist input from the hypothalamus may activate cells amine is a vasodilator that exerts its effects local in the midbrain and medulla that control spinal ly at the tissue level and when released from stor pain transmission cells via enkephalin release in age sites. The increase in histamine levels during the dorsal horn. Endogenous peptides may have a a cluster headache could explain several of its clin role in decreasing pain by inhibiting amounts of ical features, including rapid onset, increased skin substance P produced and thus modulating pain temperature on the affected side of the head, and dila sensation. Therefore, a complex neurohormonal tion of conjunctival and nasal vessels. These find system overseen by the hypothalamus is in place ings support the distinction between migraine and and may affect several systems involving the neu cluster headache on biochemical groundS.3,21 rohormonal vascular changes that occur with headache. Substance P Most researchers agree that vascular headaches Endocrinologic factors involve a CNS disturbance that is manifested by Investigations have revealed changes in the serum changes in the trigeminovascular system. These prolactin levels in male cluster headache patients, changes can release substance P and other vasoac accompanied by a significant increase during tive substances in the sensory ganglia, which exert attacks, particularly nocturnal episodes.4 Testos sensory and motor functions. Substance P neurons terone levels also vary, displaying a generalized are bipolar and therefore are capable of orthodromic decrease during cluster headaches and followed and antidromic impulse transmission. These neu by a return to baseline during periods of remis rons transmit impulses from the periphery, dilate sion.4 The use of antiandrogenic medications has vessels, constrict smooth muscle cells (for example, been studied in treatment of cluster headaches.26 causing miosis in the iris), and increase vascular This approach is based on the male predominance, permeability, allowing extravasation, glandular low incidence in prepubescent and geriatric males, secretion, release from mast cells, and excitation and reports in the literature of altered levels of 21 of autonomic ganglion cells.4,20,21,23 Therefore, the testosterone in these patients. Melatonin has a release of substance P in the trigeminovascular diurnal secretory pattern that increases nightly, pathway may account for the pain and autonomic which may be involved in the circadian rhythm of symptoms of cluster headaches.12 Other biochemi the cluster headache patient.1,4 These alterations cal pathways have been implicated in the patho in hormone production may contribute to the clus genesis of cluster headache, as agonists superim ter cycle. posed on the substance P cascade. These include vasoactive intestinal peptide and calcitonin gene-relat Metabolic/immunologic derangements ed peptide.20 Several metabolic aberrations have been observed in cluster headache patients, including alterations Central opiates in membrane phospholipids, choline, and number Central nervous system opiate levels have been and response of lymphocyte receptors for cyclic implicated as an etiologic factor in cluster headache. adenosine monophosphate; decreased numbers of Studies have demonstrated low cerebrospinal fluid receptors for interleukin-2 on leukocytes; impaired

Review article • Connors JAOA • Vol 95 • No 9 • September 1995 • 535 cytotoxicity of natural killer cells; and changes in the number or dis tribution (or both) of mast cells EPISODIC CLUSTER HEADACHE VS CHRONIC CLUSTER HEADACHE in temporal skin biopsies ipsilat eral to the cluster symptoms.4,27-29

Treatment There are two major categories of Prednisone, 40 mg/d to 80 lithium carbonate, 300 mg two treatment of cluster headaches: mg/d, then taper to four times a day, monitor level prophylactic treatment (Figure 1), aimed at the prevention or I 1 decreased frequency of attacks with or without with or without and abortive therapy (Figure 2), I I with the goal of decreasing the Calcium channel blocker (for Calcium channel blocker (for intensity and duration of an exis example, verapamil hydrochlo example, verapamil hydrochlo- tent episode. ride, 240 mg/d to 360 mg/d for ride, 240 mg/d to 360 mg/d for 2 to 6 weeks) 2 to 6 weeks) Prophylactic therapy Some specialists consider corti I costeroids the drug of choice for with or without prophylaxis of episodic cluster I headache. This regimen commonly consists of prednisone at doses of Ergotamine tartrate (for Consider H1- and H2-receptor 40 mg/d to 80 mg/d in divided example, Bellergal-S, one antagonist for adjunctive doses for approximately 5 days, tablet twice a day) treatment and tapering over 4 to 6 weeks.3,4 Triamcinolone (Aristocort) tablets I (16 mg/d for 5 days and tapered with or without over 3 to 4 weeks) may be used.4 I It is advantageous that this treat If no response, consider Nonsteroidal anti-inflammatory ment can be used in concert with methysergide maleate, 4 mg/d drug an ergotamine tartrate agent or to 8 mg/d methysergide maleate (Sansert), both of which will be discussed later in this article. Corticosteroids Figure 1. Algorithm for abortive treatment of cluster headache. may also be used in patients with chronic cluster headaches, tem- porarily, while other more desirable drug regi Calcium channel blockers may be used for mens are being instituted. Corticosteroids are con either chronic or episodic cluster headaches. This traindicated in pregnancy, severe hypertension, category of medication may exert its positive phar diabetes mellitus, peptic ulcer disease, and dur macologic effect on cluster headache by way ofinhi ing febrile or infectious illness.3o bition of vascular smooth muscle contraction. Anoth Lithium carbonate is considered by some to be er theory proposes that calcium channel blockers the drug of choice for chronic cluster headaches, may interfere with nociception by substance P, generally at doses ranging from 300 mg two to four which is a calcium-dependent process.20,32 Calci times a day.4,5 Serum lithium levels must be mon um channel blockers also function by way of a itored to avoid toxicity and should be kept at a decrease in overall vasomotor tone of cerebral blood level of less than or equal to 1.2 mEq/L .31 Side vessels, thereby protecting them from the vascular effects are plentiful and include tremor, weight changes that occur during cluster headache.4 Com gain, hypothyroidism, fluid retention, and fatigue, monly used preparations include verapamil hydro and this medication should be avoided in patients chloride (240 mg/d to 360 mg/d in divided doses)4,32 with cardiovascular or renal disease.4,31 The exact and nimodipine (120 mg/d in divided doses).33,34 mechanism of action is heretofore unknown, but Nimodipine is considered to have a potentially it may be related to the effects of lithium on sero greater effect on cerebral blood vessels because it tonin, histamine, sodium, magnesium, antidiuret is highly lipophilic (and therefore comparatively ic hormone, calcium, and REM sleep. However, expensive), and it has not been conclusively shown lithium is rapidly losing status as the drug of choice, to have any greater advantage over the other cal with verapamil hydrochloride taking its place. cium channel blockers. Nifedipine (30 mg/d to 120

536· JAOA· Vol 95 • No 9 · September 1995 Review article • Connors mg/d) also has been shown to decrease the inten significant role in cluster headache, alcohol has been sity, severity, and frequency of cluster headaches clearly demonstrated to evoke attacks during clus in some patients. Because no significant advan ter periods. 1·4 Therefore, all patients are advised tage has been demonstrated among the various to abstain from alcohol consumption during these calcium channel blockers with respect to efficacy in periods. treatment of cluster headaches, the agent used Combination of H1- and H2-receptor antago should be based on patient tolerance and side nists has been studied for treatment of cluster effects. headache based on the fact that these receptors Ergotamine (alone or in combination with phe are plentiful in the carotid system. Cimetidine nobarbital and belladonna), in divided doses, can (300 mg four times daily), ranitidine hydrochloride be an effective oral agent in the prophylaxis of (150 mg twice daily), cyproheptadine hydrochlo cluster headaches.3,4,5 ,16,22 One milligram twice ride (4 mg four times daily), hydroxyzine (10 mg daily generally is prescribed, but can be used sole to 25 mg four times daily), clemastine fumarate (1.3 ly at bedtime or 2 hours before an expected attack. mg to 2.6. mg four times daily), and chlorpheni When ergotamine is used in combination with phe ramine maleate (4 mg four times daily) have been nobarbital and belladonna (Bellergal-SA), it is used with varying degrees of success.4 ' administered at a dosage of one tablet twice daily.3,4,31 Although ergotamine is tolerated by Abortive treatment most individuals, it can cause substantial patho Ergotamine, which is a potent vasoconstrictor, logic conditions (that is, ergotism, which includes may be used orally, sublingually, and per rectum. gangrene and arteritis). Additional precautions Sublingual or rectal routes of administration are indicate that the drug should not be used in preg more efficacious because of rapid absorption: Rec nant patients, those with peripheral vascular dis tal suppositories (for example, Cafergot) may be used ease, coronary disease, or hepatic or renal disease, (one-half to one suppository) at the onset of a or febrile patients. Excessive ergotamine use may headache and repeated in 1 hour, up to two per lead to rebound headaches, gastrointestinal dis attack or five per week. The oral dose of ergotamine turbance, and paresthesias. tartrate preparations (Cafergot, Cafetrate, etc) is Methysergide has been used with success in prophylactic treatment of episodic cluster headache.4,5,33 It is an oxytocic agent that blocks serotonin. Many investigators hypothesize that • Administer oxygen, 7 Umin for 5 there are headache-inducing substances (for exam minutes ple, serotonin, histamine, bradykinins, acetyl choline), so methysergide may thus be effective I in ameliorating cluster headache by way of its If rebound headache occurs or serotonin-blocking effect. Contraindications to the headache recurs use of methysergide include pregnancy, periph eral vascular disease, atherosclerotic heart dis t ease, coronary artery disease, phlebitis or cel • Administer sumatriptan, 6 mg lulitis, pulmonary or renal disease, and subcutaneously twice a day cardiovascular disease. Significant adverse effects (maximum), as needed can occur with long-term use, such as retroperi toneal fibrosis, pleuropulmonary fibrosis, cardiac I fibrosis, gastrointestinal disturbances, and CNS or symptoms including hallucinations, ataxia, eupho I ria, insomnia, drowsiness, and lightheadedness.31 • Administer ergotamine tartrate Obviously, these side effects limit its use, and it (orally, subcutaneously, or per is recommended that this regimen be used for rectum) less than or equal to 4 to 6 months, with a break 4 of 1 to 2 months. ,31 Doses of 4 mg/d to 8 mg/d in I two to four divided doses are recommended.4,33 with or without Certain patients may experience temporary side I effects such as nausea, vomiting, muscle cramps, and myalgias, which often resolve spontaneous Nonsteroidal anti-inflammatory drug ly. However, if these symptoms persist beyond 3 days' duration, the medication should be with drawn.4 Although diet has not been found to have a Figure 2. Algorithm for prophylactic treatment of cluster headache.

Review article • Connors JAOA • Vol 95 • No 9 • September 1995 • 537 generally two tablets containing 1 mg of ergota with corticosteroids, nonsteroidal anti-inflammatory mine plus 100 mg of caffeine, followed by one drugs, antidepressants, lithium, calcium channel 4 tablet every 30 minutes, up to six per attack or a blockers, or Hl- or H2-receptor antagonists. maximum of ten tablets weekly. Parenteral ergo It is critical to remember that the use of com tamine (DHE-45 or dihydroergotamine) may be bination medications or the prescribing of a sin used if indicated to abort a cluster headache,4, 10 gle medication to a patient taking other drugs may and it is usually as effective as the other ergota cause cumulative effects. Therefore, benefit ver mine preparations. Sublingual Ergostat may be sus risk regarding potential drug interactions, used at a dose of 2 mg every 3 minutes, for three cumulative side effects, or synergy of medication treatments per day, up to five tablets (10 mg) per must be assessed. week. Several investigators3,4,7,30,35,36 have documented Discussion a 60% success rate in cessation of a cluster headache Cluster headache is a debilitating type of vascu through implementation of 100% oxygen by inhala lar headache that primarily affects men. Cluster tion. The mechanism may involve a decrease in headache causes episodes of excruciating unilat cerebral blood flow secondary to oxygen therapy.26,33 eral facial pain that is usually accompanied by ipsi Oxygen should be delivered by means of face mask lateral phenomena including nasal congestion, rhi at a rate of 7 Llmin.3,4,35,37 Hyperbaric chambers norrhea, conjunctival injection, and lacrimation. have been used for treatment of cluster headache, Patients may also experience complete or partial based on the same premise.8,9, l7,30,38 Indomethacin Horner's syndrome. Cluster headaches are either (25 mg/d to 50 mg/d) may benefit some patients as episodic or chronic, and the chronic pattern may an abortive or prophylactic measure.4 Sumatrip be either primary or secondary.1,l9 tan succinate (6 mg, subcutaneously), a serotonin Patients with cluster headache are often report uptake inhibitor, may be used for two doses max ed to have certain physical and psychologic char imally per day, separated by 1 hour. acteristics. The behavior of the cluster headache patient in the grips of an attack is the opposite of Treatment of refractory cluster headache that of the usually quiescent migraineur (that is, In some patients, cluster headaches persist and rocking, pacing, moving). Cluster headache can be recur despite medical intervention. In the past, differentiated from a variety of entities on the surgical interruption of pertinent pain pathways basis of several unique characteristics, including in the trigeminal ganglion or nervus intermedius male preponderance, absence of prodrome, brevi (or both) had been attempted, with limited suc ty of attacks (30 minutes to 2 hours), pattern of cess.5,39-4l Unfortunately, any strides in alleviat attack in "clusters," and behavior of the patient.l,9 ing pain and suffering have been overshadowed Several factors are known to provoke cluster by relapse and recurrence of symptoms in almost headache, such as nitroglycerin, histamine, alco every patient. At present, the general consensus hol, transition from REM to non-REM sleep, envi is that surgical procedures are of little value in the ronmental changes, circadian rhythm, and change treatment of this condition. in level of physical, emotional, or mental activity, Because histamine is clearly implicated in the but diet does not appear to be a factor.l-4 The pathogenesis of cluster headache, histamine desen actual mechanism is unknown, and a consider sitization has been attempted by investigators by able number of hypotheses exist regarding the using an intravenous drip of histamine if tolerat pathophysiologic process, including the realms of ed by the patient.2,5,10 This program is continued until neurobiology, intracranial hemodynamics, endocri the patient becomes headache free, although main nology, and immunology.6 ,20,21,23-26,39,40,42-45 tenance therapy has been described. Because the Treatment is basically either prophylactic or therapy itself may elicit cluster headache, this reg abortive or a combination of both and depends on imen requires close monitoring and is often admin the type of headache pattern (episodic or chron istered along with prophylactic medication and ic). All treatment regimens must be tailored to abortive therapy on hand.4 the needs of the individual patient.

Combination therapy Comment Ideally, cluster headache is best treated by find Cluster headache is a unique entity that causes ing the particular regimen that is best for the indi those afflicted a great deal of misery. At present, vidual patient. Therapy should be aimed at tai physicians can alleviate some portion of these loring the regimen to the individual. If single-agent patients' suffering, and it is hoped that researchers therapy is inadequate in controlling headaches, will elucidate the pathophysiologic mechanism combination regimens may be instituted. Ergota that will enable better control of this condition in mine or methysergide may be used in conjunction the future.

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Review article • Connors JAOA • Vol 95 • No 9 ' September 1995 ' 539