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Diagnosis and Treatment of Cluster Headache
Headaches
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Diagnosis and Treatment of Cluster Headache Lee Kudrow, MD*
The periodic character of cluster headache was first described by K. A. Ekbom in 1947. 22 Subsequently, Kunkle et al69 noted a "clustering" pattern of attacks, from which cluster headache derived its name. This disorder has been known as migrainous neuralgia,40 ciliary neuralgia,41 and histaminic cephalgia. 46 Heyck44 suggested that Eulenburg had described this condition in 1878. The earliest description of cluster headache, however, was probably recorded by Romberg, in 1840,92 who thought the cause of the condition was a tubercular abscess. CLASSIFICATION
Note that classification systems, particularly in young medical disciplines, are not static but dynamic, and apt to change every few years. In 1988, the International Headache Society Headache Classification Committee provided a modified classification for cluster headache (Table 1).42 Previous attempts at classification included the Ad Hoc Committee on the Classification of Headache in 19621 and the Migraine Research Group of the World Federation of Neurology in 1969.'1 7 The current nomenclature excludes previously described variants such as cluster vertigo;'" 36 cluster migraine,79 and cluster tic syndromes. 39, 45. 70. 72. 78, 116 The major form of cluster headache is called episodic cluster. This type is defined by attack-susceptible periods of approximately 1 to 3 months in duration, followed by attack-free periods (remission) of generally 6 months to years in duration. This type of cluster headache affects approximately 80% of a cluster headache population. fit Almost 20% of patients with cluster headache suffer the chronic cluster headache type. This was first described by Ekbom and Olivarius. 24 Chronic cluster headache is characterized by the absence of remission periods for at least 12 months. Although there are variations from patient to patient, the frequency of attacks may be greater in chronic types than in episodic types, with diminished responsiveness to prophylactic drug therapy. The subtype, primary chronic cluster headache, defines those cases in which the disorder is chronic at its onset. Secondary chronic cluster headache refers to those cases in which an episodic pattern converted to the chronic state. 24 'Director, California Medical Clinic for Headache, Encino, California
Medical Clinics of North America-Vo!' 75, No. 3, May 1991
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Table 1. Classification of Cluster Headache Cluster headache Periodicity undetermined Episodic Chronic Primary chronic Secondary chronic Chronic paroxysmal hemicrania Cluster headache-like syndrome
3.1 3.1.1 3.1.2 3.1.3 3.1.3.1 3.1.3.2 3.2 3.3
The third type of cluster headache may be considered a cluster headache variant. Chronic paroxysmal hemicrania (CPR) was first described by Sjaastad and Dale in 1974.103 More recently, an episodic type of paroxysmal hemicrania was described by Kudrow et al. 66 Paroxysmal hemicrania, whether chronic or episodic, is similar to cluster headache in intensity, location, quality of pain, and autonomic symptomatology. It differs from cluster headache by a 2- to lO-fold increased frequency of attacks, shorter duration of pain, and a complete and dramatic response to prophylactic therapy with indomethacin.
DIAGNOSTIC FEATURES Sex, Age, and Race Cluster headache is predominantly a male disorder. The male-to-female ratio ranges from approximately 4.5:1 to 6.7:1.19.32.61,72,75 The mean age of onset is approximately 10 years later than that of migraine-27 to 30 years of age. 10,12,61 In our own clinic population, the male-to-female ratio among blacks is approximately 3:1, and there is an overrepresentation of black women with cluster headache. 61 Lovshin75 first described this finding in 1961.
Incidence The incidence of cluster headache is unknown. Extrapolations from prevalence rates in 18-year-old Swedish men,23 and from population differences within headache clinics, suggest an incidence of approximately 1%.55
The Attack The following description is a first-person account of a typical cluster headache attack''': Following a period of perhaps several hours of feeling quite elated and energetic, I experienced a fullness in my ears, somewhat more on the right side than the left, and having a character similar to that which occurs during a rapid descent in an airplane or elevator. I then became aware of ear fullness and a dull discomfort at the base of my skull-extending over the entire head, on both sides, although somewhat more on the right. At this point, 2 or 3 minutes have elapsed; seemingly short but long enough for me to know that a "cluster" has indeed begun and will ultimately get worse. Such anticipation causes me considerable consternation regarding any decision to continue my activities, or cancel plans and find a place to be alone; giving way to a slowly increasing anxiety, fear, panic, and withdrawal. I became aware of myself "listening" for changes in my head, Is the cluster prematurely aborting itself, progressing further, or unchanging? A sudden stab, only fleeting, strikes my temple, then again-somewhat near the apex of my skull and upper molars in my face, always on the right side. It strikes me again, above my eyebrow. My nose is stuffed and yet runs Simultaneously. If I could sneeze, I feel the attack would end. Yet in spite of all tricks, I find myself unable to induce sneezing. While the sharp stabs continue in this fashion, a slow crescendo of dull pain presents itself in an area of a hand's length and breadth over the eye
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and temporal region. The pain area narrows into a smaller area, and yet, as if magnified, enlarges in intensity. I find myself bending my neck downwards, although slightly, as if my head is being gently pushed from behind. My neck, up to the base of my skull, is tight and feels as if I were wearing a neck collar. I feel compelled to remove my tie and loosen my shirt collar, even though I know that it will not offer me even a modicum of relief. In an effort to alter this persistent discomfort, I drop my head between my legs while seated. My face and eyes seem to fill with fluid, but the pain remains unchanged. Despite my suntan, as I look into the mirror, a gaunt, sickly pale face peers back. My right lid is only slightly drooping, and the white of my eye is charted with many red vessels, giving the eye an overall color of pink. Both pupils appear equal and constricted, as is usual for light-eyed people. Having difficulty standing in one place too long, I leave the mirror to continue alternating my pacing and sitting. As usual, I am struck with additional fear that the pain will never end, but dismiss it as impossible since even if that were the case, I would surely kill myself. The pain, now located somewhere behind my eye and slightly above it, worsens. The pain is best described as a "force" pushing with such incredible power through my eye that my head appears to be moving backwards, yielding to its resistance. The "force" wanes and waxes, but the duration of successive exacerbations seem to increase. The cluster attack is at its peak, which is celebrated by an outpouring of tears from only my right eye. I have now been in cluster for 35 minutes-lO minutes at its peak. My wife peeks into the room where I hold forth. I look up and see her expression of pity, frustration, and helplessness. She sees my tortured face as I have seen it in the mirror at this stage before: a drooling mouth, agape; gray face wet on one side; an almost closed eyelid; and smelling of pain and anguish. She closes the door and leaves, feeling hurt for me, anger for the stupidity of medical science, and guilt-since deep within her mind is the suspicion that she is the cause of my suffering. I cry for her, but more for myself. The pain is so incredible. Suddenly I am overwhelmed by a fury. I lift a chair high over my head and crash it to the floor. With a doubled fist, I strike the wall. The pain persists. Waning periods soon become longer in duration, and I allow myself to suspect that the peak is behind me-but cautiously-since I have been too often disappointed. Indeed, the pain is ending. The descent from the mountain of pain is rapid. The "force" is gone. Only severe pain remains. My nose and eye continue to run. The road back, as with all travel, covers the same territory, but faster. Stabbing, easily tolerated, is felt. Then gone. Dull, aching fullness, neck stiffness-all disappear, replaced in turn by a welcome sensation of pins and needles over the right scalp area, similar to the way one's leg feels after it has been "asleep." Thus, my head has awakened after a nightmare of torment. Eye and nose dry, I let out a sigh. I collect my pile of wet tissues that are strewn all over the floor and deposit them in a wastepaper basket. The innocent chair, now uprighted, I rub my slightly bruised fist. Thus, having ended the battle and cleaned up its field, I open the door and enter my pain-free world ... until tomorrow.
Frequency and Duration of Attacks. The mean frequency of cluster headache attacks is twice daily with a range up to 10/day. Cluster headache attacks occur once daily in approximately 50% of patients, and twice daily in 33% of patients; thcy occur with greater frequency in the remainder. 20. 71 Thc mean duration of attacks is 45 minutes, but an attack can range between 10 minutes and 3 hours. The attacks occur most frequently during sleep in 50% to 75% of patients. 20. 32. 69. 71 These attacks often awaken the patient 90 minutes after onset of sleep and are associated with the first RE~ phase of the night. This temporal relation between RE~ phase of sleep and cluster attacks was first demonstrated by Dexter and Riley,'4 and subsequently corroborated by Kudrow et
al. 68
Location and Intensity of Pain. The intensity of cluster headache pain is most often described as exquisitely severe and boring, with a sharp and burning quality, at times throbbing, but always penetrating. Location of pain is always unilateral, distributed over oculotemporal, oculofrontal, or temporal facial regions. Radiation to the teeth on one side is not unusual and may obscure the diagnosis and lead to unnecessary dental procedures.
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Associated Signs and Symptoms. Cluster headache attacks are characterized by ipsilateral lacrimation, rhinorrhea, nasal stuffiness, and conjunctival suffusion. These associated symptoms are reported to occur in 72% to 84% of patients. M When attacks have been observed, ipsilateral ptosis and miosis (partial Homer' s syndrome) were reported to occur in approximately 60% to 70% of patients. 19. 61 During the attack, many patients will pace the floor or lean forward in their chair with head in hands and rock forward and backward. The inability to lie still during an attack is pathognomonic of cluster headache pain. It is not unusual that, during some attacks, even a stoic man may smash his head or fist against the wall or floor and not infrequently cry out or even scream in desperation. It should be noted, however, that despite this great intensity of pain, suicide, although contemplated, is rarely carried out. In our own cluster headache population of 1200 patients, suicide occurred in only one case (during a remission). Horton et al47 had noted that cluster headache attacks may be provoked by even small amounts of alcohol or subcutaneous injections of histamine. Subsequently, Ekbom 21 reported provoking cluster attacks in 100% of 10 patients following sublingual administration of 1 mg of nitroglycerin. Thus, vasodilators may provoke cluster headache attacks during active cluster periods. The Cluster Period The cluster period is characterized by attack susceptibility. It is only during this period that either spontaneous or provoked attacks occur. The mean duration of cluster periods is approximately 2 months, with a range of 2 to 4 months. 19.61 Cluster periods are often cyclic in occurrence. As demonstrated in a recent study, it may be related to seasonal photoperiod changes. 56 In this study, approximately 900 cluster period onsets were recorded from 400 patients over a 10-year period. The frequency of cluster periods was found to be related to seasonal photoperiod changes (length of daylight), increasing with diminishing or lengthening photoperiods. Frequency of cluster periods peaked approximately 2 weeks following the longest and shortest days of the year Guly and January) and decreased precipitously within 2 weeks following Daylight Savings and Standard Time changes. These findings substantiate the chronobiologic nature of cluster headaches. Remission Periods Remissions are defined as periods in which attacks do not occur spontaneously and may not be provoked. Such periods may range from 1 month to 20 years. According to Ekbom,19 the average duration of remission periods is less than 2 years. Recording of remission periods of 428 patients from the California Medical Clinic for Headache revealed that 47.7% experienced remissions of 7 to 12 months; 19.2%, of 1 to 6 months; and 14.3%, of 2 years. The remainder had remissions greater than 2 years in duration. 61 DIFFERENTIAL DIAGNOSIS Few conditions may be mistaken for cluster headache. Some characteristics of cluster headache, however, may be shared by other disorders (Table 2). As differentiated from migraine, cluster headache attacks are considerably shorter, always unilateral, occur daily or several times a day, and are not usually accompanied by nausea or vomiting. The headache of pheochromocytoma, as described by Thomas et al, 109 is similar to cluster headache in duration. Attacks are less than an hour and may occur on a daily basis. It differs from cluster headache in that the headache of pheochromocytoma is generally bilateral and occipital.
Table 2. Differential Diagnosis of Cluster Headache DISORDERS
Ql ~
""
FREQUENCY
DURATION
LOCATION
INTENSITY
QUALITY
Migraine
1-3/mo
6-30 hr
Unilateral, 60%
Severe
Throbbing, 80%
Trigeminal neuralgia
Several per day
Seconds to minutes
Severe
Temporal arteritis
Persistent
Unilateral, 5th nerve distribution Unilateral, temporal
Pheochromocytoma
Daily to monthly
Less than 1 hr
Bilateral, occipital
Raeder's syndrome
Persistent
Persistent
Unilateral, supraocular
Severe in supine position Severe
Electric, lancinating, non throbbing Burning, throbbing, nonthrobbing Throbbing
Chronic and episodic paroxysmal hemicrania Cluster
4-30/day
3-45 min
1-3/day
30-90 min
Unilateral, oculofrontal, temporal Unilateral, oculofrontal, temporal
Severe
Excruciating Excruciating
Burning, throbbing, non throbbing Boring N onthrobbing, boring
OTHER FINDINGS
Nausea, 85%; vomiting, 40%; photophobia>S5%; sonophobia Trigger zones on face Chewing claudication, tender and torturous temporal artery, elevated ESR, polymyalgia Sweating, pallor, tachycardia, and rise in blood pressure Partial Horner's syndrome 1. See cluster headache 2. Rcsponse to indomethacin is pathognomonic Unilateral lacrimation, rhinorrhea, injection, partial Horner's syndrome, cannot lie down
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Temporal arteritis most often occurs in elderly populations, sometimes associated with polymyalgia rheumatica. The pain of temporal arteritis, unlike that of cluster headache, is persistent, waxing and waning throughout the day, and, most characteristically, is exacerbated by chewing. 48, '0 The pain of trigeminal neuralgia is severe, unilateral, and occurs several times a day, This is where the similarity to cluster headache ends. Unlike that of cluster headache, the pain of trigeminal neuralgia lasts for only seconds to minutes, has a lancinating, electric-like quality, and is often triggered by tactile stimulation to areas of the nose and face. '3 Raeder's syndrome 90 or pericarotid syndromelIo resembles cluster headache in location of pain, intensity, and associated partial Horner's syndrome. The pain of Raeder's syndrome, however, is persistent and severe during early stages, whereas it is dull in intensity throughout most of its course. Chronic paroxysmal hemicrania is a major variant of cluster headache. Although the presentations of both disorders are similar, treatment differs considerably. For this reason, it is important to differentiate this variant. Chronic paroxysmal hemicrania was first described by Sjaastad and Dale in 1974.103 In 1987, Sjaastad lOZ reported having been informed of approximately 80 cases of CPH throughout the international medical community. As noted in Table 2, CPH resembles cluster headache in location and intensity of pain and in autonomic nervous system symptomatology. It differs from cluster headache in frequency and duration of attacks. The mean frequency of attacks in CPH is 14/day, having a mean duration of 13 minutes. 94 In a recent report, Kudrow et al66 described an episodic variety of paroxysmal hemicrania. Attacks occurred only during specific periods and were separated by long remissions. The six patients described experienced such cycles for more than 20 years. The etiology and pathogenesis ofCPH remain unknown. As in cluster headache, ipsilateral intraocular pressure, indentation pulse amplitudes, and corneal temperatures were increased on the ipsilateral side during attacks. The magnitudes of change, however, were found to be greater in CPH. 9 , 49 Similarly, autonomic dysfunction was noted in patients with CPH and those with cluster headache. In both groups, sweating was greater on the symptomatic side during attacks, but unlike cluster headache, sweating could not be increased following pilocarpine administration or decreased by heat induction in the CPH group. 98, 104 Finally, in contrast to cluster headache, patients with CPH may have a partial response to aspirin but a most dramatic response to indomethacin. i02
PATHOPHYSIOLOGY Vascular Changes Cluster headache attacks are associated with cxtracranial vasodilation"li and increased cerebral blood flow. 2 87, \J6 Recently, Aebelholt-Krabbe et at,z described an increased regional cerebral blood flow during cluster headache attacks involving central, basal, and right parietotemporal regions. This was interpreted as being due to pain-related activity and not pathogenetic. Vascular responses to carbon dioxide and oxygen, however, were found to be diminished in the former and excessive in the latter. Thesc changes have been ascribed to impairment of autoregulatory responses" 96 or pain-related reactivity. 2 Internal carotid artery changes are also involved in cluster headache. Hprven et al49 and Broch et al 9 reported that pulse synchronous indentation pulse waves
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585
and pulse synchronous changes in eye tension by dynamic tonometry were found to be increased on the ipsilateral side during cluster headache attacks. This suggested ophthalmic artery dilation on the symptomatic side. Ekbom and Greitz 25 subsequently reported a similar finding on an angiographic study of a patient during a cluster headache attack. A segmental luminal narrowing of the ipsilateral internal carotid artery was also demonstrated. This narrowing was interpreted as resulting from vasodilation within the restrive bony canal. Compression of the sympathetic plexus may explain the attack-related partial Horner's syndrome. Cyclic Hormonal Changes Kudrow, in 197665 and 1977,64 found significantly decreased plasma testosterone levels in small patient populations during cluster periods when compared with remission periods. Although corroborated by others,26, 53, 86, 93 explanations for this finding varied and included disordered REM states,93 effects of pain, 53. 86 stress, or hypothalamic-pituitary axis dysfunction. 26, 64 Support for hypothalamie involvement evolved indirectly from ehronobiologic studies. Dyschronic biologic changes were found in neuroendocrine substances such as testosterone,26 prolactin, SR, 112 melatonin,lO, 111 cortisol,28, 84, 113 and beta-endorphins. 83 Similarly, a loss of circadian rhythmicity for blood pressure and body temperature was also reported. 29 Platelet Serotonin and Monoamine Oxidase In two reports, cerebrospinal fluid concentrations of the platelets serotonin (5HT) precursor tryptophan 9' and whole-blood 5_HTBO were found to be increased during attacks. Consistent with these findings, it was later reported that following cluster attacks, the maximal rate of uptake of platelet 5-HT decreased significantly. 108,114 Platelet monoamine oxidase (MAO) activity was also found to be significantly reduced in patients with cluster headache. 37, 74. 115 This finding, however, was explained on the basis of cigarette smoking rather than pathogenesis. Histamine The importance of histamine in the pathogenesis of cluster headache has always remained questionable despite reports of increased urine and blood histamine during attacks.' 105 It should be noted that HI and H2 receptor-antagonists had no appreciable effect on frequency or intensity of cluster headache. 6 A renewed interest in histamine was stimulated by the findings of Appenzeller et aF and others.89 Electronic microscopic examination of temporal skin biopsies from patients with cluster headache revealed increased mast cell counts and degranulation with deposition of the mast cells around cutaneous nerves. Others, however, were unable to duplicate these findings. 3 11 Appenzeller et aF suggested that release of histamine by antidromal sensory nerves may be responsible for vasodilation and pain of cluster attacks. Autonomic Nervous System Changes Some investigators were of the opinion that the cluster headache attack was mediated via the greater superficial petrosal nerve and sphenopalatine ganglion, from stimulation of parasympathetic nuclei in the hypothalamus. 34 . 95, 107 Indeed, surgical section of the seventh cranial nerve pathway, including the nervous intermedius,95 or superficial petrosal nerves 82 , 83 resulted in partial to complete relief of attacks in small patient populations. More recently, sympathetic nervous system dysfunction has become the subject of investigation. In a classical pupillometric study by Fanciullacci et al,2' topical application of 2% tyramine induced ineffective midriatic responses on the symptom-
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atic side during cluster headache attacks, interval periods, and remissions. These results suggested permanent dysfunction of unilateral sympathetic neurones. Others have also demonstrated increased unilateral facial sweating caused by sympathetic dysfunction. 98, 104
PATHOGENESIS There are three major clinicopathologic processes in the cluster headache syndrome: the cluster period, attack provocation, and pain production. Each process appears to be dependent upon the one before; hence, pain pathways are triggered by an attack-provoking mechanism, which, in turn, may only be stimulated in an altered physiologic environment defined as the cluster period. The cluster period may be characterized as a cyclically occurring, attacksusceptible period, probably caused by hypo thalamic dysfunction. 16, 61. 80. 85 The cyclic nature of cluster periods has been reported to be related to changes in seasonal photoperiods. 56 Autoregulatory function and circadian rhythmicity of neuroendocrine activity appear to be impaired, as discussed earlier. In 1983, Kudrow58 hypothesized that, as a consequence of these physiologic changes, chemoreceptor responses to hypoxemia may be blunted, resulting in impaired autoregulation of arterial oxygen concentration. Clinically, cluster attacks often occur in association with altitude, during REM sleep, and with provocation by vasodilators-conditions that may cause hypoxemia if autoregulatory mechanisms are impaired. Indeed, oxygen inhalation effectively aborts cluster attacks,6o suggesting a negative-feedback mechanism of action. Experimentally, a polysomnographic study of a small cluster headache population revealed an association of attack-onset and REM -related oxygen desaturation. 68 The relationship of cluster attack onset to hypoxemic events was further corroborated in a recent study.67 Oxygen saturation (SAO z) was monitored from 10 patients in active cluster periods, 10 patients in remission periods, and 5 nonheadache subjects before and after sublingual administration of nitroglycerin. Following administration of nitroglycerin, a significant de saturation in oxygen was found in all groups. In remission and control groups, SA0 2 values returned to baseline levels after approximately 30 minutes. In the active cluster group, however, SAO z values decreased further for an additional 20 minutes, culminating in attacks in 10 out of 10 patients. Results support the hypothesis that chemoreceptor responses to hypoxemia may be impaired during active cluster periods. 58 The more distal pathways relating to the pain of the cluster headache attacks have been alluded to earlier. The seventh cranial nerve has been considered a major pathway in this regard. 34, 95, 107 Recently, the trigeminal nerve has become a subject of great interest, as introduced by Moskowitz. 82 Sicuteri et a1 99-101 suggested that the cluster attack may be mediated by release (antidromal stimulation) of substance P from trigeminal nerves. Indeed, an antidromal mechanism mediated by histamine was suggested by Appenzeller et a!. 7
MANAGEMENT OF CLUSTER HEADACHES The principles that govern successful treatment of cluster headache differ little from those of most medical disorders. These include patient education and prophylactic and symptomatic treatment.
DIAGNOSIS AND TREAn1ENT OF CLUSTER HEADACHE
587
Patient Education Anxiety and anguish are common accompanimcnts of the active cluster period. This is due to the patient's clear recollection of the painful experience and anticipation of future attacks. It is therefore incumbent upon the clinician to give the patient a thorough discourse on cluster headache. The patient should be reassured that current treatment regimens readily prevent most attacks and rapidly abort those that break through prophylactic medications. Even successful prophylactic medication, however, will not shorten or prevent cluster periods. It should be pointed out that, in the natural course of this disorder, one third of all patients will experience permanent remission, another third may have only minor attacks that require no medication, and in the final third, the pattern of attacks will remain unchanged. 59 Patients should be instructed that alcohol may induce a cluster headache attack. Patients should be warned to avoid prolonged exposure to volatile substances such as solvents, gasoline, and oil-based paints during cluster periods. Altitude hypoxemia may induce attacks during cluster periods. This may occur at levels above 5000 feet and include airplane travel (where pressurization is equivalent to 7000-8000 feet). Ergotamine, 2 mg, 1 hour before air travel, may prevent an attack. Oxygen inhalation, 4 to 7 Llmin, administered during the attack in flight may offer complete relief. Cluster attacks expected during ski trips at higher altitudes may be prevented by oral administration of acetazolamide, 25 mg twice a day for 4 days, starting 2 days before altitude is reached. Prophylactic Treatment
Episodic Cluster Headache. Attacks limited to sleep hours are best prevented by ergotamine, 2 mg orally, administered 1 to 2 hours before bedtime. Such attacks often occur during the first REM stage of sleep approximately 90 minutes after sleep onset. In our experience, ergotamine prophylaxis has been most effective when ingested at least 2 hours before the expected attack. We have also learned that, in cluster headache, the use of ergotamine at daily dosages of 2 mg will not result in ergotamine-rebound attacks, as in migraine. Further, in our experience, clinical ergotism is unlikely at this dosage in a cluster population. Ergotamine is contraindicated, however, in the presence of peripheral vascular, cardiovascular, or cerebrovascular atheromatous disease. It should also be contraindicated during pregnancy, in liver or renal disease, serious infection, and during postsurgical periods. Attacks that occur during various times of day or night may be prevented with other prophylactic agents, such as methysergide, verapamil, lithium, or prednisone. In our clinic, for patients under 30 years of age who have suffered only one or two cluster periods, the treatment of choice is methysergide, 4 mg three to four times a day. Methysergide is most effective in the earlier course of disease and least effective in later years. An overall 65% efficacy has been reported with methysergide prophylaxis. 31, 62 Contraindications and associated complications are well established and have been reviewed elsewhere. 38 In patients over 30 years of age, particularly for those who have experienced several cluster periods, our treatment of choice is verapamil, 80 mg four times a day, spaced evenly throughout working hours, and ergotamine, 2 mg 1 hour before bedtime. Gabel and Spierings 33 reported that verapamil prophylaxis was efficacious in 70% of patients with episodic and chronic cluster headaches. Their findings corroborated Meyer and Hardenberg's81 results and our own unpublished data collected over the past 7 years. Further, we have learned that the addition of nighttime ergotamine to daily verapamil regimens will capture another 15% of patients. The beneficial action of verapamil, a calcium-entry blocker, remains unknown. Calcium-entry channels are widely distributed throughout somatic,
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LEE KUfmOW
neuronal, and vascular systems. The major side effect of verapamil prophylaxis, in our experience, is constipation, which may preclude its use in the occasional patient. Approximately 5% to 8% of our younger patients experienced girdle pain, which appears to be muscular by description. Approximately 5% to 10% of patients with episodic cluster headache may be resistant to verapamil-ergotamine prophylaxis and will require the addition of lithium, 300 mg twice a day. The success rate of lithium as the sole prophylactic agent (first reported by Ekbom in 1978)18 was found to be between 70% and 80%.17. 61. 76 Concomitant use of diuretics or severely restricted sodium diets is contraindicated; the lithium ion competes with intracellular sodium and may lead to toxicity. In the event of treatment failure with methysergide, or in patients under 40 years of age who are resistant to "triple" therapy, the recommended course of treatment includes steroids. At our clinic, the starting daily dose of prednisone is 40 mg/day in divided doses, tapered over a 3-week period. Approximately 80% of patients with episodic cluster headache and 40% of patients with chronic cluster headache should experience a medication remission. 51. 62 Attacks are expected to break through when the daily dosage falls below 15 mg. Side effects, complications, and contraindications of prednisone therapy are ubiquitously reported in the medical literature. Diverticulosis should be added to the list of contraindications because we have been alerted to two relevant cases of ruptured diverticula in patients with cluster headache over 40 years of age. This complication occurred 1 and 2 days after initiation of prednisone prophylaxis. It should also be stressed that prednisone prophylaxis should not be used for a period longer than 3 weeks to a month, because fastness to steroids may result. Chronic and Subchronic Cluster Headache. In a recent study, approximately half of the study population of patients with subchronic and chronic cluster headache were reported to be resistant to treatment. 57 Subchronic cluster headache was defined by those cases in which remissions are usually under 5 months in duration. Minnesota Multiphasic Personality Inventory (MMPI) studies revealed that 50% of patients with subchronic and chronic cluster headache had elevated scores for either depression or hysteria and were prone to addiction-characteristics associated with treatment resistance. 57 In the absence of a history of treatment resistance, neurosis, and drug abuse, or evidence for proneness to addiction, the recommended treatment regimen is the same as that for episodic cluster headache (i.e., lithium carbonate or verapamil, and ergotamine). Lithium carbonate, 300 mg twice a day, with the addition of ergotamine at bedtime, offers the same successful response as does verapamil and ergotamine. In the presence of traits that predict treatment resistance, one should initiate triple therapy with verapamil, 20 mg four times a day; ergotamine tartrate, 2 mg at bedtime; and lithium carbonate, 300 mg twice a day. Narcotic medication should be prohibited. Continued refractoriness may indicate a course of histamine desensitization. Its efficacy, alone or in combination with prophylactic agents, has been reported.]'5 Experimental Approaches. In an open-label prophylactic study, as yet not corroborated by control studies, Hering and Kuritsky43 successfully treated 11 of 15 patients with cluster headache using sodium valproate, 600 mg to 2000 mg daily. No correlation was found between efficacy and levels of valproate in plasma. Treatment was reported to be well tolerated except for mild nausea in three patients. The authors suggest that sodium valproate may act as a GABA-mimetic agent on interneurons of the hypothalamic suprachiasmatic nucleus. Their results suggest a chronobiologic role in the pathogenesis of cluster headache. An experimental approach aimed at shortening cluster periods is currently being studied at the California Medical Clinic for Headache. It entails exposure to
DIAGNOSIS AND THEATMENT OF CLUSTEH HEADACHE
589
bright-light stimulation in an effort to reset circadian pacemakers by shifting sleepwake cycles. Other chronobiologic-dependent disorders have been successfully treated in this manner. 12,73,91 In the event that all medical attempts at controlling cluster headaches satisfactorily have failed, the surgical procedure of choice appears to be radiofrequency trigeminal gangliolosis, ~athew and Hurt" reported a significant success rate among treatment-resistant patients with chronic cluster headache. A similar success rate has been enjoyed at the May Clinic (Campbell K: Personal communication, 1989). Complications of this procedure may include sensory and secretomotor changes or anesthesia dolorosa. Symptomatic Treatment of Cluster Headache Effective symptomatic treatment of attacks should be provided in the event of prophylactic medication breakthrough, in medical conditions that preclude the use of prophylactic agents, and in situations in which preventative medications are refused. Oxygen inhalation is the safest and most effective method of aborting cluster headache attacks. 6o In our experience, 70% of cluster attacks may be aborted within 10 minutes and 90% within 15 minutes. Techniques for achieving maximal success rates are as follows: (1) Oxygen inhalation should be started at the very onset of the attack. (2) The patient should assume a sitting position, upright or leaning forward. Supine or nearly supine positions may increase cavernous sinus congestion, which may aggravate rather than abate the attack. (3) The oxygen flow should be set at 7 Llmin. (4) The patient should be warned against hyperventilating, which may limit oxyhemoglobin saturation. A high level of oxygen saturation (98%-99%) needs to be sustained for several minutes to achieve relief of the attack. 67 (5) A facial mask rather than a nasocannula should be used, because associated nasal stuffiness may impede airway flow, The value of oxygen inhalation has been well documented. 4, 30, 60 There are few contraindications to short-term use. Sublingual ergotamine or medihaler preparations are also effective and, indeed, more convenient than oxygen inhalation. The medihaler should be inhaled at the onset of the attack and may be repeated three times, 5 minutes apart, if needed. The sublingual preparation is placed under the tongue at the onset of an attack and should remain unswallowed for several minutes in order to assure absorption through sublingual blood vessels. This preparation may be repeated after 10 minutes, if needed. In an emergency room situation or office setting, parenteral administration of ergotamine may be used. Dihydroergotamine, 1 mg, or ergotamine tartrate, 0.5 mg, may be given intramuscularly in the gluteal region. Other symptomatic medications include 5% cocaine hydrochloride 8 or 4% lidocaine 52 administered intranasally with the head tilted back and turned toward the ipsilateral side. The effects of these agents are limited by the patient's intranasal anatomy, proper administration, and tolerance. Their benefit is probably due to local anesthetic effects on either the sphenopalatine ganglion or nerve endings in mucosal tissue.
MANAGEMENT OF CHRONIC PAROXYSMAL HEMICRANIA The treatment of choice for chronic or episodic paroxysmal hemicrania in adults is the prophylactic administration of indomethacin. Response is complete and, indeed, diagnostic of these conditions. According to Sjaastad,102 patients should
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receive approximately 200 mg of indomethacin per day to ensure a therapeutic response. In our experience, indomethacin, 75 mg to 100 mg/day in divided doses, has been successful in all cases. We have found that indomethacin may be decreased to low maintenance levels at approximately 25 mg/day. Despite the frequently reported childhood onset of CPH, guidelines for treating children are lacking. In a recent case report, 54 a 9-year-old boy who had CPH since age 6 was successfully treated prophylactically with baby aspirin at doses of 162 mg twice a day that were maintained for 3 months. Attacks have not recurred since discontinuation of aspirin 2 years ago.
REFERENCES 1. Ad Hoc Committee on Classification of Headache. JAMA 179:717-718, 1962 2. Aebelholt-Krabbe A, Henriksen L, Olesen J: Tomagraphic determination of cerebral blood flow during attacks of cluster headache. Cephalalgia 4: 17-23, 1984 3. Aebelholt-Krabbe A, Rank F: Histological examination of the superficial temporal artery in patients suffering cluster headache. Cephalalgia 5(suppl 3):282-283, 1985 4. Anthony M: Treatment of attacks of cluster headache with oxygen inhalation. In Tyrer JH, Eadie MJ (eds): Clinical and Experimental Neurology, vo118. Sydney, Australian Association of Neurologists, 1981, p 195 5. Anthony M, Lance JW: Histaminic and serotonin in cluster headache. Arch Neurol 25:225-231, 1971 6. Anthony M, Lord GDA, Lance JW: Controlled trials of cimetidine in migraine and cluster headache. Headache 18:261-264, 1978 7. Appenzeller 0, Becker W, Ragas A: Cluster headache: Ultrastructural aspects. Neurology 28:371, 1978 8. Barre F: Cocaine as an abortive agent in cluster headache. Headache 22:69-73, 1982 9. Broch A, H0rven I, Nornes H, et al: Studies of cerebral and ocular circulation in a patient with cluster headache. Headache 10:1-13, 1970 10. Chazot G, Claustrat B, Brun J, et al: A chronobiological study of melatonin, cortisol, growth hormone and prolactin secretion in cluster headache. Cephalalgia 4:213-220, 1984 11. Cuypers J, Westphal K, Bunge ST: Mast cells in cluster headache. Acta Neurol Scand 61:327-329, 1980 12. Czeisler CA, Kronauer RE, Allan JS, et al: Bright light induction of strong (Type 0) resetting of the human circadian pacemaker. Science 244:1328-1333, 1989 13. Dalessio DJ: A reappraisal of the trigger zones of tic douloureaux. Headache 9:73-76, 1969 14. Dexter JD, Riley TL: Studies in nocturnal migraine. Headache 15:51-62, 1975 15. Diamond S, Freitag FG, Prager J, et al: Treatment of intractable cluster. Headache 26:42-46, 1986 16. Ekbom K: Pathogenesis of cluster headache. In Elau IN (ed): Migraine: Clinical, Therapeutic, Conceptual and Research Aspects. London, Chapman and Hall, 1987, pp 433-448 17. Ekbom K: Lithium for cluster headache: Review of the literature and preliminary results of long-term treatment. Headache 21:132-139, 1981 18. Ekbom K: Litium vid kroniska symptom av cluster headache. Opusc Med 19:148-156, 1978 19. Ekbom K: A clinical comparison of cluster headache and migraine. Acta Neurol Scand 46(suppI41):1-44, 1970 20. Ekbom K: Pattern of cluster headache with a note on the relation to angina pectoris and peptic ulcer. Acta Neurol Scand 46:225-237, 1970 21. Ekbom K: Nitroglycerin as a provocative agent in cluster headache. Arch NeuroI19:487493, 1968 22. Ekbom KA: Ergotamine tartrate orally in Horton's "histaminic cephalgia" (also called Harris' "ciliary neuralgia"). Acta Psychiatr Scand 46(suppl):106-113, 1947
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23. Ekbom K, Ahlborg B, Schele R: Prevalence of migraine and cluster headache in Swedish men of 18. Headache 18:9~19, 1978 24. Ekbom K, de Fine Olivarius B: Chronic migrainous neuralgia-diagnostic and therapeutic aspects. Headache 11:97~101, 1971 25. Ekbom K, Greitz T: Carotid angiography in cluster headache. Acta Radiol Diagn 10:177~ 186, 1970 26. Facchinetti F, Nappi G, Cicoli C, et al: Reduced testosterone levels in cluster headache: A stress-related phenomenon. Cephalalgia 6:29~34, 1986 27. Fanciullacci M, Pietrini U, Gatto G, et al: Latent dysautonomic pupillary lateralization in cluster headache: A pupillometric study. Cephalalgia 2:135~144, 1982 28. Ferrari E, Cane pari C, Bossolo PA, et al: Changes of biological rhythms in primary headache syndromes. Cephalalgia 3(suppl 1):58~68, 1983 29. Ferrari E, Martignoni E, Vailati A, et al: Chronobiological aspects of cluster headache: Effects of lithium therapy. In Savoldi F, Nappi G (eds): Headache. Pavia, Palladio Editore, 1979, pp 152~160 30. Fogan L: Treatment of cluster headache: A double-blind comparison of oxygen vs. air inhalation. Arch Neurol 42:362~363, 1985 31. Friedman AP, Elkind AH: Appraisal of methysergide in treatment of vascular headaches of migraine type. JAMA 184:125~130, 1963 32. Friedman AP, Mikropoulos HE: Cluster headaches. Neurology 8:653~663, 1958 33. Gabel IJ, Spierings ELH: Prophylactic treatment of cluster headache with verapamil. Headache 29:167~168, 1989 34. Gardner WJ, Stowell A, Dutlinger R: Resection of the greater superficial petrosal nerve in the treatment of unilateral headache. J Neurosurg 4:105~114, 1947 35. Gilbert GJ: Cluster headache and cluster vertigo. Headache 9:195, 1970 36. Gilbert GJ: Meniere's syndrome and cluster headaches: Recurrent paroxysmal vasodilatation. JAMA 191:691, 1965 37. Glover V, Peatfield R, Zammit-Pace R, et al: Platelet monoamine oxidase activity and headache. J Neurol Neurosurg Psychiatry 44:786~790, 1981 38. Graham JR, Suby HI, LeCompte PM, et al: Inflammatory fibrosis associated with methysergide therapy. In Friedman AP (ed): Research and Clinical Studies in Headache, vol1. Basel, Karger, 1967, pp 123~164 39. Green M, Apfalbaum RI: Cluster-tic syndrome. Headache 18:112, 1978 40. Harris W: Ciliary (migrainous) neuralgia and its treatment. Br Med J 1:457~460, 1936 41. Harris W: Neuritis and Neuralgia. London, Oxford University Press, 1926 42. Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8 (suppl 7):9~96, 1988 43. Hering R, Kuritsky A: Sodium valproate in the treatment of cluster headache: An open clinical trial. Cephalalgia 9: 195, 1989 44. Heyck H: Der cluster-kopfschmerz. Dtsch Med Wochenschr 100:1292~1293, 1975 45. Hornabrook RW: Migrainous neuralgia. NZ Med J 63:774, 1964 46. Horton BT: Histaminic cephalgia. Lancet 2:92~98, 1952 47. Horton BT, MacLean AR, Craig WM: A new syndrome of vascular headache: Results in treatment with histamine: Preliminary report. Mayo Clin Proc 14:257~260, 1939 48. Horton BT, Magath TB, Brown GE: An un described form of arteritis of the temporal vessels. Proc Stafl" Meet Mavo Clin 7:700~701, 1932 49. Hprven I, Nornes H, Sjaastad'O: Different corneal indentation pulse patterns in cluster headache and migraine. Neurology 22:92~98, 1972 50. Huston KA, Hunder GG, Lie JT, et al: Temporal arteritis: A 25-year epidemiologic, clinical, and pathological study. Ann Intern Med 88:162~167, 1978 51. Jammes JL: The treatment of cluster headache with prednisone. Dis Nerv Syst 36:375~ 376, 1975 52. Kittrelle JP, Gronse DS, Seybold M: Cluster headache: Local anaesthetic abortive agents. Arch Neurol 42:496~498, 1985 53. Klimek A: Plasma testosterone levels in patients with cluster headache. Headache 22:162~164, 1982 54. Kudrow DB, Kudrow L: Successful aspirin prophylaxis in a child with chronic paroxysmal hemicrania. Headache 29:280~281, 1989
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55. Kudrow L: Cluster headache. In Blau IN (ed): Migraine: Clinical, Therapeutic, Conceptual and Research Aspects. London, Chapman and Hall, 1987, pp 113-132 56. Kudrow L: The cyclic relationship of natural illumination to cluster period frequency [abstract). Cephalalgia 7 (suppl 6):76-77, 1987 57. Kudrow L: Subchronic cluster headache. Headache 27:197-200, 1987 58. Kudrow L: A possible role of the carotid body in the pathogenesis of cluster headache. Cephalalgia 3:241-247, 1983 59. Kudrow L: Natural history of cluster headache. Part 1. Outcome of drop-out patients. Headache 22:203-206, 1982 60. Kudrow L: Response of cluster headache attacks to oxygen inhalation. Headache 21:14, 1981 61. Kudrow L: Cluster Headache: Mechanism and Management. Oxford, Oxford University Press, 1980 62. Kudrow L: Comparative results of prednisone, methysergide and lithium therapy in cluster headache. In Greene R (ed): Current Concepts in Migraine Research. New York, Raven Press, 1978, pp 159-163 63. Kudrow L: Lithium prophylaxis for chronic cluster headache. Headache 17:15-18, 1977 64. Kudrow L: Plasma testosterone and LH levels in cluster headache. Headache 17:91-92, 1977 65. Kudrow L: Plasma testosterone levels in cluster headache: Preliminary results. Headache 16:28-31, 1976 66. Kudrow L, Esperanca P, Vijayan N: Episodic paroxysmal hemicrania? Cephalalgia 7:197201, 1987 67. Kudrow L, Kudrow DB: The association of cluster headache onset and oxygen desaturation. Headache, in press 68. Kudrow L, McGinty DS, Phillips ER, et al: Sleep apnea in cluster headache. Cephalalgia 4:33-38, 1984 69. Kunkle EC, pfeifrer JB Jr, Wilhoit WM, et al: Recurrent brief headache in "cluster" pattern. Trans Am Neurol Assoc 77:240-243, 1952 70. Kunkel RS, Dohn F: Surgical treatment of chronic migraine neuralgia. Cleveland Clin Q 41:189, 1974 71. Lance JW: Mechanisms and Management of Headache, ed 3. London, Butterworths, 1978 72. Lance JW, Anthony M: Migrainous neuralgia or cluster headache. J Neurol Sci 13:401, 1971 73. Lewy AJ, Sacks RL, Miller LS, et al: Antidepressant and circadian phase-shifting effects of light. Science 235:352-354, 1987 74. Littlewood JT, Glover V, Sandler M, et al: Migraine and cluster headache: Links between platelet monoamine oxidase activity, smoking and personality. Headache 24:30-34, 1984 75. Lovshin LL: Clinical caprices of histaminic cephalgia. Headache 1:3-6, 1961 76. Mathew NT: Clinical subtypes of cluster headache and response to lithium therapy. Headache 18:26-30, 1978 77. Mathew NT, Hurt W: Radiofrequency trigeminal gangliolysis in the treatment of chronic intractable cluster headache. Headache 25:166, 1985 78. Medina JL, Diamond S: Cluster headache variant: Spectrum of a new headache syndrome. Arch Neurol 38:705, 1981 79. Medina JL, Diamond S: The clinical link between migraine and cluster headache. Arch NeuroI34:470, 1977 80. Medina JL, Diamond S, Fareed J: The nature of cluster headache. Headache 19:309322, 1979 81. Meyer JS, Hardenberg BA: Clinical effectiveness of calcium entry blockers in prophylactic treatment of migraine and cluster headaches. Headache 23:266-277, 1983 82. Moskowitz MA: The neurobiology of vascular head pain. Ann Neurol 16:157-168, 1984 83. Nappi G, Facchinetti F, Bono G, et al: Lack of l3-endorphin and l3-lipotropin circadian rhythmicity in episodic cluster headache: A model for chronopathology. In pfaffenrath V, Lundberg P-O, Sjaastadt 0 (eds): Updating in Headache. Berlin, Springer-Verlag, 1985 84. Nappi G, Ferrari E, Polleri A, et al: Chronobiological study of cluster headache. Chronobiologia 2:140, 1981
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85. Nappi G, Savoldi F: In Headache: Diagnostic System and Taxonomic Criteria. London, John Libbey Eurotext, 1985 86. Nelson RF: Testosterone levels in cluster and non-cluster migraineurs headache patients. Headache 18:265-267, 1978 87. Norris JW, Hachinski VC, Cooper PW: Cerebral blood flow changes in cluster headache. Acta Neurol Scand 54:371-374, 1976 88. Polleri A, Nappi G, Murialdo G, et al: Changes in the 24-hour prolactin pattern in cluster headache. Cephalalgia 2:1-7, 1982 89. Prusinski A, Liberski PO: Is the cluster headache local mastocytic diaethesis? Headache 19:102, 1979 90. Raeder JG: "Paratrigeminal" paralysis of oculo-pupillary sympathetic. Brain 47:149-158, 1924 91. Richardson GS, Coleman RM, Zimmerman JC, et al: Chronotherapy: Resetting the circadian clock of patients with delayed sleep phase insomnia. Sleep 4:1-21, 1981 92. Romberg MH: A Manual of Nervous Diseases of Man. Translated by E. H. Sieveking. London, Sydenham Society, 1840 93. Romiti A, Martelletti P, Gallo MF, et al: Low plasma testosterone levels in cluster headache. Cephalalgia 3:41-44, 1982 94. Russell D: Chronic paroxysmal hemicrania: Severity, duration, and time of occurrences of attacks. Cephalalgia 4:53-56, 1984 95. Sachs E Jr: The role of the nervous intermedius in facial neuralgia: Report of four cases with observations on the pathways for taste, lacrimation and pain in the face. J Neurosurg 23:54-60, 1968 96. Sakai F, Meyer JS: Regional cerebral hemodynamics during migraine and cluster headaches measured by the 133Xe inhalation method. Headache 18:122-132, 1978 97. Salmon S, Bonciani M, Fanciullacci M, et al: A putative 5-HT central feedback in migraine and cluster headache. In Critchley M, Friedman AP, Gorini S, et al (eds): Advances in Neurology, vo133. New York, Raven Press, 1982, pp 265-274 98. Saunte C, Russell D, Sjaastad 0: Cluster headache: On the mechanisms behind attackrelated sweating. Cephalalgia 3:175-185, 1983 99. Sicuteri F, Fanciullacci M, Geppetti P, et al: Subtance P mechanism in cluster headache: Evaluation in plasma and cerebrospinal fluid. Cephalalgia 5:143-149, 1985 100. Sicuteri F, Gepetti P, Marabini S, et al: Pain relief by somatostatin in attacks of cluster headache. Pain 18:359-365, 1984 101. Sicuteri F, Raino L, Geppetti P: Substance P and endogenous opioids: How and where they could play a role in cluster headache. Cephalalgia 3(suppl 1):143-145, 1983 102. Sjaastad 0: Chronic paroxysmal hemicrania: Clinical aspects and controversies. In Elau IN (ed): Migraine: Clinical, Therapeutic, Conceptual and Research Aspects. London, Chapman and Hall, 1987, pp 135-152 103. Sjaastad 0, Dale I: Evidence for a new (?) treatable headache entity. Headache 14:105108, 1974 104. Sjaastad 0, Saunte C, Russell D, et al: Cluster headache: The sweating pattern during spontaneous attacks. Cephalalgia 1:233-244, 1981 105. Sjaastad 0, Sjaastad 0V: Urinary histamine excretion in migraine and cluster headache. J Neurol 216:91-104, 1977 106. Sjaastad 0, Sjaastad 0V: The histaminuria in vascular headache. Acta Neurol Scand 46:331-342, 1970 107. Stowell A: Physiologic mechanisms and treatment of histaminic or petrosal neuralgia. Headache 9:187-194, 1970 108. Swade CC, Carroll JD, Coppen A: Platelet 5-hydroxytryptamine accumulation in migrainous neuralgia. In Rose FC, Zilkha KJ (eds): Progress in Migraine Research, vol 1. London, Pitman, 1981, pp 89-92 109. Thomas JE, Rooke ED, Kvale WF: The neurologist's experience with pheochromocytoma: A review of 100 cases. JAMA 197:754, 1966 110. Vijayan N, Watson C: Pericarotid syndrome. Headache 18:244-254, 1978 111. Waldenlind E, Ekbom K, Friberg Y, et al: Decreased nocturnal serum melatonin levels during active cluster headache periods. Opusc Med 29:109-112, 1984 112. Waldenlind E, Gustafsson SA: Prolactin in cluster headache: Diurnal secretion, response
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to thyrotropin-releasing hormone, and relation to sex steroids and gonadotropins. Cephalalgia 7:43-54, 1987 Waldenlind E, Gustafsson SA, Ekbom K, et al: Circadian secretion of cortisol and melatonin in cluster headache during active cluster periods and remission. J Neurol Neurosurg Psychiatry 50:207-213, 1987 Waldenlind E, Ross SB, SaaE J, et al: Concentration and uptake of 5-hydroxytryptamine in platelets from cluster headache and migraine patients . Cephalalgia 5:45-54, 1985 Waldenlind E, Saaf J, Ekbom K, et al: Kinetics and thermolability of platelet monoamine oxidase in cluster headache and migraine. Cephalalgia 4:125-134, 1984 Watson P: Cluster-tic syndrome. Headache 25:123, 1985 World Federation of Neurology's Research Group on Migraine and Headache. J Neurol Sci 9:202, 1969
Address reprint requests to Lee Kudrow, MD California Medical Clinic for Headache 16542 Ventura Boulevard Encino, CA 91436
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Diagnosis and Treatment of Cluster Headache Lee Kudrow, MD*
The periodic character of cluster headache was first described by K. A. Ekbom in 1947. 22 Subsequently, Kunkle et al69 noted a "clustering" pattern of attacks, from which cluster headache derived its name. This disorder has been known as migrainous neuralgia,40 ciliary neuralgia,41 and histaminic cephalgia. 46 Heyck44 suggested that Eulenburg had described this condition in 1878. The earliest description of cluster headache, however, was probably recorded by Romberg, in 1840,92 who thought the cause of the condition was a tubercular abscess. CLASSIFICATION
Note that classification systems, particularly in young medical disciplines, are not static but dynamic, and apt to change every few years. In 1988, the International Headache Society Headache Classification Committee provided a modified classification for cluster headache (Table 1).42 Previous attempts at classification included the Ad Hoc Committee on the Classification of Headache in 19621 and the Migraine Research Group of the World Federation of Neurology in 1969.'1 7 The current nomenclature excludes previously described variants such as cluster vertigo;'" 36 cluster migraine,79 and cluster tic syndromes. 39, 45. 70. 72. 78, 116 The major form of cluster headache is called episodic cluster. This type is defined by attack-susceptible periods of approximately 1 to 3 months in duration, followed by attack-free periods (remission) of generally 6 months to years in duration. This type of cluster headache affects approximately 80% of a cluster headache population. fit Almost 20% of patients with cluster headache suffer the chronic cluster headache type. This was first described by Ekbom and Olivarius. 24 Chronic cluster headache is characterized by the absence of remission periods for at least 12 months. Although there are variations from patient to patient, the frequency of attacks may be greater in chronic types than in episodic types, with diminished responsiveness to prophylactic drug therapy. The subtype, primary chronic cluster headache, defines those cases in which the disorder is chronic at its onset. Secondary chronic cluster headache refers to those cases in which an episodic pattern converted to the chronic state. 24 'Director, California Medical Clinic for Headache, Encino, California
Medical Clinics of North America-Vo!' 75, No. 3, May 1991
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Table 1. Classification of Cluster Headache Cluster headache Periodicity undetermined Episodic Chronic Primary chronic Secondary chronic Chronic paroxysmal hemicrania Cluster headache-like syndrome
3.1 3.1.1 3.1.2 3.1.3 3.1.3.1 3.1.3.2 3.2 3.3
The third type of cluster headache may be considered a cluster headache variant. Chronic paroxysmal hemicrania (CPR) was first described by Sjaastad and Dale in 1974.103 More recently, an episodic type of paroxysmal hemicrania was described by Kudrow et al. 66 Paroxysmal hemicrania, whether chronic or episodic, is similar to cluster headache in intensity, location, quality of pain, and autonomic symptomatology. It differs from cluster headache by a 2- to lO-fold increased frequency of attacks, shorter duration of pain, and a complete and dramatic response to prophylactic therapy with indomethacin.
DIAGNOSTIC FEATURES Sex, Age, and Race Cluster headache is predominantly a male disorder. The male-to-female ratio ranges from approximately 4.5:1 to 6.7:1.19.32.61,72,75 The mean age of onset is approximately 10 years later than that of migraine-27 to 30 years of age. 10,12,61 In our own clinic population, the male-to-female ratio among blacks is approximately 3:1, and there is an overrepresentation of black women with cluster headache. 61 Lovshin75 first described this finding in 1961.
Incidence The incidence of cluster headache is unknown. Extrapolations from prevalence rates in 18-year-old Swedish men,23 and from population differences within headache clinics, suggest an incidence of approximately 1%.55
The Attack The following description is a first-person account of a typical cluster headache attack''': Following a period of perhaps several hours of feeling quite elated and energetic, I experienced a fullness in my ears, somewhat more on the right side than the left, and having a character similar to that which occurs during a rapid descent in an airplane or elevator. I then became aware of ear fullness and a dull discomfort at the base of my skull-extending over the entire head, on both sides, although somewhat more on the right. At this point, 2 or 3 minutes have elapsed; seemingly short but long enough for me to know that a "cluster" has indeed begun and will ultimately get worse. Such anticipation causes me considerable consternation regarding any decision to continue my activities, or cancel plans and find a place to be alone; giving way to a slowly increasing anxiety, fear, panic, and withdrawal. I became aware of myself "listening" for changes in my head, Is the cluster prematurely aborting itself, progressing further, or unchanging? A sudden stab, only fleeting, strikes my temple, then again-somewhat near the apex of my skull and upper molars in my face, always on the right side. It strikes me again, above my eyebrow. My nose is stuffed and yet runs Simultaneously. If I could sneeze, I feel the attack would end. Yet in spite of all tricks, I find myself unable to induce sneezing. While the sharp stabs continue in this fashion, a slow crescendo of dull pain presents itself in an area of a hand's length and breadth over the eye
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and temporal region. The pain area narrows into a smaller area, and yet, as if magnified, enlarges in intensity. I find myself bending my neck downwards, although slightly, as if my head is being gently pushed from behind. My neck, up to the base of my skull, is tight and feels as if I were wearing a neck collar. I feel compelled to remove my tie and loosen my shirt collar, even though I know that it will not offer me even a modicum of relief. In an effort to alter this persistent discomfort, I drop my head between my legs while seated. My face and eyes seem to fill with fluid, but the pain remains unchanged. Despite my suntan, as I look into the mirror, a gaunt, sickly pale face peers back. My right lid is only slightly drooping, and the white of my eye is charted with many red vessels, giving the eye an overall color of pink. Both pupils appear equal and constricted, as is usual for light-eyed people. Having difficulty standing in one place too long, I leave the mirror to continue alternating my pacing and sitting. As usual, I am struck with additional fear that the pain will never end, but dismiss it as impossible since even if that were the case, I would surely kill myself. The pain, now located somewhere behind my eye and slightly above it, worsens. The pain is best described as a "force" pushing with such incredible power through my eye that my head appears to be moving backwards, yielding to its resistance. The "force" wanes and waxes, but the duration of successive exacerbations seem to increase. The cluster attack is at its peak, which is celebrated by an outpouring of tears from only my right eye. I have now been in cluster for 35 minutes-lO minutes at its peak. My wife peeks into the room where I hold forth. I look up and see her expression of pity, frustration, and helplessness. She sees my tortured face as I have seen it in the mirror at this stage before: a drooling mouth, agape; gray face wet on one side; an almost closed eyelid; and smelling of pain and anguish. She closes the door and leaves, feeling hurt for me, anger for the stupidity of medical science, and guilt-since deep within her mind is the suspicion that she is the cause of my suffering. I cry for her, but more for myself. The pain is so incredible. Suddenly I am overwhelmed by a fury. I lift a chair high over my head and crash it to the floor. With a doubled fist, I strike the wall. The pain persists. Waning periods soon become longer in duration, and I allow myself to suspect that the peak is behind me-but cautiously-since I have been too often disappointed. Indeed, the pain is ending. The descent from the mountain of pain is rapid. The "force" is gone. Only severe pain remains. My nose and eye continue to run. The road back, as with all travel, covers the same territory, but faster. Stabbing, easily tolerated, is felt. Then gone. Dull, aching fullness, neck stiffness-all disappear, replaced in turn by a welcome sensation of pins and needles over the right scalp area, similar to the way one's leg feels after it has been "asleep." Thus, my head has awakened after a nightmare of torment. Eye and nose dry, I let out a sigh. I collect my pile of wet tissues that are strewn all over the floor and deposit them in a wastepaper basket. The innocent chair, now uprighted, I rub my slightly bruised fist. Thus, having ended the battle and cleaned up its field, I open the door and enter my pain-free world ... until tomorrow.
Frequency and Duration of Attacks. The mean frequency of cluster headache attacks is twice daily with a range up to 10/day. Cluster headache attacks occur once daily in approximately 50% of patients, and twice daily in 33% of patients; thcy occur with greater frequency in the remainder. 20. 71 Thc mean duration of attacks is 45 minutes, but an attack can range between 10 minutes and 3 hours. The attacks occur most frequently during sleep in 50% to 75% of patients. 20. 32. 69. 71 These attacks often awaken the patient 90 minutes after onset of sleep and are associated with the first RE~ phase of the night. This temporal relation between RE~ phase of sleep and cluster attacks was first demonstrated by Dexter and Riley,'4 and subsequently corroborated by Kudrow et
al. 68
Location and Intensity of Pain. The intensity of cluster headache pain is most often described as exquisitely severe and boring, with a sharp and burning quality, at times throbbing, but always penetrating. Location of pain is always unilateral, distributed over oculotemporal, oculofrontal, or temporal facial regions. Radiation to the teeth on one side is not unusual and may obscure the diagnosis and lead to unnecessary dental procedures.
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Associated Signs and Symptoms. Cluster headache attacks are characterized by ipsilateral lacrimation, rhinorrhea, nasal stuffiness, and conjunctival suffusion. These associated symptoms are reported to occur in 72% to 84% of patients. M When attacks have been observed, ipsilateral ptosis and miosis (partial Homer' s syndrome) were reported to occur in approximately 60% to 70% of patients. 19. 61 During the attack, many patients will pace the floor or lean forward in their chair with head in hands and rock forward and backward. The inability to lie still during an attack is pathognomonic of cluster headache pain. It is not unusual that, during some attacks, even a stoic man may smash his head or fist against the wall or floor and not infrequently cry out or even scream in desperation. It should be noted, however, that despite this great intensity of pain, suicide, although contemplated, is rarely carried out. In our own cluster headache population of 1200 patients, suicide occurred in only one case (during a remission). Horton et al47 had noted that cluster headache attacks may be provoked by even small amounts of alcohol or subcutaneous injections of histamine. Subsequently, Ekbom 21 reported provoking cluster attacks in 100% of 10 patients following sublingual administration of 1 mg of nitroglycerin. Thus, vasodilators may provoke cluster headache attacks during active cluster periods. The Cluster Period The cluster period is characterized by attack susceptibility. It is only during this period that either spontaneous or provoked attacks occur. The mean duration of cluster periods is approximately 2 months, with a range of 2 to 4 months. 19.61 Cluster periods are often cyclic in occurrence. As demonstrated in a recent study, it may be related to seasonal photoperiod changes. 56 In this study, approximately 900 cluster period onsets were recorded from 400 patients over a 10-year period. The frequency of cluster periods was found to be related to seasonal photoperiod changes (length of daylight), increasing with diminishing or lengthening photoperiods. Frequency of cluster periods peaked approximately 2 weeks following the longest and shortest days of the year Guly and January) and decreased precipitously within 2 weeks following Daylight Savings and Standard Time changes. These findings substantiate the chronobiologic nature of cluster headaches. Remission Periods Remissions are defined as periods in which attacks do not occur spontaneously and may not be provoked. Such periods may range from 1 month to 20 years. According to Ekbom,19 the average duration of remission periods is less than 2 years. Recording of remission periods of 428 patients from the California Medical Clinic for Headache revealed that 47.7% experienced remissions of 7 to 12 months; 19.2%, of 1 to 6 months; and 14.3%, of 2 years. The remainder had remissions greater than 2 years in duration. 61 DIFFERENTIAL DIAGNOSIS Few conditions may be mistaken for cluster headache. Some characteristics of cluster headache, however, may be shared by other disorders (Table 2). As differentiated from migraine, cluster headache attacks are considerably shorter, always unilateral, occur daily or several times a day, and are not usually accompanied by nausea or vomiting. The headache of pheochromocytoma, as described by Thomas et al, 109 is similar to cluster headache in duration. Attacks are less than an hour and may occur on a daily basis. It differs from cluster headache in that the headache of pheochromocytoma is generally bilateral and occipital.
Table 2. Differential Diagnosis of Cluster Headache DISORDERS
Ql ~
""
FREQUENCY
DURATION
LOCATION
INTENSITY
QUALITY
Migraine
1-3/mo
6-30 hr
Unilateral, 60%
Severe
Throbbing, 80%
Trigeminal neuralgia
Several per day
Seconds to minutes
Severe
Temporal arteritis
Persistent
Unilateral, 5th nerve distribution Unilateral, temporal
Pheochromocytoma
Daily to monthly
Less than 1 hr
Bilateral, occipital
Raeder's syndrome
Persistent
Persistent
Unilateral, supraocular
Severe in supine position Severe
Electric, lancinating, non throbbing Burning, throbbing, nonthrobbing Throbbing
Chronic and episodic paroxysmal hemicrania Cluster
4-30/day
3-45 min
1-3/day
30-90 min
Unilateral, oculofrontal, temporal Unilateral, oculofrontal, temporal
Severe
Excruciating Excruciating
Burning, throbbing, non throbbing Boring N onthrobbing, boring
OTHER FINDINGS
Nausea, 85%; vomiting, 40%; photophobia>S5%; sonophobia Trigger zones on face Chewing claudication, tender and torturous temporal artery, elevated ESR, polymyalgia Sweating, pallor, tachycardia, and rise in blood pressure Partial Horner's syndrome 1. See cluster headache 2. Rcsponse to indomethacin is pathognomonic Unilateral lacrimation, rhinorrhea, injection, partial Horner's syndrome, cannot lie down
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Temporal arteritis most often occurs in elderly populations, sometimes associated with polymyalgia rheumatica. The pain of temporal arteritis, unlike that of cluster headache, is persistent, waxing and waning throughout the day, and, most characteristically, is exacerbated by chewing. 48, '0 The pain of trigeminal neuralgia is severe, unilateral, and occurs several times a day, This is where the similarity to cluster headache ends. Unlike that of cluster headache, the pain of trigeminal neuralgia lasts for only seconds to minutes, has a lancinating, electric-like quality, and is often triggered by tactile stimulation to areas of the nose and face. '3 Raeder's syndrome 90 or pericarotid syndromelIo resembles cluster headache in location of pain, intensity, and associated partial Horner's syndrome. The pain of Raeder's syndrome, however, is persistent and severe during early stages, whereas it is dull in intensity throughout most of its course. Chronic paroxysmal hemicrania is a major variant of cluster headache. Although the presentations of both disorders are similar, treatment differs considerably. For this reason, it is important to differentiate this variant. Chronic paroxysmal hemicrania was first described by Sjaastad and Dale in 1974.103 In 1987, Sjaastad lOZ reported having been informed of approximately 80 cases of CPH throughout the international medical community. As noted in Table 2, CPH resembles cluster headache in location and intensity of pain and in autonomic nervous system symptomatology. It differs from cluster headache in frequency and duration of attacks. The mean frequency of attacks in CPH is 14/day, having a mean duration of 13 minutes. 94 In a recent report, Kudrow et al66 described an episodic variety of paroxysmal hemicrania. Attacks occurred only during specific periods and were separated by long remissions. The six patients described experienced such cycles for more than 20 years. The etiology and pathogenesis ofCPH remain unknown. As in cluster headache, ipsilateral intraocular pressure, indentation pulse amplitudes, and corneal temperatures were increased on the ipsilateral side during attacks. The magnitudes of change, however, were found to be greater in CPH. 9 , 49 Similarly, autonomic dysfunction was noted in patients with CPH and those with cluster headache. In both groups, sweating was greater on the symptomatic side during attacks, but unlike cluster headache, sweating could not be increased following pilocarpine administration or decreased by heat induction in the CPH group. 98, 104 Finally, in contrast to cluster headache, patients with CPH may have a partial response to aspirin but a most dramatic response to indomethacin. i02
PATHOPHYSIOLOGY Vascular Changes Cluster headache attacks are associated with cxtracranial vasodilation"li and increased cerebral blood flow. 2 87, \J6 Recently, Aebelholt-Krabbe et at,z described an increased regional cerebral blood flow during cluster headache attacks involving central, basal, and right parietotemporal regions. This was interpreted as being due to pain-related activity and not pathogenetic. Vascular responses to carbon dioxide and oxygen, however, were found to be diminished in the former and excessive in the latter. Thesc changes have been ascribed to impairment of autoregulatory responses" 96 or pain-related reactivity. 2 Internal carotid artery changes are also involved in cluster headache. Hprven et al49 and Broch et al 9 reported that pulse synchronous indentation pulse waves
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and pulse synchronous changes in eye tension by dynamic tonometry were found to be increased on the ipsilateral side during cluster headache attacks. This suggested ophthalmic artery dilation on the symptomatic side. Ekbom and Greitz 25 subsequently reported a similar finding on an angiographic study of a patient during a cluster headache attack. A segmental luminal narrowing of the ipsilateral internal carotid artery was also demonstrated. This narrowing was interpreted as resulting from vasodilation within the restrive bony canal. Compression of the sympathetic plexus may explain the attack-related partial Horner's syndrome. Cyclic Hormonal Changes Kudrow, in 197665 and 1977,64 found significantly decreased plasma testosterone levels in small patient populations during cluster periods when compared with remission periods. Although corroborated by others,26, 53, 86, 93 explanations for this finding varied and included disordered REM states,93 effects of pain, 53. 86 stress, or hypothalamic-pituitary axis dysfunction. 26, 64 Support for hypothalamie involvement evolved indirectly from ehronobiologic studies. Dyschronic biologic changes were found in neuroendocrine substances such as testosterone,26 prolactin, SR, 112 melatonin,lO, 111 cortisol,28, 84, 113 and beta-endorphins. 83 Similarly, a loss of circadian rhythmicity for blood pressure and body temperature was also reported. 29 Platelet Serotonin and Monoamine Oxidase In two reports, cerebrospinal fluid concentrations of the platelets serotonin (5HT) precursor tryptophan 9' and whole-blood 5_HTBO were found to be increased during attacks. Consistent with these findings, it was later reported that following cluster attacks, the maximal rate of uptake of platelet 5-HT decreased significantly. 108,114 Platelet monoamine oxidase (MAO) activity was also found to be significantly reduced in patients with cluster headache. 37, 74. 115 This finding, however, was explained on the basis of cigarette smoking rather than pathogenesis. Histamine The importance of histamine in the pathogenesis of cluster headache has always remained questionable despite reports of increased urine and blood histamine during attacks.' 105 It should be noted that HI and H2 receptor-antagonists had no appreciable effect on frequency or intensity of cluster headache. 6 A renewed interest in histamine was stimulated by the findings of Appenzeller et aF and others.89 Electronic microscopic examination of temporal skin biopsies from patients with cluster headache revealed increased mast cell counts and degranulation with deposition of the mast cells around cutaneous nerves. Others, however, were unable to duplicate these findings. 3 11 Appenzeller et aF suggested that release of histamine by antidromal sensory nerves may be responsible for vasodilation and pain of cluster attacks. Autonomic Nervous System Changes Some investigators were of the opinion that the cluster headache attack was mediated via the greater superficial petrosal nerve and sphenopalatine ganglion, from stimulation of parasympathetic nuclei in the hypothalamus. 34 . 95, 107 Indeed, surgical section of the seventh cranial nerve pathway, including the nervous intermedius,95 or superficial petrosal nerves 82 , 83 resulted in partial to complete relief of attacks in small patient populations. More recently, sympathetic nervous system dysfunction has become the subject of investigation. In a classical pupillometric study by Fanciullacci et al,2' topical application of 2% tyramine induced ineffective midriatic responses on the symptom-
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atic side during cluster headache attacks, interval periods, and remissions. These results suggested permanent dysfunction of unilateral sympathetic neurones. Others have also demonstrated increased unilateral facial sweating caused by sympathetic dysfunction. 98, 104
PATHOGENESIS There are three major clinicopathologic processes in the cluster headache syndrome: the cluster period, attack provocation, and pain production. Each process appears to be dependent upon the one before; hence, pain pathways are triggered by an attack-provoking mechanism, which, in turn, may only be stimulated in an altered physiologic environment defined as the cluster period. The cluster period may be characterized as a cyclically occurring, attacksusceptible period, probably caused by hypo thalamic dysfunction. 16, 61. 80. 85 The cyclic nature of cluster periods has been reported to be related to changes in seasonal photoperiods. 56 Autoregulatory function and circadian rhythmicity of neuroendocrine activity appear to be impaired, as discussed earlier. In 1983, Kudrow58 hypothesized that, as a consequence of these physiologic changes, chemoreceptor responses to hypoxemia may be blunted, resulting in impaired autoregulation of arterial oxygen concentration. Clinically, cluster attacks often occur in association with altitude, during REM sleep, and with provocation by vasodilators-conditions that may cause hypoxemia if autoregulatory mechanisms are impaired. Indeed, oxygen inhalation effectively aborts cluster attacks,6o suggesting a negative-feedback mechanism of action. Experimentally, a polysomnographic study of a small cluster headache population revealed an association of attack-onset and REM -related oxygen desaturation. 68 The relationship of cluster attack onset to hypoxemic events was further corroborated in a recent study.67 Oxygen saturation (SAO z) was monitored from 10 patients in active cluster periods, 10 patients in remission periods, and 5 nonheadache subjects before and after sublingual administration of nitroglycerin. Following administration of nitroglycerin, a significant de saturation in oxygen was found in all groups. In remission and control groups, SA0 2 values returned to baseline levels after approximately 30 minutes. In the active cluster group, however, SAO z values decreased further for an additional 20 minutes, culminating in attacks in 10 out of 10 patients. Results support the hypothesis that chemoreceptor responses to hypoxemia may be impaired during active cluster periods. 58 The more distal pathways relating to the pain of the cluster headache attacks have been alluded to earlier. The seventh cranial nerve has been considered a major pathway in this regard. 34, 95, 107 Recently, the trigeminal nerve has become a subject of great interest, as introduced by Moskowitz. 82 Sicuteri et a1 99-101 suggested that the cluster attack may be mediated by release (antidromal stimulation) of substance P from trigeminal nerves. Indeed, an antidromal mechanism mediated by histamine was suggested by Appenzeller et a!. 7
MANAGEMENT OF CLUSTER HEADACHES The principles that govern successful treatment of cluster headache differ little from those of most medical disorders. These include patient education and prophylactic and symptomatic treatment.
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Patient Education Anxiety and anguish are common accompanimcnts of the active cluster period. This is due to the patient's clear recollection of the painful experience and anticipation of future attacks. It is therefore incumbent upon the clinician to give the patient a thorough discourse on cluster headache. The patient should be reassured that current treatment regimens readily prevent most attacks and rapidly abort those that break through prophylactic medications. Even successful prophylactic medication, however, will not shorten or prevent cluster periods. It should be pointed out that, in the natural course of this disorder, one third of all patients will experience permanent remission, another third may have only minor attacks that require no medication, and in the final third, the pattern of attacks will remain unchanged. 59 Patients should be instructed that alcohol may induce a cluster headache attack. Patients should be warned to avoid prolonged exposure to volatile substances such as solvents, gasoline, and oil-based paints during cluster periods. Altitude hypoxemia may induce attacks during cluster periods. This may occur at levels above 5000 feet and include airplane travel (where pressurization is equivalent to 7000-8000 feet). Ergotamine, 2 mg, 1 hour before air travel, may prevent an attack. Oxygen inhalation, 4 to 7 Llmin, administered during the attack in flight may offer complete relief. Cluster attacks expected during ski trips at higher altitudes may be prevented by oral administration of acetazolamide, 25 mg twice a day for 4 days, starting 2 days before altitude is reached. Prophylactic Treatment
Episodic Cluster Headache. Attacks limited to sleep hours are best prevented by ergotamine, 2 mg orally, administered 1 to 2 hours before bedtime. Such attacks often occur during the first REM stage of sleep approximately 90 minutes after sleep onset. In our experience, ergotamine prophylaxis has been most effective when ingested at least 2 hours before the expected attack. We have also learned that, in cluster headache, the use of ergotamine at daily dosages of 2 mg will not result in ergotamine-rebound attacks, as in migraine. Further, in our experience, clinical ergotism is unlikely at this dosage in a cluster population. Ergotamine is contraindicated, however, in the presence of peripheral vascular, cardiovascular, or cerebrovascular atheromatous disease. It should also be contraindicated during pregnancy, in liver or renal disease, serious infection, and during postsurgical periods. Attacks that occur during various times of day or night may be prevented with other prophylactic agents, such as methysergide, verapamil, lithium, or prednisone. In our clinic, for patients under 30 years of age who have suffered only one or two cluster periods, the treatment of choice is methysergide, 4 mg three to four times a day. Methysergide is most effective in the earlier course of disease and least effective in later years. An overall 65% efficacy has been reported with methysergide prophylaxis. 31, 62 Contraindications and associated complications are well established and have been reviewed elsewhere. 38 In patients over 30 years of age, particularly for those who have experienced several cluster periods, our treatment of choice is verapamil, 80 mg four times a day, spaced evenly throughout working hours, and ergotamine, 2 mg 1 hour before bedtime. Gabel and Spierings 33 reported that verapamil prophylaxis was efficacious in 70% of patients with episodic and chronic cluster headaches. Their findings corroborated Meyer and Hardenberg's81 results and our own unpublished data collected over the past 7 years. Further, we have learned that the addition of nighttime ergotamine to daily verapamil regimens will capture another 15% of patients. The beneficial action of verapamil, a calcium-entry blocker, remains unknown. Calcium-entry channels are widely distributed throughout somatic,
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neuronal, and vascular systems. The major side effect of verapamil prophylaxis, in our experience, is constipation, which may preclude its use in the occasional patient. Approximately 5% to 8% of our younger patients experienced girdle pain, which appears to be muscular by description. Approximately 5% to 10% of patients with episodic cluster headache may be resistant to verapamil-ergotamine prophylaxis and will require the addition of lithium, 300 mg twice a day. The success rate of lithium as the sole prophylactic agent (first reported by Ekbom in 1978)18 was found to be between 70% and 80%.17. 61. 76 Concomitant use of diuretics or severely restricted sodium diets is contraindicated; the lithium ion competes with intracellular sodium and may lead to toxicity. In the event of treatment failure with methysergide, or in patients under 40 years of age who are resistant to "triple" therapy, the recommended course of treatment includes steroids. At our clinic, the starting daily dose of prednisone is 40 mg/day in divided doses, tapered over a 3-week period. Approximately 80% of patients with episodic cluster headache and 40% of patients with chronic cluster headache should experience a medication remission. 51. 62 Attacks are expected to break through when the daily dosage falls below 15 mg. Side effects, complications, and contraindications of prednisone therapy are ubiquitously reported in the medical literature. Diverticulosis should be added to the list of contraindications because we have been alerted to two relevant cases of ruptured diverticula in patients with cluster headache over 40 years of age. This complication occurred 1 and 2 days after initiation of prednisone prophylaxis. It should also be stressed that prednisone prophylaxis should not be used for a period longer than 3 weeks to a month, because fastness to steroids may result. Chronic and Subchronic Cluster Headache. In a recent study, approximately half of the study population of patients with subchronic and chronic cluster headache were reported to be resistant to treatment. 57 Subchronic cluster headache was defined by those cases in which remissions are usually under 5 months in duration. Minnesota Multiphasic Personality Inventory (MMPI) studies revealed that 50% of patients with subchronic and chronic cluster headache had elevated scores for either depression or hysteria and were prone to addiction-characteristics associated with treatment resistance. 57 In the absence of a history of treatment resistance, neurosis, and drug abuse, or evidence for proneness to addiction, the recommended treatment regimen is the same as that for episodic cluster headache (i.e., lithium carbonate or verapamil, and ergotamine). Lithium carbonate, 300 mg twice a day, with the addition of ergotamine at bedtime, offers the same successful response as does verapamil and ergotamine. In the presence of traits that predict treatment resistance, one should initiate triple therapy with verapamil, 20 mg four times a day; ergotamine tartrate, 2 mg at bedtime; and lithium carbonate, 300 mg twice a day. Narcotic medication should be prohibited. Continued refractoriness may indicate a course of histamine desensitization. Its efficacy, alone or in combination with prophylactic agents, has been reported.]'5 Experimental Approaches. In an open-label prophylactic study, as yet not corroborated by control studies, Hering and Kuritsky43 successfully treated 11 of 15 patients with cluster headache using sodium valproate, 600 mg to 2000 mg daily. No correlation was found between efficacy and levels of valproate in plasma. Treatment was reported to be well tolerated except for mild nausea in three patients. The authors suggest that sodium valproate may act as a GABA-mimetic agent on interneurons of the hypothalamic suprachiasmatic nucleus. Their results suggest a chronobiologic role in the pathogenesis of cluster headache. An experimental approach aimed at shortening cluster periods is currently being studied at the California Medical Clinic for Headache. It entails exposure to
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bright-light stimulation in an effort to reset circadian pacemakers by shifting sleepwake cycles. Other chronobiologic-dependent disorders have been successfully treated in this manner. 12,73,91 In the event that all medical attempts at controlling cluster headaches satisfactorily have failed, the surgical procedure of choice appears to be radiofrequency trigeminal gangliolosis, ~athew and Hurt" reported a significant success rate among treatment-resistant patients with chronic cluster headache. A similar success rate has been enjoyed at the May Clinic (Campbell K: Personal communication, 1989). Complications of this procedure may include sensory and secretomotor changes or anesthesia dolorosa. Symptomatic Treatment of Cluster Headache Effective symptomatic treatment of attacks should be provided in the event of prophylactic medication breakthrough, in medical conditions that preclude the use of prophylactic agents, and in situations in which preventative medications are refused. Oxygen inhalation is the safest and most effective method of aborting cluster headache attacks. 6o In our experience, 70% of cluster attacks may be aborted within 10 minutes and 90% within 15 minutes. Techniques for achieving maximal success rates are as follows: (1) Oxygen inhalation should be started at the very onset of the attack. (2) The patient should assume a sitting position, upright or leaning forward. Supine or nearly supine positions may increase cavernous sinus congestion, which may aggravate rather than abate the attack. (3) The oxygen flow should be set at 7 Llmin. (4) The patient should be warned against hyperventilating, which may limit oxyhemoglobin saturation. A high level of oxygen saturation (98%-99%) needs to be sustained for several minutes to achieve relief of the attack. 67 (5) A facial mask rather than a nasocannula should be used, because associated nasal stuffiness may impede airway flow, The value of oxygen inhalation has been well documented. 4, 30, 60 There are few contraindications to short-term use. Sublingual ergotamine or medihaler preparations are also effective and, indeed, more convenient than oxygen inhalation. The medihaler should be inhaled at the onset of the attack and may be repeated three times, 5 minutes apart, if needed. The sublingual preparation is placed under the tongue at the onset of an attack and should remain unswallowed for several minutes in order to assure absorption through sublingual blood vessels. This preparation may be repeated after 10 minutes, if needed. In an emergency room situation or office setting, parenteral administration of ergotamine may be used. Dihydroergotamine, 1 mg, or ergotamine tartrate, 0.5 mg, may be given intramuscularly in the gluteal region. Other symptomatic medications include 5% cocaine hydrochloride 8 or 4% lidocaine 52 administered intranasally with the head tilted back and turned toward the ipsilateral side. The effects of these agents are limited by the patient's intranasal anatomy, proper administration, and tolerance. Their benefit is probably due to local anesthetic effects on either the sphenopalatine ganglion or nerve endings in mucosal tissue.
MANAGEMENT OF CHRONIC PAROXYSMAL HEMICRANIA The treatment of choice for chronic or episodic paroxysmal hemicrania in adults is the prophylactic administration of indomethacin. Response is complete and, indeed, diagnostic of these conditions. According to Sjaastad,102 patients should
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receive approximately 200 mg of indomethacin per day to ensure a therapeutic response. In our experience, indomethacin, 75 mg to 100 mg/day in divided doses, has been successful in all cases. We have found that indomethacin may be decreased to low maintenance levels at approximately 25 mg/day. Despite the frequently reported childhood onset of CPH, guidelines for treating children are lacking. In a recent case report, 54 a 9-year-old boy who had CPH since age 6 was successfully treated prophylactically with baby aspirin at doses of 162 mg twice a day that were maintained for 3 months. Attacks have not recurred since discontinuation of aspirin 2 years ago.
REFERENCES 1. Ad Hoc Committee on Classification of Headache. JAMA 179:717-718, 1962 2. Aebelholt-Krabbe A, Henriksen L, Olesen J: Tomagraphic determination of cerebral blood flow during attacks of cluster headache. Cephalalgia 4: 17-23, 1984 3. Aebelholt-Krabbe A, Rank F: Histological examination of the superficial temporal artery in patients suffering cluster headache. Cephalalgia 5(suppl 3):282-283, 1985 4. Anthony M: Treatment of attacks of cluster headache with oxygen inhalation. In Tyrer JH, Eadie MJ (eds): Clinical and Experimental Neurology, vo118. Sydney, Australian Association of Neurologists, 1981, p 195 5. Anthony M, Lance JW: Histaminic and serotonin in cluster headache. Arch Neurol 25:225-231, 1971 6. Anthony M, Lord GDA, Lance JW: Controlled trials of cimetidine in migraine and cluster headache. Headache 18:261-264, 1978 7. Appenzeller 0, Becker W, Ragas A: Cluster headache: Ultrastructural aspects. Neurology 28:371, 1978 8. Barre F: Cocaine as an abortive agent in cluster headache. Headache 22:69-73, 1982 9. Broch A, H0rven I, Nornes H, et al: Studies of cerebral and ocular circulation in a patient with cluster headache. Headache 10:1-13, 1970 10. Chazot G, Claustrat B, Brun J, et al: A chronobiological study of melatonin, cortisol, growth hormone and prolactin secretion in cluster headache. Cephalalgia 4:213-220, 1984 11. Cuypers J, Westphal K, Bunge ST: Mast cells in cluster headache. Acta Neurol Scand 61:327-329, 1980 12. Czeisler CA, Kronauer RE, Allan JS, et al: Bright light induction of strong (Type 0) resetting of the human circadian pacemaker. Science 244:1328-1333, 1989 13. Dalessio DJ: A reappraisal of the trigger zones of tic douloureaux. Headache 9:73-76, 1969 14. Dexter JD, Riley TL: Studies in nocturnal migraine. Headache 15:51-62, 1975 15. Diamond S, Freitag FG, Prager J, et al: Treatment of intractable cluster. Headache 26:42-46, 1986 16. Ekbom K: Pathogenesis of cluster headache. In Elau IN (ed): Migraine: Clinical, Therapeutic, Conceptual and Research Aspects. London, Chapman and Hall, 1987, pp 433-448 17. Ekbom K: Lithium for cluster headache: Review of the literature and preliminary results of long-term treatment. Headache 21:132-139, 1981 18. Ekbom K: Litium vid kroniska symptom av cluster headache. Opusc Med 19:148-156, 1978 19. Ekbom K: A clinical comparison of cluster headache and migraine. Acta Neurol Scand 46(suppI41):1-44, 1970 20. Ekbom K: Pattern of cluster headache with a note on the relation to angina pectoris and peptic ulcer. Acta Neurol Scand 46:225-237, 1970 21. Ekbom K: Nitroglycerin as a provocative agent in cluster headache. Arch NeuroI19:487493, 1968 22. Ekbom KA: Ergotamine tartrate orally in Horton's "histaminic cephalgia" (also called Harris' "ciliary neuralgia"). Acta Psychiatr Scand 46(suppl):106-113, 1947
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23. Ekbom K, Ahlborg B, Schele R: Prevalence of migraine and cluster headache in Swedish men of 18. Headache 18:9~19, 1978 24. Ekbom K, de Fine Olivarius B: Chronic migrainous neuralgia-diagnostic and therapeutic aspects. Headache 11:97~101, 1971 25. Ekbom K, Greitz T: Carotid angiography in cluster headache. Acta Radiol Diagn 10:177~ 186, 1970 26. Facchinetti F, Nappi G, Cicoli C, et al: Reduced testosterone levels in cluster headache: A stress-related phenomenon. Cephalalgia 6:29~34, 1986 27. Fanciullacci M, Pietrini U, Gatto G, et al: Latent dysautonomic pupillary lateralization in cluster headache: A pupillometric study. Cephalalgia 2:135~144, 1982 28. Ferrari E, Cane pari C, Bossolo PA, et al: Changes of biological rhythms in primary headache syndromes. Cephalalgia 3(suppl 1):58~68, 1983 29. Ferrari E, Martignoni E, Vailati A, et al: Chronobiological aspects of cluster headache: Effects of lithium therapy. In Savoldi F, Nappi G (eds): Headache. Pavia, Palladio Editore, 1979, pp 152~160 30. Fogan L: Treatment of cluster headache: A double-blind comparison of oxygen vs. air inhalation. Arch Neurol 42:362~363, 1985 31. Friedman AP, Elkind AH: Appraisal of methysergide in treatment of vascular headaches of migraine type. JAMA 184:125~130, 1963 32. Friedman AP, Mikropoulos HE: Cluster headaches. Neurology 8:653~663, 1958 33. Gabel IJ, Spierings ELH: Prophylactic treatment of cluster headache with verapamil. Headache 29:167~168, 1989 34. Gardner WJ, Stowell A, Dutlinger R: Resection of the greater superficial petrosal nerve in the treatment of unilateral headache. J Neurosurg 4:105~114, 1947 35. Gilbert GJ: Cluster headache and cluster vertigo. Headache 9:195, 1970 36. Gilbert GJ: Meniere's syndrome and cluster headaches: Recurrent paroxysmal vasodilatation. JAMA 191:691, 1965 37. Glover V, Peatfield R, Zammit-Pace R, et al: Platelet monoamine oxidase activity and headache. J Neurol Neurosurg Psychiatry 44:786~790, 1981 38. Graham JR, Suby HI, LeCompte PM, et al: Inflammatory fibrosis associated with methysergide therapy. In Friedman AP (ed): Research and Clinical Studies in Headache, vol1. Basel, Karger, 1967, pp 123~164 39. Green M, Apfalbaum RI: Cluster-tic syndrome. Headache 18:112, 1978 40. Harris W: Ciliary (migrainous) neuralgia and its treatment. Br Med J 1:457~460, 1936 41. Harris W: Neuritis and Neuralgia. London, Oxford University Press, 1926 42. Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8 (suppl 7):9~96, 1988 43. Hering R, Kuritsky A: Sodium valproate in the treatment of cluster headache: An open clinical trial. Cephalalgia 9: 195, 1989 44. Heyck H: Der cluster-kopfschmerz. Dtsch Med Wochenschr 100:1292~1293, 1975 45. Hornabrook RW: Migrainous neuralgia. NZ Med J 63:774, 1964 46. Horton BT: Histaminic cephalgia. Lancet 2:92~98, 1952 47. Horton BT, MacLean AR, Craig WM: A new syndrome of vascular headache: Results in treatment with histamine: Preliminary report. Mayo Clin Proc 14:257~260, 1939 48. Horton BT, Magath TB, Brown GE: An un described form of arteritis of the temporal vessels. Proc Stafl" Meet Mavo Clin 7:700~701, 1932 49. Hprven I, Nornes H, Sjaastad'O: Different corneal indentation pulse patterns in cluster headache and migraine. Neurology 22:92~98, 1972 50. Huston KA, Hunder GG, Lie JT, et al: Temporal arteritis: A 25-year epidemiologic, clinical, and pathological study. Ann Intern Med 88:162~167, 1978 51. Jammes JL: The treatment of cluster headache with prednisone. Dis Nerv Syst 36:375~ 376, 1975 52. Kittrelle JP, Gronse DS, Seybold M: Cluster headache: Local anaesthetic abortive agents. Arch Neurol 42:496~498, 1985 53. Klimek A: Plasma testosterone levels in patients with cluster headache. Headache 22:162~164, 1982 54. Kudrow DB, Kudrow L: Successful aspirin prophylaxis in a child with chronic paroxysmal hemicrania. Headache 29:280~281, 1989
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55. Kudrow L: Cluster headache. In Blau IN (ed): Migraine: Clinical, Therapeutic, Conceptual and Research Aspects. London, Chapman and Hall, 1987, pp 113-132 56. Kudrow L: The cyclic relationship of natural illumination to cluster period frequency [abstract). Cephalalgia 7 (suppl 6):76-77, 1987 57. Kudrow L: Subchronic cluster headache. Headache 27:197-200, 1987 58. Kudrow L: A possible role of the carotid body in the pathogenesis of cluster headache. Cephalalgia 3:241-247, 1983 59. Kudrow L: Natural history of cluster headache. Part 1. Outcome of drop-out patients. Headache 22:203-206, 1982 60. Kudrow L: Response of cluster headache attacks to oxygen inhalation. Headache 21:14, 1981 61. Kudrow L: Cluster Headache: Mechanism and Management. Oxford, Oxford University Press, 1980 62. Kudrow L: Comparative results of prednisone, methysergide and lithium therapy in cluster headache. In Greene R (ed): Current Concepts in Migraine Research. New York, Raven Press, 1978, pp 159-163 63. Kudrow L: Lithium prophylaxis for chronic cluster headache. Headache 17:15-18, 1977 64. Kudrow L: Plasma testosterone and LH levels in cluster headache. Headache 17:91-92, 1977 65. Kudrow L: Plasma testosterone levels in cluster headache: Preliminary results. Headache 16:28-31, 1976 66. Kudrow L, Esperanca P, Vijayan N: Episodic paroxysmal hemicrania? Cephalalgia 7:197201, 1987 67. Kudrow L, Kudrow DB: The association of cluster headache onset and oxygen desaturation. Headache, in press 68. Kudrow L, McGinty DS, Phillips ER, et al: Sleep apnea in cluster headache. Cephalalgia 4:33-38, 1984 69. Kunkle EC, pfeifrer JB Jr, Wilhoit WM, et al: Recurrent brief headache in "cluster" pattern. Trans Am Neurol Assoc 77:240-243, 1952 70. Kunkel RS, Dohn F: Surgical treatment of chronic migraine neuralgia. Cleveland Clin Q 41:189, 1974 71. Lance JW: Mechanisms and Management of Headache, ed 3. London, Butterworths, 1978 72. Lance JW, Anthony M: Migrainous neuralgia or cluster headache. J Neurol Sci 13:401, 1971 73. Lewy AJ, Sacks RL, Miller LS, et al: Antidepressant and circadian phase-shifting effects of light. Science 235:352-354, 1987 74. Littlewood JT, Glover V, Sandler M, et al: Migraine and cluster headache: Links between platelet monoamine oxidase activity, smoking and personality. Headache 24:30-34, 1984 75. Lovshin LL: Clinical caprices of histaminic cephalgia. Headache 1:3-6, 1961 76. Mathew NT: Clinical subtypes of cluster headache and response to lithium therapy. Headache 18:26-30, 1978 77. Mathew NT, Hurt W: Radiofrequency trigeminal gangliolysis in the treatment of chronic intractable cluster headache. Headache 25:166, 1985 78. Medina JL, Diamond S: Cluster headache variant: Spectrum of a new headache syndrome. Arch Neurol 38:705, 1981 79. Medina JL, Diamond S: The clinical link between migraine and cluster headache. Arch NeuroI34:470, 1977 80. Medina JL, Diamond S, Fareed J: The nature of cluster headache. Headache 19:309322, 1979 81. Meyer JS, Hardenberg BA: Clinical effectiveness of calcium entry blockers in prophylactic treatment of migraine and cluster headaches. Headache 23:266-277, 1983 82. Moskowitz MA: The neurobiology of vascular head pain. Ann Neurol 16:157-168, 1984 83. Nappi G, Facchinetti F, Bono G, et al: Lack of l3-endorphin and l3-lipotropin circadian rhythmicity in episodic cluster headache: A model for chronopathology. In pfaffenrath V, Lundberg P-O, Sjaastadt 0 (eds): Updating in Headache. Berlin, Springer-Verlag, 1985 84. Nappi G, Ferrari E, Polleri A, et al: Chronobiological study of cluster headache. Chronobiologia 2:140, 1981
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