Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Cluster headache syndrome David R. Marks MD & Alan M. Rapoport MD To cite this article: David R. Marks MD & Alan M. Rapoport MD (1992) Cluster headache syndrome, Postgraduate Medicine, 91:3, 96-104, DOI: 10.1080/00325481.1992.11701227 To link to this article: http://dx.doi.org/10.1080/00325481.1992.11701227
Published online: 17 May 2016.
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Date: 17 June 2016, At: 21:33
-@CME credit article
Cluster headache syndrome Ways to abort or ward off attacks
David R. Marks, MD Alan M. Rapoport, MD
Postgraduate Medicine 1992.91:96-104.
Preview Cluster headache, one of the most painful conditions known, is encountered infrequently in clinical practice and may be difficult to recognize. The authors describe the signs and symptoms of cluster headache, tell how it can be distinguished from migraine, and outline the various forms of treatment and prophylaxis for its episodic and chronic forms.
Cluster headache is a syndrome characterized by repeated episodes of severe head and facial pain accompanied by various autonomic abnormalities. Because cluster headache is uncommon, some physicians may be unfamiliar with its presentation and treatment; in addition, it may be confused with other causes of facial pain. Proper diagnosis is crucial, because effective therapy is available. Accurate descriptions of duster headache as a specific disease entity date back to 1840. Since then, it has been known variously as sphenopalatine neuralgia, migrainous neuralgia, ciliary neuralgia, and histarninic cephalalgia. In 1952, Kunkle and colleagues1 noted the clustering pattern of headache attacks, but it was not until 1962 that the term "cluster headache" was formally recognized by the Ad Hoc Committee on Classification ofHeadache.2 Cluster headache is commonly classified as either episodic or chronic; 80% to 97% of patients with the disease have the episodic subtype. Patients with episodic duster headache generally have pe-
96
riods during which they are "headache prone," followed by periods during which no headache symptoms occur. The headache-prone periods usually last 1 to 3 months, and during this time the patient experiences at least one headache each day. Remissions last 6 months to many years. Cluster headache is considered chronic when a patient has the characteristic headache daily for at least 12 months without remission. This chronic condition can be the primary disorder, or it may reflect a progression of the episodic subtype.
Epidemiology Unlike other headache syndromes, which have a strong pattern of female predominance, duster headache is typically a disorder of middle-aged males, with a malefemale ratio of about 5: J.3 Although no good studies of prevalence have so far been performed, it is estimated that 0.4% to 1o/o of the male population is affected. Onset is usually at about 30 years of age but may occur as late as the eighth decade oflife. There does
not appear to be any strong racial or genetic predisposition.
Signs and symptoms The cluster headache is one of the most painful conditions known. The typical headache is described as excruciating, sharp, lancinating, or burning and usually occurs in an oculotemporal or oculofrontal distribution. One patient described it as "a force pushing with such incredible power through my eye that my head appears to be moving backwards, yielding to its resistance."3 The pain is generally unilateral and remains on the same side during the entire cluster period, although it may change sides during a subsequent cluster period. The location of the most severe pain often corresponds to the distribution of the first and second divisions of the trigeminal nerve. Radiation to the ipsilateral neck, occiput, mastoid, and teeth is common. Headaches occur once a day in about half of patients but may occur as often as 10 times a day. The duration ranges from minutes to hours, with an average of 60 to 90 minutes, and is remarkably consistent for a given individual. Parasympathetic hyperactivity often contributes to associated symptoms. Unilateral headache is accompanied by ipsilateral lacrimation, conjunctival injection, rhinorrhea, or nasal congestion in up to 85% of patients and an ipsilateral partial Horner's syndrome (ptosis continued
CLUSTER HEADACHE • VOL 91/NO 3/FEBRUARY 15. 1992/POSTGRADUATE MEDICINE
Postgraduate Medicine 1992.91:96-104.
Illustration: © 1992. Suzi Kilgore
VOL 91/NO 3/FEBRUARY 15, 1992/POSTGRADUATE MEDICINE • CLUSTER HEADACHE
97
The frequency of cluster headache periods appears to be related to seasonal changes in the length of daylight.
Postgraduate Medicine 1992.91:96-104.
Table 1. Distinguishing clinical features of cluster headache and migraine
Cluster
Migraine
Sex
90% male
75% female
Age < 20 yr at onset
30%
70%
Family history of that type of headache
Rare
85%
Recurrence pattern
Episodic or chronic
Random
Duration
1/2-2 hr
4-72 hr
Time of attacks
Night more often than day
Variable
Location of pain
Unilateral, periocular
Bilateral, frontotemporal
Quality of pain
Lancinating, burning
Throbbing
Associated visual aura
None
10%
Associated lacrimation, rhinorrhea, ptosis
Very common
Occasional
Associated nausea, vomiting, photophobia
Rare
Frequent
and miosis, without anhidrosis) in 60% to 70%. Partial Horner's syndrome may be permanent in a small percentage ofindividuals.4 Facial flushing and bradycardia are often associated with an attack and are probably also secondary to increased parasympathetic activity. 5 Of particular interest is the rhythmicity of duster headache. The frequency of duster periods
98
appears to be related to seasonal changes in the length of daylight. The timing of attacks follows a pattern of circadian regularity. Nearly half of patients experience symptoms at about the same time each day during the duster period6; 50o/o to 75o/o of attacks occur during sleep and are associated with the first rapid eye movement phase.7
Cluster headache versus migraine Cluster headache can usually be distinguished from migraine on the basis of its clinical presentation (table 1). The most important distinguishing feature is the timing of attacks. As has been mentioned, duster headaches occur rhythmically, recur one or more times a day, are of relatively short duration, and often occur at night. In contrast, migraines occur at random, are oflong duration, and often have their onset during the day. Cluster headache is exclusively unilateral and is often described as burning or lancinating, while migraine pain sometimes occurs bilaterally (in 40o/o of cases) and is commonly described as throbbing. Unlike patients with duster headache, those with migraine may experience a visual aura (classic migraine, now referred to as migraine with aura) and usually do not have associated symptoms such as conjunctival injection, ipsilateral tearing, rhinorrhea, or partial Horner's syndrome. Despite these differences, some patients may have symptoms characteristic of both duster headache and migraine. There are reports of migraine occurring in dusters8 and of duster headaches associated with prodromal symptoms. 9 In these rare cases, definitive diagnosis may be difficult. The term "migraineduster headache syndrome" has been proposed to describe patients with predominance of one type
CLUSTER HEADACHE • VOL 91/NO 3/FEBRUARY 15, 1992/POSTGRADUATE MEDICINE
Inhaling oxygen at the very beginning of an acute attack of cluster headache may abort the attack.
of headache who have significant symptoms characteristic of the other type. 10
Postgraduate Medicine 1992.91:96-104.
Treatment
Medical treatment (table 2) varies according to whether the goal is to abon attacks or prevent them. Surgical intervention is available for patients whose attacks resist pharmacologic therapy. ABORTIVE-According to reports, an acute attack of duster headache can be aboned in 60% to 82% of patients if they inhale oxygen at the very beginning of the headache. 11 In some of these patients, however, the headache recurs after a shon period of time. The recommended dosage is 100% oxygen at 7 L/min for about 10 minutes. The mechanism of action of oxygen inhalation therapy is unknown but may involve cerebral vasoconstriction or correction of oxyhemoglobin desaruration. Sublingual ergotamine tartrate (Ergostat) in a 2-mg dose has been used for acute attacks and has been reponed to be effective in 50% to 85% of patients. Oral ergotamine tartrate, available only in combination forms (eg, Cafergot, Wigraine), can also be used. Unfortunately, as with oxygen therapy, many patients have a breakthrough or recurrence. A parenteral form of ergotamine, dihydroergotamine mesylate (D.H.E. 45), is available for abor-
Table 2. Therapy for cluster headache Abortive agents
Inhaled oxygen Ergotamine tartrate, oral (Cafergot, Wigraine) or sublingual (Ergostat) Dihydroergotamine mesylate, intramuscular or intravenous (D.H.E. 45) Lidocaine HCI (Xylocaine), nasal drops Cocaine, nasal drops Sumatriptan (lmitrex), soon to be available Prophylactic agents
Ergotamine tartrate, oral Methysergide maleate (Sansert) Lithium carbonate Calcium channel blockers Corticosteroids Indomethacin (lndocin) Valproic acid (Depakene, Depakote) Surgery
Radiofrequency trigeminal gangliorhizolysis
tive therapy and is preferred for use in the emergency department. D.H.E. 45 is usually administered intramuscularly or intravenously in a dose of0.5 to 1 mglml. An intranasal preparation will soon be available. It is sometimes necessary to pretreat patients who are taking ergotamine with antiemetics, particularly those who are receiving intravenous D.H.E. 45. The mechanism of action of ergotamine is not known, but a vasoconstrictive effect related to stimulation of serotonin receptors has been postulated. D.H.E. 45 may also act upon primary sensory nerve fibers in the trigeminalvascular system. Nasal drops of a 4% solution of
VOL 91/NO 3/FEBRUARY 15. 1992/POSTGRADUATE MEDICINE • CLUSTER HEADACHE
either lidocaine hydrochloride (Xylocaine) or cocaine have been used in an effon to decrease afferent activity to the trigeminal nerve and thus interrupt the reflex circuits that are believed to be involved in duster attacks. Some patients have been reponed to benefit, but results have been generally disappointing. Patients using cocaine nasal drops must be closely monitored because of the potential for addiction or abuse. Topical cocaine may be absorbed systemically and cause tachycardia and vasoconstriction. Therefore, it must be used cautiously in elderly patients and in those with coronary anery disease. In general, we are opposed to the continued 99
Recurrence of cluster headaches at about the same time each day suggests a link between the attacks and the circadian rhythms of the body.
Postgraduate Medicine 1992.91:96-104.
What provokes cluster headaches? Cluster headache attacks can be triggered by alcohol ingestion, subcutaneous or intravenous injections of histamine phosphate, or sublingual nitroglycerin (Nitrosrat). However, these substances can induce headaches only when the patient is "atrack susceptible"; during periods of remission, they have no headache-inducing effect. The vasodilatory effects of these agents have implicated vascular dilatation in the pathogenesis of the syndrome. Through studies describing temporal artery swelling and facial thermographic changes during duster attacks, the association with extracranial vascular dilatation has been established.' However, cerebral blood flow studies have failed to show an association between intracranial vascular activity and duster headaches. 2 When histamine was recognized as a provocative factor in duster attacks, attention focused on its possible role in the pathogenesis of the syndrome.' Interest in this association intensified after patients with duster headache were noted to have an increased incidence of duodenal ulcers. It has been reponed that blood and urine levels of histamine increase during a duster attack. 3 One investigator4 reponed an increase in the number and degranulation of mast cells around cranial nerves
use of any narcotic in the treatment of duster headache. Sumatriptan (lrnitrex), a selective serotonin (5-hydroxytrypramine1) receptor agonist, was shown in a recent study to be effective in the treatment of acute duster headache.12 Patients received a subcura-
100
during an attack. This has not been confirmed by other investigators, however, and the importance of these observations remains in question. Histamine1 and histamine2 receptor antagonists have been used for prophylaxis of duster headache but have not been found to be efficacious. 5 The relationship between duster headache and histamine is unresolved. A relationship between changes in the number of daylight hours throughout the year and the frequency of duster attacks has been demonstrated. 6 The incidence of duster periods is highest during the weeks before and after the shonest and longest days of the year. In addition, recurrence of duster headaches at about the same time each day suggests a link between the attacks and the circadian rhythms of the body. Because the suprachiasmatic nucleus of the hypothalamus is believed to control circadian rhythms, attention has focused on its role in duster headache. The activity of the suprachiasmatic nucleus is known to be related to changes in the daily cycle of light and darkness. 7 It is possible that in duster headache patients changes in photoperiodicity inhibit the ability of the hypothalamus to regulate sympathetic and parasympathetic activity
neous injection of 6 mg within 10 minutes of the onset of an acute attack; 7 4% experienced a decrease in the severity of their headache and 46% were pain-free within another 15 minutes. In addition, the incidence of ipsilateral conjunctival injection was decreased.
These results indicate that serotonin may have a role in the pathogenesis of duster headache. Sumatriptan has been approved for use in a number of European countries, and it is expected to receive US Food and Drug Administration approval soon.
CLUSTER HEADACHE • VOL 91/NO 3/FEBRUARY 15, 1992/POSTGRADUATE MEDICINE
Postgraduate Medicine 1992.91:96-104.
For patients with episodic cluster headache, preventive therapy should be started early in the cluster period and continued until the patient is headache-free for at least 2 weeks.
and the produaion ofhormones. Further evidence of hypothalamic dysfunaion in duster headache comes from studies demonstrating abnormal secretory rhythms for beta endorphins, testosterone, cortisol, beta lipotropin, and prolaain during duster periods.8 During remission of headache, many of these cyclical hormonal abnormalities reven to normal. With greater understanding of the faaors that control rhythmicity in humans, there will likely be a better appreciation of the cause (or causes) of duster headache. Recently attention has focused on the role of oxyhemoglobin desaturation in the pathogenesis of duster headache. Studies using polysomnography
have revealed an association between oxyhemoglobin desaturation and duster attacks during episodes of sleep apnea or hypoventilation related to rapid eye movements. 9 It has also been shown that nitroglycerin induces oxyhemoglobin desaturation. This may contribute to its ability to trigger duster headache attacks in susceptible individuals. Interestingly, Kudrow and Kudrow 10 have demonstrated that nitroglycerin-induced hypoxernia triggers duster attacks only during the active duster period and not during remission. They hypothesize that abnormal chemoreceptor activity during the aaive duster period may play a role in the pathophysiology of duster headache.
References 1. Horton BT, MacLean AR, Craig WM. A new syndrome of vascular headache: results of treatment with histamine: preliminary repon. Mayo Clin Proc 1939;14(17):257-60 2. Skyhej Olsen T, Olesen J. Regional cerebral blood flow in migraine and cluster headache. In: Olesen J, Edvinsson L, eds. Basic mechanisms of headache. New York: Elsevier Science Publishing, 1988:3 77-91 3. Anthony M, Lance JW, Histamine and serotonin in cluster headache. Arch Neural 1971 ;25(3):225-31 4. Prusinski A, Liberski PO. Is the cluster headache local mastocytic diaethesis? Headache 1979:19(2):102 5. Anthony M, Lord GO, Lance JW, Controlled trials of cimetidine in migraine and cluster headache. Headache 1978:18(5):261-4
6. Kudrow L. The cyclic relationship of natural illumination to cluster period frequency. Cephalalgia 1987;7(Suppl6):76-8 7. Turek Fw. Circadian neural rhythms in mammals. Annu Rev Physiol 1985;47:49-64 8. Chazot G, Clausttat 8, Bnm J, et al. A chronobiological study of melatonin, conisol growth hormone and prolactin secretion in cluster headache. Cephalalgia 1984;4(4):213-20 9. Kudrow L, McGinty DJ, Phillips ER, et al. Sleep apnea in cluster headache. Cephalalgia 1984;4( I ):33-8 10. Kudrow L, Kudrow DB. Association of sustained oxyhemoglobin desaturation and onset of cluster headache attacks. Headache 1990;30(8):474-80
PREVENTIVE-For patients with episodic duster headache, preventive therapy should be staned early in the duster period and continued until the patient is headache-free for at least 2 weeks. Medications are then tapered gradually and are not restarted until the next duster
period. For chronic duster headache, continuous therapy may be indicated. Oral ergotamine is most effective in preventing noaurnal attacks. It is taken 1 to 2 hours before bedtime. Methysergide maleate (Sansen)
VOL 91/NO 3/FEBRUARY 15, 1992/POSTGRADUATE MEDICINE • CLUSTER HEADACHE
is especially useful in younger patients with episodic duster headache.3 It is effective in up to 70% of patients. However, it must be used with caution because of the potential for such side effeas as nausea, vomiting, abdominal cramps, edema of the lower extremities, leg continued 101
Postgraduate Medicine 1992.91:96-104.
When chronic cluster headache is resistant to pharmacologic therapy, the patient may be a candidate for surgical intervention.
David R. Marks, MD Alan M. Rapoport, MD Or Marks (left) is chief resident, department of internal medicine, Greenwich Hospital, Greenwich, Connecticut. He will begin a fellowship in July 1992 in allergy and clinical immunology at Massachusetts General Hospital in Boston. He has a special interest in the socioeconomics of healthcare and has published articles on this topic. Or Rapoport (right) is assistant clinical professor, department of neurology, Yale University School of Medicine. He is also head of the section of neurology and director of the New England Headache Treatment Program, Greenwich Hospital. He is on the board of directors of the American Association for the Study of Headache.
pain, and (more seriously) retroperitoneal fibrosis. Methysergide is a serotonin (5-hydroxytryptamine~ receptor antagonist and is believed to exert its effect by antagonizing serotonin-induced vasoconstriction. Lithium carbonate has been reported to prevent attacks in 40% of patients. 13 It is considered useful in patients over 45 years of age who have either episodic or chronic cluster headaches. Its mechanism of action is unknown, but it may
102
affect hypothalarnic function. Lithium levels and renal and thyroid function should be periodically monitored during the course of therapy. Verapamil hydrochloride (Calan, Isoptin, Verelan), nifedipine (Adalat, Procardia), nimodipine (Nimotop), and diltiazem hydrochloride (Cardizem) have all been shown to be effective in some patients. 14' 15 Verapamil is probably the most effective agent and is currently preferred by many headache
specialists. Its favorable safety profile makes it an ideal prophylactic agent for patients with chronic cluster headache. Nifedipine is not recommended, because it can cause headaches in some individuals. Prednisone is effective for most episodic cluster headaches when used over a short period of time. However, some patients relapse when the dosage is tapered. Prednisone's mechanism of action is unknown. Indomethacin (lndocin) is another anti-inflammatory agent that has been effectively used for treating cluster headaches; the usual dosage is 25 mg taken three times a day. Valproic acid (Depakene, Depakote) has also been reported to provide effective prophylaxis against cluster headache. In one study, 60% of patients with chronic cluster headache reported the complete disappearance of pain when taking valproic acid. 16 Further study is necessary to determine the most appropriate role for valproic acid in the treatment of cluster headache. SURGICAL-When chronic cluster headache is resistant to pharmacologic therapy, the patient may be a candidate for surgical intervention. Percutaneous radiofi-equency thermocoagulation of the trigeminal ganglion is most commonly performed. Pain is relieved in two thirds or more of patients. 17 Best results have been obtained in patients with completely unilateral disease. continued
CLUSTER HEADACHE • VOL 91/NO 3/FEBRUARY 15, 1992/POSTGRADUATE MEDICINE
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Potential complications of surgery include anesthesia dolorosa, corneal anesthesia, and secretomotor changes. In some patients, headaches recur ipsilaterally or develop contralaterally.
Summary Cluster headache is a syndrome of severe head and facial pain accompanied by autonomic abnormalities. Men are affected more frequendy than women. Headaches occur daily during periods of susceptibility, which may be fullowed by periods of remission. The etiology of duster headache is uncertain. Recent work
suggests that hypothalamic dysfunction and/or oxyhemoglobin desaturati.on may be involved in its pathogenesis. Effective medical regimens are available fur aborting acute attacks and fur preventing attacks. Surgical ablation of the trigeminal ganglion has been effective in some patients when conventional medical therapy has f.illed. lUll
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Address for correspondence: David R Marks, MD, Greenwich Hospital, Penyridge Rd, Greenwich, Cf 06830.
References
1. Kunkle EC, PCeiffer JB Jr, Wdhoit WM, et al. Recurrent brief headache in "cluster" pattern. Trans Am Neurol Assoc 1952;77:240-3 2. Ad Hoc Committee on Classification of Headache. Classification of headache. JAMA 1962;179(9):717-8 3. Kndrow L. Cluster headache: mechanisms and management. New York: Oxford Univ Press, 1980:10-27, 130-3 4. Ekbom K. A clinical comparison of cluster headache and migraine. Acta Neurol Scand 1970; 46(Suppl41):1-44 5. Ekbom K. Heart rate, blood pressure, and electrocardiographic changes during provoked attacks of cluster headache. Acta Neurol Scand 1970;46(2):215-24 6. Ekbom K. Patterns of cluster headache with a note on the relations to angina pectoris and peptic ulcer. Acta Neurol Scand 1970;46(2):225-37 7. Kndrow L, McGinty DJ, Phillips ER, et al. Sleep apnea in cluster headache. Cephalalgia 1984;4(1 ):33-8 8. GrnhamJ. Cluster headache. Headache 1972;11(4):175-85 9. MedinaJL, DiamondS. The clinical link between migraine and cluster headaches. Arch Neurol1977;34(8):470-2
10. Solomon S, Karfunkel P, Guglielmo KM. Migraine-duster headache syndrome. Headache 1985;25(5):236-9 11. Kndrow L Response of cluster headache attacks to oxygen inhalation. Headache 1981;21(1):
1-4 12. The Swnatriptan Cluster Headache Study Group. Treatment of acute cluster headache with sumatripran. N Engl J Med 1991 ;325(5):322-6 13. de Carolis P, de Capoa D, Agati R, et al. Episodic cluster headache: shott and long term results of prophylactic treatment. Headache 1988; 28(7):475-6 14. Gabai IJ, Spierings EL. Prophylactic treatment of cluster headache with verapamil. (Abstr) Headache 1988;28(4):302 15. Meyer JS, HardenbergJ. Clinical effectiveness of calcium entry blockers in prophylactic treatment of migraine and cluster headaches. Headache 1983;23(6):266-77 16. Hering R, Knritzky A. Sodium valproate in the treatment of cluster headache: an open clinical trial. Cephalalgia 1989;9(3): 195-8 17. Onofrio BM, CampbeiiJK. Surgical treatment of chronic cluster headache. Mayo Clin Proc 1986;61(7):537-44
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CLUSTER HEADACHE • VOL 91/NO 3/FEBRUARY 15, 1992/POSTGRADUATE MEDICINE
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Cluster headache syndrome David R. Marks MD & Alan M. Rapoport MD To cite this article: David R. Marks MD & Alan M. Rapoport MD (1992) Cluster headache syndrome, Postgraduate Medicine, 91:3, 96-104, DOI: 10.1080/00325481.1992.11701227 To link to this article: http://dx.doi.org/10.1080/00325481.1992.11701227
Published online: 17 May 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [RMIT University Library]
Date: 17 June 2016, At: 21:33
-@CME credit article
Cluster headache syndrome Ways to abort or ward off attacks
David R. Marks, MD Alan M. Rapoport, MD
Postgraduate Medicine 1992.91:96-104.
Preview Cluster headache, one of the most painful conditions known, is encountered infrequently in clinical practice and may be difficult to recognize. The authors describe the signs and symptoms of cluster headache, tell how it can be distinguished from migraine, and outline the various forms of treatment and prophylaxis for its episodic and chronic forms.
Cluster headache is a syndrome characterized by repeated episodes of severe head and facial pain accompanied by various autonomic abnormalities. Because cluster headache is uncommon, some physicians may be unfamiliar with its presentation and treatment; in addition, it may be confused with other causes of facial pain. Proper diagnosis is crucial, because effective therapy is available. Accurate descriptions of duster headache as a specific disease entity date back to 1840. Since then, it has been known variously as sphenopalatine neuralgia, migrainous neuralgia, ciliary neuralgia, and histarninic cephalalgia. In 1952, Kunkle and colleagues1 noted the clustering pattern of headache attacks, but it was not until 1962 that the term "cluster headache" was formally recognized by the Ad Hoc Committee on Classification ofHeadache.2 Cluster headache is commonly classified as either episodic or chronic; 80% to 97% of patients with the disease have the episodic subtype. Patients with episodic duster headache generally have pe-
96
riods during which they are "headache prone," followed by periods during which no headache symptoms occur. The headache-prone periods usually last 1 to 3 months, and during this time the patient experiences at least one headache each day. Remissions last 6 months to many years. Cluster headache is considered chronic when a patient has the characteristic headache daily for at least 12 months without remission. This chronic condition can be the primary disorder, or it may reflect a progression of the episodic subtype.
Epidemiology Unlike other headache syndromes, which have a strong pattern of female predominance, duster headache is typically a disorder of middle-aged males, with a malefemale ratio of about 5: J.3 Although no good studies of prevalence have so far been performed, it is estimated that 0.4% to 1o/o of the male population is affected. Onset is usually at about 30 years of age but may occur as late as the eighth decade oflife. There does
not appear to be any strong racial or genetic predisposition.
Signs and symptoms The cluster headache is one of the most painful conditions known. The typical headache is described as excruciating, sharp, lancinating, or burning and usually occurs in an oculotemporal or oculofrontal distribution. One patient described it as "a force pushing with such incredible power through my eye that my head appears to be moving backwards, yielding to its resistance."3 The pain is generally unilateral and remains on the same side during the entire cluster period, although it may change sides during a subsequent cluster period. The location of the most severe pain often corresponds to the distribution of the first and second divisions of the trigeminal nerve. Radiation to the ipsilateral neck, occiput, mastoid, and teeth is common. Headaches occur once a day in about half of patients but may occur as often as 10 times a day. The duration ranges from minutes to hours, with an average of 60 to 90 minutes, and is remarkably consistent for a given individual. Parasympathetic hyperactivity often contributes to associated symptoms. Unilateral headache is accompanied by ipsilateral lacrimation, conjunctival injection, rhinorrhea, or nasal congestion in up to 85% of patients and an ipsilateral partial Horner's syndrome (ptosis continued
CLUSTER HEADACHE • VOL 91/NO 3/FEBRUARY 15. 1992/POSTGRADUATE MEDICINE
Postgraduate Medicine 1992.91:96-104.
Illustration: © 1992. Suzi Kilgore
VOL 91/NO 3/FEBRUARY 15, 1992/POSTGRADUATE MEDICINE • CLUSTER HEADACHE
97
The frequency of cluster headache periods appears to be related to seasonal changes in the length of daylight.
Postgraduate Medicine 1992.91:96-104.
Table 1. Distinguishing clinical features of cluster headache and migraine
Cluster
Migraine
Sex
90% male
75% female
Age < 20 yr at onset
30%
70%
Family history of that type of headache
Rare
85%
Recurrence pattern
Episodic or chronic
Random
Duration
1/2-2 hr
4-72 hr
Time of attacks
Night more often than day
Variable
Location of pain
Unilateral, periocular
Bilateral, frontotemporal
Quality of pain
Lancinating, burning
Throbbing
Associated visual aura
None
10%
Associated lacrimation, rhinorrhea, ptosis
Very common
Occasional
Associated nausea, vomiting, photophobia
Rare
Frequent
and miosis, without anhidrosis) in 60% to 70%. Partial Horner's syndrome may be permanent in a small percentage ofindividuals.4 Facial flushing and bradycardia are often associated with an attack and are probably also secondary to increased parasympathetic activity. 5 Of particular interest is the rhythmicity of duster headache. The frequency of duster periods
98
appears to be related to seasonal changes in the length of daylight. The timing of attacks follows a pattern of circadian regularity. Nearly half of patients experience symptoms at about the same time each day during the duster period6; 50o/o to 75o/o of attacks occur during sleep and are associated with the first rapid eye movement phase.7
Cluster headache versus migraine Cluster headache can usually be distinguished from migraine on the basis of its clinical presentation (table 1). The most important distinguishing feature is the timing of attacks. As has been mentioned, duster headaches occur rhythmically, recur one or more times a day, are of relatively short duration, and often occur at night. In contrast, migraines occur at random, are oflong duration, and often have their onset during the day. Cluster headache is exclusively unilateral and is often described as burning or lancinating, while migraine pain sometimes occurs bilaterally (in 40o/o of cases) and is commonly described as throbbing. Unlike patients with duster headache, those with migraine may experience a visual aura (classic migraine, now referred to as migraine with aura) and usually do not have associated symptoms such as conjunctival injection, ipsilateral tearing, rhinorrhea, or partial Horner's syndrome. Despite these differences, some patients may have symptoms characteristic of both duster headache and migraine. There are reports of migraine occurring in dusters8 and of duster headaches associated with prodromal symptoms. 9 In these rare cases, definitive diagnosis may be difficult. The term "migraineduster headache syndrome" has been proposed to describe patients with predominance of one type
CLUSTER HEADACHE • VOL 91/NO 3/FEBRUARY 15, 1992/POSTGRADUATE MEDICINE
Inhaling oxygen at the very beginning of an acute attack of cluster headache may abort the attack.
of headache who have significant symptoms characteristic of the other type. 10
Postgraduate Medicine 1992.91:96-104.
Treatment
Medical treatment (table 2) varies according to whether the goal is to abon attacks or prevent them. Surgical intervention is available for patients whose attacks resist pharmacologic therapy. ABORTIVE-According to reports, an acute attack of duster headache can be aboned in 60% to 82% of patients if they inhale oxygen at the very beginning of the headache. 11 In some of these patients, however, the headache recurs after a shon period of time. The recommended dosage is 100% oxygen at 7 L/min for about 10 minutes. The mechanism of action of oxygen inhalation therapy is unknown but may involve cerebral vasoconstriction or correction of oxyhemoglobin desaruration. Sublingual ergotamine tartrate (Ergostat) in a 2-mg dose has been used for acute attacks and has been reponed to be effective in 50% to 85% of patients. Oral ergotamine tartrate, available only in combination forms (eg, Cafergot, Wigraine), can also be used. Unfortunately, as with oxygen therapy, many patients have a breakthrough or recurrence. A parenteral form of ergotamine, dihydroergotamine mesylate (D.H.E. 45), is available for abor-
Table 2. Therapy for cluster headache Abortive agents
Inhaled oxygen Ergotamine tartrate, oral (Cafergot, Wigraine) or sublingual (Ergostat) Dihydroergotamine mesylate, intramuscular or intravenous (D.H.E. 45) Lidocaine HCI (Xylocaine), nasal drops Cocaine, nasal drops Sumatriptan (lmitrex), soon to be available Prophylactic agents
Ergotamine tartrate, oral Methysergide maleate (Sansert) Lithium carbonate Calcium channel blockers Corticosteroids Indomethacin (lndocin) Valproic acid (Depakene, Depakote) Surgery
Radiofrequency trigeminal gangliorhizolysis
tive therapy and is preferred for use in the emergency department. D.H.E. 45 is usually administered intramuscularly or intravenously in a dose of0.5 to 1 mglml. An intranasal preparation will soon be available. It is sometimes necessary to pretreat patients who are taking ergotamine with antiemetics, particularly those who are receiving intravenous D.H.E. 45. The mechanism of action of ergotamine is not known, but a vasoconstrictive effect related to stimulation of serotonin receptors has been postulated. D.H.E. 45 may also act upon primary sensory nerve fibers in the trigeminalvascular system. Nasal drops of a 4% solution of
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either lidocaine hydrochloride (Xylocaine) or cocaine have been used in an effon to decrease afferent activity to the trigeminal nerve and thus interrupt the reflex circuits that are believed to be involved in duster attacks. Some patients have been reponed to benefit, but results have been generally disappointing. Patients using cocaine nasal drops must be closely monitored because of the potential for addiction or abuse. Topical cocaine may be absorbed systemically and cause tachycardia and vasoconstriction. Therefore, it must be used cautiously in elderly patients and in those with coronary anery disease. In general, we are opposed to the continued 99
Recurrence of cluster headaches at about the same time each day suggests a link between the attacks and the circadian rhythms of the body.
Postgraduate Medicine 1992.91:96-104.
What provokes cluster headaches? Cluster headache attacks can be triggered by alcohol ingestion, subcutaneous or intravenous injections of histamine phosphate, or sublingual nitroglycerin (Nitrosrat). However, these substances can induce headaches only when the patient is "atrack susceptible"; during periods of remission, they have no headache-inducing effect. The vasodilatory effects of these agents have implicated vascular dilatation in the pathogenesis of the syndrome. Through studies describing temporal artery swelling and facial thermographic changes during duster attacks, the association with extracranial vascular dilatation has been established.' However, cerebral blood flow studies have failed to show an association between intracranial vascular activity and duster headaches. 2 When histamine was recognized as a provocative factor in duster attacks, attention focused on its possible role in the pathogenesis of the syndrome.' Interest in this association intensified after patients with duster headache were noted to have an increased incidence of duodenal ulcers. It has been reponed that blood and urine levels of histamine increase during a duster attack. 3 One investigator4 reponed an increase in the number and degranulation of mast cells around cranial nerves
use of any narcotic in the treatment of duster headache. Sumatriptan (lrnitrex), a selective serotonin (5-hydroxytrypramine1) receptor agonist, was shown in a recent study to be effective in the treatment of acute duster headache.12 Patients received a subcura-
100
during an attack. This has not been confirmed by other investigators, however, and the importance of these observations remains in question. Histamine1 and histamine2 receptor antagonists have been used for prophylaxis of duster headache but have not been found to be efficacious. 5 The relationship between duster headache and histamine is unresolved. A relationship between changes in the number of daylight hours throughout the year and the frequency of duster attacks has been demonstrated. 6 The incidence of duster periods is highest during the weeks before and after the shonest and longest days of the year. In addition, recurrence of duster headaches at about the same time each day suggests a link between the attacks and the circadian rhythms of the body. Because the suprachiasmatic nucleus of the hypothalamus is believed to control circadian rhythms, attention has focused on its role in duster headache. The activity of the suprachiasmatic nucleus is known to be related to changes in the daily cycle of light and darkness. 7 It is possible that in duster headache patients changes in photoperiodicity inhibit the ability of the hypothalamus to regulate sympathetic and parasympathetic activity
neous injection of 6 mg within 10 minutes of the onset of an acute attack; 7 4% experienced a decrease in the severity of their headache and 46% were pain-free within another 15 minutes. In addition, the incidence of ipsilateral conjunctival injection was decreased.
These results indicate that serotonin may have a role in the pathogenesis of duster headache. Sumatriptan has been approved for use in a number of European countries, and it is expected to receive US Food and Drug Administration approval soon.
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For patients with episodic cluster headache, preventive therapy should be started early in the cluster period and continued until the patient is headache-free for at least 2 weeks.
and the produaion ofhormones. Further evidence of hypothalamic dysfunaion in duster headache comes from studies demonstrating abnormal secretory rhythms for beta endorphins, testosterone, cortisol, beta lipotropin, and prolaain during duster periods.8 During remission of headache, many of these cyclical hormonal abnormalities reven to normal. With greater understanding of the faaors that control rhythmicity in humans, there will likely be a better appreciation of the cause (or causes) of duster headache. Recently attention has focused on the role of oxyhemoglobin desaturation in the pathogenesis of duster headache. Studies using polysomnography
have revealed an association between oxyhemoglobin desaturation and duster attacks during episodes of sleep apnea or hypoventilation related to rapid eye movements. 9 It has also been shown that nitroglycerin induces oxyhemoglobin desaturation. This may contribute to its ability to trigger duster headache attacks in susceptible individuals. Interestingly, Kudrow and Kudrow 10 have demonstrated that nitroglycerin-induced hypoxernia triggers duster attacks only during the active duster period and not during remission. They hypothesize that abnormal chemoreceptor activity during the aaive duster period may play a role in the pathophysiology of duster headache.
References 1. Horton BT, MacLean AR, Craig WM. A new syndrome of vascular headache: results of treatment with histamine: preliminary repon. Mayo Clin Proc 1939;14(17):257-60 2. Skyhej Olsen T, Olesen J. Regional cerebral blood flow in migraine and cluster headache. In: Olesen J, Edvinsson L, eds. Basic mechanisms of headache. New York: Elsevier Science Publishing, 1988:3 77-91 3. Anthony M, Lance JW, Histamine and serotonin in cluster headache. Arch Neural 1971 ;25(3):225-31 4. Prusinski A, Liberski PO. Is the cluster headache local mastocytic diaethesis? Headache 1979:19(2):102 5. Anthony M, Lord GO, Lance JW, Controlled trials of cimetidine in migraine and cluster headache. Headache 1978:18(5):261-4
6. Kudrow L. The cyclic relationship of natural illumination to cluster period frequency. Cephalalgia 1987;7(Suppl6):76-8 7. Turek Fw. Circadian neural rhythms in mammals. Annu Rev Physiol 1985;47:49-64 8. Chazot G, Clausttat 8, Bnm J, et al. A chronobiological study of melatonin, conisol growth hormone and prolactin secretion in cluster headache. Cephalalgia 1984;4(4):213-20 9. Kudrow L, McGinty DJ, Phillips ER, et al. Sleep apnea in cluster headache. Cephalalgia 1984;4( I ):33-8 10. Kudrow L, Kudrow DB. Association of sustained oxyhemoglobin desaturation and onset of cluster headache attacks. Headache 1990;30(8):474-80
PREVENTIVE-For patients with episodic duster headache, preventive therapy should be staned early in the duster period and continued until the patient is headache-free for at least 2 weeks. Medications are then tapered gradually and are not restarted until the next duster
period. For chronic duster headache, continuous therapy may be indicated. Oral ergotamine is most effective in preventing noaurnal attacks. It is taken 1 to 2 hours before bedtime. Methysergide maleate (Sansen)
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is especially useful in younger patients with episodic duster headache.3 It is effective in up to 70% of patients. However, it must be used with caution because of the potential for such side effeas as nausea, vomiting, abdominal cramps, edema of the lower extremities, leg continued 101
Postgraduate Medicine 1992.91:96-104.
When chronic cluster headache is resistant to pharmacologic therapy, the patient may be a candidate for surgical intervention.
David R. Marks, MD Alan M. Rapoport, MD Or Marks (left) is chief resident, department of internal medicine, Greenwich Hospital, Greenwich, Connecticut. He will begin a fellowship in July 1992 in allergy and clinical immunology at Massachusetts General Hospital in Boston. He has a special interest in the socioeconomics of healthcare and has published articles on this topic. Or Rapoport (right) is assistant clinical professor, department of neurology, Yale University School of Medicine. He is also head of the section of neurology and director of the New England Headache Treatment Program, Greenwich Hospital. He is on the board of directors of the American Association for the Study of Headache.
pain, and (more seriously) retroperitoneal fibrosis. Methysergide is a serotonin (5-hydroxytryptamine~ receptor antagonist and is believed to exert its effect by antagonizing serotonin-induced vasoconstriction. Lithium carbonate has been reported to prevent attacks in 40% of patients. 13 It is considered useful in patients over 45 years of age who have either episodic or chronic cluster headaches. Its mechanism of action is unknown, but it may
102
affect hypothalarnic function. Lithium levels and renal and thyroid function should be periodically monitored during the course of therapy. Verapamil hydrochloride (Calan, Isoptin, Verelan), nifedipine (Adalat, Procardia), nimodipine (Nimotop), and diltiazem hydrochloride (Cardizem) have all been shown to be effective in some patients. 14' 15 Verapamil is probably the most effective agent and is currently preferred by many headache
specialists. Its favorable safety profile makes it an ideal prophylactic agent for patients with chronic cluster headache. Nifedipine is not recommended, because it can cause headaches in some individuals. Prednisone is effective for most episodic cluster headaches when used over a short period of time. However, some patients relapse when the dosage is tapered. Prednisone's mechanism of action is unknown. Indomethacin (lndocin) is another anti-inflammatory agent that has been effectively used for treating cluster headaches; the usual dosage is 25 mg taken three times a day. Valproic acid (Depakene, Depakote) has also been reported to provide effective prophylaxis against cluster headache. In one study, 60% of patients with chronic cluster headache reported the complete disappearance of pain when taking valproic acid. 16 Further study is necessary to determine the most appropriate role for valproic acid in the treatment of cluster headache. SURGICAL-When chronic cluster headache is resistant to pharmacologic therapy, the patient may be a candidate for surgical intervention. Percutaneous radiofi-equency thermocoagulation of the trigeminal ganglion is most commonly performed. Pain is relieved in two thirds or more of patients. 17 Best results have been obtained in patients with completely unilateral disease. continued
CLUSTER HEADACHE • VOL 91/NO 3/FEBRUARY 15, 1992/POSTGRADUATE MEDICINE
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Potential complications of surgery include anesthesia dolorosa, corneal anesthesia, and secretomotor changes. In some patients, headaches recur ipsilaterally or develop contralaterally.
Summary Cluster headache is a syndrome of severe head and facial pain accompanied by autonomic abnormalities. Men are affected more frequendy than women. Headaches occur daily during periods of susceptibility, which may be fullowed by periods of remission. The etiology of duster headache is uncertain. Recent work
suggests that hypothalamic dysfunction and/or oxyhemoglobin desaturati.on may be involved in its pathogenesis. Effective medical regimens are available fur aborting acute attacks and fur preventing attacks. Surgical ablation of the trigeminal ganglion has been effective in some patients when conventional medical therapy has f.illed. lUll
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Earn credit on this article. See CME Quiz.
Address for correspondence: David R Marks, MD, Greenwich Hospital, Penyridge Rd, Greenwich, Cf 06830.
References
1. Kunkle EC, PCeiffer JB Jr, Wdhoit WM, et al. Recurrent brief headache in "cluster" pattern. Trans Am Neurol Assoc 1952;77:240-3 2. Ad Hoc Committee on Classification of Headache. Classification of headache. JAMA 1962;179(9):717-8 3. Kndrow L. Cluster headache: mechanisms and management. New York: Oxford Univ Press, 1980:10-27, 130-3 4. Ekbom K. A clinical comparison of cluster headache and migraine. Acta Neurol Scand 1970; 46(Suppl41):1-44 5. Ekbom K. Heart rate, blood pressure, and electrocardiographic changes during provoked attacks of cluster headache. Acta Neurol Scand 1970;46(2):215-24 6. Ekbom K. Patterns of cluster headache with a note on the relations to angina pectoris and peptic ulcer. Acta Neurol Scand 1970;46(2):225-37 7. Kndrow L, McGinty DJ, Phillips ER, et al. Sleep apnea in cluster headache. Cephalalgia 1984;4(1 ):33-8 8. GrnhamJ. Cluster headache. Headache 1972;11(4):175-85 9. MedinaJL, DiamondS. The clinical link between migraine and cluster headaches. Arch Neurol1977;34(8):470-2
10. Solomon S, Karfunkel P, Guglielmo KM. Migraine-duster headache syndrome. Headache 1985;25(5):236-9 11. Kndrow L Response of cluster headache attacks to oxygen inhalation. Headache 1981;21(1):
1-4 12. The Swnatriptan Cluster Headache Study Group. Treatment of acute cluster headache with sumatripran. N Engl J Med 1991 ;325(5):322-6 13. de Carolis P, de Capoa D, Agati R, et al. Episodic cluster headache: shott and long term results of prophylactic treatment. Headache 1988; 28(7):475-6 14. Gabai IJ, Spierings EL. Prophylactic treatment of cluster headache with verapamil. (Abstr) Headache 1988;28(4):302 15. Meyer JS, HardenbergJ. Clinical effectiveness of calcium entry blockers in prophylactic treatment of migraine and cluster headaches. Headache 1983;23(6):266-77 16. Hering R, Knritzky A. Sodium valproate in the treatment of cluster headache: an open clinical trial. Cephalalgia 1989;9(3): 195-8 17. Onofrio BM, CampbeiiJK. Surgical treatment of chronic cluster headache. Mayo Clin Proc 1986;61(7):537-44
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