What are cluster headaches
Chronic pain located one side of the head. Runs from jaw, through eye and over top of head into back of neck. Starts in seconds reaching maximum pain level just as fast. Doesn't respond to normal pain medication and opiates make it worst. Oxygen in high flow works to calm them and stop attacks.
The level of pain is so high it has been likened to a gun shot wound from close range. Attacks last 30 mins to 3 hours and stop as quick as they start .
The level of pain is so high it has been likened to a gun shot wound from close range. Attacks last 30 mins to 3 hours and stop as quick as they start .
What is behind the dreaded Cluster Headache?
Just what causes one person to be a cluster headache sufferer? As with many headache disorders, the cause of cluster headache is not completely understood. But we are getting closer.
So here’s the question – what parts of the body are involved in the cluster attack? And how are they involved?
1. The hypothalamus: The hypothalamus is now thought to be the launching pad of the cluster attack. It first becomes a suspect because it controls your 24 hour clock. Cluster is a very regular disorder, in that it comes in cycles (hence the name – cluster).
About the size of a almond, the hypothalamus is found right above the brain stem. Thanks to modern imaging techniques, we can see differences in the brain of a cluster headache sufferer.
2. The trigeminal nerve: Parts of the trigeminal nerve are activated during a cluster attack. This is a very important nerve in your face and jaw. It’s involved in the eye pain, tearing and redness of cluster. It can also help bring on the congestion.
3. The sphenopalatine ganglion: A “ganglion” is a group of nerve cells. This particular ganglion is located behind the nose. Some cluster patients have found relief after surgery on the sphenopalatine ganglion.
4. Blood vessels: Changes in blood flow may be involved in cluster, but we know now it’s not as central as we once thought. There can be changes in blood flow, but the question is whether or not this is a result of an attack or a part of the cause.
5. Histamine: Histamine has been a suspect because you can sometimes trigger an attack with histamine. However, so far research has not been convincing.
We’re learning more and more about just how the hypothalamus is activating during a cluster attack. Thanks to modern imaging and analyzing techniques (such as voxel based morphometry), we can see more of what goes on during an attack. This has led to better treatments, but we still have a long way to go.
Just what causes one person to be a cluster headache sufferer? As with many headache disorders, the cause of cluster headache is not completely understood. But we are getting closer.
So here’s the question – what parts of the body are involved in the cluster attack? And how are they involved?
1. The hypothalamus: The hypothalamus is now thought to be the launching pad of the cluster attack. It first becomes a suspect because it controls your 24 hour clock. Cluster is a very regular disorder, in that it comes in cycles (hence the name – cluster).
About the size of a almond, the hypothalamus is found right above the brain stem. Thanks to modern imaging techniques, we can see differences in the brain of a cluster headache sufferer.
2. The trigeminal nerve: Parts of the trigeminal nerve are activated during a cluster attack. This is a very important nerve in your face and jaw. It’s involved in the eye pain, tearing and redness of cluster. It can also help bring on the congestion.
3. The sphenopalatine ganglion: A “ganglion” is a group of nerve cells. This particular ganglion is located behind the nose. Some cluster patients have found relief after surgery on the sphenopalatine ganglion.
4. Blood vessels: Changes in blood flow may be involved in cluster, but we know now it’s not as central as we once thought. There can be changes in blood flow, but the question is whether or not this is a result of an attack or a part of the cause.
5. Histamine: Histamine has been a suspect because you can sometimes trigger an attack with histamine. However, so far research has not been convincing.
We’re learning more and more about just how the hypothalamus is activating during a cluster attack. Thanks to modern imaging and analyzing techniques (such as voxel based morphometry), we can see more of what goes on during an attack. This has led to better treatments, but we still have a long way to go.
What is a Cluster Headache?
What the Professionals say:
CLUSTER HEADACHE
Although cluster headache ("migrainous neuralgia") had been recognized for over 100 years (von Möllendorff, 1867), Sir Charles Symonds' (1956) lucid account of this disorder brought it into focus. Recognition of the clinical entity was almost certainly retarded by a variety of confusing names that were given to this condition, such as erythroprosopalgia, Raeder's syndrome, spenopalatine neuralgia, ciliary neuralgia, vidian neuralgia, and histamine cephalalgia (Sjaastad, 1986; Grimson and Thompson, 1980). Cluster headache is now firmly established as a distinctive syndrome whose recognition is important, since it is likely to be responsive to treatment. The episodic type, the most common, is characterized by one to three short-lived attacks of periorbital pain per day over a 4 to 8 week period, followed by a pain-free interval that averages 1 year. The chronic form, sometimes called chronic migrainous neuralgia, which may begin de novo or several years after an episodic pattern has become established, is characterized by the absence of sustained periods of remission. Each type may transform into the other. The cluster syndrome is genetically, biochemically, and clinically different from migraine; propranolol is effective in treating migraine but has not been shown to be effective in cluster headache. Lithium is beneficial for the cluster headache syndrome and ineffectual in migraine. Nevertheless, the two disorders occasionally blend into one in occasional patients (Solomon, 1986), suggesting that their mechanisms bear some degree of commonality.
CLINICAL FEATURES
Cluster headache has a prevalence of approximately 69 cases per 100,000 people, and is therefore far less common that migraine (D'Alessandro et al, 1986). Men are affected more commonly than women in a proportion of 6:1. Although most patients begin experiencing headache between the ages of 20 and 50 years (mean, 30 years), the syndrome may begin as early as the first decade and as late as the eighth decade. Clearly, age alone is an insensitive diagnostic criterion (Krabbe, 1986). Women with cluster headache are more likely than men to begin experiencing attacks after the age of 50; among women, headaches usually do not correlate with menses, are likely to cease during pregnancy (Ekbom and Waldenlind, 1981), and may be initiated by use of oral contraception (Peatfield et al, 1982).
Characteristics of Pain
The pain of a cluster headache commences quickly, without warning, and reaches a crescendo within 2 to 15 minutes. It is often excruciating in intensity, and is deep, nonfluctuating, and explosive in quality; only occasionally is it pulsatile. In addition, 10 to 20 percent of patients report superimposed paroxysms of stabbing, icepick-like pains in the periorbital region that last for a few seconds and may occur once or several times in rapid succession; this paroxysmal pain usually heralds the end of an attack. The symptoms resolve in 1 to 2 minutes (Ekbom, 1975).
The pain usually begins in, around, or above the eye or the temple ; occasionally the face, neck, ear, or hemicranium may be affected (Sutherland and Eadie, 1972). It is always unilateral, and generally affects the same side in subsequent bouts. However, it may shift to the corresponding region of the opposite side in 15 percent of patients (Manzoni et al, 1983b), usually for the duration of a bout, less often switching sides within a bout. Many patients prefer to be upright and active when an attack is in progress, but this is reported with a frequency that is not high enough to be useful diagnostically (Russell, 1981).
Periodicity and Duration of the Attacks
Attacks last from 30 minutes to 2 hours (mean of 45 minutes) in about 75 percent of cases. Occasionally, attacks - especially mild ones - may be as short as 10 minutes, whereas others may last as long as several hours. Attacks range in frequency from six per 24 hours to one per week, with a mean of one to two per day. Periodicity is a characteristic feature in about 85 percent of patients: attacks of pain tend to recur at the same hour each day for the duration of the cluster bout; many individuals also experience additional attacks that occur randomly throughout the day. About 75 percent of attacks occur between 9 p.m. and 10 a.m. (Russell, 1981). Manzoni et al, (1983b) found sharp peaks for attack frequency between 1 and 2 a.m., 1 and 3 p.m., and at 9 p.m . Patients are awakened from sleep by pain paroxysms in about 50 percent of cases, usually within 2 hours of falling asleep (Lance and Anthony, 1971; Hornabrook, 1964). Nocturnal attacks are associated with rapid eye movement (REM) sleep about one-half the time in episodic cluster headache, but only rarely in the chronic form (Plaffenrath et al, 1986; Kayed and Sjaastad, 1985).
Characteristics of the Bouts
The attacks of pain are clustered in cycles that usually last 4 to 8 weeks, and are followed by a pain-free remission in 90 percent of patients. On occasion, bouts may be as short as a few days or as long as 4 months; about 10 percent of those with established cluster tempos enter a chronic phase in which the attacks may persist for an average of 4 to 5 years (Ekbom, 1986). The later the onset of the episodic disorder, the greater the chance of it becoming chronic (Kudrow, 1980). Most patients experience one to two bouts per year; however, the interval between bouts ranges from 1 month to 2 years in 80 percent of the cases and between 6 months and 2 years in 60 percent (Kudrow, 1980). In rare instances it may be as long as 25 years (Hornabrook, 1964). Eventually, the bouts cease spontaneously, but more precise data on the natural history of the disorder are not yet available.
Associated Features
Related Symptoms and Signs
Lacrimation from the eye on the affected side is the most common associated symptom. A blocked nasal passage, rhinorrhea, red eye, and sweating and pallor of the forehead and cheek are often found, but their absence does not exclude the diagnosis. These autonomic symptoms, although clinically apparent unilaterally, are present bilaterally, quantitaively more so on the symptomatic side (Saunte, 1984; Sjaastad et al, 1981). There is a rapid increase in heart rate at the onset of attacks and further rate variations become pronounced as the paroxysm proceeds, suggesting central autonomic regulatory instability. In general, a modest bradycardia occurs during an attack (Russell and Storstein, 1983). A transitory, partial Horner's syndrome (pupillary miosis and lid ptosis) occurs in two-thirds of patients when they are examined during attacks (Ekbom, 1970a) and is a useful sign in the differential diagnosis of facial pain. It is highly characteristic of the cluster headache syndrome and, after repeated occurrences, it may become a permanent feature (Riley and Moyer, 1971; Nieman and Hurwitz, 1961).
The localization of the sympathetic lesion is of some interest. The ocular sympathetic innervation is a three-neuron pathway, comprising a first-order neuron: posterolateral hypothalamus to cord levels of C8 to T3 (the ciliospinal center of Budge); a second-order neuron: (preganglionic) ciliospinal center to super cervical ganglion; and a third-order neuron: (post-ganglionic) superior cervical ganglion to the pupillary dilator muscle, the eyelid muscles, and the facial sweat glands. It is believed by many observers that in cluster headache, involvement of the third-order neuron accounts for Horner's syndrome, which occurs as the result of distention of the wall of the internal carotid artery in the carotid canal, thus compressing the sympathetic plexus that invests the carotid wall. This argument is supported by three lines of evidence. The first is the observation that hyphidrosis is restricted to the forehead (Watson and Vijayan, 1982), which is consistent with a third-order neuron lision whereas more proximal lesions usually produce deficient sweating of the entire face (Morris et al, 1984). Second, supersensititivity of the miotic pupil to direct-acting sympathomimetic agents appears to place the lesion postganglionically (Fanciullacci et al, 1982; Vijayan and Watson, 1982); and third, angiographic changes of the carotid siphon during a cluster headache attack (Ekbom and Greitz, 1970) is also consistent with sympathetic plexus compression at this locus. However, others (Sjaastad, 1987) argue that there is sparse validation for the effects of conjunctival drugs on patients with central lesions (Malonety et al, 1980; Lepore, 1985). In fact, pupillary responsiveness and hyphidrosis patterns in patients with Horner's syndrome on a central basis are not very different from the results obtained with cluster headache patients (Van der Wiel and Van Gijn, 1986; Salvesen et al, 1987). Since the first-order hypothalamic neuron is uncrossed and, therefore, capable of generating ipsilateral symptoms, and for other reasons (see below) is an attractive patheogenetic locus, the issue, in my view, remains open.
Focal neurologic symptoms of the type characteristic of migraine are very uncommon in patients with the cluster headache syndrome; however, occasional patients experience typical photopsia, teichopsia, facial paresthesia, or vertigo at the time of the attack.
Precipitating Factors
Sensitivity to alcohol during a cluster bout occurs in at least half the patients, and cases when the bout remits (Friedman and Mikropoulos, 1958); this alternating, on-off vulnerability is pathognomonic of the cluster headache syndrome. Patients who are sensitive to alcohol note that attacks are triggered within 5 to 45 minutes after the ingestion of modest amounts of alcohol: usually less than a single cocktail or glass of wine. The vast majority have noted that their sensitivity is less than total: alcohol triggers attacks in 70 to 80 percent of exposures. This factor, together with many patients' misinterpretations regarding inquiries into their drinking habits, may account for the low incidence of alcohol sensitivity in several reported series (Sutherland and Eadie, 1972; Symonds, 1956).
A number of other precipitating factors have been noted in a smaller number of patients and include stress, relaxation, exposure to heat or cold, glare, hay fever attacks, and, occasionally, the ingestion of specific foods (chocolate, eggs, dairy products).
There is some evidence that head trauma can precipitate the syndrome. Among the 180 patients studied by Manzoni et al (1983b), previous head injury was reported by 41, with loss of consciousness occurring in 20. This is significantly more frequent than is observed among patients with other types of headache; furthermore, in all patients in whom the head injury was lateralized and loss of consciousness ensued, the side involved corresponded to the side on which cluster headache later occurred. However, the mean latency in these cases was 9 years, which poses a serious question regarding the connection between head trauma and the cause of the cluster headache syndrome. Moreover, in an additional 11 of 15 patients who had undergone previous cranio-facial surgery, the side operated on was ipsilateral to that of the site of later-appearing cluster headache attacks. The latency between these latter events averaged 5 years. Kudrow has found no evidence that head trauma can precipitate the syndrome (Kudrow, 1980).
Experimentally, attacks can be triggered in nearly all patients during a bout by the administration of 1 mg nitroglycerin sublingually (Ekbom, 1968), and in about 70 percent of patients by subcutaneous histamine (Horton, 1961). There is usually a latent period of 30 to 50 minutes before headache is triggered, whereas the peak peripheral and central vascular effects of nitroglycerin occur within 3 to 4 minutes of its administration and disappear in approximately 30 minutes (Bogaert, 1987). This, the appearance of headache does not coincide with the maximal circulatory effect of nitroglycerin, and the mechanism by which nitroglycerin causes headache remains unclear. A period refractory to pharmacologic provocation occurs after spontaneous or pharmacologically induced attacks and may persist for 2 hours or more (Ekbom, 1968; Horton, 1961). Therefore, valid provocative tests must be administered during an active bout, several hours after the attack has subsided.
AMELIORATIVE FACTORS
Ekbom (1975) found that compression of the superficial temporal artery provided temporary relief for about 40 percent of his patients but just as often worsened the pain; carotid compression reduced the pain half the time, and worsened it in 25 percent of his cases. Vigorous physical exertion at the earliest sign of an attack can, in some patients, be remarkably effective in ameliorating or even aborting an attack (Atkinson, 1977; Ekbom and Lindahl, 1970).
HEREDITARY DATA
Hereditary factors are significant in migraine and might be expected to be important in the cluster headache syndrome because of their mechanistic and pharmacologic similarities. However, it is uncommon to find other examples of cluster headache in the family history. Among Kudrow's (1980) 495 patients, 18 reported the presence of the syndrome in a parent. Migraine occurs no more frequently among the cluster headache population than among random population than among random populations (Andersson, 1985). When migraine predates the commencement of cluster attacks, migraine usually ceases when the cluster attacks begin (Bickerstaff, 1959); thus, although these disorders are biologically distinct, their mechanisms are probably connected.
EXAMINATION FINDINGS
A carefully elicited history is the key to diagnosis. There are no abnormalities to be found upon a physical or laboratory investigation other than Horner's syndrome occasionally. In approximately 70 percent of patients with cluster headaches, the carotid artery is palpably tender at several points in the neck (Raskin and Prusiner, 1977). The cluster headache syndrome, with all autonomic symptoms, on-off,alcohol sensitivity, ipsilateral tender carotid artery, and clocklike periodicity of attacks, has not been associated with any underlying intracranial structural abnormalities. There have been a few cases reported of lesions producing painful disorders resembling this syndrome, and some in which coincidental anatomic anomalies were demonstrated (Tfelt-Hansen et al, 1982; Mani and Deeter, 1982; Kurizky, 1984).
Graham (1972) formed the impression that certain physical features seemed to be characteristic of cluster headache patients. These include a ruddy complexion, multifurrowed and thickened skin, and a broad, prominent chin: all contributing to a "leonine" facial appearance. However, these observations were uncontrolled, and I have been unable to confirm them. There is no evidence that important psychological variables bear on this syndrome (Cuypers et al, 1981; Kudrow, 1980).
PATHOPHYSIOLOGY
The traditional designation of cluster headache as a vascular headache disorder is probably inappropriate; the vascular alterations that occur appear to be epiphenomenal, as they are in migraine, resulting from a primary CNS discharge. The hypothalamus may well be the site of such activation, containing posterior cells that regulate autonomic functions and anterior nuclei that serve as the major circadian pacemaker in mammals (Moore-Ede et al, 1983), both of which are necessary to explain the clinical symptoms and the uncanny periodicity of cluster headache attacks. The "biologic clock" is serotonergically modulated (Mason, 1986) and is connected anatomically to the eye (Sadun et al, 1984). The drugs effective in the treatment of the cluster headache syndrome enhance serotonergic neurotransmission, as also occurs in the treatment of migraine.` This suggests that unstable serotonergic neurotransmission, at different loci, may be common to both disorders. In this section, we will review, among other data, the evidence supporting the tantalizing speculation that the cluster headache syndrome may be the result of an antidromically discharging biologic pacemaker.
Biologic Clocks
A pacemaking mechanism in mammalian brain controls circadian rhythms (from the Latin circa diem, about 1 day), which are endogenous daily cycles. The most important of these biologic clocks is believed to be the suprachiasmatic nuclei (SCN): two small cell groups in the anterior hypothalamu7s just dorsal to the optic chiasm (Schwartz et al, 1987; Moore and Card, 1985; Turek, 1985). The pacemaker generates circadian rhythms, couples them with one another, and synchronizes them with external environmental events. Events in the internal milieu are arranged in temporal sequence to permit maximal adaptation to synchronized in phase and period, by time cues such as the daily light/dark cycle; a visual pathway from retina to the SCN is necessary to mediate entrainment (Sadun et al, 1984). The function of this system is to maintain daily order in physiologic processes, such as enzyme activities, body temperature, hormone secretion, and some behaviors. A disordered pacemaker may result in illness. For example, there is evidence that in jet lag and in manic-depressive illness, circadian rhythms may not be synchronized with one another or with the sleep-wake cycle (Wehr et al, 1983).
Under normal conditions, a rhythm generated by the pacemaker is transmitted to synapses where a receptor rhythm evokes second messenger elaboration, which, in turn, modulates neurotransmission (Kafka et al, 1983). Lithium is believed to act on this second messenger system (see below).
The SCN project to, and receive afferents from, the midbrain periaqueductal gray matter (Moore, 1983), so that a functional link to the pain-modulating system is feasible. Furthermore, serotonin-containing terminals arising from the midbrain dorsal raphe nuclei distribute in a dense plexus in the SCN and are capable of serotonin uptake. There is evidence that serotonergic mechanisms are involved in the expression rather than the generation of circadian rhythms. The SCN neurons are responsive to serotonin and its release via activation of the midbrain raphe projection to the SCN (Groos et al, 1983). Intrinsic pacemaker frequency appears to be modulated serotonergically by a mechanism that has not yet been established. It is interesting that lithium experts prominent effects upon circadian rhythms (Kripke and Wyborney, 1980; Kafka et al, 1982), possibly through an enhancement of serotonergic neurotransmission (Blier and De Montigny, 1985).
Apart from the circadian periodicity of individual attacks and the periodic recurrence of bouts of cluster headache, further evidence of the role of a central pacemaker comes from hormonal studies among patients. Dampening of secretory circadian rhythms has been shown for melatonin, cortisol, testosterone, á-endorphin, á-lipotropin, and prolactin (Waldenlind et al, 1984; Chazot et al, 1984; Facchinetti et al, 1986; Nappi et al, 1985; Waldenlind and Gustafsson, 1987) during bouts; most of these rhythms revert to normal during remissions.
Additional support for a CNS disturbance as the source of cluster attacks comes from studies of brain stem auditory-evoked potentials. Slowed conduction (increased I-V interpeak latencies) was shown ipsilateral to the painful side and became more pronounced during paroxysms of pain; lithium treatment appeared to shorten the latencies (Bussone et al, 1986). Clinically, the concurrence of cluster headache and trigeminal neuralgia, the cluster-tic syndrome, in which both disorders are ameliorated by microvascular decompression of the sensory root of the trigeminal nerve, also points to a centrally mediated pain mechanism.
Cerebral Blood Flow Alterations
Dilatation of extracerebral arteries appears to be common to both migraine and cluster headache (Sakai and Meyer, 1978); enhanced pulsation of the intraocular vascular bed occurs during cluster attacks but not during migraine attacks (H›rven et al, 1972; H›rven and Sjaastad, 1977), underlining the involvement of the internal carotid artery and its branches in the cluster headache syndrome. Evidence that part of the pain of cluster headache is derived from dilatation of intracranial branches of the internal carotid artery stems from the observation of Thomas and Butler (1946) that pain may be relieved in some patients by the intrathecal injection of saline, which increases the cerebrospinal fluid pressure to 700 mm H2O.
The importance of vascular dilatation in cluster headache has been emphasized in the past because headaches may be precipitated during a bout by vasodilators such as alcohol, histamine (Horton, 1941, 1952; Hardebo et al, 1980), and nitroglycerin (Ekbom, 1968); however regional cerebral blood flow (CBF) studies in the modern era have shown only inconsistent alterations in flow during attacks, lending no support to the idea that vasodilatation is necessary to the pain mechanism (Nelson et al, 1980; Krabbe et al, 1984). Drummond and Lance (1984) and Drummond and Anthony (1985) showed that the increase in extracranial blood flow and increased temporal artery pulsations that attended individual attacks usually followed the onset of pain in affected areas, which led them to a primary neural discharge.
Reduction of the severity of angina pectoris and limb claudication has been noted during some cluster bouts (Ekbom, 1970b), suggesting that, at least in some patients, an alteration of arterial tone outside the carotid circulation also occurs.
Biochemical Mechanisms
A search for biochemical agents has been made on the presumption that the cluster headache syndrome may be mediated by a disorder of humoral control of blood vessels. The prominence of lacrimination, perspiration, and suffusion of the conjunctivae is consistent with an excessive cholinergic discharge. This reasoning led Kunkle (1959) to examine cerebrospinal fluid for acetylcholine-like activity, which he found in 4 of 14 patients at the time of headache; it was not found in 7 patients with classic migraine.
Serotonin
Serotonin alterations are more subtle in patients with cluster headache than in migraine. Medina et al (1979) found modest elevations of serotonin in whole blood during attacks of cluster headache, whereas platelet serotonin levels fall precipitously during migraine attacks. Waldenlind et al, (1985) found low whole blood serotonin levels among cluster patients both during an active bout and during remissions, comparable to levels found among migraine patients.
Erythrocyte Choline
Erythrocyte choline concentrations are low in cluster headache patients (de Belleroche et al, 1984); this is an interesting observation because lithium administration greatly increases erythrocyte choline levels, an effect that persists for months. The depressed choline level is not confined to the acute attack; it is also present between bouts. de Belleroche et al (1986) took these data a step further and showed that erythrocyte membrane phosphatidylcholine/cholesterol ratios were increased in cluster headache patients, indicating a reduced turnover of phosphatidylcholine in the red cell membrane. It is not yet clear whether these intriguing findings are related to the mechanism of the disorder.
Histamine
The possibility that histamine may be involved is supported by the reportedly higher incidence of duodenal ulceration in patients with cluster headache (Ekbom, 1970b) as well as by the precipitation of attacks with small amounts of this substance. Anthony and Lance (1971) and Medina et al, (1979) have shown that there is a modest increase in whole blood histamine during an attack; furthermore, elevations of urinary histamine were found in four of eight patients during cluster attacks (Sjaastad and Sjaastad, 1970). These reports are challenged by the lack of change in the catabolic pattern of intravenously administered C14 histamine in patients with cluster headache (Beall and Van Arsdel, 1960) and, since histamine is localized peripherally to basophilic leukocytes, caution is advised when interpreting whole blood levels (Porter and Mitchell, 1972). Patients with chronic myelogenous leukemia have very high blood levels of histamine but do not report headache. Furthermore, antihistaminic agents are disappointingly ineffective, as also has been histamine desensitization.
It has been apparent for some time that there are at least two histamine receptors, since some of the effects of histamine are not blocked by the usual antihistaminic agents (Ash and Schild, 1966). Substantial evidence for two histamine-induced vasodilatation is only partly reversed by H1 antagonists (Hardebo et al, 1980), and it now appears likely that bot H1 and H2 receptors are present in the carotid vascular bed (Saxena, 1975), the availability of H2 antagonists has renewed the interest in testing the role of histamine in cluster headache. Anthony et al, (1978) and Russell (1979) have used H1 and H2 antagonists in the therapy of cluster headache, without clear success. It is possible that the elevation of blood histamine is the result of episodes of paroxysmal vascular instability, since histamine is but one of a group of diverse substances that includes the kinins, prostaglandins, and others that are released from tissues during injury or inflammatory reactions (Beaven, 1976).
Mast Cells
Appenzeller et al (1981) found that mast cells, the major repository of histamine in many tissues, are found in increased number in the skin of the painful temporal area in cluster headache patients; this effect is particularly striking within the first 10 hours after a cluster attack. Mast cell numbers in patients outside of a cluster period are similar to those of migraineurs (Appenzeller, 1987), which suggests that these cells are increased in both types of headache as a secondary event. No differences have been found in the dermal response to histamine among cluster headache patients when the painful side was compared to the opposite side (Bogucki and Prus¡nski, 1985), which lends no support to the idea that the periodic release of histamine might stimulate trigeminal nerve endings and thus be directly implicated in the mechanism of an attack.
What the Professionals say:
CLUSTER HEADACHE
Although cluster headache ("migrainous neuralgia") had been recognized for over 100 years (von Möllendorff, 1867), Sir Charles Symonds' (1956) lucid account of this disorder brought it into focus. Recognition of the clinical entity was almost certainly retarded by a variety of confusing names that were given to this condition, such as erythroprosopalgia, Raeder's syndrome, spenopalatine neuralgia, ciliary neuralgia, vidian neuralgia, and histamine cephalalgia (Sjaastad, 1986; Grimson and Thompson, 1980). Cluster headache is now firmly established as a distinctive syndrome whose recognition is important, since it is likely to be responsive to treatment. The episodic type, the most common, is characterized by one to three short-lived attacks of periorbital pain per day over a 4 to 8 week period, followed by a pain-free interval that averages 1 year. The chronic form, sometimes called chronic migrainous neuralgia, which may begin de novo or several years after an episodic pattern has become established, is characterized by the absence of sustained periods of remission. Each type may transform into the other. The cluster syndrome is genetically, biochemically, and clinically different from migraine; propranolol is effective in treating migraine but has not been shown to be effective in cluster headache. Lithium is beneficial for the cluster headache syndrome and ineffectual in migraine. Nevertheless, the two disorders occasionally blend into one in occasional patients (Solomon, 1986), suggesting that their mechanisms bear some degree of commonality.
CLINICAL FEATURES
Cluster headache has a prevalence of approximately 69 cases per 100,000 people, and is therefore far less common that migraine (D'Alessandro et al, 1986). Men are affected more commonly than women in a proportion of 6:1. Although most patients begin experiencing headache between the ages of 20 and 50 years (mean, 30 years), the syndrome may begin as early as the first decade and as late as the eighth decade. Clearly, age alone is an insensitive diagnostic criterion (Krabbe, 1986). Women with cluster headache are more likely than men to begin experiencing attacks after the age of 50; among women, headaches usually do not correlate with menses, are likely to cease during pregnancy (Ekbom and Waldenlind, 1981), and may be initiated by use of oral contraception (Peatfield et al, 1982).
Characteristics of Pain
The pain of a cluster headache commences quickly, without warning, and reaches a crescendo within 2 to 15 minutes. It is often excruciating in intensity, and is deep, nonfluctuating, and explosive in quality; only occasionally is it pulsatile. In addition, 10 to 20 percent of patients report superimposed paroxysms of stabbing, icepick-like pains in the periorbital region that last for a few seconds and may occur once or several times in rapid succession; this paroxysmal pain usually heralds the end of an attack. The symptoms resolve in 1 to 2 minutes (Ekbom, 1975).
The pain usually begins in, around, or above the eye or the temple ; occasionally the face, neck, ear, or hemicranium may be affected (Sutherland and Eadie, 1972). It is always unilateral, and generally affects the same side in subsequent bouts. However, it may shift to the corresponding region of the opposite side in 15 percent of patients (Manzoni et al, 1983b), usually for the duration of a bout, less often switching sides within a bout. Many patients prefer to be upright and active when an attack is in progress, but this is reported with a frequency that is not high enough to be useful diagnostically (Russell, 1981).
Periodicity and Duration of the Attacks
Attacks last from 30 minutes to 2 hours (mean of 45 minutes) in about 75 percent of cases. Occasionally, attacks - especially mild ones - may be as short as 10 minutes, whereas others may last as long as several hours. Attacks range in frequency from six per 24 hours to one per week, with a mean of one to two per day. Periodicity is a characteristic feature in about 85 percent of patients: attacks of pain tend to recur at the same hour each day for the duration of the cluster bout; many individuals also experience additional attacks that occur randomly throughout the day. About 75 percent of attacks occur between 9 p.m. and 10 a.m. (Russell, 1981). Manzoni et al, (1983b) found sharp peaks for attack frequency between 1 and 2 a.m., 1 and 3 p.m., and at 9 p.m . Patients are awakened from sleep by pain paroxysms in about 50 percent of cases, usually within 2 hours of falling asleep (Lance and Anthony, 1971; Hornabrook, 1964). Nocturnal attacks are associated with rapid eye movement (REM) sleep about one-half the time in episodic cluster headache, but only rarely in the chronic form (Plaffenrath et al, 1986; Kayed and Sjaastad, 1985).
Characteristics of the Bouts
The attacks of pain are clustered in cycles that usually last 4 to 8 weeks, and are followed by a pain-free remission in 90 percent of patients. On occasion, bouts may be as short as a few days or as long as 4 months; about 10 percent of those with established cluster tempos enter a chronic phase in which the attacks may persist for an average of 4 to 5 years (Ekbom, 1986). The later the onset of the episodic disorder, the greater the chance of it becoming chronic (Kudrow, 1980). Most patients experience one to two bouts per year; however, the interval between bouts ranges from 1 month to 2 years in 80 percent of the cases and between 6 months and 2 years in 60 percent (Kudrow, 1980). In rare instances it may be as long as 25 years (Hornabrook, 1964). Eventually, the bouts cease spontaneously, but more precise data on the natural history of the disorder are not yet available.
Associated Features
Related Symptoms and Signs
Lacrimation from the eye on the affected side is the most common associated symptom. A blocked nasal passage, rhinorrhea, red eye, and sweating and pallor of the forehead and cheek are often found, but their absence does not exclude the diagnosis. These autonomic symptoms, although clinically apparent unilaterally, are present bilaterally, quantitaively more so on the symptomatic side (Saunte, 1984; Sjaastad et al, 1981). There is a rapid increase in heart rate at the onset of attacks and further rate variations become pronounced as the paroxysm proceeds, suggesting central autonomic regulatory instability. In general, a modest bradycardia occurs during an attack (Russell and Storstein, 1983). A transitory, partial Horner's syndrome (pupillary miosis and lid ptosis) occurs in two-thirds of patients when they are examined during attacks (Ekbom, 1970a) and is a useful sign in the differential diagnosis of facial pain. It is highly characteristic of the cluster headache syndrome and, after repeated occurrences, it may become a permanent feature (Riley and Moyer, 1971; Nieman and Hurwitz, 1961).
The localization of the sympathetic lesion is of some interest. The ocular sympathetic innervation is a three-neuron pathway, comprising a first-order neuron: posterolateral hypothalamus to cord levels of C8 to T3 (the ciliospinal center of Budge); a second-order neuron: (preganglionic) ciliospinal center to super cervical ganglion; and a third-order neuron: (post-ganglionic) superior cervical ganglion to the pupillary dilator muscle, the eyelid muscles, and the facial sweat glands. It is believed by many observers that in cluster headache, involvement of the third-order neuron accounts for Horner's syndrome, which occurs as the result of distention of the wall of the internal carotid artery in the carotid canal, thus compressing the sympathetic plexus that invests the carotid wall. This argument is supported by three lines of evidence. The first is the observation that hyphidrosis is restricted to the forehead (Watson and Vijayan, 1982), which is consistent with a third-order neuron lision whereas more proximal lesions usually produce deficient sweating of the entire face (Morris et al, 1984). Second, supersensititivity of the miotic pupil to direct-acting sympathomimetic agents appears to place the lesion postganglionically (Fanciullacci et al, 1982; Vijayan and Watson, 1982); and third, angiographic changes of the carotid siphon during a cluster headache attack (Ekbom and Greitz, 1970) is also consistent with sympathetic plexus compression at this locus. However, others (Sjaastad, 1987) argue that there is sparse validation for the effects of conjunctival drugs on patients with central lesions (Malonety et al, 1980; Lepore, 1985). In fact, pupillary responsiveness and hyphidrosis patterns in patients with Horner's syndrome on a central basis are not very different from the results obtained with cluster headache patients (Van der Wiel and Van Gijn, 1986; Salvesen et al, 1987). Since the first-order hypothalamic neuron is uncrossed and, therefore, capable of generating ipsilateral symptoms, and for other reasons (see below) is an attractive patheogenetic locus, the issue, in my view, remains open.
Focal neurologic symptoms of the type characteristic of migraine are very uncommon in patients with the cluster headache syndrome; however, occasional patients experience typical photopsia, teichopsia, facial paresthesia, or vertigo at the time of the attack.
Precipitating Factors
Sensitivity to alcohol during a cluster bout occurs in at least half the patients, and cases when the bout remits (Friedman and Mikropoulos, 1958); this alternating, on-off vulnerability is pathognomonic of the cluster headache syndrome. Patients who are sensitive to alcohol note that attacks are triggered within 5 to 45 minutes after the ingestion of modest amounts of alcohol: usually less than a single cocktail or glass of wine. The vast majority have noted that their sensitivity is less than total: alcohol triggers attacks in 70 to 80 percent of exposures. This factor, together with many patients' misinterpretations regarding inquiries into their drinking habits, may account for the low incidence of alcohol sensitivity in several reported series (Sutherland and Eadie, 1972; Symonds, 1956).
A number of other precipitating factors have been noted in a smaller number of patients and include stress, relaxation, exposure to heat or cold, glare, hay fever attacks, and, occasionally, the ingestion of specific foods (chocolate, eggs, dairy products).
There is some evidence that head trauma can precipitate the syndrome. Among the 180 patients studied by Manzoni et al (1983b), previous head injury was reported by 41, with loss of consciousness occurring in 20. This is significantly more frequent than is observed among patients with other types of headache; furthermore, in all patients in whom the head injury was lateralized and loss of consciousness ensued, the side involved corresponded to the side on which cluster headache later occurred. However, the mean latency in these cases was 9 years, which poses a serious question regarding the connection between head trauma and the cause of the cluster headache syndrome. Moreover, in an additional 11 of 15 patients who had undergone previous cranio-facial surgery, the side operated on was ipsilateral to that of the site of later-appearing cluster headache attacks. The latency between these latter events averaged 5 years. Kudrow has found no evidence that head trauma can precipitate the syndrome (Kudrow, 1980).
Experimentally, attacks can be triggered in nearly all patients during a bout by the administration of 1 mg nitroglycerin sublingually (Ekbom, 1968), and in about 70 percent of patients by subcutaneous histamine (Horton, 1961). There is usually a latent period of 30 to 50 minutes before headache is triggered, whereas the peak peripheral and central vascular effects of nitroglycerin occur within 3 to 4 minutes of its administration and disappear in approximately 30 minutes (Bogaert, 1987). This, the appearance of headache does not coincide with the maximal circulatory effect of nitroglycerin, and the mechanism by which nitroglycerin causes headache remains unclear. A period refractory to pharmacologic provocation occurs after spontaneous or pharmacologically induced attacks and may persist for 2 hours or more (Ekbom, 1968; Horton, 1961). Therefore, valid provocative tests must be administered during an active bout, several hours after the attack has subsided.
AMELIORATIVE FACTORS
Ekbom (1975) found that compression of the superficial temporal artery provided temporary relief for about 40 percent of his patients but just as often worsened the pain; carotid compression reduced the pain half the time, and worsened it in 25 percent of his cases. Vigorous physical exertion at the earliest sign of an attack can, in some patients, be remarkably effective in ameliorating or even aborting an attack (Atkinson, 1977; Ekbom and Lindahl, 1970).
HEREDITARY DATA
Hereditary factors are significant in migraine and might be expected to be important in the cluster headache syndrome because of their mechanistic and pharmacologic similarities. However, it is uncommon to find other examples of cluster headache in the family history. Among Kudrow's (1980) 495 patients, 18 reported the presence of the syndrome in a parent. Migraine occurs no more frequently among the cluster headache population than among random population than among random populations (Andersson, 1985). When migraine predates the commencement of cluster attacks, migraine usually ceases when the cluster attacks begin (Bickerstaff, 1959); thus, although these disorders are biologically distinct, their mechanisms are probably connected.
EXAMINATION FINDINGS
A carefully elicited history is the key to diagnosis. There are no abnormalities to be found upon a physical or laboratory investigation other than Horner's syndrome occasionally. In approximately 70 percent of patients with cluster headaches, the carotid artery is palpably tender at several points in the neck (Raskin and Prusiner, 1977). The cluster headache syndrome, with all autonomic symptoms, on-off,alcohol sensitivity, ipsilateral tender carotid artery, and clocklike periodicity of attacks, has not been associated with any underlying intracranial structural abnormalities. There have been a few cases reported of lesions producing painful disorders resembling this syndrome, and some in which coincidental anatomic anomalies were demonstrated (Tfelt-Hansen et al, 1982; Mani and Deeter, 1982; Kurizky, 1984).
Graham (1972) formed the impression that certain physical features seemed to be characteristic of cluster headache patients. These include a ruddy complexion, multifurrowed and thickened skin, and a broad, prominent chin: all contributing to a "leonine" facial appearance. However, these observations were uncontrolled, and I have been unable to confirm them. There is no evidence that important psychological variables bear on this syndrome (Cuypers et al, 1981; Kudrow, 1980).
PATHOPHYSIOLOGY
The traditional designation of cluster headache as a vascular headache disorder is probably inappropriate; the vascular alterations that occur appear to be epiphenomenal, as they are in migraine, resulting from a primary CNS discharge. The hypothalamus may well be the site of such activation, containing posterior cells that regulate autonomic functions and anterior nuclei that serve as the major circadian pacemaker in mammals (Moore-Ede et al, 1983), both of which are necessary to explain the clinical symptoms and the uncanny periodicity of cluster headache attacks. The "biologic clock" is serotonergically modulated (Mason, 1986) and is connected anatomically to the eye (Sadun et al, 1984). The drugs effective in the treatment of the cluster headache syndrome enhance serotonergic neurotransmission, as also occurs in the treatment of migraine.` This suggests that unstable serotonergic neurotransmission, at different loci, may be common to both disorders. In this section, we will review, among other data, the evidence supporting the tantalizing speculation that the cluster headache syndrome may be the result of an antidromically discharging biologic pacemaker.
Biologic Clocks
A pacemaking mechanism in mammalian brain controls circadian rhythms (from the Latin circa diem, about 1 day), which are endogenous daily cycles. The most important of these biologic clocks is believed to be the suprachiasmatic nuclei (SCN): two small cell groups in the anterior hypothalamu7s just dorsal to the optic chiasm (Schwartz et al, 1987; Moore and Card, 1985; Turek, 1985). The pacemaker generates circadian rhythms, couples them with one another, and synchronizes them with external environmental events. Events in the internal milieu are arranged in temporal sequence to permit maximal adaptation to synchronized in phase and period, by time cues such as the daily light/dark cycle; a visual pathway from retina to the SCN is necessary to mediate entrainment (Sadun et al, 1984). The function of this system is to maintain daily order in physiologic processes, such as enzyme activities, body temperature, hormone secretion, and some behaviors. A disordered pacemaker may result in illness. For example, there is evidence that in jet lag and in manic-depressive illness, circadian rhythms may not be synchronized with one another or with the sleep-wake cycle (Wehr et al, 1983).
Under normal conditions, a rhythm generated by the pacemaker is transmitted to synapses where a receptor rhythm evokes second messenger elaboration, which, in turn, modulates neurotransmission (Kafka et al, 1983). Lithium is believed to act on this second messenger system (see below).
The SCN project to, and receive afferents from, the midbrain periaqueductal gray matter (Moore, 1983), so that a functional link to the pain-modulating system is feasible. Furthermore, serotonin-containing terminals arising from the midbrain dorsal raphe nuclei distribute in a dense plexus in the SCN and are capable of serotonin uptake. There is evidence that serotonergic mechanisms are involved in the expression rather than the generation of circadian rhythms. The SCN neurons are responsive to serotonin and its release via activation of the midbrain raphe projection to the SCN (Groos et al, 1983). Intrinsic pacemaker frequency appears to be modulated serotonergically by a mechanism that has not yet been established. It is interesting that lithium experts prominent effects upon circadian rhythms (Kripke and Wyborney, 1980; Kafka et al, 1982), possibly through an enhancement of serotonergic neurotransmission (Blier and De Montigny, 1985).
Apart from the circadian periodicity of individual attacks and the periodic recurrence of bouts of cluster headache, further evidence of the role of a central pacemaker comes from hormonal studies among patients. Dampening of secretory circadian rhythms has been shown for melatonin, cortisol, testosterone, á-endorphin, á-lipotropin, and prolactin (Waldenlind et al, 1984; Chazot et al, 1984; Facchinetti et al, 1986; Nappi et al, 1985; Waldenlind and Gustafsson, 1987) during bouts; most of these rhythms revert to normal during remissions.
Additional support for a CNS disturbance as the source of cluster attacks comes from studies of brain stem auditory-evoked potentials. Slowed conduction (increased I-V interpeak latencies) was shown ipsilateral to the painful side and became more pronounced during paroxysms of pain; lithium treatment appeared to shorten the latencies (Bussone et al, 1986). Clinically, the concurrence of cluster headache and trigeminal neuralgia, the cluster-tic syndrome, in which both disorders are ameliorated by microvascular decompression of the sensory root of the trigeminal nerve, also points to a centrally mediated pain mechanism.
Cerebral Blood Flow Alterations
Dilatation of extracerebral arteries appears to be common to both migraine and cluster headache (Sakai and Meyer, 1978); enhanced pulsation of the intraocular vascular bed occurs during cluster attacks but not during migraine attacks (H›rven et al, 1972; H›rven and Sjaastad, 1977), underlining the involvement of the internal carotid artery and its branches in the cluster headache syndrome. Evidence that part of the pain of cluster headache is derived from dilatation of intracranial branches of the internal carotid artery stems from the observation of Thomas and Butler (1946) that pain may be relieved in some patients by the intrathecal injection of saline, which increases the cerebrospinal fluid pressure to 700 mm H2O.
The importance of vascular dilatation in cluster headache has been emphasized in the past because headaches may be precipitated during a bout by vasodilators such as alcohol, histamine (Horton, 1941, 1952; Hardebo et al, 1980), and nitroglycerin (Ekbom, 1968); however regional cerebral blood flow (CBF) studies in the modern era have shown only inconsistent alterations in flow during attacks, lending no support to the idea that vasodilatation is necessary to the pain mechanism (Nelson et al, 1980; Krabbe et al, 1984). Drummond and Lance (1984) and Drummond and Anthony (1985) showed that the increase in extracranial blood flow and increased temporal artery pulsations that attended individual attacks usually followed the onset of pain in affected areas, which led them to a primary neural discharge.
Reduction of the severity of angina pectoris and limb claudication has been noted during some cluster bouts (Ekbom, 1970b), suggesting that, at least in some patients, an alteration of arterial tone outside the carotid circulation also occurs.
Biochemical Mechanisms
A search for biochemical agents has been made on the presumption that the cluster headache syndrome may be mediated by a disorder of humoral control of blood vessels. The prominence of lacrimination, perspiration, and suffusion of the conjunctivae is consistent with an excessive cholinergic discharge. This reasoning led Kunkle (1959) to examine cerebrospinal fluid for acetylcholine-like activity, which he found in 4 of 14 patients at the time of headache; it was not found in 7 patients with classic migraine.
Serotonin
Serotonin alterations are more subtle in patients with cluster headache than in migraine. Medina et al (1979) found modest elevations of serotonin in whole blood during attacks of cluster headache, whereas platelet serotonin levels fall precipitously during migraine attacks. Waldenlind et al, (1985) found low whole blood serotonin levels among cluster patients both during an active bout and during remissions, comparable to levels found among migraine patients.
Erythrocyte Choline
Erythrocyte choline concentrations are low in cluster headache patients (de Belleroche et al, 1984); this is an interesting observation because lithium administration greatly increases erythrocyte choline levels, an effect that persists for months. The depressed choline level is not confined to the acute attack; it is also present between bouts. de Belleroche et al (1986) took these data a step further and showed that erythrocyte membrane phosphatidylcholine/cholesterol ratios were increased in cluster headache patients, indicating a reduced turnover of phosphatidylcholine in the red cell membrane. It is not yet clear whether these intriguing findings are related to the mechanism of the disorder.
Histamine
The possibility that histamine may be involved is supported by the reportedly higher incidence of duodenal ulceration in patients with cluster headache (Ekbom, 1970b) as well as by the precipitation of attacks with small amounts of this substance. Anthony and Lance (1971) and Medina et al, (1979) have shown that there is a modest increase in whole blood histamine during an attack; furthermore, elevations of urinary histamine were found in four of eight patients during cluster attacks (Sjaastad and Sjaastad, 1970). These reports are challenged by the lack of change in the catabolic pattern of intravenously administered C14 histamine in patients with cluster headache (Beall and Van Arsdel, 1960) and, since histamine is localized peripherally to basophilic leukocytes, caution is advised when interpreting whole blood levels (Porter and Mitchell, 1972). Patients with chronic myelogenous leukemia have very high blood levels of histamine but do not report headache. Furthermore, antihistaminic agents are disappointingly ineffective, as also has been histamine desensitization.
It has been apparent for some time that there are at least two histamine receptors, since some of the effects of histamine are not blocked by the usual antihistaminic agents (Ash and Schild, 1966). Substantial evidence for two histamine-induced vasodilatation is only partly reversed by H1 antagonists (Hardebo et al, 1980), and it now appears likely that bot H1 and H2 receptors are present in the carotid vascular bed (Saxena, 1975), the availability of H2 antagonists has renewed the interest in testing the role of histamine in cluster headache. Anthony et al, (1978) and Russell (1979) have used H1 and H2 antagonists in the therapy of cluster headache, without clear success. It is possible that the elevation of blood histamine is the result of episodes of paroxysmal vascular instability, since histamine is but one of a group of diverse substances that includes the kinins, prostaglandins, and others that are released from tissues during injury or inflammatory reactions (Beaven, 1976).
Mast Cells
Appenzeller et al (1981) found that mast cells, the major repository of histamine in many tissues, are found in increased number in the skin of the painful temporal area in cluster headache patients; this effect is particularly striking within the first 10 hours after a cluster attack. Mast cell numbers in patients outside of a cluster period are similar to those of migraineurs (Appenzeller, 1987), which suggests that these cells are increased in both types of headache as a secondary event. No differences have been found in the dermal response to histamine among cluster headache patients when the painful side was compared to the opposite side (Bogucki and Prus¡nski, 1985), which lends no support to the idea that the periodic release of histamine might stimulate trigeminal nerve endings and thus be directly implicated in the mechanism of an attack.