Cluster Headache in Two Sisters. Pupillary Response to Phenylephrine and Tyramine

Two sisters with cluster headache were studied with respect to the pupillary responses to instillation into the conjunctival sac of a single drop of a 1% solution of phenylephrine and a 2% solution of tyramine. The changes in pupillary diameters were documented by photographic pupillometry prior to and at 15, 30, 60, and 90 minutes after the instillations.
Of the two sisters, one (case A) was examined during a symptom-free interval, when she had been free from cluster headache attacks for 2 1/2 years. When the cluster headaches recurred, retesting was performed. The other sister (case B) had been free from cluster headaches for 9 years, when she was examined.
The findings indicate hypofunction within the postganglionic sympathetic nerve fibers during a cluster headache period. The hypofunction is bilateral, and thus, can not be a consequence of the unilateral cluster headache attacks. During remissions, tyramine induces a marked mydriasis, particularly on the symptomatic side, tentatively indicating an excessive release of stored monoamines.     

Coexistence of pupillary and heart sympathergic asymmetries in cluster headache

Ten cluster headache patients and 10 healthy controls were subjected to electrocardiographic and pupillometric procedures in a search for cardiac and pupillary sympathergic asymmetry. Sympathergic stimulation was provoked by hyperventilation and by instilling tyramine into both eyes. In the control group, hyperventilation changed neither the T-wave form and polarity nor the QTc. Tyramine provoked an equal mydriasis on the two sides. In cluster headache sufferers, hyperventilation produced changes in the T-wave form and polarity as well as an increase of the QTc due to a disproportionate shortening of the R-R and Q-T intervals. An unequal mydriasis was noted after tyramine instillation due to less marked response on the symptomatic side. The observed electrocardiographic abnormalities are considered an expression of an asynchronous repolarization attributed to a sympathergic asymmetry. It is postulated that both the cardiac and pupillary sympathetic imbalance associated with cluster headache are central in origin.     

The trigemino-pupillary response in cluster headache

Central impairment of the integrative neural systems controlling vegetative function and pain perception has been demonstrated in cluster headache (CH). Recently, we described the human pupillary response (trigeminal reflex) to quantified (painless and painful) corneal stimulation with a combined neurophysiological and pharmacological technique. In this study, the trigeminal reflex was evaluated in 26 subjects with episodic cluster headache. During the active phase of the disease, on the side of the pain we observed reduced mydriasis to electrical stimuli with an intensity equal to the corneal reflex threshold, and on both sides to stimuli with intensity that equalled the pain threshold. No difference was found when amplitude of the miotic phase was compared in the different groups. These suggest disordered pupillary activation in response to pain, probably sympathetic in origin, which is bilateral, detectable also during the remission phase and which cannot be explained simply by the antidromic release of pain-related peptides.     

Recurrence of Cluster Headache After Carotid Thrombendarterectomy

SYNOPSIS
The pathophysiology of cluster headache is largely unknown. One important contributing factor may be an abnormal intracranial-extracranial hemodynamic state. A male patient suffered from chronic left-sided cluster headache for about 15 years. After the institution of lithium therapy the symptoms abated. He was completely free from cluster headache for more than 20 years, until the first postoperative day after a thrombo-endarterectomy for symptomatic 70% carotid stenosis.
This case report indicates the importance of abrupt carotid hemodynamic changes along with dysfunction of the cephalic sympathetic nervous system in the initiation of cluster headache.     

Cluster headache pathogenesis: A pupillometric study

Thirty-two cluster headache patients and healthy controls (n = 16-20 for the various tests) were examined by means of a Whitaker pupillometer during pain-free intervals. Eye drops of the sympathomimetic agents tyramine, hydroxyamphetamine, and phenylephrine were instilled into the conjunctival sacs on separate occasions, and pupillary diameters recorded at standard time intervals. The mydriatic responses of the two pupils were compared. A moderate, but statistically significant, basal relative miosis was found on the pain side in cluster headache. The symptomatic-side pupils were less responsive than their counterparts when stimulated with tyramine and hydroxyamphetamine, the difference being statistically significant for the OH-amphetamine test. With the phenylephrine test, however, the mydriasis on the symptomatic side significantly exceeded that of the contralateral pupil. This pattern of reactions does not quite correspond to those of "ordinary" Horner's syndrome (1st, 2nd, and 3rd neuron lesion). There are, however, gross similarities with the recently reported pattern in central sympathetic neuron dysfunction. In cluster headache there is probably a "Horner-like picture" rather than a proper Horner's syndrome.     

A sleep study in cluster headache

Cluster headache (CH) is a primary headache with a close relation to sleep. CH presents a circa-annual rhythmicity; attacks occur preferably during the night, in rapid eye movement (REM) sleep, and they are associated with autonomic and neuroendocrine modifications. The posterior hypothalamus is the key structure for the biological phenomenon of CH. Our aim is to describe a 55-year-old man presenting a typical episodic CH, in whom we performed a prolonged sleep study, consisting of a 9-week actigraphic recording and repeated polysomnography, with evaluation of both sleep macrostructure and microstructure. During the acute bout of the cluster we observed an irregular sleep-wake pattern and abnormalities of REM sleep. After the cluster phase these alterations remitted. We conclude that CH was associated, in this patient, with sleep dysregulation involving the biological clock and the arousal mechanisms, particularly in REM. All these abnormalities are consistent with posterior hypothalamic dysfunction.     

Pupil responsiveness in cluster headache: A dynamic TV pupillometric evaluation

In this study the variations in pupil diameter induced by different stimuli (dark-light adaptation, light reflex, electric stimulation of the sural nerve) were investigated in episodic (in the active or remission phases) and in chronic cluster headache (CH) patients. Pupil size monitoring was performed with a monocular, infrared TV pupillometer, and sural nerve stimuli were applied after the pain threshold had been measured as the flexion reflex threshold of the biceps femoris muscle (RIII reflex). The results were compared with those obtained in patients with "peripheral" (third neuron) Horner's syndrome and in healthy sex- and age-matched controls. On the symptomatic side we found an impairment of pupil response to light flashes and nociceptive stimuli; similar findings were sometimes evident on the pain-free side, too. These results substantiate previous observations that in cluster headache a dysfunction of the integrative central nervous system pathways also exists intercritically and mostly bilaterally, involving both autonomic regulation and pain perception mechanisms.     

Cardiovascular autonomic function tests in cluster headache

While facial autonomic signs are prominent during cluster headache (CH) attacks, cardiovascular autonomic changes have been described in few CH patients. Cardiovascular autonomic function tests (AFT) can be used to assess general autonomic function in CH patients in different stages of the disease. We aimed to assess whether general autonomic function is changed in CH patients during a cluster period. AFT was performed both during a cluster period, but outside an actual attack, and outside a cluster period in 18 patients. Heart rate variability was studied at rest, during deep breathing, after standing up and during a Valsalva manoeuvre. Blood pressure (BP) changes were recorded at rest, during standing up and during sustained handgrip. Measurements during and outside the cluster period were compared using the paired t-test. AFT measurements revealed no significant differences between the two measurements, except for diastolic BP in rest, which was higher during the cluster period [80.3 (SD 12.2) vs. 74.8 (SD 9.0), P = 0.04]. Autonomic dysfunction during a cluster period, but outside an attack, does not include systemic cardiovascular control.     

The Enhanced Ciliospinal Reflex in Asymptomatic Patients With Cluster Headache is Due to Preganglionic Sympathetic Mechanisms

An amplified ciliospinal reflex response has been documented in patients with cluster headache, lacking a Horner like syndrome. The mechanism is unknown, Tentatively, it may be due to an increased release of monoamines from post-ganglionic sympathetic nerve endings or an increased density of postsynaptic adrenergic receptors in the dilatator muscle of the iris.
The instillation of a 1% phenylephrine solution into the conjunctival sac induces mydriasis by stimulating postsynaptic adrenergic receptors in the dilatator muscle of the iris, while the instillation of a 2% tyramine solution causes mydriasis by releasing noradrenaline from the presynaptic sympathetic nerve terminals in the iris.
According to these premises, a positive correlation shouId be expected between the ciliospinal reflex response and the pupillary response to tyramine, if the enhanced ciliospinal so-flex response was due to an increased presynaptic release of monoamines. No such correlation was found. Nor was there any positive correlation between the ciliospinal reflex response and the pupillary response to phenylephrine, contradicting an increased density of postsynaptic monoaminergic receptors in the dilatator muscle of the iris as the explanation. However, there was a significant positive correlation between the pupillary responses to phenylephrine and tyramine, ruling out any functionally caused "denervation" hypersensitivity in the dilatator muscle of the iris.
It is concluded that the amplified ciliospinal reflex response in cluster headache patients (lacking a Horner-like syndrome) reflects compensatory pathophysiological mechanisms proximal to the third-order sympathetic neuron.     

Baclofen in cluster headache

Cluster headache is a rare, severe, clinically well-characterized disorder that occurs in both episodic and chronic forms. The painful short-lived attacks occur unilaterally and are associated with signs and symptoms of autonomic involvement. They are difficult to treat, and reported prophylactic therapies include ergotamine, steroids, methysergide, lithium carbonate, verapamil, valproate, capsaicin, leuprolide, clonidine, methylergonovine maleate, and melatonin. Baclofen, an antispastic agent, has been shown to have an antinociceptive action. Its efficacy in the treatment of neuralgias, central pain following spinal lesions or painful strokes, migraine, and medication misuse chronic daily headache suggested that it may prevent cluster headache attacks. Nine cluster headache patients received baclofen, 15 to 30 mg, in three divided doses. Within a week, six of nine patients reported the cessation of attacks. One was substantially better and became attack free by the end of the following week. In the remaining two patients, the attacks worsened and corticosteroids were prescribed. In this pilot study, baclofen seemed to be effective and well tolerated for the prevention of cluster headache.     

Increase in plasma methionine-enkephalin levels during the pain attack in episodic cluster headache

Since high levels of endogenous opioids (endorphins, enkephalins) were found in brain areas classically related to nociception, their peripheral levels in humans were studied in different pain syndromes yielding contradictory results. This study was undertaken to assess changes in plasma methionine-enkephalin (met-enkephalin) levels in patients with episodic cluster headache associated with the pain period. Twenty-nine patients, 24 in the cluster period (6 of them during an attack) and 3 in the remission period were studied. Two other patients were subjected to a longitudinal follow-up. Plasma met-enkephalin levels were determined by radioimmunoassay (RIA) with specific antibody. Plasma peptide concentration (pmol/ml) was higher (p less than 0.001) in patients during the pain attack (3.97 +/- 1.18) than in controls (0.25 +/- 0.03). When measured 4 and 48 h after the pain attack lower levels were found (0.46 +/- 0.06) which decreased to control values after 24 h. These results may suggest involvement of peripheral enkephalins in pain modulation in patients with episodic cluster headache.     

Evaluation of lithium response in episodic cluster headache: a retrospective case series

Objective.— In this study, we attempted to evaluate the response to lithium treatment and its tolerability in the prevention of episodic cluster headache (CH) and to identify clinical predictors of response. Background.— Verapamil and lithium are the most widely used drugs in the prevention of CH attacks. Lithium is considered a second‐line treatment in part because of its potentially severe adverse drug reactions (ADRs). Evidence for the efficacy of lithium in CH prevention is greater in chronic than in episodic patients. In addition, because of its narrow therapeutic window and ADRs (which can be significantly reduced with proper periodical monitoring of blood levels), lithium is recommended only in chronic CH, when other drugs are ineffective or potentially harmful. Methods.— Our primary aim was to determine whether lithium reduced the number of attacks per day (attack frequency). We compared attack frequency in 3 periods: run‐in, the first, and the second week of lithium treatment. Responders were defined as patients showing at least a 50% reduction in attack frequency. Results.— Lithium response was evaluated in 26 patients. Treatment led to a significant reduction in attack frequency within 2 weeks in a percentage of 77% of responders and 23% of nonresponders. Responders and nonresponders did not differ in terms of demographic and clinical characteristics. Only 15% of patients experienced mild ADRs. Conclusion.— Our study provides additional evidence on the effectiveness of lithium in the prevention of episodic CH. It also shows the tolerability of lithium, given the short duration of treatment and low dosage.     

CACNA1A gene polymorphisms in cluster headache

Cluster headache (CH) is a primary headache disorder where the aetiological and pathophysiological mechanisms still are largely unknown. An increased risk of CH in first- and second-degree relatives suggests the importance of genetic factors. Mutations of the P/Q type calcium channel alpha 1 subunit (CACNA1A) gene on chromosome 19p13 have been shown to cause several neurological disorders with a wide clinical spectrum, mainly episodic diseases. Missense mutations of the gene cause familial hemiplegic migraine (FHM) and it is also likely to be involved in the more common forms of migraine. The CACNA1A gene is thus a promising candidate gene for CH. In this study we performed an association analysis of an intragenic polymorphic (CA)n-repeat with marker D19S1150 and a (CAG)n-repeat in the 3'UTR region, in 75 patients with CH according to IHS criteria and 108 matched controls. Genotypes and allele frequencies were similarly distributed in patients and controls. Linkage disequilibrium between the two markers was similar in patients and controls. We conclude that an importance of the CACNA1A gene in sporadic CH is unlikely.     

Double-blind placebo-controlled trial of lithium in episodic cluster headache

Lithium is widely used in the prophylaxis of episodic cluster headache without formal evidence of efficacy. Placebo-controlled clinical trials are not easy in conditions characterized by frequent severe pain. In this study, it was assumed that lithium would work quickly if at all, and placebo response would be zero. Strict diagnostic criteria excluded uncertain or atypical cases. Patients were male in so-far untreated episodes expected to last for at least 3 weeks more. In a double-blind, placebo-controlled comparison of matched parallel groups, treatment was either slow-release lithium carbonate, 800 mg/day, or placebo. After 7 days, compliance was estimated by tablet count, blood was taken for lithium assay, efficacy was assessed (attacks stopped or substantially improved) and adverse reactions were recorded. The study was stopped after planned sequential analysis of the 27th patient (13 on lithium, 14 on placebo). Estimated compliance was usually but not always good. Plasma lithium levels were mostly in the range 0.5–0.6 mmol/1 on lithium, zero on placebo. Cessation of attacks within 1 week occurred in two patients in each group, substantial improvement in 6/14 (43%) on placebo, 8/13 (62%; NS) on lithium. Only minor adverse events were reported. Lithium treatment was therefore associated with a useful subjective improvement rate but the assumptions made at outset had proved wrong. The trial was stopped because superiority over placebo could not be demonstrated. There were lessons for future trials.     

Efficacy of transdermal clonidine in short-term treatment of cluster headache: a pilot study

Some clinical as well as pharmacological indications seem to suggest that a reduction of the noradrenergic tone occurs in cluster headache (CH), during both the active and remission periods. But sharp fluctuations of the sympathetic system may trigger the attacks. Clonidine, an alpha-2-adrenergic presynaptic agonist, regulates the sympathetic tone in the central nervous system. Therefore, a continuous administration of low-dose clonidine could be potentially beneficial in the active phase of CH by antagonizing the variations in noradrenergic tone. After a run-in week, we administered transdermal clonidine (5–7.5 mg) for one week to 13 patients suffering from CH, either episodic (8 cases) or chronic (5 cases). During clonidine treatment, the mean weekly frequency of attacks dropped from 17.7 ±7.0 to 8.7 ±6.6 ( p = 0.0005), the pain intensity of attacks measured on the visual analogue scale from 98.0 ± 7.2 to 41.1 ± 36.1 mm ( p = 0.001), and the duration from 59.3 ± 21.9 to 34.3 ± 24.6 min ( p = 0.02). This open pilot study strongly suggests that transdermal clonidine may be an effective drug in the preventive treatment of CH. Its efficacy is possibly due to its central sympatho-inhibition, which reduces or prevents the occurrence of fluctuations of noradrenaline release that may induce the attacks.     

beta-Receptor response to noradrenaline in cluster headache. A study of adipose tissue lipolysis

We have previously shown decreased lipolysis in both phases of cluster headache (CH), as an indication of a sympathetic dysregulation. Reduced lipolysis could be a result of diminished beta-receptor sensitivity in adipose tissue. The aim of this study was to measure the lipolytic response to noradrenaline in 10 CH patients in remission and in 10 healthy subjects, to estimate beta-receptor function. Microdialysis technique was used to measure the increase of glycerol, the end-product of lipolysis, during infusion of noradrenaline into the adipose tissue. Noradrenaline infusion resulted in a distinct elevation of glycerol. The average glycerol increase was significantly higher in CH patients (121% +/- 48) than in healthy subjects (77% +/- 41) (P < 0.05), which indicates increased beta-receptor response to noradrenaline in CH patients in remission. This may be due to up-regulated beta-receptor sensitivity, secondary to reduced sympathetic outflow and a primary autonomic disturbance in CH.     

Dynamic mechanical (brush) allodynia in cluster headache

OBJECTIVE: To examine the occurrence of dynamic mechanical (brush) allodynia (BA) in patients with cluster headache (CH). BACKGROUND: Cutaneous allodynia was described in migraine. It was related to sensitization of neurons in the trigeminal nucleus caudalis (TNC). This phenomenon has not been previously described in cluster headache. METHODS: We examined adult patients with episodic or chronic CH for the presence of BA. Demographic data and the characteristics of CH were obtained through a questionnaire. Allodynia testing was performed by repetitively applying a 4x4-inch gauze pad to skin areas in the trigeminal and cervical dermatomes. Degree of allodynia was measured on a 100-mm visual analog scale (VAS). The relations between the location and severity of headache and allodynia were assessed. RESULTS: Ten patients (all male, mean age 39.3) were included in the study. Seven had episodic CH (ECH) and 3 had chronic CH (CCH). Two patients were in acute attack when tested for BA. In total, 4 (40%) of the 10 patients had BA (2 [28.6%] of the 7 with ECH and 2 [66.7%] of the 3 with CCH). Median disease duration was 22 years for patients with BA and 12 years for patients without BA. Of the two patients in acute attack, one had BA, ipsilateral to the headache, which was reduced 20 minutes after treatment, along with reduced headache severity. CONCLUSIONS: This is the first report on the occurrence of cutaneous allodynia in CH. The presence of BA in CH may be related to CH type (episodic vs. chronic) and to the duration of disease. These results support the concept that allodynia in CH may result from a time-dependent process of neuronal sensitization.     

Decreasing incidence of cluster headache: a population-based study in Olmsted County, Minnesota

The incidence of medically recognized cluster headache within Olmsted County, Minnesota, from 1989 through 1990, was determined by using modified International Headache Society criteria. The results were compared with previously published incidence data from 1979 through 1981. The overall age- and sex-adjusted incidence decreased from 9.8/100,000 person-years in 1979-1981 to 2.07/100,000 person-years in 1989-1990.     

Possible predictive factors in the evolution of episodic to chronic cluster headache

The purpose of our study was to identify general factors and distinctive clinical features differentiating patients with chronic cluster headache (CH) evolved from episodic CH and patients with episodic CH. Our study sample included 28 patients suffering from chronic CH evolved from episodic CH and 258 patients with episodic CH; all were referred to the Headache Center of Parma between December 1975 and June 1998. Patients with episodic CH were selected from all episodic CH referrals (n = 485) and selection was based on the duration of the disorder, which was to exceed the average period needed for an episodic form to turn into a chronic form (4.5 years for females and 7.0 years for males). At CH onset, the mean age for patients with chronic CH evolved from episodic CH was older than for those with episodic CH. Among patients with chronic CH, more were smokers or heavy drinkers, and had suffered a head injury. Clinically, episodic CH evolving into chronic CH was characterized by a high frequency of cluster periods, a larger proportion of patients with attacks not occurring strictly within cluster periods, and remission periods lasting less than 6 months. Possible predictive factors in the development of chronic CH appear to be CH onset from the third decade of life onward, the occurrence of more than one cluster period a year, and the short-lived duration of remission periods. The role played by head injury and cigarette smoking in the evolution of the disorder still cannot be established with certainty.