Latent dysautonomic pupillary lateralization in cluster headache. A pupillometric study

Forty-five patients with cluster headache in the asymptomatic phase were studied by electronic pupillography, testing autonomic function of both pupils pharmacologically. Topical sympathetically-acting mydriatics, tyramine and cocaine and the cholinoceptor blocker, homatropine, induced defective mydriatic responses on the symptomatic side, indicating latent impairment of sympathetic function. The abnormality was found in interattack intervals of the cluster period or during intercluster phases. The tyramine test can be proposed for objective diagnosis of cluster headache. We postulate that cluster attacks are triggered and lateralized by a permanent latent unilateral sympathetic dysfunction. Lithium reduced the mydriatic response to tyramine of the pupil contralateral to the pain, thus restoring the equilibrium between both pupils; this therapy may correct the asymmetric sympathetic function by attenuating the activity in the asymptomatic side.     

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.     

Sweat gland and pupillary responsiveness in Horner''s syndrome

Eight patients with Horner's syndrome (five with a 1st neuron lesion and three with a 2nd neuron lesion) were examined for their pupillary responses to pharmacologic stimulation with tyramine (2%) and with phenylephrine (1%) eye drops. The same patients were also evaluated for their forehead sweating pattern on stimulation with body heating and pilocarpine injection, using the Evaporimeter. Five patients had a brain stem (1st sympathetic neuron) lesion, while three patients had had a traumatic C8-Th1 root avulsion and hence had a preganglionic neuron lesion. The average response with the phenylephrine eye test and the pilocarpine sweat test differed markedly between the two groups; only the central neuron lesion group had a supersensitivity reaction to both drugs. These procedures may be of diagnostic value in localizing the lesion in patients with a Horner's syndrome of unknown etiology. Patients with 3rd neuron lesion have not been examined with this combination of techniques.     

Cluster headache: Combined assessment with pupillometry and evaporimetry

Twenty-nine patients with cluster headache have been examined with the pupillometer and the evaporimeter. Pupils were dilated by sympathicomimetic drugs instilled into the conjunctival sacs, and responses of the two sides were compared. Forehead sweating was stimulated by body heating and by pilocarpine injection, and sweat evaporation on the two sides was compared. Most patients demonstrated the known patterns of hyposecretion on heating, of pilocarpine supersensitivity, and of deficient pupillary dilatation on OH-amphetamine stimulation on the symptomatic side and a supersensitivity of this pupil to phenylephrine. There were deviations from the rule for all methods of testing. Sixteen patients demonstrated a typical supersensitivity response of the pupil and of the sweat glands on the symptomatic side. Six patients had no such response, and seven patients had a discrepancy between the pupillary and the sweat gland response to stimulation, supersensitivity being present in one system only. There was a high degree of concordance between the results of the various methods of examination.     

Cluster headache: On the significance of so-called minibouts

Cluster headache periods (bouts) have, at the lower end of the scale, been supposed to last for periods as short as 1-2 weeks. Patients who usually have bouts of ordinary duration occasionally have brief attacks in the remission phase ("abortive attacks"). The group described here had a temporal pattern, clearly at variance with both these patterns: The six patients had mostly or entirely bouts of less than 1 week's duration. We have termed such short-lasting bouts minibouts, on the supposition that such cases belong within the cluster headache cycle. All the patients were men and had a history of unilateral headache without side shift, and usually the solitary attacks had some autonomic accompaniments, although of a moderate degree. In four cases only mild attacks occurred, whereas in two cases the attacks were rather severe and not consistent with full working ability. The group as such may not be homogeneous. The nosologic status of patients with bouts lasting only 1-2 days is somewhat uncertain. As long as the substrate of cluster headache is not outlined, the lower end of duration of minibouts cannot be accurately identified. The fact that three patients recently have experienced bouts of ordinary length strengthens the view that such cases really belong to the cluster headache cycle.     

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.     

Substance P in the human iris: Possible involvement in echothiophate-induced miosis in cluster headache

Substance P-like immunoreactivity (SP-LI) was measured by radioimmunoassay in iris, choroid, and retina obtained from men after death. Although present in different amounts, SP-LI, eluting as authentic SP or SP sulfoxide in the high-performance liquid chromatography system, was found in the three ocular structures. The retina contained higher concentrations of SP-LI than the iris and choroid. The possible functional involvement of iris SP was studied in 22 episodic cluster headache (CH) patients by using the anticholinesterase agent echothiophate iodide (EI), which also induces an atropine-resistant miosis, putatively due to release of SP from trigeminal sensory neurons. In CH patients EI eye drops instilled into both eyes provoked a prolonged miosis with a more marked response in the pupil of the symptomatic eye. It is proposed that the hyperfunction of SP-containing neurons may coexist with the previously documented sympathetic hypofunction in the innervation of the symptomatic pupil of CH.     

Burden of cluster headache

The aim was to analyse the socioeconomic burden of cluster headache in patients from a tertiary headache centre. One hundred consecutive patients from the Danish Headache Centre were invited to an interview about the socioeconomic impact of cluster headache. Work absence and use of medical services were compared with a Danish population-based survey. Eighty-five patients participated; 78% reported restrictions in daily living and 13% also outside of cluster periods; 25% reported a major decrease in their ability to participate in social activities, family life and housework. The disease caused lifestyle changes for 96%, most frequently in sleeping habits and avoidance of alcohol. The absence rate among patients was 30%, which was significantly higher than 12% among the general population (P < 0.001). Use of health services due to headache was also higher among the patients (P < 0.001). Cluster headache, although periodic in most cases, has considerable impact on social functions, quality of life and use of healthcare.     

Valsalva-induced cluster headache

A case valsalva-induced cluster headache is presented. Cluster attacks induced by valsalva manoeuvres alone were only recently described, and such patients have features of cough headache and cluster headache. Attacks occurred a couple of times a week in the patient presented, solely triggered by valsalva manoeuvres including coughing, sneezing or straining and not by exercising.     

Pain induces decrease of blood flow in the common carotid arteries in cluster headache attacks

Eighteen cluster headache patients and five controls were studied using ultrasound duplex techniques to measure blood flow in the common carotid arteries after nitroglycerin and placebo administration. Vessel diameter and blood flow tended to be greater before nitroglycerin in patients in the cluster headache period than in patients out of period and controls. Nitroglycerin tended to increase blood flow only in patients not in the cluster period and in controls. There was a significant decrease in common carotid blood flow and increase in vascular resistance related to maximum pain in both nitroglycerin-induced and spontaneous cluster headache attacks. Blood flow did not reach the initial flow values after the attack was over. In one patient a hyperventilation attack only temporarily decreased the pain. We suggest that the decrease in blood flow and increase in vascular resistance may be due to constriction of intracranial arteries by reflex activation of sympathetic efferents, rather than to decrease of arterial CO₂ tension.     

Orbital phlebography in patients with cluster headache

Thirteen patients with cluster headache in an active stage were investigated with orbital phlebography. About 60% of the patients showed pathologic changes on the phlebograms, such as changes in the appearance of the superior ophthalmic vein. Five patients had pathologic changes on both sides and three patients on one side only. All patients with unilateral pathologic findings on orbital phlebography had the attacks on the same side. The phlebographic findings in these patients with cluster headache were very similar to those of patients with the Tolosa-Hunt syndrome. There is also some similarity in the symptoms in the two disorders. It has previously been suggested that the Tolosa-Hunt syndrome is caused by venous vasculitis, and the present findings to some extent support the idea that cluster headache may have the same etiology.     

Migraine in patients with cluster headache

One hundred and twenty seven patients with cluster headache have been compared with 122 patients with migraine. Twenty of the patients with cluster headache have had migraine attacks but only 2 still have migraine attacks after the onset of cluster headache. No migraine patients had cluster headache. Among the 127 patients with cluster headache, one of the parents suffered from cluster headache in 4.7% of the cases. Among the 122 patients with migraine, 0.8% had a parent with cluster headache. Among the 122 patients with migraine 54.9% had parents with migraine, and in the cluster headache group 23.6% of the patients had one parent with migraine. The coexistence of migraine and cluster headache is rare. The two types of headache, as far as the heredity pattern is concerned, are independent entities.     

Pupillary functional asymmetry in patients with muscle contraction headache

Twenty-five patients with 'muscle contraction headache' (MCH) underwent tyramine pupillary tests, and 15 of them also underwent physiologic pupillary tests and cold pressor tests. Twenty healthy controls underwent tyramine pupillary tests, physiologic pupillary tests, and cold pressor tests. In the tyramine pupillary tests and the physiologic pupillary tests, the controls showed a symmetric mydriasis. In contrast, MCH patients showed asymmetric mydriasis after tyramine instillation and in the physiologic pupillary tests. In the cold pressor tests MCH patients reacted in the same manner as the controls. It is suggested that MCH patients have pupillary sympathetic imbalance. The role of this imbalance in the pathogenesis of MCH remains uncertain.     

New-onset cluster headache in middle-age and elderly women

Cluster headache is usually considered to affect young men. We hereby report on new-onset cluster headache in middle-aged and elderly women. We performed a retrospective chart review of female patients diagnosed with cluster headache (IHS criteria), and studied the charts of women in whom the headache started after the age of 50 years. Out of 168 patients (26 women, 15%) diagnosed with cluster headache, the headache started after the age of 50 years in seven women, of whom three reported past tension-type or migraine headaches. The mean age at the beginning of the headache was 61 +/- 8 years (range 52--72 years). In all cases, the pain was severe, strictly unilateral, and accompanied by at least one autonomic symptom. The average duration of the pain was 70 min (range 20 min--3 h), recurring daily for an average period of 7 weeks (range 1--16 weeks). Five patients had 1--2 pain attacks each day, while the other two experienced up to eight episodes of pain in 1 day. In two patients the periodicity of the pain was currently undetermined. In the remainder, the headache periods recurred every 1--4 years. Cluster headache is commonly considered to be a young-male disorder, but middle-aged and elderly women may also be affected. The characteristics of the pain and its manner of occurrence were similar in our cases to those reported in the young-male population.     

Premonitory and prodromal symptoms in cluster headache

Warning symptoms in 150 cluster headache patients were studied by focusing on attacks occurring during waking hours. Warnings were divided into prodromes that started minutes before the pain of individual attacks (122 patients) and premonitory symptoms preceding the onset of cluster periods by days to weeks (12 patients). Pathogenetic and therapeutic implications are discussed.     

A case of parasellar meningioma mimicking cluster headache

A medical history of a 46-year-old male is reported. At 23 years of age, he started having diffuse pain in the left side of his head for up to 30 min once or twice a month. At 28, the pain changed into left-sided cluster headache-like attacks with 2-3 h duration and with ipsilateral conjunctival injection, lacrimation, and rhinnorhea, but with short-lasting free intervals of about two to three weeks. At 36, the pattern of the attacks corresponded to chronic migrainous neuralgia. At 40, the symptoms changed to painful ophthalmoplegia-picture. A left-sided parasellar meningioma was then diagnosed. Removal of the tumor caused complete amelioration. The case history is suggested to support the hypothesis that the cavernous sinus region is involved in cluster headache.     

Episodic cluster headache and narcolepsy: a case report

A patient who first presented with episodic cluster headache later developed narcolepsy. In spite of REM sleep alterations associated with narcolepsy, the frequency and distribution of pain attacks did not change when narcolepsy occurred and were similar to those seen in cases of episodic cluster without narcolepsy. The lack of influence of narcolepsy on the pattern of cluster pains questions the role of REM sleep states in triggering pain in episodic cluster.     

Cluster headache-like headache, Hageman trait deficiency, retrobulbar neuritis, and giant aneurysm

A 56-year-old, previously reported woman with cluster headache-like headache with bouts of unilateral (the side of predominance changing through the years) severe headache had a familial history (three generations) of partial Hageman factor deficiency and bleeding episodes. A giant aneurysm was found to be lodged in the anterior communicating artery on the left side. Clinically, the features were atypical for cluster headache: onset at a young age (14 years), episodes of retrobulbar neuritis appearing at the side of pain, etc. Studies of forehead sweating indicated that the right side was the pathologic one, from an autonomic point of view, as did pupillometric studies. However, during attacks, which were left-sided at the time, forehead sweating was marked laterally on the left side and on the upper eyelid, but not on the right. The "signal" usually reaching the autonomically stigmatized side during attacks of cluster headache, therefore, did not seem to reach the sweat glands on that (the right) side during the attack in the present case. This headache may, therefore, be distinct from cluster headache, both from a clinical and from an autonomic function point of view.     

Cluster headache: pupillometric patterns as a function of the degree of anisocoria

Fifty-three patients with cluster headache, mean age 42.6 years, were examined by means of pupillometry. Pharmacological stimulation was carried out by the instillation of eye drops; the sympathomimetic agents hydroxyamphetamine (a norepinephrine releaser) and phenylephrine (an agent acting directly on the postsynaptic receptors) were applied. Pupillary dilatation was measured at set time intervals, comparing the responses of the symptomatic and non-symptomatic sides. The material was divided into groups according to the degree of basal anisocoria. The subgroup with the most pronounced basal miosis of the symptomatic side demonstrated a uniform pattern of deficient symptomatic side dilatation after OH-amphetamine and supersensitivity to phenylephrine. The other groups demonstrated the same general pattern, but to a far lesser degree. In cluster headache, the extent of nonresponsiveness to OH-amphetamine and of phenylephrine supersensitivity on the symptomatic side thus, at least partly, seems to be a function of the degree of anisocoria. The response pattern in cluster headache seems to differ from that of 3rd neuron Horner's syndrome with an anisocoria of the same extent.     

Hereditary haemochromatosis in two cousins with cluster headache

A 60-year-old woman with secondary chronic cluster headache had increased serum ferritin and serum transferrin saturation and was homozygous for the C282Y mutation in the HFE gene, which is indicative of hereditary haemochromatosis. Treatment with venesection that normalized her iron stores led to a radical improvement of her headache complaints that had been daily for several years. Later, the headache returned to some degree in spite of normal serum ferritin levels. Her cousin, a 33-year-old man who had had episodic cluster headache for several years, also had increased transferrin saturation and was compound heterozygous for two mutations, a genotype known to be associated with a slightly increased frequency of haemochromatosis. This is the first report of a headache disorder in a patient with hereditary haemochromatosis. The coexistence of the two disorders may be a mere coincidence, but the temporary improvement of headache from depletion of iron stores may indicate a causal relation, possibly mediated by iron deposits in pain-modulating centres in the brainstem.