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.     

Dysfunction of the sympathetic nervous system in cluster headache

Ocular sympathetic function was studied in 13 cluster headache patients during and between attacks and several weeks or months after attacks had subsided. The pupillary response to tyramine eyedrops and facial sweating and flushing in response to body heating and to the taste of chilies were also investigated during remission. Pupillary dilatation lag on the symptomatic side persisted between bouts and correlated significantly with loss of thermoregulatory sweating in the lower part of the forehead. In six patients in remission, pupillary dilatation in response to tyramine eyedrops was impaired on the symptomatic side, whereas five patients showed no sign of ocular sympathetic deficit. These findings indicate that incomplete sympathetic deficit persisted on the symptomatic side in a subgroup of cluster headache patients during remission. In most of this subgroup the pattern of sympathetic deficit was consistent with impaired function of postganglionic cervical sympathetic fibres.     

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.     

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.     

Ergotamine abuse. Do patients benefit from withdrawal?

A follow-up study of 40 patients (migraine 39, cluster headache 1) previously treated for ergotamine abuse was conducted. Their statements regarding ergotamine intake were checked using butalbital (contained in the suppositories abused by 90% of the patients) as a tracer, and later by contact with the family doctor. Eleven patients abused ergotamine again during a median observation time of 21 months. Nineteen patients had more than a 50% reduction in headache days after withdrawal and half of the patients were relieved of other symptoms of ergotamine toxicity. Even with a failure rate of approximately 25% it is concluded that efforts to withdraw after abuse of ergotamine are worthwhile.     

Uraemic sympathetic neuropathy after haemodialysis and transplantation

Autonomic function in patients with uraemia treated conservatively, by haemodialysis, and by transplantation was evaluated by the pupillary reaction to tyramine, the Valsalva manoeuvre and a postural tolerance test. The pupillary reaction to tyramine is diminished in haemodialysis patients compared with control subjects. Renal transplantation improves, but does not correct the pupillary reaction to tyramine. The frequency of the diminished response roughly correlates with the degree of renal insufficiency, with results of a Valsalva manoeuvre, and with postural tolerance tests. Our data show that uraemic autonomic dysfunction is improved by successful renal transplantation, but not by adequate haemodialysis.     

Reduced serotonin vascular sensitivity in ergotamine abusers

The action of ergotamine on the 5-hydroxytryptamine (5-HT) venous sensitivity was studied in ergotamine abuser and non-abuser migraine patients. Ergotamine abusers showed reduced 5-HT hand vein contraction during abuse, compared to seven days after ergotamine withdrawal. In non-ergotamine users, the 5-HT venoconstriction was not significantly modified 12 h after a single intramuscular ergotamine (0.25 mg) administration. Even the administration of ergotamine locally into the vein did not change the venospasm of 5-HT given acutely in the same vein. Therefore, it seems that the 5-HT antagonism does not contribute to the therapeutic effect of ergotamine during the migraine attack. Moreover, the reduced 5-HT responsiveness during ergotamine abuse may possibly be compatible with the chronic headache present in some abusers, the withdrawal headache attacks and the abuse itself.     

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.     

Ciliospinal Reflex Response in Cluster Headache

The ciliospinal reflex response is mainly mediated by second- and third-order sympathetic nerves to the dilatator muscle of the iris. As the pupillary response to various pharmacological agents indicates a sympathetic dysfunction in patients with cluster headache, the ciliospinal reflex was studied in 25 patients. Five of these patients with cluster headache exhibited a Horner-like syndrome (miosis, ptosis) on the symptomatic side. The pupillary responses to phenylephrine and tyramine showed that the Horner-like syndrome was due to postganglionic sympathetic nerve dysfunction. Their ciliospinal reflex response on the symptomatic side was significantly less than in controls and in other patients with cluster headache, lacking a Horner-like syndrome. This also applied to the nonsymptomatic side compared to the majority of cluster headache patients without any clinical evidence of sympathetic nerve dysfunction.
These findings seem to delineate those patients with a Horner-like syndrome as a subgroup, distinctly separated from the majority of cluster headache patients. Furthermore, the findings indicate that the Horner-like syndrome is not a consequence of repeated attacks of headache over many years, but is a manifestation of bilateral cephalic sympathetic dysfunction being more marked on the symptomatic side.
In 18 (72%) of our 25 patients, an asymmetric and lower ciliospinal reflex response on the symptomatic side was seen. In 3 (12%) patients, there was no difference in the response. In 4 patients (16%), the incorrect side was indicated by an asymmetric reflex response. Two of these patients (8%) had suffered from cluster headache on alternating sides.
In summary, the findings support the concept that dysfunction of the sympathetic nervous system, whether peripheral or central, is involved in the pathophysiology of cluster headache.     

Ergotamine abuse: Results of ergotamine discontinuation, with special reference to the plasma concentrations

Twenty-three patients suffering from continuous headache linked with habitual daily use of ergotamine tartrate were studied. Their headaches were classified clinically, and possible side effects of ergotamine medication, plasma levels of ergotamine, and occurrence of withdrawal symptoms after discontinuation of drug abuse were recorded. Seventeen of the patients were clinically diagnosed as suffering from "ergotamine headache", and seven of them complained of coldness in the extremities. Plasma ergotamine levels were measured by using a radioimmunoassay. In almost half of the patients the 1 h plasma levels after the daily dose were below the detection limit of the procedure (0.12 ng/ml). The duration and severity of the withdrawal symptoms did not correlate with the doses and plasma levels of ergotamine. In only 4 of the 21 patients who were followed up for 3 to 6 months did headache symptoms not improve after ergotamine withdrawal. The results indicate that even small (0.5–1.0 mg/day) doses of ergotamine tartrate taken regularly may cause continuous headache symptoms and withdrawal symptoms after discontinuation.     

Cervical Sympathetic Deficit in Unilateral Migraine Headache

Pupil diameter was measured during the headache-free interval in 38 migraine sufferers selected from the general community. In each case, at least 70 percent of attacks recurred on the same side. Anisocoria was greater than in 40 control subjects, but miosis was not consistently greater on the usual side of headache. Average pupil diameter was similar in migraine sufferers and controls. In patients with pupillary dilation lag on the usual side of headache, miosis persisted after 4% cocaine eyedrops. These findings suggest that cervical sympathetic outflow was lower on the usual side of headache in a subgroup of migraine sufferers. Pupillary dilatation to tyramine eyedrops was greater in control subjects than in migraine sufferers, consistent with decreased function of post-ganglionic cervical sympathetic fibres. Pupillary dilatation to 1% phenylephrine eyedrops did not differ consistently between the headache and headache-free sides, and was similar in migraine sufferers and controls. Thus, adrenergic supersensitivity of the pupils was not evident in this community sample of migraine sufferers. Vasodilatation or swelling of the arterial wall in the carotid canal could cause minor cervical sympathetic deficit in patients with frequent or severe attacks of migraine. Loss of sympathetic vascular tone could increase vasodilatation and pain during attacks.     

The influence of ergotamine abuse on psychological and cognitive functioning

Migraine patients abusing ergotamine often have chronic daily headaches associated with tiredness, sleep and memory disturbances, and reduced general well-being. We quantified psychological and cognitive functioning in 12 migraine patients with and 12 without ergotamine abuse (> or = 5 days/week for > or = 6 months) and 12 healthy controls. Psychological functioning assessed by Symptom Checklist-90 (SCL-90) and Profile Of Mood State (POMS), was impaired in ergotamine abusers compared to healthy controls. Cognitive functioning divided into four domains: attention (critical flicker frequency analysis and mental control subscale of the Wechsler Memory Scale (WMS), speed of information processing (reaction time tasks and lexical decision tasks), memory (four subscales of the WMS) and cognitive flexibility (trailmaking test and WMS digits backwards), was impaired in ergotamine abusers in speed of information processing and cognitive flexibility. These differences disappeared after correction for total SCL-90 scores. In conclusion, ergotamine abuse is associated with high psychological distress but not with structural impaired cognitive functioning.     

Long-term outcome of patients with headache and drug abuse after inpatient withdrawal: five-year follow-up

Thirty-eight patients with "chronic daily" headache and ergotamine and/or analgesics abuse according to the criteria proposed by the international Headache Society were re-investigated 5 years after inpatient drug withdrawal. At the end of the observation period, 19 patients (50.0%) had their headaches on only 8 days per month or less, 18 patients (47.4%) were free of symptoms or had only mild headaches. A close correlation was found between the frequency of headache and the duration of drug abuse, as well as between the intensity of headache and the number of tablets taken per month. Frequency and intensity of headache had changed within the first 2 years after withdrawal, but remained stable afterwards. Fifteen patients (39.5%) reported on recurrent drug abuse. Patients with migraine showed a tendency towards a better prognosis compared to patients with tension-type headache or with combined migraine and tension-type headache. The results of this study highlight the long-term efficacy of inpatient drug withdrawal in patients with headache and ergotamine and/or analgesics abuse.     

Tolfenamic Acid and Ergotamine Abuse

SYNOPSIS
Thirteen migraine patients using ergotamine tartrate on a daily basis for their headaches were found to have developed the so called "ergotamine headache," a dull constant headache always reappearing if the patient did not take their daily doses. They were treated with tolfenamic acid, an inhibitor of prostaglandin synthesis and action, combined with chlordiazepoxide during the acute withdrawal phase after discontinuing their daily habit of taking ergotamine. As a whole, the results of the discontinuation of the use of ergotamine were encouraging in the group of these patients showing a serious medical problem. None of the patients relapsed into ergotamine abuse, and during the subsequent 3–6 months nine of the patients also treated their migraine attacks solely with tolfenamic acid.     

Oculosympathetic alterations in migraine patients

Oculosympathetic function was studied in 20 headache-free migraine patients and in 20 controls. Pupillary investigation was performed under basal conditions, and after instillation of tyramine (2%) and phenylephrine (1%) eyedrops. Each test was performed twice shortly after a spontaneous attack and then repeated after 7 and 15 days. In the patients, the normal mydriatic response induced by tyramine was significantly ( p <0.001) reduced and phenylephrine instillation caused a significant ( p <0.01) pupillary dilatation in both the assessments performed shortly after the attack. These abnormal responses were bilateral in all patients and slightly anisocoric in some. They were significantly ( p <0.001 ) more pronounced in the patients who had pain and pronounced vascular features. The reduced oculosympathetic response to tyramine, as well as the hypersensitivity to phenylephrine, was less evident 7 days after the attack and absent after 15 days. A transient and bilateral post-ganglionic oculosympathetic hvpofunction, with adrenoceptor hypersensitivity, was found to be temporally related to the migraine attack, regardless of the side or predominant side of pain.     

History of the use of ergotamine and dihydroergotamine in migraine from 1906 and onward

Dale showed in 1906 in a seminal work that ergot inhibits the pressor effect of adrenaline. Stoll at Sandoz isolated ergotamine from ergot in 1918. Based on the belief that migraine was due to increased sympathetic activity, ergotamine was first used in the acute treatment of migraine by Maier in Switzerland in 1925. In 1938 Graham and Wolff demonstrated the parallel decrease of temporal pulsations and headache after ergotamine i.v. This inspired the vascular theory of Wolff: an initial cerebral vasoconstriction followed by an extracranial vasodilation. Dihydroergotamine (DHE) was introduced as an adrenolytic agent in 1943. It is still in use parenterally and by the nasal route. Before the triptan era ergotamine and DHE had widespread use as the only specific antimigraine drugs. From 1950 the world literature on ergotamine was dominated by two adverse events: ergotamine overuse headache and the relatively rare overt ergotism. Recently, oral ergotamine, which has an oral bioavailability of < 1%, has been inferior to oral triptans in randomized clinical trials. A European Consensus in 2000 concluded that ergotamine is not a drug of first choice. In an American review of 2003 it was suggested that ergotamine may be considered in the treatment of selected patients with moderate to severe migraine.     

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.     

Dopamine D2-receptor imaging with 123I-iodobenzamide SPECT in migraine patients abusing ergotamine: does ergotamine cross the blood brain barrier?

Two migraine patients were studied by in vivo SPECT using the dopamine D2-receptor specific radioligand ¹²³I-3-iodo-6-methoxybenzamide (¹²³I-IBZM) during ergotamine abuse and after withdrawal. Results were compared with 15 healthy controls. Striatum/cerebellum and striatum/occipital cortex ratios of count rate density were calculated as a semiquantitative measurement for striatal dopamine D2-receptor binding potential. No differences were found in striatal uptake of ¹²³I-IBZM between healthy controls and the patients when on or off ergotamine. Preliminary evidence suggests that ergotamine may not occupy striatal dopamine D2-receptors to a large extent and thus may not cross the blood brain barrier in large quantities.     

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.     

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.