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SYNOPSIS To analyse from which extracranial tissues the pain of common migraine arises, 50 patients with typical common migraine were studied during the attack. Systematic recording of pain in 18 regions of the head and neck was followed by systematic palpation of 26 cranial and neck muscles and tendon insertions. All 50 patients were tender, and tenderness corresponded to pain in all but 2 cases. The most frequent sites of tenderness were: sternocleidomastoid, anterior temporal, neck and shoulder muscles, the coronoid process and occipital insertions. Referred pain was found in 73% of patients. Major pathways were sternocleidomastoid to temporofrontal area or occiput, occiput to vertex or temporofrontal area, neck to vertex or brow. The most tender spots were infiltrated with lidocaine 1.5% or saline double blindly. Results were judged clinically and by visual analog scales. 2648 patients were symptom free after 70 minutes which is significantly better than with medical treatment (p<0.01). There was no difference between lidocaine and saline. The study demonstrates that pericranial muscles and tendon insertions are important for common migraine pain.

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.

Topiramate (TPM) has shown efficacy in migraine prophylaxis in two large placebo-controlled, dose-ranging trials. We conducted a randomised, double-blind, multicentre trial to evaluate the efficacy and safety of two doses of topiramate vs placebo for migraine prophylaxis, with propranolol (PROP) as an active control. Subjects with episodic migraine with and without aura were randomised to TPM 100 mg/d, TPM 200 mg/d, PROP 160 mg/d (active control), or placebo. The primary efficacy measure was the change in mean monthly migraine frequency from the baseline phase relative to the double-blind treatment phase. Five hundred and seventy-five subjects were enrolled from 61 centres in 13 countries. TPM 100 mg/d was superior to placebo as measured by reduction in monthly migraine frequency, overall 50% responder rate, reduction in monthly migraine days, and reduction in the rate of daily rescue medication use. The TPM 100 mg/d and PROP groups were similar with respect to reductions in migraine frequency, responder rate, migraine days, and daily rescue medication usage. TPM 100 mg/d was better tolerated than TPM 200 mg/d, and was generally comparable to PROP. No unusual or unexpected safety risks emerged. These findings demonstrate that TPM 100 mg/d is effective in migraine prophylaxis. TPM 100 mg/d and PROP 160 mg/d exhibited similar efficacy profiles.

Several personal descriptions of migraine with aura from 1870 onwards reported a slow, gradual progression of symptoms. Lashley in 1941 meticulously chartered his own auras and concluded that the symptomatology reflected a cortical process progressing with a speed of 3 mm/min across the primary visual cortex. Leão described cortical spreading depression (CSD) in rabbits in 1944 and noticed its similarity to the migraine aura. Despite these scattered pieces of evidence, the prevailing theory was that the migraine aura was caused by a vasospasm and cortical ischaemia. The advent of a technique for measurements of regional cerebral blood flow (rCBF) in 1974 made it possible to detect spreading oligaemia during migraine aura. Between 1981 and 1990 a series of studies of rCBF during migraine attacks showed reduced brain blood flow posteriorly spreading slowly and contiguously anteriorly and crossing borders of supply of major cerebral arteries. These observations refuted the ischaemic hypothesis. The human studies showed initial hyperaemia followed by prolonged hypoperfusion. The relation between aura and CSD was known to cause short-lasting, and therefore not obvious vasodilation and it was considerably strengthened by the demonstration of a long-lasting oligaemia in rats in the wake of CSD. In the primates CSD is not easily elicited, but it has in recent years been clearly demonstrated in patients with brain trauma and stroke. Finally, mutations for familial hemiplegic migraine have been expressed in mice and lower the threshold for CSD. The seminal papers on rCBF and CSD published in the 1980s caused a dramatic shift in our concepts of migraine aura. They moved attention from ischaemia to CSD and thereby to the brain itself, and paved the way for subsequent discoveries of brainstem mechanisms.

Harold Wolff's theory of vasodilation in migraine is well-known. Less known is his search for a perivascular factor that would damage local tissues and increase pain sensitivity during migraine attacks. Serotonin was found to be among the candidate agents to be included. In the same period, serotonin was isolated (1948) and, because of its actions, an anti-serotonin drug was needed. Methysergide was synthesized from lysergic acid (LSD) by adding a methyl group and a butanolamid group. This resulted in a compound with selectivity and high potency as a serotonin (5-HT) inhibitor. Based on the possible involvement of serotonin in migraine attacks, it was introduced in 1959 by Sicuteri as a preventive drug for migraine. The clinical effect was often excellent, but 5 years later it was found to cause retroperitoneal fibrosis after chronic intake. Consequently, the use of the drug in migraine declined considerably, but it was still used as a 5-HT antagonist in experimental studies. In 1974 Saxena showed that methysergide had a selective vasoconstrictor effect in the carotid bed and in 1984 he found an atypical receptor. This finding provided an incentive for the development of sumatriptan. Bredberg et al. showed that methysergide is probably a prodrug for its active metabolite methylergometrine. Whereas methysergide is 'a clean drug', methylergometrine is 'a relatively dirty drug' with additional dopaminergic activity. The mechanism for the preventive effect of methysergide (methylergometrine) in migraine remains elusive. We describe the rise, fall and subsequent use as a third-choice drug of the first effective migraine prophylactic, methysergide.

The effects of ergotamine and dihydroergotamine on cerebral blood now was investigated 4 hours after i.v. injection as these drugs might be of importance for migraine treatment. Eight normal male volunteers (not suffering from migraine) received 0.5 mg ergotamine and 1 mg dihydroergotamine i.v. Cerebral blood flow was measured by the xenon-133 inhalation method and single-photon-emission computerized tomography before and after intravenous acetazolamide administration (1 g). Cerebral blood flow was measured before and 4 hours after ergotamine and dihydroergotamine administration. Strain-gauge measurements of toe-arm systolic gradients were used to monitor the effect of the drug on leg arteries. Mean hemispheric and regional cerebral blood flow was unchanged after either drug (mean ± SEM, ml/100 g/min): for ergotamine, 57 ± 3 before and 57 ± 3 at 4 hours; for dihydroergotamine, 54 ± 2 before and 55 ± 2 at 4 hours. The acetazolamide response was unchanged as well. Only ergotamine decreased the toe-arm systolic gradient significantly (22 mm Hg at maximum after 240 minutes; p<0.02). Thus, our study did not support the belief that ergot alkaloids should be withheld from patients during attacks of classic migraine, but this has to be investigated further. The discrepancy in the peripheral effects of ergotamine and dihydroergotamine might also be of clinical Importance. (Stroke 1987;18:120-123) T HE USE of ergotamine (E) in the treatment of classic migraine, where transient neurological symptoms form part of the attack, has been controversial for a long time since it was feared that E, a potent constrictor of peripheral arteries, might also increase the risk of ischemia by an effect on the cerebral vasculature and induce permanent neurological symptoms. E is in fact a potent vasoconstrictor of human basilar arteries in vitro, 1 and a lowering of regional cerebellar blood flow in vivo has been reported.2 Serious cases of reversible cerebral arteriopathy with segmental stenosis and even completed strokes have been reported after E was administered in inappropriately high doses.3 On the other hand, many patients have been treated with E during classic migraine attacks without any serious cerebrovascular side effects.The controversy of whether to treat classic migraine attacks by E or not was apparently solved when Hachinski et al* demonstrated that intramuscular injection of 0.2-1.0 mg ergotamine tartrate did not change cerebral blood flow (CBF) in 16 subjects when measured before and 15-20 minutes after drug administration. At this time, soon after injection, E has a pressor effect -an effect on the arterioles -but only a minor vasoconstrictory effect on the arteries per se.* Before concluding that E has no effect on CBF, the problem should be reinvestigated at a time when the effect on arteries should be maximal, i.e., 4-6 hours after administration of E.6 An alternative to E in classicFrom the

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