Five years after its introduction in the clinic, however, the first serious side effects, notably retroperitoneal fibrosis,62 were published. The frequency was estimated at 1/1000. The frequency was later reestimated at 1/5000.63 Cardiac and pulmonary AZD9668 fibrosis was described shortly thereafter,64 but in lower frequencies. It is still used as a

fourth choice prophylactic drug in migraine and cluster headache, the administration of which is discontinued for 2 months every half a year. Interestingly, the discovery of methysergide provided an incentive for the development of sumatriptan, when evidence was found for an “atypical” 5-HT receptor in the carotid bed of pigs that was later identified as a 5-HT1B receptor.65 Methysergide appeared to have a partial agonist action upon this receptor, whereas it blocks 5-HT2

receptor.66 Therefore, methysergide not only is an effective prophylactic drug, but also played an important role as a 5-HT antagonist and partial agonist in pharmacological studies. Spreading Oligemia of Cerebral Blood Flow (1981).— The vascular theory with respect to the pathophysiology of migraine led researchers to study regional cerebral blood flow (rCBF).67 The prerequisite for a precise characterization of rCBF during migraine was the development of a multichannel imaging system with intracarotid injection of Xenon-133 and 254 detectors, which resulted in a spatial resolution of 1 cm by Lassen et al.68 Six patients with migraine with aura were followed with serial measurements of rCBF with the intracarotid Xenon-133 method from the normal state see more into the aura phase, and in 3 cases into the headache phase12 (see Fig. 5). During the aura phase all patients developed rCBF reduction (oligemia), which only in one case approached critical values. Oligemia MCE gradually spread anteriorly in the course of 15 to 45 minutes (Fig. 5). In 4 cases severe headache occurred concomitantly with oligemia. The paper was concluded by stating that “the results indicate that the vasospastic model of

the migraine attack is too simplistic. Alteration in neuronal function, in the blood–brain barrier (BBB), or in some other brain process is more likely to be the primary event of the attack.”12 CSD of Leão was considered (Lauritzen, personal communication, 2008), but as noted above, at the time, CSD was known to be associated with hyperemia (vide supra)51,69 and therefore contradicted the assumption of CSD being the primary neuronal process underlying the spreading oligemia. The migraine patients in Olesen’s study12 belonged to a series of approximately 250 patients undergoing carotid arteriography for various diagnostic reasons. The carotid catheterization with a catheter placed using the Seldinger technique and angiography most likely induced the migraine aura.