ACE-DD is related with von Willebrand factor (vWF), venous thrombophilia, hypercoagulability, increased vascular smooth muscle tone, and lacunar infarction. Angiotensin-converting enzyme gene deletion polymorphism (ACE-DD) is another possible connection. MTHFR gene encodes for a key enzyme for the metabolism of folate and homocysteine and is associated with susceptibility to MA. Polymorphism in the MTHFR (methylenetetrahydrofolate reductase) gene is the candidate gene with mediates increased risk of ischemic stroke in MA. The genetic association between ischemic stroke and MA has been suggested. In men, the association with migraine and stroke is still controversial. Regarding MO, no additional risk for stroke has been found from updated meta-analyses. The risk increases with an increased frequency of migraine attack. MA has been consistently reported as a stroke risk factor, with a pooled relative risk of 2.16 (95% CI 1.53-3.03) and a population-attributable risk of 3.5%. The risk varies with the subtypes of migraine. Cigarette smoking is still an important risk enhancer after age of 45. Potential risk factors for ischemic stroke in migraine include younger (45 years) migraineurs also show an increased risk of stroke, although the association may be either greater or less in the age over 65. Population-based studies and prospective studies consistently reported two-fold increased risk of ischemic stroke in patients with overall migraine. The Collaborative Group for the Study of Stroke in Young Women first suggested the relative risk (RR) of migraine for stroke was 2.0. Migraine is an indirect or associated contributor to stroke. Migraine-related stroke refers to any stroke that occurs in migraineurs, and its incidence rate ranges from 1.44/100,000 to 1.7/100,000 persons per year. Taken together, CSD, which is a unique pathophysiologic mechanism of migraine aura, may precipitate an ischemic stroke. In human migraineurs, increased matrix metalloprotease is also found during migraine attacks and headache-free periods. In addition to oligemia itself, an animal CSD model shows depolarization-induced ipsilateral release of matrix metalloprotease and subsequent altered integrity of the blood brain barrier. However, actual incidence of migrainous infarction is very rare despite of high prevalence of migraine, therefore cerebral blood flow even during the oligemic phase of CSD seen to be above the ischemic threshold. When the hemodynamic response to cortical spreading depression is inverted under pathological conditions, spreading depression can cause severe vasoconstriction instead of vasodilation. As well as MA, patients with migraine without aura (MO) also show posterior hypoperfusion during an attack in MR perfusion and PET studies.
Cerebral oligemia starts in aura phase, spreads gradually anteriorly, and is followed by hyperemia in a MA attack. The concept of “cortical spreading depression (CSD)” has been accepted as the main pathogenetic mechanism of migraine aura.