Strongest evidence for a key role of SD in migraine aura comes from a functional MRI study that showed retinotopic congruence between the visual aura perception and SD-typical BOLD signal changes traversing the occipital cortex. SD is characterized by prompt, self-propagating neuronal depolarization waves that spread at a speed of 3–5 mm/min. Since the initial description by Leão in 1944, spreading depolarization (SD) has been recognized as the electrophysiological correlate of migraine aura. Brainstem aura symptoms are rare but particularly common in familial hemiplegic migraine. Visual symptoms are the most commonly encountered aura feature. The clinical characteristics of migraine aura included in the formal migraine classification International Classification of Headache Disorders (ICHD-3) are visual, sensory, language, or motor symptoms as well as brainstem symptoms. At least two migraine attacks preceded by an aura are needed to establish the diagnosis of migraine with aura (MA). Aura symptoms characteristically occur up to 1 h prior to the headache, but sometimes can overlap with the headache phase. Thirty percent of migraineurs develop transient neurological symptoms in the setting of an attack, the so-called migraine aura. The high prevalence of migraine and the resulting disability places migraine among the top diseases culminating in a high socioeconomic burden. Migraine is a chronic or episodic neurological disorder that is typically characterized by throbbing or pulsatile unilateral headaches lasting for 4–72 h. Therapeutic targeting of SD and microembolic events, or potential causes thereof, will be promising for treatment of aura and may also prevent ischemic infarction in vulnerable brains. Preclinical models suggest a key role for enhanced SD susceptibility and microembolization to explain both the occurrence of migraine attacks and the increased stroke risk in migraineurs. Indeed, recent imaging studies document an accelerated infarct progression with only little potentially salvageable brain tissue in acute stroke patients with a migraine history, suggesting an increased vulnerability towards cerebral ischemia. At the same time, studies suggest an increased incidence of coagulopathy, atrial fibrillation and patent foramen ovale among migraineurs, providing a possible path for microembolic induction of SD and, in rare instances, stroke in hyperexcitable brains. Migraine patients are at risk for particularly cardioembolic stroke. Recent epidemiologic and imaging studies suggest that these preclinical findings can be extrapolated to migraine patients. Pharmacological suppression of the genetically enhanced SD susceptibility normalizes the stroke phenotype in familial hemiplegic migraine mutant mice. The severe stroke phenotype can be explained by SD-related downstream events that exacerbate the metabolic mismatch, including pericyte contraction and neuroglial inflammation. Migraine mutant mice also exhibit an increased frequency of ischemia-triggered SDs upon experimental stroke, associated with accelerated infarct growth and worse outcomes. Upon experimentally induced SD, these mice develop aura-like neurological symptoms, akin to patients with the respective mutations. Increased SD susceptibility has been demonstrated in migraine animal models, including transgenic mice carrying human mutations for the migraine-associated syndrome CADASIL and familial hemiplegic migraine (type 1 and 2). Spreading depolarization (SD), a slowly propagating wave of neuronal depolarization, is the electrophysiologic event underlying migraine aura and a known headache trigger. Preclinical models have provided us with possible mechanisms to explain the increased vulnerability of migraineurs’ brains towards ischemia and suggest a key role for enhanced cerebral excitability and increased incidence of microembolic events. Interestingly, stroke risk is highest for migraineurs who are young and otherwise healthy. Migraine, especially with aura, is a risk factor for both ischemic and hemorrhagic stroke. Population-based studies have highlighted a close relationship between migraine and stroke.
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