References for this Personal View were identified through searches of PubMed with the search terms “migraine”, “cortical spreading depression”, “cerebrovascular”, “cardiovascular”, “patent foramen ovale”, and “pathophysiology” in combination with “stroke”, “ischemia”, “coagulation”, “hypoxia”, “CADASIL”, “white matter lesions”, “carotid puncture”, “cholesterol”, “atherosclerosis”, “dissection”, “Raynaud”, “Sjögren's syndrome”, “SLE”, and “antiphospholipid antibody”. Preference was given
Personal ViewMigraine aura pathophysiology: the role of blood vessels and microembolisation
Introduction
Migraine headache can occur as a comorbidity of ischaemic stroke, carotid or vertebral artery dissection, arteriovenous malformations, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL syndrome), or platelet disorders (eg, thrombocytosis) among other disorders (panel).1, 2, 3, 4, 5 Although difficult to identify a unifying hypothesis linking these disorders to migraine pathogenesis, a disturbance within brain vessels might be common to a subset of patients who have migraine with aura. Migraine with aura has been identified as an independent risk factor for ischaemic stroke6 and possibly for white matter hyperintensities, suggesting common pathophysiological mechanisms that implicate the neurovascular unit.7, 8 Although several possibilities can explain the comorbidity of migraine and vascular diseases (eg, shared mutations or a consequence of repeated migraine attacks), an emerging hypothesis, which we find persuasive, places stroke and migraine on a continuum of vascular complications caused by, for example, focal and transient hypoperfusion. Recent experimental data in mice indicate that cerebral microembolism triggers cortical spreading depression (CSD), a biological substrate for migraine aura, without causing requisite tissue injury.9 Although the brain's vulnerability to injury is well recognised, it is only with the help of emerging data from experiments in animals that we are now able to examine the possibility that even focal, brief hypoxic-ischaemic episodes could trigger CSD without an obvious or enduring tissue signature. If this possibility is true in human beings, blood vessel and blood flow disorders would then be acknowledged as a migraine trigger, and vascular causes and risk factors for migraine with aura would be more aggressively sought.
In this Personal View, we first consider the evidence and possible mechanisms that link CSD to migraine aura and local hypoperfusion. We then examine what is known about blood vessel and microcirculatory disorders implicated in migraine with aura to identify the important subset of patients in whom these conditions might be linked. Because migraine is a disorder of brain function and CSD is a putative biological substrate for migraine aura, we begin with a brief description of the relevance and pathophysiological importance of CSD.
Section snippets
Migraine aura and CSD
CSD is a slowly propagating wave of neuronal and glial depolarisation that can be evoked in the cortex, cerebellum, basal ganglia, thalamus, and hippocampus. Although well documented and easily evoked in the lissencephalic brain, only recently has its existence been unequivocally shown in the human brain in the context of subarachnoid haemorrhage, malignant stroke, and head injury.10, 11, 12 CSD provides the most likely explanation for migraine visual aura, although the evidence from patients
Migraine and cerebral microembolism
The association between migraine, stroke, and patent foramen ovale (PFO) remains controversial and incomplete. Although the aggregate of the clinical evidence is more convincing than individual reports, initial reports linking PFO with migraine aura had severe selection bias and the quality of the evidence has therefore been judged as only moderate to low. Furthermore, a recent population-based study in the elderly did not confirm this association.26 However, data from most studies indicate
Susceptibility to migraine aura of vascular origin
CADASIL syndrome, an autosomal dominant disorder, is a prototypical disorder that emphasises a strong link between blood vessels and migraine aura.4 20–40% of patients with CADASIL have migraine with aura, often as the first symptom of the disease. Caused by mutations in NOTCH3, which encodes a transmembrane receptor expressed by vascular smooth muscle cells, this disorder affects both systemic and cerebral blood vessels. More than 95% of point mutations have been identified in the
Platelets, coagulation disorders, endothelial dysfunction, inflammation, and migraine
Although insufficient, some evidence from small, unvalidated clinical studies lends some support to a possible association between platelet and coagulation disorders and migraine, as well as between migraine and endothelial dysfunction.64 However, most of these early studies were done on small samples with mostly unreliable and questionable methods that are now not considered appropriate. In a recent study, patients with migraine had significantly more platelet-leukocyte aggregates in their
Migraine as a risk factor for ischaemic cerebrovascular disorders
Migraine with aura has been consistently identified as an independent risk factor for ischaemic stroke.6, 74, 75, 76, 77, 78 Several potential mechanisms have been hypothesised, including alterations in vasoreactivity and cerebral blood flow due to vessel wall dysfunction, release of vasoactive substances such as prostaglandins and endothelins, and, as discussed above, platelet hyperactivity and paradoxical embolism through a cardiac or extracardiac shunt. We presume that focal areas of
Conclusions
Although an increasing amount of evidence lends support to an association between migraine with aura and ischaemic cerebrovascular disorders, a causative relationship is difficult to prove and a coherent vascular aetiology is unlikely to account for the triggering of all types of migraine with aura. Nevertheless, the multitude of clinical observations, as well as recent experimental data, suggest a common pathophysiology for these disorders, and indicate that, at least in a subset of patients
Search strategy and selection criteria
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