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PATHOPHYSIOLOGY — Migraine is thought to have a polygenetic and multifactorial etiology [1]

Migraine



PATHOPHYSIOLOGY — Migraine is thought to have a polygenetic and multifactorial etiology [1] . No consistent genetic basis has been established for migraine, with the exception of familial hemiplegic migraine (see "Familial hemiplegic migraine" below).


No single theory or hypothesis can explain all of the phenomena that occur with migraine. The once popular vascular theory of migraine, which suggested that vascular headaches such as migraine and cluster headaches were caused by the dilatation of blood vessels, while the aura of migraine resulted from vasoconstriction, is no longer considered viable in its original form. Nevertheless, it may well be that vasodilatation plays an important role in the severe throbbing head pain that is characteristic of migraine; vasodilatation itself is probably an epiphenomenon, resulting from instability in the central neurovascular control mechanism [2] .


The current state of knowledge in this field suggests that a primary neuronal dysfunction leads to a sequence of changes intracranially and extracranially that account for migraine, including the three phases of premonitory symptoms, aura, and headache [3] . Individuals prone to migraine have a genetic migrainous threshold that renders them susceptible to an acute migraine attack depending upon the balance between excitation and inhibition at various levels of the nervous system. Both genetic and environmental factors are important [4] .


Trigeminovascular system — A primary event may occur in the brainstem involving diffuse projections from the locus ceruleus to other parts of brain, which causes an unstable trigeminovascular reflex, thereby allowing excessive discharge of part of the spinal nucleus of the trigeminal nerve and basal thalamic nuclei.


Support for the role of the brainstem in the pathogenesis of migraine is derived from a study that used positron emission tomography to examine changes in regional cerebral blood flow as an index of neuronal activity in the human brain during spontaneous migraine attacks [5] . During the attacks, increased blood flow was found in the cerebral hemispheres in the cingulate, auditory, and visual association cortices, and in the brainstem. However, only the brainstem activation persisted after the injection of sumatriptan had induced complete relief from headache, phono- and photophobia. These findings support the idea that the pathogenesis of migraine is related to an imbalance in activity between brainstem nuclei regulating antinociception and vascular control.


Antidromic stimulation of the trigeminal nerve results in the release of substance P, calcitonin gene-related peptide, and other vasoactive polypeptides causing pain and vasodilatation in experimental models, leading to the sequence of events labeled as "neurogenic inflammation." Temporary sensitization of central trigeminal neurons during acute migraine attacks has also been observed [6] . Locus ceruleus projections to the cerebral cortex may initiate cortical hypoperfusion and cortical spreading depression (CSD), which can explain the aura of migraine. (See "Migraine aura" below).


Cortical spreading depression — A causal association between migraine aura and headache is supported by evidence that both are linked to the phenomenon known as cortical spreading depression (CSD) of Leao [7] . CSD is a self propagating wave of neuronal and glial depolarization that spreads across the cerebral cortex. CSD appears to: Cause the aura of migraine Activate trigeminal nerve afferents Alter blood-brain barrier permeability by matrix metalloproteinase (MMP) activation and upregulation [8]


The activation of trigeminal afferents by CSD in turn causes inflammatory changes in the pain-sensitive meninges that generates the headache of migraine through central and peripheral reflex mechanisms [9] .


Role of serotonin — Serotonin (released from brainstem serotonergic nuclei) also plays an important role in the pathogenesis of migraine; this is probably mediated via its direct action upon the cranial vasculature, through its role in central pain control pathways and through cerebral cortical projections of brainstem serotonergic nuclei [10] .


The exact mechanism of serotonin action remains obscure. A decline in serotonergic function has been noted during acute migraine attacks, resulting in vasodilation of cranial vessels and sensitization of meningeal afferents of the trigeminal nerve [11] . Between attacks, patients who have migraine without aura appear to have increased brain serotonin synthesis [12] .


Role of CGRP — The calcitonin gene-related peptide (CGRP) may also play a central role in migraine pathophysiology. CGRP is a 37 amino acid neuropeptide that is expressed in trigeminal ganglia nerves and is a potent vasodilator of cerebral and dural vessels [13-15] .


CGRP may mediate trigeminovascular pain transmission from intracranial vessels to the central nervous system as well as neurogenic inflammation. However, the evidence is conflicting. Stimulation of the trigeminal ganglion induces the release of CGRP [16] , and CGRP infusion can trigger a migraine attack in migraineurs [17] . Although an earlier study found elevation of CGRP levels in external jugular venous blood during migraine attack [18] , this result was not reproduced in a subsequent study [19] . In addition, CGRP did not activate or sensitize meningeal nociceptors in an animal model [20] .


Elevated CGRP levels are normalized in patients with migraine following administration of the serotonin 1b/1d receptor agonist sumatriptan [21] , suggesting that triptans may act to control migraine at least in part by reducing CGRP levels.


Pharmacologic modulation of CGRP levels offers the promise of future treatment options for acute migraine attacks; there is evidence from preliminary randomized clinical trials that two different investigational CGRP receptor antagonists are effective for treating acute migraine attacks [22,23] .


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MIGRAINE AND STROKE MIGRAINE IS A COMPLEX CONDITION WHICH
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