Pathophysiology of Migraine

Pathophysiology of Migraine

Sheena K Aurora
Published: NeuroScience 2007 - Supplement to EU/US Neurological Disease 2007 Issue 1 (BTG)
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There have been remarkable strides in the last decade in unravelling the mystery of primary headache disorders. The vascular theory has been superseded by the neurovascular phenomenon, which seems to be the permissive triggering factor in migraine and cluster headache. This has been achieved through new imaging modalities such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Prior to the use of these imaging techniques it was impossible to study primary headache disorders since these headaches had no structural basis. There is now an increasing body of evidence to suggest that the brain is primarily involved in cluster and migraine headaches and that the vessel dilatation is an epiphenomenon.

The exact pathogenesis of migraine remains to be determined. Theories describing migraine pathophysiology have moved between primary vascular and primary neural mechanisms. Harold G Wolff, a pioneer of the vascular theory of migraine, proposed that the neurological symptoms of the migraine aura were caused by cerebral vasoconstriction, and the headache by vasodilatation.1 Lashley’s experience2 of his own visual aura led him to believe the cortical spreading depression (CSD) of Leão to be the primary cause, thus promulgating the neural theory of migraine.3,4 Newer imaging techniques have made it possible to study the very early events of migraine, thus both theories have been reconciled by contemporary proponents of a neurovascular mechanism. There is evidence of an inherited disorder that occurs in susceptible individuals. There is also an increasing body of evidence to suggest that central neuronal hyperexcitability is a pivotal physiological disturbance predisposing individuals to migraine.5 The reasons for increased neuronal excitability may be multifactorial. Through genetic studies, abnormality of calcium channels has been introduced as a potential mechanism of interictal neuronal excitability.6 Mutant voltage-gated P/Q type calcium channel genes probably influence presynaptic neurotransmitter release, possibly of excitatory or inhibitory amino-acid systems. Other genetic studies have demonstrated dysfunction in the ATP1A2 gene, which encodes an ion pump.7 Recently, data in episodic ataxia and hemiplegic migraine patients with no mutation in either CACNA1A or ATP1A2 demonstrated that a heterozygous mutation in EAAT1 can lead to decreased glutamate uptake, which can contribute to neuronal hyperexcitability to cause seizures, hemiplegia and episodic ataxia.8

Mechanisms of Aura
The unpredictable and elusive nature of migraine has prevented many investigators from systematically studying migraine aura. Studies by Cao et al. – in which migraine was reliably visually triggered in 50% of subjects – allowed the immediate early events of the migraine attack to be measured for the first time.9 A red and green chequerboard was used for visual stimulation since migraineurs are known to be sensitive to linear stimuli. Using the recently developed fMRI methods – based on the blood-oxygenlevel dependent (fMRI-BOLD) technique – the authors were able to measure the second-to-second activation of the occipital cortex to visual stimulation with millimetre resolution. None of six normal controls developed a headache and displayed normal patterns of BOLD signals on visual activation. Six patients with migraine with aura (MwA) and two patients with migraine without aura (MwoA) had experienced visually triggered headache and two also had accompanying visual change. Headache was preceded by suppression of brain activation, which slowly propagated into the contiguous occipital cortex at a rate ranging from 3 to 6mm/min. This neuronal suppression was accompanied by an increase in baseline contrast intensity, indicative of vasodilatation and tissue hyperoxygenation. The baseline contrast increases indicated that tissue hyperoxygenation was similar to that witnessed in experimental CSD.10 These spreading events accompanied visually triggered headache whether or not it was associated with visual change. In this study patients were selected based on a history of visually triggered headache, so generalising these findings to all migraine patients must be done with caution. Nevertheless, previously hypothesised mechanisms of CSD in migraine were clarified by this study, and the previously controversial findings of ischaemia accompanying migraine aura were not supported. Spontaneous MwA has been described by Hadjiakani et al.11 with similar changes on BOLD functional MRI to those described by Cao et al.9 Although it was only a case report, a critical study demonstrated spreading events on PET during MwoA.12 These studies and one critical case report demonstrate spreading-like events of blood flow during migraine. These phenomena are reminiscent of CSD, and convincing proof of this came from magnetoencephalogram (MEG) studies discussed later in this review.

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