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Pathogenesis of Migraine
Dr. Larry Robbins
Posted July 1999
Excerpt from Dr. Robbins "Management of Headache
and Headache Medications"

Migraine is primarily a genetic illness, creating a "headache milieu" in the brain. In familial hemiplegic migraine, the locus was found on chromosome 19pl3. Gene therapy may eventually be utilized for migraine.

During the aura of migraine, there is a decrease in cerebral blood flow, spreading across the cortex at 2-3mm./min. This oligemia begins occipitally and does not respect vascular territories, rendering vasoconstriction an unlikely explanation. Actual ischemia rarely, if ever,occurs. The oligemia may also occur in migraine without aura. The aura is primarily a neuronal phenomenon. One theory states that low brain magnesium, identified in migraine with aura, may increase NMDA receptor activity, leading to the aura phase. It is remarkable in migraineurs how much depression of cortical activity can occur without being evident clinically.

Neurogenic inflammation is important in the generation of the migraine pain. Calcitonin gene-related peptide (CGRP) is one of the main neuropeptides involved in the inflammation. Other peptides that may be involved include neurokinin A, vasoactive intestinal polypeptide, and substance P. Plasma proteins leak into the dura mater as a result of the neurogenic inflammation. Triptans or DHE prevent the leakage of certain of these proteins. The blood-brain barrier is probably not functioning normally during migraine; this may allow drugs better access to the brain. Venous CGRP is elevated during migraine (and cluster), and may serve as a useful migraine marker.

The brainstem is most likely crucial in activating the migraine pain. Long-duration migraine, or recurrence of migraine, may involve continuous activation of the brainstem. The aminergic nuclei in the brainstem play some role in migraine. When the locus ceruleus (the primary noradrenalin nucleus) is stimulated, blood-brain barrier permeability and blood flow are affected. These brainstem nuclei may be where certain drugs, such as anti-depressants, have their effect on migraine.

The trigeminal nerve, plus the upper dorsal cervical roots carry the pain of headache. The trigeminal nucleus caudalis, plus its extension into the high cervical cord, carries the pain produced by structures surrounding the brain. From the trigeminal nucleus caudalis, the pain information travels to the thalamus via the quintothalamic tract. From the thalamus, various projections proceed to the cortex.