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Migraine: then and now

James W Lance
Med J Aust 1996; 164 (9): 519-520.
Published online: 6 May 1996
Editorial

Migraine: then and now

Better understanding of the neurobiology of migraine is leading to better treatment

MJA 1996; 164: 519-520

Migraine is debilitating for its victims and frustrating for their friends and relatives. The Australian National Health Survey of 57 000 people in 1989-1990 found that 12.2% had experienced a headache in the preceding two weeks.1 Extrapolation to the entire Australian population implies that 280 000 people suffered a migraine attack and two million some lesser form of headache in that two-week period. The annual cost of migraine to the community, considering loss of productivity and cost of medical services, has been estimated at $302-$721 million by the Centre for Applied Economic Research, University of New South Wales.2

National Migraine Week (12-18 May) may help to increase public awareness of this problem. In addition, the Migraine Foundation, a subsidiary of the Australian Brain Foundation, has recently been established to promote education and to encourage research and the formation of self-help groups in the community.

When is a headache a migraine? Whether migraine has a place at one end of a headache spectrum or is a separate entity remains controversial. The International Headache Society has established criteria for the diagnosis of migraine, to standardise headache classification for surveys and clinical trials.3The Classification Committee's general description of migraine is "an idiopathic headache disorder manifesting in attacks lasting 4-72 hours", with the characteristics of common unilateral location, pulsating quality, moderate or severe intensity, aggravation by physical activity and association with nausea and photophobia. Nevertheless, a third of migraine headaches are bilateral, and not all throb or are accompanied by nausea and photophobia.

About 25% of those affected describe premonitory symptoms the night before -- a feeling of elation, craving for sweet foods or excessive yawning. Between 25% and 40% experience a visual aura at some time, but only 10% describe typical fortification spectra (zigzag visual hallucinations) or spreading scintillating scotomas. Such neurological symptoms usually precede the headache, but may occur without an ensuing headache or may appear while a headache is in progress. However, most migraine headaches occur without such symptoms.

Varieties of migraine are designated hemiplegic, basilar, ophthalmoplegic or retinal, depending on the area of the brain rendered ischaemic. A migraine headache lasting longer than 72 hours is termed "status migrainosus". Neurological symptoms persisting for more than seven days indicate a migrainous infarction.

Genetic factors contribute about half of the susceptibility to migraine, and the gene for some kinships with familial hemiplegic migraine has been localised to chromosome 19.4

Neurobiology of migraine
Modern techniques have improved our knowledge of both aura and headache mechanisms.

Aura: Regional cerebral blood flow studies show a reduction in cortical perfusion, starting in the parieto-occipital region during a visual aura and spreading forward at 2-3 mm/min. This corresponds to the speed at which fortification spectra appear to move over the field of vision and that of "spreading cortical depression" observed by Leâo as an artefact in experimental animals in the 1940s.5

Recently, magnetic resonance imaging and positron emission tomography (PET) showed a similar spreading pattern of diminished metabolism in a patient with migraine with blurred vision but no classical aura.6 Although needing confirmation, this raises the possibility of cortical oligaemia in migraine attacks that lack an aura; this would account for the impaired vision, loss of concentration and poor memory that often accompany migraine headache.

Headache pain: Since the work of Wolff and his colleagues in the 1940s and 1950s, dilatation of the superficial temporal artery and its branches has been regarded as the main cause of headache pain. However, recent studies have shown that this applies to only about a third of migraine patients. Measurements of velocity of blood flow with transcranial Doppler ultrasound have shown that the middle cerebral artery dilates during migraine headache and returns to normal when the headache resolves after the injection of sumatriptan.7

Cerebral oedema may also be a feature of some migraine attacks, as there have been two reports of skull defects bulging during the headache phase.8 "Neurogenic inflammation" (with extravasation of protein from dural vessels) has been implicated, brought about by release of vasodilator peptides, such as calcitonin gene-related peptide (CGRP) and substance P.9,10 This effect can be blocked by sumatriptan and dihydroergotamine.

It is also possible that the blood-brain barrier breaks down during migraine headache, allowing access of drugs that are normally excluded. When sumatriptan is administered during the aura phase it does not prevent the ensuing migraine headache, despite its prompt action once headache is established, suggesting that it can enter the brain only after the headache starts.

How can we link the initiating cerebral events and the vascular changes? Stimulation of the brainstem nuclei, locus coeruleus and raphe dorsalis has been shown in animals to alter both intracranial and extracranial blood flow.11 In humans, some patients with implanted electrodes which stimulate the periaqueductal grey matter or thalamus for relief of bodily pain have developed migraine-like headaches, some associated with visual symptoms.12 PET scans during and after migraine headache have shown increased metabolic activity in the region of the periaqueductal grey matter and locus coeruleus on the side of the migraine headache, which persisted after the headache.13

What has happened to the "serotonin story"? It is now thought that the discharge of serotonin (5-hydroxytryptamine, 5-HT) by platelets at the onset of migraine headache14 may reflect similar changes in the central nervous system, as serotonin plays a key role in pain control. Serotonin is also a potent vasoconstrictor in the cranial circulation. Increase in knowledge of the many 5-HT receptors has led to the synthesis of agents which act as agonists of these receptors. Prophylactic medications, such as pizotifen and methysergide, act predominantly on 5-HT2 receptors in the central nervous system.

The newest antimigraine drug, sumatriptan, is a highly selective agonist of the D-subtype of 5-HT1 receptors. It constricts cranial arteries, interferes with the release of vasodilator peptides and may also have central actions (as yet unknown), if, as has been proposed, the blood-brain barrier breaks down during migraine headache. Already other 5-HT1D agonists, such as 311C90 (zolmitriptan) and MK462, are undergoing clinical trials for the management of migraine headache.

Continued research on these drugs and on the receptor sites for serotonin and other neurotransmitters involved in the migraine syndrome promises new therapeutic avenues in the treatment of migraine.

James W Lance
Consultant Neurologist, Institute of Neurological Sciences
Prince Henry and Prince of Wales Hospitals, Sydney, NSW

  1. Australian Bureau of Statistics. National Health Survey: summary of results. 1989-1990. Canberra: ABS, 1991. (Catalogue No. 4364.0.)
  2. Parry TG. The prevalence and costs of migraine in Australia. Centre for Applied and Economic Research working paper. Sydney: CAER, University of New South Wales, 1992.
  3. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8 Suppl 7: 13-96.
  4. Merikangas KR. Sources of genetic complexity of migraine. In: Sandler M, Ferrari M, Harnett S, editors. Migraine: pharmacology and genetics. London: Chapman and Hall, 1996: 254-274.
  5. Leâo AAP. Spreading depression of activity in the cerebral cortex. J Neurophysiol 1944; 7: 359-390.
  6. Woods RP, Iacoboni M, Mazziotta JC. Bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med 1994; 331: 1689-1692.
  7. Friberg L, Olesen J, Iversen HK, Sperling B. Migraine pain associated with middle cerebral artery dilatation: reversal by sumatriptan. Lancet 1991; 338: 13-17.
  8. Lance JW. Swelling at the site of a skull defect during migraine headache. J Neurol Neurosurg Psychiatry 1995; 59: 641.
  9. Moskowitz MA, Cutrer EM. Trigeminovascular system and migraine. Semin Headache Manage 1996; 1: 7-9.
  10. Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993; 33: 48-56.
  11. Lance JW, Lambert GA, Goadsby PJ, Zagami AS. Contribution of experimental studies to understanding the pathophysiology of migraine. In: Sandler M, Collins GM, editors. Migraine: a spectrum of ideas. Oxford: Oxford University Press, 1990: 21-39.
  12. Raskin NH, Hosobuchi Y, Lamb S. Headache may arise from perturbation of brain. Headache 1987; 27: 416-420.
  13. Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous human migraine attacks. Nature Med 1995; 1: 658-660.
  14. Anthony M, Hinterberger H, Lance JW. Serotonin in migraine and stress. Arch Neurol 1967; 16: 544-552.

©MJA 1999

© 1999 Medical Journal of Australia.

  • James W Lance


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