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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
- Australian Bureau of Statistics. National Health Survey: summary
of results. 1989-1990. Canberra: ABS, 1991. (Catalogue No. 4364.0.)
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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.
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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.
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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.
-
Leâo AAP. Spreading depression of activity in the cerebral cortex.
J Neurophysiol 1944; 7: 359-390.
-
Woods RP, Iacoboni M, Mazziotta JC. Bilateral spreading cerebral
hypoperfusion during spontaneous migraine headache. N Engl J
Med 1994; 331: 1689-1692.
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Friberg L, Olesen J, Iversen HK, Sperling B. Migraine pain
associated with middle cerebral artery dilatation: reversal by
sumatriptan. Lancet 1991; 338: 13-17.
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Lance JW. Swelling at the site of a skull defect during migraine
headache. J Neurol Neurosurg Psychiatry 1995; 59: 641.
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Moskowitz MA, Cutrer EM. Trigeminovascular system and migraine.
Semin Headache Manage 1996; 1: 7-9.
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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.
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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.
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Raskin NH, Hosobuchi Y, Lamb S. Headache may arise from
perturbation of brain. Headache 1987; 27: 416-420.
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Weiller C, May A, Limmroth V, et al. Brain stem activation in
spontaneous human migraine attacks. Nature Med 1995; 1:
658-660.
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Anthony M, Hinterberger H, Lance JW. Serotonin in migraine and
stress. Arch Neurol 1967; 16: 544-552.
©MJA 1999
© 1999 Medical Journal of Australia.
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