What Causes Migraine?

The pathogenesis of migraine is not yet fully understood. For many years, vascular dysfunction was thought to be the main underlying cause of migraine. However, recent studies have indicated that the primary event is neurological and involves the trigeminovascular system.

At least three mechanisms are thought to be involved in the pathogenesis of migraine headache. These are:

• neurogenic inflammation
• extracranial vasodilation
• decreased inhibition of central pain transmission.

In addition, serotonin appears to play a role, as do genetic and hormonal factors.

Neurogenic inflammation

Studies show that migraine triggers induce neurochemical stimulation and activation of the brain stem and the trigeminal nuclei. Stimulation of the trigeminal ganglion promotes release of the inflammatory mediator substance P and calcitonin gene-related peptide from the trigeminal nerves, which cause neurogenic inflammation and distension of the blood vessels. This induces dilation of both extracranial and intracranial blood vessels, the latter located in the meninges and large cerebral arteries.
 

Extracranial vasodilation

The extracranial arteries are innervated by sensory nerves from the trigeminal ganglion and are, consequently, pain-sensitive. Clinical and experimental evidence supports the involvement of the temporal artery in migraine. The diameter of this artery is increased in sufferers between attacks compared with non-sufferers.

Decreased inhibition of central pain transmission

Encephalin is an endogenous opioid and inhibits the transmission of pain signals in the central nervous system. Encephalin levels in the cerebrospinal fluid are reduced during migraine headache.

Serotonin

Altered levels of the neurotransmitter serotonin (5-HT) and its metabolite 5-hydroxyindole acetic acid (5-HIAA) have been found in the platelets, plasma, cerebrospinal fluid and urine of migraineurs. Moreover, reduced plasma 5-HT levels are evident in migraine sufferers between attacks, compared with non-sufferers. These observations suggest that 5-HT plays a central role in the pathophysiology of migraine, and have been vital to the development of specific anti-migraine medications that interact with 5-HT receptors.

5-HT_1B/1D receptor agonists (triptans), including zolmitriptan (Zomig), are a highly effective class of drugs that can eliminate all symptoms of migraine, including headache pain, nausea, and photo- and phonophobia. Preclinical studies have shown that 5-HT_1B/1D receptor agonists can inhibit trigeminal nerve excitation, which may account for the clinical resolution of headache pain following the acute treatment of migraine with a triptan.

Genetic factors

Although migraine is a familial disorder, the precise number of migraine susceptibility loci and genes remains unknown, and research in the area is hampered by the lack of an objective diagnostic method. Familial hemiplegic migraine (FHM) is the only known autosomal dominant subtype of migraine. In 50–75% of affected families, FHM is caused by mutations in the calcium-ion channel gene CACNA1A, located on chromosome 19. In other families, a locus has been mapped on chromosome 1. The role of these loci in typical migraine is more complex and remains unknown. However, some data suggest that there may be susceptibility loci for migraine with aura on chromosome 19 (distinct from CACNA1A), on chromosome 4, or on the X chromosome.^[21]

Hormonal factors

Oestrogen has a potent effect on the central serotonergic, noradrenergic and opiatergic neurons and is an important endogenous trigger of migraine in women.

• This trigger may account for the 3-times-higher prevalence of migraine in women than in men and the finding that the frequency and nature of migraine headaches can change during menarche, pregnancy and menopause.
• Around 60% of female migraineurs experience attacks associated with the menstrual cycle, and 7–25% experience migraine attacks almost exclusively during menstruation.^{[1, 2]}

References:
1. Johannes CB, Linet MS, Stewart WF, Celentano DD, Lipton RB, Szklo M. Relationship of headache to phase of the menstrual cycle among young women: a daily diary study. Neurology 1995;45: 1076-82.
2. Kornstein SG, Parker AJ. Menstrual migraines: etiology, treatment, and relationship to premenstrual syndrome. Curr Opin Obstet Gynecol 1997;9: 154-9.