Migraine is in essence a familial episodic disorder whose key marker is headache, with certain associated features [Tables and ]. It is these features that give crucial clues to its pathophysiology and, ultimately, will provide insights leading to new treatments.
Table 1 Features of migraine as included in the International Classification of Headache Disorders – second edition Repeated episodes of headache (4–72 h) with the following features
Neuroanatomical processing of vascular head pain
The essential elements to be considered are:
- Genetics of migraine
- Physiological basis for the aura
- Anatomy of head pain, particularly that of the trigeminovascular system
- Physiology and pharmacology of activation of the peripheral branches of the ophthalmic branch of the trigeminal nerve
- Physiology and pharmacology of the trigeminal nucleus, in particular its caudal most part, the trigeminocervical complex
- Brainstem and diencephalic modulatory systems that influence trigeminal pain transmission and other sensory modality processing
Migraine is a form of sensory processing disturbance with wide ramifications for central nervous system function, and while pain is used as the exemplar symptom, a brain-centered explanation provides a framework to understand all the manifestations of migraine.
Genetics of migraine
One of the most important aspects of the pathophysiology of migraine is the inherited nature of the disorder.[3
] It is clear from clinical practice that many patients have first-degree relatives who also suffer from migraine. Transmission of migraine from parents to children has been reported as early as the seventeenth century, and numerous published studies have reported a positive family history.
Studies of twin pairs are the classical method to investigate the relative importance of genetic and environmental factors. A Danish study included 1,013 monozygotic and 1,667 dizygotic twin pairs of the same gender, obtained from a population-based twin register.[4
] The pairwise concordance rate was significantly higher among monozygotic than among dizygotic twin pairs (P
<0.05). Several studies have attempted to analyze the possible mode of inheritance in migraine families, and conflicting results have been obtained. Both twin studies and population-based epidemiological surveys strongly suggest that migraine without aura is a multifactorial disorder, caused by a combination of genetic and environmental factors. An unexplained but epidemiologically well-established predisposition relates to methyltetrahydrofolate reductase gene mutation C677T that is certainly overrepresented in migraine with aura.[5
] The presence of aura seems to be associated, in rarer inherited cases, such as CADASIL or autosomal-dominant retinal vasculopathy with cerebral leukodystrophy, with structural protein dysfunction[6
] and perhaps with an embryonic syndrome that includes patent foramen ovale.[7
] Such a view makes the small excess stroke risk for young migraineurs unsurprising,[8
] and suggests a common genetics as opposed to a pathophysiological link for migraine pain. Remarkably, and importantly for patients and clinicians, the most recent population-based epidemiological data suggest that migraine carries no excess risk for cognitive function compared with age- and sex-matched controls. In that French cohort, the presence or absent of changes in brain magnetic resonance imaging was also not predictive of cognitive decline.
Familial hemiplegic migraine
In approximately 50% of the reported families, Familial hemiplegic migraine (FHM) has been assigned to chromosome 19p13. Few clinical differences have been found between chromosome 19-linked and -unlinked FHM families.[3
] Indeed, the clinical phenotype does not associate particularly with the known mutations. The most striking exception is cerebellar ataxia, which occurs in approximately 50% of the chromosome 19-linked, but in none of the unlinked families. Another less-striking difference includes the fact that patients from chromosome 19-linked families are more likely to have attacks that can be triggered by minor head trauma or are that associated with coma.[9
The biological basis for the linkage to chromosome 19 is mutations involving the Cav
2.1 (P/Q) type voltage-gated calcium channel CACNA1A
] Now known as FHM-I, this mutation is responsible for about 50% of the identified families. One consequence of this mutation may be enhanced glutamate release. Mutations in the ATP1A2
gene have been identified to be responsible for about 20% of the FHM families.[11
] Interestingly, the phenotype of some FHM-II involves epilepsy. The gene codes for a Na+
ATPase, and the mutation results in a smaller electrochemical gradient for Na+
. One effect of this change is to reduce or inactivate astrocytic glutamate transporters, leading to a build-up of synaptic glutamate. A mis-sense mutation (Q1489K) in SCN1A
has been reported as FHM-III.[12
] This mutation affects a highly conserved amino acid in a part of the channel that contributes to its rapid closure after opening in response to membrane depolarization (fast inactivation). This represents a gain of function: instead of the channel rapidly closing, allowing the membrane to repolarize fully after an action potential, the mutated channel allows a persistent sodium influx.
Taken together, the known mutations suggest that migraine, or at least the neurological manifestations currently called the aura, are ionopathies. Linking the channel disturbance for the first time to the aura process has demonstrated that human mutations expressed in a knock-in mouse produce a reduced threshold for cortical spreading depression.[13
] Furthermore, studies of trigeminal dural-evoked nociceptive activation using Fos protein expression in these knock-in mice demonstrate reduced second-order neuronal activation compared with wild-type animals and enhanced fos protein expression in certain thalamic nuclei.[14
] The data suggest that the brunt of the pathophysiological burden in this mutation may fall on thalamo-cortical mechanisms.
Migraine aura is defined as a focal neurological disturbance manifest as visual, sensory or motor symptoms. It is seen in about 30% of patients, and it is clearly neurally driven. The case for the aura being the human equivalent of the cortical spreading depression (CSD) of Leao has been well made.[15
] In humans, visual aura has been described as affecting the visual field, suggesting the visual cortex, and it starts at the center of the visual field, propagating to the periphery at a speed of 3 mm/min.[16
] This is very similar to spreading depression described in rabbits.[17
] Blood flow studies in patients have also shown that a focal hyperemia tends to precede the spreading oligemia, and again this is similar to what would be expected with spreading depression. After this passage of oligemia, the cerebrovascular response to hypercapnia in patients is blunted while autoregulation remains intact.[18
] Again, this pattern is repeated with experimental spreading depression. An interesting recent study suggested that female mice are more susceptible generally to CSD than male mice,[19
] which would be consistent with the excess risk of migraine in females after menarche that is still with them, on a population basis, into menopause and afterwards. Human observations, including a recent study showing that ketamine that is well known to block CSD in animals can ameliorate prolonged aura in patients,[20
] have rendered the arguments reasonably sound that human aura has as equivalent in animals’ cortical spreading depression. An area of controversy surrounds whether aura in fact triggers the rest of the attack, and is indeed painful. The current data in humans, in particular the very well-recognised phenomenon of migraine aura without headache, suggest that it is indeed not painful.
Therapeutic manipulation of aura
Tonabersat is a CSD inhibitor has completed clinical trials in migraine. Tonabersat (SB-220453) inhibits CSD, CSD-induced nitric oxide (NO) release and cerebral vasodilation.[21
] Tonabersat does not constrict isolated human blood vessels, but does inhibit trigeminally induced craniovascular effects.[22
] Tonabersat has been shown to be ineffective in migraine when reduced attacks of pain are taken as the endpoint,[23
] yet can reduce aura frequency.[24
] Remarkably, topiramate, a proven preventive agent in migraine, also inhibits CSD in cat and rat,[25
] and in the rat with prolonged dosing.[26
] Topiramate inhibits trigeminal neurons activated by nociceptive intracranial afferents,[27
] but not by a mechanism local to the trigeminocervical complex,[28
] and thus CSD inhibition may be a model system to contribute to the development of preventive medicines, particularly agents to prevent aura. The model predicts that agents interacting with Na+
-based mechanisms might be effective, as would glutamate–AMPA receptor mechanisms, but not GABAergic mechanisms, at least directly. Glutamate, NMDA-mediated effects have been reported to important in CSD, and in an active-controlled study of migraine with prolonged aura.[20
] These may suggest some way forward for the management of at least the most disabled group who have persistent or prolonged aura.