It is becoming increasingly clear that primary headache disorders such as migraine are strongly influenced by heterogeneous genetic factors. Familial hemiplegic migraine (FHM), an uncommon autosomally dominant subtype, has been shown to occur because of defects within a single gene. In roughly 60% of families studied, the mutation is located on chromosome 19 and codes the α₁ A subunit of a brain-specific P/Q type calcium channel. In another 20% of families, the mutation lies in a gene on chromosome 1 that encodes the α₂ subunit of a Na⁺ K⁺ pump. Even within a rare subtype such as FHM, the genetic basis is complex, which predicts even greater heterogeneity for the more common forms such as migraine with and without aura. Several genetic linkage sites have been identified for these more common forms.

In the late 1930s, investigators proposed the vasogenic theory of migraine, which hypothesized that intracranial vasoconstriction was responsible for the aura of migraine and that
the headache resulted from rebound dilation and distention of cranial vessels. This theory was based on the observations that: (a) cranial vessels were important in the generation of headache; (b) extracranial vessels became distended and pulsated during a migraine attack in many patients; and, (c) vasoconstrictive substances such as ergots could abort the headache, whereas vasodilatory substances such as nitrates tended to provoke the headache. The competing neurogenic theory held that migraine was caused by a brain dysfunction. According to this hypothesis, when precipitating factors exceed cerebral threshold, a migraine attack occurred, and although vascular changes might occur during a migraine attack, they were the result rather than the cause of the attack. Proponents of the neurogenic theory pointed out that migraine aura symptoms could often not be explained on the basis of vasoconstriction within a single cerebrovascular distribution, and that prodromal symptoms such as euphoria, hunger, thirst or fluid retention that preceded headache in some by as much as 24 hours.

Because the duration of headache frequently exceeds the duration of the initiating stimulus, it is likely that sensitization within the trigeminal and upper cervical pain pathways contributes to the prolongation of headaches. Sensitizing events may occur in both the peripheral and central portions of these pathways.

Peripheral sensitization: There is increasing experimental evidence that, once activated, C-fibers release neuropeptides (i.e., substance P, neurokinin A, and calcitonin gene–related peptide) that generate a neurogenic inflammatory response within the meninges. This response consists of increased plasma leakage from meningeal vessels, vasodilation, and activation of mast cells and endothelial cells. Once set into motion, this process may act to lower the threshold of the C-fibers to further activation and, as a result, prolong and intensify the headache attack. Drugs known to be effective in ending a migraine attack such as dihydroergotamine (DHE) or sumatriptan have been shown to act at serotonin (5-HT) receptor subtypes to block the release of neuropeptides and the development of neurogenic inflammation.

Central Sensitization: Animal studies indicate that inflammatory or chemical C-activation results in expansion of receptive fields and recruitment of previously nonnociceptive neurons into the transmission of painful information. The changes are clinically reflected as hyperalgesia (lowered pain thresholds) and allodynia (the generation of a painful response by normally nonpainful stimuli). Analogous clinical phenomena are seen in headache disorders. For example, minor head movements, bending, or coughing, which normally do not cause pain, are perceived as painful during or in the hours following a migraine attack. Recent studies by Burstein et al. have demonstrated the stimulation of meningeal nociceptors, causes a lowering of the activation thresholds for convergent previously nonpainful skin stimulation. Subsequent studies of human subjects during migraine attacks have also demonstrated the development of cutaneous allodynia both within the areas innervated by the trigeminal nerve and in extratrigeminal areas.

It is crucial to examine each patient carefully, especially when there are atypical elements in the history. A basic neurologic examination should be performed that addresses the following six components.

Three findings on examination should be considered as signs of possible serious pathology:

Laboratory tests should be obtained to confirm the presence of abnormalities suspected from the history and physical examination and should be appropriate for the pathology suspected. Laboratory, electroencephalographic, or neuroimaging “fishing trips” are discouraged because they rarely provide useful information, can delay treatment, and can divert attention
away from more relevant findings. At present, the computerized tomography (CT) scan is the imaging study most likely to be available in the acute setting. There are three major indications for an urgent CT scan:

CT scanning is most useful for identifying recent intracerebral and extracerebral hemorrhages, hydrocephalus and brain abscesses, or other space-occupying lesions.