Pathophysiology of Migraine - Kompetenznetz Parkinson

the dura mater, the intracranial segments of the trigeminal,
the vagus, and glossopharyngeal nerves, and the
proximal portions of the large intracranial vessels including
the basilar, vertebral, and carotid branches, 2,3 are
highly pain-sensitive structures. Depolarization of small
caliber pseudounipolar neurons projecting from the
trigeminal ganglion, which invest these meningeal structures
and cerebral vessels, 4 results in activation of
second-order neurons within the brainstem areas of the
medullary trigeminal nucleus caudalis (TNC) and the
dorsal horn of upper cervical spinal cord segments. 5
Stimulation of trigeminal nociceptive neurons results
in activation patterns, organized somatotopically along
the rostrocaudal axis of the brainstem 6 in a pattern
consistent with the classical ‘‘onionskin’’ distribution
seen in the sensory deficits experienced in patients after
trigeminal tractotomy. Once activated, second-order
neurons in the TNC and cervical dorsal horn are
modulated by projections from the nucleus raphe magnus,
periaqueductal gray, 7 rostral trigeminal nuclei, 8 and
descending cortical inhibitory systems. 9 These activated
second-order neurons project to other brainstem nuclei,
10,11 as well as the contralateral dorsomedial and
ventroposteromedial nuclei of the thalamus. 6 Trigeminal
pain is also associated with activation in several cortical
areas, including the insular cortex, anterior cingulate
cortex, and somatosensory cortex. 12 In the primary
somatosensory cortex, trigeminal painful stimulation
results in a laminar configuration similar to that observed
within the brainstem trigeminal nuclei with V1 more
caudal, V2 more rostral, and V3 medial, abutting the
area of activation observed after stimulation of the
thumb. 6
Traditional Theories of Migraine Pathogenesis:
Brain versus Vessel
Two competing theories dominated the discussion of
migraine pathogenesis throughout the 20th century. The
vasogenic theory, which viewed migraine as a form of
vascular dysregulation and assumed that the aura was
due to a transient vasoconstriction-induced hypoxemia,
dominated the discussion until the 1980s. According to
the vasogenic theory, migraine headache was caused by a
rebound vasodilation that resulted in a mechanical depolarization
of primary nociceptive neurons within the
walls of engorged intra- and extracerebral vessels. 13 One
of the mainstays of the vasogenic theory was the fact that
it was consistent with the observed headache inducing
effects of vasodilating drugs, such as nitroglycerin, and
the therapeutic effects of ergotamines, which were
known to be potent vasoconstrictors. Reports of no
efficacy from the nonvasoconstrictive substance P antagonists
in acute migraine also seemed to favor the vasogenic
hypothesis. 14 However, recent imaging studies
revealed that the headache induced by nitroglycerin
PATHOPHYSIOLOGY OF MIGRAINE/CUTRER 121
begins well after the resolution of vasodilation when
vessels are at their normal baseline caliber. 15,16 In addition,
other vasodilating substances, like vasoactive intestinal
peptide, do not induce migraine headache. 17
The alternative neurogenic theory viewed migraine
as a disorder of the brain in which vascular
changes were the result of neuronal dysfunction. Proponents
of this theory pointed to the fact that multiple
neurologic symptoms often occur during a single aura
that are difficult to localize within a single neurovascular
territory. Also in favor of the neurogenic theory were
findings from neuroimaging studies conducted during
spontaneous, classical visual auras, which indicated that
the decreases in cortical blood flow observed during aura
are not sufficient to cause ischemia, and that subsequent
vasodilation does not take place until well after the onset
of headache. 18–20 In addition, multiple nonvasoconstrictive
treatments are known to be effective in migraine. 21
Unfortunately, at this point in time, if viewed rigidly,
neither theory alone can account for all of the clinical and
treatment response characteristics of migraine.
Genetic Factors
There is accumulating evidence that migraine is a complex
genetic disorder. The influence of inheritance in
migraine has long been recognized. Over the past several
years, investigators have identified three distinct single
gene defects that may account for familial hemiplegic
migraine (FHM), a rare autosomal dominantly inherited
form of migraine. The first defect to be identified was for
FHM type 1 and was found in a gene known as
CACNA1A located on chromosome 19p13. CAC-
NA1A codes for the a 1 -subunit of a brain specific
voltage-gated P/Q-type calcium channel. 22 A second
defect (linked to FHM type 2) has been identified on
chromosome 1q23 in the ATP1A2 gene that encodes
the a 2 -subunit of a Na þ /Kþ pump. 23 More recently, a
third mutation on chromosome 2q24 has been associated
with FHM type 3. This mutation occurs in the voltagegated
sodium channel SCN1A. 24 At least 17 different
mutations within the CACNA 1A have been linked to
migraine or other related clinical syndromes. In addition
to unilateral motor weakness, patients with FHM experience
typical visual, sensory, and/or language auras with
some attacks of FHM. Just as in the more common
forms of migraine, FHM is more common in women
than in men, possibly implicating hormonal shifts in
migraine pathogenesis.
Linkage analysis and various association studies
have implicated numerous polymorphisms in the more
common forms of migraine: migraine with aura (MA)
and migraine without aura (MO). It is increasingly
evident that the common forms of migraine are based
on complex, heterogeneic genetics (Table 1). The obvious
complexity of the underlying genetics will likely be
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