Treatment for Migraine Aura?
Treatment for Migraine Aura?
abstract & commentary
Source: Kaube H, et al. Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine. Neurology 2000;55:139-141.
Migraine aura is characterized by transient reversible neurologic symptoms. Recent dynamic blood flow studies have correlated such clinical symptoms with slowly spreading perfusion changes across the cortex. The pattern resembles the cortical spreading depression (CSD) phenomenon observed in experimental animals. In such models, CSD is mediated by both the diffusion of extracellular potassium and excitatory amino acids. In fact, CSD can be blocked in animals by glutamate NMDA receptor antagonists. Kaube and colleagues attempted the first known clinical study using the NMDA antagonist ketamine to halt aura symptoms in patients diagnosed with familial hemiplegic migraine (FHM).
The study was unblinded given the severity of the aura symptoms and the potential psychotropic side effects of ketamine. Patients were instructed to self-administer 25 mg of intranasal ketamine at the first onset of aura. The response was measured by self-assessment questionnaires completed every 15 minutes and extensive follow-up interviews. Eleven patients from seven families with diagnosed FHM were enrolled and 25 migraine aura attacks were treated. Genetic linkage analysis to FHM locus CACNA1A on chromosome 19p13.1 was performed on all seven families. Five patients from three families reported improvement after ketamine for all 14 attacks. Improvement was defined as reduction in duration and severity of neurologic symptoms as none spread from one symptom to another. Six patients had no benefit after 11 treated attacks. Kaube et al make special note that only two patients reported a reduction in headache severity after ketamine. Furthermore, they noted that the response was not related to the presence or absence of a proven linkage to the chromosome 19p13 locus. Kaube et al conclude that migraine aura can be selectively attenuated by the NMDA antagonist ketamine. This provides further evidence that migraine aura is caused by CSD and that NMDA antagonists might be useful in the management of severe migraine.
COMMENTARY
Several points are worth noting. The methodological compromises of this study greatly limit the degree to which conclusions can be drawn. Migraine is too complicated and its symptoms are too subjective to rely on unblinded subjects and observers as well as nonplacebo controlled trials. Furthermore, a rating scale might help actually to quantitate the severity of aura symptoms and the subsequent response to ketamine. Future studies correlated with functional imaging would be equally important. But these are not criticisms as much as questions that are provoked by such an intriguing study. It raises not only the issue of CSD and aura but suggests possible treatment options to explore. The observation that blocking the aura did not necessarily prevent headache is important. In the current trigeminal vascular model of migraine, neurogenic inflammation is presumed to be induced around cranial vasculature by CSD. In other words, migraine aura and migraine headache are serial processes. However, it may be that both aura and headache follow in parallel from a central process. Indeed, Diener and colleagues (Nat Med 1995;1:658-660) have suggested a brainstem location for such a "migraine generator" based upon PET studies of spontaneous migraine attacks. —jeffrey reich
A dose of 25 mg of intranasal ketamine in familial hemiplegic migraine patients was shown to:
a. provoke an actual migraine aura and headache.
b. inhibit the duration and severity of migraine aura.
c. inhibit the intensity and severity of migraine headache.
d. inhibit the "brainstem generator" associated with migraine.
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