Anticonvulsant Hypersensitivity Syndrome (AHS) is a delayed drug reaction associated with the use of carbamazepine, phenytoin, and phenobarbital. This uncommon, though potentially fatal, multisystem disorder appears to be a hypersensitivity reaction to the arene metabolites of these drugs. The most common clinical presentation of this disorder includes fever, rash and lymphadenopathy. Onset generally occurs within 2-4 weeks of initiating therapy, but may take as long as 3 months. DISCUSSION Carbamazepine, Phenytoin and Phenobarbital all share a common structural feature, an aromatic benzene ring. The normal in vivo behavior of this drug involves conversion of the aromatic benzene ring into a highly unstable arene oxide metabolite via the cytochrome P450 system. These metabolites are highly electrophilic compounds that disrupt cellular function. The most common theory behind the mechanism of AHS is believed to occur as a result of deficient epoxide hydrolase, an enzyme responsible for the detoxification of the arene oxide metabolite. A deficiency in this enzyme results in a buildup of the toxic metabolites, and the subsequent cytotoxicity and hypersensitivity ensues.1 AHS is most common among elderly black males, and overall prevalence is higher in the African-American population. It occurs in about one in 1,000 to one in 10,000 exposures. It is postulated that there may be a genetic determining factor associated with AHS. Familial occurrence of hypersensitivity has been observed, and findings suggest that it follows an autosomal pattern of inheritance. While initial onset (with first drug exposure) may appear within one week to three months, symptoms may occur as soon as one day after re-initiating therapy with the same drug (rechallenge). Cross-sensitivity between these three anticonvulsants is very high. Between 50-75% of patients with AHS showed in vitro cross-sensitivity to the other two drugs. The cross-sensitivity between these three anticonvulsants may explain why patients worsen with subsequent use of the other two anticonvulsants associated with this syndrome. 1,2,3
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