Seizure exacerbation and status epileptics related to carbamazepine‐10,11‐epoxide

Abstract

Over a 3-year period, we encountered 6 adults whose seizure control unexpectedly deteriorated with the occurrence of partial status epilepticus and daily multiple seizures. Analysis of the case histories and subsequent clinical follow-up for 1 1/2 to 3 years disclosed the following evidence that demonstrates the role of carbamazepine-epoxide in the development of the seizure exacerbation: (1) There were high serum carbamazepine-epoxide concentrations while serum carbamazepine concentrations were lower than or the same as baseline levels; (2) all patients were taking drugs that are known to increase serum carbamazepine-epoxide concentrations; (3) status epilepticus failed to respond to intravenous phenytoin loading; (4) seizure exacerbation in all patients was corrected by withholding carbamazepine dose; (5) seizure exacerbation recurred in 1 patient who resumed the same dose of carbamazepine; and (6) there were no prior status epilepticus or daily multiple seizures despite previous toxicities with other antiepileptic drugs in 3 patients. Our experience shows that inconspicuous elevation of carbamazepine-epoxide levels during polytherapy may precipitate a distinct state of drug toxicity characterized by severe exacerbation of seizures. Mental retardation may be a predisposition to this condition.

Antiepileptic Drugs as a Cause of Worsening Seizures

“…Since generalized slow EEG activities may be paced by the same thalamocortical network responsible for spike-andwave generation (152,1.53), an action of CBZ on this network may result in facilitation of generalized epileptogenesis. Paradoxical seizure responses in some patients have been associated with high blood levels of CBZ-10,ll -epoxide (79,80), leading to the suggestion that this active metabolite may play a pathogenetic role. However, because there is no evidence that CBZ-10,l lepoxide differs significantly from the parent drug in modes of action, its contribution to the generation of paradoxical seizure responses may be limited to an effect additive to that of CBZ itself.…”

Case Files of the University of California San Francisco Medical Toxicology Fellowship: Lamotrigine Toxicity

“…One theory is that the anticonvulsant in high concentrations may have a depressant effect on inhibitory interneurons resulting in disinhibition of excitatory neurons and facilitation of epileptic discharges [9]. Carbamazapine remains the most commonly cited anticonvulsant to cause seizures in overdose, with one case series suggesting that the 10,11-epoxide may be responsible [10]. Another suggested mechanism is that some seizures are precipitated by drowsiness and the sedation produced by anticonvulsant overdose may encourage those susceptible seizure disorders [8].…”

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“…The elimination of CBZ was not affected by VAL; K e and t 1/2 were not changed when VAL was coadministered significantly. CYP3A4 is the most important enzyme involved in the metabolism of CBZ as it leads to the formation of the active metabolite CBZ 10,11-epoxide, which appears to contribute to the toxicity and efficacy of CBZ 20,21 . CYP3A6 is responsible for CBZ metabolism in the rabbit 22 .…”