Induction of Partial Epileptic Seizures by Flumazenil

Abstract

Summary:Purpose: This study addressed the efficacy of flumazenil (FMZ) to induce or activate interictal or ictal epileptic discharges in patients with medically intractable partial epilepsies.Methods: Flumazenil, 1 mg, was injected intravenously in 67 patients undergoing presurgical monitoring for epilepsy surgery, 49 of whom had been treated with benzodiazepines (BZDs) before flumazenil was given. Continuous video electroencephalogram (EEG) monitoring with surface or intracranial electrodes was used to evaluate interictal EEG activity, ictal discharges, and the occurrence and semiology of clinically manifest epileptic seizures.Results: Interictal epileptiform potentials did not change in frequency or distribution after FMZ. In patients not pretreated with BZDs, epileptic seizures could not be provoked. In eight of the 49 patients pretreated with BZDs, epileptic seizures occurred within 30 min of FMZ application. Seizure semiology and regional EEG onset were identical to seizures recorded without FMZ. Patients operated on according to seizure-onset localization with FMZ had a >75% reduction in seizure frequency or became seizure free.Conclusions: Seizure induction by FMZ seems to be a valid method for evaluating seizure semiology and localization of the seizure-onset zone during presurgical monitoring of patients with medically intractable localization-related epilepsies. Key Words: Flumazenil-Benzodiazepine receptor antagonistEpilepsy-Activation method-Presurgical monitoring.For presurgical evaluation of medically intractable epilepsy, the recording of seizures is a neccessary prerequisite for localization of the epileptogenic zone. Often activation methods like hyperventilation (l), sleep withdrawal, and drug application (eg, methohexital) (2,3,4) are used to register seizures during the limited time available for telemetry.Flumazenil (FMZ; Anexate) is a selective, competitive benzodiazepine (BZD) receptor antagonist with very low intrinsic activity at the BZD binding site (5-9), whose oral and intravenous application is well tolerated in healthy subjects (10). As BZDs are effective anticonvulsants, application of a receptor antagonist could have a proconvulsive effect. In accordance with this assumption, FMZ has been reported to attenuate the anticonvulsant effect of diazepam (DZP), even to induce seizures after BZD treatment in animal models of seizures (1 1 inhibitory effect of FMZ on kindling (19,24,25) and an anticonvulsant effect on its own (19,(26)(27)(28)(29)(30). The competition of FMZ with proconvulsive, endogenous, inverse BZP-receptor agonists ( 3 1,32) has been suggested as a possible mechanism of an anticonvulsive effect (30,33).In humans, the effects of FMZ on epileptic activity have also been controversial. Whereas some studies have reported the induction or worsening of seizures (12,(34)(35)(36)(37)(38), other authors found a suppression of interictal discharges (33,3941) or a reduction in seizure frequency with FMZ treatment (39,42,43). FMZ has even been reported by Gallager et al. (44) and...

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