Preclinical signal for a disease-modifying effect on seizure cluster severity with intermittent diazepam treatment.

Abstract

OBJECTIVE: In epilepsy, daily treatment provides only symptomatic seizure control, leaving a significant unmet need for a treatment that affects the underlying predisposition to seizures. Here, in a first-of-its-kind study, we test the hypothesis that intermittent treatment of seizure clusters with diazepam in the kainic acid post-status epilepticus rat model of acquired epilepsy has an enduring effect on the seizure cluster phenotype, suggestive of potential disease modification. METHODS: Following kainic acid-induced status epilepticus, rats with epilepsy were monitored for occurrence of seizure clusters (&#x2265;2 seizures in 24&#x2009;h) for a 3-week baseline period before entering a 6-week treatment period using a previously established multidose regimen of diazepam (n&#x2009;=&#x2009;7) or vehicle (n&#x2009;=&#x2009;9) upon identification of a seizure cluster. In a subsequent 2-week outcome period during which no rats received diazepam, we evaluated changes in seizure cluster size, burden (cluster size&#x2009;&#xd7;&#x2009;severity), duration, and other phenotype parameters. RESULTS: A total of 3396 seizures and 216 seizure clusters were included for analysis. During the outcome period, time between seizures in a cluster (also interseizure interval [ISI]) was significantly longer in the diazepam group (log ISI = .25 longer, SE = .08, p&#x2009;<&#x2009;.0001), and the proportion of clustered seizures with an ISI of &#x2264;30&#x2009;min increased in the outcome period in the vehicle group (p&#x2009;=&#x2009;.023) but was stable in the diazepam group. Despite the occurrence of rebound seizures during the treatment period, improvement in several phenotypical parameters, including severity and proportion of seizures in a cluster, supported a positive impact of intermittent diazepam treatment on seizure cluster biology. SIGNIFICANCE: Changes in several seizure cluster phenotypical parameters were suggestive of an enduring disease-modifying effect of diazepam, despite an apparent rebound effect of intermittent diazepam treatment on seizure frequency. Further study is warranted using a model incorporating a background antiseizure medication regimen to potentially attenuate the unexpected rebound seizures.