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 (≥2 seizures in 24 h) for a 3‐week baseline period before entering a 6‐week treatment period using a previously established multidose regimen of diazepam ( n = 7) or vehicle ( n = 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 × 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 < .0001), and the proportion of clustered seizures with an ISI of ≤30 min increased in the outcome period in the vehicle group ( p = .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.
Wu et al. (2026) studied this question.