Abstracts

Rationale: Prompt treatment of seizure cluster (SC) in epilepsy with a benzodiazepine immediate-use seizure medication (ISM) can lead to rapid seizure termination and reduce the risks associated with SC, including potential injury and progression to status epilepticus. In a clinical study of diazepam (DZP) nasal spray for acute treatment of SC, repeated use over 1 year was linked to a significant increase in the time between SC episodes (ie, SEIzure interVAL [SEIVAL]), suggesting the value of exploring a potential disease-modifying effect of DZP. The objective of this study was to investigate and describe the impact of DZP on SC biology using the post-kainic acid status epilepticus (KASE) rat model of chronic epilepsy.

Methods: The study included a 3-wk baseline, 6-wk intervention, and a 2-wk washout period. During baseline, rats with confirmed epilepsy were monitored by continuous video-electroencephalography (vEEG) to confirm the development of spontaneous SC (defined by ≥2 seizures in 24 h). During intervention, rats with a confirmed SC within the prior 24 h were randomized to receive 3 intraperitoneal injections of DZP (3 mg/kg, n=7) or vehicle (VEH, 1 mL/kg, n=9) each 1 h apart. This dosing schedule has been shown to result in accumulation of DZP in rat plasma at levels similar to those seen in humans receiving DZP to treat SC (Guignet et al, Epilepsia Open. 2024. In press). Continuous vEEG was used to monitor for subsequent SC during all study periods, including the washout period with no intervention. SC features evaluated included size (number of seizures in 1 SC), severity (Racine Behavioral Scale), burden (sum of size × severity), duration (days), and distribution (by severity, by clustered vs single seizures).

Results: 20/28 (71%) rats displayed ≥3 SC during baseline and proceeded to the intervention and washout phase. DZP significantly reduced seizure burden 0–12 h post-dose compared to no change with VEH; however, there tended to be a rebound effect with increased SC burden (Fig 1) and size 12–24 h post DZP dose. Even with a rebound effect, SC duration remained stable with DZP while it trended toward an increase with VEH. Seizure severity significantly decreased over time with DZP treatment vs VEH (Fig 2), and a decrease in convulsive seizures continued during the washout period. Notably, during washout, both SC burden and size lessened with DZP while it worsened or did not change with VEH.

Conclusions: In this study using the rat KASE model of chronic epilepsy, the decreasing seizure severity over time with DZP treatment and the sustained effect of DZP on SC severity, burden, and size during the washout period supports its disease-modifying potential on SC biology. The observed rebound effect possibly masked a potential greater effect of DZP on SC burden and size during the intervention phase. Future studies are needed to understand and confirm these findings in rats receiving background antiseizure medications to mitigate the rebound effect and better replicate clinical practice where ISMs may be administered.

Funding:
Neurelis, Inc.