Abstracts

Rationale: Studies of electrographic status epilepticus (ESE) therapies in rodents using conventional analysis approaches have uncertain translational relevance as they typically have assessed treatment effects using measures of electroencephalogram (EEG) power that do not identify ESE onset or termination in a manner corresponding with the approach used in critical care neurology. This study assesses the potential of allopregnanolone (ALLO), an allosteric modulator of GABA-A receptors, to terminate electrographic status epilepticus (ESE) induced by the organophosphate (OP) nerve agent soman using a new analysis approach based on the 2021 ACNS Standardized Critical Care EEG Terminology definition of electrographic seizure (ESz). We compared the effects of the current standard-of-care treatment for OP-induced status epilepticus, which is 2 doses of midazolam (MDZ), with 1 dose of MDZ followed by ALLO on ESE induced in rats by soman. This study was intended to explore the potential of ALLO as a replacement for a second MDZ dose when an initial MDZ dose fails to terminate status epilepticus.


Methods: Rats with chronic cortical screw EEG electrodes were treated with soman (121 µg/kg, SC) and 30 min later with MDZ at a dose that produces plasma levels comparable to those obtained with the recommended human dose (0.65 mg/kg, IM), followed in 10 min by either MDZ or ALLO (12 or 24 mg/kg, IM). The EEG was recorded continuously for up to 4 h following treatment. Epileptiform discharges (ED; spikes or sharp waves) were identified in the EEG records based on amplitude and duration using NeuroScore. ESz was identified in EEG recordings algorithmically and ESE was defined as seizure burden of 20% or more during the epoch being analyzed. An R software routine was developed that walked the ED-time records with a 10 s window to define the presence or absence of ESz at each sequential 1 s based on the occurrence of >25 discharges in the 10 s period.


Results: Of 48 rats administered soman, 30 were analyzed for treatment efficacy using the new algorithm. 13 rats were not analyzed due to death after the onset of ESE and before a treatment could be administered. The remaining 5 rats were not analyzed as the dosing was incorrect. One or 2 doses of MDZ failed to reduce the seizure burden, demonstrating that the ESE in this model is benzodiazepine refractory. ALLO 12 mg/kg transiently terminated ESE after dosing, with relapse on average 60 min after dosing. ALLO 24 mg/kg eliminated ESE during the entire 4 h recording.


Conclusions: A new analysis approach has been developed that identifies ESE according to currently accepted clinical criteria. Using this method, MDZ failed to terminate ESE whereas ALLO at a high dose was effective, supporting the potential utility of high dose ALLO in the treatment of benzodiazepine-refractory status epilepticus. The novel analysis method may have application broadly in the study of treatments for status epilepticus.


Funding: NINDS grant U54NS079202.