Continuous seizure emergency evoked in mice with pharmacological, electrographic, and pathological features distinct from status epilepticus.

Abstract

Benzodiazepines are the standard of care for the management of sustained seizure emergencies, including status epilepticus (SE) and seizure clusters. Seizure clusters are a variably defined seizure emergency wherein a patient has multiple seizures above a baseline rate, with intervening periods of recovery, distinguishing clusters from SE. Although these seizure emergencies are phenotypically distinct, the precise pathophysiological and mechanistic differences between SE and seizure clusters are understudied. Emergency-specific preclinical models may differentiate the behavioral and pathological mechanisms that are acutely associated with seizure emergencies and seizure termination to better manage these events. Herein we characterize a novel model of sustained seizure emergency induced in CF-1mice through the combined administration of high-dose phenytoin (PHT; 50mg/kg, i.p.) and pentylenetetrazol (PTZ; 100mg/kg, s.c.). We presently describe a mouse model of sustained seizure emergency that is pathologically, pharmacologically, and behaviorally distinct from SE. Acute administration of PHT 1h prior to PTZ led to significantly more mice with unremitting continuous seizure activity (CSA; 73.4%) vs vehicle-pretreated mice (13.8%; p<.0001). CSA was sensitive to lorazepam and valproic acid when administered at seizure onset and 30 minutes later. Carbamazepine worsened seizure control and post-CSA survival. Mice in CSA exhibited electroencephalography (EEG) patterns distinct from kainic acid-induced SE and PTZ alone, clearly differentiating CSA from SE and PTZ-induced myoclonic seizures. Neuropathological assessment by Fluoro-Jade C staining of brains collected 24 h post-CSA revealed no neurodegeneration in any mouse that underwent CSA, whereas there was widespread neuronal death in brains from KA-SE mice. Finally, immunohistochemistry revealed acute seizure-induced astrogliosis (glial fibrillary acid protein; GFAP) in hippocampal structures, whereas hippocampal neuronal nuclei (NeuN) protein expression was only reduced in KA-SE mice. We present a novel mouse model on which to further elucidate the mechanistic differences between sustained seizure emergencies (ie, SE and seizure clusters) to improve clinical interventions and define mechanisms of seizure termination.