Authors :
Presenting Author: Donna Nguyen, BS – US Army Medical Research Institute of Chemical Defense
Marcio de Araujo Furtado, PhD – BioSEaD, LLC; Jerome Niquet, PhD – Neurology – David Geffen School of Medicine at UCLA; Emily Linz, BA – US Army Medical Research Institute of Chemical Defense; Caroline Schultz, BS – US Army Medical Research Institute of Chemical Defense; Michael Stone, BS – US Army Medical Research Institute of Chemical Defense; Claude Wasterlain, MD, L.Sc.D. – Neurology – David Geffen School of Medicine at UCLA; Lucille Lumley, PhD – US Army Medical Research Institute of Chemical Defense
Rationale: Status epilepticus (SE) is an emergency condition that requires prompt response to effectively control. The standard first line treatment after SE onset is a benzodiazepine, but protective potency is lost in a time-dependent manner resulting in long-term effects such as neuropathology and epileptogenesis. This development requires the addition of second and third line antiseizure medications (ASMs) to mitigate SE severity. Preclinical models have shown the efficacy of simultaneous administration of ketamine and midazolam in reducing epileptogenesis in a delayed treatment model of cholinergic-induced SE, but with incomplete neuroprotective effects. Third generation ASMs have been of interest in polytherapy models for their safety, tolerability, and lack of sedative effects. Lacosamide and rufinamide are both FDA-approved ASMs with mechanisms focused on voltage-gated sodium channel inactivation. We evaluated the protective effects of midazolam, ketamine, and third generation ASMs lacosamide or rufinamide against cholinergic-induced SE.
Methods:
Adult male rats were exposed to a seizure-inducing dose of an organophosphorous (OP) chemical, which is an inhibitor of cholinesterase, and treated with atropine sulfate and an oxime one minute later and with midazolam, midazolam-lacosamide, midazolam-rufinamide, midazolam-ketamine-lacosamide, or midazolam-ketamine-rufinamide combination therapies 40 minutes after seizure onset. Control rats received saline and were treated with midazolam. After exposure, toxic signs were monitored for 5 h and seizure duration and the development of spontaneous recurrent seizures (SRS) were monitored for 14 days. Brain tissue was assessed for SE-induced neurodegeneration, neuronal loss, and loss of GABAergic neurons.
Results: Compared to midazolam monotherapy, midazolam-ketamine-lacosamide triple therapy reduced OP-induced behavioral toxic signs, 24 h seizure duration, EEG power integral, incidence of SRS, and loss of GABAergic interneurons. Lacosamide and rufinamide triple therapies reduced the percent change in EEG power bands after treatment, neuronal loss, and weight loss observed in rats treated with midazolam monotherapy. The majority of rats survived in all treatment groups following OP exposure but rats treated with midazolam-rufinamide dual therapy experiencing a 100% survival rate, which was greater than those that received vehicle.
Conclusions: Protective effects were observed when lacosamide or rufinamide were administered as adjunct treatments to midazolam and ketamine in a delayed treatment model of OP-induced SE. Differing levels of protection between lacosamide and rufinamide triple therapies were observed with regard to the epileptogenesis, EEG power integral, and brain regions protected from neuropathology, suggesting lacosamide triple therapy may provide better efficacy in protecting from the long-term effects of refractory SE. Overall, both drugs were well tolerated in these combination models and future studies should further explore these two ASMs as a viable treatment against SE.
Funding:
Research was supported by NINDS U01 NS074926 and by an interagency agreement between the USAMRICD and NIAID/NIH.