Abstracts

Rationale: Nerve agents block acetylcholinesterase activity, leading to excessive stimulation of cholinergic neurons and subsequent emergence of status epilepticus (SE). The current standard field treatment for nerve agent-induced SE is diazepam, which becomes less effective as treatment is delayed and may not lead to permanent seizure control. Add-on or replacement therapies could benefit not just nerve agent casualties, but those experiencing SE of other etiologies. Levetiracetam, a commonly prescribed antiepileptic drug, has been reported to successfully control clinical SE cases, particularly those that are categorized as benzodiazepine-resistant. This study examined the efficacy of levetiracetam as a co-therapy with diazepam against nerve agent-induced seizures using a validated guinea pig model. Methods: Male Hartley guinea pigs were surgically prepared with cortical screw electrodes to record brain electroencephalographic (EEG) activity. One week later, animals were pretreated with 0.026 mg/kg pyridostigmine intramuscularly (IM) 30 minutes prior to subcutaneous challenge with 2 x LD50 of soman (56 µg/kg). One min after soman challenge, the animals received 2 mg/kg atropine sulfate IM + 25 mg/kg 2-PAM Cl IM. EEG activity was recorded continuously for at least 5 hr after exposure and 30 min the next day. Anticonvulsant treatments were administered 40 minutes after the onset of SE. Diazepam was delivered IM at a dose of 4.8 mg/kg. Levetiracetam was delivered IP at 5 doses ranging from 100 – 1000 mg/kg. Results: The number of animals in each group with no SE termination, temporary SE termination based upon presence of epileptiform EEG activity on the second day of recording, or lasting SE termination evidenced by no epileptiform EEG activity on the second day of recording are shown in the table below, along with the latency to termination (mean ± SEM) for animals in which it was observed. A one-way ANOVA reveals no effect of treatment upon latency to termination (p = 0.1730). No group that received diazepam + levetiracetam exceeded the 50% lasting SE termination rate that was observed in the diazepam alone group. Conclusions: These data indicate that levetiracetam shows no potential benefit in improving the degree or speed of SE control when administered in conjunction with the currently fielded medical countermeasure diazepam. However, because of its antiepileptic activity, levetiracetam may yet prove to be useful for mitigating the latent epilepsy that emerges after nerve agent-induced SE. Funding: This research was supported by the Defense Threat Reduction Agency - Joint Service and Technology Office, Medical S&T Division. H.M. was supported in part by an appointment to the Research Participation Program for the U.S. Army Medical Research and Materiel Command administered by the Oak Ridge Institute for Science and Education through an agreement between the U.S. Department of Energy and U.S. Army Medical Research and Materiel Command.