Abstracts

Rationale: Monotherapy is preferred for treatment of chronic epilepsy, but there is little evidence that this should apply to the treatment of status epilepticus (SE), an acute, life-threatening event of limited duration. Recent studies have shown that SE involves multiple neurotransmitter pathways, yet our current guidelines recommend an initial treatment targeting only GABAergic networks (Glauser et al 2016). During SE, trafficking of synaptic GABAA and glutamate receptors causes both a failure of GABAergic inhibition and an increase in glutamatergic excitation. This suggests that therapy targeting both inhibitory and excitatory networks may be more effective than monotherapy. We compared the effect of treating SE with a single drug to those of combinations including a GABAA agonist, an NMDA antagonist and an antiepileptic drug (AED) acting at a non-benzodiazepine site. Methods: We used a rat model of severe SE induced by high-dose lithium and pilocarpine (Tetz et al 2006). The EEG was recorded for 24 hrs after SE onset. Outcome measures were termination of SE, and acute neuronal injury by Fluoro-Jade B (FJB) staining at 48 hours. Our treatment stimulated remaining synaptic GABAA receptors with benzodiazepines, reduced glutamatergic excitation with an NMDA antagonisr, and added a drug which enhanced inhibition and/or reduced excitation at a non-GABA site, since GABA agonists can only partially restore GABA inhibition when treatment is delayed 40 min Results: Treatment was given 40 min. after onset of EEG seizures. Benzodiazepine monotherapy reduced mortality but did not stop SE. Midazolam 9-18 mg/kg (M), ketamine 10-30 mg/kg (K), valproate 90-270 mg/kg (V), and other AEDs failed to stop SE. Combinations of low-dose midazolam (1-3 mg/kg) with ketamine (10-30 mg/kg) and valproate (30-90 mg/kg) reduced the number of post-treatment seizures and terminated SE (p < 0.001 vs M). Two-drug combinations which included an NMDA antagonist were also significantly more effective than monotherapy in this model. Isobolograms showed synergism between the therapeutic but not between the toxic effects of these drugs. Neuropathological studies revealed widespread neuronal injury in sham-treated and in midazolam-treated SE, but neuronal injury was absent in most brain regions except the dentate hilus (50% reduction) in all ketamine-treated rats. Conclusions: These results suggest that combinations of a GABAA agonist, an NMDA antagonist and an AED are far more effective and less toxic than monotherapy in this model of SE. Addition of an NMDA antagonist to the initial treatment of SE had major benefits for both SE termination and neuropathological consequences. Funding: Supported by the Research Service of VHA, by grants NS13515 and NS 05974 from NINDS, and by the James and Debbie Cho Foundation.