Abstracts

Rationale: In spite of the increasing number of drugs available, treatment of refractory status epilepticus (RSE) remains a significant challenge. Seizure-induced pharmacoresistance is difficult to overcome, especially when treatment is delayed. Mortality remains high and most survivors carry severe long-term sequellae. Better treatments are urgently needed. Combinations of drugs which target SE-induced changes in synaptic GABAA and glutamate receptors have been successful in animal models of RSE, but the ideal drug combination has not been defined. This study compared monotherapy with combinations of drugs which include brivaracetam and with combinations which include levetiracetam. Results suggest that brivaracetam-including combinations are more effective in stopping seizures than all other treatments studied.  Methods: We treated RSE 40 minutes after EEG seizure onset in a severe, very high-dose lithium 5 mEq/kg-pilocarpine 320 mg/kg model (Tetz et al. 2006). The EEG was recorded for 24 hrs after seizure onset. Outcome measures were reduction of EEG power integral during the first hour post-treatment, and acute neuronal injury by Fluoro-Jade B (FJB) staining at 48 hours. Our treatment stimulated remaining synaptic GABAA receptors with benzodiazepines, reduced excessive glutamatergic excitation with an NMDA antagonist, and added two drugs which act at a non-GABA site (the presynaptic SV2A vesicle wall protein), since GABA agonists can only partially restore GABA inhibition when treatment is delayed 40 min.  Results: Seizures were refractory to high-dose midazolam (9 mg/kg), ketamine (90 mg/kg), levetiracetam (300-900 mg/kg) or brivaracetam (90 mg/kg), but a combination brivaracetam (30 mg/kg) - midazolam (3 mg/kg) - ketamine (30 mg/kg) rapidly reduced the post-treatment EEG Power Integral from 355 +-127 (midazolam group) to -171+- 93, which was below pre-seizure baseline, showing that seizures had been terminated. EEG power before treatment was the same in all groups. The number of post-treatment seizures was reduced from 49 +- 8 (midazolam group) to 3 +- 1 (brivaracetam combination group). The number of post-treatment spikes went from 2238 +- 262 (midazolam group) to 125 +- 29 (brivaracetam combination group). This experiment suggests that a brivaracetam-containing combination effectively stops seizures in RSE refractory to high-dose monotherapy.In the same model, we compared the combination midazolam-ketamine-brivaracetam 30 mg/kg to midazolam-ketamine-levetiracetam (100 mg/kg or 300 mg/kg). The brivaracetam combination reduced the number of post-treatment seizures to 3 +- 1 versus 15 +- 5 (Levetiracetam 100 mg/kg combination, p<0.01) or 11 +- 2 (Levetiracetam 300 mg/kg combination, P<0.05). The brivaracetam-including combination reduced the one-hour EEG power integral to -171 +- 93 compared to 169 +- 55 (Leviracetam 100 mg/kg combination, p<0.05) and to 282 +- 129 (Levetiracetam 300 mg/kg combination, p<0.01). Post-treatment spikes were reduced to 125 +- 29 (Brivaracetam group) versus 1209 +- 295 (Levetiracetam 100 mg/kg group, p<0.001) and 298 +- 24 (Levetiracetam 300 mg/kg group, p<0.05). Studies of acute neuronal injury showed strong neuroprotection in all groups treated with ketamine.  Conclusions: This experiment demonstrates that brivaracetam in more effective than higher-dose levetiracetam in stopping seizures in this model of RSE, and confirms that combinations of a GABAA receptor allosteric stimulator, a NMDA receptor antagonist and an antiepileptic drug are superior to monotherapy in treating RSE.  Funding: Supported by VA Research Service, by research grants NS 13515 and NS 074926 from NIH/NINDS, and by a research grant from UCB, and by the James and Debbie Cho Foundation.