To test perampanel as a treatment of benzodiazepine-unresponsive status epilepticus (RSE),  neuronal injury, blood-brain barrier breakdown and cell-mediated inflammation.

SE remains a therapeutic challenge, and better treatments are urgently needed. The potent AMPA receptor antagonist perampanel may negate SE-induced increase in synaptic AMPA receptors. We evaluated it as a second-line treatment of severe, benzodiazepine-refractory SE (RSE).

SE was induced in adult male Sprague-Dawley rats by high-dose lithium (5 mEq/kg)/pilocarpine (320 mg/kg), EEG/video was recorded for 18 hrs. Midazolam (1 mg/kg; ip) was injected i.p. 40 min after SE onset. Perampanel (0.5, 1, 2 or 4  mg/kg), was injected i.p. 60 min. after seizure onset if SE continued. Neuropathology was studied 48 hours after SE onset. Brain sections were stained for markers of neuronal injury (Fluoro Jade B), blood-brain barrier breakdown (Immunoglobulin G, IgG) and cell-mediated inflammation (macrophages), rated on a 0-5+ scale and compared by t-test.

Post-midazolam perampanel reduced EEG power integral  during the first hour after treatment to a value below the pre-seizure baseline, demonstrating that seizures were terminated (mean ± SE -101 ±80; p<0.0001 vs midazolam alone, 703 ±55). Perampanel (4 mg/kg) reduced Fluoro Jade B staining in CA1 from 4+ (median, interquartile range 4-4, midazolam alone, n=10) to 0 ( 0-0, p<0.0001). It also reduced neuronal injury  in CA3, thalamus, parietal cortex, pyriform and entorhinal cortex, and amygdala. IgG leak was reduced in CA1, thalamus, pyriform cortex and amygdala. Macrophage infiltration was reduced from 4+ ( 1-4) to 0 ( 0-0, p<0,0001) in CA1, and significantly reduced in CA3, thalamus, parietal cortex, pyriform and entorhinal cortex.

Perampanel given 60 minutes after seizure onset stops RSE and potently reduces its neuropathological consequences, including neuronal injury, blood-brain barrier breakdown and cell-mediated inflammation in this model of severe benzodiazepine-refractory SE. It  deserves further evaluation as a treatment of RSE.