Abstracts

Rationale: Pharmacoresistance remains a challenge in the treatment of status epilepticus (SE). Benzodiazepine monotherapy, which is the standard treatment, fails to stop seizures (SZ) in 35% to 69% of cases of SE, and many survivors show behavioral/neuropathological sequellae. Better treatments are urgently needed. In rodent models, drug combinations targeting SE-induced maladaptive changes in synaptic GABAA and glutamate receptors stop refractory SE, but the optimal combination is uncertain. Rapid brain penetration might help in treating SE. In a previous study, brivaracetam (BRV)-including combinations were more effective in stopping SZ than levetiracetam (LEV)-including combinations (2019 AES abstract). This study suggests that BRV-including combinations also resulted in a significant reduction of acute neuropathology.

Methods: We treated RSE 40 minutes after EEG seizure onset in model of a severe SE-induced by high-dose lithium 5 mEq/kg-pilocarpine 320 mg/kg (Tetz et al. 2006). The EEG was recorded for 24 h after seizure onset. Acute neuronal injury (Fluoro-Jade B staining), brain-blood barrier (BBB) leakage (IgG immunocytochemistry) and cell inflammation were studied 48 h after SE onset. 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 GABAA agonists can only partially restore GABA inhibition when treatment is delayed 40 min. 

Results: SZ were refractory to high-dose midazolam (9 mg/kg), ketamine (90 mg/kg), LEV (300-900 mg/kg) or BRV (90 mg/kg), but a combination BRV (30 mg/kg) - midazolam (3 mg/kg) - ketamine (30 mg/kg) rapidly reduced several parameters of SE severity: the EEG power integral at 1 and 6 h (suggesting that SE stopped and did not recur) , the time needed to reach an EEG amplitude of twice the pre-seizure baseline, and the total number of SZ and spikes recorded. This BRV-including combination was superior to the combination LEV (100 mg/kg) - midazolam (3 mg/kg) - ketamine (30 mg/kg) in that treatment paradigm. The BRV- including combination significantly reduced neuronal injury in 6 of 7 regions studied. The LEV-including combination also reduced neuronal injury in 5 regions, but the combination with BRV reached a higher degree of significance in 4 of them. The BRV-including combination reduced neuronal injury better (Two-Way ANOVA; p< 0.001) than the LEV-including combination. Both combinations eliminated SE-induced macrophage infiltration in 6 out of 7 regions. Both combinations completely blocked SE-induced BBB leakage.