Perampanel as a candidate for polytherapy in Stage 1 Plus status epilepticus: biological rationale and translational limits.

BACKGROUND: Stage 1 Plus (S1P) is a proposed operational framework for treatment-naïve status epilepticus (SE) in which first-line treatment with benzodiazepine (BDZ) is unlikely to terminate seizures, thereby suggesting a possible role for early polytherapy. The proposed S1P framework includes candidate high-risk phenotypes associated with early BDZ failure: prolonged SE beyond the proposed semiology-specific treatment threshold, acute symptomatic etiologies (especially primary central nervous system causes), and nonconvulsive SE (NCSE) with coma. Different types and levels of evidence support these phenotypes. TRANSLATIONAL RATIONALE: Prolonged SE is associated with rapid, time-dependent receptor trafficking that reduces synaptic inhibition via GABA-A receptors while increasing excitatory receptor availability, including surface recruitment of Ca2+-permeable AMPA receptors and increased NMDA receptor signaling. In experimental models, NMDA/AMPA receptor antagonism can retain antiseizure effects, supporting testing of early anti-glutamatergic polytherapy. Human evidence for the AMPA antagonist perampanel (PER) in SE remains largely observational and is concentrated in refractory/super-refractory SE, with frequent late introduction and substantial confounding by concomitant therapies. OBJECTIVE: This critical translational review examines whether PER is a biologically plausible adjunct to BDZ as an anti-AMPA polytherapy approach in S1P. We discuss whether early combined therapy in treatment-naïve S1P SE may improve seizure termination. CONCLUSIONS: Receptor-trafficking models provide a biologically plausible and timing-aligned rationale for BDZ plus AMPA antagonism. Early BDZ plus PER is therefore biologically plausible and deserves prospective testing, but rapid achievement of therapeutic exposure within the proposed S1P window may be limited by enteral administration, and current human evidence is insufficient to support its clinical use in S1P.