Perampanel, Brivaracetam, Cenobamate, Stiripentol, and Ganaxolone in Lennox-Gastaut Syndrome: A Comprehensive Narrative Review.

Lennox-Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by treatment-resistant seizures and significant morbidity. Despite multiple approved anti-seizure medications (ASMs), optimal seizure control remains elusive. This has led to ongoing interest in newer ASMs, including those not specifically approved for LGS. This review evaluates the emerging evidence on the use of these agents in LGS management. We conducted a comprehensive literature search of PubMed, Web of Science, and Embase to identify studies examining perampanel, brivaracetam, cenobamate, ganaxolone, and stiripentol in LGS populations. Both randomized controlled trials and observational studies were included. Perampanel was studied in approximately 300 patients across one Phase 3 trial and seven observational studies, showing responder rates of 26-69% with particular efficacy for generalized tonic-clonic and myoclonic seizures, though behavioral side effects (irritability, aggression) were dose-related concerns. Brivaracetam demonstrated inconsistent efficacy in 59 patients across six studies (0-61.5% responder rates) but offered better behavioral tolerability than levetiracetam. Cenobamate showed exceptional promise in 223 patients across seven studies with 50-85% responder rates and significant polypharmacy reduction, though requiring careful titration. Ganaxolone demonstrated efficacy in LGS-like CDKL5 deficiency phenotypes with 28.2% drop seizure reduction versus placebo. Stiripentol showed potential benefit for generalized seizures in limited LGS data. Several newer ASMs show therapeutic promise in LGS. Perampanel offers the most extensive evidence base, cenobamate demonstrates exceptional efficacy potential, while brivaracetam provides an alternative for levetiracetam-intolerant patients. Further controlled studies are needed to define optimal treatment algorithms.