Abstracts

Rationale: Approximately 30% of individuals with epilepsy are drug-resistant, including one-third with Juvenile Myoclonic Epilepsy (JME) and up to 60% with PCDH19-related epilepsy. These syndromes pose therapeutic challenges due to limited efficacy of conventional anti-seizure medications (ASMs). Cenobamate is a novel ASM with dual mechanisms—persistent sodium current inhibition and positive allosteric modulation of GABA-A receptors. Though approved for focal-onset seizures, emerging data suggest potential benefit in generalized epilepsies. We present two cases demonstrating significant clinical response to off-label cenobamate use in generalized epilepsy syndromes.

Methods: Retrospective case series of two females with drug-resistant generalized epilepsy syndromes treated with off-label cenobamate.

Results: Case 1 (JME): A 22-year-old female with JME experienced absence, myoclonic, and generalized tonic-clonic seizures (GTCs) refractory to multiple ASMs, including valproate, lamotrigine, topiramate, and zonisamide. Valproate produced partial control but led to adverse effects, including hair loss, tremor, and elevated liver enzymes. Despite VNS implantation, breakthrough GTCs persisted. Cenobamate was initiated in mid-2024. With gradual titration to 150 mg/day and valproate discontinuation, she achieved a 50% reduction in annual GTCs (from 8 to 4/year) and marked improvement in myoclonic and absence seizures, with enhanced tolerability.
Case 2 (PCDH19 Epilepsy): A 22-year-old female diagnosed with PCDH19-related epilepsy at 15 months exhibited recurrent febrile and afebrile seizures, evolving into drug-resistant clusters. Trials of oxcarbazepine, zonisamide, and lacosamide failed; VNS and cannabidiol (Epidiolex) offered partial benefit. Cenobamate was added in mid-2021 and titrated to 200 mg/day by 2023. She subsequently achieved seizure-free intervals exceeding 100–198 days. Epidiolex was successfully withdrawn, and lamotrigine reduced from 150 mg to 100 mg/day without adverse effects.

Conclusions: These cases highlight the promising role of cenobamate as an off-label adjunctive treatment in refractory generalized epilepsies. In both patients, cenobamate significantly reduced seizure frequency and allowed withdrawal or dose reduction of prior ASMs with unfavorable side-effect profiles. Given its favorable pharmacodynamic profile and real-world efficacy, further clinical trials are warranted to assess cenobamate’s broader applicability in generalized and genetic epilepsies.

Funding: No funding has been received in support of this abstract.