Seizure-type-specific treatment responses in Lennox-Gastaut Syndrome: A comprehensive review of pharmacological, neuromodulatory, dietary, and surgical therapies.

Lennox-Gastaut Syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, presenting significant challenges for treatment. This comprehensive review examines seizure-type-specific response patterns to various therapeutic interventions in LGS. We conducted an extensive literature review of randomized controlled trials, observational studies, and real-world evidence, covering research up to February 2025. Our analysis shows that atonic seizures respond particularly well to corpus callosotomy (CC) and Vagus Nerve Stimulation (VNS), with CC demonstrating superior efficacy. Generalized tonic-clonic seizures (GTCS) show favorable responses to antiseizure medications (ASMs) such as felbamate, lamotrigine, topiramate, fenfluramine, lacosamide, and perampanel. Myoclonic seizures tend to respond better to clonazepam, topiramate, zonisamide, brivaracetam, and perampanel, but may show limited responsiveness to neuromodulation and CC. Atypical absence seizures may respond to valproate, topiramate, and rufinamide, but show poor responses to brivaracetam and perampanel. The ketogenic diet and resective epilepsy surgery demonstrate broad efficacy across seizure types, although specific data for each type remain limited. VNS is most effective for atonic and tonic seizures, with less consistent responses in GTCS and focal seizures. Emerging neuromodulation techniques, including deep brain stimulation (DBS) and responsive neurostimulation (RNS), show promise, particularly for tonic and GTCS, but further investigation is needed. This review underscores the importance of tailoring treatment to predominant seizure types and calls for more rigorous, seizure-type-specific outcome reporting in future clinical trials, along with the need for long-term studies. The findings advocate for a precision, network-based approach to treatment, where therapeutic decisions are guided by individual seizure patterns and supported by evidence-based, seizure-type-specific efficacy data.