Search

Lennox-Gastaut syndrome (LGS) is a severe, childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, specific electroencephalogram (EEG) patterns, and significant cognitive and behavioral impairments. To date, eight anti-seizure medications (ASMs) have been specifically approved by the U.S. Food and Drug Administration (FDA) for the treatment of LGS: clonazepam, felbamate, lamotrigine, topiramate, rufinamide, clobazam, cannabidiol, and fenfluramine. Additionally, several other ASMs, including valproate, are frequently used off-label for LGS management. As the therapeutic landscape for LGS expands, clinicians are increasingly faced with complex decisions regarding optimal ASM selection. This narrative review explores evolving treatment strategies, offering a consensus-based treatment algorithm designed by a panel of U.S.- based experts. We analyze both FDA-approved and off-label ASMs, drawing on data from randomized controlled trials, open-label extensions, and real-world studies to assess each drug's efficacy and safety profile. A key challenge in comparing ASMs lies in the heterogeneity of study designs and outcome measures. This review addresses these limitations and considers crucial factors influencing ASM selection, such as seizure outcomes, safety profiles, cognitive and behavioral outcomes, drug-drug interactions, and rational polypharmacy. Barriers to access, including economic and regulatory hurdles, are also discussed. The proposed treatment algorithm emphasizes a personalized approach to LGS management, recommending valproate or clobazam as first-line treatments, followed by individualized combinations based on the specific patient profile and associated comorbidities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. MSP servs as a consultant for Stoke Therapeutics, Neurelis, UCB, Pyros, Azurity, Marinus, and Jazz. Research funding has been provided to MSP’s institution by Takeda, UCB, Stoke, Encoded, Neurocrine, and Biocodex. MSP also holds unpaid board memberships with the Child Neurology Foundation, Pediatric Epilepsy Research Consortium, Lennox-Gastaut Foundation, and Dravet Syndrome Foundation. The other authors declare no potential conflicts of interest with respect to the research, authorship, and publication of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Neuromodulation techniques, including vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS), have emerged as important treatment options for patients with LGS who do not respond adequately to antiseizure medications. This review, developed with input from the Pediatric Epilepsy Research Consortium (PERC) LGS Special Interest Group, provides practical guidance for clinicians on the use of these neuromodulation approaches in patients with LGS. We discuss patient selection criteria, expected seizure and non-seizure outcomes, potential complications, and device management considerations for each technique. The review also covers initiation and titration strategies, ongoing care requirements, and emerging data on combining multiple neuromodulation modalities. While all three approaches can reduce seizure frequency in patients with LGS, with commonly reported responder rates ranging from 50 % to 60 %, their impacts on cognition, behavior and quality of life are more variable. Careful patient selection, individualized programming, and long-term follow-up are essential to optimize outcomes with neuromodulation in this challenging patient population. Further research is needed to identify optimal candidates, determine the ideal timing during patients' clinical course to consider neuromodulation, develop standardized outcome measures, and evaluate the comparative effectiveness and cost-effectiveness of different neuromodulation techniques for LGS., (Copyright © 2025 Elsevier B.V. All rights reserved.)