Real‐world outcomes of responsive neurostimulation in patients with Lennox–Gastaut syndrome: A multicenter retrospective study

Abstract Objective Lennox–Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy (DEE) characterized by multiple seizure types and high resistance to antiseizure medication (ASM), often necessitating nonpharmacologic therapies, including neuromodulation. Responsive neurostimulation (RNS), a closed‐loop brain‐responsive neuromodulation device, has emerged as an adjunctive treatment option for drug‐resistant epilepsy (DRE), but evidence on its safety and effectiveness in LGS remains limited. This study examines real‐world outcomes of RNS therapy in patients with LGS‐associated DRE. Methods This retrospective multicenter study included patients with LGS who underwent RNS implantation before December 2024 across four Level 4 National Association of Epilepsy Centers (NAEC) in the United States. Demographic, clinical, surgical, and outcome data were systematically collected using a standardized case report form and analyzed. Results Thirty‐seven patients met inclusion criteria. At the time of RNS implantation, 95% of patients were pediatric (mean age 12.9 years, range 3.6–28.8) with a median follow‐up of 24.5 months. All patients had generalized tonic seizures; additional seizure types included tonic–clonic (62%), atonic (50%), atypical absence (19%), and other (54%). The pooled responder rate (≥50% seizure reduction) was 62%, including 10% with ≥90% reduction. Thalamic‐only stimulation of the bilateral centromedian nucleus (CMN) was the most common electrode configuration (76%), followed by cortico‐thalamic targeting to the CMN and bi‐frontal regions (18%). Among responders, 83% received thalamic‐only CMN stimulation. ASM reduction occurred in 10% of patients. Adverse events were reported in 13%, primarily implant‐related infections, with 4 patients requiring explantation. Stimulation‐related side effects occurred in 27% and resolved with programming adjustments in 80%. Significance RNS targeting thalamic and cortico‐thalamic networks resulted in seizure reduction in the majority of this predominantly pediatric LGS cohort. Therapy was generally well‐tolerated with few serious adverse events, supporting its potential role as an adjunctive treatment option for DRE in LGS. Plain Language Summary Lennox–Gastaut syndrome is a severe form of epilepsy that is often hard to control with medications. This study evaluated responsive neurostimulation (RNS), an implanted device that monitors brain activity and delivers electrical stimulation to help stop seizures before they spread. In 37 mostly pediatric patients, about 60% had their seizures reduced by at least half, and some improved even more. The treatment was generally safe, and most side effects could be managed by adjusting the device.