Comparative efficacy of neuromodulation therapies in Lennox–Gastaut syndrome: A systematic review and meta‐analysis of vagus nerve stimulation, deep brain stimulation, and responsive neurostimulation

Abstract Objective Lennox–Gastaut syndrome (LGS) is a childhood onset developmental and epileptic encephalopathy characterized by multiple seizure types that are often refractory to traditional antiseizure medications. Neuromodulation therapies including vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS) have emerged as potential treatment options, but their comparative efficacy remains unclear. Methods We conducted a systematic review and meta‐analysis of studies reporting outcomes of neuromodulation therapies in patients with LGS. A comprehensive search of electronic databases was performed through July 26, 2024. The primary outcome was the proportion of patients achieving ≥50% seizure reduction. Random‐effects models were used to calculate pooled estimates, and meta‐regression analyses were performed to identify potential effect modifiers. Results Fifty‐four studies comprising 1350 patients were included in the analysis (VNS: 37 studies, 1242 patients; DBS: 11 studies, 81 patients; RNS: six studies, 27 patients). The overall pooled responder rate was 55.4% (95% confidence interval [CI] = 48.0%–62.8%). DBS showed the highest responder rate (69.7%, 95% CI = 51.3–88.1%), followed by RNS (63.0%, 95% CI = 30.9–95.1%) and VNS (50.6%, 95% CI = 43.0–58.2%). Meta‐regression analysis revealed that intervention type was a significant moderator of treatment effect, with VNS showing significantly lower efficacy compared to DBS ( p = .0305). In the DBS subgroup, a later onset of epilepsy was a significant positive predictor of response ( p = .0051). Twenty studies qualitatively described quality‐of‐life outcomes, most commonly noting improved alertness and attention, although heterogeneous assessments precluded meta‐analysis. Twenty‐seven studies reported complications; VNS was linked to stimulation‐related side effects, whereas DBS and RNS had higher rates of serious device‐related issues. Significance This meta‐analysis suggests that all three neuromodulation therapies are effective for seizure reduction in LGS, with DBS and RNS demonstrating potentially superior efficacy compared to VNS. These findings may help guide treatment selection for patients with LGS, although prospective comparative studies are needed.