Invasive Neuromodulation in Lennox-Gastaut Syndrome: A Systematic Review and Meta-Analysis

Lennox-Gastaut syndrome (LGS) is a highly drug-resistant epileptic encephalopathy. The high seizure burden in LGS contributes to substantial morbidity, reduced quality of life, and increased mortality, underscoring the need for alternative therapeutic strategies such as invasive neuromodulation.

We aimed to synthesize the efficacy and safety of invasive neuromodulation-vagus-nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS)-for seizure control in LGS.

We performed a systematic review and meta-analysis (International Prospective Register of Systematic Reviews, CRD420251088693). PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched from inception to November 2025. Studies enrolling individuals of any age with LGS who underwent VNS, DBS, or RNS were eligible; mixed-etiology studies were retained if individual patient data permitted LGS-specific extraction. Two reviewers screened records and extracted summary data. The primary outcomes were the proportion crossing predefined thresholds (0%-25%, <50%, ≥50%, ≥70%, and ≥90% seizure reduction). Adverse events were summarized descriptively.

From 1058 records, 71 studies (47 VNS [1618 patients], 16 DBS [110 patients], and eight RNS [37 patients]) involving 1765 patients met the inclusion criteria. Overall, 55.76% (95% CI 48.39-62.88) experienced a ≥50% seizure reduction. DBS yielded the highest responder rate (78.50%; 65.48-87.55), followed by RNS (53.57%; 35.44-70.80) and VNS (48.72%; 41.04-56.46). Only 18.64% (12.05-27.69) reached a ≥90% reduction, and seizure freedom was rare. Age-band subgroup analyses showed no efficacy difference between pediatric, adult, and mixed-age cohorts (interaction p > 0.1). Adverse events were modality-specific yet predominantly mild and manageable; infections occurred in <5% of cases. Risk of bias was serious or critical in most observational studies; overall Grading of Recommendations Assessment, Development and Evaluation certainty was very low.

Invasive neuromodulation can provide meaningful seizure reduction for LGS, with DBS showing the most favorable efficacy signal, but the evidence is low. Head-to-head randomized trials are required to confirm relative effectiveness and optimize target selection.