Closed-Loop, Subgaleal Intersectional Short-Pulse Stimulation for the Treatment of Therapy-Resistant Epilepsy in Adults

Approximately one-third of epilepsy patients do not respond to antiseizure medications (ASM), are not suitable candidates for curative surgical interventions, or have unsuccessful surgical therapies. Currently, the available repertoire to treat this patient pool is limited. Only a few viable solutions have been approved by the US Food and Drug Administration (FDA): deep brain stimulation (DBS), vagus nerve stimulation (VNS), and responsive neurostimulation (RNS). However, these almost exclusively lack adaptability, the ability for continuous monitoring for extended periods, and closed-loop stimulation with high accuracy and spatiotemporal specificity while requiring invasive implantation strategies that pose several risk factors to the patients involved. We sought to improve these aspects as we developed a minimally invasive, adaptive neuromonitoring tool combined with automatic epileptic seizure detection and intersectional short-pulse (ISP) stimulation to immediately terminate pathological brain activity without the need to wait long periods (i.e., weeks to months) for the seizure-altering effect to build up. We conducted a first-in-patient study assessing the safety, feasibility, and effectiveness of ISP stimulation delivered transcranially through subgaleally implanted electrodes in patients with epilepsy. Our preliminary evidence shows that ictal ISP stimulation instantaneously reduced seizure duration by 53%, modulated spectral content, and effectively inhibited secondary generalization. Moreover, closed-loop ISP stimulation reduced seizure incidence by 83% within the first three days of inpatient treatment. The combination of a minimally invasive implantation strategy with precise, closed-loop ISP delivery demonstrated promising safety and acute efficacy and supports ISP as a candidate therapy for drug-resistant epilepsy. This trial is registered at ClinicalTrials.gov, identifier NCT07041619 .