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

One-third of epilepsy patients do not fully respond to antiseizure medications (ASM), are not candidates for curative surgical interventions, or have unsuccessful surgical therapies. Safe and effective therapies remain limited for these treatment-resistant epilepsy (TRE) patients. Several palliative neurostimulation devices were approved by the US Food and Drug Administration (FDA) and other regulatory agencies: vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS). Only RNS is responsive and can continuously monitor electroencephalographic (EEG) activity, but its closed-loop stimulation is limited by spatiotemporal accuracy. VNS, RNS, and DBS require invasive implantations that can cause adverse outcomes. We developed a minimally invasive tool with automatic seizure detection that can deliver therapeutic intersectional short-pulse (ISP) stimulation to terminate pathological brain activity. The therapy exerts an immediate effect, reducing seizures from the onset of treatment, without the prolonged adaptation period typically required by other neurostimulation approaches. We assessed the safety, feasibility, and effectiveness of ISP stimulation delivered transcranially through subgaleal electrodes in epilepsy patients with focal seizure and with Lennox-Gastaut syndrome. Ictal ISP stimulation reduced seizure duration by 52% in average, modulated spectral content, and inhibited secondary generalization. Among patients with multiple daily seizures, closed-loop ISP stimulation reduced seizure incidence >80% within days of inpatient treatment. Minimally invasive implantation strategy with precise, closed-loop ISP delivery can safely and effectively reduce seizure activity in TRE patients. This trial is registered at ClinicalTrials.gov, identifier NCT07041619.