Goldman, Alica M

Immune-mediated epilepsies represent an etiologically unique category defined by immune activation within the central nervous system that initiates a pathophysiological cascade resulting in seizures, encephalopathy, and sometimes epileptogenesis with long-term epilepsy. Once considered rare and largely confined to paraneoplastic or postinfectious syndromes, immune-mediated and inflammatory mechanisms are now recognized across a broad spectrum ranging from acute autoimmune encephalitis with reversible seizures, new-onset refractory status epilepticus, or febrile illness-related refractory status epilepticus, to chronic autoimmune-associated epilepsy and drug-refractory structural epilepsies. This review integrates historical perspectives, mechanistic insights from animal and human studies, and contemporary clinical frameworks. It synthesizes advances in neuroimmunology, clinical phenotyping, diagnostics, immunomodulatory and antiseizure therapies, neuromodulation, and patient and family centered outcomes, and outlines future directions focused on biomarker-driven precision medicine, disease-modifying strategies, and interdisciplinary care models.

Abstract Objective This study was undertaken to evaluate the safety and effectiveness of responsive thalamic stimulation as adjunctive therapy for drug‐resistant idiopathic generalized epilepsy (IGE) with generalized tonic–clonic seizures (GTCSs). Methods NAUTILUS is a prospective, multicenter, single‐blind, randomized sham‐controlled pivotal trial. Patients were ≥12 years of age with drug‐resistant IGE and ≥2 GTCSs over a 3‐month baseline. Bilateral depth leads were targeted to the centromedian thalamus. One month later, patients were randomized to Active (responsive stimulation, n = 44) or Sham (no stimulation, n = 43). The effectiveness evaluation period (EEP) began 3 months postimplant through 1 year. After a second GTCS in the EEP, patients transitioned to open‐label active stimulation. The primary safety endpoint was the serious adverse device‐related event (SADE) rate at 84 days postimplant. The primary effectiveness endpoint was time‐to‐second‐GTCS during the EEP. Additional endpoints included median percent change in days with any generalized seizure, GTCS frequency, and responder rate (RR). Results Eighty‐seven patients were implanted across 23 US centers. The SADE rate was significantly below the performance goal (6.9%, p < .0001), with no adverse effects on cognition, mood, or sleep. The prespecified primary effectiveness endpoint was not significant. However, a post hoc mixed‐effects model considering all EEP days demonstrated greater GTCS reduction in the originally randomized Active group (61%) compared to patients originally randomized to Sham (49%, p = .030). Eighteen‐month outcomes included 76.8% median GTCS reduction, 62.5% RR, 40% GTCS‐free at that timepoint, and 77.8% median reduction in days with any generalized seizure. More than 90% of patients and 86% of physicians reported improvement on Global Impression of Change scales. Significance NAUTILUS is the first randomized controlled neuromodulation trial in IGE. Responsive thalamic stimulation provided a clinically meaningful and durable reduction in seizures with an acceptable safety profile, offering a much‐needed option for drug‐resistant IGE.