Beyond Biomarkers: Empiric Immunotherapy in Refractory Epilepsy and the Search for Responders

Sustained Rescue of Seizure Control in Patients With Highly Refractory Chronic Epilepsy Using Empiric Immunotherapy Doran E, Kelly A, Stanila R, Healy L, Doherty CP. Epilepsia . 2025 Aug;66(8):2743-2753. Objective: Following emerging evidence of autoimmune-associated seizures in medication-refractory epilepsy, we began offering a trial of immunotherapy to selected patients. Here, we review this approach's treatment response, predictive clinical features, and utility. Methods: This was a retrospective single-center cohort study (2018–2022) of empiric, palliative immunotherapy in 31 adults with highly refractory, highly active epilepsy. Since 2018, in line with the International League Against Epilepsy's addition of “immune” as an etiology in the Classification of Epilepsy, we initiated immunotherapy after comprehensive antiseizure medication failures while at the same time screening for an autoimmune origin. The workup included assessing clinical features, serum autoantibody testing, cerebrospinal fluid testing (where feasible), magnetic resonance imaging (MRI), and electroencephalography. All patients received intravenous methylprednisolone or IV immunoglobulin according to previously published protocols, and follow-up was for at least 12 months. Results: Nine patients (29%) in this highly refractory cohort demonstrated a sustained treatment response, measured as a greater than 50% improvement in seizure frequency for at least 12 months. Three patients (10%) became seizure-free. Six patients (20%) were classified as partial responders and experienced an initial response that was not sustained. Apart from a trend toward a diagnosis of focal epilepsy, we did not identify any specific serological, clinical, electrodiagnostic, or imaging features with statistical significance that were predictive of treatment response. Significance: This patient group demonstrated a reasonable response rate to an immunotherapy trial. These findings are surprising but support the consideration of an immunotherapy trial in patients with refractory epilepsy. Requirements for repeated courses of immunotherapy differed significantly between patients, and this is an area of interest for further research. The basis for response in this cohort remains unclear; in some cases, antiseizure medication changes may have contributed; however, without any apparent autoimmune features, we consider potential blood–brain barrier repair or a placebo effect as hypothetical alternative mechanisms of action for the response to immunotherapy.