Intravenous Immunoglobulin in Autoimmune Encephalitis in Adults (ENCEPH-IG): A Randomised Double-Blind Placebo-Controlled Trial

Background Autoimmune encephalitides are a group of neuroinflammatory disorders which are potentially treatable with immunotherapy. Corticosteroids are widely used, but the role of early intravenous immunoglobulin (IVIG) remains uncertain and has not been studied in a randomised control trial (RCT). ENCEPH-IG was designed to evaluate whether IVIG improved the outcome of autoimmune encephalitis in adults. Methods ENCEPH-IG was a UK multicentre, blinded superiority RCT of IVIG in adults with suspected autoimmune encephalitis. Patients were randomised 1:1 to receive IVIG or placebo, in addition to intravenous methylprednisolone followed by an oral prednisolone. The primary outcome was time to recovery, as defined by achieving a Glasgow Outcome Scale-Extended score of ≥5 on two consecutive assessments. Results The trial was terminated early because of slow site set-up and low recruitment. 21 patients were randomised; 10 received IVIG and 11 received placebo across 11 hospital sites. At 12 months, 10 patients (48%) achieved recovery (5 in the IVIG group and 5 in the placebo group). Median time to recovery was shorter in the IVIG arm (10 weeks [IQR 8–16]) than the placebo arm (20 weeks [IQR 16–32]). Serious adverse events (SAEs) affected 9/11 patients (82%) in the placebo arm, and 6/10 patients (60%) in intervention arm. The majority of SAEs were infections. Conclusion ENCEPH-IG could not determine the efficacy of early IVIG in autoimmune encephalitis in adults because of slower than expected recruitment and early trial termination. The impact of the COVID-19 pandemic on research infrastructure, differing IVIG availability across UK NHS sites and varying local practice affecting the degree of clinical equipoise all contributed to this. Future trials in autoimmune encephalitis should consider adaptive trial designs, allowing the assessment of multiple therapies, with agility to reflect the rapidly changing scientific advances in treatment, while retaining the power to assess clinically relevant outcome measures.