The Urgent Need for Evidence Over Anecdote: Equipoise in the ExTINGUISH Clinical Trial in Anti-NMDAR Encephalitis

ObjectiveDetermine whether treatment and outcomes have changed in patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis since the last extensive review of the literature in January of 2019. BackgroundAnti-NMDAR encephalitis is a rare and devastating disease associated with severe neurologic and psychiatric symptoms and is defined by the presence of antibodies against the NMDAR within the cerebrospinal fluid (CSF). There remain no FDA-approved treatments for anti-NMDAR encephalitis, and no placebo-controlled clinical trials have been completed to provide evidence for management of this disease. Treatment continues to be based on expert opinion and consensus. Design/MethodsWe conducted a systematic literature review in PubMed from January-2019 to April-2024. Detailed demographic and clinical information were extracted from English-language articles containing individual data from patients with anti-NMDAR encephalitis. Data were compared to previously published literature reviews to determine if treatment and outcomes have evolved. Results319 articles met inclusion criteria, including data from 641 unique patients. We report detailed demographic, clinical, treatment, and outcome data. No improvement in mRS was noted despite earlier first-line treatment, increased use of second-line immunotherapy, and a trend towards shorter length of hospitalization compared to prior analyses. The mortality rate remained steady at 6.9%; 20.1% of patients had an mRS between 3 and 5 at last follow-up. ConclusionsSince initial discovery, there have been advances in the treatment of anti-NMDAR encephalitis, but no gains in the last several years, and it is unlikely further improvements will occur without well-designed clinical trials. There is a clear need for evidence over anecdote in the treatment of anti-NMDAR encephalitis. Informed treatment decisions by patients and family requires awareness of ongoing trials as a treatment option. This onus lies within the neurologic community as a whole. Advancement of treatment for rare neurologic diseases depends on the broad support of the neurologic community for high-quality, randomized placebo-controlled clinical trials.