AUTOIMMUNE ENCEPHALITIS: DIAGNOSTIC CHALLENGES, CLINICAL DIFFERENTIATION FROM INFECTIOUS CAUSES, AND EVOLVING IMMUNOTHERAPEUTIC STRATEGIES

Abstract

Autoimmune encephalitis (AE) is a diverse group of inflammatory brain disorders that involve the production of antibodies against either neuronal, synaptic or glial antigens, and/or T cells. It has advanced from a largely paraneoplastic notion to a wide range of diseases, such as antibody-mediated syndromes involving cell surfaces, antigen-mediated syndromes involving intracellular antigens, post-infectious encephalitis, immune checkpoint inhibitor-induced encephalitis, and clinically probable antibody-negative AE. The main clinical problem is to identify a proper clinical syndrome early, in addition to identifying a neural antibody, which also needs to be differentiated from the other inflammatory disorders, malignancy, and epilepsy-related states, toxic-metabolic encephalopathy and primary psychiatric illness. Thus, a safe diagnostic approach combines tempo, phenotype and magnetic resonance imaging (MRI), electroencephalography (EEG), studies of cerebrospinal fluid (CSF), paired serum-CSF antibody testing, microbiological studies, and tumor screening based on the phenotype. The course of therapy with acyclovir should be started when herpes simplex virus encephalitis is considered possible, but should not be unnecessarily delayed in a severe, clinically coherent AE syndrome if it has been reasonably excluded or controlled. High dose corticosteroid, intravenous immunoglobulin and/or plasma exchange are first line agents and rituximab/cyclophosphamide for non-response, severe disease or relapse. Other targeted therapies (tocilizumab, bortezomib, daratumumab, FcRn antagonists and others) are promising but have limited evidence in the form of observational evidence, small case series, or ongoing trials. The recovery process is often delayed and good motor outcome is possible in the presence of ongoing cognitive, psychiatric, language and epilepsy-related disabilities. Future progress relies on biomarkers validated in multiple trials, and standardized outcome measures, as well as randomized and adaptive trials and equitable precision-medicine frameworks which integrate clinical information, immunophenotyping and multi-omics. (Abboud et al., 2021; Almweisheer et al., 2026; Chen et al., 2026; Thilak et al., 2026).