Antibody-negative autoimmune encephalitis: From clinical diagnosis to antigen discovery

Autoimmune encephalitis (AE) comprises immune-mediated brain disorders that may occur despite the absence of detectable neuronal antibodies. These antibody-negative presentations comprise a broader spectrum that includes antibody-negative but probable autoimmune encephalitis (ANPRA) as well as clinically defined syndromes such as definite antibody-negative autoimmune limbic encephalitis, MOG-IgG-negative ADEM, and antibody-negative Bickerstaff brainstem encephalitis. Apparent antibody-negativity may reflect assay limitations, antibodies against as-yet unidentified neural antigens, or immune-mechanisms not dominated by detectable humoral responses, including T-cell-mediated and innate-immune pathways, after alternative diagnoses have been reasonably excluded. Assay methodology, antigen panel selection and paired serum/CSF testing are critical and can reveal previously unrecognized neural reactivity in a subset of patients initially classified as antibody-negative. Emerging antigen-discovery strategies, including tissue-based screening, protein arrays, immunoprecipitation-mass spectrometry, and PhIP-Seq, may identify novel neural targets and refine disease classification. This review summarizes current knowledge and emerging approaches to improve recognition and stratification of antibody-negative AE.