This study investigates the clinical and paraclinical progression of N-methyl-D-aspartate (NMDA) receptor antibody encephalitis, a predominantly non-paraneoplastic disorder affecting both sexes. The authors developed a sensitive cell-based assay for detecting NMDA receptor antibodies in serum and cerebrospinal fluid (CSF), and a quantitative fluorescent immunoprecipitation assay for serial studies. They found that NMDA receptor antibodies were primarily of the immunoglobulin G1 subclass and could activate complement on NMDA receptor-expressing human embryonic kidney cells. Among 44 patients with NMDA receptor antibodies, 80% did not have a detected tumor, with a higher proportion of non-Caucasians (29%). Good clinical outcomes, defined by reduced modified Rankin scores, correlated with decreased NMDA receptor antibody levels and early administration of immunotherapies in non-paraneoplastic patients. The temporal analysis of neurological features suggested a two-stage progression: early features characterized by neuropsychiatric symptoms and seizures, followed by later features such as movement disorders, dysautonomia, and changes in consciousness. The study emphasizes the importance of early intensive immunotherapy and suggests that the neurological disease occurs in two main stages.This study investigates the clinical and paraclinical progression of N-methyl-D-aspartate (NMDA) receptor antibody encephalitis, a predominantly non-paraneoplastic disorder affecting both sexes. The authors developed a sensitive cell-based assay for detecting NMDA receptor antibodies in serum and cerebrospinal fluid (CSF), and a quantitative fluorescent immunoprecipitation assay for serial studies. They found that NMDA receptor antibodies were primarily of the immunoglobulin G1 subclass and could activate complement on NMDA receptor-expressing human embryonic kidney cells. Among 44 patients with NMDA receptor antibodies, 80% did not have a detected tumor, with a higher proportion of non-Caucasians (29%). Good clinical outcomes, defined by reduced modified Rankin scores, correlated with decreased NMDA receptor antibody levels and early administration of immunotherapies in non-paraneoplastic patients. The temporal analysis of neurological features suggested a two-stage progression: early features characterized by neuropsychiatric symptoms and seizures, followed by later features such as movement disorders, dysautonomia, and changes in consciousness. The study emphasizes the importance of early intensive immunotherapy and suggests that the neurological disease occurs in two main stages.