CSF-Positive, Seronegative Anti-NMDAR Encephalitis: Systematic Review and Analysis

Anti–N-methyl-d-aspartate receptor (NMDAR) encephalitis is a rare neuropsychiatric disorder, typically diagnosed through cerebrospinal fluid (CSF) antibody testing. Although most cases of anti-NMDAR encephalitis are seropositive, some patients have CSF antibodies despite negative serum results. The authors conducted a systematic review of cases by searching multiple databases. Key clinical features, demographic information, and the results of various diagnostic investigations were analyzed to assess the presentation and outcomes of seronegative anti-NMDAR encephalitis cases. Clinical screening tools were applied among individuals who sought care in psychiatric services. In total, 128 clinical cases of seronegative, CSF-positive anti-NMDAR encephalitis were identified, with a female-to-male ratio of 1:0.6 and a median age of 25 years. Overall, 17 patients (13%) had an ovarian teratoma, 11 (9%) had a current or recent pregnancy, 55 (43%) had reported comorbid central nervous system (CNS) diagnoses, and 37 (29%) had other antineuronal antibodies. Of 17 (13%) cases involving initially only psychiatric or cognitive symptoms, all except two patients developed neurological symptoms. At 1 week after hospitalization, clinical screening criteria would have identified between 82% and 100% of cases with available data. Patients with seronegative anti-NMDAR encephalitis represent a medically complex subgroup with distinctive clinical features. In psychiatric practice, the development of atypical psychiatric and neurological symptoms should prompt additional consideration of CSF testing for encephalitis. The high rates of coexisting CNS disorders and of other antineuronal antibodies among patients with seronegative anti-NMDAR encephalitis need further examination to determine the possibility of overlapping syndromes or false-positive antibody results.