Clinical features of seronegative, but CSF antibody-positive, anti-NMDA receptor encephalitis

OBJECTIVE: To determine the frequency of anti-NMDA receptor encephalitis without detectable serum NMDAR antibodies and to compare the clinical features of these patients with those with NMDAR antibodies in serum and CSF. METHODS: This is a retrospective assessment of serum antibody status and clinical features of 489 patients with anti-NMDAR encephalitis, defined by the presence of NMDAR antibodies in the CSF, and available paired serum/CSF samples examined at Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi I Sunyer, Barcelona, between January 2007 and December 2017. NMDAR antibodies were determined with rat brain immunostaining, in-house cell-based assay (CBA), and a commercial CBA. Patients were considered seronegative if NMDAR antibodies were undetectable with the 3 indicated techniques. RESULTS: Serum NMDAR antibodies were not detected in 75 of 489 (15%) patients. Compared with the 414 seropositive patients, the seronegative were older (23.5 years [interquartile range (IQR): 17–43] vs 20.5 [IQR: 14–31]; p < 0.0001) and less frequently women (39 [52%] vs 313 [76%]; p < 0.001) and had less tumors (6 [9%] vs 128 [32%]; p < 0.001). In multivariate analysis, older age at diagnosis (odds ratio [OR]: 1.35 [per decade]; 95% confidence interval [CI]: 1.10–1.67), absence of tumor (OR: 0.14; 95% CI: 0.05–0.43), and less need for intensive care unit admission (OR: 0.35; 95% CI: 0.18–0.69) were independent variables associated with the absence of serum NMDAR antibodies. Time to diagnosis, treatment with immunotherapy, relapses, and outcome were similar in seronegative and seropositive patients. CONCLUSIONS: NMDAR antibodies are not detected in the serum of 15% of the patients with anti-NMDAR encephalitis. These patients appear to be older and have milder neurologic symptoms with less frequency of tumors.