For 60% of acute febrile encephalitis cases, the cause is unknown. Autoantibodies directed against different synaptic proteins or receptors in patients with autoimmune encephalitis have recently been described and could indicate a differential diagnosis of infectious encephalitis.

The aim of this study was to retrospectively investigate the presence of autoantibodies directed against synaptic proteins or receptors in patients with acute febrile encephalitis. Samples were collected in France in 2007 during a national prospective study.

A total of 253 patients with acute febrile encephalitis were enrolled in 2007. Clinical data were collected with a standardized questionnaire. When possible, cerebrospinal fluid CSF was collected and stored at −80 °C. A total of 108 CSF samples were available for retrospective autoantibody screening. Among the 108 patients, infectious etiology had been detected in 38 cases (35%); of these 38 patients, 29 (27%) had viral encephalitis, and 9 (8%) had bacterial encephalitis. No specific diagnosis was indicated for the other 70 patients (65%). Autoantibodies were detected using a cell-based assay in which HEK293 cells were transfected with plasmids coding for different synaptic proteins or receptors.

Two patients had anti-NMDA receptor antibodies (NMDAR-Abs), and all patients were negative for anti-Lgi1, CASPR2, GABABR, AMPAR, and mGluR5 antibodies. The two patients with NMDAR-Abs presented neurological and psychiatric symptoms typical of NMDAR-Abs encephalitis.

Autoimmune etiology seems to be rare (less than 2%) in patients with acute febrile encephalitis. However, patients should be systematically screened for the presence of NMDAR-Abs, particularly patients presenting with psychiatric symptoms.