To report a novel autoimmune encephalitis in which the antibodies target neurexin-3α, a cell adhesion molecule involved in the development and function of synapses.

Five patients with encephalitis and antibodies with a similar pattern of brain reactivity were selected. Antigen precipitation and determination of antibody effects on cultured rat embryonic neurons were performed with reported techniques.

Immunoprecipitation and cell-based assays identified neurexin-3α as the autoantigen of patients' antibodies. All 5 patients (median age 44 years, range 23–50; 4 female) presented with prodromal fever, headache, or gastrointestinal symptoms, followed by confusion, seizures, and decreased level of consciousness. Two developed mild orofacial dyskinesias, 3 needed respiratory support, and 4 had findings suggesting propensity to autoimmunity. CSF was abnormal in all patients (4 pleocytosis, 1 elevated immunoglobulin G [IgG] index), and brain MRI was abnormal in 1 (increased fluid-attenuated inversion recovery/T2 in temporal lobes). All received steroids, 1 IV immunoglobulin, and 1 cyclophosphamide; 3 partially recovered, 1 died of sepsis while recovering, and 1 had a rapid progression to death. At autopsy, edema but no inflammatory cells were identified. Cultures of neurons exposed during days in vitro (div) 7–17 to patients' IgG showed a decrease of neurexin-3α clusters as well as the total number of synapses. No reduction of synapses occurred in mature neurons (div 18) exposed for 48 hours to patients' IgG. Neuronal survival, dendritic morphology, and spine density were unaffected.

Neurexin-3α autoantibodies associate with a severe but potentially treatable encephalitis in which the antibodies cause a decrease of neurexin-3α and alter synapse development.