Anti-NMDA receptor encephalitis, autoimmunity, and psychosis

Abstract

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a recently-discovered synaptic autoimmune disorder in which auto-antibodies target NMDARs in the brain, leading to their removal from the synapse. Patients manifest with prominent psychiatric symptoms - and in particular psychosis - early in the disease course. This presentation converges with long-standing evidence on multiple fronts supporting the glutamatergic model of schizophrenia. We review mechanisms underlying disease in anti-NMDAR encephalitis, and discuss its role in furthering our understanding of neural circuit dysfunction in schizophrenia.

Keywords: Autoimmune; Encephalitis; NMDA; Schizophrenia.

Figure 1. Typical clinical course of illness in anti-NMDAR encephalitis

Following a viral prodrome, patients experience prominent psychiatric symptoms in the early weeks of the disorder. This is followed by progressive neurological involvement, often requiring ICU-level care. Prolonged behavioral and cognitive and behavioral symptoms are common, though most patients make a near complete recovery with early and aggressive treatment.

Figure 2. Demonstration of NMDA receptor antibodies during initial presentation and at relapse in the same patient

Antibodies to NMDA receptors demonstrated with three different techniques: Immunohistochemistry optimized for synaptic antigens (A, B), live cultured neurons (C, D), and a human kidney cell line (HEK) recombinantly expressing GluN1 subunit of the NMDAR (E-J). Panels (A, C, and E-G) show reactivity of CSF of the patient obtained during the recovery phase of the initial episode, and panels (B, D, and H-J) show the reactivity at relapse. In all panels the CSF was used at dilution of 1:5. In A and B the antibody-labeling of the NMDAR is shown in brown (avidin-biotin peroxidase technique); in C and D in green fluorescence (nuclei of neurons stained blue with DAPI), and in E and H in green fluorescence. The red fluorescence in F and I correspond to a commercial monoclonal antibody against the GluN1 subunit of the NMDAR directed against an epitope different from that identified by patient’s antibodies (the co-localization of reactivities is shown in yellow in G and J). The titers of antibodies were determined using serial dilutions of CSF (titer defined as the highest dilution where reactivity was visible), resulting in 1/5 at recovery phase of initial episode and 1/80 at relapse (not shown). Bar in B=50 µm, D=10 µm, and J=10 µm.