Herpes simplex virus encephalitis is a trigger of brain autoimmunity

Abstract

In 5 prospectively diagnosed patients with relapsing post-herpes simplex encephalitis (HSE), N-methyl-D-aspartate receptor (NMDAR) antibodies were identified. Antibody synthesis started 1 to 4 weeks after HSE, preceding the neurological relapse. Three of 5 patients improved postimmunotherapy, 1 spontaneously, and 1 has started to improve. Two additional patients with NMDAR antibodies, 9 with unknown neuronal surface antibodies, and 1 with NMDAR and unknown antibodies, were identified during retrospective assessment of 34 HSE patients; the frequency of autoantibodies increased over time (serum, p=0.004; cerebrospinal fluid, p=0.04). The 3 retrospectively identified NMDAR antibody-positive patients also had evidence of relapsing post-HSE. Overall, these findings indicate that HSE triggers NMDAR antibodies and potentially other brain autoimmunity.

Figure 1. Clinical course, treatment, and CSF/serum NMDAR antibody titers in four patients with neurological relapses post-HSE

Scaling of X-axes is different in all patients reflecting length of follow-up. Broken x-axis represents discontinuous axis and change of tick interval. Right y-axis and grey curve: quantitative measure of disease severity Pediatric Cerebral Performance Category, PCPC(1=normal,2=mild disability, 3=moderate disability, 4=severe disability, 5= coma or vegetative state, 6=dead). Left y-axis: filled boxes NMDAR antibody titer in CSF, empty diamonds NMDAR antibody titer in serum (multiplied x100 to fit the same axis as CSF). Camera symbol represent available video segments in the supplementary video. IVIg: intravenous immunoglobulins, IvMP: intravenous methylprednisolone, or steroids: oral steroids, Ritux: rituximab, CycP: cyclophosphamide.

Figure 2. Determination and frequency of antibodies to NMDAR and uncharacterized cell-surface antigens in a retrospective cohort of patients with HSE

A: HEK cells expressing GluN1/GluN2 subunits of the NMDAR incubated with CSF of the indicated patients (left column, green fluorescence), and a monoclonal antibody to GluN1 (middle column, red); the merged immunostaining is shown in the right column. Nuclei of neurons demonstrated with DAPI. Scale bar 10μm. Note that only patient #7 had antibodies to NMDAR (a similar staining was obtained with cells transfected only with GluN1, not shown). B and C: Reactivity of the CSF of the same patients with sagittal sections of rat brain (B), and live rat hippocampal neurons (C). The CSF of patient #7 shows a typical pattern of NMDAR reactivity with the neuropil of hippocampus as well as with the cell-surface of neurons; the CSF of patient #8 shows reactivity with a neuropil antigen expressed on the cell-surface of neurons (the identity of the antigen is unknown), and the CSF of patient #37 was negative in both tests. Scale bar in B 500μm; Scale bar in C 10μm. D: Percentage of patients’ serum and CSF samples harboring IgG antibodies to NMDAR (black) or to other neuronal cell-surface antigens (grey) during and after the first week of HSE; the identity of other neuronal antigens was unknown. Frequency increased over time (serum p=0.004, CSF p=0.04, Mann Whitney U test).