Clinical significance of IgM and IgA class anti-NMDAR antibodies in herpes simplex encephalitis

Background: Herpes simplex encephalitis (HSE) is a devastating disease, often leaving patients with severe disabilities. It has been shown that IgG anti-N-methyl-o-aspartate receptor (NMDAR) antibodies appear in approximately 25% of HSE patients and could be associated with impaired recovery of cognitive performance. Objectives: To characterize the prevalence of IgM and IgA anti-NMDAR antibodies in HSE patients, in relation to subsequent development of IgG anti-NMDAR and correlation to cognitive performance. Study design: A total of 48 subjects were included from a previously described cohort of patients with HSE verified by HSV-1 PCR. Cerebrospinal fluid (CSF) and serum samples drawn close to onset of disease, after 14-21 days of iv aciclovir treatment and after 90 days of follow-up, were analyzed for the presence of IgM and IgA anti-NMDAR, and related to IgG anti-NMDAR. Antibody levels were correlated to the recovery of cognitive performance, as estimated by the Mattis Dementia Rating Scale (MDRS), for a total of 24 months. Results: In total, 27 of 48 (56%) study subjects were anti-NMDAR positive, defined as the presence of IgG (12/ 48, 25%), IgM (14/48, 29%) or IgA (13/48, 27%) antibodies in CSF and/or serum. IgM or IgA anti-NMDAR did not predict subsequent IgG autoimmunization and did not correlate to cognitive outcome. IgG anti-NMDAR serostatus, but not antibody titers, correlated to impaired recovery of cognitive performance. Conclusions: A majority of HSE patients develop IgG, IgM or IgA anti-NMDAR antibodies. However, the predictive value and clinical relevance of non-IgG isotypes remains to be shown in this setting.