One Brain, Two Specialties, Converging Mechanisms: Neuronal Autoantibodies as a Rare Cause of Postpartum Psychosis.

Abstract

The onset of severe psychotic and affective symptomswithin the first 4–6 weeks after childbirth, termed postpartum or puerperal psychosis, is one of the most striking phenotypes in psychiatry and neurology (1). The onset is typically abrupt, and the decline rapid (1). Postpartum psychosis is a psychiatric emergency and can be incredibly disruptive to the mother, child, and family alike. Sadly, postpartum psychosis can also be destructive via maternal self-harm (2) and, very rarely, infanticide (3). In this issue of the Journal, Bergink et al. (4) identify neuronal autoantibodies linked to autoimmune encephalitis as a specific, albeit rare, cause of psychosis in the postpartum period. The authors collected serum samples from 96 consecutive women with postpartum psychosis evaluated in a specialized mother and child inpatient psychiatric unit in the Netherlands between 2005 and 2012. Antibodies against the GluN1/NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor were identified in two (2%) of the women with postpartum psychosis, including one who had experienced a prior episode of postpartum psychosis. Neither woman had an ovarian teratoma, and neither exhibited other classic features of anti-NMDA receptor encephalitis, such as seizure, amnesia, autonomic instability, or coma. However, the observed antibody reactivitywas typical ofwhat is seen in anti-NMDAreceptorencephalitis,anautoimmuneencephalitis syndrome with prominent psychiatric features (5). An additional two (2%) women exhibited abnormal neuropil staining indicative of abnormal autoantibody reactivity to an unidentified extracellular antigen(s). By contrast, none of the 64 healthy postpartum women exhibited neuronal cellsurface antibodies or neuropil reactivity on serum testing. The authors conclude that NMDA receptor antibodies were likely causative of or contributory to the postpartum psychiatric syndrome in these select cases and that testing for NMDA receptor antibodies should become part of the diagnostic evaluation for postpartum psychosis (4). The emerging recognition that autoantibodies can target neuronal cell-surface and synaptic CNS antigens and cause brain dysfunctionhas revolutionized clinical neurology (6, 7). Autoantibodies from patients have been identified against several synaptic receptors, such as NMDA, AMPA, GABAa, GABAb, mGluR5, and glycine, as well as ion channel and associated membrane proteins, such as LGI1 and CASPR2. The practical implication is that many cases of encephalitis that at one timemight have been called “viral” or “idiopathic” are now recognized to be autoimmune in origin and are generally responsive to immunosuppression. By contrast, classical “paraneoplastic” disorders associated with antibodies against intracellular antigens, such as Hu and CRMP-5, are highly correlated with the presence of a tumor, tend to respond poorly to immunosuppression, and exhibit pan-neuronal destruction with prominent T-cell infiltration. Unlike neuronal cell-surface antibodies, antibodies to intracellular antigens in classical paraneoplastic syndromes are probably not directly pathogenic but are rather humoral markers of an antitumoral immune response (8). Anti-NMDA receptor encephalitis isanarchetypical autoimmune encephalitis syndrome. It is a disease of the young; 95%of cases occur in patients under age 45 and 37% in children under age 18 (5). There is a femalepredominance (5). Patients with NMDA receptor encephalitis tend to exhibit a characteristic clinical syndrome heralded by a vague prodrome of headache, fever, nausea, vomiting, and upper respiratory infectiontype symptoms, followed by the acute onset of prominent psychiatric symptoms, including agitation, anxiety, disordered thinking, hallucinations, delusions, and unusual behavior (9). Some patientswith anti-NMDA receptor encephalitismay even gettriagedinitially toapsychiatricservice.Thesyndromeusually progresses within days to include prominent amnesia, language dysfunction, and seizures (9). A subset of patients will decline rapidly with autonomic dysfunction and reduced level of consciousness to the point of coma, requiring extended stays in the intensive care unit sometimes for months on end (9). Abnormal movements are common. CSF examination usually reveals a pleocytosis andoligoclonal banding (5, 9). BrainMRI is usually normal or nonspecific but can show focal T2/fluid-attenuated As the diagnostic endeavors of neurology and psychiatry reconverge ... it will be increasingly important for psychiatrists to be aware of autoimmune encephalitis syndromes with prominent psychiatric features and available antibody testing.