Summary Background Early immunotherapy administration improves outcomes in patients with N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis. As most patients with NMDAR-antibody encephalitis present to psychiatrists, the psychopathology of NMDAR-antibody encephalitis needs to be clearly defined to encourage accurate clinical identification and prompt treatment. Methods For this systematic review, we searched PubMed for all studies published in English between Jan 1, 2005, and Oct 7, 2017, to identify individually reported adult patients (≥18 years) who satisfied consensus criteria for definite NMDAR-antibody encephalitis. After generating a list of 50 fine-grained, lower-level features, we extracted psychopathological data in addition to demographic and aetiological data. The lower-level features were later ordered within higher-level categories. As a means of quality control, we filtered the data according to proxy markers of psychiatric involvement in their description. Subsequently, we compared lower-level features from individual patient data with operationalised psychiatric syndromes using a constrained combination approach and principal component analysis, and did a network analysis to explore the inter-relationships between multiple lower-level features. The review protocol was prospectively registered with PROSPERO, number CRD42017068981. Findings Of 1096 records identified in PubMed, 333 satisfied inclusion criteria and described 1100 patients in total with NMDAR-antibody encephalitis. The psychopathology of 505 (46%) patients with reported psychiatric symptoms was described in more detailed terms than only psychiatric or behavioural. 464 (91%) of the 505 patients were from papers in which patient data were reported individually. The remainder of the analyses focused exclusively on these 464 patients. Median age was 27 years (IQR 22–34), 368 (79%) of 464 patients were female and in 147 (32%), NMDAR-antibody encephalitis was associated with ovarian teratoma. The five higher-level categories into which the 464 patients most frequently grouped were behaviour (316 [68%]), psychosis (310 [67%]), mood (219 [47%]), catatonia (137 [30%]), and sleep disturbance (97 [21%]). The overall pattern of lower-level features was statistically stable across subgroups classified by age, sex, pregnancy association, presence of ovarian teratoma, prior herpes simplex virus encephalitis, and isolated psychiatric presentations (two-way ANOVA p=0·6–0·9). Constrained combination and principal component analyses found that mixtures of mood and psychosis syndromes fit each patient better than any single diagnosis alone, particularly for the patients in the psychiatric-described subgroup (mean ΔAkaike information criterion −0·04 in non-psychiatric-described subgroup vs 0·61 in psychiatric-described subgroup). The overlapping nature of the higher-level features was also enriched upon analysis of the psychiatric-d...

The recent discovery of several potentially pathogenic autoantibodies has helped identify patients with clinically distinctive central nervous system diseases that appear to benefit from immunotherapy. The associated autoantibodies are directed against the extracellular domains of cell-surface–expressed neuronal or glial proteins such as LGI1, N-methyl-D-aspartate receptor, and aquaporin-4. The original descriptions of the associated clinical syndromes were phenotypically well circumscribed. However, as availability of antibody testing has increased, the range of associated patient phenotypes and demographics has expanded. This in turn has led to the recognition of more immunotherapy-responsive syndromes in patients presenting with cognitive and behavioral problems, seizures, movement disorders, psychiatric features, and demyelinating disease. Although antibody detection remains diagnostically important, clinical recognition of these distinctive syndromes should ensure early and appropriate immunotherapy administration. We review the emerging paradigm of cell-surface–directed antibody–mediated neurological diseases, describe how the associated disease spectrums have broadened since the original descriptions, discuss some of the methodological issues regarding techniques for antibody detection and emphasize considerations surrounding immunotherapy administration. As these disorders continue to reach mainstream neurology and even psychiatry, more cell-surface–directed antibodies will be discovered, and their possible relevance to other more common disease presentations should become more clearly defined.

IntroductionN‐methyl‐D‐aspartate receptor (NMDAR) antibody encephalitis is mediated by immunoglobulin G (IgG) autoantibodies directed against the NR1 subunit of the NMDAR. Around 20% of patients have an underlying ovarian teratoma, and the condition responds to early immunotherapies and ovarian teratoma removal. However, despite clear therapeutic relevance, mechanisms of NR1‐IgG production and the contribution of germinal center B cells to NR1‐IgG levels are unknown.MethodsClinical data and longitudinal paired serum NR1‐reactive IgM and IgG levels from 10 patients with NMDAR‐antibody encephalitis were determined. Peripheral blood mononuclear cells from these 10 patients, and two available ovarian teratomas, were stimulated with combinations of immune factors and tested for secretion of total IgG and NR1‐specific antibodies.ResultsIn addition to disease‐defining NR1‐IgG, serum NR1‐IgM was found in 6 of 10 patients. NR1‐IgM levels were typically highest around disease onset and detected for several months into the disease course. Moreover, circulating patient B cells were differentiated into CD19+CD27++CD38++ antibody‐secreting cells in vitro and, from 90% of patients, secreted NR1‐IgM and NR1‐IgG. Secreted levels of NR1‐IgG correlated with serum NR1‐IgG (p < 0.0001), and this was observed across the varying disease durations, suggestive of an ongoing process. Furthermore, ovarian teratoma tissue contained infiltrating lymphocytes which produced NR1‐IgG in culture.InterpretationSerum NR1‐IgM and NR1‐IgG, alongside the consistent production of NR1‐IgG from circulating B cells and from ovarian teratomas suggest that ongoing germinal center reactions may account for the peripheral cell populations which secrete NR1‐IgG. Cells participating in germinal center reactions might be a therapeutic target for the treatment of NMDAR‐antibody encephalitis. Ann Neurol 2018;83:553–561

The autoimmune encephalitis (AE) syndromes have been characterised by the detection of autoantibodies in serum and/or cerebrospinal fluid which target the extracellular domains of specific neuroglial antigens. The clinical syndromes have phenotypes which are often highly characteristic of their associated antigen-specific autoantibody. For example, the constellation of psychiatric features and the multi-faceted movement disorder observed in patients with NMDAR antibodies are highly distinctive, as are the faciobrachial dystonic seizures observed in close association with LGI1 antibodies. These typically tight correlations may be conferred by the presence of autoantibodies which can directly access and modulate their antigens in vivo. AE remains an under-recognised clinical syndrome but one where early and accurate detection is critical as prompt initiation of immunotherapy is closely associated with improved outcomes. In this review of a rapidly emerging field, we outline molecular observations with translational value. We focus on contemporary methodologies of autoantibody detection, the evolution and distinctive nature of the clinical phenotypes, generalisable therapeutic paradigms, and finally discuss the likely mechanisms of autoimmunity in these patients which may inform future precision therapies.

Psychotic disorders are common and disabling. Overlaps in clinical course in addition to epidemiological and genetic associations raise the possibility that autoimmune mechanisms may underlie some psychoses, potentially offering novel therapeutic approaches. Several immune loci including the major histocompatibility complex and B-cell markers CD19 and CD20 achieve genome-wide significance in schizophrenia. Emerging evidence suggests a potential role via neurodevelopment in addition to classical immune pathways. Additionally, lymphocyte biology is increasingly investigated. Some reports note raised peripheral CD19 and reduced CD3 lymphocyte counts, with altered CD4 : CD8 ratios in acute psychosis. Also, post-mortem studies have found CD3 and CD20 lymphocyte infiltration in brain regions that are of functional relevance to psychosis. More specifically, the recent paradigm of neuronal surface antibody-mediated (NSAb) central nervous system disease provides an antigen-specific model linking adaptive autoimmunity to psychopathology. NSAbs bind extracellular epitopes of signalling molecules that are classically implicated in psychosis such as NMDA and GABA receptors. This interaction may cause circuit dysfunction leading to psychosis among other neurological features in patients with autoimmune encephalitis. The detection of these cases is crucial as autoimmune encephalitis is ameliorated by commonly available immunotherapies. Meanwhile, the prevalence and relevance of these antibodies in people with isolated psychotic disorders is an area of emerging scientific and clinical interest. Collaborative efforts to achieve larger sample sizes, comparison of assay platforms, and placebo-controlled randomized clinical trials are now needed to establish an autoimmune contribution to psychosis.

ObjectiveThere are now a large number of requests for N-methyl-d-aspartate receptor autoantibody (NMDAR-Ab) tests, and it is important to assess the clinical relevance of all results, particularly when they are reported as ‘Low Positive’.MethodsThe clinical data of 56 patients found Positive or Low Positive by the Oxford live cell-based assay were reviewed. An autoimmune basis for the condition was assigned as ‘Definite’, ‘Possible’ or ‘Unlikely’. The number of core features (encephalopathy, psychiatric, cognitive, epileptic, extrapyramidal and inflammatory cerebrospinal fluid (CSF)) was tabulated.ResultsTwenty-five (44.6%) patients had a Definite NMDAR-Ab encephalitis (eight ovarian teratomas, one Hodgkin’s lymphoma), 18 (32.1%) a Possible NMDAR-Ab encephalitis and 13 (23.2%) an Unlikely autoimmune syndrome. Serum NMDAR-Ab levels were higher in patients with tumours. Positive NMDAR-Abs were found not only in patients with three or more core features and a Definite syndrome, but also in five patients classified as Possible. Conversely, Low Positive NMDAR-Abs were present in 7 Definite cases as well as in 13 Possible cases. Unlikely patients had mainly Low Positive antibodies and fewer core features. CSF NMDAR-Abs, only available in 11 pairs and at varying time points, broadly related to serum levels and were Positive in 3/3 patients with tumours but in only 2/5 Definite patients, and none of the Possible or Unlikely cases.InterpretationUsing live cell-based assays, Positive and Low Positive antibodies can be of clinical significance. The number of core clinical features should help to select those patients in whom an immunotherapy intervention might be considered, irrespective of the antibody level.

Autoantibodies against the extracellular domain of the N-methyl-d-aspartate receptor (NMDAR) NR1 subunit cause a severe and common form of encephalitis. To better understand their generation, we aimed to characterize and identify human germinal centres actively participating in NMDAR-specific autoimmunization by sampling patient blood, CSF, ovarian teratoma tissue and, directly from the putative site of human CNS lymphatic drainage, cervical lymph nodes. From serum, both NR1-IgA and NR1-IgM were detected more frequently in NMDAR-antibody encephalitis patients versus controls (both P &lt; 0.0001). Within patients, ovarian teratoma status was associated with a higher frequency of NR1-IgA positivity in serum (OR = 3.1; P &lt; 0.0001) and CSF (OR = 3.8, P = 0.047), particularly early in disease and before ovarian teratoma resection. Consistent with this immunoglobulin class bias, ovarian teratoma samples showed intratumoral production of both NR1-IgG and NR1-IgA and, by single cell RNA sequencing, contained expanded highly-mutated IgA clones with an ovarian teratoma-restricted B cell population. Multiplex histology suggested tertiary lymphoid architectures in ovarian teratomas with dense B cell foci expressing the germinal centre marker BCL6, CD21+ follicular dendritic cells, and the NR1 subunit, alongside lymphatic vessels and high endothelial vasculature. Cultured teratoma explants and dissociated intratumoral B cells secreted NR1-IgGs in culture. Hence, ovarian teratomas showed structural and functional evidence of NR1-specific germinal centres. On exploring classical secondary lymphoid organs, B cells cultured from cervical lymph nodes of patients with NMDAR-antibody encephalitis produced NR1-IgG in 3/7 cultures, from patients with the highest serum NR1-IgG levels (P &lt; 0.05). By contrast, NR1-IgG secretion was observed neither from cervical lymph nodes in disease controls nor in patients with adequately resected ovarian teratomas. Our multimodal evaluations provide convergent anatomical and functional evidence of NMDAR-autoantibody production from active germinal centres within both intratumoral tertiary lymphoid structures and traditional secondary lymphoid organs, the cervical lymph nodes. Furthermore, we develop a cervical lymph node sampling protocol that can be used to directly explore immune activity in health and disease at this emerging neuroimmune interface.

Autoimmune encephalitis (AE) mediated by antibodies against synaptic and neuronal surface targets frequently presents with a psychiatric syndrome. In these patients, removal of autoantibodies treats the disease and outcomes are closely linked to early intervention. The discovery of these autoantibodies in isolated psychiatric syndromes has raised the possibility that these patients may derive similar benefits from immunotherapy, a potentially transformational approach to the treatment of mental illness. Although open-label case series suggest impressive therapeutic outcomes, the pathological relevance of these autoantibodies outside of canonical presentations is debated. The advent of diagnostic criteria for AE attempts to facilitate its prompt identification but risks prematurely neglecting the potential scientific and clinical significance of isolated syndromes that do not satisfy these criteria. Here, we propose using a syndrome-level taxonomy that has occasional, but not necessary, overlap with AE: synaptic and neuronal autoantibody-associated psychiatric syndromes or “SNAps”. This will prevent confusion with AE and act heuristically to promote active investigation into this rare example of psychopathology defined on a molecular level. We suggest that this concept would have application in other autoantibody-associated syndromes including seizure, cognitive, and movement disorders, in which similar issues arise. We review putative direct and indirect mechanisms and outline experimentally testable hypotheses that would help to determine prospectively in whom autoantibody detection is relevant, and as important, in whom it is not. We summarize a pragmatic approach to autoantibody testing and management in severe mental illness in order to promptly diagnose AE and advocate a research-orientated experimental medicine paradigm for SNAps, where there is greater equipoise. We conclude that SNAps remains a nascent area of clinical neuroscience with great potential and in ongoing need of psychiatry-led basic and clinical research.