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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.

Objectives/Aims NMDAR-antibody encephalitis frequently presents with psychiatric symptoms. However, new-onset mental illness does not usually receive detailed biomedical investigations. Yet, early diagnosis and treatment correlates with improved outcomes. Here we used detailed psychiatric phenotyping to explore the nature of mental state abnormalities in this immunologically-defined illness. Methods Prospective and retrospective semi-structured interviews with patients, carers, and clinicians in five consecutive cases of definite NMDAR-antibody encephalitis (all female, median age=20 years, range=16–30, ovarian teratoma in 4). Weekly multi-disciplinary assessment using the Neuropsychiatric Inventory Nursing Home version (NPI-NH) in 2/5. Network analysis was used to evaluate connectedness of psychopathologic features and a qualitative synthesis distilled recurrent psychopathologic features. Finally, each time point was compared with operationalised diagnoses using an automated classifier and plotted with corresponding symptom complexes over time. Results All had psychiatric features at onset and were seen first by general practitioners or emergency departments. All received an incorrect initial diagnosis (1 neurological, 4 primary psychiatric). Two patients were referred to mental health services and detained while three were admitted to a general hospital. Psychiatric diagnoses spanned psychotic, mood, and stress categories. None had a personal or family history of serious mental illness or substance misuse. Despite the atypicality all were ascribed to non-specific psycho-social aetiologies. Autoimmune encephalitis was then first suspected between 4–28 days from onset (median=21 days) because of the psychopathology (n=2) or development of clear-cut seizures or movement disorder (n=3). 10 consistently reported features were identified: sleep disturbance, nightmares, mixed unstable mood, perplexity, incoherent repetitive speech, musical ±visual hallucinosis, catatonic facies, possession-like/drugged, dissociative-disorganised, and regressed behaviour. The symptom complex peaked rapidly (within 3 weeks). The peak burden was large and crossed multiple psychopathologic domains. Overall the syndrome is poorly-described by any single primary disorder; mixtures of mixed mood-psychotic-catatonic disorders performed best. Furthermore, it showed clear qualitative and hence diagnostic shifts between onset, peak, and resolution. Conclusions The psychopathology of NMDAR-antibody encephalitis is complex and dynamic, likely contributing to diagnostic difficulties. However, it appears stereotyped between individuals, hence sensitive features can be derived. Inconsistency with psychosis and/or mood disorder constructs and better approximation with ‘mixtures of mixtures’ suggests specificity is possible but similar studies with primary disorder comparators are needed. As the disease can only be ruled out with cerebrospinal fluid antibody testing the practical implication is that the mental health system needs to embrace lumbar puncture as a routine part of practice in high risk groups.

In 1997, two prescient case reports described an encephalopathy associated with ovarian teratoma presenting with a psychiatric illness that responded to tumour resection.1,2 10 years later, Dalmau and colleagues3 first reported an association between this syndrome and antibodies against the NMDA receptor. NMDAR-antibody encephalitis is notable for a clinical-radiological paradox of often normal structural MRI but severe and disabling illness. In 2017, Peer and colleagues4 reported the largest functional imaging analysis of such patients to date.

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.

Objective There 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’. Methods The 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. Results Twenty-five (44.6%) patients had a Definite NMDAR-Ab encephalitis (eight ovarian teratomas, one Hodgkin9s 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. Interpretation Using 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.

The nematode Caenorhabditis elegans is an established model organism for studying neurobiology. UNC-63 is a C. elegans nicotinic acetylcholine receptor (nAChR) α-subunit. It is an essential component of the levamisole-sensitive muscle nAChR (L-nAChR) and therefore plays an important role in cholinergic transmission at the nematode neuromuscular junction. Here, we show that worms with the unc-63(x26) allele, with its αC151Y mutation disrupting the Cys-loop, have deficient muscle function reflected by impaired swimming (thrashing). Single-channel recordings from cultured muscle cells from the mutant strain showed a 100-fold reduced frequency of opening events and shorter channel openings of L-nAChRs compared with those of wild-type worms. Anti-UNC-63 antibody staining in both cultured adult muscle and embryonic cells showed that L-nAChRs were expressed at similar levels in the mutant and wild-type cells, suggesting that the functional changes in the receptor, rather than changes in expression, are the predominant effect of the mutation. The kinetic changes mimic those reported in patients with fast-channel congenital myasthenic syndromes. We show that pyridostigmine bromide and 3,4-diaminopyridine, which are drugs used to treat fast-channel congenital myasthenic syndromes, partially rescued the motility defect seen in unc-63(x26). The C. elegans unc-63(x26) mutant may therefore offer a useful model to assist in the development of therapies for syndromes produced by altered function of human nAChRs. Fil: Jones, Andrew K.. University of Oxford; Reino Unido Fil: Rayes, Diego Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina Fil: Al Diwani, Adam. University of Oxford; Reino Unido Fil: Maynard, Thomas P. R.. University of Oxford; Reino Unido Fil: Jones, Rachel. University of Oxford; Reino Unido Fil: Hernando, Guillermina Silvana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina Fil: Buckingham, Steven D.. University of Oxford; Reino Unido Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina Fil: Sattelle, David B.. University of Manchester; Reino Unido

Background Immunoglobulin G (IgG) against the NR1-subunit of the N-methyl-D-aspartate (NMDAR) receptor mediates NMDAR-antibody encephalitis (NMDAR-Ab-E). This multi-stage illness presents with an acute severe psychiatric syndrome, alongside other neurological features, similar to human and animal NMDAR antagonist models. The disease is associated with an ovarian teratoma in around 20% of cases. The cellular immunity underlying this disease is not well understood. While antibody-modifying immunotherapies often promote disease resolution, the illness can be refractory to these treatments correlating with sub-optimal outcomes. NR1-IgG can be detected several years after clinical resolution, which may be via ongoing germinal centre reactions or the establishment of antibody-secreting cells as long-lived plasma cells in bone marrow niches. These two divergent models implicate use of differing immunotherapies to target these cells. Here we investigate the contribution of ongoing germinal centre reactions to disease progression, potentially informing disease mechanisms and guide targeted immunotherapy. Methods We hypothesised that recurrent antigen-driven germinal centre reactions would be associated with active generation of NR1-specific IgM and IgG and NR1-specific circulating B cells. We validated a NR1-IgM cell based assay establishing specificity cut-offs by screening healthy and disease control cohorts alongside a previously collected NMDAR-Ab-E cohort (n=46). Following this we went on to explore the temporal evolution of NR1-IgG and NR1-IgM titres in a prospective cohort (n=12). To investigate the lymphocyte characteristics, we stimulated ovarian teratoma lymphocytes and peripheral blood mononuclear cells (PBMCs) from multiple time points under varying cytokine conditions to understand whether these circulating cells showed capacity for NR1-IgG and IgM generation. Results We found a 43% prevalence rate of NR1-IgM in the historic cohort. We then confirmed that NR1-IgM binding was specific by its selective depletion after anti-IgM precipitation but not with protein G. In the prospective cohort, we noted often high titres of IgM (up to 1:500) most commonly early in the disease but persisting for around 2 years. NR1-IgM levels varied in titre alongside NR1-IgG spikes. Consistently, culture experiments of patient lymphocytes (PBMCs and tumour-derived) produced varying degrees of NR1-IgM and NR1-IgG under conditions associated with B cell proliferation. The NR1-IgG levels correlated with serum NR1-titres suggesting these circulating B cells made a proportional contribution to serum levels. Discussion Ongoing germinal centre reactions likely contribute much of the circulating NR1-specific B cell population in NMDAR-Ab-E. Autoimmunisation at these centres represents an as yet unexplored therapeutic target in this and potentially other autoimmune encephalopathies. Regional specificity of these reactions including lymph nodes draining sources of NR1-antigen require further direct evaluation.

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. © 2014 American Neurological Association.

An elderly woman presented with disorganised thinking, unusual behaviour and clustered episodes of speech arrest accompanied by right-sided face and arm twitching. The following investigations were normal: interictal electroencephalography, brain MRI, cerebrospinal fluid viral PCR and cell count and voltage-gated potassium channel-complex, N-methyl-d-aspartate receptor, gamma-aminobutyric acid (B) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, glycine receptor, glutamic acid decarboxylase and paraneoplastic antibodies. The syndrome showed partial spontaneous resolution but 1 year later, typical postencephalopathic features persisted including disinhibition and alteration of sleep-wake cycle. The most likely clinical diagnosis was autoimmune encephalitis and the broader differential diagnoses are discussed within the article. This case demonstrates the need to be aware of this under-recognised and potentially treatable entity.

Lumbar puncture (LP) is a commonly performed procedure in diagnosis and management of neurological conditions. LP is generally safe, however there are a number of potentially serious complications, including epidural haematoma and cerebral herniation. The risks of these should be considered and minimised prior to undertaking LP.Our regional neuroscience centre provides an outpatient LP service for patients throughout southeast England. Referrals from distant hospitals meant there was frequently no access to important clinical information, including indication for LP, past medical history, or medication history until the day of the procedure, and no access to results of investigations such as coagulation profile, platelet count, or intracranial imaging. Furthermore, there was limited capacity or time available in the day ward to perform these tests prior to LP. As a result, patients were either having LPs cancelled on the day of the procedure, were delayed by several hours on the day of the procedure for investigations, or were subject to the risk of having the LP performed without the knowledge of these key safety indicators.To address this issue we implemented an LP safety checklist to be completed by referring neurologists, providing details of the patient’s medical history and results of investigations performed locally. In doing this, we increased the proportion of patients with an available platelet count prior to LP from 25% to 89%, and available coagulation profile from 18% to 82%. In addition, we saw a qualitative increase in the confidence of junior doctors in the safety of the LP clinic, as measured by a survey taken before and after the implementation of this system.This simple intervention made a rapid and remarkable difference to the safety and efficiency of this outpatient LP clinic. We would encourage other units to adopt this approach to address similar problems in a variety of outpatient settings.