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Objective N-methyl-D-aspartate receptor antibody (NMDAR-Ab) encephalitis is a well-recognised clinico-immunological syndrome that presents with neuropsychiatric symptoms cognitive decline, movement disorder and seizures. This study reports the clinical features, management and neurological outcomes of paediatric NMDAR-Ab-mediated neurological disease in the UK. Design A prospective surveillance study. Children with NMDAR-Ab-mediated neurological diseases were voluntarily reported to the British Neurological Surveillance Unit (BPNSU) from November 2010 to December 2011. Initial and follow-up questionnaires were sent out to physicians. Results Thirty-one children fulfilled the criteria for the study. Eight presented during the study period giving an incidence of 0.85 per million children per year (95% CI 0.64 to 1.06); 23 cases were historical. Behavioural change and neuropsychiatric features were present in 90% of patients, and seizures and movement disorders both in 67%. Typical NMDAR-Ab encephalitis was reported in 24 children and partial phenotype without encephalopathy in seven, including predominantly psychiatric (four) and movement disorder (three). All patients received steroids, 22 (71%) received intravenous immunoglobulin, 9 (29%) received plasma exchange,and 10 (32%) received second-line immunotherapy. Of the 23 patients who were diagnosed early, 18 (78%) made a full recovery compared with only 1 of 8 (13%) of the late diagnosed patients (p=0.002, Fisher's exact test). Seven patients relapsed, with four needing additional second-line immunotherapy. Conclusions Paediatric NMDAR-Ab-mediated neurological disease appears to be similar to adult NMDAR-Ab encephalitis, but some presented with a partial phenotype. Early treatment was associated with a quick and often full recovery.

The diagnostic criteria for N-methyl-d-aspartate receptor antibody (NMDAR-Ab) encephalitis require the presence of CSF antibodies against the NMDAR, whereas serum antibodies are considered specific only if accompanied by CSF antibodies. Current assays include in-house immunochemistry (IHC), or cell-based assays (CBA) which use live (L-CBA) or fixed cells (F-CBA), and commercially available fixed-cells CBA (C-CBA), but these have not been compared in parallel. We compared the L-CBA with F-CBA, C-CBA, and IHC using sera and CSFs archived from > 30,000 received for testing and previously positive by L-CBA. Referring neurologists, if identified, provided “definite” or “unlikely” diagnoses of NMDAR-Ab encephalitis for 31 paired serum-CSF samples and 53 unpaired sera. There was good concordance between paired sera and CSFs, with 13/16 “definite” pairs positive, and 7/8 “unlikely” pairs negative in all in-house assays. In unpaired “definite” sera, L-CBA was most sensitive. However, 19/24 serum samples from “unlikely” patients were positive by L-CBA, with only 5/24 and 1/24 positive by F-CBA and IHC, respectively. In available samples, C-CBA demonstrated high sensitivity for CSF, but surprisingly low sensitivity for serum. Overall, regardless of the technique, CSF results were accurate and easy to interpret, but if CSF is unavailable, negative serum C-CBA results in cases with suspected NMDAR-Ab encephalitis could be repeated by a more sensitive in-house assay. Although these assays are sensitive, particularly for CSF, referral of sera with low pre-test probability should be avoided to reduce clinically-irrelevant “false positive” results.

Myasthenia gravis (MG) is a neuromuscular, autoimmune disease caused by autoantibodies that target postsynaptic proteins, primarily the acetylcholine receptor (AChR) and inhibit signaling at the neuromuscular junction. The majority of patients under 50 y with AChR autoantibody MG have thymic lymphofollicular hyperplasia. The MG thymus is a reservoir of plasma cells that secrete disease-causing AChR autoantibodies and although thymectomy improves clinical scores, many patients fail to achieve complete stable remission without additional immunosuppressive treatments. We speculate that thymus-associated B cells and plasma cells persist in the circulation after thymectomy and that their persistence could explain incomplete responses to resection. We studied patients enrolled in a randomized clinical trial and used complementary modalities of B cell repertoire sequencing to characterize the thymus B cell repertoire and identify B cell clones that resided in the thymus and circulation before and 12 mo after thymectomy. Thymus-associated B cell clones were detected in the circulation by both mRNA-based and genomic DNA-based sequencing. These antigen-experienced B cells persisted in the circulation after thymectomy. Many circulating thymus-associated B cell clones were inferred to have originated and initially matured in the thymus before emigration from the thymus to the circulation. The persistence of thymus-associated B cells correlated with less favorable changes in clinical symptom measures, steroid dose required to manage symptoms, and marginal changes in AChR autoantibody titer. This investigation indicates that the diminished clinical response to thymectomy is related to persistent circulating thymus-associated B cell clones.

Atypical B cell (atBC) subsets display significant heterogeneity across autoimmune diseases, complicating efforts to define their role and therapeutic potential. We hypothesized that this heterogeneity reflects the responses to specific immunopathology, resulting in disease-specific profiles. The myasthenia gravis (MG) subtypes acetylcholine receptor (AChR)-positive MG and muscle-specific kinase (MuSK)-positive MG provide an ideal model to explore atBCs due to the distinct immune mechanisms driven by IgG1-3 and IgG4 autoantibodies, respectively in the disease. CD11c and IgD CD27 double-negative (DN) B cells were analyzed by spectral flow cytometry in non-autoimmune controls, AChR-MG, and MuSK-MG. Results were correlated with clinical parameters and antibody levels. In MG subtypes, atBC subsets were further examined for the impact of disease onset and prior rituximab treatment. CD11c B cells were stimulated to assess antibody secreting cell (ASC) differentiation. CD11c and DN2 B cells were increased in late-onset AChR-MG, while MuSK-MG featured expanded DN3 B cells linked to disease severity. CD20 expression in atBCs was differentially expressed between MG subtypes, with higher levels in late-onset AChR-MG and significantly reduced levels in MuSK-MG. CD11c B cells were reduced after anti-CD20 treatment in MuSK-MG, whereas DN B cells were unaffected. Functionally, CD11c B cells from MuSK-MG exhibited greater ASC differentiation and autoantibody production. MG subtypes exhibit distinct atBC profiles linked to immunopathology and disease onset. These findings reveal subtype-specific pathways that regulate atBCs and highlight their potential as therapeutic targets in both IgG1-3- and IgG4-mediated autoimmunity.

Patients with autoimmune encephalitides, especially those with antibodies to the N-methyl-d-aspartate receptor (NMDAR), often present with prominent psychosis and respond well to immunotherapies. Although most patients progress to develop various neurological symptoms, it has been hypothesised that a subgroup of patients with first-episode psychosis (FEP) suffer from a forme fruste of autoimmune encephalitis. Without accurate identification, this immunotherapy-responsive subgroup may be denied disease-modifying treatments. Thirty studies addressing aspects of this hypothesis were identified in a systematic review. Amongst other shortcomings, 15/30 reported no control group and only 6/30 determined cerebrospinal fluid (CSF) autoantibodies. To ourselves address these—and other—limitations, we investigated a prospectively ascertained clinically well-characterised cohort of 71 FEP patients without traditional neurological features, and 48 healthy controls. Serum and CSF were tested for autoantibodies against seven neuronal surface autoantigens using live cell-based assays. These identified 3/71 (4%) patient sera with weak binding to either contactin-associated protein-like 2, the NMDAR or glycine receptor versus no binding from 48 control samples (p = 0.28, Fisher’s test). The three seropositive individuals showed no CSF autoantibodies and no differences from the autoantibody-negative patients in their clinical phenotypes, or across multiple parameters of peripheral and central inflammation. All individuals were negative for CSF NMDAR antibodies. In conclusion, formes frustes of autoimmune encephalitis are not prevalent among FEP patients admitted to psychiatric care. Our findings do not support screening for neuronal surface autoantibodies in unselected psychotic patients.

Seizures are a prominent feature in N-Methyl-D-Aspartate receptor antibody (NMDAR antibody) encephalitis, a distinct neuro-immunological disorder in which specific human autoantibodies bind and crosslink the surface of NMDAR proteins thereby causing internalization and a state of NMDAR hypofunction. To further understand ictogenesis in this disorder, and to test a potential treatment compound, we developed an NMDAR antibody mediated rat seizure model that displays spontaneous epileptiform activity in vivo and in vitro. Using a combination of electrophysiological and dynamic causal modelling techniques we show that, contrary to expectation, reduction of synaptic excitatory, but not inhibitory, neurotransmission underlies the ictal events through alterations in the dynamical behaviour of microcircuits in brain tissue. Moreover, in vitro application of a neurosteroid, pregnenolone sulphate, that upregulates NMDARs, reduced established ictal activity. This proof-of-concept study highlights the complexity of circuit disturbances that may lead to seizures and the potential use of receptor-specific treatments in antibody-mediated seizures and epilepsy.Sukhvir Wright et al. present a NMDAR antibody-induced model of encephalitis in rats and use in vitro, in vivo, and in silico electrophysiology to examine alterations in neural circuit behavior. Their results suggest that reduction of NMDARs leads to increased excitability and seizure activity, and highlights the potential use of receptor-specific treatments in antibody-mediated seizures and epilepsy.

CNS disorders can be caused by IgG antibodies to neuronal surface proteins, and these antibodies have the potential to cross the placenta. Since some of them target proteins involved in neurodevelopment, such as contactin-associated protein-2 (CASPR2), we hypothesised that they could alter developing neuronal circuits in utero and lead to neurodevelopmental disorders in the children. A dual approach to the study was undertaken. First, we studied pregnancy serum samples from two population-based Danish cohorts: a cohort of women with postpartum psychosis and a cohort of mothers of children with mental retardation and other disorders of psychological development (MR–DPD), each with individually matched controls. We screened them for the presence of antibodies to CASPR2. Then, we assessed the effects of in-utero exposure to the antibodies in a mouse maternal-to-fetal model. The combined results from these two cohorts showed that maternal antibodies to CASPR2 were associated with an increased risk of MR–DPD in the children: eight (4·4%) of 182 mothers of MR–DPD children had CASPR2 antibodies compared with only three (0·9%) of 347 mothers of children without this diagnosis (p=0·01). This association was explored by injection of mouse dams with IgG purified from CASPR2-antibody-positive patients, or from healthy controls. The mouse offspring had long-term behavioural sequelae, manifested as deficits in social interaction and social activities, and increased repetitive, non-social behaviours. When they were culled at 12 months, their brains showed abnormal migration of cortical projection neurons, increased microglial activation, and reduction in the number of glutamatergic synapses, confirming that there had been long-term changes in neurodevelopment. CASPR2 was identified as a specific target for maternal antibodies that can alter brain development in utero, resulting in long-term behavioural deficits and permanent abnormalities at the cellular and synaptic level. These results should encourage further epidemiological and experimental studies to confirm and explore further how CASPR2 and other maternal antibodies can lead to neurodevelopmental disorders in children. EC was funded by the Programme for Advanced Medical Education at the Calouste Gulbenkian Foundation. This work was also supported by the Stanley Medical Research Institute. Resources were provided by the Nuffield Department of Clinical Neurosciences.

ObjectivePatients with myasthenia gravis without acetylcholine receptor (AChR) or muscle-specific kinase (MuSK) antibodies detected by radioimmunoprecipitation assays (RIAs) are classified as seronegative myasthenia gravis (SNMG). Live cell-based assays (l-CBAs) can detect additional antibodies to clustered AChR, MuSK and low-density lipoprotein receptor-related protein 4 (LRP4), but positivity rates are variable and both clinical relevance and utility of CBA platforms remain unclear.MethodsSera from 82 patients with SNMG were tested by l-CBAs. Human embryonic kidney cells were transfected to individually express clustered AChR, MuSK or LRP4; or transfected to jointly express both clustered adult AChR and MuSK. Sera from 30 and 20 patients positive by RIA for AChR or MuSK antibodies were used as comparators.Results53 of 82 (72%) patients with SNMG had generalised and 29 (28%) had ocular disease. The clustered AChR CBA detected antibodies in 16 of 82 patients (19.5%; including 4 patients with solely fetal AChR antibodies), while 7 of 82 (8.5%) patients had MuSK antibodies. A novel exploratory combined adult AChR-MuSK l-CBA efficiently detected all these antibodies in a subset of the SNMG cohort. No LRP4 antibodies were identified. Overall, patients with SNMG with clustered AChR antibodies, CBA-positive MuSK-MG or triple seronegative were younger, had less severe disease than patients with RIA-positive MG and had a better clinical outcome when immunotherapy was started soon after disease onset, although the time interval from onset to immunotherapy was not different when compared with patients with RIA-positive MG.ConclusionAround one-third of patients with SNMG had AChR or MuSK antibodies by l-CBAs, which were efficiently detected with a combined l-CBA. The results in this large and unselected cohort of patients with MG demonstrate the diagnostic usefulness of performing CBAs and the importance of making these tests more widely available.

Specimen mammography during image guided breast surgery is a daily occurrence. The process of specimen travel, imaging and reporting may take 20-30 minutes. An intraoperative method to obtain digital specimen mammograms may expedite the process. We compared intraoperative digital specimen mammography (IDSM) as well as standard specimen mammography (SSM) on 121 consecutive image guided lumpectomies. Each lumpectomy specimen had IDSM obtained followed by travel to radiology for SSM. Surgical decisions were based on all imaging obtained. Data included 1) the ability of each imaging method to identify the target lesion, 2) degree of concordance of surgical interpretation of IDSM compared to radiologist interpretation of SSM, 3) the time required from lumpectomy to surgical review of images from each method, and 4) potential operative time savings. Intraoperative digital specimen mammography (IDSM) was equally as accurate as standard x-ray film specimen mammography. There was no significant difference between 1) the frequency of identification of the target lesion by surgeon or radiologist, 2) lack of identification of any lesion, or 3) frequency of involved margins using imaging criteria. However, there was a marked difference in 1) the time needed to obtain images ready to read, 2) the ability to re-excise tissue promptly, and 3) the overall operating room time with an average decrease of 19 minutes. Intraoperative digital specimen mammography (IDSM) was equally accurate as SSM obtained in this study. Use of this new technology allows surgeons to quickly view specimen images which translate into shorter more efficient operations.