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Rather, atypical NMDAR expression is either a response to anti-tumor immune reactions or property of the dysmorphic neuronal tissue that facilitates such an anti-NMDAR antibody-mediated response. When analyzing low-grade tumors with different glial and neuronal composition from patients without reported autoimmune encephalitis, e.g., I pilocytic astrocytoma i , I dysembryoplastic neuroepithelial tumor i , or I ganglioglioma i , atypical NMDAR expression was detected only on dysmorphic neurons in I ganglioglioma i - and in the aforementioned NMDARE-associated ovarian teratomas (Fig. Immunostaining of fresh-frozen patient tumor with patient CSF (green) and commercial anti-NR1 (red) overlaps (yellow) confirming atypical NMDAR expression (s). This confirmed atypical NMDAR expression on the patient's dysmorphic neurons and suggested that autoantibodies binding the tumor were also responsible for NMDARE (Fig. [Extracted from the article]

Anti-neuronal autoantibodies have been reported as the cause of several neurologic disorders other than encephalitis. Unfortunately, data are mostly based on serum analysis. Predictions about pathogenicity are thus limited. To determine the presence of so far unidentified autoantibody-derived neuroreactivity we analyzed cerebrospinal fluid (CSF) of children with neurological disorders other than encephalitis. We did a retrospective analysis of CSF from 254 children with various neurologic diseases other than encephalitis and searched for reactivity against neuronal surface antigens by immunofluorescence on unfixed murine brain sections (tissue-based assay, TBA) and by commercial cell-based assays (CBA). A semi-quantitative fluorescence score classified our results and we described the clinical course of all positive patients with strong neuroreactivity. Strong anti-neuronal IgG immunoreactivity of unknown antigen specificity was detected in CSF samples of 10 pediatric patients (4%, n = 10/254) with unsolved neurological disorders. CSF inflammatory markers were elevated. Most patients did not or only partly recover. Five screening-positive patients presented with a combination of headache and visual impairment due to optic nerve atrophy. Our data suggest to consider inflammatory, autoantibody-related etiologies, especially in cases without definite diagnoses. We present an overview of CSF neuroreactivity in children with neurological disorders other than encephalitis, indicating the presence of unidentified anti-neuronal autoantibodies. As TBA enables screening for unknown autoantibodies, we suggest this method as a second step if commercial CBAs do not yield a result. Further studies are necessary to characterize such antibodies, evaluate pathogenicity, and answer the question whether positive CSF neuroreactivity should prompt an immunotherapeutic approach. [ABSTRACT FROM AUTHOR]

Objective: To evaluate disease symptoms, and clinical and magnetic resonance imaging (MRI) findings and to perform longitudinal volumetric MRI analyses in a European multicenter cohort of pediatric anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) patients.Methods: We studied 38 children with NMDARE (median age = 12.9 years, range =1-18) and a total of 82 MRI scans for volumetric MRI analyses compared to matched healthy controls. Mixed-effect models and brain volume z scores were applied to estimate longitudinal brain volume development. Ordinal logistic regression and ordinal mixed models were used to predict disease outcome and severity.Results: Initial MRI scans showed abnormal findings in 15 of 38 (39.5%) patients, mostly white matter T2/fluid-attenuated inversion recovery hyperintensities. Volumetric MRI analyses revealed reductions of whole brain and gray matter as well as hippocampal and basal ganglia volumes in NMDARE children. Longitudinal mixed-effect models and z score transformation showed failure of age-expected brain growth in patients. Importantly, patients with abnormal MRI findings at onset were more likely to have poor outcome (Pediatric Cerebral Performance Category score > 1, incidence rate ratio = 3.50, 95% confidence interval [CI] = 1.31-9.31, p = 0.012) compared to patients with normal MRI. Ordinal logistic regression models corrected for time from onset confirmed abnormal MRI at onset (odds ratio [OR] = 9.90, 95% CI = 2.51-17.28, p = 0.009), a presentation with sensorimotor deficits (OR = 13.71, 95% CI = 2.68-24.73, p = 0.015), and a treatment delay > 4 weeks (OR = 5.15, 95% CI = 0.47-9.82, p = 0.031) as independent predictors of poor clinical outcome.Interpretation: Children with NMDARE exhibit significant brain volume loss and failure of age-expected brain growth. Abnormal MRI findings, a clinical presentation with sensorimotor deficits, and a treatment delay > 4 weeks are associated with worse clinical outcome. These characteristics represent promising prognostic biomarkers in pediatric NMDARE. ANN NEUROL 2020 ANN NEUROL 2020;88:148-159. [ABSTRACT FROM AUTHOR]

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis related to autoantibody-mediated synaptic dysfunction. Cerebrospinal fluid-derived human monoclonal NR1 autoantibodies showed low numbers of somatic hypermutations or were unmutated. These unexpected germline-configured antibodies showed weaker binding to the NMDAR than matured antibodies from the same patient. In primary hippocampal neurons, germline NR1 autoantibodies strongly and specifically reduced total and synaptic NMDAR currents in a dose- and time-dependent manner. The findings suggest that functional NMDAR antibodies are part of the human naïve B cell repertoire. Given their effects on synaptic function, they might contribute to a broad spectrum of neuropsychiatric symptoms. Ann Neurol 2019;85:771-776. [ABSTRACT FROM AUTHOR]

Highlights • Polyclonal CSF immunoreactivity in a patient with GABAAR encephalitis. • CSF and commercial antibodies differ on regional, cellular and subcellular levels. • They label complementary populations of GABAergic neurons in some brain areas. • Monoclonal human antibodies will facilitate investigation of antibody pathogenicity. Abstract The y-aminobutyric acid A receptor (GABA A R) participates in most neurophysiological processes. Mutations cause epilepsy and neuropsychiatric pathologies. Recently a severe encephalitis with refractory seizures and antibodies against GABA A Rs has been described. Considering the complex subunit distribution of GABA A Rs, binding patterns of human GABA A R antibodies will help to understand the pathophysiology underlying diverse clinical pictures. We therefore investigated the cerebrospinal fluid (CSF) reactivity of a patient with GABA A R encephalitis using immunocytochemistry on murine brain sections and compared its specificity with commercial GABA A R antibodies. The immunoreactivity of the patient's CSF showed excellent agreement with previously reported GABA A R mRNA expression. Colocalization with neuronal and glial markers verified the neuronal specificity of GABA A R. Patient antibodies strongly bound to neuropil in the external layers of the olfactory bulb, CA1 and CA2 of the hippocampus, neocortex, pallidum and granular cells of the cerebellum. Distribution patterns suggest the presence of polyclonal CSF GABA A R antibodies targeting multiple receptor subunits. The comparison with commercial antibodies revealed large overlap, but also specific differences. For example, commercial antibodies accumulated on dendrites, while CSF created a homogeneous neuropil signal. The number of GABAergic synapses stained with CSF exceeded those labeled with the commercial antibodies. In some areas, commercial antibodies and CSF even stained complementary populations of GABAergic neurons. The data indicate the presence of additional anti-neuronal autoantibodies in the CSF, which could be assessed in future studies with individual recombinant monoclonal antibodies from CSF B cells. This strategy would confirm antibody pathogenicity and likely explain variable clinical pictures in autoimmune encephalitis patients. [ABSTRACT FROM AUTHOR]