Search

Simple Summary: Autoantibodies against the metabotropic glutamate receptor 5 (mGluR5) have been linked to Ophelia syndrome, a combination of limbic encephalitis and Hodgkin lymphoma (HL). We studied mGluR5 expression in 57 pediatric HL and NHL by immunohistochemistry to explore the relationship between mGluR5 antibody formation and HL. All lymphoma tissues displayed mGluR5 staining, especially HL Reed–Sternberg cells. There was no staining in age-matched healthy lymph nodes, and we did not find GRM5 transcripts in RNA-sequencing data from normal lymphocytes. Lower mGluR5 levels in HL correlated with younger patients and EBV-positive tumors. Cases of paraneoplastic and neurological symptoms were found exclusively in the HL cohort. The frequent presence of mGluR5 in lymphoma tissue suggests a possible role in tumor development. This finding is in line with reports that glutamatergic signaling affects the outcome in other cancers. However, further studies in larger cohorts are needed to evaluate the impact of mGluR5 on HL severity. Autoantibodies targeting the neuronal antigen metabotropic glutamate receptor 5 (mGluR5) have been identified in patients with Ophelia syndrome, which describes a co-occurrence of paraneoplastic limbic encephalitis and Hodgkin lymphoma (HL). Little data exist regarding frequency and function of mGluR5 in HL and its potential role in causing seropositive paraneoplastic disease. We studied a representative cohort of pediatric HL and NHL patients (n = 57) using immunohistochemistry and fluorescence staining to investigate mGluR5 expression. All lymphoma tissues displayed positive mGluR5 staining, with focus on Hodgkin–Reed–Sternberg (H-RS) cells. We did not detect any mGluR5 staining in tumor-free lymph nodes, which is consistent with the absence of GRM5 transcripts in RNA-sequencing data from non-malignant B and T cells. The frequent presence in pediatric lymphoma falls in line with reports of mGluR5 expression and associated tumor progression in other malignancies. We tested for correlation with clinical features, focusing on disease progression and neurological symptoms. Low mGluR5 expression in H-RS cells correlated with young patient age (<15 years) and positive histology for EBV infection. Paraneoplastic or neurological symptoms were found exclusively in HL patients. While an impact of mGluR5 on HL severity remains possible, a prognostic value of mGluR5 expression levels requires further investigation. [ABSTRACT FROM AUTHOR]

Background and Objectives: Anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is the most common form of autoimmune encephalitis in children and adults. Although our understanding of the disease mechanisms has progressed, little is known about estimating patient outcomes. Therefore, the NEOS (anti- N MDAR E ncephalitis O ne-Year Functional S tatus) score was introduced as a tool to predict disease progression in NMDARE. Developed in a mixed-age cohort, it currently remains unclear whether NEOS can be optimized for pediatric NMDARE., Methods: This retrospective observational study aimed to validate NEOS in a large pediatric-only cohort of 59 patients (median age of 8 years). We reconstructed the original score, adapted it, evaluated additional variables, and assessed its predictive power (median follow-up of 20 months). Generalized linear regression models were used to examine predictability of binary outcomes based on the modified Rankin Scale (mRS). In addition, neuropsychological test results were investigated as alternative cognitive outcome., Results: The NEOS score reliably predicted poor clinical outcome (mRS ≥3) in children in the first year after diagnosis ( p = 0.0014) and beyond ( p = 0.036, 16 months after diagnosis). A score adapted to the pediatric cohort by adjusting the cutoffs of the 5 NEOS components did not improve predictive power. In addition to these 5 variables, further patient characteristics such as the " Herpes simplex virus encephalitis (HSE) status" and "age at disease onset" influenced predictability and could potentially be useful to define risk groups. NEOS also predicted cognitive outcome with higher scores associated with deficits of executive function ( p = 0.048) and memory ( p = 0.043)., Discussion: Our data support the applicability of the NEOS score in children with NMDARE. Although not yet validated in prospective studies, NEOS also predicted cognitive impairment in our cohort. Consequently, the score could help identify patients at risk of poor overall clinical outcome and poor cognitive outcome and thus aid in selecting not only optimized initial therapies for these patients but also cognitive rehabilitation to improve long-term outcomes., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Autoantibodies targeting the GABAA receptor (GABAAR) hallmark an autoimmune encephalitis presenting with frequent seizures and psychomotor abnormalities. Their pathogenic role is still not well-defined, given the common overlap with further autoantibodies and the lack of patient-derived mAbs. Five GABAAR mAbs from cerebrospinal fluid cells bound to various epitopes involving the α1 and γ2 receptor subunits, with variable binding strength and partial competition. mAbs selectively reduced GABAergic currents in neuronal cultures without causing receptor internalization. Cerebroventricular infusion of GABAAR mAbs and Fab fragments into rodents induced a severe phenotype with seizures and increased mortality, reminiscent of encephalitis patients' symptoms. Our results demonstrate direct pathogenicity of autoantibodies on GABAARs independent of Fc-mediated effector functions and provide an animal model for GABAAR encephalitis. They further provide the scientific rationale for clinical treatments using antibody depletion and can serve as tools for the development of antibody-selective immunotherapies., Competing Interests: Disclosures: No disclosures were reported., (© 2021 Kreye et al.)