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Background: New-generation, cell-based assays have demonstrated a robust association of serum autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis, and brainstem encephalitis, as well as with neuromyelitis optica (NMO)-like or acute-disseminated encephalomyelitis (ADEM)-like presentations. However, only limited data are yet available on cerebrospinal fluid (CSF) findings in MOG-IgG-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD)., Objective: To describe systematically the CSF profile in children with MOG-EM., Material and Methods: Cytological and biochemical findings (including white cell counts [WCC] and differentiation; frequency and patterns of oligoclonal bands; IgG/IgM/IgA and albumin concentrations and CSF/serum ratios; intrathecal IgG/IgM/IgA fractions; locally produced IgG/IgM/IgA concentrations; immunoglobulin class patterns; IgG/IgA/IgM reibergrams; Link index; measles/rubella/zoster [MRZ] reaction; other anti-viral and anti-bacterial antibody indices; CSF total protein; CSF L-lactate) from 108 lumbar punctures in 80 pediatric patients of mainly Caucasian descent with MOG-EM were analyzed retrospectively., Results: Most strikingly, CSF-restricted oligoclonal IgG bands, a hallmark of multiple sclerosis (MS), were absent in 89% of samples (N = 96), and the MRZ reaction, the most specific laboratory marker of MS known so far, in 100% (N = 29). If present at all, intrathecal IgG synthesis was low, often transient and mostly restricted to acute attacks. Intrathecal IgM synthesis was present in 21% and exclusively detectable during acute attacks. CSF WCC were elevated in 54% of samples (median 40 cells/μl; range 6-256; mostly lymphocytes and monocytes; > 100/μl in 11%). Neutrophils were present in 71% of samples; eosinophils, activated lymphocytes, and plasma cells were seen only rarely (all < 7%). Blood-CSF barrier dysfunction (as indicated by an elevated albumin CSF/serum ratio) was present in 46% of all samples (N = 79) and at least once in 48% of all patients (N = 67) tested. CSF alterations were significantly more frequent and/or more pronounced in patients with acute spinal cord or brain disease than in patients with acute ON and varied strongly depending on attack severity. CSF L-lactate levels correlated significantly with the spinal cord lesions load (measured in vertebral segments) in patients with acute myelitis (p = 0.0099). An analysis of pooled data from the pediatric and the adult cohort showed a significant relationship of QAlb (p < 0.0005), CST TP (p < 0.0001), and CSF L-lactate (p < 0.0003) during acute attacks with age., Conclusion: MOG-IgG-associated EM in children is characterized by CSF features that are distinct from those in MS. With regard to most parameters, no marked differences between the pediatric cohort and the adult cohort analyzed in Part 1 were noted. Our findings are important for the differential diagnosis of pediatric MS and MOG-EM and add to the understanding of the immunopathogenesis of this newly described autoimmune disease.

Background: Autoimmune encephalitis is a new spectrum of autoimmune disorders of the central nervous system (CNS), which are characterized by pathogenic autoantibodies against neuronal surface antigens. Clinical presentations range from acute to subacute encephalopathy with neurological and psychiatric symptoms, and life-threatening autonomic dysfunction in severe cases. There exist no approved therapies nor is data available from controlled clinical trials. Patients are usually treated with diverse combinations of immunotherapy. However, effect of immunotherapy on antibody-producing cells and thus on levels of pathogenic autoantibodies is insufficient. Therefore, therapeutic response is sometimes prolonged with necessity of long-time intensive care treatment and also irreversible deficits occur in severe cases. This trial will investigate the efficacy and safety of bortezomib, a proteasome inhibitor known to selectively deplete plasma cells, in patients with severe autoimmune encephalitis who have been treated with rituximab with insufficient response., Methods: Generate-Boost is an investigator-initiated, multicenter, double-blinded, randomized controlled phase II trial which will be conducted in specialized neurological hospitals within the GENERATE (GErman NEtwork for Research on AuToimmune Encephalitis) network in Germany. Adult patients with severe autoimmune encephalitis (modified Rankin scale, mRS ≥ 3), autoantibodies against neuronal surface antigens, and pretreatment with rituximab are eligible for study participation. Fifty patients will be randomized 1:1 and undergo up to 3 cycles (each 21 days with 4 s. c. applications) of bortezomib or placebo. All patients will receive concomitant medication with dexamethasone, acyclovir and co-trimoxazole. The primary efficacy endpoint is the mRS score 17 weeks after first treatment application. Secondary endpoints are neurocognitive function, antibody titers, markers of neuronal cell damage, length of ICU/hospital stay, and mRS and Glasgow coma scale scores throughout the trial up to week 17. General and bortezomib-specific adverse events are monitored continuously., Discussion: The expected outcome of the study is to obtain first reliable data on a hypothesis-driven therapeutic option in severe and difficult-to-treat autoimmune encephalitis. If treatment with bortezomib is beneficial in these cases, this will be the basis for implementation in the current guidelines., Trial Registration: Clinicaltrials.gov , NCT03993262 . Registered June 20, 2019; German Clinical Trials Register, DRKS00017497.

Background: Motor and cognitive deficits and consequently mobility problems are common in geriatric patients. The currently available methods for diagnosis and for the evaluation of treatment in this vulnerable cohort are limited. The aims of the ComOn (COgnitive and Motor interactions in the Older populatioN) study are (i) to define quantitative markers with clinical relevance for motor and cognitive deficits, (ii) to investigate the interaction between both motor and cognitive deficits and (iii) to assess health status as well as treatment outcome of 1000 geriatric inpatients in hospitals of Kiel (Germany), Brescia (Italy), Porto (Portugal), Curitiba (Brazil) and Bochum (Germany)., Methods: This is a prospective, explorative observational multi-center study. In addition to the comprehensive geriatric assessment, quantitative measures of reduced mobility and motor and cognitive deficits are performed before and after a two week's inpatient stay. Components of the assessment are mobile technology-based assessments of gait, balance and transfer performance, neuropsychological tests, frailty, sarcopenia, autonomic dysfunction and sensation, and questionnaires to assess behavioral deficits, activities of daily living, quality of life, fear of falling and dysphagia. Structural MRI and an unsupervised 24/7 home assessment of mobility are performed in a subgroup of participants. The study will also investigate the minimal clinically relevant change of the investigated parameters., Discussion: This study will help form a better understanding of symptoms and their complex interactions and treatment effects in a large geriatric cohort.

Background: IgG-class autoantibodies to N-Methyl-D-Aspartate (NMDA)-type glutamate receptors define a novel entity of autoimmune encephalitis. Studies examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting results. We measured NMDA antibodies in a large, well phenotyped sample of Parkinson patients without and with cognitive impairment ( n  = 296) and controls ( n  = 295) free of neuropsychiatric disease. Detailed phenotyping and large numbers allowed statistically meaningful correlation of antibody status with diagnostic subgroups as well as quantitative indicators of disease severity and cognitive impairment., Methods: NMDA antibodies were analysed in the serum of patients and controls using well established validated assays. We used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic characteristics., Results: The frequency of NMDA IgA/IgM antibodies was lower in Parkinson patients (13%) than in controls (22%) and higher than in previous studies in both groups. NMDA IgA/IgM antibodies were neither significantly associated with diagnostic subclasses of Parkinson disease according to cognitive impairment, nor with quantitative indicators of disease severity and cognitive impairment. A positive NMDA antibody status was positively correlated with age in controls but not in Parkinson patients., Conclusion: It is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease e.g. to Parkinson disease with dementia, while NMDA IgG antibodies define a separate disease of its own., Competing Interests: Ethics committee approval was obtained for all studies involved (Dept. of Neurology of Kiel University, Landscape, popgen).Nothing to report.F. Hopfner received grants from the German Research Council (DFG), Stefanie H. Müller, Dagmar Steppat, Joanna Miller, Nele Schmidt, Claudia Schulte, Petra Neuser, Inga Liepelt-Scarfone, Brit Mollenhauer, Lucas Tittmann, Monika Balzer-Geldsetzer, Simon Baudrexel, Elke Kalbe, Oliver Riedel report no disclosures. Richard Dodel has received lecture fees from Novartis, Lilly, Octapharma, Pfizer and has received research support from the EU Horizon 2020, the AOK Gesundheitskasse Hessen, AOK Gesundheitskasse Sachsen und Thüringen, the M.J.Fox Foundation, the Internationale Parkinson Fonds and the Faber-Stiftung. Frank Leypoldt, Klaus-Peter Wandinger Andre Franke received grants from the German Research Council (DFG). Wolfgang Lieb was supported by a grant from the German Federal Ministry of Education and Research (01EY1103). Daniela Berg is a member of the UCB advisory board and receives grants from Michael J. Fox Foundation, Janssen Pharmaceutica N.V., German Parkinson’s Disease Association (dPV), BMWi, BMBF, Parkinson Fonds Deutschland gGmbH, UCB Pharma GmbH, TEVA Pharma GmbH, EU, Novartis Pharma GmbH, Lundbeck, and Damp foundation. Ruediger Hilker-Roggendorf has received speaker honoraria from Medtronic, Orion, GlaxoSmithKline, TEVA, Cephalon, Solvay, Desitin, Ipsen, Merz, Archimedes Pharma and Boehringer Ingelheim as well as travel funding from Medtronic, Allergan and Cephalon. He has served on a scientific advisory board for Cephalon and has received research funding from the Deutsche Parkinson Vereinigung (dPV), Bundesministerium für Bildung und Forschung and Goethe University Frankfurt. Alexander Storch has received funding from the Deutsche Forschungsgemeinschaft (German Research Association) and the Helmholtz-Association. He has received honoraria for presentations/advisory boards/consultations from AbbVie, Bial, Bayer, Grünenthal, Teva, Desitin and UCB. He has received royalties from Kohlhammer Verlag and Elsevier Press. He serves as an editorial board member of Stem Cells, Stem Cells International, Open Biotechnology Journals, and jbc The Journal of Biological Chemistry. Annika Spottke, Jörg B. Schulz, Karsten Witt and Hans-Ulrich Wittchen report no disclosures. Jan Kassubek has received consulting fees as an advisory board member and honoraria as a speaker from UCB Pharma, Bial, Teva Pharmaceuticals, AbbVie, Zambon, Medtronic, Novartis, Desitin, Boehringer Ingelheim. Thomas Klockgether receives/has received research support from the Deutsche Forschungsgemeinschaft (DFG), the Bundesministerium für Bildung und Forschung (BMBF), the Bundesministerium für Gesundheit (BMG), the Robert Bosch Foundation. the European Union (EU), and the National Institutes of Health (NIH). He serves on the editorial board of The Cerebellum and the Journal of Neurology. He has received consulting fees from Biohaven. Ullrich Wüllner served as consultant and lecturer and on advisory boards for Boehringer-Ingelheim, Glaxo-SmithKline, Pfizer Pharma GmbH, UCB Pharma and received grant/research funding from BMBF, DFG, NAF, dPV and the EU (6th framework). Claudia Trenkwalder reports personal fees from Britannia, during the conduct of the study; grants from Michael J. Fox Foundation, the European Commission Horizon 2020 Program: ‘Propag-Ageing’, MundiPharma, Vifor, personal fees from Britannia, Novartis, UCB, MundiPharma, Vifor, Benevolent, Orion Pharma, Pfizer, personal fees from Grünenthal, UCB and AbbVie., outside the submitted work. Kathrin Reetz is funded by the German Federal Ministry of Education and Research (BMBF 01GQ1402), has received honoraria for presentations from Lilly and research grants from Pfizer, Merck and the Alzheimer Forschung Initiative e.V. (AFI 13812). Günther Deuschl has received lecture fees from UCB, Medtronic and Desitin and has been serving as a consultant for Medtronic, Sapiens, Boston Scientific and Britannica. He received royalties from Thieme publishers. He receives through his institution funding for his research from the German Research Council, the German Ministery of Education and Health and Medtronic. All authors are government employees. Gregor Kuhlenbäumer receives research support from the German Research Council (DFG) and the Christian-Albrechts-University Kiel.