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Introduction: The understanding of the pathophysiology of multiple sclerosis (MS) has evolved alongside the characterization of cytokines and chemokines in cerebrospinal fluid (CSF) and serum. However, the complex interplay of pro- and anti-inflammatory cytokines and chemokines in different body fluids in people with MS (pwMS) and their association with disease progression is still not well understood and needs further investigation. Therefore, the aim of this study was to profile a total of 65 cytokines, chemokines, and related molecules in paired serum and CSF samples of pwMS at disease onset., Methods: Multiplex bead-based assays were performed and baseline routine laboratory diagnostics, magnetic resonance imaging (MRI), and clinical characteristics were assessed. Of 44 participants included, 40 had a relapsing-remitting disease course and four a primary progressive MS., Results: There were 29 cytokines and chemokines that were significantly higher in CSF and 15 in serum. Statistically significant associations with moderate effect sizes were found for 34 of 65 analytes with sex, age, CSF, and MRI parameters and disease progression., Discussion: In conclusion, this study provides data on the distribution of 65 different cytokines, chemokines, and related molecules in CSF and serum in newly diagnosed pwMS., Competing Interests: KB has participated in meetings sponsored by, received travel funding from, or received honoraria for acting as an advisor/speaker for Roche, Biogen, TEVA, Sanofi-Genzyme, Merck, and Novartis. AB was an employee of VASCage – Research Centre on Vascular Ageing and Stroke and has participated in meetings sponsored by or received travel funding from Novartis, Sanofi-Genzyme, Merck, Almirall, and Biogen. DR was an employee of VASCage – Research Centre on Vascular Ageing and Stroke. MA received speaker honoraria and/or travel grants from Biogen, Merck, Novartis, and Sanofi. RB has participated in meetings sponsored by and received travel grants from Biogen, Novartis, and Sanofi. AZ has participated in meetings sponsored by and received speaking honoraria or travel funding from Biogen, Merck, Sanofi-Genzyme and Teva. SW has participated in meetings sponsored by and received honoraria or travel funding from Allergan, Biogen, Ipsen Pharma, Merck, Novartis, Roche, Sanofi Genzyme, Teva, and Bristol Myers Squibb. TB has participated in meetings sponsored by and received honoraria lectures, advisory boards, and consultations from pharmaceutical companies marketing treatments for MS: Allergan, Bayer, Biogen, Bionorica, BMS/Celgene, GSK, GW/Jazz Pharma, Horizon, Janssen-Cilag, MedDay, Merck, Novartis, Octapharma, Roche, Sandoz, Sanofi-Genzyme, Teva, and UCB. FP has participated in meetings sponsored by and received honoraria lectures, advisory boards, consultations or travel funding from Bayer, Biogen, Merck, Novartis, Sanofi-Genzyme, Teva, Celgene, and Roche. Her institution has received research grants from Roche. FD has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Almirall, Alexion, Biogen, Celgene, Genzyme-Sanofi, Horizon, Janssen, Merck, Novartis Pharma, Roche, and TEVA ratiopharm. His institution has received research grants from Biogen and Genzyme Sanofi. He is a section editor of the MSARD Journal Multiple Sclerosis and Related Disorders and a review editor of Frontiers Neurology. HH has participated in meetings sponsored by and received speaker honoraria or travel funding from Bayer, Biogen, Celgene, Merck, Novartis, Sanofi-Genzyme, Siemens, and Teva, and received honoraria for acting as consultant for Biogen, Celgene, Novartis, and Teva. MR was supported by a research support from Euroimmun and Roche. The University Hospital and Medical University of Innsbruck Austria, employer of Dr. Reindl receives payments for antibody assays MOG, AQP4, and other autoantibodies and for MOG and AQP4 antibody validation experiments organized by Euroimmun Lübeck, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Berek, Bauer, Rudzki, Auer, Barket, Zinganell, Lerch, Hofer, Grams, Poskaite, Wurth, Berger, Di Pauli, Deisenhammer, Hegen and Reindl.)

To determine whether there is a correlation between myelin oligodendrocyte glycoprotein (MOG) antibody-associated diseases and varicella zoster virus (VZV) infection. We provide a case report and performed a study to determine the frequency of MOG antibodies (MOG-IgG) in neurological VZV infections. Patients admitted to the Medical University of Innsbruck from 2008-2020 with a diagnosis of a neurological manifestation of VZV infection (n=59) were included in this study; patients with neuroborreliosis (n=34) served as control group. MOG-IgG was detected using live cell-based assays. In addition, we performed a literature review focusing on MOG and aquaporin-4 (AQP4) antibodies and their association with VZV infection. Our case presented with VZV-associated longitudinally extensive transverse myelitis and had MOG-IgG at a titer of 1:1280. In the study, we did not detect MOG-IgG in any other patient neither in the VZV group (including 15 with VZV encephalitis/myelitis) nor in the neuroborreliosis group. In the review of the literature, 3 cases with MOG-IgG and additional 9 cases with AQP4 IgG associated disorders in association with a VZV infection were identified. MOG-IgG are rarely detected in patients with VZV infections associated with neurological diseases., Competing Interests: FDP has participated in meetings sponsored by, received honoraria (lectures, advisory boards, consultations) or travel funding from Almirall, Bayer, Biogen, Celgene, Janssen, Merck, Novartis, Sanofi-Genzyme, Roche and Teva. Her institution has received research grants from Roche. KB has participated in meetings sponsored by and received travel funding from Roche. MA received speaker honoraria and/or travel grants from Biogen, Merck, Novartis and Sanofi. AB has participated in meetings sponsored by Merck and Biogen. TB has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for multiple sclerosis: Almirall, Biogen, Biologix, Bionorica, Celgene/BMS, GSK, MedDay, Merck, Novartis, Roche, Sandoz, Sanofi/Genzyme, TG Pharmaceuticals, TEVA-ratiopharm and UCB. His institution has received financial support in the last 12 months by unrestricted research grants (Biogen, Bayer, Celgene/BMS, Merck, Novartis, Roche, Sanofi/Genzyme, and TEVA ratiopharm) and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, Merck, Novartis, Roche, Sanofi/Genzyme, and TEVA. GB has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Celgene, Lilly, Merck, Novartis, Roche, Sanofi-Genzyme and Teva, and received honoraria for consulting Biogen, Celgene, Roche and Teva. AZ has participated in meetings sponsored by, received speaking honoraria or travel funding from Biogen, Merck, Sanofi-Genzyme and Teva. FDe has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Almirall, Alexion, Biogen, Celgene, Genzyme-Sanofi, Merck, Novartis Pharma, Roche, and TEVA ratiopharm. His institution has received research grants from Biogen and Genzyme Sanofi. He is section editor of the MSARD Journal (Multiple Sclerosis and Related Disorders). MR was supported by a research support from Euroimmun and Roche. His institution receives payments for antibody assays (MOG, AQP4, and other autoantibodies) and for MOG and AQP4 antibody validation experiments organized by Euroimmun (Lübeck, Germany). HH has participated in meetings sponsored by, received speaker honoraria or travel funding from Bayer, Biogen, Merck, Novartis, Sanofi-Genzyme, Siemens, Teva, and received honoraria for acting as consultant for Biogen and Teva. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Di Pauli, Morschewsky, Berek, Auer, Bauer, Berger, Bsteh, Rhomberg, Schanda, Zinganell, Deisenhammer, Reindl and Hegen.)

Background: Reports on typical routine cerebrospinal fluid (CSF) findings are outdated owing to novel reference limits (RL) and revised diagnostic criteria of Multiple Sclerosis (MS)., Objective: To assess routine CSF parameters in MS patients and the frequency of pathologic findings by applying novel RL., Methods: CSF white blood cells (WBC), CSF total protein (CSF-TP), CSF/serum albumin quotient (Q alb ), intrathecal synthesis of immunoglobulins (Ig) A, M and G, oligoclonal IgG bands (OCB) were determined in patients with clinically isolated syndrome (CIS) and MS., Results: Of 541 patients 54% showed CSF pleocytosis with a WBC count up to 40/μl. CSF cytology revealed lymphocytes, monocytes and neutrophils in 99%, 41% and 9% of patients. CSF-TP and Q alb were increased in 19% and 7% applying age-corrected RL as opposed to 34% and 26% with conventional RL. Quantitative intrathecal IgG, IgA and IgM synthesis were present in 65%, 14% and 21%; OCB in 95% of patients. WBC were higher in relapsing than progressive MS and predicted, together with monocytes, the conversion from CIS to clinically definite MS. Intrathecal IgG fraction was highest in secondary progressive MS., Conclusions: CSF profile in MS varies across disease courses. Blood-CSF-barrier dysfunction and intrathecal IgA/IgM synthesis are less frequent when the novel RL are applied., Competing Interests: KB has participated in meetings sponsored by and received travel funding from Roche and Biogen. GB has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Celgene, Lilly, Merck, Novartis, Sanofi-Genzyme and Teva, and received honoraria for consulting Biogen, Celgene, Merck, Novartis, Roche and Teva. MA received speaker honoraria and/or travel grants from Biogen, Merck, Novartis and Sanofi. FP has participated in meetings sponsored by, received honoraria (lectures, advisory boards, consultations) or travel funding from Bayer, Biogen, Merck, Novartis, Sanofi-Genzyme, Teva, Celgene and Roche. Her institution has received research grants from Roche. AZ has participated in meetings sponsored by, received speaking honoraria or travel funding from Biogen, Merck, Sanofi-Genzyme and Teva. TB has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for MS: Allergan, Biogen, Biologix, Bionorica, Celgene, Eisei, MedDay, Merck, Novartis, Roche, Sanofi-Genzyme, Teva, UCB. His institution has received financial support in the past 12 months by unrestricted research grants (Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, Teva) and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Aventis, Teva. FD has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Almirall, Alexion, Biogen, Celgene, Genzyme-Sanofi, Merck, Novartis Pharma, Roche, and TEVA ratiopharm. His institution has received research grants from Biogen and Genzyme Sanofi. He is section editor of the MSARD Journal (Multiple Sclerosis and Related Disorders). HH has participated in meetings sponsored by, received speaker honoraria or travel funding from Bayer, Biogen, Merck, Novartis, Sanofi-Genzyme, Siemens, Teva, and received honoraria for acting as consultant for Teva and Biogen., (Copyright © 2021 Berek, Bsteh, Auer, Di Pauli, Zinganell, Berger, Deisenhammer and Hegen.)

Highly sensitive reporter-gene assays have been developed that allow both the direct vascular endothelial growth factor (VEGF) neutralizing activity of bevacizumab and the ability of bevacizumab to activate antibody dependent cellular cytotoxicity (ADCC) to be quantified rapidly and in a highly specific manner. The use of these assays has shown that in 46 patients with ovarian cancer following four cycle of bevacizumab treatment, and in longitudinal samples from the two patients that respond to bevacizumab therapy from a small cohort of patients with glioblastoma, that there is a reasonably good correlation between bevacizumab drug levels determined by ELISA and bevacizumab activity, determined using either the VEGF-responsive reporter gene, or the ADCC assays. One of the two primary non-responders with glioblastoma exhibited high levels of ADCC activity suggesting reduced bevacizumab Fc engagement in vivo in contrast to the other primary non-responder, and the two secondary non-responders with a decreasing bevacizumab PK profile, determined by ELISA that exhibited low to undetectable ADCC activity. Drug levels were consistently higher than bevacizumab activity determined using the reporter gene assay in serial samples from one of the secondary non-responders and lower in some samples from the other secondary non-responder and ADCC activity was markedly lower in all samples from these patients suggesting that bevacizumab activity may be partially neutralized by anti-drug neutralizing antibodies (NAbs). These results suggest that ADCC activity may be correlated with the ability of some patients to respond to treatment with bevacizumab while the use of the VEGF-responsive reporter-gene assay may allow the appearance of anti-bevacizumab NAbs to be used as a surrogate maker of treatment failure prior to the clinical signs of disease progression., (Copyright © 2020 Lallemand, Ferrando-Miguel, Auer, Iglseder, Czech, Gaber-Wagener, Di Pauli, Deisenhammer and Tovey.)

Inflammatory demyelinating CNS syndromes include, besides their most common entity multiple sclerosis (MS), several different diseases of either monophasic or recurrent character-including neuromyelitis optica spectrum disorders (NMOSDs) and acute disseminated encephalomyelitis (ADEM). Early diagnostic differentiation is crucial for devising individual treatment strategies. However, due to overlapping clinical and paraclinical features diagnosis at the first demyelinating event is not always possible. A multiplicity of potential biological markers that could discriminate the different diseases was studied. As the use of autoantibodies in patient management of other autoimmune diseases, is well-established and evidence for the critical involvement of B cells/antibodies in disease pathogenesis in inflammatory demyelinating CNS syndromes increases, antibodies seem to be valuable diagnostic tools. Since the detection of antibodies against aquaporin-4 (AQP-4), the understanding of immunopathogenesis and diagnostic management of NMOSDs has dramatically changed. However, for most inflammatory demyelinating CNS syndromes, a potential antigen target is still not known. A further extensively studied possible target structure is myelin oligodendrocyte glycoprotein (MOG), found at the outermost surface of myelin sheaths and oligodendrocyte membranes. With detection methods using cell-based assays with full-length, conformationally correct MOG, antibodies have been described in early studies with a subgroup of patients with ADEM. Recently, a humoral immune reaction against MOG has been found not only in monophasic diseases, but also in recurrent non-MS diseases, particularly in pediatric patients. This review presents the findings regarding MOG antibodies as potential biological markers in discriminating between these different demyelinating CNS diseases, and discusses recent developments, clinical implementations, and data on immunopathogenesis of MOG antibody-associated disorders.

Background: Risk of natalizumab-related progressive multifocal leukoencephalopathy is associated with the presence of anti-JC-virus (JCV) antibodies. Objective: To investigate the impact of disease-modifying treatments (DMT) on the longitudinal evolution of anti-JCV antibody index. Methods: Patients with multiple sclerosis who had serum sampling at intervals of 6 ± 3 months over up to 6 years and who either started DMT (interferon-β, glatiramer acetate or natalizumab) during the observation period with at least one serum sample available before and after treatment initiation or received no DMT during the observation period were included. Anti-JCV antibody serological status and index were determined by 2-step second-generation anti-JCV antibody assay. Results: A total of 89 patients were followed for a median time of 55.2 months. Of those, 62 (69.7%) started DMT and 27 (30.3%) were without therapy during the observation period. Variation of longitudinal anti-JCV antibody index ranged from 9 to 15% and was similar in patients with and without DMT. Applying a mixed model considering the combined effects of treatment and time as well as individual heterogeneity did not show a significant change of anti-JCV antibody index by the start of treatment with interferon-β, glatiramer acetate, or natalizumab. Conclusion: Evaluated DMTs do not impact longitudinal anti-JCV antibody index evolution.