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Background: Diagnosing multiple sclerosis (MS) is challenging due to diverse symptoms and the absence of specific biomarkers. Concurrent autoimmune diseases (AID) or non-specific antibodies further complicate diagnosis, progression monitoring, and management. Data on AID prevalence in MS patients are sparse. This study aims to identify concurrent AIDs alongside MS., Methods: In this retrospective single-center study, we analyzed patient records at our university hospital from 2010 to 2017, focusing on cases suspected of inflammatory demyelinating disease. The 2017 McDonald criteria were applied. Additionally, we measured neurofilament light (NfL) levels from available CSF samples in our biobank., Results: We identified a total of 315 patients, of whom 66% were women. In total, 13.7% of all patients had concurrent AID, while 20.3% had isolated antibody findings without AID. The most common AID was autoimmune thyroiditis (8.9%), followed by chronic inflammatory skin diseases (1.6%), arthritis (1%), type 1 diabetes (1%), Sjögren's syndrome (0.6%), and inflammatory bowel diseases (0.6%). Cardiolipin antibodies were the most frequent isolated antibody finding (8.6%). Our data showed that, from the perspective of the initial demyelinating event, neither comorbid AID nor isolated antibodies significantly influenced relapses or MS progression over a median follow-up of 9 months. Standard CSF parameters and NfL levels were similar between the groups at the time of MS diagnosis., Conclusion: Our study shows that AIDs, particularly autoimmune thyroiditis, frequently occur at the onset of MS. The proportion of AIDs commonly treated with immunomodulatory therapy in our cohort was similar to that observed in the general population. Comorbid AID did not affect NfL levels, indicating similar disease activity. Future research should explore new AID emergence during the course of MS, especially considering the increased incidence of rheumatic diseases later in life., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the institutional ethics committee (no. 8172-BO-K-2018). Consent for publication Not applicable. Competing interests The authors declare no conflict of interest. Outside the submitted work, the authors received honoraria for lectures, travel grants, or research grants. KFJ received research support from Else Kröner Fresenius Foundation and travel compensation and congress fee from Merck and Novartis. TT received honoraria from Boehringer Ingelheim, Janssen and Galapagos. LML reports no disclosures. FFK received travel grants from Merck and Novartis. AH reports no disclosures. LH reports no disclosures. YEG reports no disclosures. PS reports no disclosures. KWS reports honoraria for lectures or travel reimbursements for attending meetings from Biogen, Merck, Bavarian Nordic and Bristol-Myers Squibb as well as research support from Bristol-Myers Squibb. JS received lecture fees from Merck and Sanofi, and travel grant from Novartis and Sanofi. MPW received speaker or consultancy honoraria from Alexion, Bayer Healthcare, Biogen, Biologix, Bristol Myers Squibb, Celgene, Genilac, Imcyse, IXICO, Icometrix, Medison, Merck-Serono, Novartis, Roche, Sanofi-Genzyme, and publication royalties from Springer and Elsevier. TW reports honoraria for lectures and travel grants from Abbvie, Biogen, Boehringer Ingelheim, Celgene, Chugai, CSL Behring, Euroimmun, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, Siemens, Takeda, UCB. CK received lecture and consultancy fees from Biogen, Roche, and Novartis. RP received honoraria for lecturing and consulting from Alexion, Bayer Healthcare, Biogen, Bristol-Mayers Squibb, Hexal, Merck Serono, Mylan, Novartis, Roche, Sanofi Genzyme. He received research funds from Merck Serono and Novartis. HT has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Alexion, Bayer, Biogen, Bristol-Myers Squibb, Celgene, Diamed, Fresenius, Fujirebio, GlaxoSmithKline, Horizon, Janssen-Cilag, Merck, Novartis, Roche, Sanofi-Genzyme, Siemens, and Teva. All not related to the present work. SG received consulting and/or speaker honoraria from Alexion, Alnylam Pharmaceuticals, AstraZeneca, GSK, Pfizer and Merck. His research is supported by the Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, Hannover Biomedical Research School (HBRS), Alnylam Pharmaceuticals and CSL Behring. TS reports research support from Alnylam Pharmaceuticals, CSL Behring, Novartis, Siemens; honoraria for lectures and travel expenses for attending meetings from Alexion, Alnylam Pharmaceuticals, argenx, Bayer Vital, Biogen, Bristol Myers Squibb, Celgene, Centogene, CSL Behring, Euroimmun, Grifols, Hexal AG, Horizon, Janssen-Cilag, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Siemens, Swedish Orphan Biovitrum, Teva, Viatris; consultant fees from Alexion, Alnylam Pharmaceuticals, Biogen, Centogene, CSL Behring, Grifols, Hexal AG, Janssen-Cilag, Merck Serono, Novartis, Roche, Sanofi, Swedish Orphan Biovitrum, Viatris., (© 2024. The Author(s).)

Background: The humanized monoclonal anti-CD20-antibody ofatumumab is highly effective in treating relapsing multiple sclerosis (MS)., Objective: This study aimed to investigate the immanent effect of ofatumumab on the peripheral immune system, particularly targeting B and T cells expressing CD20., Methods: Blood samples of 53 MS patients receiving ofatumumab were collected prior to first application and after one week, two weeks and three months. Multicolor flow cytometry was used to phenotype peripheral blood mononuclear cells, and immunoglobulin (Ig) concentrations were measured by nephelometry., Results: Among CD20 + lymphocytes, 13 % co-expressed CD3 (identifying them as CD3 + CD20 + T lymphocytes), with a noticeable shift in the CD4/CD8-ratio towards CD8 + T cells. One week after administering ofatumumab, a significant reduction of CD20 + lymphocytes with complete depletion of CD3 + CD20 + T lymphocytes was observed, persisting during the investigation period. During the treatment, IgM levels showed a slight but significant decrease, whereas IgA and IgG levels remained stable., Conclusion: Ofatumumab effectively depletes CD20 + lymphocytes already after the first administration. This depletion affects not only B cells, but also a small proportion of T cells (CD3 + CD20 + ), affirming the hypothesis that the anti-inflammatory effects of CD20 + cell depletion might extend to the reduction of CD3 + CD20 + T lymphocytes., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. Outside the submitted work, some authors received honoraria for lectures, travel grants, or research grants. FFK received travel compensation from Merck, Novartis, BMS and Alexion as well as a German Research Foundation (DFG)–funded fellowship as part of the Clinician Scientist Program (PRACTIS) at Hannover Medical School. SG reports research support from Alnylam Pharmaceuticals, CSL Behring, Else Kröner Fresenius Foundation, Deutsche Forschungsgemeinschaft and Hannover Biomedical Research School (HBRS) and consulting and/or speaker honoraria from Alexion, Alnylam Pharmaceuticals, AstraZeneca, GSK, Pfizer and Merck. MWH received research support from Myelitis e. V., speaker honoraria from selpers og, Horizon and Alexion, and reimbursement of travel expenses and compensation for serving on an advisory board from Alexion. None of this interfered with the current manuscript. NM received honoraria for scientific lectures from Novartis, Merck, and Biogen as well as a German Research Foundation (DFG)–funded fellowship as part of the Clinician Scientist Program (PRACTIS) at Hannover Medical School. LGL received a German Research Foundation (DFG)–funded fellowship as part of the Clinician Scientist Program (Young Academy, Project number 413,617,135) at Hannover Medical School. SN has no conflict of interest to declare. TSe received research support from Ellen Schmidt Scholarship of the Hannover Medical School, financial support for conference attendance fees from Abbvie, and honoraria for preparation of a manuscript by Springer. DR has no conflict of interest to declare. KFJ received research support from Else Kröner Fresenius Foundation and travel compensation and congress fee from Merck and Novartis. DT has no conflict of interest to declare. ALS has no conflict of interest to declare. JRK has no conflict of interest to declare. RJ has no conflict of interest to declare. ThS reports research support from the German Ministry for Education and Research (BMBF: CurePML01EN2302), Bristol Myers Squibb Foundation for Immuno-Oncology (FA 19–010), Claudia von Schilling Foundation for Breast Cancer Research, Else Kröner Fresenius Foundation, Genzyme Neuroimmunology Fellowship, Hannover Biomedical Research School (HBRS), VHV Foundation, Alnylam Pharmaceuticals, CSL Behring, Novartis; honoraria for lectures and travel expenses for attending meetings from Alexion, Alnylam Pharmaceuticals, argenx, Bayer Vital, Biogen, Bristol Myers Squibb, Celgene, Centogene, CSL Behring, Euroimmun, Grifols, Hexal AG, Janssen-Cilag, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Siemens, Swedish Orphan Biovitrum, Teva, Viatris; consultant fees from Alexion, Alnylam Pharmaceuticals, Biogen, Centogene, CSL Behring, Grifols, Hexal AG, Janssen-Cilag, Merck Serono, Novartis, Roche, Sanofi, Swedish Orphan Biovitrum, Viatris. PS has no conflict of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Sjögren's syndrome is an autoimmune disease characterized by sicca symptoms and various extraglandular manifestations including vasculitis. Neurological involvement occurs frequently (Neuro-Sjögren) and often mimics immune neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP)., Objectives: We aim to assess relevant differences in vessel density (VD) in Optical Coherence Tomography Angiography (OCTA) in those diseases to use it as an easily available diagnostic tool., Design: Prospective, monocentric pilot-study., Methods: OCTA (Heidelberg Engineering OCT SPECTRALIS) of the superficial vascular plexus, intermediate capillary plexus (ICP) and deep capillary plexus (DCP) of the retina was prospectively performed in Neuro-Sjögren, age-matched CIDP patients ( n  = 31, each), and healthy controls ( n  = 30). Vessel density (VD) and foveal avascular zone (FAZ) was measured with Erlangen Angio Tool., Results: Significantly lower VD were found for the DCP and ICP in Neuro-Sjögren and CIDP patients compared to healthy controls ( p  = 0.0002 and <0.0001). When group comparison was age-adjusted, these differences were not found anymore. Different frequencies of "low" retinal blood flow in each layer comparing Neuro-Sjögren and CIDP patients were not found. FAZ revealed no significant differences between patients with Neuro-Sjögren, CIDP and healthy controls., Conclusion: This study found no significant differences in VD or the foveal avascular zone between Neuro-Sjögren and CIDP patients using OCTA, suggesting that inflammatory vascular changes in the retina are uncommon in Neuro-Sjögren patients., (© The Author(s) 2024.)

Background: Data on cognition in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are limited to studies with small sample sizes. Therefore, we aimed to analyse the extent, characteristics and the longitudinal course of potential cognitive deficits in patients with MOGAD., Methods: The CogniMOG-Study is a prospective, longitudinal and multicentre observational study of 113 patients with MOGAD. Individual cognitive performance was assessed using the Paced Auditory Serial Addition Task (PASAT), the Symbol Digit Modalities Test (SDMT) and the Multiple Sclerosis Inventory Cognition (MuSIC), which are standardised against normative data from healthy controls. Cognitive performance was assessed at baseline and at 1-year and 2-year follow-up assessments. Multiple linear regression was used to analyse demographic and clinical predictors of cognitive deficits identified in previous correlation analyses., Results: At baseline, the study sample of MOGAD patients showed impaired standardised performance on MuSIC semantic fluency (mean=-0.29, 95% CI (-0.47 to -0.12)) and MuSIC congruent speed (mean=-0.73, 95% CI (-1.23 to -0.23)). Around 1 in 10 patients showed deficits in two or more cognitive measures (11%). No decline in cognition was observed during the 1-year and 2-year follow-up period. Cerebral lesions were found to be negatively predictive for SDMT (B=-8.85, 95% CI (-13.57 to -4.14)) and MuSIC semantic fluency (B=-4.17, 95% CI (-6.10 to -2.25)) test performance., Conclusions: Based on these data, we conclude that MOGAD patients show reduced visuomotor processing speed and semantic fluency to the extent that the disease burden includes cerebral lesions., Competing Interests: Competing interests: SP, CStern, SJ, MK-K, VH, J-PS, MG, RS, JRK, AW, FTB, PSS and BK report no disclosures relevant to the manuscript. TK has received speaker honoraria and/or personal fees for advisory boards from Merck, Roche Pharma, Alexion/Astra Zeneca, Horizon, Chugai and Biogen. JH reports grants from the Friedrich-Baur-Stiftung, Merck and Horizon, personal fees and non-financial support from Alexion, Horizon, Roche, Merck, Novartis, Biogen, BMS and Janssen, and non-financial support from the Guthy-Jackson Charitable Foundation and The Sumaira Foundation. DE received speaker honoraria from Alexion and Horizon/Amgen. BW received grants from the German Ministry of Education and Research, Deutsche Forschungsgemeinschaft, Dietmar Hopp Foundation and Klaus Tschira Foundation, grants and personal fees from Merck, Novartis and personal fees from Alexion, INSTAND, Roche. MS has received consulting and/or speaker honoraria from Alexion, Bayer, Biogen, Bristol-Myers-Squibb, Merck, Horizon, Roche and Sanofi Genzyme. CW has received institutional support from Novartis, Alexion, Sanofi Genzyme, Biogen, Merck, Roche and Hexal. SG reports research support from Alnylam Pharmaceuticals, CSL Behring, Else Kröner Fresenius Foundation, Deutsche Forschungsgemeinschaft and Hannover Biomedical Research School (HBRS) and consulting and/or speaker honoraria from Alexion, Alnylam Pharmaceuticals, AstraZeneca, GSK, Pfizer and Merck all outside the submitted work. LK received compensation for serving on Scientific Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Genzyme, Horizon, Janssen, Merck Serono, Novartis, Roche and Viatris. She received speaker honoraria and travel support from Argenx, Bayer, Biogen, Bristol-Myers Squibb, Genzyme, Grifols, Merck Serono, Novartis, Roche, Santhera and Teva. She receives research support from the German Research Foundation, the IZKF Münster, IMF Münster, Biogen, Immunic AG, Novartis and Merck Serono. OA reports grants from the German Ministry of Education and Research (BMBF) and the German Research Foundation (DFG); grants and personal fees from Biogen and Novartis; and travel support and personal fees from Alexion, Almirall, MedImmune, Merck Serono, Roche, Sanofi, Viela Bio/Horizon Therapeutics and Zambon. MR received speaker honoraria from Novartis, Bayer Vital, Roche, Alexion, Horizon and Ipsen and travel reimbursement from Bayer Schering, Biogen Idec, Merz, Genzyme, Teva, Roche, Horizon and Merck, none related to this study. IA has received research support from Diamed and Chugai, speaking honoraria, travel grants and compensation for serving on a scientific advisory board from Alexion, Horizon, Roche, Merck and Sanofi-Aventis/Genzyme, all unrelated to this study. CSchwake has received speaker honoraria from Alexion and travel support from Novartis and UCB. All not related to the content of this manuscript. IK has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, Almirall, Bayer, Biogen, GlaxoSmithKline, Hexal, Horizon, Merck, Neuraxpharm, Roche/Chugai and Sanofi. RR received speaking honorar from Roche unrelated to this study. PS received travel reimbursement by UCB. JB-S has received research support from NEMOS e.V. and Bayer AG, personal compensation from Alexion, speaking honoraria and travel grants from Bayer Healthcare, Horizon, Novartis and Sanofi-Aventis/Genzyme, in addition received compensation for serving on a scientific advisory board of Roche and Merck, all unrelated to the presented work. FP receives honoraria for lecturing, and travel expenses from Guthy Jackson Foundation, Bayer, Biogen, Merck Serono, Sanofi Genzyme, Novartis, Viela Bio, Roche, UCB, Mitsubishi Tanabe, Celgene and support for attending meetings from Alexion. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Einstein Foundation, Guthy Jackson Charitable Foundation, EU FP7 Framework Program, Biogen, Genzyme, Merck Serono, Novartis, Bayer, Roche, Parexel and Almirall. FP serves on advisory boards and steering committees for Celgene, Roche, UCB and Merck and is associate editor of Neurology, Neuroimmunology & Neuroinflammation and academic editor for PLoS ONE. CT has received honoraria for consultation and expert testimony from Alexion Pharma Germany. None of this interfered with the current report. MWH received research support from Myelitis e. V., speaker honoraria from selpers og, Horizon, and Alexion, and reimbursement of travel expenses and compensation for serving on an advisory board from Alexion. None of this interfered with the current manuscript., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To evaluate the performance of serum neurofilament light chain (NfL) and cerebrospinal fluid (CSF) phosphorylated neurofilament heavy chain (pNfH) as diagnostic biomarkers for the differentiation between motor neuron disease (MND) and multifocal motor neuropathy (MMN)., Methods: This retrospective, monocentric study included 16 patients with MMN and 34 incident patients with MND. A subgroup of lower motor neuron (MN) dominant MND patients (n = 24) was analyzed separately. Serum NfL was measured using Ella automated immunoassay, and CSF pNfH was measured using enzyme-linked immunosorbent assay. Area under the curve (AUC), optimal cutoff values (Youden's index), and correlations with demographic characteristics were calculated., Results: Neurofilament concentrations were significantly higher in MND compared to MMN (p < 0.001), and serum NfL and CSF pNfH correlated strongly with each other (Spearman's rho 0.68, p < 0.001). Serum NfL (AUC 0.946, sensitivity and specificity 94%) and CSF pNfH (AUC 0.937, sensitivity 90.0%, specificity 100%) performed excellent in differentiating MND from MMN. Optimal cutoff values were ≥ 44.15 pg/mL (serum NfL) and ≥ 715.5 pg/mL (CSF pNfH), respectively. Similar results were found when restricting the MND cohort to lower MN dominant patients. Only one MMN patient had serum NfL above the cutoff. Two MND patients presented with neurofilament concentrations below the cutoffs, both featuring a slowly progressive disease., Conclusion: Neurofilaments are valuable supportive biomarkers for the differentiation between MND and MMN. Serum NfL and CSF pNfH perform similarly well and elevated neurofilaments in case of diagnostic uncertainty underpin MND diagnosis., (© 2024. The Author(s).)

Optic neuritis is often an initial symptom in multiple sclerosis (MS) or clinically isolated syndrome (CIS), yet comprehensive studies using the 2017 McDonald criteria for MS are scarce. Patient records from our academic centre (2010-2018) were reviewed. Using the 2017 McDonald criteria, three groups were formed: MS optic neuritis (optic neuritis with confirmed MS), CIS optic neuritis (optic neuritis without confirmed MS) and suspected optic neuritis (sON). We compared clinical and paraclinical findings among the groups to identify predictors for CIS- or MS-optic neuritis. The study included 129 MS, 108 CIS, and 44 sON cases. The combination of visual impairment, dyschromatopsia, and retrobulbar pain was observed in 47% of MS patients, 42% of CIS patients, and 30% of sON patients. Dyschromatopsia was the strongest indicator of MS or CIS diagnosis in the backward regression model. 56% of MS patients had relative afferent pupillary defect, 61% optic nerve anomalies within magnetic resonance imaging, and 81% abnormal visual evoked potentials. Our results emphasize the challenges in diagnosing optic neuritis, as not all patients with objectively diagnosed MS exhibit the triad of typical symptoms. To address potentially missing clinical features, incorporating additional paraclinical findings is proposed., (© 2024. The Author(s).)

Multiple sclerosis is a chronic autoimmune disease of the central nervous system characterized by myelin loss, axonal damage, and glial scar formation. Still, the underlying processes remain unclear, as numerous pathways and factors have been found to be involved in the development and progression of the disease. Therefore, it is of great importance to find suitable animal models as well as reliable methods for their precise and reproducible analysis. Here, we describe the impact of demyelination on clinically relevant gray matter regions of the hippocampus and cerebral cortex, using the previously established cuprizone model for aged mice. We could show that bioinformatic image analysis methods are not only suitable for quantification of cell populations, but also for the assessment of de- and remyelination processes, as numerous objective parameters can be considered for reproducible measurements. After cuprizone-induced demyelination, subsequent remyelination proceeded slowly and remained incomplete in all gray matter areas studied. There were regional differences in the number of mature oligodendrocytes during remyelination suggesting region-specific differences in the factors accounting for remyelination failure, as, even in the presence of oligodendrocytes, remyelination in the cortex was found to be impaired. Upon cuprizone administration, synaptic density and dendritic volume in the gray matter of aged mice decreased. The intensity of synaptophysin staining gradually restored during the subsequent remyelination phase, however the expression of MAP2 did not fully recover. Microgliosis persisted in the gray matter of aged animals throughout the remyelination period, whereas extensive astrogliosis was of short duration as compared to white matter structures. In conclusion, we demonstrate that the application of the cuprizone model in aged mice mimics the impaired regeneration ability seen in human pathogenesis more accurately than commonly used protocols with young mice and therefore provides an urgently needed animal model for the investigation of remyelination failure and remyelination-enhancing therapies., (© 2023 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Objective: Progression prediction is a significant unmet need in people with progressive multiple sclerosis (pwPMS). Studies on glial fibrillary acidic protein (GFAP) have either been limited to single center with relapsing MS or were based solely on Expanded Disability Status Scale (EDSS), which limits its generalizability to state-of-the-art clinical settings and trials applying combined outcome parameters., Methods: Serum GFAP and NfL (neurofilament light chain) were investigated in EmBioProMS participants with primary (PP) or secondary progressive MS. Six months confirmed disability progression (CDP) was defined using combined outcome parameters (EDSS, timed-25-foot walk test (T25FW), and nine-hole-peg-test (9HPT))., Results: 243 subjects (135 PPMS, 108 SPMS, age 55.5, IQR [49.7-61.2], 135 female, median follow-up: 29.3 months [17.9-40.9]) were included. NfL (age-) and GFAP (age- and sex-) adjusted Z scores were higher in pwPMS compared to HC (p < 0.001 for both). 111 (32.8%) CDP events were diagnosed in participants with ≥3 visits (n = 169). GFAP Z score >3 was associated with higher risk for CDP in participants with low NfL Z score (i.e., ≤1.0) (HR: 2.38 [1.12-5.08], p = 0.025). In PPMS, GFAP Z score >3 was associated with higher risk for CDP (HR: 2.88 [1.21-6.84], p = 0.016). Risk was further increased in PPMS subjects with high GFAP when NfL is low (HR: 4.31 [1.53-12.13], p = 0.006)., Interpretation: Blood GFAP may help identify pwPPMS at risk of progression. Combination of high GFAP and low NfL levels could distinguish non-active pwPMS with particularly high progression risk., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Blood-cerebrospinal fluid (CSF) barrier dysfunction is pivotal for diagnosing immune-mediated neuropathies, especially in spinal nerve root inflammation. Typically, either total CSF protein or the CSF to serum albumin ratio (Q Alb ) is measured. Total CSF protein measurements have limitations, notably its fixed reference value regardless of age, in contrast to the age-dependent reference for Q Alb . Our goal was to evaluate both markers in patients with immune-mediated neuropathies., Methods: In our multicenter research, we collected retrospective CSF data from patients suffering from immune-mediated neuropathies across four German research centers. These parameters were analyzed in relation to their clinical characteristics., Results: Out of 419 samples, 36 (8.6%) displayed a notable variation between total CSF protein and Q Alb values. A detailed analysis revealed that patients displaying elevated Q Alb but normal total CSF protein levels were significantly younger at disease onset ( p  = 0.01), at the time of diagnosis ( p  = 0.005), and when undergoing lumbar puncture ( p  = 0.001) compared to patients with elevated CSF protein and normal Q Alb levels. These effects were especially evident for the subgroup of samples derived by female patients., Discussion: Our work confirms the crucial role of Q Alb in diagnosing immune-mediated neuropathies and particularly its efficacy as a marker for evaluating the blood-CSF barrier in patients with an earlier disease onset. Considering the significance of the albumin quotient, its assessment is especially advisable in younger patients of female sex to avoid missing a potential barrier dysfunction that might be falsely negative when using total protein., Competing Interests: TSe reports support for attending meetings by Abbvie. SG reports research support from Alnylam Pharmaceuticals, CSL Behring, Else Kröner Fresenius Foundation, Deutsche Forschungsgemeinschaft and Hannover Biomedical Research School (HBRS) and consulting and/or speaker honoraria from Alexion, Alnylam Pharmaceuticals, AstraZeneca, GSK, Pfizer and Merck all outside the submitted work. JM reports research grants by Biogen and Deutsche Forschungsgemeinschaft, stock/stock options at Biontech and CureVac, as well as support for attending meetings and/or travel by Biogen, Novartis and Alnylam. JM also received honoraria or lectures/ manuscripts by Biogen. KP reports research grants by Biogen idec, Novartis, Celgene, CSL Behring, Grifols, honoraria for lectures from CSL Behring, Grifols, participation on an Advisory Board 2021 by Celgene and non-paid consultant activity for patients organizations POTS and Dysautonomie e.V. TSk reports honoraria for lectures and travel expenses for attending meetings from Alexion, Alnylam Pharmaceuticals, argenx, Bayer Vital, Biogen, Celgene, Centogene, CSL Behring, Euroimmun, Janssen-Cilag, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Siemens, Swedish Orphan Biovitrum, Teva, Viatris. His research is supported by the German Ministry for Education and Research (BMBF), Bristol-Myers Squibb Foundation for Immuno-Oncology, Claudia von Schilling Foundation for Breast Cancer Research, Else Kröner Fresenius Foundation, Hannover Biomedical Research School (HBRS), Alnylam Pharmaceuticals, CSL Behring, Novartis, Sanofi Genzyme, VHV Foundation. 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 © 2024 Seeliger, Gingele, Güzeloglu, Heitmann, Lüling, Kohle, Preßler, Stascheit, Motte, Fisse, Grüter, Pitarokoili and Skripuletz.)

Objectives: Detection and prediction of disability progression is a significant unmet need in people with progressive multiple sclerosis (PwPMS). Government and health agencies have deemed the use of patient-reported outcomes measurements (PROMs) in clinical practice and clinical trials a major strategic priority. Nevertheless, data documenting the clinical utility of PROMs in neurological diseases is scarce. This study evaluates if assessment of PROMs could track progression in PwPMS., Methods: Emerging blood Biomarkers in Progressive Multiple Sclerosis (EmBioProMS) investigated PROMs (Beck depression inventory-II (BDI-II), multiple sclerosis impact scale-29 (MSIS-29), fatigue scale for motor and cognition (FSMC)) in PwPMS (primary [PPMS] and secondary progressive MS [SPMS]). PROMs were evaluated longitudinally and compared between participants with disability progression (at baseline; retrospective evidence of disability progression (EDP), and during follow up (FU); prospective evidence of confirmed disability progression (CDP)) and those without progression. In an independent cohort of placebo participants of the phase III ORATORIO trial in PPMS, the diagnostic and prognostic value of another PROMs score (36-Item Short Form Survey [SF-36]) regarding CDP was evaluated., Results: EmBioProMS participants with EDP in the two years prior to inclusion (n = 136/227), or who suffered from CDP during FU (number of events= 88) had worse BDI-II, MSIS-29, and FSMC scores compared to PwPMS without progression. In addition, baseline MSIS29 physical above 70th, 80th, and 90th percentiles predicted future CDP/ progression independent of relapse activity in EmBioProMS PPMS participants (HR of 3.7, 6.9, 6.7, p = 0.002, <0.001, and 0.001, respectively). In the placebo arm of ORATORIO (n = 137), the physical component score (PCS) of SF-36 worsened at week 120 compared to baseline, in cases who experienced progression over the preceding trial period (P = 0.018). Worse PCS at baseline was associated with higher hazard ratios of disability accumulation over the subsequent 120 weeks (HR: 2.01 [30 th- ], 2.11 [20 th- ], and 2.8 [10 th percentile], P = 0.007, 0.012 and 0.005, respectively)., Conclusions: PROMs could provide additional, practical, cost-efficient, and remotely accessible insight about disability progression in PMS through standardized, structured, and quantifiable patient feedback., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AA received research funding from DMSG, AMSEL, Bavarian MS Trust. MK received travel funding, speaker honoraria and research support from Bristol Myers Squibb, Merck, Novartis and Roche, all not related to this manuscript. MS received consulting and/or speaker honoraria from Alexion, Bayer, Biogen, Bristol-Myers-Squibb, Merck, Roche, and Sanofi Genzyme; none related to this work. JH reports a grant for OCT research from the Friedrich-Baur-Stiftung and Merck, personal fees and non-financial support from Merck, Alexion, Novartis, Roche, Celgene, Biogen, Bayer and Horizon and non-financial support of the Sumaira-Foundation and Guthy-Jackson Charitable Foundation, all outside the submitted work. UKZ has received speaking fees, travel support, and financial support for research activities from Alexion, Almirall, Bayer, Biogen, Celgene, Janssen, Merck Serono, Novartis, Octapharm, Roche, Sanofi Genzyme, Teva as well as EU, BMBF, BMWi and DFG. None resulted in a conflict of interest. IK has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Alexion, Almirall, Bayer, Biogen, Hexal, Horizon, Merck, Neuraxpharm, Roche/Chugai and Sanofi, all outside the submitted work. AS has no personal pecuniary interests to disclose, other than being the lead of the German MS Registry, which receives project funding from a range of public and corporate sponsors, recently including The German Innovation Fund (G-BA), The German Retirement Insurance, The German MS Trust, The German MS Society, Biogen, BMS, Merck, Novartis, Roche, and Sanofi. All outside the submitted work. AH received travel funding, consulting and/or speaker honoraria from Alexion, Argenx and Horizon; none related to this manuscript. MCK has served on advisory boards and received speaker fees / travel grants from Merck, Sanofi-Genzyme, Novartis, Biogen, Jansen, Alexion, Celgene / Bristol-Myers Squibb and Roche and received research grants from Merck, Sanofi-Genzyme and Celgene / Bristol-Myers Squibb. SG reports research support from Alnylam Pharmaceuticals, CSL Behring, Else Kröner Fresenius Foundation, Deutsche Forschungsgemeinschaft and Hannover Biomedical Research School (HBRS) and consulting and/or speaker honoraria from Alnylam Pharmaceuticals and Merck all outside the submitted work. HK was an employee and shareholder of F. Hoffmann–La Roche Ltd during completion of the work related to this manuscript. He is currently an employee and shareholder of UCB Farchim SA, Bulle, Switzerland. JO reports grants from Hoffmann La-Roche, Biogen, Novartis, and Sanofi Genzyme, personal fees from Hoffmann La-Roche, Biogen, Teva, Novartis, Celgene, Medday Pharmaceuticals, EMD Serono, Sanofi Genzyme, Web MD Global and Allergan, employment from Hoffmann La-Roche and is a shareholder of Hoffmann La-Roche. QW, SC are employee and shareholder of F. Hoffmann–La Roche Ltd. TF reports personal fees for consultancies (including data monitoring committees) in the past three years from Bayer, BiosenseWebster, Cardialysis, CSL Behring, Enanta, Fresenius Kabi, Galapagos, IQVIA, Immunic, Janssen, Kyowa Kirin, Lilly, Liva Nova, Minoryx, Mylan, Novartis, Roche, Vifor; all outside the submitted work. UZ received grants from the European Research Council (ERC), German Ministry of Education and Research (BMBF), German Research Foundation (DFG), Takeda Pharmaceutical Company Ltd., and consulting fees from CorTec GmbH, all not related to this work. TK has received speaker honoraria and/or personal fees for advisory boards from Bayer Healthcare, Merck, Novartis Pharma, Sanofi-Aventis/Genzyme, Roche Pharma, Alexion/Astra Zeneca and Biogen as well as grant support from Novartis and Chugai Pharma in the past. HT received consulting and/or speaker honoraria from Alexion, Bayer, Biogen, Celgene, GSK, Jannssen, Merck, Novartis, Roche, Sanofi Genzyme and TEVA; none related to this work. All other authors report no conflict of interest in relation to this work., (Copyright © 2023. Published by Elsevier B.V.)

The clinical implications of the presence of anti-N-methyl-D-aspartate receptor (NMDAR)-specific intrathecal immunoglobulin G synthesis and whether it determines the diagnosis of anti-NMDAR encephalitis have not been thoroughly investigated yet. Thus, the aim of this study was to investigate whether the detection of intrathecal anti-NMDAR-specific IgG synthesis contributes to the diagnostic confirmation of anti-NMDAR encephalitis, to disease severity, and to prognosis in patients with positive serum anti-NMDAR-IgG. In this study, patients with detectable anti-NMDAR IgG in serum and/or cerebrospinal fluid (CSF) were included and separated into two groups that either met the 2016 criteria by Graus et al. of definite anti-NMDAR encephalitis (n = 27) or did not (n = 15). In a total, of 80 paired CSF/serum samples, antibody titers were titrated manually and end-point titer levels were carefully determined in a blinded manner to the subgroup attribution. The disease course was assessed via the modified Rankin Scale (mRS) and prognosis was estimated by the anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score. With respect to whether the diagnostic Graus criteria for definite anti-NMDAR encephalitis were fulfilled, a significantly unequal distribution of intrathecal anti-NMDAR antibody-specific synthesis could be shown with a high negative predictive value in case of a negative anti-NMDAR antibody-specific index (NMDAR AI, p = .008. OR = 23.9, sensitivity = 1.0, specificity = 0.4, negative predictive value = 1). A weak correlation was found between the CSF antibody titer and mRS value at the time of sample collection (r s  = .37, p = .008, 95% CI [.09, .59]). During the disease course a higher delta-mRS value formed of the mRS at initial presentation minus that at the last recorded presentation correlated with a higher NMDAR AI at first lumbar puncture (r s  = - .56, p = .017, 95% CI [- .83, - .11]). No association with the prognostic NEOS score was found. In conclusion, a negative antibody-specific index for anti-NMDAR IgG antibodies has a highly negative predictive value for the diagnosis of anti-NMDAR encephalitis. Yet, a positive NMDAR AI alone does not allow the diagnosis of anti-NMDAR encephalitis., (© 2023. Springer Nature Limited.)

Background: There is limited and inconsistent information on the prevalence of cognitive impairment in neuromyelitis optica spectrum disorders (NMOSD)., Objective: To assess cognitive performance and changes over time in NMOSD., Methods: This study included data from 217 aquaporin-4-IgG-seropositive (80%) and double-seronegative NMOSD patients. Cognitive functions measured by Symbol Digit Modalities Test (SDMT), Paced Auditory Serial-Addition Task (PASAT), and/or Multiple Sclerosis Inventory Cognition (MuSIC) were standardized against normative data ( N  = 157). Intraindividual cognitive performance at 1- and 2-year follow-up was analyzed. Cognitive test scores were correlated with demographic and clinical variables and assessed with a multiple linear regression model., Results: NMOSD patients were impaired in SDMT ( p  = 0.007), MuSIC semantic fluency ( p  < 0.001), and MuSIC congruent speed ( p  < 0.001). No significant cognitive deterioration was found at follow-up. SDMT scores were related to motor and visual disability ( p Bon  < 0.05). No differences were found between aquaporin-4-IgG-seropositive and double-seronegative NMOSD., Conclusions: A subset of NMOSD patients shows impairment in visual processing speed and in semantic fluency regardless of serostatus, without noticeable changes during a 2-year observation period. Neuropsychological measurements should be adapted to physical and visual disabilities.

Objective: This study aimed to assess cranial nerve involvement in a large adult cohort of patients with immune-mediated neuropathy undergoing immunoglobulin treatment by measuring blink reflex R1 latency prolongation in correlation with clinical findings and nerve conduction studies., Methods: 104 patients underwent blink reflex examination and ulnar nerve conduction studies and were assessed by the Inflammatory Neuropathy Cause and Treatment disability score, the revised Amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) and focused clinical examination., Results: Prolonged R1 latencies were identified in 23 of 104 patients (22.1 %). These patients had more severe functional impairments according to the ALSFRS-R, yet only five clinically presented with bulbar dysfunction, facial- or trigeminal nerve impairment. Overall R1 latency was inversely correlated to ulnar motor conduction velocity. In preliminary follow-up assessments under continuous immunoglobulin treatment, prolonged R1 latencies partially improved., Conclusions: Cranial nerve involvement is a common feature in immune-mediated neuropathies and is associated with a more severe disease stage. Here, R1 prolongation was detected less frequently compared to previously reported untreated cohorts., Significance: Blink reflex studies can detect subclinical cranial nerve involvement in immune-mediated neuropathies. Further studies are needed to evaluate the clinical utility of measuring R1 latency., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Conflict of Interest SK, MMK and RD report no disclosures. LHM received travel grants from ITF Pharma and Biohaven Pharmaceuticals outside the submitted work. TSe was funded by the Ellen-Schmidt-Scholarship of the Hannover mediacal School and received financial congress attendance support by Abbvie outside the submitted work. SG reports research support from Alnylam Pharmaceuticals, CSL Behring, Else Kröner Fresenius Foundation, Deutsche Forschungsgemeinschaft and Hannover Biomedical Research School (HBRS) and honoraria for lectures from Alnylam and Merck all outside the submitted work. OSK received scientific grants, travel grants and/or honoraria from the German Neuromuscular Society (Deutsche Gesellschaft fuer Muskelkranke (DGM e.V.)), Novartis, Biogen GmbH, Biermann Verlag GmbH, MK + S - Medizin, Kommunikation & Service GmbH and the Jain Foundation outside the submitted work. MS reports grants and/or personal fees from Bayer Healthcare, Takeda, CSL Behring, Sanofi-Genzyme, Grifols, Merck-Serono, Roche, Novartis, Teva, Alexion, Janssen, outside the submitted work. SP received honoraria from Biogen, Cytokinetics, Inc., Desitin Pharma, Novartis, Roche, Teva outside the submitted work. TSk reports research support from Alnylam Pharmaceuticals, Bristol-Myers Squibb Foundation for Immuno-Oncology, Claudia von Schilling Foundation, CSL Behring, Else Kröner Fresenius Foundation, Sanofi Genzyme, VHV Stiftung and honoraria for lectures and travel grants from Alexion, Alnylam Pharmaceuticals, Bayer Vital, Biogen, Celgene, Centogene, CSL Behring, Euroimmun, Janssen, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Siemens, Sobi, Teva, all outside the submitted work. AO received honoraria from Biogen outside the submitted work., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Diagnosis and treatment of patients with immune-mediated neuropathies is challenging due to the heterogeneity of the diseases., Objectives: To assess similarities and differences in the current care of patients with immune-mediated polyneuropathies in specialized centers in Germany within the German neuritis network "Neuritis Netz"., Material and Methods: We conducted a cross-sectional survey of nine neurological departments in Germany that specialize in the care of patients with immune-mediated neuropathies. We assessed the diagnosis, the approach to diagnostic work-up and follow-up, typical symptoms at manifestation and progression of the disease, and treatment data., Results: This report includes data from 1529 patients per year treated for immune-mediated neuropathies, of whom 1320 suffered from chronic inflammatory demyelinating polyneuropathy (CIDP). Diagnostic work-up almost always included nerve conduction studies, electromyography, and lumbar puncture in accordance with current guidelines. The use of ultrasound, biopsy, and MRI varied. The most important clinical parameter for therapy monitoring in all centers was motor function in the clinical follow-up examinations. A wide range of different immunosuppressants was used for maintenance therapy in about 15% of patients., Conclusions: These data provide important epidemiological insights into the care of patients with immune-mediated neuropathies in Germany. The further development of specific recommendations for treatment and follow-up examinations is necessary to ensure a uniform standard of patient care. This effort is greatly facilitated by a structured collaboration between expert centers such as Neuritis Netz., (© 2022. The Author(s).)

Sjögren's syndrome is a potentially treatable cause of Small Fiber Neuropathy (SFN)-a condition that severely affects patients' quality of life. We therefore aimed to characterize patients with SFN and Sjögren's syndrome to raise awareness of this disease and facilitate its early recognition as an essential step for appropriate treatment. In 97 SFN patients (median age 48 years, 77% female), we studied the clinical features associated with Sjögren's syndrome compared to the idiopathic SFN subtype. According to the current ACR/EULAR classification criteria (Shiboski et al., Ann Rheum Dis 76:9-16, 2017), 24/97 individuals (25%, median age 48.5 years, 75% female) were diagnosed with Sjögren's syndrome. We did not observe any differences in SFN-defining sensory plus symptoms. Furthermore, intraepidermal nerve fiber densities (IENFD) were significantly lower in patients with SFN and Sjögren's syndrome (mean 2.6 ± 1.2/mm) compared to patients with idiopathic SFN (mean 3.2 ± 1.5/mm; p = 0.048). There were no significant group differences when analyzing cerebrospinal fluid (CSF) parameters. We conclude that Sjögren's syndrome-associated SFN is difficult to distinguish from idiopathic forms based on initial clinical symptoms and CSF results. However, lower IENFD values in patients with Sjögren's syndrome-associated SFN might indicate a distinct different pathomechanism in this entity compared to idiopathic SFN., (© 2022. The Author(s).)

Background and Objectives: To evaluate the effects of the coronavirus disease 2019 (COVID-19) pandemic on the life of patients with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated diseases (MOGAD)., Methods: This multicenter, cross-sectional study included data of 187 patients recruited from 19 different German and Austrian Neuromyelitis Optica Study Group (NEMOS) centers between July 2021 and March 2022. The effects of the pandemic on immunotherapeutic treatment and access to care, the possible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the potential effect of vaccination against SARS-CoV-2 on disease incidence and relapse risk were assessed using a patient questionnaire. Health-related quality of life (HRQoL) was measured with the EuroQoL Group 5-Dimension 5-Level Scale (EQ-5D-5L). Demographic and clinical characteristics were retrieved from the NEMOS database., Results: One hundred eighty-seven patients (75% women; median age 47 [range 21-86] years; median disease duration 5.5 [range 0-67] years; median Expanded Disability Status Scale 2.0 [range 0-8.0]; 51% aquaporin-4 immunoglobulin G (AQP4-IgG)-positive, 36% myelin oligodendrocyte glycoprotein (MOG)-IgG-positive 13% double-seronegative) were analyzed. Most patients maintained excellent access to healthcare services throughout the pandemic. Immunotherapy was not changed in 88% of patients. Ninety-one percent of all patients were satisfied with medical care during the pandemic. Nearly two-thirds (64%) of patients rated their risk of infection with SARS-CoV-2 as low or moderate. Among this study sample, 23 patients (12%) knowingly acquired an infection with SARS-CoV-2 and predominantly had a nonsevere course of illness (n = 22/23, 96%). The SARS-CoV-2 vaccination rate was 89%, with 4 cases of confirmed attack or first manifestation of NMOSD/MOGAD occurring in temporal association with the vaccination (range 2-9 days). The reported HRQoL did not decline compared with a prepandemic assessment (mean EQ-5D-5L index value 0.76, 95% bootstrap confidence interval [CI] 0.72-0.80; mean EQ-VAS 66.5, 95% bootstrap CI 63.5-69.3)., Discussion: This study demonstrates that, overall, patients with NMOSD/MOGAD affiliated with specialized centers received ongoing medical care during the pandemic. Patients' satisfaction with medical care and HRQoL did not decrease., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Sjögren's syndrome (SS) is an autoimmune disease characterized by sicca symptoms and various extra-glandular manifestations. The diagnosis of SS requires sicca symptoms, anti-SSA(Ro)-antibody positivity, and/or pathological focus scores on a minor salivary gland biopsy. Previous studies have investigated different biomarkers in order to avoid invasive diagnostic procedures. It was found that kappa and lambda free light chains (KFLC and LFLC) in saliva are specific for SS. Methods: FLC concentrations in saliva and serum were determined in 130 patients-50 with SS and neurological involvement (Neuro-Sjögren) and 80 neurological controls. The EULAR SS disease activity index and patient reported index (ESSPRI) were determined in patients with SS. Results: Patients with SS revealed increased pain and decreased saliva production according to the ESSPRI and Saxon test, respectively, with increasing FLC concentrations in the saliva. No significant differences in serum and salivary protein concentrations were observed between patients with SS and controls. Conclusion: KFLC and LFLC concentrations in saliva are not suitable to distinguish patients with Neuro-Sjögren and neurological control subjects, thus a diagnostic biopsy is still required. The association of salivary KFLC and LFLC concentrations with saliva production and ESSPRI pain score suggests a complex relationship between dryness and pain in patients with SS.

Background: Patients with Sjögren's syndrome and polyneuropathy more frequently develop cranial nerve affection when compared to patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We therefore aimed to analyze trigeminal corneal nerve fibre characteristics in both patient groups., Methods: A total of 26 patients with Sjögren's syndrome associated neuropathy and 29 patients with CIDP were recruited at our university hospital and compared to 6 healthy controls. Dry eye symptoms and signs were assessed via clinical examination and the Ocular Disease Surface Index questionnaire. Trigeminal corneal nerve fibres were analyzed via corneal confocal microscopy (CCM) as a non-invasive in vivo microscopy., Results: CCM revealed significantly reduced corneal nerve fibre density and corneal nerve fibre main branch density in the Neuro-Sjögren group when compared with healthy controls. There were no significant group differences between the Neuro-Sjögren and the CIDP group for any of the microscopic parameters. Dry eye assessment showed similarly reduced scores for both patient groups, while healthy controls showed better results for objective dry eye signs. There was no correlation between microscopic parameters of the corneal confocal microscopy and parameters of dry eye assessment., Conclusions: Our data revealed trigeminal corneal nerve affection in patients with neuropathy associated with Sjögren's syndrome and patients with CIDP detected by CCM. No difference was found between both neuropathy groups indicating that CCM is not able to distinguish between both entities.

Background : Since the 1990s, transplantations of hematopoietic and mesenchymal stem cells (HSCT and MSCT) and dendritic cell (DCT) have been investigated for the treatment of neurological autoimmune disorders (NADs). With the growing number of transplanted patients, awareness of neuroimmunolgical complications has increased. Therefore, an overview of SCT for the most common NADs and reports of secondary immunity after SCT is provided. Methods : For this narrative review, a literature search of the PubMed database was performed. A total of 86 articles reporting on different SCTs in NADs and 61 articles dealing with immune-mediated neurological complications after SCT were included. For multiple sclerosis (MS), only registered trials and phase I/II or II studies were considered, whereas all available articles on other disorders were included. The different transplantation procedures and efficacy and safety data are presented. Results : In MS patients, beneficial effects of HSCT, MSCT, and DCT with a decrease in disability and stabilization of disease activity have been reported. These effects were also shown in other NADs mainly in case reports. In seven of 132 reported patients with immune-mediated neurological complications, the outcome was fatal. Conclusions : Phase III trials are ongoing for MS, but the role of SCT in other NADs is currently limited to refractory patients due to occasional serious complications.

Background: The intrathecal humoral response is the characteristic diagnostic finding in the cerebrospinal fluid (CSF) analysis of patients with multiple sclerosis (MS). Although the average age of MS patients increases, little is known about the sensitivity of diagnostic markers in elderly MS patients. Methods: In this retrospective two-center study, intrathecal free light chains kappa fraction (FLCk IF) and oligoclonal bands (OCB) were studied in a large cohort of patients with early and late onset relapsing (RMS) and progressive (PMS) MS. Furthermore, the humoral immune profile in CSF was analyzed, including the polyspecific intrathecal immune response measured as the MRZ reaction. Results: While the frequency of CSF-specific OCB did not differ between early and late onset RMS and PMS, the sensitivity of positive FLCk IF and absolute FLCk IF values were lower in PMS. The positivity of the MRZ reaction was equally frequent in early and late onset RMS and PMS. PMS patients had higher local IgA concentrations than RMS patients ( p = 0.0123). Conclusions: OCB are slightly superior to FLCk IF in progressive MS in terms of sensitivity for detecting intrathecal immunoglobulin synthesis. The MRZ reaction, as the most specific parameter for MS, is also applicable in patients with late onset and progressive MS.

Myelin loss with consecutive axon degeneration and impaired remyelination are the underlying causes of progressive disease in patients with multiple sclerosis. Astrocytes are suggested to play a major role in these processes. The unmasking of distinct astrocyte identities in health and disease would help to understand the pathophysiological mechanisms in which astrocytes are involved. However, the number of specific astrocyte markers is limited. Therefore, we performed immunohistochemical studies and analyzed various markers including GFAP, vimentin, S100B, ALDH1L1, and LCN2 during de- and remyelination using the toxic murine cuprizone animal model. Applying this animal model, we were able to confirm overlapping expression of vimentin and GFAP and highlighted the potential of ALDH1L1 as a pan-astrocytic marker, in agreement with previous data. Only a small population of GFAP-positive astrocytes in the corpus callosum highly up-regulated LCN2 at the peak of demyelination and S100B expression was found in a subset of oligodendroglia as well, thus S100B turned out to have a limited use as a particular astroglial marker. Additionally, numerous GFAP-positive astrocytes in the lateral corpus callosum did not express S100B, further strengthening findings of heterogeneity in the astrocytic population. In conclusion, our results acknowledged that GFAP, vimentin, LCN2, and ALDH1L1 serve as reliable marker to identify activated astrocytes during cuprizone-induced de- and remyelination. Moreover, there were clear regional and temporal differences in protein and mRNA expression levels and patterns of the studied markers, generally between gray and white matter structures., (© 2022. The Author(s).)

Background: Oligoclonal bands represent intrathecal immunoglobulin G (IgG) synthesis and play an important role in the diagnosis of multiple sclerosis (MS). Kappa free light chains (KFLC) are increasingly recognized as an additional biomarker for intrathecal Ig synthesis. However, there are limited data on KFLC in neurological diseases other than MS., Methods: This study, conducted at two centers, retrospectively enrolled 346 non-MS patients. A total of 182 patients were diagnosed with non-inflammatory and 84 with inflammatory neurological diseases other than MS. A further 80 patients were classified as symptomatic controls. Intrathecal KFLC production was determined using different approaches: KFLC index, Reiber's diagram, Presslauer's exponential curve, and Senel's linear curve., Results: Matching results of oligoclonal bands and KFLC (Reiber's diagram) were frequently observed (93%). The Reiber's diagram for KFLC detected intrathecal KFLC synthesis in an additional 7% of the patient samples investigated (4% non-inflammatory; 3% inflammatory), which was not found by oligoclonal band detection., Conclusions: The determination of both biomarkers (KFLC and oligoclonal bands) is recommended for routine diagnosis and differentiation of non-inflammatory and inflammatory neurological diseases. Due to the high sensitivity and physiological considerations, the assessment of KFLC in the Reiber's diagram should be preferred to other evaluation methods.

Background: Cerebrospinal fluid (CSF) samples from patients with non-inflammatory neurological diseases are used for control groups in biomarker studies. Since large amounts of CSF are withdrawn, patients with idiopathic intracranial hypertension (IIH) or normal pressure hydrocephalus (NPH) are especially suitable. The serially taken CSF portions are usually collected in different tubes. We aimed to investigate whether the later random choice of one of these tubes for CSF investigations might harbor the risk of different CSF protein findings due to the so-called ventriculo-lumbar CSF gradient., Methods: Patients with IIH (9) and NPH (7) were included. CSF was serially taken and collected in six tubes of 5 mL each. Concentrations and CSF-serum quotients of immunoglobulins, albumin and the virus-specific antibody index (AI) were determined in the first, fourth and sixth CSF fraction., Results: CSF immunoglobulin and albumin concentrations and CSF-serum protein quotients were significantly lower in the fourth and sixth CSF fraction compared with the first CSF fraction. Virus-specific AI did not significantly differ in the different CSF fractions., Conclusions: CSF protein analytics should be performed in the first CSF fraction in order to avoid different measurement results and achieve comparability within a control group and between different control and patient groups.

Background and Objectives: To evaluate costs and health-related quality of life (HRQoL) of neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD)., Methods: In this multicenter cross-sectional study, data on consumption of medical and nonmedical resources and work ability were assessed via patient questionnaires. Costs were analyzed in Euros for 2018 from the societal perspective. HRQoL was captured by the EuroQoL Group 5 Dimension 5 Level Scale (EQ-5D-5L) questionnaire. Clinical data were retrieved from the Neuromyelitis Optica Study Group (NEMOS) database., Results: Two hundred twelve patients (80% women, median age 50 [19-83] years, median disease duration 7 [0-43] years, median Expanded Disability Status Scale [EDSS] score 3.5 [0-8.5], 66% aquaporin-4 immunoglobulin G [IgG] positive, 22% MOG IgG positive, 12% double seronegative) were analyzed. The mean total annual per capita cost of illness accounted for €59,574 (95% CI 51,225-68,293 or US dollars [USD] 70,297, 95% CI 60,445-80,586), and the mean index value of the EQ-5D-5L was 0.693 (95% CI 0.65-0.73). The most important cost drivers were informal care costs (28% of total costs), indirect costs (23%), and drugs (16%), especially immunotherapeutics. Costs showed a positive correlation with disease severity (ρ = 0.56, 95% CI 0.45-0.65); in the EDSS score 6.5 to 8.5 subgroup, the mean annual costs were €129,687 (95% CI 101,946-160,336 or USD 153,031, 95% CI 120,296-189,196). The HRQoL revealed a negative correlation to disease severity (ρ = -0.69, 95% CI -0.76 to -0.61); in the EDSS score 6.5 to 8.5 subgroup, the EQ-5D-5L mean index value was 0.195 (95% CI 0.13-0.28). Neither antibody status nor disease duration influenced the total annual costs or HRQoL., Discussion: These German data from the era without approved preventive immunotherapies show enormous effects of the diseases on costs and quality of life. An early and cost-effective therapy should be provided to prevent long-term disability and to preserve quality of life., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Chronic kidney disease (CKD) is a common condition that increases mortality and the risk of cardiovascular and other morbidities regardless of underlying renal condition. Chronic inflammation promotes renal fibrosis. Recently, renal B cell infiltrates were described in chronic kidney disease of various etiologies beyond autoimmunity., Methods: We here investigated B cells and indicators of tertiary lymphoid structure formation in human renal biopsies. Renal function was studied during long-term B cell depletion in human patients with membranous nephropathy and with CKD of unknown origin., Results: Cytokine profiles of tertiary lymphoid structure formation were detected in human renal interstitium in a range of kidney diseases. Complex B cell structures consistent with tertiary lymphoid organ formation were evident in human membranous nephropathy. Here, B cell density did not significantly associate with proteinuria severity, but with worse excretory renal function. Proteinuria responses mostly occurred within the first 6 months of B cell depletion. In contrast, recovery of excretory kidney function was observed only after 18 months of continuous therapy, consistent with a structural process. Renal tertiary lymphatic structures were also detected in the absence of autoimmune kidney disease. To start to address whether B cell depletion may affect CKD in a broader population, we assessed kidney function in neurologic patients with CKD of unknown origin. In this cohort, eGFR significantly increased within 24 months of B cell depletion., Conclusion: Long-term B cell depletion associated with significant improvement of excretory kidney function in human CKD. Kinetics and mechanisms of renal B cell aggregation should be investigated further to stratify the impact of B cells and their aggregates as therapeutic targets., (© 2021 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Background: Hereditary Transthyretin-Related Amyloidosis, a clinically heterogeneous autosomal dominant disease caused by pathogenic variants in the TTR gene, is characterized by the deposition of insoluble misfolded protein fibrils. The diagnosis, especially in non-endemic areas, is typically delayed by 4-5 years; a misdiagnosis due to clinical heterogeneity is common. The study objective was to define the prevalence of Hereditary Transthyretin-Related Amyloidosis in patients with polyneuropathy and/or cardiomyopathy of no obvious aetiology., Method: A multicenter observational "Epidemiological analysis for the hereditary Transthyretin-Related AMyloidosis"-TRAM study was performed in Germany, Austria, and Switzerland., Results: A total of 5141 participants were recruited by 50 neurologic and 27 cardiologic specialized centres. Genetic analysis demonstrated a 1.1% Hereditary Transthyretin-Related Amyloidosis positivity rate among patients with polyneuropathy and/or cardiomyopathy of not obvious aetiology. Twenty-one various TTR variants ( TTR -positive) were identified. Body Mass Index was lower in the TTR -positive patients as an indicator for the involvement of the autonomic nervous system; the age of onset of clinical manifestations was higher in TTR -positive patients. There were no other genotype-phenotype correlations or the prevalence of specific clinical manifestations in TTR -positive patients., Conclusions: Our data support the fact that Hereditary Transthyretin-Related Amyloidosis is underdiagnosed in polyneuropathy and cardiomyopathy patients. Routine implementation of genetic testing is recommended in patients with unexplained polyneuropathy and/or cardiomyopathy to accelerate the earlier diagnosis and the time-sensitive treatment initiation.KEY MESSAGESMore than 5.000 participants with CM and/or PNP of no obvious aetiology were recruited in the observational "Epidemiological analysis for the hereditary Transthyretin-Related AMyloidosis" TRAM study and screened for pathogenic TTR variants.The study demonstrated >1% of patients with CM and/or PNP of unclear aetiology are positive for a pathogenic TTR variant.Routine genetic testing is recommended in patients with unexplained CM and/or PNP to accelerate the initial diagnosis and timely treatment initiation.

Background: The determination of kappa free light chains (KFLC) in cerebrospinal fluid (CSF) is an upcoming biomarker for the detection of an intrathecal immunoglobulin synthesis. Since renal function impairment leads to altered serum KFLC and albumin concentrations, interpretation of KFLC in CSF may be influenced by these parameters., Methods: In this two-center study, the influence of renal function (according to the CKD-EPI creatinine equation) on KFLC and albumin concentrations was investigated in patients with "physiological" (n = 139), "non-inflammatory" (n = 146), and "inflammatory" (n = 172) CSF profiles in respect to the KFLC index and the evaluation in quotient diagrams in reference to the hyperbolic reference range (KFLC IF)., Results: All sample groups displayed declining KFLC indices and KFLC IF values with decreasing renal function ( P -values between <.0001 and .0209). In "inflammatory" CSF profile samples, 15% of the patients presented a KFLC index <5.9 while 10% showed an intrathecal KFLC fraction below Q Kappa (lim), suggesting possible false negative KFLC results., Conclusions: The influence of renal function should be considered while interpreting KFLC results in patients with neuroinflammatory diseases. The interpretation of KFLC in quotient diagrams is less susceptible to renal function impairment than the KFLC index and should be preferentially used., Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Inflammatory attacks and demyelination in the central nervous system (CNS) are the key factors responsible for the damage of neurons in multiple sclerosis (MS). Remyelination is the natural regenerating process after demyelination that also provides neuroprotection but is often incomplete or fails in MS. Currently available therapeutics are affecting the immune system, but there is no substance that might enhance remyelination. Cytidine-S-diphosphate choline (CDP-choline), a precursor of the biomembrane component phospholipid phosphatidylcholine was shown to improve remyelination in two animal models of demyelination. However, the doses used in previous animal studies were high (500 mg/kg), and it is not clear if lower doses, which could be applied in human trials, might exert the same beneficial effect on remyelination. The aim of this study was to confirm previous results and to determine the potential regenerative effects of lower doses of CDP-choline (100 and 50 mg/kg). The effects of CDP-choline were investigated in the toxic cuprizone-induced mouse model of de- and remyelination. We found that even low doses of CDP-choline effectively enhanced early remyelination. The beneficial effects on myelin regeneration were accompanied by higher numbers of oligodendrocytes. In conclusion, CDP-choline could become a promising regenerative substance for patients with multiple sclerosis and should be tested in a clinical trial.

Free light chains (FLC) are a promising biomarker to detect intrathecal inflammation in patients with inflammatory central nervous system (CNS) diseases, including multiple sclerosis (MS). The diagnostic use of this biomarker, in particular the kappa isoform of FLC ("KFLC"), has been investigated for more than 40 years. Based on an extensive literature review, we found that an agreement on the correct method for evaluating KFLC concentrations has not yet been reached. KFLC indices with varying cut-off values and blood-CSF-barrier (Q Albumin ) related non-linear formulas for KFLC interpretation have been investigated in several studies. All approaches revealed high diagnostic sensitivity and specificity compared with the oligoclonal bands, which are considered the gold standard for the detection of intrathecally synthesized immunoglobulins. Measurement of KFLC is fully automated, rater-independent, and has been shown to be stable against most pre-analytic influencing factors. In conclusion, the determination of KFLC represents a promising diagnostic approach to show intrathecal inflammation in neuroinflammatory diseases. Multicenter studies are needed to show the diagnostic sensitivity and specificity of KFLC in MS by using the latest McDonald criteria and appropriate, as well as standardized, cut-off values for KFLC concentrations, preferably considering non-linear formulas such as Reiber's diagram.

Background and Purpose: The phenotype of Sjögren's syndrome-associated neuropathy has been better characterized in recent years. However, Sjögren's syndrome-associated neuropathy remains an underdiagnosed entity with only few insights considering the pathomechanisms of nerve damage. Nerve ultrasound has proven to be a useful and efficient tool in detecting nerve damage of autoimmune origin. We, therefore, aimed to evaluate this method for Sjögren's syndrome-associated neuropathy., Methods: Patients with Sjögren's syndrome and clinical signs of neuropathy underwent sonographic examination of both median and ulnar nerves. Nerve thickening was classified for cross-sectional areas of >12 mm² at the median nerve and for >10 mm² at the ulnar nerve. Fascicle thickening was documented for cross-sectional areas ≥5 mm² at the median and ≥3 mm² at the ulnar nerve., Results: Forty-three patients were included in the analysis (median age 60 years [interquartile range 53-73 years], female rate 60%). 31/43 patients (72%) showed abnormalities on nerve ultrasound, while nerve thickening was found more frequently than fascicle thickening (90% vs. 52% of patients with sonographic abnormalities, respectively). Abnormal findings were observed more frequently at the median nerve and in proximal localization. Abnormal findings on nerve conduction studies were evident in 36/43 patients (84%). Nerve conduction studies revealed a tendency of demyelinating nerve damage patterns being associated with abnormal findings on nerve ultrasound., Conclusions: In addition to nerve conduction studies, nerve ultrasound may have a supporting role in the diagnosis of Sjögren's syndrome-associated neuropathy. Also, our data support an immune-mediated inflammatory demyelinating pathogenesis of Sjögren's syndrome-associated neuropathy., (© 2021 American Society of Neuroimaging.)

Background: This study addresses the challenging characterisation and differentiation of CIDP versus CIDP in association with Sjögren's syndrome to facilitate the process in clinical routine., Methods: Patients with both CIDP and Sjögren's syndrome and CIDP without Sjögren's syndrome were compared concerning relevant differences in clinical, laboratory and electrophysiological findings. 154 patients who fulfilled the diagnostic EFNS/PNS criteria for CIDP were included in the analysis. 54 of these patients additionally fulfilled the ACR/EULAR classification criteria for Sjögren's syndrome., Results: The frequency of female patients was higher in patients with CIDP and Sjögren's syndrome (52%) versus CIDP patients without Sjögren's syndrome (28%). Furthermore, the occurrence of cranial nerve impairment was significantly higher in patients with Sjögren's syndrome (39% versus 14%). There were no significant group differences in the evaluation of initial symptoms, severity of disability judged by INCAT disability scale score, presence or distribution of sensory deficits, limb weakness and the presence of ataxia, pain or dysautonomia, CSF laboratory or electrophysiological findings., Conclusions: In conclusion, our data indicate that cranial nerve impairment and female gender might represent red flags for an additional Sjögren's syndrome in patients with CIDP. The patterns of clinical disabilities and electrophysiological findings due to peripheral nerve damage are similar in both CIDP entities., (© 2021. Springer-Verlag GmbH, DE part of Springer Nature.)

Studies show that psychiatric symptoms in adults and children are sometimes associated with serum neural autoantibodies. The significance of serum neural autoantibodies associated with psychiatric symptoms in children remains often unclear, but might be relevant for the extent and occurrence of psychiatric disease manifestation in later life, as well as therapy and outcome. For this narrative review, we sought articles listed in PubMed and published between 1988 and 2020 addressing the maternal-fetal transfer of neural autoantibodies and psychiatric disorders associated with serum neural autoantibodies. We identified six major subgroups of psychiatric disorders in children that are associated with serum neural autoantibodies: patients with attentional deficit hyperactivity disorder, autism spectrum disorder, obsessive compulsive disorder, Gilles de la Tourette syndrome, psychosis and catatonia. Furthermore, we summarized study findings from maternal-fetal transfer of Contactin-associated protein-like 2, N-methyl-D-aspartate receptor and fetal brain autoantibodies associated with behavioral effects in animals and humans. We hypothesize that the maternal transfer of serum neuronal autoantibodies during or after birth could result (1) in the ignition of an autoimmune-mediated inflammation having neurodevelopmental consequences for their children (autoimmune-priming-attack hypothesis) and (2) has a potential impact on the later manifestation of psychiatric disorders. Through this narrative review, we propose a diagnostic pathway for the clinical diagnosis of a potentially autoimmune origin of psychiatric symptoms in children while considering recent guidelines.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a curative treatment for hematologic malignancies. Acute and chronic graft-versus-host disease (GvHD) are the major immune-mediated complications after alloHSCT. However, there is controversy whether neurologic complications after alloHSCT might represent manifestations of GvHD. We report three patients who acquired distinct, severe immune-mediated peripheral or central nervous system diseases after alloHSCT without other, concomitant GvHD manifestations. One patient had been diagnosed with B-cell chronic lymphocytic leukemia and two patients with high risk myelodysplastic syndrome. Patient #1 presented as LGI1- and GAD-IgG positive immune-mediated encephalitis, patient #2 was diagnosed with MOG-IgG positive encephalomyelitis, and patient #3 had chronic inflammatory polyneuropathy associated with SSA(Ro)-IgG positive Sjögren's syndrome. 100% donor chimerism was detectable in the peripheral blood in all three. The specific antibodies were undetectable in donors' and patients' blood before alloHSCT suggesting that the antibodies had arisen from the transplanted donor immune system. Early intensive immunotherapy led to improvement of clinical symptoms and stability of the neurological disease, however, at the cost of losing the graft-versus-malignancy effect in one patient. In conclusion, we provide evidence of isolated, severe allo-immune diseases of the peripheral and central nervous system as complications of alloHSCT ("neuro-GvHD"). Interdisciplinary surveillance and thorough diagnostic work-up are needed for early diagnosis and treatment of neuro-immunologic complications after alloHSCT to improve the otherwise poor outcome.

Background: IgPro20 is the first approved subcutaneous immunoglobulin (SCIg) preparation for the treatment of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Two different doses of the SCIg preparation were investigated in the pivotal PATH study. Real-world data, and particularly the efficacy of an equivalent dose switch from intravenous immunoglobulin (IVIg) to SCIg, are still not available., Methods: In this prospective observational study, 41 patients with CIDP treated with intravenous immunoglobulin (IVIg) were changed to an equivalent (1:1) dose of IgPro20 1 week after last IVIg treatment. Patients were examined at the time of switch from IVIg to SCIg, after 3 and after 6 months and efficacy, treatment preferences and systemic and local reactions were assessed., Results: Various clinical outcome parameters demonstrated overall stability regarding disability, general activity and social participation, grip and muscle strength, as well as gait impairment. Treatment satisfaction remained unchanged between IVIg and SCIg therapy. However, 88% of patients favoured treatment with subcutaneous IgPro20 over IVIg 6 months after switch to IgPro20., Conclusion: Results demonstrate that the switch of IVIg to an equivalent dose of SCIg represents an effective and preferred treatment option for CIDP patients., Competing Interests: Conflict of interest statement: The authors declare no conflict of interest. Outside the submitted work, the authors received honoraria for lectures, travel grants, or research grants. Stefan Gingele reports research support from Else Kröner Fresenius Stiftung and honoraria for lectures from Merck and Alnylam. Moritz Koch, Anna Christina Saparilla, Gudrun Körner, Jarle von Hörsten, Marina Gingele, Tabea Seeliger, Franz Felix Konen and Martin Hümmert declare that they have no conflict of interest. Alexandra Neyazi reports research support from Internal Funding of the MHH (HiLF) and honoria for lectures from Novartis and Merck. Martin Stangel has received honoraria for scientific lectures or consultancy from Alexion, Bayer Healthcare, Biogen, Celgene, CSL Behring, Grifols, Janssen, Merck-Serono, NeuroTransData, Novartis, Roche, Sanofi Aventis, Takeda, and Teva. His institution received research support from Sanofi Aventis, Novartis and Merck-Serono. Thomas Skripuletz reports research support from Bristol-Myers Squibb, Claudia von Schilling Foundation, Else Kröner Fresenius Stiftung, Hannover Biomedical Research School (HBRS), Sanofi Aventis and honoraria for lectures and travel grants from Alexion, Alnylam, Bayer Vital, Biogen, Celgene, Centogene, CSL Behring, Euroimmun, Merck, Novartis, Roche, Sanofi Aventis, Siemens., (© The Author(s), 2021.)

The loss of myelinating oligodendrocytes is a key characteristic of many neurological diseases, including Multiple Sclerosis (MS). In progressive MS, where effective treatment options are limited, peripheral immune cells can be found at the site of demyelination and are suggested to play a functional role during disease progression. In this study, we hypothesize that metabolic oligodendrocyte injury, caused by feeding the copper chelator cuprizone, is a potent trigger for peripheral immune cell recruitment into the central nervous system (CNS). We used immunohistochemistry and flow cytometry to evaluate the composition, density, and activation status of infiltrating T lymphocytes in cuprizone-intoxicated mice and post-mortem progressive MS tissues. Our results demonstrate a predominance of CD8 + T cells along with high proliferation rates and cytotoxic granule expression, indicating an antigenic and pro-inflammatory milieu in the CNS of cuprizone-intoxicated mice. Numbers of recruited T cells and the composition of lymphocytic infiltrates in cuprizone-intoxicated mice were found to be comparable to those found in progressive MS lesions. Finally, amelioration of the cuprizone-induced pathology by treating mice with laquinimod significantly reduces the number of recruited T cells. Overall, this study provides strong evidence that toxic demyelination is a sufficient trigger for T cells to infiltrate the demyelinated CNS. Further investigation of the mode of action and functional consequence of T cell recruitment might offer promising new therapeutic approaches for progressive MS., (© 2020 The Authors. GLIA published by Wiley Periodicals LLC.)

Approval of nusinersen, an intrathecally administered antisense oligonucleotide, for the treatment of 5q-spinal muscular atrophy (SMA) marked the beginning of a new therapeutic era in neurological diseases. Changes in routine cerebrospinal fluid (CSF) parameters under nusinersen have only recently been described in adult SMA patients. We aimed to explore these findings in a real-world setting and to identify clinical and procedure-associated features that might impact CSF parameters. Routinely collected CSF parameters (leukocyte count, lactate, total protein, CSF/serum albumin quotient (QAlbumin), oligoclonal bands) of 28 adult SMA patients were examined for up to 22 months of nusinersen treatment. Total protein and QAlbumin values significantly increased in the first 10 months, independent of the administration procedure. By month 14, no further increases were detected. Two patients developed transient pleocytosis. In two cases, positive oligoclonal bands were found in the beginning and in four patients throughout the whole observation period. No clinical signs of inflammatory central nervous system disease were apparent. Our data confirm elevated CSF total protein and QAlbumin during nusinersen treatment. These alterations may be caused by both repeated lumbar punctures and the interval between procedures rather than by the medication itself. Generally, there were no severe alterations of CSF routine parameters. These results further underline the safety of nusinersen therapy.

Cerebrospinal fluid analysis is an essential part of the diagnostic workup in various neurological disorders. Evidence of an intrathecal immunoglobulin synthesis, as demonstrated by Reiber's diagram or the more sensitive oligoclonal bands (OCB), are typical for neuroinflammatory diseases, and normally not expected in non-inflammatory neurological diseases. Therefore, patients with non-inflammatory neurological diseases are often used in control groups in studies investigating autoimmune diseases of the central nervous system. However, data about the frequency of intrathecal immunoglobulin synthesis in non-inflammatory neurological disease are scarce. The cerebrospinal fluid (CSF) records of a total of 3622 patients were screened and 2114 patients included with presumably non-inflammatory neurological diseases like dementia, idiopathic peripheral neuropathy, motoneuron disease, stroke, and epileptic seizures. Evidence of an intrathecal immunoglobulin synthesis can be found with low frequency also in non-inflammatory neurological diseases. A much higher rate of patients showed intrathecal immunoglobulin synthesis as demonstrated by OCB than by Reiber's diagram. In patients with disorders of the peripheral nervous system the frequency of OCB was much lower than in patients presenting with central nervous system manifestations. Evidence of an intrathecal immunoglobulin synthesis should not automatically lead to exclusion of non-inflammatory neurological diseases but should rather prompt the way to investigate for the origin of the intrathecal immunoglobulin synthesis.

Background: Autoimmune-mediated encephalitis is a disease that often encompasses psychiatric symptoms as its first clinical manifestation's predominant and isolated characteristic. Novel guidelines even distinguish autoimmune psychosis from autoimmune encephalitis. The aim of this review is thus to explore whether a wide range of psychiatric symptoms and syndromes are associated or correlate with autoantibodies., Methods: We conducted a PubMed search to identify appropriate articles concerning serum and/or cerebrospinal fluid (CSF) autoantibodies associated with psychiatric symptoms and syndromes between 2000 and 2020. Relying on this data, we developed a diagnostic approach to optimize the detection of autoantibodies in psychiatric patients, potentially leading to the approval of an immunotherapy., Results: We detected 10 major psychiatric symptoms and syndromes often reported to be associated with serum and/or CSF autoantibodies comprising altered consciousness, disorientation, memory impairment, obsessive-compulsive behavior, psychosis, catatonia, mood dysfunction, anxiety, behavioral abnormalities (autism, hyperkinetic), and sleeping dysfunction. The following psychiatric diagnoses were associated with serum and/or CSF autoantibodies: psychosis and schizophrenia spectrum disorders, mood disorders, minor and major neurocognitive impairment, obsessive-compulsive disorder, autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), anxiety disorders, eating disorders and addiction. By relying on these symptom clusters and diagnoses in terms of onset and their duration, we classified a subacute or subchronic psychiatric syndrome in patients that should be screened for autoantibodies. We propose further diagnostics entailing CSF analysis, electroencephalography and magnetic resonance imaging of the brain. Exploiting these technologies enables standardized and accurate diagnosis of autoantibody-associated psychiatric symptoms and syndromes to deliver early immunotherapy., Conclusions: We have developed a clinical diagnostic pathway for classifying subgroups of psychiatric patients whose psychiatric symptoms indicate a suspected autoimmune origin., Competing Interests: The authors declare no conflict of interest., (© 2020 The Author(s).)

Introduction: Remyelination is a highly effective regenerative process that can restore axon function, prevent axonal loss, and reverse clinical deficits after demyelination. Hence, the promotion of remyelination is a logical goal in patients with multiple sclerosis (MS) in which remyelination is often insufficient. However, despite great progress regarding the development of immunomodulatory therapies for MS and an abundance of promising evidence from preclinical experiments so far, no therapy has convincingly demonstrated clinically significant remyelination properties. Therefore, enhancing myelin repair is an urgent and unmet need in MS., Areas Covered: We searched clinicaltrials.gov and pubmed.ncbi.nlm.nih.gov and focused on therapeutic agents in development from the preclinical stage to clinical phase II. We selected agents for which data are available from in vitro experiments and at least one toxic demyelination animal model that reached at least phase I in clinical development in MS patients., Expert Opinion: The evidence to promote remyelination is very promising for several agents, some of which possess anti-muscarinergic properties. Since remyelination is a complex process that involves various coordinated steps, a combination of different therapeutic approaches addressing different aspects of this regenerative mechanism may be reasonable. Furthermore, suitable surrogate markers of remyelination are necessary for proof-of-concept clinical trials.