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Background and purpose: Monitoring of the disease course of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) remains challenging because nerve conduction studies do not adequately correlate with functional disability. The prognostic value of pathological spontaneous activity (PSA) in needle electromyography (EMG) in different CIDP subgroups in a longitudinal context has, to date, not been analysed. We aimed to determine whether PSA was a prognostic marker or a marker of disease activity in a cohort of patients with CIDP. Methods: A total of 127 patients with CIDP spectrum disorder were retrospectively analysed over 57 ± 47 months regarding the occurrence of PSA (fibrillations and positive sharp waves). The presence of PSA at diagnosis, newly occurring PSA, and continuously present PSA were longitudinally correlated with clinical disability using the Inflammatory Neuropathy Cause and Treatment Overall Disability Sum Score (INCAT‐ODSS) and CIDP subtype. Results: Pathological spontaneous activity occurred in 49.6% of all CIDP patients at first diagnosis. More frequent evidence of PSA was significantly associated with a higher INCAT‐ODSS at the last follow‐up. Continuous and new occurrence of PSA were associated with higher degree of disability at the last follow‐up. The majority of patients with sustained evidence of PSA were characterized by an atypical phenotype, higher degree of disability, and the need for escalation of treatment. Conclusions: Pathological spontaneous activity was associated with a higher degree of disability and occurred more frequently in atypical CIDP variants according to the longitudinal data of a large cohort of patients with CIDP. Our results showed that EMG examination was an adequate marker for disease progression and should be evaluated during the disease course. [ABSTRACT FROM AUTHOR]

Background. Nerve conduction studies represent the gold standard in the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) and play a central role in the EFNS/PNS criteria. However, the highly extensive examination protocol of those criteria and the question how to further monitor are relevant problems in daily medical practice. Hence, the aim of this cross-sectional study is to establish a practical and applicable strategy a) conducting the EFNS/PNS criteria and b) monitoring disease related disability in a large cohort of CIDP patients. Methods. As part of a prospective cohort study, we conducted a bilateral neurographic examination of the median nerve (mot.+sens.), ulnar nerve (mot.+sens.), radial nerve (sens.), tibial nerve (mot.), peroneal nerve (mot.+sens.), and sural nerve (sens.) in 95 CIDP patients. The EFNS/PNS criteria were applied on the collected neurographic data and compared with the INCAT overall disability sum score (INCAT-ODSS) and INCAT sensory score (ISS) to quantify disease disabilities. Results. In total, 95 CIDP patients (f:m 1:3.32; mean age 59±12y; 52% atypical CIDP; mean disease duration 74±60 months) were recruited, thereof 25 at initial diagnosis. All patients fulfilled the electrophysiological EFNS/PNS diagnosis criteria for CIDP. At initial diagnosis, the median nerve met the single parameters of the EFNS/PNS criteria most frequently with 72%, followed by the tibial nerve with 66%, ulnar nerve with 46%, and peroneal nerve with 22%. In total, the criterion of prolonged distal cMAP duration was met most frequently (32%), followed by an abnormal temporal dispersion (16%) and absence of F-waves (13%). However, we identified axonal damage as the parameter related with clinical disability (p < 0.001), not demyelination. Thus, distal cMAP and sNAP amplitudes could be identified as predictive markers of disability, especially in the upper limbs (related to INCAT-ODSS: ulnar nerve: R2 = 0.219; median nerve: R2 = 0.099; peroneal nerve: R2 = 0.044; tibial nerve: R2 = 0.034; related to ISS: ulnar nerve: R2 = 0.118; radial nerve: R2 = 0.112; sural nerve: R2 = 0.096; peroneal nerve: R2 = 0.084; median nerve: R2 = 0.082). The neurographic parameters of the upper limbs might relate to a greater extent to the total disability than those of the lower limbs, since nerves of the lower limbs have already shown extensive axonal damage (71% of distal cMAP amplitudes of the peroneal nerve and 45% of the tibial nerve <1 mV). Conclusions. Although the majority of CIDP patients reveal symptoms predominant of the legs, the examination of the upper limbs has proven to be essential for both initial diagnosis and disease monitoring, underlining CIDP as a systemic disease. Especially the determination of the distal cMAP duration was a sensitive parameter in the detection of CIDP. The total disability is largely determined by the degree of axonal damage. Therefore, neuroprotection should have an important additional role in the CIDP therapy in the future. [ABSTRACT FROM AUTHOR]

Introduction. In this study we evaluated the autonomic neural function in Parkinson's disease (PD) by combining the use of clinical scoring, functional evaluation with head-up tilt test (HUTT) and morphological studies of the vagus nerve (VN) with nerve ultrasound (NU). This allowed us to correlate morphological changes of the VN with markers of parasympathetic dysfunction from HUTT. Patients/Methods. In our study we used NU to compare the mean values of the cross-sectional area (CSA) of the VNs of 80 PD patients with those of controls (n=40) and patients with chronic inflammatory demyelinating polyneuropathy (CIDP) (n=76). In 69 cases HUTT data was analyzed concerning the presence of orthostatic hypotension (OH), postural orthostatic tachycardia syndrome (POTS) and chronotropic incompetence (CI). Functional haemodynamic parameters in HUTT were used to evaluate parasympathetic functions and correlate them with VN CSA (n=65). Results. In PD, the CSA of right / left VN was significantly smaller compared to the right/left VN of the control and CIDP patients (Table 1). Based on HUTT, 60.5 % of the patients were diagnosed with autonomic dysfunction (OH n=11, CI n=31, POTS n=1). Patients with OH showed significantly higher UPDRS-III values than those with CI (p=0.025). The CSA of the VN correlated inversely with heart rate and positively with parameters representing parasympathetic modulation through vagal activity (Fig. 1). Conclusion. By using NU significant morphological differences of the CSA of the VN were detected in CIDP, PD and a healthy control group. Furthermore, we demonstrated for the first time that anatomical characteristics of the VN correlate with parameters of parasympathetic function from the spectral analysis of cardiovascular parameters in HUTT for PD. This finding enables a new interpretation of the anatomical characteristics of the VN for PD patients and diagnosis of autonomic dysfunction. ▪ Fig. 1. Schematic presentation of the inverse correlation of the cross-sectional area of the right vagus nerve with the heart rate. Positive correlation with markers of parasympathetic activity HFnu-RRI. (Spearman Correlation). Abbreviations: HR=heart rate, HFnuRRI = high frequency power of the RR-Interval, bpm= beats per minute, CSA= cross-sectional area Table 1. Demographical and epidemiological characteristics as well as the cross-sectional area (CSA) of the vagus nerve. All values are provided as mean ± standard deviation. ▪ Abbreviations: INCAT/ODSS = inflammatory neuropathy cause and treatment/overall disability sum score, MDS-UPDRS III= MDS-Unified Parkinson's Disease Rating Scale, SCOPA-AUT= Scales for Outcomes in Parkinson's Disease- Autonomic Dysfunction, PDQ39 = Parkinson's Disease Questionnaire, CSA = cross sectional area. [ABSTRACT FROM AUTHOR]

Objective We studied the immunmodulatory effects of triamcinolone applied intrathecally in the animal model of experimental autoimmune neuritis (EAN) in Lewis rats. Background Therapeutic efficacy of intravenous corticosteroids in chronic autoimmune neuritis has been shown in several randomized, placebo-controlled studies, although the exact mechanisms of action remain unclear. Intrathecal drug administration is an alternate route of delivery in order to bypass the blood-nerve barrier and achieve a direct effect on the nerve roots. Methods Active EAN was induced by immunization with the P2 aa 53–78 myelin peptide in Lewis rats followed by intrathecal application of 0.6 mg/kg or 1.2 mg/kg traimcinolone once daily on day 11 p.i (post-immunisation). The clinical severity score was assessed daily until day 23 p.i.. Nerve conduction studies and histological analyses of the sciatic nerves for demyelination and inflammatory infiltrates as well as flow cytometric analyses of the peripheral lymph nodes and spleen were performed at the disease maximum (day 18 p.i.). Results Therapeutic treatment with 0.6 and 1.2 mg/kg Triamcinolone applied intrathecally on day 11 p.i. significantly ameliorated clinical signs of neuritis by reducing proximal as well as distal demyelination in the nerve conduction studies. Further, histological analyses revealed a significantly lower degree of T cells and macrophages infiltrates accompanied with a decrease of proinflammatory cytokines (IFN-g and TNF-a) and an increase of anti-inflammatory cytokines (IL-10, IL-4) in the sciatic nerves at the disease maximum. Furthermore, Schwann cells death markers (caspase-3) showed a reduced Schwann cells apoptosis on triamcinolone treatment. Conclusions Intrathecal administration of triamcinolone in the rat model of autoimmune neuritis is a safe and effective immunomodulatory option with a anti-degenerative potential. Further studies are required in order to investigate the safety and efficacy of intrathecal triamcinolone application in patients with autoimmune neuritis. [ABSTRACT FROM AUTHOR]

Purpose: Corneal confocal microscopy is a noninvasive imaging technique to analyze corneal nerve fibers and corneal inflammatory cells (CICs). The amount of CICs is a potential biomarker of disease activity in chronic autoinflammatory diseases. To date, there are no standardized criteria for the morphological characterization of CICs. The aim was to establish a protocol for a standardized morphological classification of CICs based on a literature search and to test this protocol for applicability and reliability., Methods: A systematic review of the literature about definitions of CICs was conducted. Existing morphological descriptions were translated into a structured algorithm and applied by raters. Subsequently, the protocol was optimized by reducing and defining the criteria of the cell types. The optimized algorithm was applied by 4 raters. The interrater reliability was calculated using Fleiss kappa (K)., Results: A systematic review of the literature revealed no uniform morphological criteria for the differentiation of the individual cell types in CICs. Our first protocol achieved only a low level of agreement between 3 raters (K = 0.09; 1062 rated cells). Our revised protocol was able to achieve a higher interrater reliability with 3 (K = 0.64; 471 rated cells) and 4 (K = 0.61; 628 rated cells) raters., Conclusions: The indirect use of criteria from the literature leads to a high error rate. By clearly defining the individual cell types and standardizing the protocol, reproducible results were obtained, allowing the introduction of this protocol for the future evaluation of CICs in the corneal confocal microscopy., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The value of a sural nerve biopsy for the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is controversial. Evidence-based recommendations for its implementation are lacking. We investigated factors leading to biopsy and analyzed biopsy outcomes and consequences, assessed the predictability of biopsy outcomes through clinical parameters to avoid unnecessary biopsies, and compared results with electrophysiological and clinical severity to determine their prognostic value., Methods: 190 sural nerve biopsies were analyzed in two cohorts. One consisted of 163 biopsies and the second of 72 biopsies from the prospective Immune-mediated Neuropathies Biomaterial and Data registry (INHIBIT). Both have an intersection of 45 patients. 75 data sets from patients without biopsy were used. Analysis of nerve conduction studies, treatment, overall disability sum score (ODSS), biopsy outcomes, and diagnosis was performed., Results: 51% of biopsied patients received the diagnosis CIDP (77% fulfilled EFNS/PNS criteria), 21% were not CIDP typical, and 27% were unspecific. Biopsied patients responded less frequently to immunotherapies at time of biopsy than non-biopsied patients (p = 0.003). Immunotherapy was initiated more frequently after biopsy (p < 0.001) and more often with intravenous immunoglobulins (p < 0.0001). 76% of all biopsied patients met the electrophysiological criteria for CIDP. Sensory nerve action potential amplitudes of 0 µV still provide 73% of histological diagnostic value. Histologic signs of degeneration predicted ODSS worsening after 1 year (p = 0.028) but disease severity did not correlate with histological damage severity., Discussion: The main indication for nerve biopsy was the treatment of refractory cases of autoimmune neuropathies with the therapeutic consequence of treatment initiation or escalation. Sural biopsy also provided prognostic information. Even with extinguished sural SNAP, the biopsy can still have diagnostic value., (© 2024. The Author(s).)

Background and Objectives: To develop a composite score to assess the severity of the multiple symptoms present in anti-IgLON5 disease., Methods: The anti-IgLON5 disease composite score (ICS) was designed to evaluate 17 symptoms divided into 5 clinical domains (bulbar, sleep, movement disorders, cognition, and others). Each symptom was scored from 0 (absent/normal) to 3 or 6 (severe) depending on the contribution of the symptom to neurologic disability with a maximum ICS of 69. The ICS was tested in patients from 2 cohorts (Barcelona, Spain, and GENERATE, Germany) that included cases personally seen by the authors (internal) and patients whose ICS was obtained from information of questionnaires completed by the referring neurologists (external). Test-retest and interrater reliabilities of the ICS were assessed by the intraclass coefficient (ICC) and the correlation between the ICS and modified Rankin scale (mRS) with the nonparametric Spearman rank coefficient. The Wilcoxon signed rank test was used to compare the ICS at diagnosis of anti-IgLON5 disease and follow-up in a subset of patients with available clinical information., Results: A total of 86 patients (46 from Barcelona cohort; 40 from GENERATE cohort) were included. The median ICS was 15 (range 2-31). The ICS was higher in the Barcelona cohort than in the German cohort (18 vs 12, p < 0.001), due to higher partial scores in sleep and movement disorder domains. There were no significant differences in the ICS between internal and external patients (15 vs 14, p = 0.96). The ICS correlated with the mRS score ( r = 0.429, p < 0.001). Test-retest and interrater reliabilities were excellent with an ICC of 0.997 (95% CI 0.992-0.999) and 0.973 (95% CI 0.925-0.990), respectively. ICS was retested during follow-up in 27 patients, and it was similar to that at diagnosis in 10 clinically stable patients (median ICS at diagnosis 11.5 vs 11.5 at follow-up; p = 1), higher in 8 patients who worsened (12.5 vs 18; p = 0.012), and lower in 9 patients who improved after immunotherapy (14 vs 10; p = 0.007)., Discussion: The ICS is a valid method to assess the extension and severity of the different clinical manifestations of anti-IgLON5 disease.

Background and Purpose: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease with humoral and cellular autoimmunity causing demyelination of peripheral nerves, commonly treated with intravenous immunoglobulins (IVIg). The neonatal Fc receptor (FcRn), encoded by the FCGRT gene, prevents the degradation of immunoglobulin G (IgG) by recycling circulating IgG. A variable number of tandem repeat (VNTR) polymorphism in the promoter region of the FCGRT gene is associated with different expression levels of mRNA and protein. Thus, patients with genotypes associated with relatively low FcRn expression may show a poorer treatment response to IVIg due to increased IVIg degradation., Methods: VNTR genotypes were analyzed in 144 patients with CIDP. Patients' clinical data, including neurological scores and treatment data, were collected as part of the Immune-Mediated Neuropathies Biobank registry., Results: Most patients (n = 124, 86%) were VNTR 3/3 homozygotes, and 20 patients (14%) were VNTR 2/3 heterozygotes. Both VNTR 3/3 and VNTR 2/3 genotype groups showed no difference in clinical disability and immunoglobulin dosage. However, patients with a VNTR 2 allele were more likely to receive subcutaneous immunoglobulins (SCIg) than patients homozygous for the VNTR 3 allele (25% vs. 9.7%, p = 0.02) and were more likely to receive second-line therapy (75% vs. 54%, p = 0.05)., Conclusions: The VNTR 2/3 genotype is associated with the administration of SCIg, possibly reflecting a greater benefit from SCIg due to more constant immunoglobulin levels without lower IVIg levels between the treatment circles. Also, the greater need for second-line treatment in VNTR 2/3 patients could be an indirect sign of a lower response to immunoglobulins., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Experimental autoimmune neuritis is a common animal model for acute human immune-mediated polyneuropathies. Although already established in 1955, a number of pathophysiological mechanisms remain unknown. In this study, we extensively characterize experimental autoimmune neuritis progression in Lewis rats, including new insights into the integrity of small nerve fibres, neuropathic pain and macrophage activation. Acute experimental autoimmune neuritis was induced with P2 53-78 peptide and consequently investigated using the gait analysis system CatWalk XT, electrophysiological and histopathological analyses, quantitative polymerase chain reaction (PCR), dorsal root ganglia outgrowth studies, as well as the von Frey hair and Hargreaves tests. For the longitudinal setup, rats were sacrificed at Day (d) 10 (onset), d15 (peak), d26 (recovery) and d29 (late recovery). We confirmed the classical T-cell and macrophage-driven inflammation and the primarily demyelinating nature of the experimental autoimmune neuritis. The dual role of macrophages in experimental autoimmune neuritis is implicated by the high number of remaining macrophages throughout disease progression. Furthermore, different subpopulations of macrophages based on Cx3-motif chemokine receptor 1 ( Cx3cr1) , platelet factor 4 (Pf4) and macrophage galactose-type lectin-1 (Mgl1) expressions were identified. In addition, modulation of the sensory system in experimental autoimmune neuritis was detected. An outgrowth of small fibres in the plantar skin at the onset and peak of the experimental autoimmune neuritis was evident parallel to the development of acute hyperalgesia mediated through transient receptor potential vanilloid 1 modulation. Our data depict experimental autoimmune neuritis as a primary demyelinating disease with implicated axonal damage, a small unmyelinated fibre impairment throughout the disease progression course, and underline the pivotal role of macrophages in the effector and during the recovery stage., Competing Interests: R.K. received research funding from The LFB Group, France and the Ruhr-University Bochum, not related to this work. T.G. received travel reimbursement from Sanofi Genzyme and Biogen Idec, none related to this manuscript. J.M. received travel grants from Biogen idec, Novartis AG, Teva and Eisai GmbH; his research was funded by the Klaus Tschira Foundation and the Ruhr-University, Bochum (FoRUM programme), Hertie Foundation; Biogen idec and Deutsche Forschungsgemeinschaft, none related to this work. R.G. serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd, Biogen Idec, Bayer Schering Pharma and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd, Bayer Schering Pharma and Novartis; serves as an editor for Therapeutic Advances in Neurological Diseases and on the editorial boards of Experimental Neurology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd, Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono and Novartis, none related to this manuscript. K.P. received travel funding and speaker honoraria from Biogen, Novartis, CSL Behring and Bayer Schering Pharma and funding from the Ruhr-University, Bochum (FORUM programme), none related to this work. The remaining authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: To evaluate magnetic resonance neurography (MRN) for the longitudinal assessment of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)., Methods: Prospective examination of twelve CIDP patients by neurological assessment, MRN, and nerve conduction studies in 2016 and 6 years later in 2022. Imaging parameters were compared with matched healthy controls and correlated with clinical and electrophysiological markers. The MRN protocol included T2-weighted imaging, diffusion tensor imaging (DTI), T2 relaxometry, and magnetization transfer imaging (MTI)., Results: Nerve cross-sectional area (CSA) was increased in CIDP patients compared to controls (plexus: p = 0.003; sciatic nerve: p < 0.001). Over 6 years, nerve CSA decreased in CIDP patients, most pronounced at the lumbosacral plexus (p = 0.015). Longitudinally, changes in CSA correlated with changes in the inflammatory neuropathy cause and treatment validated overall disability sum score (INCAT/ODSS) (p = 0.006). High initial nerve CSA was inversely correlated with changes in the INCAT/ODSS over 6 years (p < 0.05). The DTI parameter fractional anisotropy (FA) showed robust correlations with electrodiagnostic testing both cross-sectionally and longitudinally (p < 0.05). MTI as a newly added imaging technique revealed a significantly reduced magnetization transfer ratio (MTR) in CIDP patients (p < 0.01), suggesting underlying changes in macromolecular tissue composition, and correlated significantly with electrophysiological parameters of demyelination (p < 0.05)., Interpretation: This study provides evidence that changes in nerve CSA and FA reflect the clinical and electrophysiological course of CIDP patients. Initial nerve hypertrophy might predict a rather benign course or better therapy response., (© 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.)

Introduction: Serum neurofilament light chain (sNfL) is a marker for axonal degeneration. Patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) often report a fluctuation of symptoms throughout one treatment cycle with intravenous immunoglobulins (IVIG). The aim of this study was to determine whether sNfL is suitable to quantify patient-reported symptom fluctuations., Methods: Twenty-nine patients with the diagnosis of CIDP or a CIDP-variant under treatment with IVIG were recruited in this study and underwent examination before IVIG infusion, in the middle of the treatment interval, and before their next IVIG infusion. Patients were surveyed regarding symptom fluctuations at the last visit and divided into two groups: those with and without fluctuations of symptoms. At the first visit, sociodemographic and disease-specific data were collected. Clinical scores were assessed at every examination. sNfL values were compared between both groups at the different time points after conversion into Z-scores-adjusted for age and body mass index., Results: Patients with CIDP show elevated sNfL Z-scores (median at baseline: 2.14, IQR: 1.0). There was no significant change in sNfL Z-scores or questionnaire scores within the treatment cycle in either group. There was no significant difference in sNfL levels between the patients with and without symptom fluctuations., Conclusions: CIDP patients show elevated sNfL levels. However, sNfL is not suitable to reflect patient-reported fluctuations of symptoms. This indicates that symptom fluctuations during treatment with IVIG in patients with CIDP are not caused by a neuroaxonal injury. Furthermore, repeated sNfL measurements within one treatment cycle with IVIG seem to have no benefit for symptom monitoring., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objectives: Anti-IgLON5 disease is a recently discovered neurologic disorder combining autoimmunity and neurodegeneration. Core manifestations include sleep disorders, bulbar symptoms, gait abnormalities, and cognitive dysfunction, but other presentations have been reported. Hallmarks are autoantibodies targeting the neuronal surface protein IgLON5, a strong human leukocyte antigen system Class II association, and brainstem and hypothalamus-dominant tau deposits. The purpose of this cohort study was to visualize tau deposition in vivo with the second-generation tau-PET tracer., Methods: A cohort of 4 patients with anti-IgLON5 disease underwent a dynamic PET scan with [18F]PI-2620. One patient received a follow-up scan. Z-deviation maps and a 2-sample t test in comparison with healthy controls (n = 10) were performed. Antibody titers, neurofilament light chain, and disease duration were correlated with brainstem binding potentials., Results: Patients demonstrated increased [18F]PI2620 tau binding potentials in the pons, dorsal medulla, and cerebellum. The longitudinal scan after 28 months showed an increase of tracer uptake in the medulla despite immunotherapy. Higher antibody titers and neurofilament light chain correlated with higher tracer retention., Discussion: The results indicate that tau depositions in anti-IgLON5 disease can be visualized with [18F]PI-2620 and might correlate with the extent of disease. For validation, a larger longitudinal study is necessary., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Depression has a major impact on the disease burden of multiple sclerosis (MS). Analyses of overlapping MS and depression risk factors [smoking, vitamin D (25-OH-VD) and Epstein-Barr virus (EBV) infection] and sex, age, disease characteristics and neuroimaging features associated with depressive symptoms in early MS are scarce., Objectives: To assess an association of MS risk factors with depressive symptoms within the German NationMS cohort., Design: Cross-sectional analysis within a multicenter observational study., Methods: Baseline data of n  = 781 adults with newly diagnosed clinically isolated syndrome or relapsing-remitting MS qualified for analysis. Global and region-specific magnetic resonance imaging (MRI)-volumetry parameters were available for n  = 327 patients. Association of demographic factors, MS characteristics and risk factors [sex, age, smoking, disease course, presence of current relapse, expanded disability status scale (EDSS) score, fatigue (fatigue scale motor cognition), 25-OH-VD serum concentration, EBV nuclear antigen-1 IgG (EBNA1-IgG) serum levels] and depressive symptoms (Beck Depression Inventory-II, BDI-II) was tested as a primary outcome by multivariable linear regression. Non-parametric correlation and group comparison were performed for associations of MRI parameters and depressive symptoms., Results: Mean age was 34.3 years (95% confidence interval: 33.6-35.0). The female-to-male ratio was 2.3:1. At least minimal depressive symptoms (BDI-II > 8) were present in n  = 256 (32.8%), 25-OH-VD deficiency (<20 ng/ml) in n  = 398 (51.0%), n  = 246 (31.5%) participants were smokers. Presence of current relapse [coefficient ( c ) = 1.48, p  = 0.016], more severe fatigue ( c  = 0.26, p  < 0.0001), lower 25-OH-VD ( c  = -0.03, p  = 0.034) and smoking ( c  = 0.35, p  = 0.008) were associated with higher BDI-II scores. Sex, age, disease course, EDSS, month of visit, EBNA1-IgG levels and brain volumes at baseline were not., Conclusion: Depressive symptoms need to be assessed in early MS. Patients during relapse seem especially vulnerable to depressive symptoms. Contributing factors such as fatigue, vitamin D deficiency and smoking, could specifically be targeted in future interventions and should be investigated in prospective studies., (© The Author(s), 2023.)

Autoimmune neuropathy associated with antibodies against pan-neurofascin is a new subtype of nodo-paranodopathy. It is relevant because it is associated with high morbidity and mortality. Affected patients often require intensive care unit treatment for several months, and data on the reversibility and long-term prognosis are limited. The pathogenicity including IgG subclass-associated mechanisms has not been unravelled, nor directly compared to anti-neurofascin-155 IgG4-related pathology. Understanding the underlying pathology might have a direct impact on treatment of these severely affected patients. By a multicentre combined prospective and retrospective approach, we provide clinical data of a large cohort of patients with anti-neurofascin-associated neuropathy (n = 18) including longitudinal titre and neurofilament light chain assessment via Ella® and relate clinical data to in vitro pathogenicity studies of anti-neurofascin antibodies. We assessed antibody binding characteristics and the pathogenic effects of anti-pan-neurofascin versus neurofascin-155 antibodies on living myelinating dorsal root ganglia co-cultures. Additionally, we analysed the IgG subclass profile and the complement binding capacity and effector functions considering the effects of intravenous immunoglobulin preparations via enzyme-linked immunosorbent and cell-based assays. In contrast to chronic neurofascin-155 IgG4-associated neuropathy, anti-pan-neurofascin-associated disease presented with a high morbidity and mortality, but as a monophasic and potentially reversible disorder. During follow-up, antibodies were no longer detectable in 8 of 11 patients. Anti-pan-neurofascin had direct access to the nodes of Ranvier in myelinating cultures titre-dependently, most probably inducing this severe phenotype. Antibody preincubation led to impaired paranode formation, destruction of paranodal architecture and alterations on paranodal myelin and sensory neurons in the cultures, with more severe effects than neurofascin-155 antibodies. Besides IgG4, subclass IgG3 was detected and associated with complement binding and cytotoxic effects in vitro. As a possible correlate of axonal damage in vivo, we detected highly increased serum neurofilament light chain levels (sNF-L), correlating to serum C3a. Still, sNF-L was not identified as a marker for poor prognosis, but rather as an intra- and interindividual marker for acuteness, severity and course, with a strong decrease during recovery. Our data provide evidence that anti-pan-neurofascin antibodies directly attack the node and induce severe and acute, but potentially reversible, nodo-paranodal pathology, possibly involving complement-mediated mechanisms. Screening for autoantibodies thus is crucial to identify this subset of patients who benefit from early antibody-depleting therapy. Titre and sNF-L might serve as valuable follow-up parameters. The prospect of a favourable outcome has high relevance for physicians, patients and relatives during months of critical care., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: SARS-CoV-2 pandemic is especially compromising for patients with autoimmune diseases with or without immunomodulatory treatment. This study aimed to investigate the longitudinal changes in the health care of patients with immune-mediated neuropathies during the COVID-19 pandemic., Methods: We performed a longitudinal study using questionnaires in a prospective cohort of patients with immune-mediated neuropathies at two timepoints of the pandemic: May-July 2021 and May-July 2022., Results: The cohort consisted of 73 patients (55 male), mean age 62 years, 68 patients with CIDP, 5 with other immune neuropathies. In 2021, 19.2% of the patients reported a reduced number of physician-patient-contacts, while 13.7% reported this in 2022. Nevertheless, the overall health-care situation worsened from 2021 to 2022: 15.1% reported reduced overall healthcare in 2021, 26.0% in 2022. In 2021, 29.4% of patients reported absence of physio-/occupational therapy, while 34.4% reported this in 2022. Switching immunomodulatory treatment and stretching of treatment intervals occurred more often in 2022 (38.4%) than in 2021 (27.4%). 12 COVID-19-infections occurred overall, with typical only mild symptoms. The rate of fully vaccinated patients was 61.6% and 98.6% in May-July 2021 and 2022, respectively. Only minor side-effects after vaccination were reported., Conclusion: Despite mitigation of COVID-19 restrictions from 2021 to 2022, the health-care situation of patients worsened in this time. Reasons could be the international shortage of immunoglobulins during the pandemic and reduced physio/ergotherapy due to lingering regulatory restrictions. Vaccination rate was high in our cohort of patients compared to the general German population and CIDP did not seem to be a risk factor for severe SARS-CoV-2 infections., (© 2022. The Author(s).)

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).)

Anti-IgLON5 disease is a newly defined clinical entity characterized by a progressive course with high disability and mortality rate. While precise pathogenetic mechanisms remain unclear, features characteristic of both autoimmune and neurodegenerative diseases were reported. Data on immunotherapy are limited, and its efficacy remains controversial. In this study, we retrospectively investigated an anti-IgLON5 disease cohort with special focus on clinical, serological and genetic predictors of the immunotherapy response and long-term outcome. Patients were recruited from the GENERATE (German Network for Research on Autoimmune Encephalitis) registry. Along with clinical parameters, anti-IgLON5 immunoglobulin (Ig)G in serum and CSF, anti-IgLON5 IgG1-4, IgA and IgM in serum, neurofilament light chain and glial fibrillary acidic protein in serum as well as human leukocyte antigen-genotypes were determined. We identified 53 patients (symptom onset 63.8 ± 10.3 years, female:male 1:1.5). The most frequent initial clinical presentations were bulbar syndrome, hyperkinetic syndrome or isolated sleep disorder [at least one symptom present in 38% (20/53)]. At the time of diagnosis, the majority of patients had a generalized multi-systemic phenotype; nevertheless, 21% (11/53) still had an isolated brainstem syndrome and/or a characteristic sleep disorder only. About one third of patients [28% (15/53)] reported subacute disease onset and 51% (27/53) relapse-like exacerbations during the disease course. Inflammatory CSF changes were evident in 37% (19/51) and increased blood-CSF-barrier permeability in 46% (21/46). CSF cell count significantly decreased, while serum anti-IgLON5 IgG titre increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 [55% (24/44)] was associated with higher serum anti-IgLON5 IgG titres. Neurofilament light chain and glial fibrillary acidic protein in serum were substantially increased (71.1 ± 103.9 pg/ml and 126.7 ± 73.3 pg/ml, respectively). First-line immunotherapy of relapse-like acute-to-subacute exacerbation episodes resulted in improvement in 41% (11/27) of patients and early initiation within the first 6 weeks was a predictor for therapy response. Sixty-eight per cent (36/53) of patients were treated with long-term immunotherapy and 75% (27/36) of these experienced no further disease progression (observation period of 20.2 ± 15.4 months). Long-term immunotherapy initiation during the first year after onset and low pre-treatment neurofilament light chain were significant predictors for a better outcome. In conclusion, subacute disease onset and early inflammatory CSF changes support the primary role of autoimmune mechanisms at least at initial stages of anti-IgLON5 disease. Early immunotherapy, prior to advanced neurodegeneration, is associated with a better long-term clinical outcome. Low serum neurofilament light chain at treatment initiation may serve as a potential biomarker of the immunotherapy response., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The process of myelination is essential to enable rapid and sufficient signal transduction in the nervous system. In the peripheral nervous system, neurons and Schwann cells engage in a complex interaction to control the myelination of axons. Disturbances of this interaction and breakdown of the myelin sheath are hallmarks of inflammatory neuropathies and occur secondarily in neurodegenerative disorders. Here, we present a coculture model of dorsal root ganglion explants and Schwann cells, which develops a robust myelination of peripheral axons to investigate the process of myelination in the peripheral nervous system, study axon-Schwann cell interactions, and evaluate the potential effects of therapeutic agents on each cell type separately. Methodologically, dorsal root ganglions of embryonic rats (E13.5) were harvested, dissociated from their surrounding tissue, and cultured as whole explants for 3 days. Schwann cells were isolated from 3-week-old adult rats, and sciatic nerves were enzymatically digested. The resulting Schwann cells were purified by magnetic-activated cell sorting and cultured under neuregulin and forskolin-enriched conditions. After 3 days of dorsal root ganglion explant culture, 30,000 Schwann cells were added to one dorsal root ganglion explant in a medium containing ascorbic acid. The first signs of myelination were detected on day 10 of coculture, through scattered signals for myelin basic protein in immunocytochemical staining. From day 14 onward, myelin sheaths were formed and propagated along the axons. Myelination can be quantified by myelin basic protein staining as a ratio of the myelination area and axon area, to account for the differences in axonal density. This model provides experimental opportunities to study various aspects of peripheral myelination in vitro, which is crucial for understanding the pathology of and possible treatment opportunities for demyelination and neurodegeneration in inflammatory and neurodegenerative diseases of the peripheral nervous system.

In inflammatory neuropathies, oxidative stress results in neuronal and Schwann cell (SC) death promoting early neurodegeneration and clinical disability. Treatment with the short-chain fatty acid propionate showed a significant immunoregulatory and neuroprotective effect in multiple sclerosis patients. Similar effects have been described for patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Therefore, Schwann cell's survival and dorsal root ganglia (DRG) outgrowth were evaluated in vitro after propionate treatment and application of H2O2 or S-nitroso-N-acetyl-D-L-penicillamine (SNAP) to evaluate neuroprotection. In addition, DRG resistance was evaluated by the application of oxidative stress by SNAP ex vivo after in vivo propionate treatment. Propionate treatment secondary to SNAP application on DRG served as a neuroregeneration model. Histone acetylation as well as expression of the free fatty acid receptor (FFAR) 2 and 3, histone deacetylases, neuroregeneration markers, and antioxidative mediators were investigated. β-hydroxybutyrate was used as a second FFAR3 ligand, and pertussis toxin was used as an FFAR3 antagonist. FFAR3, but not FFAR2, expression was evident on SC and DRG. Propionate-mediated activation of FFAR3 and histone 3 hyperacetylation resulted in increased catalase expression and increased resistance to oxidative stress. In addition, propionate treatment resulted in enhanced neuroregeneration with concomitant growth-associated protein 43 expression. We were able to demonstrate an antioxidative and neuroregenerative effect of propionate on SC and DRG mediated by FFAR3-induced histone acetylases expression. Our results describe a pathway to achieve neuroprotection/neuroregeneration relevant for patients with immune-mediated neuropathies.

The aim of this prospective study was to investigate autonomic function in Parkinson's disease with a multidimensional approach including clinical evaluation tools, head-up tilt test and morphological studies of the vagus nerve. Head-up tilt test parameters including high frequency power of the heart frequency interval, the ratio of low frequency power of the distance between two consecutive R waves in electrocardiogram (RR interval) to the high frequency and low frequency power of systolic blood pressure were used to evaluate parasympathetic, cardiac sympathetic and vasomotor sympathetic functions, respectively, in 80 patients with Parkinson's disease. We examined the cross-sectional area of the vagus nerves bilaterally using nerve ultrasound and compared mean values with a control group of healthy subjects ( n = 40) as well as patients with chronic inflammatory demyelinating polyneuropathy ( n = 76). The cross-sectional area of right/left vagus nerve of Parkinson's patients was significantly lower compared to the right/left vagus nerve of the control group and of chronic demyelinating polyneuropathy patients. Furthermore, the cross-sectional area of the right vagus nerve was significantly larger from the one of the left vagus nerve for all groups. Based on tilt test, 43 patients (disease duration 7 ± 5, age at evaluation 71 ± 9, Hoehn and Yahr score 2.8 ± 8) were diagnosed with autonomic dysfunction (orthostatic hypertension n = 11, chronotropic incompetence n = 31, postural orthostatic tachycardia syndrome n = 1). Patients with orthostatic hypotension showed significantly higher Unified Parkinson's Disease Rating Scale-III values than those with chronotropic incompetence. The cross-sectional area of the vagus nerve correlated inversely with heart rate in rest and supine position and positively with tilt test parameters representing parasympathetic modulation through vagal activity [high frequency power of the distance between two consecutive R waves in electrocardiogram (RR interval)] at rest. We demonstrate for the first time that morphological characteristics of the vagus nerve correlate with parameters of parasympathetic function from the spectral analysis of cardiovascular parameters in tilt test for Parkinson's patients. This correlation reveals the impact of the atrophy of vagal atrophy for autonomic function in Parkinson's disease. Nerve ultrasound of the vagus nerve could potentially be used as an adjunct to tilt table examination to diagnose autonomic dysfunction., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Purpose: Pain, fatigue and depression in chronic inflammatory demyelinating polyneuropathy (CIDP) are often underestimated, as the focus lies on sensorimotor dysfunction and gait instability. The aim of this study was to investigate their prevalence, characteristics and contribution to disability in a prospective cohort of 84 patients with CIDP., Methods: Pain, fatigue, depression and quality of life were measured using the Pain Detect Questionnaire, Krupp's Fatigue Severity Scale, Beck Depression Inventory II and the German Short-Form 36 Health Survey. Sensorimotor deficits and disability were assessed using the Inflammatory Neuropathy Cause and Treatment overall disability score, the Rasch-built Overall Disability Scale, the Medical Research Council sum score and the Inflammatory Neuropathy Cause and Treatment sensory sum score. The interrelation between the five factors was assessed using analysis of variance and linear regression analysis., Results: Pain was reported in 62%, mostly of moderate and severe intensity, whereas pain characteristics indicated neuropathic pain (NP) in 29%. Sensory dysfunction was stronger in NP patients compared to pain-free patients (p = 0.001). Pain of any type, especially NP, was associated with more pronounced fatigue symptoms (p = 0.010). Depressive symptoms were more frequent in patients with pain compared to the pain-free patients (61% vs. 33%, p = 0.02) and were more severe and frequent in NP than in non-NP patients (p = 0.005). Patients with pain had a worse physical quality of life than pain-free patients (p = 0.001)., Conclusion: Pain, depression and fatigue are relevant disability factors in CIDP affecting quality of life. Sensory dysfunction is associated with NP. Therefore, evaluation of CIDP-related disability should include pain and sensory function for adequate monitoring of therapeutic interventions., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Echogenicity of peripheral nerves in high-resolution ultrasound (HRUS) provides insight into the structural damage of peripheral nerves in various polyneuropathies. The aim of this study was to compare nerve echogenicity in different primarily axonal or demyelinating polyneuropathies to examine the significance of this parameter. Performing semi-automated echogenicity analysis and applying Image J, we retrospectively used HRUS images of 19 patients with critical illness polyneuropathy (CIP), and 27 patients with chemotherapy-induced polyneuropathy (CIN) and compared them to 20 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). The fraction of black representing echogenicity was measured after converting the images into black and white. The nerves of patients with progressive CIDP significantly differed from the hyperechogenic nerves of patients with other polyneuropathies at the following sites: the median nerve at the forearm (p < 0.001), the median nerve at the upper arm (p < 0.004), and the ulnar nerve at the upper arm (p < 0.001). The other polyneuropathies showed no notable differences. Altogether, the comparison of echogenicity between different polyneuropathies supports the assumption that there are differences depending on the genesis of the structural nerve damage. However, these differences are slight, and cannot be used to show clear differences between each polyneuropathy form.

Background and Purpose: Monitoring of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is challenging in daily medical practice because the interrelationship between clinical disability, CIDP subtype, and neuronal degeneration is still elusive. The aim of this prospective cohort study was to investigate the role of different electrophysiological variables in CIDP monitoring., Methods: Comprehensive bilateral nerve conduction studies (NCS) and structured clinical examinations were performed in 95 patients with typical CIDP and CIDP variants (age at inclusion 58.6 ± 11.6 years; median [range] inflammatory neuropathy cause and treatment overall disability score (INCAT-ODSS) 3 [0-9]), at time of first diagnosis in 25 of these patients (based on data from the prospective Immune-mediated Neuropathies Biobank registry). After 12 months, 33 patients underwent follow-up examination. Typical CIDP patients and patients with CIDP variants were characterized electrophysiologically and each individual NCS variable and the overall sum score for axonal damage and demyelination were then correlated to clinical disability scores (INCAT-ODSS, modified Medical Research Council (MRS) sum score, and INCAT sensory score)., Results: As opposed to demyelination markers, the NCS axonal damage variable correlated strongly with disability at both first diagnosis and advanced disease stages in cross-sectional and longitudinal analyses. Distal compound muscle action potential amplitudes of the upper limbs were found to have the strongest correlation with overall clinical function. Typical and atypical CIDP variants had distinct electrophysiological characteristics but, in typical CIDP, axonal degeneration markers were more strongly associated with clinical disability., Conclusions: Total disability is largely determined by the degree of axonal damage, especially in typical CIDP. Although most patients have symptoms predominantly in the legs, NCS of the upper limbs are essential for the monitoring of patients with CIDP and CIDP variants., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: Chronic inflammatory demyelinating polyneuropathy (CIDP) may have a similar clinical and electrophysiological presentation to non-inflammatory axonal polyneuropathies (NIAPs) when secondary axonal damage occurs. We aimed to investigate if nerve ultrasound can help to differentiate CIDP with additional secondary axonal damage from NIAP., Methods: In a retrospective analysis, the cross-sectional area (CSA) of the peripheral nerves measured by ultrasound at six suitable nerve sites was compared in 95 patients with CIDP and 82 patients with NIAP. We developed the adjusted Bochum ultrasound score (aBUS) ranging from 0 to 6 resulting from the number of sites with enlarged CSA (median, ulnar, radial, and sural nerve)., Results: The mean CSA of patients with CIDP was enlarged at all six nerve sites compared with the mean CSA of patients with NIAP. A total of 21 patients with CIDP did not meet 2010 electrophysiological diagnostic criteria (European Academy of Neurology/Peripheral Nerve Society Guideline, EFNS/PNS criteria) for CIDP at examination timepoint but only in further follow-up, while 25 patients with NIAP fulfilled electrophysiological EFNS/PNS criteria for CIDP as "possible" or "probable" CIDP. To increase diagnostic power, we included aBUS measured by ultrasound in patients classified as "possible" or "probable" resulting in an improved specificity of 94% and a sensitivity of 59%, compared to a specificity of the EFNS/PNS criteria alone of 60% and sensitivity of 78%., Conclusion: Using nerve ultrasound and the aBUS as a complementary method to distinguish CIDP from NIAP in case of secondary axonal damage can facilitate the diagnosis of CIDP., Competing Interests: JM has no personal pecuniary interests to disclose, received travel grants and supply from Biogen, Novartis, Celgene (BristolMyersSquibb), Teva and Eisai, and the author's research is funded by Klaus Tschira Foundation, Hertie Foundation and Ruhr-University, Bochum (FORUM-program), none related to this study. TG received travel reimbursement from Sanofi Genzyme and Biogen Idec, none related to this manuscript. M-SY has received speaker honoraria from CSL Behring and Grifols, a scientific grant from CSL Behring, none related to this manuscript. RG serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Novartis; serves as an editor for Therapeutic Advances in Neurological Diseases and on the editorial boards of Experimental Neurology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis, none related to this manuscript. KP received travel funding and speaker honoraria from Biogen Idec, Novartis and Bayer Schering Pharma and funding from the Ruhr-University, Bochum (FORUM-program), none related to this study. AF received research funding from Georgius Agricola Stiftung Ruhr and Ruhr-University, Bochum (FORUM-program), received honoraria and travel grants from Novartis AG, Sanofi and Eisai GmbH, none related to this study, and owns shares of Fresenius SE & Co., Gilead Sciences, Medtronic PLC and Novartis AG. 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 © 2022 Brünger, Motte, Grüter, Mork, Bulut, Carolus, Athanasopoulos, Yoon, Gold, Pitarokoili and Fisse.)

Proteasome inhibition with bortezomib has been reported to exert an immunomodulatory action in chronic autoimmune neuropathies. However, bortezomib used for the treatment of multiple myeloma induces a painful toxic polyneuropathy at a higher concentration. Therefore, we addressed this controversial effect and evaluated the neurotoxic and immunomodulatory mode of action of bortezomib in experimental autoimmune neuritis. Bortezomib-induced neuropathy was investigated in Lewis rats using the von Frey hair test, electrophysiological, qPCR and histological analyses of the sciatic nerve as well as dorsal root ganglia outgrowth studies. The immunomodulatory potential of bortezomib was characterized in Lewis rats after experimental autoimmune neuritis induction with P2 53-78 peptide. Clinical, electrophysiological, histological evaluation, von Frey hair test, flow cytometric and mRNA analyses were used to unravel the underlying mechanisms. We defined the toxic concentration of 0.2 mg/kg bortezomib applied intraperitoneally at Days 0, 4, 8 and 12. This dosage induces a painful toxic neuropathy but preserves axonal regeneration in vitro . Bortezomib at a concentration of 0.05 mg/kg significantly ameliorated experimental autoimmune neuritis symptoms, improved experimental autoimmune neuritis-induced hyperalgesia and nerve conduction studies, and reduced immune cell infiltration. Furthermore, proteasome inhibition induced a transcriptional downregulation of Nfkb in the sciatic nerve, while its inhibitor Ikba (also known as Nfkbia ) was upregulated. Histological analyses of bone marrow tissue revealed a compensatory increase of CD138 + plasma cells. Our data suggest that low dose bortezomib (0.05 mg/kg intraperitoneally) has an immunomodulatory effect in the context of experimental autoimmune neuritis through proteasome inhibition and downregulation of nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NFKB). Higher bortezomib concentrations (0.2 mg/kg intraperitoneally) induce sensory neuropathy; however, the regeneration potential remains unaffected. Our data empathizes that bortezomib may serve as an attractive treatment option for inflammatory neuropathies in lower concentrations., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

The assessment of disease activity is fundamental in the management of chronic inflammatory demyelinating polyneuropathy (CIDP). Previous studies with small patient numbers found an increase of corneal immune cell infiltrates as a potential marker of inflammation in patients with CIDP. However, its clinical relevance remained unclear. The present study aimed to determine whether the amount of corneal inflammatory cells (CIC) measured by corneal confocal microscopy (CCM) detects disease activity in CIDP. CIC were measured in 142 CCM-investigations of 97 CIDP-patients. Data on clinical disease activity, disability (INCAT-ODSS) and need for therapy escalation at the timepoint of CCM, 3 and 6 months later were analyzed depending CIC-count. Pathological spontaneous activity during electromyography was examined as another possible biomarker for disease activity in comparison to CIC-count. An increased CIC-count at baseline was found in patients with clinical disease activity and disability progression in the following 3-6 months. An increase to more than 25 CIC/mm 2 had a sensitivity of 0.73 and a specificity of 0.71 to detect clinical disease activity and a sensitivity of 0.77 and a specificity of 0.64 to detect disability progression (increasing INCAT-ODSS) in the following 6 months. An increase to more than 50 CIC/mm 2 had a sensitivity of about 0.51 and a specificity of 0.91 to detect clinical disease activity and a sensitivity of 0.53 and a specificity of 0.80 to detect disability progression. CIC count is a non-invasive biomarker for the detection of disease activity in the following 6 months in CIDP., (© 2021. The Author(s).)

Objective: To evaluate the European Federation of Neurological Societies (EFNS)/Peripheral Nerve Society (PNS) diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP) in a cohort of patients diagnosed and treated for CIDP in a tertiary university hospital., Methods: In a monocentric retrospective study of 203 CIDP patients, diagnosed according to expert opinion, we evaluated the EFNS/PNS diagnostic criteria. Clinical course and nerve conduction studies (NCS) over 1 year from first referral were studied. Secondarily, we compared the clinical and paraclinical characteristics, including nerve ultrasound, of patients who failed with those who fulfilled the criteria in order to identify clinically relevant differences., Results: At 1 year, 182 (89.7%) patients fulfilled the criteria (156/76.9% definite, 22/10.8% probable, and 4/2% possible). Twenty-one (10.3%) patients did not because the electrodiagnostic criteria remained negative. These still showed signs of demyelination but did not reach the cut-off values. They also presented typical, albeit less pronounced, multifocal nerve enlargement in ultrasonography. Mean disability at presentation and 1 year after was significantly lower. Most importantly, a relevant proportion of these patients also responded to therapy (6/21 = 28.6% vs. 82/182 = 45.3% of those fulfilling the criteria)., Interpretation: CIDP diagnosis could be established for 89.7% of patients over the course of 1 year using EFNS/PNS criteria. The remaining patients (10.3%) presented with milder disability, less accentuated demyelination, but otherwise similar characteristics and still considerable probability of treatment response. Failure to fulfill diagnostic criteria should not automatically preclude treatment. Nerve ultrasound should be considered as a complementary diagnostic tool to detect signs of inflammation in CIDP., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Purpose: We evaluated muscle echointensity as a marker for secondary axonal damage in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) using ultrasonography. Findings were correlated with clinical disability and muscular strength., Methods: Eighty patients with CIDP (40 with typical and 40 with atypical CIDP) were examined clinically, including assessment of Medical Research Council (MRC) sum score and Inflammatory Neuropathy Cause and Treatment Overall Disability Sum Score (INCAT-ODSS). Echointensity in eight proximal and distal muscles of the arms and legs was evaluated by muscle ultrasonography using the Heckmatt scale., Results: Alterations of echointensity occurred most frequently in the distal leg muscles, with a median (range) Heckmatt score of 1.5 (1-4). There were no differences between typical and atypical CIDP patients with regard to Heckmatt score. Alterations of echointensity correlated to disability and muscle strength. The arm score of the INCAT-ODSS correlated to Heckmatt score for the distal arm muscles (r = 0.23, p = 0.046) and the leg score of the INCAT-ODSS correlated to Heckmatt scores for the proximal (r = 0.34, p = 0.002) and distal leg muscles (r = 0.33, p = 0.004). MRC sum score, as well as individual MRC scores for arm and leg muscles, correlated to Heckmatt scores of the corresponding muscle groups (r = -0.25, p = 0.02 for MRC sum score)., Conclusion: Increased muscle echointensity, reflecting fibrosis and fatty infiltration due to secondary axonal damage, correlated to muscular strength and disability in a large cohort of CIDP patients. Alterations of echointensity occur in both typical and atypical CIDP patients and are pronounced in the distal leg muscles., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Up to 20% of patients with chronic immune-mediated sensorimotor neuropathies (CIN) do not respond adequately to first-line therapies. However, studies on further treatment are scarce., Methods: We analyzed retrospectively 200 CIN patients regarding disease characteristics and response to therapy with cyclophosphamide (CYP), rituximab (RTX), and bortezomib (BTZ). Treatment response was defined as improvement or stabilization of inflammatory neuropathy cause and treatment overall disability score (INCAT-ODSS)., Results: A total of 48 of 181 patients (26.5%) received therapy with CYP, RTX, or BTZ. The most frequently and first used therapy was CYP (69%). More than 40% of patients needed a second or third treatment. Overall, 71 treatments were applied in 48 patients. The combination of up to all three treatments enhanced the response-rate to 90%. Treatment within 24 months after initial diagnosis resulted in significantly higher response rate than late treatment (79% versus 50 %, p  = 0.04, χ 2 -test, n  = 46) and in lower disability in long-term follow up (INCAT-ODSS 3.8 versus 5.8, p  = 0.02, t -test, n  = 48). Patients with Lewis-Sumner syndrome ( n  = 9) and autoantibody mediated neuropathies ( n  = 13) had excellent response rates after treatment with RTX (90-100%). In contrast, typical chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) showed a response rate of 64% in CYP, 64% in RTX, and 75% in BTZ., Conclusion: Treatment with CYP, RTX, or BTZ was effective in this cohort of CIN refractory to first-line treatment. Our data increase evidence for an early use of these therapies. High efficacy of RTX in Lewis-Sumner syndrome in contrast to typical CIDP suggests a distinct pathophysiology., Competing Interests: Conflict of interest statement: Jeremias Motte: received travel grants from Biogen idec, Novartis AG, Teva, and Eisai GmbH, his research is funded by Klaus Tschira Foundation and Ruhr-University, Bochum (FoRUM-program); none related to this work. Anna Lena Fisse: received research funding by Georgius Agricola Stiftung Ruhr and Ruhr-University, Bochum (FoRUM-program), received honoraria and travel grants from Novartis AG, Sanofi, and Eisai GmbH, none related to this work. Owns shares of Fresenius SE & Co., Gilead Sciences, Medtronic PLC, and Novartis AG. Nuray Köse: none Thomas Grüter: received travel reimbursement from Sanofi Genzyme and Biogen Idec, none related to this manuscript. Hannah Mork: none Diamantis Athanasopoulos: none Miriam Fels: none Susanne Otto: none Ines Siglienti: none Christiane Schneider-Gold: has received a FoRUM grant (F 701-2010) from the Ruhr-University of Bochum and consulting and speaker’s honoraria from Alexion Pharmaceuticals, Amicus Therapeutics, Bayer Schering, CSL Behring, Grünenthal, Lupin Pharmaceuticals, and TEVA. Kerstin Hellwig: Received speaker honoraria, consultancy fees and research support from Bayer Healthcare, Biogen, Novartis, Merck, Teva, and Roche. Min-Suk Yoon has received speaker honoraria from CSL Behring and Grifols, a scientific grant from CSL Behring, none related to this manuscript. Ralf Gold: Serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Novartis; serves as editor for Therapeutic Advances in Neurological Diseases and on the editorial boards of Experimental Neurology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis, none related to this manuscript. Because this author is the Editor-in-Chief of Therapeutic Advances in Neurological Disorders, the peer review process was managed by alternative members of the Board and the submitting Editor was not involved in the decision-making process. Kalliopi Pitarokoili: received travel funding and speaker honoraria from Biogen Idec, Novartis and Bayer Schering Pharma and funding from the Ruhr-University, Bochum (FORUM-Program), none related to this work., (© The Author(s), 2021.)

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the most common chronic inflammatory neuropathy. CIDP is diagnosed according to the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria, which combine clinical features with the electrophysiological evidence of demyelination. However, firstly, diagnosis is challenging, as some patients e.g. with severe early axonal damage do not fulfil the criteria. Secondly, objective and reliable tools to monitor the disease course are lacking. Thirdly, about 25% of CIDP patients do not respond to evidence-based first-line therapy. Recognition of these patients is difficult and treatment beyond first-line therapy is based on observational studies and case series only. Individualized immunomodulatory treatment does not exist due to the lack of understanding of essential aspects of the underlying pathophysiology. Novel diagnostic imaging techniques and molecular approaches can help to solve these problems but do not find enough implementation. This review gives a comprehensive overview of novel diagnostic techniques and monitoring approaches for CIDP and how these can lead to individualized treatment and better understanding of pathophysiology., Competing Interests: Competing interestsThe authors declare that they have no competing interest., (© The Author(s) 2020.)

Purpose: This study aimed at evaluating whether removal of the ureteral stent the day before scheduled secondary intervention facilitates spontaneous ureteral stone passage and thus can spare the pre-stented patient this surgery., Methods: Retrospective analysis of a single-centre consecutive series of 216 patients after previous stenting due to a symptomatic ureteral stone from 01/2013 to 01/2018. Indwelling stents were removed under local anaesthesia. Patients were told to filter their urine overnight. Multivariate analysis was performed to assess predictive factors for spontaneous stone passage., Results: 34% (74/216) of patients had spontaneous stone passage while the stent was indwelling. Of the remaining 142 patients, 41% (58/142) had spontaneous stone passage within 24 h after stent removal. Only 84/216 (39%) patients needed secondary intervention. Multivariate logistic regression analysis of all 216 patients showed a significant association between spontaneous stone passage and smaller stone size (p < 0.001), distal stone location (p = 0.046) and stent dwell time (p = 0.02). Predictive factors for spontaneous stone passage after stent removal were smaller size (p < 0.001), distal location (p = 0.001), and stone movement while the stent was indwelling (p = 0.016). A treatment strategy was established that helps select patients suitable for conservative management., Conclusions: The majority (61%) of ureteral stones passed spontaneously after pre-stenting; 34% while the stent was indwelling, 27% within 24 h after stent removal. Besides distal stone location, stone size (< 6 mm) and stone movement (≥ 5 cm) while the stent is indwelling indicate patients who are likely to pass their ureteral stone spontaneously after stent removal. The treatment strategy (decision tree) presented here helps identify those patients., Trial Registration: https://doi.org/10.1186/ISRCTN12112914 .

Objective: To determine the prevalence of antibodies to Epstein-Barr virus (EBV) in a large cohort of patients with early multiple sclerosis (MS)., Methods: Serum samples were collected from 901 patients with a clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS) participating in the German National MS cohort, a prospective cohort of patients with early MS with stringent inclusion criteria. Epstein-Barr nuclear antigen (EBNA)-1 and viral capsid antigen (VCA) antibodies were measured in diluted sera by chemiluminescence immunoassays (CLIAs). Sera of EBNA-1 and VCA antibody-negative patients were retested undiluted by an EBV IgG immunoblot. For comparison, we retrospectively analysed the EBV seroprevalence across different age cohorts, ranging from 0 to >80 years, in a large hospital population (N=16 163) from Berlin/Northern Germany., Results: EBNA-1 antibodies were detected by CLIA in 839 of 901 patients with CIS/RRMS. Of the 62 patients without EBNA-1 antibodies, 45 had antibodies to VCA as detected by CLIA. In all of the remaining 17 patients, antibodies to EBV were detected by immunoblot. Altogether, 901 of 901 (100%) patients with CIS/RRMS were EBV-seropositive. EBV seropositivity increased with age in the hospital population but did not reach 100% in any of the investigated age cohorts., Conclusion: The complete EBV seropositivity in this large cohort of patients with early MS strengthens the evidence for a role of EBV in MS. It also suggests that a negative EBV serology in patients with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS., Competing Interests: Competing interests: SA reports no disclosures. BE reports no disclosures. M-MH received travel expenses from Bayer Health Care and honoraria for an advisory board from Merck Serono GmbH. LA reports no disclosures. FL serves as an advisory board member for Roche Pharma and has received travel grants from Teva Pharma. SG reports no disclosures. LK received compensation for serving on scientific advisory boards (Genzyme, Novartis Pharma); speaker honoraria and travel support (CSL Behring, Merck Serono, Roche, Novartis Pharma); research support (Biogen, Novartis Pharma). SGM receives honoraria for lecturing, and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Bundesinstitut für Risikobewertung (BfR), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, Gemeinsamer Bundesausschuss (G-BA), German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology and Alexion, Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, HERZ Burgdorf, Merck Serono, Novartis, ONO Pharma, Roche, and Teva.CS reports no disclosures.TG received travel reimbursement from Biogen Idec; not related to this work. BT received personal speaker honoraria and consultancy fees as a speaker and advisor from Bayer Healthcare, Biogen, CSL Behring, GRIFOLS, Merck Serono, Novartis, Octapharma, Roche, Sanofi Genzyme, TEVA und UCB Pharma. His University received unrestricted research grants from Biogen-idec, Novartis, TEVA, Bayer Healthcare, CSL-Behring, GRIFOLS, Octapharma, Sanofi Genzyme und UCB Pharma; none related to this work.FP serves on the scientific advisory board for Novartis; received speaker honoraria and travel funding from Bayer, Novartis, Biogen Idec, Teva, Sanofi-Aventis/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, and Shire; is an academic editor for PLoS ONE; is an associate editor for Neurology® Neuroimmunology & Neuroinflammation; consulted for SanofiGenzyme, Biogen Idec, MedImmune, Shire, and Alexion; and received research support from Bayer, Novartis, Biogen Idec, Teva, Sanofi-Aventis/Genzyme, Alexion, Merck Serono, German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin, EU FP7 Framework Program, Guthy Jackson Charitable Foundation, and National Multiple Sclerosis of the USA; none related to this work. FTB received personal compensation for speaking and attending advisory boards from Actelion, Bayer, Biogen, Genzyme, Merck, Novartis, Teva and Roche; financial support, through his institution, to attend scientific meetings or for investigator initiated studies from Actelion, Bayer, Biogen, Genzyme, Merck, Novartis and Teva. TK received travel expenses and personal compensations from Bayer Healthcare, Teva Pharma, Merck-Serono, Novartis, Sanofi-Aventis/Genzyme, Roche and Biogen, as well as grant support from Bayer-Schering AG, Novartis and Chugai Pharma; and none related to this work. FW received honoraria from Genzyme, Novartis, TEVA, Bayer and Biogen for speaking or for serving on a scientific advisory board, a travel grant for the attention of a scientific meeting from Merck-Serono and Novartis and grant support from Merck-Serono, Novartis and from the Federal Ministry of Education and Research (BMBF, Projects Biobanking and Omics in ControlMS as part of the Competence Network Multiple Sclerosis). MS received honoraria for scientific lectures or consultancy from Bayer Healthcare, Biogen, Baxter/Baxalta, CSL Behring, Euroimmune, Grifols, Merck-Serono, Novartis, Roche, Sanofi-Aventis, and Teva. His institution received research support from Bayer Healthcare, Biogen Idec, Genzyme, Merck-Serono, Novartis, and Teva; and none related to this work. AB received personal compensation from Merck Serono, Biogen, Bayer, Novartis, TEVA, Roche, Sanofi/Genzyme, Celgene, Alexion and grants for congress trips and participation from Biogen, TEVA, Novartis, Sanofi/Genzyme, Merck Serono, Celgene; none related to this work. BW reports grants from Deutsche Forschungsgemeinschaft, grants from Bundesministerium für Forschung und Technologie, grants from Dietmar Hopp Stiftung, grants from Klaus Tschira Stiftung, grants and personal fees from Merck Serono, personal fees from Biogen, personal fees from Bayer Healthcare, personal fees from TEVA, grants and personal fees from Novartis, grants and personal fees from Sanofi Genzyme, personal fees from Roche, outside the submitted work. CH received research grants and speaker honoraria from Biogen, Genzyme, Roche, and Merck; none related to this work. UKZ received speaker fees from Aventis, Almirall, Biogen, Bayer, Merck, Novartis, Roche, and Teva. CW has received institutional fees for consultancy, speaking, or research from Novartis, Biogen, Sanofi-Genzyme and Roche. GA reports no disclosures.NH reports no disclosures.HW receives honoraria for acting as a member of scientific advisory boards and as a consultant for Biogen, Evgen, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, as well as speaker honoraria and travel support from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche Ltd, Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, TEVA, and WebMD Global. Professor Wiendl is acting as a paid consultant for Abbvie, Actelion, Biogen, IGES, Novartis, Roche, Sanofi-Genzyme, and the Swiss Multiple Sclerosis Society. His research is funded by the BMBF, DFG, Else Kröner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children’s Foundation, Biogen GmbH, GlaxoSmithKline GmbH, and Roche Pharma AG, Sanofi-Genzyme. SB has received honoria and compensation for travel from Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme and Roche. BH served on scientific advisory boards for F. Hoffmann-La Roche Ltd, Novartis, Bayer AG, and Genentech; he has served as DMSC member for Allergy Care and TG Therapeutics; he or his institution have received speaker honoraria from Biogen Idec, Teva Neuroscience, Merck Serono, Medimmune, Novartis, Desitin, and F. Hoffmann-La Roche Ltd; his institution has received research support from Chugai Pharmaceuticals; holds part of two patents; one for the detection of antibodies and T cells against KIR4.1 in a subpopulation of patients with MS and one for genetic determinants of neutralizing antibodies to interferon β during the last 3 years. RG serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd, Biogen Idec, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Novartis; serves as editor for Therapeutic Advances in Neurological Diseases and on the editorial boards of Experimental Neurology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis; none related to this work. AS received speaker honoraria and/or travel compensation for activities with Almirall Hermal GmbH, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme; none related to this work. KR received research support from Novartis, Merck Serono, German Ministry of Education and Research, European Union, Stiftung Charité (BIH Clinical Fellow), Arthur Arnstein Stiftung Berlin, as well as speaking fees and travel grants from Bayer Healthcare, Biogen Idec, Merck Serono, Sanofi-Aventis/Genzyme, Teva Pharmaceuticals, Roche, Novartis, and Guthy Jackson Charitable Foundation., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)