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International audience; Abstract The term ‘neuromyelitis optica spectrum disorders’ (NMOSD) is used as an umbrella term that refers to aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica (NMO) and its formes frustes and to a number of closely related clinical syndromes without AQP4-IgG. NMOSD were originally considered subvariants of multiple sclerosis (MS) but are now widely recognized as disorders in their own right that are distinct from MS with regard to immunopathogenesis, clinical presentation, optimum treatment, and prognosis. In part 1 of this two-part article series, which ties in with our 2014 recommendations, the neuromyelitis optica study group (NEMOS) gives updated recommendations on the diagnosis and differential diagnosis of NMOSD. A key focus is on differentiating NMOSD from MS and from myelin oligodendrocyte glycoprotein antibody-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD), which shares significant similarity with NMOSD with regard to clinical and, partly, radiological presentation, but is a pathogenetically distinct disease. In part 2, we provide updated recommendations on the treatment of NMOSD, covering all newly approved drugs as well as established treatment options.

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]

Supplemental material, sj-docx-1-msj-10.1177_13524585231172145 for Attack adjudication in neuromyelitis optica spectrum disorder: Substantiation of criteria by magnetic resonance imaging and biomarkers in N-MOmentum by Brian G Weinshenker, Dean M Wingerchuk, Ari J Green, Jeffrey L Bennett, Ho Jin Kim, Sean J Pittock, Kazuo Fujihara, Friedemann Paul, Gary Cutter, Romain Marignier, Orhan Aktas, Hans-Peter Hartung, Dewei She, Michael Smith, William Rees, Kristina Patterson, Daniel Cimbora, Eliezer Katz and Bruce AC Cree in Multiple Sclerosis Journal

Additional file 3: Table S3. Exclusion criteria and additional information of included studies.

Supplemental material, sj-docx-1-msj-10.1177_13524585231184738 for Intravenous immunoglobulin treatment for acute attacks in myelin oligodendrocyte glycoprotein antibody disease by Itay Lotan, John J Chen, Yael Hacohen, Omar Abdel-Mannan, Sara Mariotto, Saif Huda, Emily Gibbons, Adi Wilf-Yarkoni, Mark A Hellmann, Hadas Stiebel-Kalish, Sean J Pittock, Eoin P Flanagan, Negar Molazadeh, Monique Anderson, Rebecca Salky, Gabriela Romanow, Patrick Schindler, Ankelien Solveig Duchow, Friedemann Paul and Michael Levy in Multiple Sclerosis Journal

Additional file 2: Table S2. Summary of fields of view and dimensions used to define retinal regions in included studies.

Additional file 1: Table S1. OCT-A metrics and regions assessed in the included studies with term definitions.

Supplemental material, sj-docx-1-msj-10.1177_13524585231151212 for Cognition in patients with neuromyelitis optica spectrum disorders: A prospective multicentre study of 217 patients (CogniNMO-Study) by Martin W Hümmert, Carlotta Stern, Friedemann Paul, Ankelien Duchow, Judith Bellmann-Strobl, Ilya Ayzenberg, Carolin Schwake, Ingo Kleiter, Kerstin Hellwig, Sven Jarius, Brigitte Wildemann, Makbule Senel, Achim Berthele, Katrin Giglhuber, Felix Luessi, Matthias Grothe, Luisa Klotz, Rasmus Schülke, Stefan Gingele, Jürgen H Faiss, Annette Walter, Clemens Warnke, Florian Then Bergh, Orhan Aktas, Marius Ringelstein, Jan-Patrick Stellmann, Vivien Häußler, Joachim Havla, Hannah Pellkofer, Tania Kümpfel, Bruno Kopp and Corinna Trebst in Multiple Sclerosis Journal

Supplemental material, sj-docx-1-msj-10.1177_13524585231184738 for Intravenous immunoglobulin treatment for acute attacks in myelin oligodendrocyte glycoprotein antibody disease by Itay Lotan, John J Chen, Yael Hacohen, Omar Abdel-Mannan, Sara Mariotto, Saif Huda, Emily Gibbons, Adi Wilf-Yarkoni, Mark A Hellmann, Hadas Stiebel-Kalish, Sean J Pittock, Eoin P Flanagan, Negar Molazadeh, Monique Anderson, Rebecca Salky, Gabriela Romanow, Patrick Schindler, Ankelien Solveig Duchow, Friedemann Paul and Michael Levy in Multiple Sclerosis Journal

Additional file 4: Table S2: Spearman correlation analysis with and without rituximab intervention in the NMOSD group. n.s.: not significant; *: p < 0.01.

Supplemental material, sj-docx-1-msj-10.1177_13524585231151212 for Cognition in patients with neuromyelitis optica spectrum disorders: A prospective multicentre study of 217 patients (CogniNMO-Study) by Martin W Hümmert, Carlotta Stern, Friedemann Paul, Ankelien Duchow, Judith Bellmann-Strobl, Ilya Ayzenberg, Carolin Schwake, Ingo Kleiter, Kerstin Hellwig, Sven Jarius, Brigitte Wildemann, Makbule Senel, Achim Berthele, Katrin Giglhuber, Felix Luessi, Matthias Grothe, Luisa Klotz, Rasmus Schülke, Stefan Gingele, Jürgen H Faiss, Annette Walter, Clemens Warnke, Florian Then Bergh, Orhan Aktas, Marius Ringelstein, Jan-Patrick Stellmann, Vivien Häußler, Joachim Havla, Hannah Pellkofer, Tania Kümpfel, Bruno Kopp and Corinna Trebst in Multiple Sclerosis Journal

Additional file 1: Figure S1. The gating strategy in the NK/NKT panel of this study. After excluding doublet cells, lymphocyte subsets were extracted using FSCs and SSCs. Next, dead cells were excluded by Live/Dead staining, and nucleated cells were gated with CD45. After using CD3 and CD14, a subset of CD3-positive CD14-negative CD56-positive cells was defined as NKT cells and a subset of CD3-negative CD14-negative CD56-positive cells as NK cells for downstream analysis. For each subset, We analyzed CD16-positive, CD35-positive, CD88-positive, CD69-positive, and CD83-positive rates; for NKT cells, we also analyzed TCR Vα24-positive rates.

Background: Multiple sclerosis (MS) is one of the most prevalent chronic inflammatory diseases caused by demyelination and axonal damage in the central nervous system. Structural retinal imaging via optical coherence tomography (OCT) shows promise as a noninvasive biomarker for monitoring of MS. There are successful reports regarding the application of Artificial Intelligence (AI) in the analysis of cross-sectional OCTs in ophthalmologic diseases. However, the alteration of sub-retinal thicknesses in MS is noticeably subtle compared to other ophthalmologic diseases. Therefore, raw cross-sectional OCTs are replaced with multilayer segmented OCTs for discrimination of MS and healthy controls (HCs). Methods: To conform to the principles of trustworthy AI, interpretability is provided by visualizing the regional layer contribution to classification performance with the proposed occlusion sensitivity approach. The robustness of the classification is also guaranteed by showing the effectiveness of the algorithm while being tested on the new independent dataset. The most discriminative features from different topologies of the multilayer segmented OCTs are selected by the dimension reduction method. Support vector machine (SVM), random forest (RF), and artificial neural network (ANN) are used for classification. Patient-wise cross-validation (CV) is utilized to evaluate the performance of the algorithm, where the training and test folds contain records from different subjects. Results: The most discriminative topology is determined to square with a size of 40 pixels and the most influential sub-retinal layers are the ganglion cell and inner plexiform layer (GCIPL) and inner nuclear layer (INL). Linear SVM resulted in 88% Accuracy (with standard deviation (std) = 0.49 in 10 times of execution to indicate the repeatability), 78% precision (std=1.48), and 63% recall (std=1.35) in the discrimination of MS and HCs using macular multilayer segmented OCTs. Conclusion: The proposed classification algorithm is expected to help neurologists in the early diagnosis of MS. This paper distinguishes itself from other studies by employing two distinct datasets, which enhances the robustness of its findings in comparison with previous studies with lack of external validation. This study aims to circumvent the utilization of deep learning methods due to the limited quantity of the available data and convincingly demonstrates that favorable outcomes can be achieved without relying on deep learning techniques.

Additional file 3: Table S1: Spearman correlation analysis for the NMOSD group between the parameters. n.s.: not significant; *: p < 0.05; **: p < 0.01; ***: p < 0.001; ****: p < 0.0001.

Additional file 2: Figure S2. Analysis of TCR Vα24-Jα18-positive NKT cells. The downstream analysis of NKT cells with TCR Vα24-Jα18-positive gating among the NMOSD group showed significantly higher CD83 expression against the Normal Control group (D).

ZusammenfassungDer Nachweis von Autoantikörpern gegen Nerven- oder Gliazellen ermöglicht heute bei zahlreichen neurologischen und psychiatrischen Symptomkomplexen die frühe und spezifische Diagnose einer Autoimmunenzephalitis. Damit hat sich auch die Herangehensweise an die immuntherapeutische Behandlung dieser Krankheitsgruppe fundamental verändert, ebenso wie das Verständnis der zugrunde liegenden Pathophysiologie und der auslösenden Faktoren. Die noch immer wachsende Zahl neuer Autoantikörper erfordert ein regelmäßiges Update über den Stand der Antikörperdiagnostik, die Häufigkeit assoziierter Tumoren sowie das antikörperspezifische Spektrum klinischer Symptome, die von Wesensänderungen und kognitiven Störungen über epileptische Anfälle und Bewegungsstörungen bis hin zu vegetativen und Bewusstseinsstörungen führen. Der Beitrag fasst die aktuellen Neuerungen zusammen, die sich im klinischen Spektrum von Enzephalitiden, in der bildgebenden und Liquordiagnostik, in der Prognoseabschätzung, in der Etablierung innovativer Immuntherapien, in der Anwendung diagnostischer Pfade bereits vor dem Eintreffen des Antikörperbefundes und im Verständnis der Krankheitsentstehung ergeben.

BackgroundInebilizumab is an anti-CD19 antibody approved for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults with aquaporin-4 autoantibodies. The relationship between B-cell, plasma-cell (PC), and immunoglobulin depletion with longitudinal reductions in NMOSD activity after inebilizumab treatment was characterised post hoc in an exploratory analysis from the N-MOmentum study (NCT02200770).MethodsPeripheral blood CD20+ B cells, PC gene signature, and immunoglobulin levels were assessed throughout N-MOmentum (follow-up ≥2.5 years); correlations with clinical metrics and magnetic resonance imaging (MRI) lesion activity were assessed.FindingsInebilizumab induced durable B-cell and PC depletion within 1 week versus placebo. Although no association was observed between B-cell counts at time of attack and NMOSD activity, depth of B-cell depletion after the first dosing period correlated with clinical outcomes. All participants receiving inebilizumab demonstrated a robust long-term therapeutic response, and participants with ≤4cells/μL after the first 6-month dosing interval had persistently deeper B-cell depletion, lower annualised attack rates (estimated rate [95% CI]: 0.034 [0.024-0.04] vs 0.086 [0.056-0.12]; p=0.045), fewer new/enlarging T2 MRI lesions (0.49 [0.43-0.56] vs 1.36 [1.12-1.61]; p&nbsp

Background:Spectral-domain (SD-) optical coherence tomography (OCT) can reliably measure axonal (peripapillary retinal nerve fiber layer [pRNFL]) and neuronal (macular ganglion cell + inner plexiform layer [GCIPL]) thinning in the retina. Measurements from 2 commonly used SD-OCT devices are often pooled together in multiple sclerosis (MS) studies and clinical trials despite software and segmentation algorithm differences; however, individual pRNFL and GCIPL thickness measurements are not interchangeable between devices. In some circumstances, such as in the absence of a consistent OCT segmentation algorithm across platforms, a conversion equation to transform measurements between devices may be useful to facilitate pooling of data. The availability of normative data for SD-OCT measurements is limited by the lack of a large representative world-wide sample across various ages and ethnicities. Larger international studies that evaluate the effects of age, sex, and race/ethnicity on SD-OCT measurements in healthy control participants are needed to provide normative values that reflect these demographic subgroups to provide comparisons to MS retinal degeneration.Methods:Participants were part of an 11-site collaboration within the International Multiple Sclerosis Visual System (IMSVISUAL) consortium. SD-OCT was performed by a trained technician for healthy control subjects using Spectralis or Cirrus SD-OCT devices. Peripapillary pRNFL and GCIPL thicknesses were measured on one or both devices. Automated segmentation protocols, in conjunction with manual inspection and correction of lines delineating retinal layers, were used. A conversion equation was developed using structural equation modeling, accounting for clustering, with healthy control data from one site where participants were scanned on both devices on the same day. Normative values were evaluated, with the entire cohort, for pRNFL and GCIPL thicknesses for each decade of age, by sex, and across racial groups using generalized estimating equation (GEE) models, accounting for clustering and adjusting for within-patient, intereye correlations. Change-point analyses were performed to determine at what age pRNFL and GCIPL thicknesses exhibit accelerated rates of decline.Results:The healthy control cohort (n = 546) was 54% male and had a wide distribution of ages, ranging from 18 to 87 years, with a mean (SD) age of 39.3 (14.6) years. Based on 346 control participants at a single site, the conversion equation for pRNFL was Cirrus = -5.0 + (1.0 × Spectralis global value). Based on 228 controls, the equation for GCIPL was Cirrus = -4.5 + (0.9 × Spectralis global value). Standard error was 0.02 for both equations. After the age of 40 years, there was a decline of -2.4 m per decade in pRNFL thickness (P < 0.001, GEE models adjusting for sex, race, and country) and -1.4 m per decade in GCIPL thickness (P < 0.001). There was a small difference in pRNFL thickness based on sex, with female participants having slightly higher thickness (2.6 m, P = 0.003). There was no association between GCIPL thickness and sex. Likewise, there was no association between race/ethnicity and pRNFL or GCIPL thicknesses.Conclusions:A conversion factor may be required when using data that are derived between different SD-OCT platforms in clinical trials and observational studies; this is particularly true for smaller cross-sectional studies or when a consistent segmentation algorithm is not available. The above conversion equations can be used when pooling data from Spectralis and Cirrus SD-OCT devices for pRNFL and GCIPL thicknesses. A faster decline in retinal thickness may occur after the age of 40 years, even in the absence of significant differences across racial groups.

Background: White matter lesions (WMLs) on brain magnetic resonance imaging (MRI) in multiple sclerosis (MS) may contribute to misdiagnosis. In chronic active lesions, peripheral iron-laden macrophages appear as paramagnetic rim lesions (PRLs). Objective: To evaluate the sensitivity and specificity of PRLs in differentiating MS from mimics using clinical 3T MRI scanners. Method: This retrospective international study reviewed MRI scans of patients with MS ( n = 254), MS mimics ( n = 91) and older healthy controls ( n = 217). WMLs, detected using fluid-attenuated inversion recovery MRI, were analysed with phase-sensitive imaging. Sensitivity and specificity were assessed for PRLs. Results: At least one PRL was found in 22.9% of MS and 26.1% of clinically isolated syndrome (CIS) patients. Only one PRL was found elsewhere. The identification of ⩾1 PRL was the optimal cut-off and had high specificity (99.7%, confidence interval (CI) = 98.20%–99.99%) when distinguishing MS and CIS from mimics and healthy controls, but lower sensitivity (24.0%, CI = 18.9%–36.6%). All patients with a PRL showing a central vein sign (CVS) in the same lesion ( n = 54) had MS or CIS, giving a specificity of 100% (CI = 98.8%–100.0%) but equally low sensitivity (21.3%, CI = 16.4%–26.81%) Conclusion: PRLs may reduce diagnostic uncertainty in MS by being a highly specific imaging diagnostic biomarker, especially when used in conjunction with the CVS.

Background: White matter lesions (WMLs) on brain magnetic resonance imaging (MRI) in multiple sclerosis (MS) may contribute to misdiagnosis. In chronic active lesions, peripheral iron-laden macrophages appear as paramagnetic rim lesions (PRLs). Objective: To evaluate the sensitivity and specificity of PRLs in differentiating MS from mimics using clinical 3T MRI scanners. Method: This retrospective international study reviewed MRI scans of patients with MS (n = 254), MS mimics (n = 91) and older healthy controls (n = 217). WMLs, detected using fluid-attenuated inversion recovery MRI, were analysed with phase-sensitive imaging. Sensitivity and specificity were assessed for PRLs. Results: At least one PRL was found in 22.9% of MS and 26.1% of clinically isolated syndrome (CIS) patients. Only one PRL was found elsewhere. The identification of ⩾1 PRL was the optimal cut-off and had high specificity (99.7%, confidence interval (CI) = 98.20%–99.99%) when distinguishing MS and CIS from mimics and healthy controls, but lower sensitivity (24.0%, CI = 18.9%–36.6%). All patients with a PRL showing a central vein sign (CVS) in the same lesion (n = 54) had MS or CIS, giving a specificity of 100% (CI = 98.8%–100.0%) but equally low sensitivity (21.3%, CI = 16.4%–26.81%) Conclusion: PRLs may reduce diagnostic uncertainty in MS by being a highly specific imaging diagnostic biomarker, especially when used in conjunction with the CVS.

We aimed to evaluate SIGLEC1 (CD169) as a biomarker in multiple sclerosis (MS) and Neuromyelitis optica spectrum disorder (NMOSD) and to evaluate the presence of SIGLEC1(+) myeloid cells in demyelinating diseases. We performed flow cytometry-based measurements of SIGLEC1 expression on monocytes in 86 MS patients, 41 NMOSD patients and 31 healthy controls. Additionally, we histologically evaluated the presence of SIGLEC1(+) myeloid cells in acute and chronic MS brain lesions as well as other neurological diseases. We found elevated SIGLEC1 expression in 16/86 (18.6%) MS patients and 4/41 (9.8%) NMOSD patients. Almost all MS patients with high SIGLEC1 levels received exogenous interferon beta as an immunomodulatory treatment and only a small fraction of MS patients without interferon treatment had increased SIGLEC1 expression. In our cohort, SIGLEC1 expression on monocytes was—apart from those patients receiving interferon treatment - not significantly increased in patients with MS and NMOSD, nor were levels associated with more severe disease. SIGLEC1(+) myeloid cells were abundantly present in active MS lesions as well as in a range of acute infectious and malignant diseases of the central nervous system, but not chronic MS lesions. The presence of SIGLEC1(+) myeloid cells in brain lesions could be used to investigate the activity in an inflammatory CNS lesion.

Background: Optic neuritis (ON) is a frequent presentation of multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein-antibody disease (MOGAD) at onset. The pathophysiology underlying these diseases, especially MOGAD, is still being elucidated. While obesity has been reported to potentially be a risk factor for MS, this has not been explored in NMOSD or MOGAD. We aimed to investigate a possible association between obesity (body mass index [BMI] >30 kg/m²) and patients with MOGAD, NMOSD or MS. Methods: Multicenter non-interventional retrospective data collection from a first ever demyelinating attack of ON in patients subsequently diagnosed with MOGAD, NMOSD or MS between 2005-2020. The following data was collected: age, gender, ethnicity, BMI at disease onset and the etiology of ON after diagnostic work-up. A mixed model analysis was performed to assess the ability of obesity or BMI to predict MOGAD-ON and distinguish MOGAD-ON from NMOSD- and MS-ON. Main outcome measures included BMI in patients with acute ON and subsequent diagnosis of MOGAD, NMOSD or MS. Results: One-hundred and eighty-three patients were included: 44 with MOGAD, 49 with NMOSD, and 90 with MS. A higher BMI was significantly associated with a diagnosis of MOGAD-ON (pConclusion: This study suggests an association between obesity and MOGAD. Our finding requires further exploration, but could have significant pathophysiologic implications if confirmed in larger prospective studies.

The visual system offers unparalleled precision in the assessment of neuroaxonal damage. With the majority of patients with multiple sclerosis (MS) experiencing afferent and efferent visual dysfunction, outcome measures capturing these deficits provide insight into neuroaxonal injury, even in those with minimal disability. Ideal for use in clinical trials, visual measures are generally inexpensive, accessible, and reproducible. Quantification of visual acuity, visual fields, visual quality of life, and electrophysiologic parameters allows assessment of function, whereas optical coherence tomography (OCT) provides reliable measures of the structural integrity of the anterior afferent visual pathway. The technology of oculomotor biometrics continues to advance, and discrete measures of fixation, smooth pursuit, and saccadic eye movement abnormalities are ready for inclusion in future trials of MS progression. Visual outcomes allow tracking of neuroaxonal injury and aid in distinguishing MS from diseases such as neuromyelitis optica spectrum disorder (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated diseases (MOGAD). OCT has also provided unique insights into pathophysiology, including the identification of foveal pitting in NMOSD, possibly from damage to Müller cells, which carry an abundance of aquaporin-4 channels. For some study designs, the cost-benefit ratio favors visual outcomes over more expensive MRI outcomes. With the next frontier of therapeutics focused on remyelination and neuroprotection, visual outcomes are likely to take center stage. As an international community of collaborative, committed, vision scientists, this review by the International MS Visual System Consortium (IMSVISUAL) outlines the quality standards, informatics, and framework needed to routinely incorporate vision outcomes into MS and NMOSD trials.

BackgroundPatients with anti-aquaporin-4 antibody seropositive (AQP4-IgG+) neuromyelitis optica spectrum disorders (NMOSDs) frequently suffer from optic neuritis (ON) leading to severe retinal neuroaxonal damage. Further, the relationship of this retinal damage to a primary astrocytopathy in NMOSD is uncertain. Primary astrocytopathy has been suggested to cause ON-independent retinal damage and contribute to changes particularly in the outer plexiform layer (OPL) and outer nuclear layer (ONL), as reported in some earlier studies. However, these were limited in their sample size and contradictory as to the localisation. This study assesses outer retinal layer changes using optical coherence tomography (OCT) in a multicentre cross-sectional cohort.Method197 patients who were AQP4-IgG+ and 32 myelin-oligodendrocyte-glycoprotein antibody seropositive (MOG-IgG+) patients were enrolled in this study along with 75 healthy controls. Participants underwent neurological examination and OCT with central postprocessing conducted at a single site.ResultsNo significant thinning of OPL (25.02±2.03 µm) or ONL (61.63±7.04 µm) were observed in patients who were AQP4-IgG+ compared with patients who were MOG-IgG+ with comparable neuroaxonal damage (OPL: 25.10±2.00 µm; ONL: 64.71±7.87 µm) or healthy controls (OPL: 24.58±1.64 µm; ONL: 63.59±5.78 µm). Eyes of patients who were AQP4-IgG+ (19.84±5.09 µm, p=0.027) and MOG-IgG+ (19.82±4.78 µm, p=0.004) with a history of ON showed parafoveal OPL thinning compared with healthy controls (20.99±5.14 µm); this was not observed elsewhere.ConclusionThe results suggest that outer retinal layer loss is not a consistent component of retinal astrocytic damage in AQP4-IgG+ NMOSD. Longitudinal studies are necessary to determine if OPL and ONL are damaged in late disease due to retrograde trans-synaptic axonal degeneration and whether outer retinal dysfunction occurs despite any measurable structural correlates.

OBJECTIVE Fatigue is a frequent and severe symptom in multiple sclerosis (MS), but its pathophysiological origin remains incompletely understood. We aimed to examine the predictive value of subcortical gray matter volumes for fatigue severity at disease onset and after four years by applying structural equation modeling (SEM). METHODS This multi-center cohort study included 601 treatment-naive MS patients after the first demyelinating event. All patients underwent a standardized 3T MRI protocol. A subgroup of 230 patients with available clinical follow-up data after four years was also analyzed. Associations of subcortical volumes (included into SEM) with MS-related fatigue were studied regarding their predictive value. In addition, subcortical regions that have a central role in the brain network (hubs) were determined through structural covariance network (SCN) analysis. RESULTS Predictive causal modeling identified volumes of the caudate (s [standardized path coefficient]=0.763, p=0.003 [left]; s=0.755, p=0.006 [right]), putamen (s=0.614, p=0.002 [left]; s=0.606, p=0.003 [right]) and pallidum (s=0.606, p=0.012 [left]; s=0.606, p=0.012 [right]) as prognostic factors for fatigue severity in the cross-sectional cohort. Moreover, the volume of the pons was additionally predictive for fatigue severity in the longitudinal cohort (s=0.605, p=0.013). In the SCN analysis, network hubs in patients with fatigue worsening were detected in the putamen (p=0.008 [left]; p=0.007 [right]) and pons (p=0.0001). INTERPRETATION We unveiled predictive associations of specific subcortical gray matter volumes with fatigue in an early and initially untreated MS cohort. The colocalization of these subcortical structures with network hubs suggests an early role of these brain regions in terms of fatigue evolution. This article is protected by copyright. All rights reserved.

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%)

Supplemental material, sj-docx-11-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-pdf-2-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-pdf-6-mso-10.1177_20552173221109770 for Prediction of high and low disease activity in early MS patients using multiple kernel learning identifies importance of lateral ventricle intensity by Claudia Chien, Moritz Seiler, Fabian Eitel, Tanja Schmitz-Hübsch, Friedemann Paul and Kerstin Ritter in Multiple Sclerosis Journal – Experimental, Translational and Clinical

Additional file 1. Table S1. Patient and subgroup characteristics.

Supplemental material, sj-docx-1-msj-10.1177_13524585221118677 for Paramagnetic rims are a promising diagnostic imaging biomarker in multiple sclerosis by Isobel Meaton, Amjad Altokhis, Christopher Martin Allen, Margareta A Clarke, Tim Sinnecker, Dominik Meier, Christian Enzinger, Massimiliano Calabrese, Nicola De Stefano, Alain Pitiot, Antonio Giorgio, Menno M Schoonheim, Friedemann Paul, Mikolaj A Pawlak, Reinhold Schmidt, Cristina Granziera, Ludwig Kappos, Xavier Montalban, Àlex Rovira, Jens Wuerfel and Nikos Evangelou in Multiple Sclerosis Journal

Supplemental material, sj-docx-4-mso-10.1177_20552173221109770 for Prediction of high and low disease activity in early MS patients using multiple kernel learning identifies importance of lateral ventricle intensity by Claudia Chien, Moritz Seiler, Fabian Eitel, Tanja Schmitz-Hübsch, Friedemann Paul and Kerstin Ritter in Multiple Sclerosis Journal – Experimental, Translational and Clinical

Additional file 1. Supplementary table 1. The titers of AQP4 and MOG antibodies.

Supplemental material, sj-docx-13-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Additional file 1: Table S1. Clinical parameters investigated for correlation with the reactive hyperemia index (RHI).

Supplemental material, sj-docx-5-mso-10.1177_20552173221109770 for Prediction of high and low disease activity in early MS patients using multiple kernel learning identifies importance of lateral ventricle intensity by Claudia Chien, Moritz Seiler, Fabian Eitel, Tanja Schmitz-Hübsch, Friedemann Paul and Kerstin Ritter in Multiple Sclerosis Journal – Experimental, Translational and Clinical

Supplemental material, sj-docx-12-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-17-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-18-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-19-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-1-msj-10.1177_13524585221118677 for Paramagnetic rims are a promising diagnostic imaging biomarker in multiple sclerosis by Isobel Meaton, Amjad Altokhis, Christopher Martin Allen, Margareta A Clarke, Tim Sinnecker, Dominik Meier, Christian Enzinger, Massimiliano Calabrese, Nicola De Stefano, Alain Pitiot, Antonio Giorgio, Menno M Schoonheim, Friedemann Paul, Mikolaj A Pawlak, Reinhold Schmidt, Cristina Granziera, Ludwig Kappos, Xavier Montalban, Àlex Rovira, Jens Wuerfel and Nikos Evangelou in Multiple Sclerosis Journal

Supplemental material, sj-docx-16-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-9-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-12-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-17-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-pdf-3-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-8-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-14-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-8-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal