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Elisabeth G Celius,1 Heidi Thompson,2 Maija Pontaga,3 Dawn Langdon,4 Alice Laroni,5 Stanca Potra,6 Trishna Bharadia,7 David Yeandle,8 Jane Shanahan,9 Pieter van Galen,10 Nektaria Alexandri,11 Jürg Kesselring12 1Deparment of Neurology, Oslo University Hospital and University of Oslo, Oslo, Norway; 2The Neurology Centre, Craigavon Area Hospital, Portadown, UK; 3MS in the 21st Century Steering Group, Riga, Latvia; 4Department of Psychology, Royal Holloway, University of London, London, UK; 5Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Italy and IRCCS Ospedale Policlinico San Martino, Genoa, Italy; 6Patient Member of the MS in the 21st Century Steering Group, Bucharest, Romania; 7Patient Member of the MS in the 21st Century Steering Group, Buckinghamshire, UK; 8Patient Member of the MS in the 21st Century Steering Group, Southampton, UK; 9Patient Member of the MS in the 21st Century Steering Group, Ascot, UK; 10Patient Member of the MS in the 21st Century Steering Group, Overijse, Belgium; 11Global Medical Affairs, Neurology and Immunology, Merck KGaA, Darmstadt, Germany; 12Department of Neurology & Neurorehabilitation, Kliniken Valens, Valens, SwitzerlandCorrespondence: Elisabeth G CeliusDepartment of Neurology, Oslo University Hospital, Rikshospitalet, Postboks 4950 Nydalen, Oslo 0424, NorwayTel +47 91 50 27 70Email uxelgu@ous-hf.noPurpose: Multiple sclerosis (MS) prognosis is often uncertain. This literature review considers patients’ understanding of, and perspectives on, MS progression to better comprehend the unmet needs of people with MS (PwMS), in order to improve treatment adherence and quality of life (QoL).Methods: Literature searches for peer-reviewed papers concerning patient perspectives on the progression of MS and comparable conditions, published between January 2000 and January 2020, were conducted.Results: Little qualitative evidence exists that examines PwMS’ perspectives on MS progression. The understanding and meaning ascribed to terms such as “disease progression” vary. Some PwMS find disease labels stigmatizing, confusing, and disconnected from reality. The lack of a clear definition of progression and discrepancies between PwMS and healthcare professional (HCP) perspectives may contribute to misunderstanding and poor communication. Patient descriptions of progression and relapses include symptoms in addition to those evaluated by standard severity and disability measures. Compared with HCPs, PwMS are still focused on relapse prevention but place higher priority on QoL and ascribe different relative importance to the causes of poor adherence to treatment plans. PwMS want to discuss progression and likely prognosis. Such communication needs to be personalized and delivered with sensitivity, at an appropriate time. Poor treatment adherence may arise from a lack of understanding and poor communication, particularly around treatment goals. The few studies that directly considered patient perspectives on the progression of comparable conditions supported and extended the perspectives of PwMS. Lack of adequate communication by HCPs was the most common theme.Conclusion: Patient perspectives on disease progression in MS and other chronic progressive conditions are under-investigated and under-reported. The limited evidence available highlights the importance of providing adequate information and effective HCP communication. While further studies are needed, the current evidence base offers information and insights that may help HCPs to enhance patient care, well-being, and treatment adherence.Keywords: multiple sclerosis, disease progression, patient engagement, shared decision-making, communication

Background: Genetic and clinical observations have indicated T cells are involved in MS pathology. There is little insight in how T cells are involved and whether or not these can be used as markers for MS. Objectives: Analysis of the gene expression profiles of circulating CD8+ T cells of MS patients compared to healthy controls. Methods: RNA from purified CD8+ T cells was sequenced and analyzed for differential gene expression. Pathway analyses of genes at several p-value cutoffs were performed to identify putative pathways involved. Results: We identified 36 genes with significant differential gene expression in MS patients. Four genes reached at least 2-fold differences in expression. The majority of differentially expressed genes was higher expressed in MS patients. Genes associated to MS in GWAS showed enrichment amongst the differentially expressed genes. We did not identify enrichment of specific pathways amongst the differentially expressed genes in MS patients. Conclusions: CD8+ T cells of MS patients show differential gene expression, with predominantly higher activity of genes in MS patients. We do not identify specific biological pathways in our study. More detailed analysis of CD8+ T cells and subtypes of these may increase understanding of how T cells are involved in MS. [ABSTRACT FROM AUTHOR]

Aim. This paper is a report of a study to examine the degree to which socio-demographic variables, clinical variables and health-related quality of life are related to perceptions of disease severity and changes in disease severity in patients with multiple sclerosis. Background. Studies have shown that patients with multiple sclerosis report lower quality of life than the general population. Method. Questionnaires measuring health-related quality of life and perceived multiple sclerosis severity were mailed twice, 1 year apart, in May/June of 2000 and 2001, (t1 and t2), to patients with confirmed multiple sclerosis in Oslo, Norway ( n = 502). Clinical data about disease onset and course were retrieved from the Oslo City Multiple Sclerosis Registry. Findings. Among the 313 (62·4%) people who responded at both times, those with primary progressive disease course reported higher perceived multiple sclerosis severity ( P < 0·001), more mental health problems ( P = 0·004) and lower physical functioning ( P < 0·001) than those with a relapsing remitting/secondary progressive disease course. Patients with primary progressive disease course reported higher mean scores for multiple sclerosis severity at t2 than at t1. Multivariate regression analysis showed that social functioning was the only factor with statistically significant relationships to perceived multiple sclerosis severity among all sub-domains of health-related quality of life or personal factors. However, physical impairment was also independently related to patients' ratings of changes in multiple sclerosis severity during the year and illness severity 1 year later. Conclusion. In addition to patients' physical impairment, healthcare workers should pay special attention to issues related to their social functioning. [ABSTRACT FROM AUTHOR]

Natalizumab (Tyasabri®) is the first monoclonal antibody approved for use in relapsing-remitting multiple sclerosis. Based on indirect comparison, it seems more effective than alternative drugs in terms of reductions in disability progression, relapse rate and increase in quality of life during the initial 2 years of treatment. The annual direct drug cost of natalizumab is approximately €25,500 compared with €12,800-13,500 for alternative drugs, and the budgetary implications make it important to compare the health benefit and the cost of treatment. However, the long-term effect on disability and quality of life is uncertain, and neither the effect as second-line monotherapy nor the effect compared with alternative treatments has been established. The manufacturer has calculated cost per quality-adjusted life year to €36,000-64,000 compared with alternative drugs and €46,500-76,000 compared with best supportive care. Two studies comparing cost per relapse avoided with other drugs have reached conflicting results. Given the high socioeconomic burden of multiple sclerosis, natalizumab may be cost effective from a societal perspective, however, the models used to reach this conclusion rest on several uncertain assumptions. [ABSTRACT FROM AUTHOR]

Objective: Toexplore the relationship between fatigue, sociodemographic and clinical variables in a population of patients with multiple sclerosis (MS). Rationale: There is a need to identify empirical relationships with possible antecedents of fatigue among patients with MS. Methods: A mailed questionnaire designed to survey sociodemographic variables and the Fatigue Severity Scale (FSS) was mailed to 502 individuals from the population of patients with definite MS in the city of Oslo. A total of 368 (73%) responded. Clinical data were collected from the Oslo City MS-Registry. Results: The prevalence of fatigue in this population was 60.1%. The FSS score showed a negative correlation with education (r=-0.15, P<0.01) and a positive correlation with age (r=0.20, P<0.001) and time since disease onset (r=0.11, P<0.05). When controlled for gender, level of education and time since disease onset, the data showed a positive relationship between fatigue and age (P<0.001) among patients with primary progressive (PP) disease. This relationship between age and fatigue was not found among patients with relapsing-remitting/secondary progressive (RR/SP) disease. Conclusion: The negative relationship between level of formal education (FE) and fatigue among individuals with RR/SP disease suggests that behavioral factors may be among the antecedents of fatigue in this patient group. In contrast to normative data from the general population, our findings revealed no differences in fatigue related to gender. Thus, this study supports the hypothesis that there are disease-specific antecedents of fatigue among patients with MS. [ABSTRACT FROM AUTHOR]

An abstract of the article "The SH2D2A Gene and Susceptibility to Multiple Sclerosis," is presented.

Background: Patient pathways (PPs) are presented as a panacea solution to enhance health system functions. It is a complex concept that needs to be described and communicated well. Modeling plays a crucial role in promoting communication, fostering a shared understanding, and streamlining processes. Only a few existing systematic reviews have focused on modeling methods and standardized modeling languages. There remains a gap in consolidated knowledge regarding the use of diverse visual modeling languages., Objective: This scoping review aimed to compile visual modeling languages used to represent PPs, including the justifications and the context in which a modeling language was adopted, adapted, combined, or developed., Methods: After initial experimentation with the keywords used to describe the concepts of PPs and visual modeling languages, we developed a search strategy that was further refined and customized to the major databases identified as topically relevant. In addition, we consulted gray literature and conducted hand searches of the referenced articles. Two reviewers independently screened the articles in 2 stages using preset inclusion criteria, and a third reviewer voted on the discordance. Data charting was done using an iteratively developed form in the Covidence software. Descriptive and thematic summaries were presented following rounds of discussion to produce the final report., Results: Of 1838 articles retrieved after deduplication, 22 satisfied our inclusion criteria. Clinical pathway is the most used phrase to represent the PP concept, and most papers discussed the concept without providing their operational definition. We categorized the visual modeling languages into five categories: (1) general purpose-modeling language (GPML) adopted without major extension or modification, (2) GPML used with formal extension recommendations, (3) combination of 2 or more modeling languages, (4) a developed domain-specific modeling language (DSML), and (5) ontological modeling languages. The justifications for adopting, adapting, combining, and developing visual modeling languages varied accordingly and ranged from versatility, expressiveness, tool support, and extensibility of a language to domain needs, integration, and simplification., Conclusions: Various visual modeling languages were used in PP modeling, each with varying levels of abstraction and granularity. The categorization we made could aid in a better understanding of the complex combination of PP and modeling languages. Standardized GPMLs were used with or without any modifications. The rationale to propose any modification to GPMLs evolved as more evidence was presented following requirement analyses to support domain constructs. DSMLs are infrequently used due to their resource-intensive development, often initiated at a project level. The justifications provided and the context where DSMLs were created are paramount. Future studies should assess the merits and demerits of using a visual modeling language to facilitate PP communications among stakeholders and use evaluation frameworks to identify, modify, or develop them, depending on the scope and goal of the modeling need., (©Binyam Bogale, Märt Vesinurm, Paul Lillrank, Elisabeth Gulowsen Celius, Ragnhild Halvorsrud. Originally published in the Interactive Journal of Medical Research (https://www.i-jmr.org/), 15.11.2024.)

During the COVID-19 pandemic, people with multiple sclerosis (MS) and their healthcare providers have faced unique challenges related to the interaction between SARS-CoV-2, underlying neurological disease and the use of disease-modifying treatments (DMTs). Key concerns arose, primarily related to the possibility that SARS-CoV-2 infection could trigger the initial demyelinating event or exacerbate disease activity. Another major concern was the safety and efficacy of the COVID-19 vaccines, especially for patients undergoing specific treatments that could weaken their antibody responses. In the post-infection phase, identifying long COVID in patients with MS has been complicated due to the large overlap between post-infection sequelae and MS symptoms. In addition, disruptions in health and rehabilitation services have made it difficult for MS patients to access care. This Series article explores current evidence on the interaction between MS and SARS-CoV-2, identifies the challenges posed by the COVID-19 pandemic in the care of patients with MS, and discusses the significant adoption of digital health solutions, including telemedicine and new technology-based rehabilitation approaches. Based on lessons learned, recommendations and future directions are offered for managing patients with MS, rethinking healthcare systems and improving health outcomes in the post-COVID-19 pandemic era., Competing Interests: LP has received personal fees and non-financial support from Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Viatris. GA has received compensation for consulting services, speaking honoraria or participation in advisory boards from Merck, Roche, and Horizon Therapeutics; travel support for scientific meetings from Novartis, Roche, ECTRIMS and EAN. She serves as editor for Europe of the Multiple Sclerosis Journal—Experimental, Translational and Clinical journal; and as a member of the editorial and scientific committee of Acta Neurológica Colombiana. She is a member of the International Women in Multiple Sclerosis (iWiMS) network executive committee, of the European Biomarkers in Multiple Sclerosis (BioMS-eu) steering committee, and of the MOGAD Eugene Devic European Network (MEDEN) steering group. EGC has received educational and/or consultancy fees from Alexion, Almirall, Biogen, Bristol-Myers Squibb, Janssen, Sanofi, Merck, Novartis, Roche and Teva. DG has received educational and consultancy fees from Amgen, Almirall, Biogen, Biomerieux, Diasorin, Eli Lilly, Janssen, PDB Biotec, Qiagen, Quidel. She was partially supporedt by the Italian Ministry of Health, Ricerca Corrente, Linea 1. JK has received grants and consulting fees from F. Hoffmann-La Roche Ltd, Biogen, Teva, Merck, Novartis, Immunic, Celgene and Sanofi (payments to institution); reports speaker relationships with F. Hoffmann-La Roche Ltd, Biogen, Celgene, Teva, Merck, Novartis, Sanofi and Viatris (payments to institution). DK has received educational and consultancy fees from Biogen, Teva, Merck and Roche. LL has received educational and consultancy fees from Biogen, Teva, Merck, Roche, Novartis, Bristol-Myers Squibb, Almirall, Horizon, Alexion, Sanofi. CL has received consulting or travel fees from Biogen, Novartis, Roche, Sanofi, Teva and Merck, and research grant from Biogen. MPS has received consulting fees from Biogen, Novartis, Roche, Sanofi, Merck, Alexion, Bristol-Myers Squibb, Immunic. DS has received financial support for conference travel and/or speaker honoraria from. Novartis, Biogen, Merck, Teva, Janssen-Cilag, and Roche and is also supported by the Charles University: Cooperation Program in Neuroscience and by the National Institute for. Neurological Research project funded by the European Union–Next Generation EU. (Programme EXCELES, ID Project No. LX22NPO5107). TZ has received consulting or serving on speaker bureaus for Alexion, Biogen, Bristol-Myers Squibb, Roche, Sandoz, Novartis, Merck, Teva and Sanofi, as well as research support from Biogen, Novartis, Merck, Roche and Sanofi. MDF participated on advisory boards and steering committees for and received speaker or writing honoraria, research support and funding for travelling from Alexion, BMS, Bayer, Biogen Idec, Genzyme, Horizon, Janssen, Merck, Mylan, Novartis, Roche, Siemens Healthineers, Teva and Viatris., (© 2024 The Author(s).)

Objective: To evaluate: (1) the distribution of gray matter (GM) atrophy in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), and relapsing-remitting multiple sclerosis (RRMS); and (2) the relationship between GM volumes and white matter lesions in various brain regions within each disease., Methods: A retrospective, multicenter analysis of magnetic resonance imaging data included patients with MOGAD/AQP4+NMOSD/RRMS in non-acute disease stage. Voxel-wise analyses and general linear models were used to evaluate the relevance of regional GM atrophy. For significant results (p < 0.05), volumes of atrophic areas are reported., Results: We studied 135 MOGAD patients, 135 AQP4+NMOSD, 175 RRMS, and 144 healthy controls (HC). Compared with HC, MOGAD showed lower GM volumes in the temporal lobes, deep GM, insula, and cingulate cortex (75.79 cm 3 ); AQP4+NMOSD in the occipital cortex (32.83 cm 3 ); and RRMS diffusely in the GM (260.61 cm 3 ). MOGAD showed more pronounced temporal cortex atrophy than RRMS (6.71 cm 3 ), whereas AQP4+NMOSD displayed greater occipital cortex atrophy than RRMS (19.82 cm 3 ). RRMS demonstrated more pronounced deep GM atrophy in comparison with MOGAD (27.90 cm 3 ) and AQP4+NMOSD (47.04 cm 3 ). In MOGAD, higher periventricular and cortical/juxtacortical lesions were linked to reduced temporal cortex, deep GM, and insula volumes. In RRMS, the diffuse GM atrophy was associated with lesions in all locations. AQP4+NMOSD showed no lesion/GM volume correlation., Interpretation: GM atrophy is more widespread in RRMS compared with the other two conditions. MOGAD primarily affects the temporal cortex, whereas AQP4+NMOSD mainly involves the occipital cortex. In MOGAD and RRMS, lesion-related tract degeneration is associated with atrophy, but this link is absent in AQP4+NMOSD. ANN NEUROL 2024;96:276-288., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Fatigue affects 60-90% of people with multiple sclerosis (MS). It reduces quality of life and the ability to work. The cause of fatigue in MS remains unknown. Several disease-modifying treatments (DMTs) slow the disease process in relapsing MS by suppressing neuroinflammation. We aimed to investigate if treatment with a DMT is associated with lower rates of fatigue., Methods: In this cross-sectional study of the MS population in three counties in Norway, we used the Fatigue Scale for Motor and Cognitive Functions (FSMC) and the Hospital Anxiety and Depression Scale (HADS) to assess patient-reported fatigue, anxiety and depression. Clinical data were retrieved from the electronic patient record system. We categorized DMTs as high-efficacy therapy or moderate-efficacy therapy. High-efficacy drugs included fingolimod, natalizumab, ocrelizumab, rituximab, alemtuzumab, daclizumab, and autologous hematopoietic stem cell transplantation. Moderate-efficacy drugs included interferons, glatiramer acetate, dimethyl fumarate, and teriflunomide. We included persons with relapsing MS only., Results: Of 1142 patients, 80% had fatigue. Fifty-six percent of the patients were on DMTs (25% on moderate-efficacy treatment and 30% on high-efficacy treatment), 18% had discontinued treatment and 26% had never received any DMT. Sex, level of disability as measured by the Multiple Sclerosis Severity Score, anxiety and depression were independently associated with fatigue. Moderate-efficacy treatment was associated with less fatigue, but not after adjustment for other variables. There was no association between high-efficacy treatment and fatigue., Conclusion: We found no independent relationship between the use of disease-modifying treatment and fatigue in MS., Competing Interests: Declaration of Competing Interest LB has received unrestricted research grants from Sanofi, and advisory board honoraria from Sanofi, Merck and Biogen CSS has received unrestricted research grants from Sanofi and Novartis, and advisory board and/or speaker honoraria from Sanofi, Merck, BMS, Novartis and Biogen HØF has received unrestricted research grants from Biogen and Novartis, and advisory board and/or speaker honoraria Sanofi, Merck and Biogen PBH has received funding for travel or speaker's fees from Novartis, UCB, Biogen, Teva and Sanofi. HO has no conflicts of interest. CB has no conflicts of interest. EGC has received unrestricted research grants from Sanofi, and advisory board and/or speaker honoraria from Biogen, BMS, Janssen, Merck, Novartis, Roche, Sanofi and Teva., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Balance impairment is frequent in people with multiple sclerosis (pwMS) and affects risk of falls and quality of life. By using inertial measurement units (IMUs) on the Single Leg Stance Test (SLS) we aimed to discriminate healthy controls (HC) from pwMS and detect differences in balance endurance and quality. Thirdly, we wanted to test the correlation between instrumented SLS parameters and self-reported measures of gait and balance. Fifty-five pwMS with mild (EDSS<4) and moderate disability (EDSS≥4) and 20 HC performed the SLS with 3 IMUs placed on the feet and sacrum and filled the Twelve Item Multiple Sclerosis Walking Scale (MSWS-12) questionnaire. A linear mixed model was used to compare differences in the automated balance measures. Balance duration was significantly longer in HC compared to pwMS ( p  < 0.001) and between the two disability groups ( p  < 0.001). Instrumented measures identified that trunk stability (normalized mediolateral and antero-posterior center of mass stability) had the strongest association with disability (R 2 marginal 0.30, p  < 0.001) and correlated well with MSWS-12 ( R  = 0.650, p  < 0.001). PwMS tended to overestimate own balance compared to measured balance duration. The use of both self-reported and objective assessments from IMUs can secure the follow-up of balance in pwMS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Berg-Hansen, Moen, Klyve, Gonzalez, Seeberg, Celius, Austeng and Meyer.)

Immune responses in people with multiple sclerosis (pwMS) receiving disease-modifying therapies (DMTs) have been of significant interest throughout the COVID-19 pandemic. Lymphocyte-targeting immunotherapies, including anti-CD20 treatments and sphingosine-1-phosphate receptor (S1PR) modulators, attenuate Ab responses after vaccination. Evaluation of cellular responses after vaccination, therefore, is of particular importance in these populations. In this study, we used flow cytometry to analyze CD4 and CD8 T cell functional responses to SARS-CoV-2 spike peptides in healthy control study participants and pwMS receiving 5 different DMTs. Although pwMS receiving rituximab and fingolimod therapies had low Ab responses after both 2 and 3 vaccine doses, T cell responses in pwMS taking rituximab were preserved after a third vaccination, even when an additional dose of rituximab was administered between vaccine doses 2 and 3. PwMS taking fingolimod had low detectable T cell responses in peripheral blood. CD4 and CD8 T cell responses to SARS-CoV-2 variants of concern Delta and Omicron were lower than to the ancestral Wuhan-Hu-1 variant. Our results indicate the importance of assessing both cellular and humoral responses after vaccination and suggest that, even in the absence of robust Ab responses, vaccination can generate immune responses in pwMS.

MRI and clinical features of myelin oligodendrocyte glycoprotein (MOG)-antibody disease may overlap with those of other inflammatory demyelinating conditions posing diagnostic challenges, especially in non-acute phases and when serologic testing for MOG antibodies is unavailable or shows uncertain results. We aimed to identify MRI and clinical markers that differentiate non-acute MOG-antibody disease from aquaporin 4 (AQP4)-antibody neuromyelitis optica spectrum disorder and relapsing remitting multiple sclerosis, guiding in the identification of patients with MOG-antibody disease in clinical practice. In this cross-sectional retrospective study, data from 16 MAGNIMS centres were included. Data collection and analyses were conducted from 2019 to 2021. Inclusion criteria were: diagnosis of MOG-antibody disease; AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis; brain and cord MRI at least 6 months from relapse; and Expanded Disability Status Scale (EDSS) score on the day of MRI. Brain white matter T2 lesions, T1-hypointense lesions, cortical and cord lesions were identified. Random forest models were constructed to classify patients as MOG-antibody disease/AQP4-neuromyelitis optica spectrum disorder/multiple sclerosis; a leave one out cross-validation procedure assessed the performance of the models. Based on the best discriminators between diseases, we proposed a guide to target investigations for MOG-antibody disease. One hundred and sixty-two patients with MOG-antibody disease [99 females, mean age: 41 (±14) years, median EDSS: 2 (0-7.5)], 162 with AQP4-neuromyelitis optica spectrum disorder [132 females, mean age: 51 (±14) years, median EDSS: 3.5 (0-8)], 189 with multiple sclerosis (132 females, mean age: 40 (±10) years, median EDSS: 2 (0-8)] and 152 healthy controls (91 females) were studied. In young patients (<34 years), with low disability (EDSS < 3), the absence of Dawson's fingers, temporal lobe lesions and longitudinally extensive lesions in the cervical cord pointed towards a diagnosis of MOG-antibody disease instead of the other two diseases (accuracy: 76%, sensitivity: 81%, specificity: 84%, P < 0.001). In these non-acute patients, the number of brain lesions < 6 predicted MOG-antibody disease versus multiple sclerosis (accuracy: 83%, sensitivity: 82%, specificity: 83%, P < 0.001). An EDSS < 3 and the absence of longitudinally extensive lesions in the cervical cord predicted MOG-antibody disease versus AQP4-neuromyelitis optica spectrum disorder (accuracy: 76%, sensitivity: 89%, specificity: 62%, P < 0.001). A workflow with sequential tests and supporting features is proposed to guide better identification of patients with MOG-antibody disease. Adult patients with non-acute MOG-antibody disease showed distinctive clinical and MRI features when compared to AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis. A careful inspection of the morphology of brain and cord lesions together with clinical information can guide further analyses towards the diagnosis of MOG-antibody disease in clinical practice., (© 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.)

Introduction: The effect of disease-modifying therapies (DMT) on vaccine responses is largely unknown. Understanding the development of protective immunity is of paramount importance to fight the COVID-19 pandemic., Objective: To characterise humoral immunity after mRNA-COVID-19 vaccination of people with multiple sclerosis (pwMS)., Methods: All pwMS in Norway fully vaccinated against SARS-CoV-2 were invited to a national screening study. Humoral immunity was assessed by measuring anti-SARS-CoV-2 SPIKE RBD IgG response 3-12 weeks after full vaccination, and compared with healthy subjects., Results: 528 pwMS and 627 healthy subjects were included. Reduced humoral immunity (anti-SARS-CoV-2 IgG <70 arbitrary units) was present in 82% and 80% of all pwMS treated with fingolimod and rituximab, respectively, while patients treated with other DMT showed similar rates as healthy subjects and untreated pwMS. We found a significant correlation between time since the last rituximab dose and the development of humoral immunity. Revaccination in two seronegative patients induced a weak antibody response., Conclusions: Patients treated with fingolimod or rituximab should be informed about the risk of reduced humoral immunity and vaccinations should be timed carefully in rituximab patients. Our results identify the need for studies regarding the durability of vaccine responses, the role of cellular immunity and revaccinations., Competing Interests: Competing interests: ARL research fundings from Sanofi. SW has received speaker honoraria from and served on scientific advisory boards for Biogen, Janssen-Cilag, Sanofi and Novartis. ØT has received speaker honoraria from and served on scientific advisory boards for Biogen, BMS, Jansen, Sanofi, Merck and Novartis. TH has received speaker honoraria and/or unrestricted research grants from Biogen, Merck, Roche, Novartis, Sanofi and Bristol-Myers Squibb, and participated in clinical trials organised by Merck, Sanofi and Roche. TB has received unrestricted research grants from Biogen Idec and Sanofi Genzyme. MK-M has received unrestricted research grants to his institution; scientific advisory board and speaker honoraria from Biogen, Merck, Novartis, Roche and Sanofi, and has participated in clinical trials organised by Biogen, Merck, Novartis, Roche and Sanofi. HFH has received honoraria for lecturing or advice from Biogen, Merck, Roche, Novartis and Sanofi. AS is shareholder of Age Labs, a molecular diagnostics company that discovers, develops and commercialises diagnostic tests for the early detection of age-related diseases. EGC has received honoraria for lecturing and advice from Biogen, BMS, Janssen, Merck, Novartis, Roche and Sanofi., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Treatment with cladribine tablets (CladT), an immune reconstitution therapy for relapsing multiple sclerosis (RMS), involves two short courses of treatment in Year 1 and Year 2. Most patients achieve sustained efficacy with CladT, but a small proportion may experience new disease activity (DA). Following completion of the indicated dose, physicians may have questions relating to the long-term management of these patients. Since the EU approval of CladT over 5 years ago, real-world evidence (RWE) is increasing and may provide some insights and guidance for clinical practice. We describe a systematic literature review (SLR) of RWE and provide expert opinions relating to six questions regarding the long-term use of CladT., Methods: Pertinent clinical questions were developed by a steering committee (SC) of 14 international multiple sclerosis (MS) experts regarding breakthrough DA in Year 1, new DA after 2 years or more of treatment, long-term management of stable patients, and whether additional courses of CladT may be required or safe. An SLR was performed in EMBASE and PubMed using the population, intervention, comparators, outcomes, study design (PICOS) framework to identify relevant studies within the last 15 years. Searches of key congress proceedings for the last 2-3 years were also performed. Following review of the results and RWE, the SC drafted and agreed on expert opinion statements for each question., Results: A total of 35 publications reporting RWE for CladT were included in this review. In the real world, breakthrough DA in Year 1 is of low incidence (1.1-21.9%) but can occur, particularly in patients switching from anti-lymphocyte trafficking agents. In most patients, this DA did not lead to treatment discontinuation. Reported rates of DA after the full therapeutic effect of CladT has been achieved (end of Year 2, 3 or 4) range from 12.0 to 18.7% in the few studies identified. No RWE was identified to support management decisions for stable patients in Year 5 or later. Views among the group were also diverse on this question and voting on expert opinion statements was required. Only two studies reported the administration of additional courses of CladT, but detailed safety outcomes were not provided., Conclusions: RWE for the long-term use of CladT in the treatment of RMS is increasing, however, gaps in knowledge remain. Where possible, the RWE identified through the SLR informed expert statements, but, where RWE is still lacking, these were based solely on experiences and opinion, providing some guidance on topics and questions that occur in daily clinical practice. More real-world studies with longer-term follow-up periods are needed and highly anticipated., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Background: Cancer is a major cause of death, but how cancer influences mortality risk in Multiple Sclerosis (MS) is unclear., Objectives: Determine all-cause mortality and mortality following a cancer diagnosis among MS patients compared with matched population controls., Methods: Norwegian MS patients born 1930 - 1979 (n= 6950) followed-up 1953 - 2016, were matched with 37 922 controls. We compared incident cancer diagnosis from the Cancer Registry of Norway, date of death from the Cause of Death Registry, education from the National Education Database, by multivariate Cox proportional hazard regression., Results: Hazard ratio (HR) and 95% confidence interval (CI) for all-cause mortality among MS patients was 4.97 (4.64 - 5.33), and 2.61 (2.29 - 2.98) for mortality following a cancer diagnosis. Mortality in MS was highest following urinary- (2.53: 1.55 - 4.14), colorectal- (2.14: 1.47 - 3.11), hematological- (1.76: 1.08 - 2.88), ovarian - 2.30 (1.73-3.06) and breast cancer diagnosis (2.61: 1.85 - 3.68), compared to controls. High education was inversely associated with mortality among MS patients., Conclusions: All-cause mortality was five- fold and mortality following a cancer diagnosis was two- fold increased among MS patients. Mortality following specific cancers raises the possibility of diagnostic neglect., Competing Interests: Competing interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: N.G., T.R., J.H.A., A.V., R.M., and E.B. reports no disclosures. K.M.M. reports grants or personal fees from Biogen, Novartis, Roche, Teva and Sanofi, outside the submitted work. E.G.C. reports grants or personal fees from Almirall, Biogen, Merck, Novartis, Roche, Sanofi Genzyme and Teva, outside the submitted work. Ø.T. reports personal fees from Biogen, Merck, Sanofi, Roche, and Teva, outside the submitted work., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: No evidence of disease activity with three components (NEDA-3) is achieved if the person with MS (pwMS) has no new MRI lesions, no new relapses and no change in Expanded disability status scale (EDSS) over 1 year. Whether NEDA-3 is a good tool in measuring disease activity is up for discussion, but it is superior to the individual parameters separately and user-friendly. There is disagreement on whether NEDA-3 is a good predictor of long-term disability., Methods: This is a retrospective cohort study using real-world data with limited selection bias from the complete MS population at two hospitals in the southeast of Norway. We included pwMS diagnosed between 2006 and 2017 who had enough information to determine time to failure of NEDA-3 after diagnosis., Results: Of 536 pwMS, only 38% achieved NEDA 1 year after diagnosis. PwMS achieving NEDA were more likely to be started on a high efficacy drug as the initial drug, but there were no demographic differences. Mean time to NEDA failure was 3.3 (95% CI 2.9-3.7) years. Starting a high efficiacy therapy was associated with an increased risk of sustaining NEDA as compared to those receiving moderate efficacy therapy. PwMS who achieved NEDA at year one had a mean time to EDSS 6 of 33.8 (95% CI 30.9-36.8) years vs. 30.8 (95% CI 25.0-36.6) years in pwMS who did not achieve NEDA, p < 0.001. When rebaselining NEDA 1 year after diagnosis, 52.2% achieved NEDA in the 1st year after rebaseline, mean time to NEDA failure was 3.4 (95% CI 3.0-3.7) years and mean time to EDSS 6 was 44.5 (95% CI 40.4-48.5) years in pwMS achieving NEDA vs. 29.6 (95% CI 24.2-35.0) years in pwMS not achieving NEDA, p < 0.001. After rebaseline, pwMS with a high efficacy therapy as the initial drug had a mean time from diagnosis to NEDA fail of 4.8 years (95% CI 3.9-5.8) vs. 3.1 years (95% CI 2.7-3.5) in pwMS started on a moderate efficacy therapy, p < 0.001. In pwMS with NEDA failure at year one, 70% failed one, 28% failed two and 2% failed three components. New MRI lesions were the most common cause of NEDA failure (63%), followed by new relapses (50%) and EDSS change (25%)., Conclusion: NEDA-3 from rebaseline after 1 year, once treatment is stabilized, can predict the long-term disease course in MS. Starting a high efficacy DMT is associated with longer time to NEDA failure than moderate therapies. Finally, most pwMS only fail one component and new MRI lesions are the most likely cause of NEDA failure., Competing Interests: Author CS has received personal compensation for lectures and/or serving on scientific advisory boards from Sanofi, Merck, Novartis, BMS, and Biogen Idec and received unrestricted research grants from Sanofi and Novartis. Author HF has received unrestricted research grants from Biogen Idec and Novartis. Author KB has received personal compensation for lectures and/or serving on advisory boards from Biogen, Novartis, and Merck. Author LB has received unrestricted research grants from Sanofi, and advisory board honoraria from Sanofi, Merck, and Biogen. Author PB-H has received advisory board and/or speaker honoraria from Novartis, UCB, Teva, Merck, and Biogen Idec. Author EC has received personal compensation for lectures and / or serving on scientific advisory boards for Almirall, Biogen, BMS, Janssen, Genzyme, Merck, Novartis, Roche, and Teva. Her department has received unrestricted research grants from Biogen, Novartis, Merck, and Genzyme. The remaining author declares 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 Simonsen, Flemmen, Broch, Brekke, Brunborg, Berg-Hansen and Celius.)

Background: Knowledge concerning exposure to abuse in adulthood and in pregnancy in people with multiple sclerosis (MS) is sparse., Objective: To determine the occurrence of adult abuse and abuse in relation to pregnancy in women with MS and their risk of revictimization (repeated abuse as adults after childhood abuse)., Methods: This cross-sectional study comprised pregnant women from the Norwegian Mother, Father and Child Cohort study. Information on abuse was acquired through self-completed questionnaires. We used logistic regression to estimate adjusted odds ratios (aORs) with 95% confidence intervals (CIs)., Results: We identified 106 women with MS at enrollment through linkage with national health registries. The reference group consisted of 77,278 women without MS. Twenty-seven women (26%) with MS reported any adult abuse compared to 15,491 women (20%) without MS, aOR 1.33 (0.85-2.09). Twenty-two (21%) women with MS reported systematic emotional abuse compared to 13% without MS, aOR 1.75 (1.08-2.83). Ten women (10%) with MS reported sexual abuse, compared to 6% without MS, aOR 1.72 (0.89-3.33). More women with MS reported rape as an adult, aOR 2.37 (1.02-5.49). Women with MS had higher risk of revictimization as adults, after childhood abuse, aOR 2.23 (1.22-4.10). The risk of abuse during pregnancy or 6 months preceding pregnancy was similar between the groups., Conclusions: Women with MS had increased occurrence of systematic emotional abuse, rape, and revictimization as adults, compared to women without MS., (© 2022. The Author(s).)

Objectives: Fatigue is one of the leading causes of reduced quality of life and inability to work in people with multiple sclerosis (pwMS). Currently, no treatment effectively ameliorates fatigue. We still know little about what causes fatigue and which factors may contribute to fatigue. Knowledge about socioeconomic factors' role in fatigue might help us recognize strategies for the management of fatigue. Our aim was to explore whether socioeconomic factors are associated with the presence or level of perceived fatigue., Methods: This is a cross-sectional study of the MS population in three Norwegian counties. We used the Fatigue Scale for Motor and Cognitive Functions to assess self-reported fatigue, and obtained socioeconomic data from Statistics Norway and questionnaires. To assess self-reported anxiety and depression, we employed the Hospital Anxiety and Depression Scale. Clinical data were gathered from the hospital record system., Results: The response rate was 64% (1599/2512). Seventy percent of the respondents were female, and the mean age was 52 years. Higher levels of education were associated with lower levels of fatigue. Receiving a disability pension, being divorced and having children were all factors associated with higher levels of fatigue, as were low parental education, low income, current smoking, and autoimmune comorbidities. We found a higher prevalence of anxiety and depression in pwMS with fatigue compared to those without fatigue CONCLUSION: Female sex, high level of disability, anxiety, depression and socioeconomic factors were independently associated with fatigue in contemporary patients with MS. These factors should be considered when devising management strategies., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The discrepancy between chronological age and the apparent age of the brain based on neuroimaging data - the brain age delta - has emerged as a reliable marker of brain health. With an increasing wealth of data, approaches to tackle heterogeneity in data acquisition are vital. To this end, we compiled raw structural magnetic resonance images into one of the largest and most diverse datasets assembled (n=53542), and trained convolutional neural networks (CNNs) to predict age. We achieved state-of-the-art performance on unseen data from unknown scanners (n=2553), and showed that higher brain age delta is associated with diabetes, alcohol intake and smoking. Using transfer learning, the intermediate representations learned by our model complemented and partly outperformed brain age delta in predicting common brain disorders. Our work shows we can achieve generalizable and biologically plausible brain age predictions using CNNs trained on heterogeneous datasets, and transfer them to clinical use cases., Competing Interests: Declaration of Competing Interest Declarations of interest: None, (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The aim of this work was to determine whether wearable inertial measurement units (IMUs) could detect gait improvements across different disability groups of people with Multiple Sclerosis (pwMS) by the six-minute walk test (6MWT) during a rehabilitation stay in a specialized rehabilitation center. Forty-six pwMS and 20 healthy controls (HC) were included in the study. They performed the 6MWT with two inertial measurement units (IMUs) placed on the feet. Thirty-two of the pwMS were retested at the end of the stay. PwMS were divided in a mild-disability and a moderate-disability group. The 6MWT was divided in six sections of 1 min each for technical analysis, and linear mixed models were used for statistical analyses. The comparison between the two disability groups and HC highlighted significant differences for each gait parameter (all p < 0.001). The crossing effect between the test-retest and the two disability groups showed greater improvement for the moderate-disability group. Finally, the gait parameter with the higher effect size, allowing the best differentiation between the disability groups, was the foot flat ratio (R 2  = 0.53). Gait analyses from wearable sensors identified different evolutions of gait patterns during the 6MWT in pwMS with different physical disability. The measured effect of a short-time rehabilitation on gait with 6MWT was higher for pwMS with higher degree of disability. Using IMUs in a clinical setting allowed to identify significant changes in inter-stride gait patterns. Wearable sensors and key parameters have the potential as useful clinical tools for focusing on gait in pwMS., (© 2022. The Author(s).)

Objective: To study whether exposure to childhood emotional, sexual or physical abuse is associated with subsequent multiple sclerosis (MS) development., Methods: A nationwide, prospective cohort study based on participants in the Norwegian Mother, Father and Child cohort study. Enrolment took place 1999-2008, with follow-up until 31 December 2018. Childhood abuse before age 18 years was obtained from self-completed questionnaires. We identified MS diagnoses through data-linkage with national health registries and hospital records. The Cox model was used to estimate HRs for MS with 95% CIs, adjusting for confounders and mediators., Results: In this prospective cohort study, 14 477 women were exposed to childhood abuse and 63 520 were unexposed. 300 women developed MS during the follow-up period. 71 of these (24%) reported a history of childhood abuse, compared with 14 406 of 77 697 (19%) women that did not develop MS. Sexual abuse (HR 1.65, 95% CI 1.13 to 2.39) and emotional abuse (HR 1.40, 95% CI 1.03 to 1.90) in childhood were both associated with an increased risk of developing MS. The HR of MS after exposure to physical abuse was 1.31 (95% CI 0.83 to 2.06). The risk of MS was further increased if exposed to two (HR 1.66, 95% CI 1.04 to 2.67) or all three abuse categories (HR 1.93, 95% CI 1.02 to 3.67)., Interpretation: Childhood sexual and emotional abuse were associated with an increased risk of developing MS. The risk was higher when exposed to several abuse categories, indicating a dose-response relationship. Further studies are needed to identify underlying mechanisms., Competing Interests: Competing interests: KE has received unrestricted research grant from Novartis. ØT has received speaker honoraria from and served on scientific advisory boards for Biogen, Sanofi-Aventis, Merck and Novartis. AB has received unrestricted research from Novartis. EGC has received honoraria for lecturing and advice from Biogen, Bristol Meyers Squibb, Janssen, Novartis, Merck, Roche and Sanofi, and her department has received grants from Novartis and Sanofi. AKD has received project funding from Pfizer. TH has received speaker honoraria from Biogen, Merck, Novartis, Roche, Bristol Myers Squibb, and Sanofi, and has participated in clinical trials organised by Biogen, Merck, and Roche. K-MM has received unrestricted research grants to his institution; scientific advisory board and speaker honoraria from Biogen, Merck, Novartis, Roche and Sanofi, and has participated in clinical trials organised by Biogen, Merck, Novartis, Roche and Sanofi. CFT has served on scientific advisory board for Astra Zeneca. SW has received honoraria from Biogen, Novartis and Sanofi. NEG has received honoraria from UCB, Ra, Argenx, Roche, Merck, Immunovant, Alexion. M-HB has received personal honoraria for lecturing from Teva, Lilly, Eisai and Novartis, and consultancy honoraria and unrestricted research support from Novartis. Institutional contract research fees from Sanofi., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We aimed to determine whether retinal vessel diameters and retinal oxygen saturation in newly diagnosed patients with multiple sclerosis (pwMS) are different from those of a healthy population. Retinal blood vessel diameters were measured using imaging with a spectrophotometric non-invasive retinal oximeter. Twenty-three newly diagnosed untreated relapsing-remitting MS (RRMS) patients (mean age: 32.2 ± 7.5 years, age range = 18-50 years, 56.5% female) were measured and compared to 23 age- and sex-matched healthy controls (HCs) (mean age: 34.8 ± 8.1 years). Patients with Optic Neuritis were excluded. Retinal venular diameter (143.8 µm versus 157.8 µm: mean; p = 0.0013) and retinal arteriolar diameter (112.6 µm versus 120.6 µm: mean; p = 0.0089) were smaller in pwMS when compared with HCs, respectively. There was no significant difference in the oxygen saturation in retinal venules and arterioles in pwMS (mean: 60.0% and 93.7%; p = 0.5980) compared to HCs (mean: 59.3% and 91.5%; p = 0.8934), respectively. There was a significant difference in the median low contrast visual acuity (2.5% contrast) between the pwMS and the HC groups ( p = 0.0143) Retinal arteriolar and venular diameter may have potential as objective biomarkers for MS.

Objective: Several studies report an impact of socioeconomic factors on access to disease modifying treatment (DMT) in multiple sclerosis (MS), with a trend of less access to more deprived persons. We investigated the impact of socioeconomic status (SES) on access to treatment in a well-defined Norwegian MS cohort., Methods: This is a study of a population-based Norwegian MS cohort. We collected detailed information on disease development, progression, and DMT administered. Socioeconomic data was obtained from Statistics Norway and a questionnaire., Results: We included 1314 persons with relapsing remitting MS at the prevalence date 01/01/2018. The population ever treated with DMTs is younger at onset, has shorter time from onset to diagnosis and lower expanded disability status score (EDSS) at diagnosis. The persons with MS (pwMS) with the highest levels of education, and those who are married are more likely to be ever treated with DMT. In the subgroup treated with a high efficacy DMT as a first drug, the pwMS are younger at prevalence date (39.9 years (SD 12.1)) compared with those who are not treated with a high efficacy DMT as first drug (43.8 years (SD 10.3)). The subgroup treated with a high efficacy DMT as a first drug has a 0.5 point higher EDSS at diagnosis compared to those not treated with a high efficacy DMT as a first drug. The level of education, household income and marital status are inversely related to access to high efficacy DMT as a first drug. None of the above differences persist when analyzing the subgroup diagnosed within the last six years (2012-2017)., Conclusions: Since 2012, the pwMS in this Norwegian cohort are treated equally with DMT in terms of different measures of socioeconomic position., (Copyright © 2022. Published by Elsevier B.V.)

Background: Therapeutic inertia (TI) is a worldwide phenomenon that affects 60 to 90% of neurologists and up to 25% of daily treatment decisions during management of multiple sclerosis (MS) patients. A large volume of MS patients are women of childbearing age, and desire for pregnancy is a complex variable often affecting MS care. The objective of this study was to determine the effect of desire for pregnancy on decisions to escalate treatment during management of MS patients., Methods: 300 neurologists with expertise in MS from 20 countries were invited to participate in the study. Participants were presented with 12 pairs of simulated MS patient profiles reflective of case scenarios encountered in clinical practice. Participants were asked to select the ideal candidate for treatment escalation from modest to higher-efficacy therapies. Disaggregated discrete choice experiments were used to estimate the weight of factors and attributes affecting physicians' decisions when considering treatment selection. An excel calculator that provides estimates as the percentage of participants that would escalate treatment for a simulated case-scenario was constructed., Results: 229 (76.3%) completed the study. The mean age (SD) of study participants was 44 (±10) years. The mean (SD) number of MS patients seen per month by each neurologist was 18 (±16). Non-MS specialists were significantly less likely to escalate treatment than MS specialists across mild, moderate, and severe patient cases. These differences were accentuated when case scenarios introduced a desire for pregnancy. The findings were consistent when MRI-lesions, severity of symptoms, and number of relapses were included., Conclusions: Desire for pregnancy differentially influences decisions to escalate treatment, suggesting knowledge-to-action gaps between MS and non-MS specialists. Our findings indicate the need for educational strategies to overcome these gaps and improve clinical outcomes for MS patients who desire pregnancy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Whether disease-modifying therapies (DMTs) influence cancer in multiple sclerosis (MS) is uncertain., Objectives: Assess incidence of cancer diagnosis among Norwegian MS patients compared to the general population in 1953 to 1995 and 1996 to 2017-reflecting era before and after introduction of DMTs., Methods: We performed a nationwide cohort study comprising 6949 MS patients and 37,922 controls, matched on age, sex and county. The cohort was linked to Norwegian Cancer Registry, Cause of Death Registry and National Educational database. We used Poisson regression to calculate incidence rate ratio (IRR) of cancer., Results: During 1953-1995 MS patients had similar cancer frequency compared to controls (IRR: 1.11 (95% Confidence Intervals (CI): 0.90-1.37)), although MS patients had increased frequency of cancer in endocrine glands (IRR: 2.51 (1.27-4.93). During 1996-2017 we identified significant increased frequency of cancer among MS patients compared to controls (IRR: 1.38 (95% CI: 1.28-1.52): in brain (IRR: 1.97 (1.41-2.78)), meninges (IRR: 2.44 (1.54-3.77)), respiratory organs (IRR: 1.96 (1.49-2.63)). The excess cancer diagnosis was most frequent among MS patients ≥ 60 years of age (HR 1.30 (1.15-1.47))., Conclusion: Incidence of cancer among MS patients compared to controls was higher in 1996 to 2017, corresponding in time to the introduction of DMT for MS. This was observed more frequently among MS patients older than 60 years of age., (Copyright © 2021. Published by Elsevier B.V.)

Background: The duration and features of the multiple sclerosis (MS) prodrome are not well defined. We aimed to ascertain whether people with a future MS diagnosis have more days of absence and perform worse in upper secondary school than age, gender and county-matched controls., Methods: Using registry data from the southeast of Norway, we identified people with MS born ≥1978. Statistics Norway provided information on grades and days of absence in cases and matched controls. We looked at absence in the three years of upper secondary school and grades in the compulsory subjects Norwegian, English, mathematics and physical education., Results: We identified 107 cases with disease onset one year or more after graduation and 626 controls. There were no significant differences in absence or grades achieved in the population as a whole or in those with disease onset within four years of diagnosis, and no association between time to disease onset and days of absence or grades., Conclusion: There was no difference in days of absence or grades achieved in upper secondary school in the four years leading up to disease onset in cases compared to controls. A potential prodrome may not affect cognition enough to impact school achievements., (Copyright © 2021. Published by Elsevier B.V.)

Objective: The identification of potential risk factors for disease severity is of great importance in the treatment of multiple sclerosis. The influence of socioeconomic status on progression in multiple sclerosis (MS) is sparsely investigated. Our aim was to investigate how socioeconomic status in adolescence influences disease progression in later life., Methods: A total of 1598 patients with multiple sclerosis from a well-defined population in Norway were included. Detailed information on disease progression, measured by expanded disability status scale (EDSS) and multiple sclerosis severity score (MSSS), were combined with data on socioeconomic factors. We used residency and parental level of education at patients' age 16 and exposure to second-hand smoking as a measure of socioeconomic status in adolescence, adjusting for the same variables as well as use of disease modifying treatments at prevalence date 01.01.18., Results: High maternal level of education at patients' age 16 was significantly associated with less pronounced disease progression measured by MSSS (β-coefficient -0.58, p = 0.015), younger age and lower EDSS at disease onset, and shorter time from onset to diagnosis. No significant associations were found for paternal education level and MSSS. The use of any disease modifying treatment before prevalence date was significantly associated with disease progression (β-coefficient -0.49, p=0.004), while residence, current and second-hand smoking were not., Conclusion: This study on a population-based, real-world cohort shows that the parental level of education has a significant impact on a timely diagnosis of MS. In addition to disease modifying treatment, maternal level of education also had an impact on disease progression in later life., (Copyright © 2021. Published by Elsevier B.V.)

Background: Moderate and high efficacy disease modifying therapies (DMTs) have a profound effect on disease activity. The current treatment guidelines only recommend high efficacy DMTs for patients with highly active MS. The objective was to examine the impact of initial treatment choice in achieving no evidence of disease activity (NEDA) at year 1 and 2. Methods: Using a real-world population-based registry with limited selection bias from the southeast of Norway, we determined how many patients achieved NEDA on moderate and high efficacy DMTs. Results: 68.0% of patients who started a high efficacy DMT as the first drug achieved NEDA at year 1 and 52.4% at year 2 as compared to 36.0 and 19.4% of patients who started a moderate efficacy DMT as a first drug. The odds ratio (OR) of achieving NEDA on high efficacy drugs compared to moderate efficacy drugs as a first drug at year 1 was 3.9 (95% CI 2.4-6.1, p < 0.001). The OR for high efficacy DMT as the second drug was 2.5 (95% CI 1.7-3.9, p < 0.001), and was not significant for the third drug. Patients with a medium or high risk of disease activity were significantly more likely to achieve NEDA on a high efficacy therapy as a first drug compared to moderate efficacy therapy as a first drug. Conclusions: Achieving NEDA at year 1 and 2 is significantly more likely in patients on high-efficacy disease modifying therapies than on moderate efficacy therapies, and the first choice of treatment is the most important. The immunomodulatory treatment guidelines should be updated to ensure early, high efficacy therapy for the majority of patients diagnosed with MS., Competing Interests: CS has received unrestricted research grant from Sanofi and Novartis, advisory board and/or speaker honoraria from Sanofi, Merck, Novartis, and Biogen Idec. HF has received unrestricted research grant Biogen Idec and Novartis, advisory board and/or speaker honoraria Sanofi, Merck, and Biogen Idec. LB has received an unrestricted grant from Sanofi Genzyme and advisory board honoraria from Merck. PB-H has received advisory board and/or speaker honoraria from Novartis, UCB, Sanofi, Merck, and Biogen Idec. EC has received unrestricted research grants from Novartis and Sanofi, advisory boards and/or speaker honoraria (Almirall, Biogen Idec, Merck, Roche, Novartis, Sanofi, and Teva). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Simonsen, Flemmen, Broch, Brunborg, Berg-Hansen, Moen and Celius.)

Objectives: Over the past few decades, there has been an improvement in the rate of disability progression in multiple sclerosis (MS) patients, and most studies relate this evolvement to the introduction of disease-modifying therapies. However, several other factors have changed over this period, including access to MRI and newer diagnostic criteria. The aim of this study is to investigate changes in the natural course of MS over time in a near-complete and geographically well-defined population from the south-east of Norway., Methods: We examined disease progression and demographics over two decades and assessed the effect of disease-modifying therapies using linear mixed-effect models., Results: In a cohort of 2097 patients, we found a significant improvement in disability as measured by the Expanded Disability Status Scale (EDSS) stratified by age, and the improvement remained significant after adjusting for time on disease-modifying medications, gender and progressive MS at onset. The time from disease onset to EDSS 6 in the total cohort was 29.8 years (95% CI 28.5-31.1) and was significantly longer in patients diagnosed after 2006 compared to patients diagnosed before. There are significant differences between patient demographics, as well as time to EDSS 6, in the near-complete, geographically well-defined population compared to an additional cohort from the capital Oslo and its suburbs., Conclusion: The natural course of MS is improving, but the improvement seen in disease progression has multifaceted explanations. Our study underlines the importance of completeness of data, relevant timeframes and demographics when comparing different MS populations. Studies on incomplete populations should be interpreted with caution.

Objective: The prevalence of multiple sclerosis (MS)-related fatigue may have changed due to new diagnostic criteria and new disease modifying drugs. We aimed to assess the prevalence of fatigue in a contemporary MS cohort, and to explore associations between fatigue and clinical and demographic factors., Methods: This is a cross-sectional study of the MS population in three Norwegian counties. Fatigue was assessed with the Fatigue Scale for Motor and Cognitive Functions (FSMC). We also assessed self-reported anxiety, depression and daytime sleepiness., Results: The response rate was 64% (1599/2512). The mean age of the participants was 52 ± 13 years, median EDSS was 2.5 (IQR 1.5-3.0) and median disease duration from onset was 16 years (IQR 8-25). We found a prevalence of fatigue of 81%. Women had a higher prevalence of fatigue than men (83% vs 78%, p = 0.02). The prevalence increased with age (p < 0.001) and with increasing disease severity (p < 0.001), but in multivariate analyses, only sex and disease severity remained independent determinants of fatigue. Anxiety, depression, and daytime sleepiness were more prevalent in patients with fatigue than in those without fatigue (all p-values < 0.001)., Conclusion: The prevalence of fatigue is high in contemporary patients with MS. Fatigue is associated with female sex and level of disability, as well as with anxiety, depression and excessive daytime sleepiness., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)