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Background and Objectives: Levels of activated complement proteins in the CSF are increased in people with multiple sclerosis (MS) and are associated with clinical disease severity. In this study, we determined whether complement activation profiles track with quantitative MRI metrics and liquid biomarkers indicative of disease activity and progression., Methods: Complement components and activation products (Factor H and I, C1q, C3, C4, C5, Ba, Bb, C3a, C4a, C5a, and sC5b-9) and liquid biomarkers (neurofilament light chain, glial fibrillary acidic protein [GFAP], CXCL-13, CXCL-9, and IL-12b) were quantified in the CSF of 112 patients with clinically isolated syndromes and 127 patients with MS; longitudinal MRIs according to a standardized protocol of the Swiss MS cohort were assessed. We used multivariable models to analyze associations of the 12 complement parameters as individual independent variables and longitudinal brain volumes, T2-weighted (T2w) lesion volumes, contrast-enhancing (CELs) and paramagnetic rim lesions (PRLs), and molecular biomarkers as dependent variables, respectively., Results: Strongest associations with accelerated brain atrophy were found for C4a: doubling of C4a CSF levels was associated with an additional brain volume loss of -0.24% (95% CI -0.31% to -0.16%; p < 0.0001) per year, followed by Ba and C3a (-0.22% [-0.29% to -0.15%]) and -0.13% ([-0.21 to -0.06]; both p < 0.001). Doubling of C3a, Ba, and C4a levels correlated with 2.2- (1.6-3.0; p < 0.0001), 2.0- (1.3-3.1; p = 0.0038), and 1.8-fold (1.2-2.6; p = 0.0029) increased longitudinal T2w lesion volumes; C3a and Ba were associated with 2.5- (1.4-4.6; p = 0.0022) and 3.3-fold (1.5-7.2; p = 0.0024) higher odds for CELs and 2.6- (1.7-4.0; p < 0.0001) and 2.3-fold (1.3-4.3; p = 0.006) increased PRL incidence rates. C1q, C3a, and C4a were associated with higher GFAP levels, and CXCL-13, CXCL-9, and IL-12b analyses showed consistent patterns with strongest associations for C1q, followed by Ba, C3a, and C4a., Discussion: Intrathecal complement activation is consistently associated with MRI metrics and liquid biomarkers indicative for MS disease activity and progression. Our results demonstrate that aberrant complement activation is strongly associated with structural brain damage in MS. Therapeutic targeting of the complement system might limit disability accumulation due to MS.

Few data are available regarding vaccine induced SARS-CoV-2 specific T cell responses over time and after booster doses in multiple sclerosis (MS) patients on different disease modifying treatments. We measured SARS-CoV-2 specific CD4 + T cell responses in 72 samples collected from 36 MS patients. The percentage of CD4 + CTV low CD25 + ICOS + T cells after stimulation with Spike Recombinant Protein was 29.9 (17.0-43.6) on teriflunomide, 32.4 (11.9-42.5) on ocrelizumab, but much lower (0.6 [0.3-5.9]) on sphingosine-1-phospate receptor modulators (β = -26.35, p = 0.003). SARS-CoV-2 specific T cells were mainly of Th1 type and stable over time and after booster vaccine doses. mRNA vaccines elicit strong and persistent CD4+ T cell responses against SARS-CoV-2 in MS patients on anti-CD20 and teriflunomide, but not in those on sphingosine-1-phospate receptor modulators., Competing Interests: Declaration of competing interest The employer (Department of Neurology, Regional Hospital Lugano (EOC), Lugano, Switzerland) receives financial support from Abbvie, Biogen Idec, Lundbeck, Merck, Novartis Roche, Sanofi, Teva. The submitted work is not related to these agreements., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Purpose: Lower urinary tract symptoms (LUTS) significantly affect quality of life (QoL) of multiple sclerosis (MS) patients, and pharmacotherapy has limited efficacy. We investigated efficacy and safety of the implantable StimRouter neuromodulation system for treating refractory LUTS in MS., Methods: This prospective, single-center, clinical trial was conducted at the Multiple Sclerosis Center of Lugano, Switzerland, involving MS patients treated with self-administered percutaneous tibial nerve stimulation delivered by StimRouter over 24 weeks. Changes in video-urodynamic parameters as well as LUTS severity were measured by Overactive Bladder Questionnaire (OAB-q), QoL using the Multiple Sclerosis Quality of Life (MSQoL-54), and treatment satisfaction using a 1-10 visual analogue scale. Adverse events were also recorded., Results: Of 23 MS patients recruited, six had neurogenic detrusor overactivity (NDO), five had detrusor sphincter dyssynergia (DSD), and 12 had both NDO and DSD. Of patients with NDO, median bladder volume at first uninhibited contraction significantly increased from baseline to week 24 (median = 136 mL, interquartile range [IQR] = 101-244 mL vs. 343 mL, IQR = 237-391 mL; β = 138.2, p = 0.001). No significant changes of urodynamic parameters were found in patients with DSD. OAB-q symptom scores progressively decreased, and OAB-q quality of life scores increased (β = -0.50, p < 0.001 and β = 0.47, p < 0.001, respectively), whereas MSQoL-54 scores did not significantly change (β = 0.24, p = 0.084) in the overall population. Treatment satisfaction was overall high (median = 8, IQR = 6-9). No serious adverse events were recorded., Conclusions: StimRouter represents a minimally invasive, magnetic resonance imaging-compatible, self-administered neuromodulation device leading to objective and subjective improvements of OAB symptoms and related QoL in MS patients with refractory LUTS., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Objectives: Progression independent of relapse activity (PIRA) is a crucial determinant of overall disability accumulation in multiple sclerosis (MS). Accelerated brain atrophy has been shown in patients experiencing PIRA. In this study, we assessed the relation between PIRA and neurodegenerative processes reflected by (1) longitudinal spinal cord atrophy and (2) brain paramagnetic rim lesions (PRLs). Besides, the same relationship was investigated in progressive MS (PMS). Last, we explored the value of cross-sectional brain and spinal cord volumetric measurements in predicting PIRA., Methods: From an ongoing multicentric cohort study, we selected patients with MS with (1) availability of a susceptibility-based MRI scan and (2) regular clinical and conventional MRI follow-up in the 4 years before the susceptibility-based MRI. Comparisons in spinal cord atrophy rates (explored with linear mixed-effect models) and PRL count (explored with negative binomial regression models) were performed between: (1) relapsing-remitting (RRMS) and PMS phenotypes and (2) patients experiencing PIRA and patients without confirmed disability accumulation (CDA) during follow-up (both considering the entire cohort and the subgroup of patients with RRMS). Associations between baseline MRI volumetric measurements and time to PIRA were explored with multivariable Cox regression analyses., Results: In total, 445 patients with MS (64.9% female; mean [SD] age at baseline 45.0 [11.4] years; 11.2% with PMS) were enrolled. Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change [MD-APC] -1.41; p = 0.004) and higher PRL load (incidence rate ratio [IRR] 1.93; p = 0.005). Increased spinal cord atrophy (MD-APC -1.39; p = 0.0008) and PRL burden (IRR 1.95; p = 0.0008) were measured in patients with PIRA compared with patients without CDA; such differences were also confirmed when restricting the analysis to patients with RRMS. Baseline volumetric measurements of the cervical cord, whole brain, and cerebral cortex significantly predicted time to PIRA (all p ≤ 0.002)., Discussion: Our results show that PIRA is associated with both increased spinal cord atrophy and PRL burden, and this association is evident also in patients with RRMS. These findings further point to the need to develop targeted treatment strategies for PIRA to prevent irreversible neuroaxonal loss and optimize long-term outcomes of patients with MS.

We report the analysis of 1 year of data from the first cohort of 15 patients enrolled in an open-label, first-in-human, dose-escalation phase I study (ClinicalTrials.gov: NCT03282760, EudraCT2015-004855-37) to determine the feasibility, safety, and tolerability of the transplantation of allogeneic human neural stem/progenitor cells (hNSCs) for the treatment of secondary progressive multiple sclerosis. Participants were treated with hNSCs delivered via intracerebroventricular injection in combination with an immunosuppressive regimen. No treatment-related deaths nor serious adverse events (AEs) were observed. All participants displayed stability of clinical and laboratory outcomes, as well as lesion load and brain activity (MRI), compared with the study entry. Longitudinal metabolomics and lipidomics of biological fluids identified time- and dose-dependent responses with increased levels of acyl-carnitines and fatty acids in the cerebrospinal fluid (CSF). The absence of AEs and the stability of functional and structural outcomes are reassuring and represent a milestone for the safe translation of stem cells into regenerative medicines., Competing Interests: Declaration of interests S.P. is founder, CSO, and shareholder (>5%) of CITC Ltd. and Chair of the Scientific Advisory Board at ReNeuron plc., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Disease-modifying treatments (DMTs) can increase the risk of infections in multiple sclerosis (MS). Aged individuals are usually excluded from clinical trials, and there is uncertainty regarding safety of immunosuppressive DMTs in these patients., Objective: To investigate the association of DMTs, ageing and other clinical variables with risk of infections in MS patients., Methods: Prospective single-centre observational study collecting information on occurrence, type and grade of infections in patients followed at the MS centre, Lugano (Switzerland). Associations with infection risk were tested using multivariable Poisson and Cox regressions., Results: A total of 503 patients were included (injectables/untreated, n = 127; orals, n = 139; monoclonal antibodies (MAB), n = 237) and 326 infections recorded over 12.6 (11.6-14.0) months. As compared to injectable DMTs/no treatment, MAB and oral DMTs were positively associated with infection incidence (IRR = 2.32, 95% confidence interval (CI) = 1.39-3.89, p = 0.001; IRR = 2.04, 95% CI = 1.19-3.49, p = 0.009, respectively). After excluding COVID-19, the effect of MAB was stronger among patients <50 years (IRR = 5.90, 95% CI = 2.80-12.45, p < 0.001) than >50 years (IRR = 1.95, 95% CI = 0.91-4.15, p = 0.084). Higher disability and male sex were the only variables associated with severe infections., Conclusion: Treatment with MAB and oral DMTs is associated with higher incidence of infections, with a stronger effect in young MS patients. Disability appears the main predictor of severe infections regardless of treatment., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The employer (Department of Neurology, Regional Hospital Lugano (EOC), Lugano, Switzerland) receives financial support from Teva, Merck Serono, Biogen Idec, Bayer Schering, Genzyme, Roche and Novartis. The submitted work is not related to these agreements.

Importance: Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity in people with MS (MS); however, data on the association between NfL level and disability accumulation have been conflicting., Objective: To determine whether and when NfL levels are elevated in the context of confirmed disability worsening (CDW)., Design, Setting, and Participants: This study included 2 observational cohorts: results from the Expression, Proteomics, Imaging, Clinical (EPIC) study at the University of California San Francisco (since 2004) were confirmed in the Swiss Multiple Sclerosis Cohort (SMSC), a multicenter study in 8 centers since 2012. Data were extracted from EPIC in April 2022 (sampling July 1, 2004, to December 20, 2016) and SMSC in December 2022 (sampling June 6, 2012, to September 2, 2021). The study included 2 observational cohorts in tertiary MS centers. All participants of both cohorts with available NfL results were included in the study, and no eligible participants were excluded or declined to participate., Exposure: Association between NfL z scores and CDW., Main Outcome Measures: CDW was defined as Expanded Disability Status Scale (EDSS) worsening that was confirmed after 6 or more months and classified into CDW associated with clinical relapses (CDW-R) or independent of clinical relapses (CDW-NR). Visits were classified in relation to the disability worsening events into CDW(-2) for 2 visits preceding event, CDW(-1) for directly preceding event, CDW(event) for first diagnosis of EDSS increase, and the confirmation visit. Mixed linear and Cox regression models were used to evaluate NfL dynamics and to assess the association of NfL with future CDW, respectively., Results: A total of 3906 EPIC visits (609 participants; median [IQR] age, 42.0 [35.0-50.0] years; 424 female [69.6%]) and 8901 SMSC visits (1290 participants; median [IQR] age, 41.2 [32.5-49.9] years; 850 female [65.9%]) were included. In CDW-R (EPIC, 36 events; SMSC, 93 events), NfL z scores were 0.71 (95% CI, 0.35-1.07; P < .001) units higher at CDW-R(-1) in EPIC and 0.32 (95% CI, 0.14-0.49; P < .001) in SMSC compared with stable MS samples. NfL elevation could be detected preceding CDW-NR (EPIC, 191 events; SMSC, 342 events) at CDW-NR(-2) (EPIC: 0.23; 95% CI, 0.01-0.45; P = .04; SMSC: 0.28; 95% CI, 0.18-0.37; P < .001) and at CDW-NR(-1) (EPIC: 0.27; 95% CI, 0.11-0.44; P < .001; SMSC: 0.09; 95% CI, 0-0.18; P = .06). Those findings were replicated in the subgroup with relapsing-remitting MS. Time-to-event analysis confirmed the association between NfL levels and future CDW-R within approximately 1 year and CDW-NR (in approximately 1-2 years)., Conclusions and Relevance: This cohort study documents the occurrence of NfL elevation in advance of clinical worsening and may hint to a potential window of ongoing dynamic central nervous system pathology that precedes the diagnosis of CDW.

Background: Detecting new and enlarged lesions in multiple sclerosis (MS) patients is needed to determine their disease activity. LeMan-PV is a software embedded in the scanner reconstruction system of one vendor, which automatically assesses new and enlarged white matter lesions (NELs) in the follow-up of MS patients; however, multicenter validation studies are lacking., Purpose: To assess the accuracy of LeMan-PV for the longitudinal detection NEL white-matter MS lesions in a multicenter clinical setting., Study Type: Retrospective, longitudinal., Subjects: A total of 206 patients with a definitive MS diagnosis and at least two follow-up MRI studies from five centers participating in the Swiss Multiple Sclerosis Cohort study. Mean age at first follow-up = 45.2 years (range: 36.9-52.8 years); 70 males., Field Strength/sequence: Fluid attenuated inversion recovery (FLAIR) and T1-weighted magnetization prepared rapid gradient echo (T1-MPRAGE) sequences at 1.5 T and 3 T., Assessment: The study included 313 MRI pairs of datasets. Data were analyzed with LeMan-PV and compared with a manual "reference standard" provided by a neuroradiologist. A second rater (neurologist) performed the same analysis in a subset of MRI pairs to evaluate the rating-accuracy. The Sensitivity (Se), Specificity (Sp), Accuracy (Acc), F1-score, lesion-wise False-Positive-Rate (aFPR), and other measures were used to assess LeMan-PV performance for the detection of NEL at 1.5 T and 3 T. The performance was also evaluated in the subgroup of 123 MRI pairs at 3 T., Statistical Tests: Intraclass correlation coefficient (ICC) and Cohen's kappa (CK) were used to evaluate the agreement between readers., Results: The interreader agreement was high for detecting new lesions (ICC = 0.97, Pvalue < 10 -20 , CK = 0.82, P value = 0) and good (ICC = 0.75, P value < 10 -12 , CK = 0.68, P value = 0) for detecting enlarged lesions. Across all centers, scanner field strengths (1.5 T, 3 T), and for NEL, LeMan-PV achieved: Acc = 61%, Se = 65%, Sp = 60%, F1-score = 0.44, aFPR = 1.31. When both follow-ups were acquired at 3 T, LeMan-PV accuracy was higher (Acc = 66%, Se = 66%, Sp = 66%, F1-score = 0.28, aFPR = 3.03)., Data Conclusion: In this multicenter study using clinical data settings acquired at 1.5 T and 3 T, and variations in MRI protocols, LeMan-PV showed similar sensitivity in detecting NEL with respect to other recent 3 T multicentric studies based on neural networks. While LeMan-PV performance is not optimal, its main advantage is that it provides automated clinical decision support integrated into the radiological-routine flow., Evidence Level: 4 TECHNICAL EFFICACY: Stage 2., (© 2023 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Despite strong recommendations for coronavirus disease 2019 (Covid-19) vaccination by multiple sclerosis (MS) organizations, some persons with MS (pwMS) remain vaccine hesitant. The Swiss MS Registry conducted a survey to explore Covid-19 vaccine hesitancy, self-reported side effects and changes in MS symptoms following vaccination in adult pwMS., Methods: Self-reported data were analyzed cross-sectionally. Multivariable logistic regression was used to explore participant characteristics associated with Covid-19 vaccine hesitancy., Results: Of 849 respondents, 73 (8.6%) were unvaccinated. Hesitation to vaccinate was most often a personal preference (N = 42, 57.53%). Factors negatively associated with vaccine hesitancy included older age (OR = 0.97 per year, 95% CI [0.94, 0.99]) and regularly seeing healthcare professionals (OR = 0.25, 95% CI [0.07, 0.85]). A history of confirmed Covid-19 infection (OR = 3.38, 95% CI [1.69, 6.77]) and being underweight (OR = 4.50, 95% CI [1.52, 13.36]) were positively associated with vaccine hesitancy. Of 768 participants who provided information, 320 (41.2%) and 351 (45.2%) reported vaccination side effects after the first and second vaccinations, respectively. Changes in MS symptoms were reported by 49 (6.3%) participants after the first and 67 (9.0%) participants after the second vaccination, and were most often described as increased or new-onset fatigue (N = 17/49 (34.7%) after the first and N = 21/67 (31.3%) after the second dose)., Conclusions: Covid-19 vaccine hesitancy was low among surveyed pwMS. The risk of vaccine hesitancy was higher among younger pwMS, those with a history of Covid-19 infection, and those without regular contact with healthcare professionals., Competing Interests: Declaration of Competing Interest Mina Stanikić reports employment by Roche branch in Serbia, Roche d.o.o., from February 2019 to February 2020. Christian P Kamm has received honoraria for lectures as well as research support from Biogen, Novartis, Almirall, Teva, Merck, Sanofi Genzyme, Roche, Janssen, Eli Lilly, Celgene and the Swiss MS Society. Ente Ospedaliero Cantonale (employer) received compensation for Chiara Zecca's speaking activities, consulting fees, or research grants from Almirall, Biogen Idec, Bristol Meyer Squibb, Lundbeck, Merck, Novartis, Sanofi, Teva Pharma, Roche. Chiara Zecca is recipient of a grant for senior researchers provided by AFRI (Area Formazione accademica, Ricerca e Innovazione), EOC. Ente Ospedaliero Cantonale (employer) received compensation for Claudio Gobbi's speaking activities, consulting fees, or research grants from Almirall, Biogen Idec, Bristol Meyer Squibb, Lundbeck, Merck, Novartis, Sanofi, Teva Pharma, Roche. Anke Salmen has received speaker honoraria and/or travel compensation for activities with Bristol Myers Squibb, Novartis, Roche and research support of Baasch Medicus Foundation and the Swiss MS society, not related to this work. Andrew Chan has served on advisory boards for, and received funding for travel or speaker honoraria from Actelion-Janssen, Almirall, Bayer, Biogen, Celgene, Sanofi-Genzyme, Merck, Novartis, Roche and Teva, all for hospital research funds; and research support from Biogen, Genzyme and UCB. Eric Twomey, Milo A. Puhan, Vladeta Ajdacic-Gross and Viktor von Wyl declare no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Importance: There is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS)., Objective: To determine how serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) correlate with features of disease progression vs acute focal inflammation in MS and how they can prognosticate disease progression., Design, Setting, and Participants: Data were acquired in the longitudinal Swiss MS cohort (SMSC; a consortium of tertiary referral hospitals) from January 1, 2012, to October 20, 2022. The SMSC is a prospective, multicenter study performed in 8 centers in Switzerland. For this nested study, participants had to meet the following inclusion criteria: cohort 1, patients with MS and either stable or worsening disability and similar baseline Expanded Disability Status Scale scores with no relapses during the entire follow-up; and cohort 2, all SMSC study patients who had initiated and continued B-cell-depleting treatment (ie, ocrelizumab or rituximab)., Exposures: Patients received standard immunotherapies or were untreated., Main Outcomes and Measures: In cohort 1, sGFAP and sNfL levels were measured longitudinally using Simoa assays. Healthy control samples served as the reference. In cohort 2, sGFAP and sNfL levels were determined cross-sectionally., Results: This study included a total of 355 patients (103 [29.0%] in cohort 1: median [IQR] age, 42.1 [33.2-47.6] years; 73 female patients [70.9%]; and 252 [71.0%] in cohort 2: median [IQR] age, 44.3 [33.3-54.7] years; 156 female patients [61.9%]) and 259 healthy controls with a median [IQR] age of 44.3 [36.3-52.3] years and 177 female individuals (68.3%). sGFAP levels in controls increased as a function of age (1.5% per year; P < .001), were inversely correlated with BMI (-1.1% per BMI unit; P = .01), and were 14.9% higher in women than in men (P = .004). In cohort 1, patients with worsening progressive MS showed 50.9% higher sGFAP levels compared with those with stable MS after additional sNfL adjustment, whereas the 25% increase of sNfL disappeared after additional sGFAP adjustment. Higher sGFAP at baseline was associated with accelerated gray matter brain volume loss (per doubling: 0.24% per year; P < .001) but not white matter loss. sGFAP levels remained unchanged during disease exacerbations vs remission phases. In cohort 2, median (IQR) sGFAP z scores were higher in patients developing future confirmed disability worsening compared with those with stable disability (1.94 [0.36-2.23] vs 0.71 [-0.13 to 1.73]; P = .002); this was not significant for sNfL. However, the combined elevation of z scores of both biomarkers resulted in a 4- to 5-fold increased risk of confirmed disability worsening (hazard ratio [HR], 4.09; 95% CI, 2.04-8.18; P < .001) and PIRA (HR, 4.71; 95% CI, 2.05-9.77; P < .001)., Conclusions and Relevance: Results of this cohort study suggest that sGFAP is a prognostic biomarker for future PIRA and revealed its complementary potential next to sNfL. sGFAP may serve as a useful biomarker for disease progression in MS in individual patient management and drug development.

Background: Multiple sclerosis (MS) impacts education, future career pathways and working capability and therefore may negatively impact the financial situation of persons with MS (pwMS) in Switzerland. We therefore investigated the financial situation and its influencing sociodemographic and disease-specific factors of pwMS compared to the general Swiss population with focus on material deprivation (MD)., Methods: Data on the financial situation of pwMS were collected via a specific questionnaire added to the regular, semi-annual follow-up assessments of the Swiss Multiple Sclerosis Registry. Questions were taken in an unmodified format from the standardized "Statistics on Income and Living Conditions" (SILC) questionnaire 2019 of the Federal Statistical Office of Switzerland which evaluates the financial situation of the general Swiss population, enabling a direct comparison of pwMS with the general Swiss population., Results: PwMS were 1.5 times more frequently affected by MD than the general Swiss population (6.3% of pwMS versus 4.2% of the general Swiss population) which was confirmed in a multivariable logistic regression analysis of pooled SILC and Swiss Multiple Sclerosis Registry (SMSR) data. High symptom burden, having only mandatory schooling, well as having a pending disability insurance application (as opposed to no application or receiving benefits) were associated with a higher odds of MD whereas higher education, older age, having a Swiss citizenship, living with a spouse or a partner or being currently employed were independently associated with a lower odds of MD., Conclusion: MS has a negative impact on the financial situation and is associated with MD. PwMS with a high symptom burden at the transition from work force to receiving disability benefits appeared to be vulnerable for MD. Higher education, older age, having a Swiss citizenship, living with a spouse or a partner or being currently employed were independently associated with a lower odds of MD., Competing Interests: Declaration of Competing Interest Kamm CP has received honoraria for lectures as well as research support from Biogen, Novartis, Almirall, Teva, Merck, Sanofi Genzyme, Roche, Janssen, Eli Lilly, Celgene and the Swiss MS Society (SMSG). Sanak L has no disclosures to report. Von Wyl V has no disclosures to report. Chan A has received speakers’/board honoraria from Actelion (Janssen/J&J), Almirall, Bayer, Biogen, Celgene (BMS), Genzyme, Merck KGaA (Darmstadt, Germany), Novartis, Roche, and Teva, all for hospital research funds. He received research support from Biogen, Genzyme, and UCB, the European Union, and the Swiss National Foundation. He serves as associate editor of the European Journal of Neurology, on the editorial board for Clinical and Translational Neuroscience and as topic editor for the Journal of International Medical Research. Stanikic M reports employment by Roche branch in Serbia, Roche d.o.o. from February 2019 to February 2020. Zina-Mary Manjaly has no disclosures to report. Zecca C is recipient of a grant for senior reseachers provided by AFRI (Area Formazione accademica, Ricerca e Innovazione), EOC. Ente Ospedaliero Cantonale (employer) received compensation for C.Z.’s speaking activities, consulting fees, or research grants from Almirall, Biogen Idec, Bristol Meyer Squibb, Lundbeck, Merck, Novartis, Sanofi, Teva Pharma, Roche. Calabrese P. has received speakers’/board honoraria from Almirall, Biogen, Celgene (BMS), Genzyme, Novartis, Roche, Schwabe and Teva., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: To evaluate the combined contribution of brain and cervical cord damage in predicting 5-year clinical worsening in a multicentre cohort of definite multiple sclerosis (MS) patients., Methods: Baseline 3.0T brain and cervical cord T2-weighted and three-dimensional T1-weighted MRI was acquired in 367 patients with MS (326 relapse-onset and 41 progressive-onset) and 179 healthy controls. Expanded Disability Status Scale (EDSS) score was obtained at baseline and after a median follow-up of 5.1 years (IQR=4.8-5.2). At follow-up, patients were classified as clinically stable/worsened according to EDSS changes. Generalised linear mixed models identified predictors of clinical worsening, evolution to secondary progressive (SP) MS and reaching EDSS=3.0, 4.0 and 6.0 milestones at 5 years., Results: At follow-up, 120/367 (33%) patients with MS worsened clinically; 36/256 (14%) patients with relapsing-remitting evolved to SPMS. Baseline predictors of EDSS worsening were progressive-onset versus relapse-onset MS (standardised beta (β)=0.97), higher EDSS (β=0.41), higher cord lesion number (β=0.41), lower normalised cortical volume (β=-0.15) and lower cord area (β=-0.28) (C-index=0.81). Older age (β=0.86), higher EDSS (β=1.40) and cord lesion number (β=0.87) independently predicted SPMS conversion (C-index=0.91). Predictors of reaching EDSS=3.0 after 5 years were higher baseline EDSS (β=1.49), cord lesion number (β=1.02) and lower normalised cortical volume (β=-0.56) (C-index=0.88). Baseline age (β=0.30), higher EDSS (β=2.03), higher cord lesion number (β=0.66) and lower cord area (β=-0.41) predicted EDSS=4.0 (C-index=0.92). Finally, higher baseline EDSS (β=1.87) and cord lesion number (β=0.54) predicted EDSS=6.0 (C-index=0.91)., Conclusions: Spinal cord damage and, to a lesser extent, cortical volume loss helped predicting worse 5-year clinical outcomes in MS., Competing Interests: Competing interests: MAR received speakers’ honoraria from Bayer, Biogen Idec, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche and Teva, and receives research support from the MS Society of Canada and Fondazione Italiana Sclerosi Multipla. PV received speakers’ honoraria from Biogen Idec. AM received speakers’ honoraria from Biogen Idec. Ente Ospedaliero Cantonale (EOC, employer) received compensation for CG’s speaking activities, consulting fees or research grants from AbbVie, Almirall, Biogen Idec, Bristol Myers Squibb, Genzyme, Lundbeck, Merck, Novartis, Teva Pharma, Roche. EOC received compensation for CZ’s speaking activities, consulting fees or research grants from AbbVie, Almirall, Biogen Idec, Bristol Myers Squibb, Genzyme, Lundbeck, Merck, Novartis, Teva Pharma, Roche. CZ holds a grant from EOC for senior researchers. FB serves as an Editorial Board member of Neuroradiology, Neurology, Multiple Sclerosis Journal and Radiology; he has serves as steering committee or IDMC member for Biogen, Merck, Prothena, EISAI accepted consulting fees from Biogen-IDEC, IXICO Ltd, Jansen Merck Serono, Novartis, and Roche. He has received grants from the Amyloid Imaging to Prevent Alzheimer’s Disease Initiative (Innovative Medicines Initiative), the European Progression of Neurological Disease Initiative (H2020), UK MS Society, Dutch MS Society, NIHR University College London Hospital Biomedical Research Centre, the European Committee for Treatment and Research in Multiple Sclerosis and the MRI in MS network. MMS serves on the Editorial Boards of Neurology and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, ARSEP, Amsterdam Neuroscience and ZonMW and has received compensation for consulting services or speaker honoraria from Atara Biotherapeutics, Biogen, Celgene/Bristol Myers Squibb, Sanofi-Genzyme, MedDay and Merck. EMS has nothing to disclose. HV has received research grants from Merck Serono, Novartis and Teva, speaker honoraria from Novartis, and consulting fees from Merck Serono; all funds paid directly to his institution. AG received speaker and consulting fees from Biogen, Bristol Myers Squibb, Coloplast, Merck Serono, Mylan, Novartis, Roche, Sanofi-Genzyme, and Teva. AB received speaker’s honoraria and/or compensation for consulting service and/or speaking activities from Biogen, Roche, Merck, Celgene, Coloplast and Genzyme. OC is NIHR Research Professor (RP-2017-08-ST2-004). She also receives funding from MRC, UK and National MS Society and, NIHR and Rosetrees Trust. MY has nothing to disclose. AR serves on scientific advisory boards for Novartis, Sanofi-Genzyme, SyntheticMR and OLEA Medical, and has received speaker honoraria from Bayer, Sanofi-Genzyme, Merck-Serono, Teva Pharmaceutical Industries, Novartis, Roche, BMS and Biogen Idec. JS-G declares grants and personal fees from Genzyme, Almirall, Biogen, Celgene, Merck, Bayer, Biopass, Bial, Novartis, Roche and Teva, outside the submitted work; JS-G is Associate Editor of Multiple Sclerosis Journal and Scientific Director of Revista de Neurologia. JP has received support for scientific meetings and honoraria for advisory work from Merck Serono, Novartis, Chugai, Alexion, Roche, Medimmune, Argenx, UCB, Mitsubishi, Amplo, Janssen, Sanofi. Grants from Alexion, Roche, Medimmune, Amplo biotechnology and UCB. Patent ref P37347WO and licence agreement Numares multimarker MS diagnostics Shares in AstraZeneca. Acknowledges Partial funding by Highly specialised services NHS England. LM was funded by an MRC fellowship (G0901996). AG has received honoraria for lecturing, travel expenses for attending meetings and financial support for research from Novartis, Biogen, Merck Serono, Sanofi-Genzyme, Roche. PE has received travel expenses from Bayer Health Care and is member of the Editorial Board of the Journal of Neuroimaging. CL received a research grant by the German Federal Ministry for Education and Research, BMBF, German Competence Network Multiple Sclerosis (KKNMS), grant no.01GI1601I, has received consulting and speaker’s honoraria from Biogen Idec, Bayer Schering, Daiichi Sanykyo, Merck Serono, Novartis, Sanofi, Genzyme and TEVA. BB received financial support by the German Federal Ministry for Education and Research, BMBF, German Competence Network Multiple Sclerosis (KKNMS), grant no.01GI1601I. MM reports grants and personal fees from Sanofi Genzyme, Merck Serono, Novartis and Almirall. She was awarded a MAGNIMS-ECTRIMS fellowship in 2020. PP received speakers’ honoraria from Biogen Idec, Novartis, Bristol, Myers Squibb, Genzyme and Excemed and was supported by a senior research fellowship FISM—Fondazione Italiana Sclerosi Multipla—cod. 2019/BS/009 and financed or co-financed with the ‘5 per mille’ public funding. MF is Editor-in-Chief of the Journal of Neurology and Associate Editor of Human Brain Mapping, Neurological Sciences and Radiology; received compensation for consulting services and/or speaking activities from Almirall, Alexion, Bayer, Biogen Idec, Celgene, Eli Lilly, Genzyme, Merck-Serono, Neopharmed Gentili, Novartis, Roche, Sanofi, Takeda and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla and ARiSLA (Fondazione Italiana di Ricerca per la SLA)., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Informal and formal volunteering engagement is a proxy for social integration and may have beneficial effects for physical and mental well-being in persons with multiple sclerosis (pwMS). As literature on the topic among the pwMS is lacking, this study aimed to determine frequency and type of volunteering performed by pwMS and to identify factors associated with volunteering., Methods: Cross-sectional, self-reported data of 615 pwMS participating in the Swiss Multiple Sclerosis Registry were analyzed using descriptive statistics to determine frequency and type of volunteering engagement. Univariable and multivariable generalized linear models with binomial distribution and log link function were used to identify factors associated with volunteering. Age, sex, employment status and gait disability were added to the multivariable model as fixed confounders. Sociodemographic, health-, work- and daily activity-related factors were included in the analysis., Results: About one third (29.4%) of participants reported engagement in volunteering activities, most often through charities (16.02%) and cultural organizations (14.36%). In the multivariable model, participants who had a university degree were more likely to volunteer than those with lower level of education (RR = 1.48 95% CI [1.14; 1.91]). The ability to pursue daily activities (as measured by the EQ-5D subscale) was strongly associated with participation in volunteering among pwMS. Compared with pwMS who had no or only slight limitations in daily activities, those with severe problems were markedly less likely to engage in volunteering (RR = 0.41, 95% CI [0.21; 0.80]) . Finally, pwMS who reported caring for and supporting their family (i.e., being a homemaker) were more likely to engage in volunteering activities than those who did not (RR = 1.52, 95% CI [1.15; 2.01])., Conclusion: Nearly one in three pwMS engaged in diverse volunteering activities. Having a university degree, being less limited in daily activities and being a homemaker increased the probability of pursuing volunteering activities. Contingent on individual-level motivations, resources or physical abilities, pwMS who experience challenges in performing daily activities or social barriers should be made aware of barrier-free offers of socially inclusive and volunteering activities, often provided by the national MS societies and health leagues., Competing Interests: Declaration of Competing Interest Mina Stanikić reports employment by Roche branch in Serbia, Roche d.o.o., from February 2019 to February 2020. The employer of Chiara Zecca receives support for advisor activities, speaking or grants from Celgene, Genzyme, Lilly, Merck, Novartis, Roche, and grants from Abbvie, Almirall, Biogen Idec, Celgene, Genzyme, Lilly, Merck, Novartis, Roche, Teva Pharma. Pasquale Calabrese has received honoraria for speaking at scientific meetings, serving at scientific advisory boards and consulting activities from Abbvie, Actelion, Almirall, Bayer-Schering, Biogen, EISAI, Lundbeck, Merck Serono, Novartis, Sanofi-Aventis and Teva. He also receives research grants from the Swiss Multiple Sclerosis Society (SMSG), and the Swiss National Research Foundation. Mathias Mettler, Urban Schwegler, Chloé Sieber, Vladeta Ajdacic-Gross, Stephanie Rodgers, Christina Haag, Susanne Kägi, Irene Rapold and Viktor von Wyl declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Objectives: Some disease-modifying treatments impair response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in multiple sclerosis (MS), potentially increasing the risk of breakthrough infections. We aimed to investigate longitudinal SARS-CoV-2 antibody dynamics and memory B cells after 2 and 3 messenger RNA (mRNA) vaccine doses and their association with the risk of COVID-19 in patients with MS on different treatments over 1 year., Methods: Prospective observational cohort study in patients with MS undergoing SARS-CoV-2 mRNA vaccinations. Antispike (anti-S) immunoglobulin G (IgG) titers were measured by chemiluminescence microparticle immunoassay. Frequencies of spike-specific memory B cells were measured on polyclonal stimulation of peripheral blood mononuclear cells and screening of secreted antibodies by ELISA., Results: We recruited 120 patients with MS (58 on anti-CD20 antibodies, 9 on sphingosine 1-phosphate (S1P) receptor modulators, 15 on cladribine, 24 on teriflunomide (TFL), and 14 untreated) and collected 392 samples up to 10.8 months after 2 vaccine doses. When compared with untreated patients, anti-CD20 antibodies (β = -2.07, p < 0.001) and S1P modulators (β = -2.02, p < 0.001) were associated with lower anti-S IgG, while TFL and cladribine were not. Anti-S IgG decreased with months since vaccine (β = -0.14, p < 0.001), independently of treatments. Within anti-CD20 patients, anti-S IgG remained higher in those with greater baseline B-cell counts and were not influenced by postvaccine anti-CD20 infusions. Anti-S IgG increase after a 3rd vaccine was mild on anti-CD20 and S1P modulators. Spike-specific memory B-cell responses were weaker on S1P modulators and anti-CD20 than on TFL and influenced by postvaccine anti-CD20 infusions. The frequency of breakthrough infections was comparable between DMTs, but the risk of COVID-19 was predicted by the last measured anti-S IgG titer before infection (OR = 0.56, 95% CI = 0.37-0.86, p = 0.008)., Discussion: Postvaccine anti-S IgG titers decrease over time regardless of MS treatment and are associated with breakthrough COVID-19. Both humoral and specific memory B-cell responses are diminished on S1P modulators. Within anti-CD20-treated patients, B-cell count at first vaccine determines anti-S IgG production, whereas postvaccine anti-CD20 infusions negatively affect spike-specific memory B cells., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The aim of our study was to investigate whether self-reported feeling of loneliness (FoL) and COVID-19-specific health anxiety were associated with the presence of depressive symptoms during the first coronavirus disease 2019 (COVID-19) wave. Questionnaires of 603 persons of the Swiss Multiple Sclerosis Registry (SMSR) were cross-sectionally analyzed using descriptive and multivariable regression methods. The survey response rate was 63.9%. Depressive symptoms were assessed by the Beck Depression Inventory-Fast Screen (BDI-FS). COVID-19-specific health anxiety and FoL were measured using two 5-item Likert scaled pertinent questions. High scoring FoL (2.52, 95% confidence interval (CI) (2.06-2.98)) and/or COVID-19 specific health anxiety (1.36, 95% CI (0.87-1.85)) were significantly associated with depressive symptoms. Further stratification analysis showed that the impact of FoL on depressive symptoms affected all age groups. However, it was more pronounced in younger PwMS, whereas an impact of COVID-19 specific health anxiety on depressive symptoms was particularly observed in middle-aged PwMS. FoL and COVID-19-specific health anxiety were age-dependently associated with depressive symptoms during the first COVID-19 wave in Switzerland. Our findings could guide physicians, health authorities, and self-help groups to better accompany PwMS in times of public health crises., (© 2022. The Author(s).)

Background: Electronic health diaries hold promise in complementing standardized surveys in prospective health studies but are fraught with numerous methodological challenges., Objective: The study aimed to investigate participant characteristics and other factors associated with response to an electronic health diary campaign in persons with multiple sclerosis, identify recurrent topics in free-text diary entries, and assess the added value of structured diary entries with regard to current symptoms and medication intake when compared with survey-collected information., Methods: Data were collected by the Swiss Multiple Sclerosis Registry during a nested electronic health diary campaign and during a regular semiannual Swiss Multiple Sclerosis Registry follow-up survey serving as comparator. The characteristics of campaign participants were descriptively compared with those of nonparticipants. Diary content was analyzed using the Linguistic Inquiry and Word Count 2015 software (Pennebaker Conglomerates, Inc) and descriptive keyword analyses. The similarities between structured diary data and follow-up survey data on health-related quality of life, symptoms, and medication intake were examined using the Jaccard index., Results: Campaign participants (n=134; diary entries: n=815) were more often women, were not working full time, did not have a higher education degree, had a more advanced gait impairment, and were on average 5 years older (median age 52.5, IQR 43.25-59.75 years) than eligible nonparticipants (median age 47, IQR 38-55 years; n=524). Diary free-text entries (n=632; participants: n=100) most often contained references to the following standard Linguistic Inquiry and Word Count word categories: negative emotion (193/632, 30.5%), body parts or body functioning (191/632, 30.2%), health (94/632, 14.9%), or work (67/632, 10.6%). Analogously, the most frequently mentioned keywords (diary entries: n=526; participants: n=93) were "good," "day," and "work." Similarities between diary data and follow-up survey data, collected 14 months apart (median), were high for health-related quality of life and stable for slow-changing symptoms such as fatigue or gait disorder. Similarities were also comparatively high for drugs requiring a regular application, including interferon beta-1a (Avonex) and glatiramer acetate (Copaxone), and for modern oral therapies such as fingolimod (Gilenya) and teriflunomide (Aubagio)., Conclusions: Diary campaign participation seemed dependent on time availability and symptom burden and was enhanced by reminder emails. Electronic health diaries are a meaningful complement to regular structured surveys and can provide more detailed information regarding medication use and symptoms. However, they should ideally be embedded into promotional activities or tied to concrete research study tasks to enhance regular and long-term participation., (©Chloé Sieber, Deborah Chiavi, Christina Haag, Marco Kaufmann, Andrea B Horn, Holger Dressel, Chiara Zecca, Pasquale Calabrese, Caroline Pot, Christian Philipp Kamm, Viktor von Wyl, Swiss Multiple Sclerosis Registry. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 05.10.2022.)

Background and Objectives: To define the boundaries and the overlaps between fatigue, sleepiness and depression in patients with multiple sclerosis (MS) by using different tools for each dimension, including instrumental sleep analysis., Methods: In this cross-sectional, observational study, 71 MS patients (males/females: 20/51; mean age: 48.9 ± 10.5 years) filled in clinical questionnaires and performed polysomnography followed by maintenance of wakefulness test (MWT). Frequency and reciprocal overlap of sleepiness, fatigue and depression in MS were expressed by Eulero-Venn diagrams; standard multiple regression was used to assess the ability of symptoms to predict each other., Results: There was a high percentage of fatigued (70%), somnolent (45%) and depressed (27%) patients. Fatigue had the strongest overlap and correlated with both depression (beta: 0.52, p < 0.001) and sleepiness (beta: 0.74, p < 0.001). Somnolence and depression were nearly always accompanied by fatigue and were well differentiated from each other by MWT. Four MS subgroups were identified that had: (1) fatigue only; (2) fatigue and sleepiness (3) fatigue and depression; (4) fatigue, sleepiness and depression., Discussion: The subjective and objective tools are not able to clearly distinguish fatigue from sleepiness and depression, while only a test of vigilance can be helpful in separating somnolence and depression from each other., (© 2022. The Author(s).)

Background: Multiple sclerosis (MS) patients with cognitive impairment (CI) frequently suffer from sleep disturbances and emotional symptoms. The aim of this study was to investigate the relationship between CI and sleep disturbances and the role of anxiety and depression on this relationship in MS patients., Methods: Prospective cross-sectional study including 80 MS patients that underwent neurologic, cognitive, psychiatric assessment, and polysomnographic registration. Partial correlations analysis adjusted by demographic and clinical variables were used to investigate associations between cognitive and sleep measures. Moderator role effect of psychiatric symptoms was also explored with linear models., Results: Thirty-six MS patients had CI. In all patients, worse performances at global, memory and attention cognitive domains were correlated with reduced sleep efficacy and longer periods of nocturnal wake (NW), while poor attention performances were associated with reduced REM-sleep (r = 0.26, p = 0.022). Memory performances were also negatively correlated with anxiety (r = -0.27, p = 0.015). The relationship between NW and memory performances was moderated by trait anxiety (p < 0.001)., Conclusions: Our findings suggest that low sleep efficiency, NW, and reduced REM-sleep might affect cognitive abilities in MS. Higher trait anxiety appeared to impact on the relationship between increased NW and poor memory performances. Treatment of sleep and psychiatric disturbances may contribute to mitigating cognitive disorders in MS., (Copyright © 2022. Published by Elsevier B.V.)

Importance: The mechanisms driving neurodegeneration and brain atrophy in relapsing multiple sclerosis (RMS) are not completely understood., Objective: To determine whether disability progression independent of relapse activity (PIRA) in patients with RMS is associated with accelerated brain tissue loss., Design, Setting, and Participants: In this observational, longitudinal cohort study with median (IQR) follow-up of 3.2 years (2.0-4.9), data were acquired from January 2012 to September 2019 in a consortium of tertiary university and nonuniversity referral hospitals. Patients were included if they had regular clinical follow-up and at least 2 brain magnetic resonance imaging (MRI) scans suitable for volumetric analysis. Data were analyzed between January 2020 and March 2021., Exposures: According to the clinical evolution during the entire observation, patients were classified as those presenting (1) relapse activity only, (2) PIRA episodes only, (3) mixed activity, or (4) clinical stability., Main Outcomes and Measures: Mean difference in annual percentage change (MD-APC) in brain volume/cortical thickness between groups, calculated after propensity score matching. Brain atrophy rates, and their association with the variables of interest, were explored with linear mixed-effect models., Results: Included were 1904 brain MRI scans from 516 patients with RMS (67.4% female; mean [SD] age, 41.4 [11.1] years; median [IQR] Expanded Disability Status Scale score, 2.0 [1.5-3.0]). Scans with insufficient quality were excluded (n = 19). Radiological inflammatory activity was associated with increased atrophy rates in several brain compartments, while an increased annualized relapse rate was linked to accelerated deep gray matter (GM) volume loss. When compared with clinically stable patients, patients with PIRA had an increased rate of brain volume loss (MD-APC, -0.36; 95% CI, -0.60 to -0.12; P = .02), mainly driven by GM loss in the cerebral cortex. Patients who were relapsing presented increased whole brain atrophy (MD-APC, -0.18; 95% CI, -0.34 to -0.02; P = .04) with respect to clinically stable patients, with accelerated GM loss in both cerebral cortex and deep GM. No differences in brain atrophy rates were measured between patients with PIRA and those presenting relapse activity., Conclusions and Relevance: Our study shows that patients with RMS and PIRA exhibit accelerated brain atrophy, especially in the cerebral cortex. These results point to the need to recognize the insidious manifestations of PIRA in clinical practice and to further evaluate treatment strategies for patients with PIRA in clinical trials.

Background: Spatio-temporal evolution of cord atrophy in multiple sclerosis (MS) has not been investigated yet., Objective: To evaluate voxel-wise distribution and 1-year changes of cervical cord atrophy in a multicentre MS cohort., Methods: Baseline and 1-year 3D T1-weighted cervical cord scans and clinical evaluations of 54 healthy controls (HC) and 113 MS patients (14 clinically isolated syndromes (CIS), 77 relapsing-remitting (RR), 22 progressive (P)) were used to investigate voxel-wise cord volume loss in patients versus HC, 1-year volume changes and clinical correlations (SPM12)., Results: MS patients exhibited baseline cord atrophy versus HC at anterior and posterior/lateral C1/C2 and C4-C6 ( p < 0.05, corrected). While CIS patients showed baseline volume increase at C4 versus HC ( p < 0.001, uncorrected), RRMS exhibited posterior/lateral C1/C2 atrophy versus CIS, and PMS showed widespread cord atrophy versus RRMS ( p < 0.05, corrected). At 1 year, 13 patients had clinically worsened. Cord atrophy progressed in MS, driven by RRMS, at posterior/lateral C2 and C3-C6 ( p < 0.05, corrected). CIS patients showed no volume changes, while PMS showed circumscribed atrophy progression. Baseline cord atrophy at posterior/lateral C1/C2 and C3-C6 correlated with concomitant and 1-year disability ( r = -0.40/-0.62, p < 0.05, corrected)., Conclusions: Voxel-wise analysis characterized spinal cord neurodegeneration over 1 year across MS phenotypes and helped to explain baseline and 1-year disability.

Introduction: Several disease-modifying therapies (DMTs), covering a broad spectrum of mechanisms of action, have been approved by regulatory agencies for the treatment of relapsing-remitting multiple sclerosis (RRMS). However, only little is known about the current real-world treatment situation in Switzerland. Based on data from a diverse population of 668 persons with RRMS from the Swiss Multiple Sclerosis Registry (SMSR), the present study aims to fill this gap with a descriptive, cross-sectional approach., Methods: Data originated from the SMSR baseline questionnaire and follow-up surveys. Data on current health status and life situation in the last 6 months were extracted from the survey distributed throughout 2020 and 2021, while data on disease-modifying therapy (DMT) histories were included from preceding surveys. Initially, data was stratified into three DMT groups according to the current DMT status (NO (No DMT), CONTINUED (DMT started more than 6 months ago), and NEW (DMT started less than 6 months ago)). In a subsequent analysis, the sample was stratified into groups corresponding to the five most frequently prescribed DMTs. Self-reported outcomes including therapy discontinuation or interruption, relapses and side-effects in the last 6 months were analyzed per group. Life and health situation parameters were also determined and analyzed., Results: The study population consisted of 445 (66.6%) individuals belonging to the CONTINUED, 84 (12.6%) to the NEW, and 139 (20.8%) to the NO group. Within the NO group, 24 (17.3%) reported relapses. Furthermore, self-reported relapses (28 (33.3%)), side-effects (39 (46.4%)), and treatment discontinuations or interruptions (30 (35.7%)) occurred more frequently in the NEW compared to the CONTINUED group (37 (8.3%), 125 (28.1%), 8 (1.8%), respectively). The three groups also differed with respect to age, time since diagnosis, number of symptoms, DMT history, and health-related quality of life. The five most frequently prescribed DMTs included fingolimod (33.4%), dimethyl fumarate (25.0%), ocrelizumab (23.6%), natalizumab (10.6%) and teriflunomide (7.5%). The frequency of self-reported relapses ranged from 9.7% to 13.6%. Notable differences were found in the number of self-reported side-effects, ranging from 9.1% with natalizumab to 56.7% with dimethyl fumarate., Discussion: This cross-sectional analysis suggested that the majority of individuals with RRMS in Switzerland continuously receive tolerable DMT. However, groups not receiving DMT or struggling with side-effects or continued disease worsening while on DMT still persist. It is conceivable that the number of self-reported symptoms indicates the need for more detailed clarification of the DMT characteristics and expectations of treatment outcomes. Injectable DMTs no longer play a major role in the treatment of RRMS in Switzerland and a trend toward an early use of potent drugs is emerging., (Copyright © 2022. Published by Elsevier B.V.)

Background: In multiple sclerosis (MS), cortical, subcortical and infratentorial structural damage may have a differential contribution to clinical disability according to disease phases., Purpose: To determine the relative contributions of cortical, deep (D) grey matter (GM), cerebellar and cervical cord damage to MS disability milestones., Methods: Multi-centre 3T brain and cervical cord T 2 - and three-dimensional (3D) T 1 -weighted images were acquired from 198 MS patients (139 relapsing-remitting (RR) MS, 59 progressive (P) MS) and 67 healthy controls. Brain/cord lesion burden, cortical thickness (CTh), DGM and cerebellar volumetry and cord cross-sectional area (CSA) were quantified. Random forest analyses identified predictors of expanded disability status scale (EDSS) disability milestones (EDSS = 3.0, 4.0 and 6.0)., Results: MS patients had widespread atrophy in all investigated compartments versus controls ( p -range: ⩽0.001-0.05). Informative determinants of EDSS = 3.0 were cord CSA, brain lesion volume, frontal CTh and thalamic and cerebellar atrophy (out-of-bag (OOB) accuracy = 0.84, p -range: ⩽0.001-0.05). EDSS = 4.0 was mainly predicted by cerebellar and cord atrophy, frontal and sensorimotor CTh and cord lesion number (OOB accuracy = 0.84, p -range: ⩽0.001-0.04). Cervical cord CSA ( p = 0.001) and cord lesion number ( p = 0.003) predicted EDSS = 6.0 (OOB accuracy = 0.77)., Conclusion: Brain lesion burden, cortical and thalamic atrophy were the main determinants of EDSS = 3.0 and 4.0, while cord damage played a major contribution to EDSS = 6.0.

Study Objectives: To carry out an analysis of leg movement activity during sleep in a polysomnography dataset of patients with multiple sclerosis (MS) in comparison to idiopathic restless legs syndrome (iRLS) and healthy controls., Methods: In this cross-sectional, observational, instrumental study, 57 patients (males/females: 11/46; mean age 46.2 ± 10.2 years) with a diagnosis of MS underwent a telephone interview assessing the 5 standard diagnostic criteria for RLS and polysomnography. Sleep architecture and leg movement activity during sleep were subsequently compared: 1) 40 patients with MS without RLS (MS-RLS) vs 28 healthy controls; 2) 17 patients with MS with RLS (MS+RLS) vs 35 patients with iRLS; 3) MS+RLS vs MS-RLS., Results: MS-RLS and MS+RLS presented increased sleep latency, percentage of sleep stage N1, and reduced total sleep time compared to healthy controls and iRLS, respectively. The periodic limb movements during sleep (PLMS) index was higher in MS-RLS than in healthy controls ( P = .035) and lower in MS+RLS compared to iRLS ( P = .024). PLMS in MS+RLS were less periodic, less often bilateral, and with shorter single movements compared to the typical PLMS in iRLS., Conclusions: MS is a risk factor for RLS, PLMS, and for a lower sleep quality in comparison to healthy patients. PLMS in MS+RLS are fewer and shorter if compared to iRLS. Our results suggest a dissociation between motor (PLMS) and sensory symptoms (RLS sensory component) in RLS secondary to MS, with possible treatment implications., Citation: Ferri R, Sparasci D, Castelnovo A, et al. Leg movement activity during sleep in multiple sclerosis with and without restless legs syndrome. J Clin Sleep Med . 2022;18(1):11-20., (© 2022 American Academy of Sleep Medicine.)

Study Objectives: To assess the frequency of restless legs syndrome (RLS), periodic limb movements during sleep (PLMS), and their overlap in a large sample of patients with multiple sclerosis (MS). To compare clinical and paraclinical findings among four subgroups of patients: RLS-/PLMS- (patients without RLS and PLMS), RLS+/PLMS- (patients with RLS and without PLMS), RLS-/PLMS (patients without RLS and with PLMS), and RLS+/PLMS+ (patients with both RLS and PLMS)., Methods: In this cross-sectional, observational, instrumental study, 86 patients (M/F: 27/59; mean age 48.0 ± 10.8 years) with a diagnosis of MS underwent a telephone interview assessing the five standard diagnostic criteria for RLS. Seventy-six participants underwent polysomnography (PSG) and maintenance of wakefulness test (MWT). Instrumental and clinical findings were subsequently statistically compared to investigate their association with RLS and PLMS index (PLMSI)., Results: RLS and PLMS (PLMSI ≥15/h) frequency in patients with MS were of 31.4% and 31.6%, respectively. Among patients with RLS, 37.5% had a PLMSI of at least 15/h. RLS-/PLMS+ group showed higher wake after sleep onset (p = 0.01), stage shifts per hour (p = 0.03), increased stage N1 (p = 0.03), and reduction in stage N3 (p = 0.01) compared to RLS-/PLMS-. RLS had no influence on clinical and PSG parameters (p = 0.45)., Conclusions: RLS is highly frequent in patients with MS. The frequency of PLMS is comparable to the general population. The low percentage of patients with RLS having a high PLMSI, together with the absence of correlation between RLS and female gender and older age, supports the existence of a distinct symptomatic form of RLS in MS., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Neurogenic bowel dysfunctions (NBDs) in the form of both fecal incontinence (FI) and functional constipation (FC) are frequent in multiple sclerosis (MS) patients and significantly affect their quality of life. Therapeutic options are limited., Objective: To investigate effectiveness of percutaneous posterior tibial nerve stimulation (PTNS) in MS patients suffering from FI and FC., Methods: Prevalence and severity of FI and FC were prospectively collected among MS patients undergoing 12 weeks of PTNS for neurogenic bladder. The Cleveland Clinic Fecal Incontinence Score (CCFIS) and the Rome III criteria were used to define FI and FC, respectively. Subjective treatment satisfaction was estimated using the Benefit Satisfaction and Willingness to Continue (BSWC) questionnaire., Results: A total of 60 patients undergoing PTNS suffered from NBDs (25 FI+/FC+, 5 FI+/FC-, 30 FI-/FC+). Median CCFIS decreased after PTNS from 12.0 (11.0-13.0) to 8.5 (7.0-11.0, p  < 0.001), with particular improvements in liquid and flatal incontinence, pads' need, and lifestyle restrictions. Seven patients became FC free after PTNS and no patients developed FC during the study ( p  = 0.023). More than 50% of the patients were satisfied and willing to continue PTNS at study end., Conclusion: PTNS represents a valid minimally invasive alternative treatment for MS patients suffering from NBDs.

Background and Purpose: Fatigue is amongst the most frequent and disabling symptoms of multiple sclerosis and a close relation between fatigue and sleep quality has been hypothesized. In this study the contribution of sleep disturbances measured by clinical and polysomnographic parameters to fatigue in multiple sclerosis was investigated., Methods: This was a prospective instrumental study performed at the Neurocenter of Southern Switzerland. Demographic data and clinical characteristics including fatigue (as measured by the modified fatigue impact scale [MFIS]), neurological disability, psychiatric symptoms, medications and sleep-related variables were collected at baseline visit and by a home full-night polysomnography. The associations between sleep-related variables and the MFIS were tested using partial correlations adjusted by demographic and sleep-unrelated clinical factors., Results: Seventy-six patients were included in the study, of whom 53 (69.7%) had an MFIS ≥38 points (median 49.5, interquartile range 31.0-62.0). MFIS scores were positively associated with age, neurological disability, symptoms of depression and anxiety, and use of benzodiazepines and selective serotonin reuptake inhibitors. When adjusting for these variables, the presence of restless legs syndrome (RLS) (r = 0.37, p = 0.005) and periodic leg movements index (r = -0.33, p = 0.014) were associated with MFIS. Excessive daytime sleepiness, total sleep time, sleep efficiency, respiratory disturbances, and percentage of time spent in the different sleep stages (N1, N2, N3 and rapid eye movement) were not associated with fatigue., Conclusions: Multiple sclerosis patients with a diagnosis of RLS had significantly higher global fatigue scores compared to those without RLS. Future studies should investigate whether medical treatment of RLS can ameliorate fatigue., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: We aimed to determine in relapsing multiple sclerosis (MS) whether intrathecal synthesis of immunoglobulin (Ig) M and IgG is associated with outcomes reflecting inflammatory activity and chronic worsening., Methods: We compared cerebrospinal fluid analysis, clinical and magnetic resonance imaging data, and serum neurofilament light chain (sNfL) levels at baseline and follow-up in 530 patients with relapsing MS. Patients were categorized by the presence of oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (intrathecal fraction [IF]: IgG IF and IgM IF ). Relationships with the time to first relapse, sNfL concentrations, T2-weighted (T2w) lesions, MS Severity Score (MSSS), and time to initiation of high-efficacy therapy were analyzed in covariate-adjusted statistical models., Results: By categorical analysis, in patients with IgM IF the median time to first relapse was 28 months shorter and MSSS on average higher by 1.11 steps compared with patients without intrathecal immunoglobulin synthesis. Moreover, patients with IgM IF had higher sNfL concentrations, more new/enlarging T2w lesions, and higher total T2w lesion counts (all p ≤ 0.01). These associations were absent or equally smaller in patients who were positive for only OCGB or OCGB/IgG IF . Furthermore, quantitative analyses revealed that in patients with IgM IF  ≥ median, the time to first relapse and to initiation of high-efficacy therapy was shorter by 32 and by 203 months, respectively (both p < 0.01), in comparison to patients with IgM IF  < median. Dose-dependent associations were also found for IgM IF but not for IgG IF with magnetic resonance imaging-defined disease activity and sNfL., Interpretation: This large study supports the value of intrathecal IgM synthesis as an independent biomarker of disease activity and severity in relapsing MS. ANN NEUROL 2021;90:477-489., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Phase II and observational studies support the use of rituximab in multiple sclerosis. Standard protocols are lacking, but studies suggest comparable efficacy between low- and high-dose regimens., Objective: To evaluate effectiveness and safety of de-escalating rituximab dose from 1000 to 500 mg/6 months in multiple sclerosis., Methods: Patients were switched from rituximab 1000 to 500 mg/6 months and prospectively followed for 12 months. Relapses, disability, occurrence of brain/spinal magnetic resonance imaging (MRI) lesions, serum neurofilament light chain (NfL), CD19 +  B cell, and IgG concentrations were analyzed., Results: Fifty-nine patients were included (37 relapsing-remitting, 22 secondary progressive). No relapses occurred, with no difference in expanded disability status scale (EDSS) between baseline (4 (2.5-4.5) and 12 months (3.5 (2.5-5.5) p  = 0.284). Overall, three new T2 lesions appeared during follow-up. NfL concentration was stable between baseline (7.9 (5.9-45.2) pg/mL) and 12 months (9.1 (5.9-21.3) pg/mL, p  = 0.120). IgG concentrations decreased with greater rituximab load (coefficient = -0.439, p  = 0.041). IgG deficient patients had greater risk of infections (OR = 6.27, 95% CI = 1.71-22.9, p  = 0.005)., Conclusion: De-escalating rituximab dose from 1000 to 500 mg/6 months is safe, results in clinical and radiological stability, and does not affect serum NfL over 12 months. Rituximab load negatively influences IgG concentrations, and IgG deficient patients are at higher risk of infections.

Background: Longitudinal evolution of cortical thickness (CTh) in different MS phenotypes has been rarely studied., Aim: To investigate the regional pattern and 1-year progression of cortical thinning in relapsing-remitting (RR) and progressive (P) MS., Methods: 3T high-resolution T1-weighted magnetic resonance imaging (MRI) was obtained from 86 patients (75 RRMS, 11 PMS) and 34 healthy controls (HC) at three European sites at baseline and 1-year follow-up. Using FreeSurfer, baseline CTh between-group differences, longitudinal CTh changes and their correlations with clinical and MRI variables were assessed., Results: Baseline frontal, parietal and sensorimotor atrophy was found in MS versus HC. Such pattern was driven by RRMS, while PMS showed additional parietal, insular and sensorimotor cortical atrophy versus RRMS. At 1-year versus baseline, additional frontal and temporal cortical thinning was detected in RRMS patients, while a widespread CTh reduction was found in PMS patients (significant at time-by-group interaction vs RRMS). In MS, baseline fronto-parietal atrophy correlated with more severe disability and higher lesion volume. Baseline inferior parietal CTh decrease and 1-year temporal cortical thinning correlated with more severe disability., Conclusion: Parieto-temporal baseline CTh abnormalities and thinning pattern over time characterized the main MS clinical phenotypes and were associated with 1-year disability worsening.

Objective: To compare and characterize major depressive disorder (MDD) subtypes (i.e., pure atypical, pure melancholic and mixed atypical-melancholic) and depression symptoms in persons with multiple sclerosis (PwMS) with persons without MS (Pw/oMS) fulfilling the DSM-5 criteria for a past 12-month MDD., Methods: MDD in PwMS (n = 92) from the Swiss Multiple Sclerosis Registry was compared with Pw/oMS (n = 277) from a Swiss community-based study. Epidemiological MDD diagnoses were based on the Mini-SPIKE (shortened form of the Structured Psychopathological Interview and Rating of the Social Consequences for Epidemiology). Logistic and multinomial regression analyses (adjusted for sex, age, civil status, depression and severity) were computed for comparisons and characterization. Latent class analysis (LCA) was conducted to empirically identify depression subtypes in PwMS., Results: PwMS had a higher risk for the mixed atypical-melancholic MDD subtype (OR = 2.22, 95% CI = 1.03-4.80) compared to Pw/oMS. MDD in PwMS was specifically characterized by a higher risk of the two somatic atypical depression symptoms 'weight gain' (OR = 6.91, 95% CI = 2.20-21.70) and 'leaden paralysis' (OR = 3.03, 95% CI = 1.35-6.82) and the symptom 'irritable/angry' (OR = 3.18, 95% CI = 1.08-9.39)., Conclusions: MDD in PwMS was characterized by a higher risk for specific somatic atypical depression symptoms and the mixed atypical-melancholic MDD subtype. The pure atypical MDD subtype, however, did not differentiate between PwMS and Pw/oMS. Given the high phenomenological overlap with MS symptoms, the mixed atypical-melancholic MDD subtype represents a particular diagnostic challenge., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Gay matter (GM) involvement is clinically relevant in multiple sclerosis (MS). Using source-based morphometry (SBM), we characterized GM atrophy and its 1-year evolution across different MS phenotypes., Methods: Clinical and MRI data were obtained at 8 European sites from 170 healthy controls (HCs) and 398 patients with MS (34 with clinically isolated syndrome [CIS], 226 with relapsing-remitting MS [RRMS], 95 with secondary progressive MS [SPMS], and 43 with primary progressive MS [PPMS]). Fifty-seven HCs and 144 with MS underwent 1-year follow-up. Baseline GM loss, atrophy progression, and correlations with disability and 1-year clinical worsening were assessed., Results: SBM identified 26 cerebellar, subcortical, sensory, motor, and cognitive GM components. GM atrophy was found in patients with MS vs HCs in almost all components ( p range <0.001-0.04). Compared to HCs, patients with CIS showed circumscribed subcortical, cerebellar, temporal, and salience GM atrophy, while patients with RRMS exhibited widespread GM atrophy. Cerebellar, subcortical, sensorimotor, salience, and frontoparietal GM atrophy was found in patients with PPMS vs HCs and in patients with SPMS vs those with RRMS. At 1 year, 21 (15%) patients had clinically worsened. GM atrophy progressed in MS in subcortical, cerebellar, sensorimotor, and fronto-temporo-parietal components. Baseline higher disability was associated ( R 2 = 0.65) with baseline lower normalized brain volume (β = -0.13, p = 0.001), greater sensorimotor GM atrophy (β = -0.12, p = 0.002), and longer disease duration (β = 0.09, p = 0.04). Baseline normalized GM volume (odds ratio 0.98, p = 0.008) and cerebellar GM atrophy (odds ratio 0.40, p = 0.01) independently predicted clinical worsening (area under the curve 0.83)., Conclusion: GM atrophy differed across disease phenotypes and progressed at 1 year in MS. In addition to global atrophy measures, sensorimotor and cerebellar GM atrophy explained baseline disability and clinical worsening., (© 2021 American Academy of Neurology.)

Background: Data on cancer prevalence and incidence in multiple sclerosis (MS) patients are controversial. This study is aimed at estimating cancer risk in MS patients., Methods: Nested case-control study using data collected between 01/01/1987 and 28/02/2016 from the United Kingdom Clinical Practice Research Datalink. Cancer diagnoses after first MS code (index date) was counted in 10,204 MS patients and 39,448 controls matched by sex, age, general practitioner, and registration year. Cancer rates were compared using multivariable Cox regression models. Ethics approval was not required., Results: Cancer was reported in 433 (4.41%) MS patients and 2014 (5.31%) controls after index date. Cancer risk was associated with gender (HR for female = 0.88, 95% CI = 0.81-0.96, p = 0.004), age at index date (HR = 1.06, 95% CI = 1.06-1.07, p < 0.001), and index year (HR = 1.01, 95% CI = 1.00-1.02, p = 0.016), but not with MS status (HR = 0.95, 95% CI = 0.86-1.05, p = 0.323). A significant interaction between MS status and index year was found (HR = 1.02, 95% CI = 1.00-1.04, p = 0.022). Cancer risk was positively associated with index year among MS patients (HR = 1.03, 95% CI = 1.01-1.05; p = 0.010), but not controls (HR = 1.01, 95% CI = 0.99-1.02; p = 0.144). MS patients compared to controls had no increased risk for any specific cancer type., Conclusions: Overall cancer risk was similar in multiple sclerosis patients and matched controls. The frequency of cancer diagnoses has increased over time among MS patients but not in controls.

Introduction: Physiotherapy may alleviate many multiple sclerosis (MS) symptoms, yet very little is known about physiotherapy accessibility and possible barriers in persons with MS (pwMS). We therefore aimed to elucidate physiotherapy use and possible access-barriers using data from 1493 pwMS from the Swiss Multiple Sclerosis Registry (SMSR), a patient-centered, longitudinal, observational MS study., Methods: We used data of the SMSR to investigate the question at hand in a multivariable logistic regression model with regularly receiving physiotherapy (yes/no) as the outcome. Potential explanatory variables were investigated following an AIC-driven model selection approach and consisted of a priori specified socio-demographic variables, health status, and personal or social mobility variables. As a last step, the impact of physiotherapist supply on regular use was assessed in the final model. Missing data were handled by multiple imputation (main analysis), and complete case sensitivity analyses were performed., Results: The main analysis included 1493 participants. In the multivariable logistic regression, positive associations were found between the use of physiotherapy and the following variables: having a primary-progressive MS (Odds Ratio (OR) [95% Confidence Intervals] 1.97 [1.18; 3.29]), being more severely impaired (EDSS 4-6.5 OR 1.84 [1.16; 2.91]), higher number of current symptoms (1 OR 3.31 [1.63; 6.74], 2-3 OR 3.43 [1.8; 6.53], 4-5 OR 4.44 [2.28; 8.66], 6-7 OR 4.06 [1.90; 8.70], 8-9 OR 3.87 [1.71; 8.75], being on disability pension (OR 1.75 [1.24; 2.46], or having applied for it OR 2.25 [1.31; 3.85]), having gait problems (OR 1.58 [1.11; 2.23]), having been in a rehabilitation clinic in the past 12 months (OR 4.43 [2.17; 9.03]), and currently being on disease-modifying treatment (OR 1.61 [1.12; 2.31]). Negative associations were found for a higher quality of life (OR 0.92 [0.85; 0.98]), working more than 80% (OR 0.47 [0.30; 0.75]) and being from the French language region (OR 0.66 [0.47; 0.94]). No association between physiotherapist supply and regular physiotherapy use was detected., Discussion: In a large, Swiss-based MS population, little evidence for socio-demographic barriers to physical therapy was found. Physiotherapy uptake was higher among pwMS with more impairments, lower health-related quality of life, or who have been discharged recently from inpatient rehabilitation. The uptake differences by language region warrant further investigations., (Copyright © 2020. Published by Elsevier B.V.)

Background: Rituximab, an anti-CD20 monoclonal antibody leading to B lymphocyte depletion, is increasingly used as an off-label treatment option for multiple sclerosis (MS)., Objective: To investigate the effectiveness and safety of rituximab in relapsing-remitting (RR) and progressive MS., Methods: This is a multicenter, retrospective study on consecutive MS patients treated off-label with rituximab in 22 Italian and 1 Swiss MS centers. Relapse rate, time to first relapse, Expanded Disability Status Scale (EDSS) progression, incidence of adverse events, and radiological outcomes from 2009 to 2019 were analyzed., Results: A total of 355/451 enrolled subjects had at least one follow-up visit and were included in the outcome analysis. Annualized relapse rate significantly decreases after rituximab initiation versus the pre-rituximab start year in RRMS (from 0.86 to 0.09, p  < .0001) and in secondary-progressive (SP) MS (from 0.34 to 0.06, p  < .0001) and had a slight decrease in primary-progressive (PP) MS patients (from 0.12 to 0.07, p  = 0.45). After 3 years from rituximab start, the proportion of patients with a confirmed EDSS progression was 14.6% in the RRMS group, 24.7% in the SPMS group, and 41.5% in the PPMS group. No major safety concerns arose., Conclusion: Consistently with other observational studies, our data show effectiveness of rituximab in reducing disease activity in patients with MS.

Background: Mechanisms associated with cervical spinal cord (CSC) and upper thoracic spinal cord (TSC) atrophy in multiple sclerosis (MS) are poorly understood., Objective: To assess the influence of brain, CSC and TSC T2-hyperintense lesions on cord atrophy and disability in MS., Methods: Thirty-four MS patients underwent 3T brain, cervical and thoracic cord magnetic resonance imaging (MRI) and Expanded Disability Status Scale (EDSS) score assessment. CSC/TSC lesion number and volume (LV), whole-brain and cortico-spinal tract (CST) LVs were obtained. Normalized whole CSC and upper TSC cross-sectional areas (CSAn) were also derived. Age- and sex-adjusted regression models assessed associations of brain/cord lesions with CSAn and EDSS and identified variables independently associated with CSAn and EDSS with a stepwise variable selection., Results: CSC CSAn (β = -0.36, p  = 0.03) and TSC CSAn (β = -0.60, p  < 0.001) were associated with CSC T2 LV. EDSS (median = 3.0) was correlated with CSC T2 LV (β = 0.42, p  = 0.01), brain (β = 0.34, p  = 0.04) and CST LV (β = 0.35, p  = 0.03). The multivariate analysis retained CSC LV as significant predictor of CSC CSAn ( R 2  = 0.20, p  = 0.023) and TSC CSAn ( R 2  = 0.51, p  < 0.001) and retained CSC and CST LVs as significant predictors of EDSS ( R 2  = 0.55, p  = 0.001)., Conclusions: CSC LV is an independent predictor of cord atrophy. When neurological impairment is relatively mild, central nervous system (CNS) lesion burden is a better correlate of disability than atrophy.

Background: Multiple sclerosis (MS) notably affects adults of working age. For persons with MS (PwMS), being employed enhances their quality of life and it may be regarded as an indicator of overall functioning. Thus, ensuring work participation in PwMS is of general public health interest., Objective: To examine relevant socio-demographic, MS-, health- and work-related factors, including psychosocial working conditions, associated with currently working PwMS in Switzerland and their expected work retention., Methods: Using cross-sectional data of PwMS in the Swiss MS Registry (n = 541, median age = 48 [IQR 40;55]), multivariable logistic regression models were computed. First, currently working PwMS were characterised in comparison with those not currently working. Second, expected work retention, operationalized as subjective judgement "likely to work in the same job in 2 years", was examined within the group of currently working PwMS., Results: The factors age (OR 0.96, 95% CI 0.92-0.99), sex (OR 0.28, 95% CI 0.13-0.60), highest achieved job position (OR 1.21, 95% CI 1.01-1.46), health-related quality of life (HRQoL) (OR 1.02, 95% CI 1.01-1.04) and the number of MS symptoms (OR 0.90, 95% CI 0.82-0.98) were associated with currently working PwMS. Moreover, HRQoL (OR 1.07, 95% CI 1.04-1.10) and psychosocial working conditions, such as job resources (e.g. autonomy, control or social support) (OR 2.83, 95% CI 1.50-5.33) and job demands (e.g. workload, time pressure) (OR 0.41, 95% CI 0.18-0.90) were important factors for expected work retention among this group., Conclusions: Resourceful psychosocial working conditions are crucial for PwMS to maintain employment. Employers could contribute to work retention among PwMS by creating a work environment with resourceful psychosocial working conditions and providing, for instance, social support.

Multiple sclerosis (MS) is a mainly demyelinating, autoimmune, and disabling neurological disease. In addition to well-known clinically evident symptoms such as coordination or motor problems, increasing attention has been posed to a constellation of less evident symptoms significantly contributing to the clinical impact of MS. Among others, sleep symptoms have been only recently explored. This systematic review summarizes objective sleep findings detected by using polysomnography and their relationship with clinical variables in MS patients. While it is well known that sleep disorders are frequent in MS, objective clinical data are still scarce. Literature based on subjective reports indicate sleep disorders as highly frequent in MS patients; however, objective data are still scarce. New large case-control instrumental investigations are warranted to establish the real objective entity and impact of sleep comorbidities., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Objective: Spinal cord atrophy is a clinically relevant feature of multiple sclerosis (MS), but longitudinal assessments on magnetic resonance imaging using segmentation-based methods suffer from measurement variability, especially in multicenter studies. We compared the generalized boundary shift integral (GBSI), a registration-based method, with a standard segmentation-based method., Methods: Baseline and 1-year spinal cord 3-dimensional T1-weighted images (1mm isotropic) were obtained from 282 patients (52 clinically isolated syndrome [CIS], 196 relapsing-remitting MS [RRMS], 34 progressive MS [PMS]), and 82 controls from 8 MAGNIMS (Magnetic Resonance Imaging in Multiple Sclerosis) sites on multimanufacturer and multi-field-strength scans. Spinal Cord Toolbox was used for C2-5 segmentation and cross-sectional area (CSA) calculation. After cord straightening and registration, GBSI measured atrophy based on the probabilistic boundary-shift region of interest. CSA and GBSI percentage annual volume change was calculated., Results: GBSI provided similar rates of atrophy, but reduced measurement variability compared to CSA in all MS subtypes (CIS: -0.95 ± 2.11% vs -1.19 ± 3.67%; RRMS: -1.74 ± 2.57% vs -1.74 ± 4.02%; PMS: -2.29 ± 2.40% vs -1.29 ± 3.20%) and healthy controls (0.02 ± 2.39% vs -0.56 ± 3.77%). GBSI performed better than CSA in differentiating healthy controls from CIS (area under the curve [AUC] = 0.66 vs 0.53; p = 0.03), RRMS (AUC = 0.73 vs 0.59; p < 0.001), PMS (AUC = 0.77 vs 0.53; p < 0.001), and patients with disability progression from patients without progression (AUC = 0.59 vs 0.50; p = 0.04). Sample size to detect 60% treatment effect on spinal cord atrophy over 1 year was lower for GBSI than CSA (CIS: 106 vs 830; RRMS: 95 vs 335; PMS: 44 vs 215; power = 80%; alpha = 5%)., Interpretation: The registration-based method (GBSI) allowed better separation between MS patients and healthy controls and improved statistical power, when compared with a conventional segmentation-based method (CSA), although it is still far from perfect. ANN NEUROL 2019 ANN NEUROL 2019;86:704-713., (© 2019 American Neurological Association.)

Background: Interferon beta (IFNB) and Glatiramer acetate, long-term first line disease modifying treatments (DMTs) for multiple sclerosis (MS), have different injection frequencies crucial for injection site related side effects. We aimed at investigating whether switching to intramuscular IFNB-1a injected once/week with the Avonex®Pen™ device improves treatment tolerability and quality of life in stable MS patients., Methods: Clinically stable MS patients, whom their treating neurologist switched from high frequency injectable DMTs to weekly intramuscular IFNB-1a because of bothersome injection site reactions, were included. Injection site and systemic tolerability were measured by a composite 100 mm visual analogue scale at screening, months 4 and 12. Treatment satisfaction, quality of life, relapses and EDSS progression were also recorded. The primary endpoint was change in injection site tolerability from screening to Month 4. Descriptive statistics and Wilcoxon paired signed-rank tests were applied., Results: The median injection site tolerability and systemic tolerability were significantly improved at months 4 (n = 36) and 12 (n = 33) [change -51.60 (IQR: -60.13, -39.60) mm (p < 0.0001); -26.00 (-54.00, 2.25) mm (p = 0.002)]. Median treatment satisfaction was significantly improved at month 12 [change of 18.00 (2.00, 47.50) mm (p = 0.0003)]. Physical and mental components of the SF-36 did not change significantly, and 30/33 (90.9%) and 33/33 (100%) patients were free from relapses and EDSS progression at month 12., Conclusions: Weekly intramuscular IFNB-1a may represent an alternative treatment option for clinically stable MS patients suffering from intolerable injection-related side effects under treatment with high frequency injectable DMTs., (Copyright © 2019. Published by Elsevier B.V.)

Importance: Therapeutic options for patients with secondary progressive multiple sclerosis (SPMS) are limited., Objective: To analyze disability progression in patients with SPMS treated with rituximab compared with matched control patients never treated with rituximab., Design, Setting, and Participants: This retrospective cohort study analyzed data obtained from patients with SPMS at 3 multiple sclerosis centers located in Basel and Lugano, Switzerland, and Amsterdam, the Netherlands, from 2004 to 2017. Patients were included for analysis if they had received a diagnosis of SPMS, were treated (57 eligible; 54 included) or never treated (504 eligible; 59 included) with rituximab, and had at least 1 follow-up visit. The variables used for propensity score matching were sex, age, Expanded Disability Status Scale (EDSS) score, and disease duration. Follow-up duration was up to 10 years, with a mean (SD) of 3.5 (2.6) years for rituximab-treated patients and 5.4 (2.4) years for controls in the total cohort and a mean (SD) of 3.5 (2.7) years for rituximab-treated patients and 4.8 (2.2) years for controls in the matched cohort., Exposures: Comparing EDSS score progression in patients with SPMS (treated with rituximab vs not treated with rituximab) using propensity score matching., Main Outcomes and Measures: The primary end point was progression of EDSS score after baseline, and the secondary end point was time to confirmed disability progression., Results: After 1:1 propensity score matching, 44 matched pairs (88 patients) were included in the analysis. At baseline, patients treated with rituximab had a mean (SD) age of 49.7 (10.0) years, mean (SD) disease duration of 18.2 (9.4) years, and mean (SD) EDSS score of 5.9 (1.4), and 26 (59%) were women, whereas controls had a mean (SD) age of 51.3 (7.4) years, mean (SD) disease duration of 19.4 (8.7) years, and mean (SD) EDSS score of 5.70 (1.29), and 27 (61%) were women. In the covariate-adjusted analysis of the matched set, patients with SPMS who were treated with rituximab had a significantly lower EDSS score during a mean (SD) follow-up of 3.5 (2.7) years (mean difference, -0.52; 95% CI, -0.79 to -0.26; P < .001). Time to confirmed disability progression was significantly delayed in the rituximab-treated group (hazard ratio, 0.49; 95% CI, 0.26-0.93; P = .03)., Conclusions and Relevance: In this study, patients with SPMS treated with rituximab had a significantly lower EDSS score for up to 10 years of follow-up and a significantly delayed confirmed progression compared with matched controls, suggesting that B-cell depletion by rituximab may be therapeutically beneficial in these patients. A prospective randomized clinical trial with a better level of evidence is needed to confirm the efficacy of rituximab in such patients.

Objective: Early diagnosis and treatment initiation significantly influence long-term disability outcome in multiple sclerosis (MS). We aimed at identifying prodromal symptoms of MS in primary care settings., Methods: This was a nested case-control study comparing the occurrence of various symptoms in MS patients versus controls at 0 to 2, 2 to 5, and 5 to 10 years before index date (first MS record). A total of 10,204 incident MS cases were identified within the United Kingdom Clinical Practice Research Datalink between January 1, 1987 and February 28, 2016 (median age = 47 years, interquartile range [IQR] = 39-57, females = 7,308 [71.6%]). Patients were matched to 39,448 controls with no MS record by sex, year of birth, general practitioner, and year of registration (age = 47 years, IQR = 39-56, females = 28,248 [71.6%]). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using conditional logistic regression., Results: MS patients had significantly higher risk of presenting up to 10 years prior to index date with gastric, intestinal, urinary, and anorectal disturbances, anxiety, depression, insomnia, fatigue, headache, and various types of pain. MS risk progressively increased with each additional symptom presented (0-2 years: OR = 1.51, 95% CI = 1.47-1.55, p < 0.001; 2-5 years: OR = 1.29, 95% CI = 1.25-1.33, p < 0.001; 5-10 years: OR = 1.20, 95% CI = 1.15-1.26, p < 0.001). Sensitivity analyses in patients with age at index < 40 years and no neurological disturbances prior to symptoms of interest showed consistent results., Interpretation: Various clinical disturbances precede MS diagnosis by several years, supporting a prodromal phase to the disease and improving our clinical knowledge of early MS. Integrating these symptoms in the diagnostic procedure may help earlier disease identification. Ann Neurol 2018., (© 2018 American Neurological Association.)

Background: Despite positive results from phase II and observational studies, Rituximab (RTX) is not currently approved for multiple sclerosis (MS) treatment and can only be used off-label., Objective: To characterize MS patients treated with RTX and investigate its effectiveness and safety in a clinical practice setting., Methods: Observational analysis of data collected from MS patients at the Neurocenter of Southern Switzerland. Relapses, EDSS worsening, MRI lesion accrual and "evidence of disease activity" (EDA) status were described by Cox regression. RTX and natalizumab treated patients were matched by propensity scores., Results: Out of 453 MS patients, 82 were treated with RTX, 43 (52.4%) relapsing-remitting (RRMS) and 39 (47.6%) progressive MS (median age = 48 [40-54] years, females n = 60 [73.2%], EDSS = 4.0 [2.5-6.0], median follow-up = 1.5 [1.0-2.5] years). Three relapses occurred and 59 (75.6%) patients had not EDA at follow-up end. Time to EDA was similar in RTX and natalizumab treated RRMS patients (HR = 1.64, 95%CI = 0.46-5.85, p = 0.44). Twenty-four patients presented non infusion related adverse events (infections), requiring RTX discontinuation in 6 individuals., Conclusion: These results provide further evidence for RTX being effective in MS treatment, to a similar extent to natalizumab in RRMS. Clinicians must be vigilant for the potential occurrence of infections.

Objective: Neurofilament light chains (NfL) are unique to neuronal cells, are shed to the cerebrospinal fluid (CSF), and are detectable at low concentrations in peripheral blood. Various diseases causing neuronal damage have resulted in elevated CSF concentrations. We explored the value of an ultrasensitive single-molecule array (Simoa) serum NfL (sNfL) assay in multiple sclerosis (MS)., Methods: sNfL levels were measured in healthy controls (HC, n = 254) and two independent MS cohorts: (1) cross-sectional with paired serum and CSF samples (n = 142), and (2) longitudinal with repeated serum sampling (n = 246, median follow-up = 3.1 years, interquartile range [IQR] = 2.0-4.0). We assessed their relation to concurrent clinical, imaging, and treatment parameters and to future clinical outcomes., Results: sNfL levels were higher in both MS cohorts than in HC (p < 0.001). We found a strong association between CSF NfL and sNfL (β = 0.589, p < 0.001). Patients with either brain or spinal (43.4pg/ml, IQR = 25.2-65.3) or both brain and spinal gadolinium-enhancing lesions (62.5pg/ml, IQR = 42.7-71.4) had higher sNfL than those without (29.6pg/ml, IQR = 20.9-41.8; β = 1.461, p = 0.005 and β = 1.902, p = 0.002, respectively). sNfL was independently associated with Expanded Disability Status Scale (EDSS) assessments (β = 1.105, p < 0.001) and presence of relapses (β = 1.430, p < 0.001). sNfL levels were lower under disease-modifying treatment (β = 0.818, p = 0.003). Patients with sNfL levels above the 80th, 90th, 95th, 97.5th, and 99th HC-based percentiles had higher risk of relapses (97.5th percentile: incidence rate ratio = 1.94, 95% confidence interval [CI] = 1.21-3.10, p = 0.006) and EDSS worsening (97.5th percentile: OR = 2.41, 95% CI = 1.07-5.42, p = 0.034)., Interpretation: These results support the value of sNfL as a sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS. Ann Neurol 2017;81:857-870., (© 2017 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Introduction and Hypothesis: Bladder dysfunction is a frequent symptom complex in patients with multiple sclerosis (MS) and often compromises the patient's quality of life. Pharmacotherapy has been poorly studied in the MS population showing contradictory results and reduced compliance owing to intolerable side effects. A new neuromodulation technique known as percutaneous tibial nerve stimulation (PTNS) has shown good efficacy and safety in the treatment of neurogenic and non-neurogenic lower urinary tract symptoms. In this article we review the literature and critically summarise the scientific evidence supporting the use of PTNS in the treatment of lower urinary tract symptoms (LUTS) in patients with MS., Methods: We performed a computer-aided literature search in PubMed and EMBASE up to January 2015 to identify randomised controlled trials, case-control trials and prospective observational cohort studies., Results: A total of 7 open-label, prospective studies and 313 MS patients were included. Three studies reported clinical and urodynamic outcomes at 3 to 9 months after PTNS; one study assessed the long-term efficacy of PTNS; two studies reported the acute effect of PTNS on urodynamic findings; one study assessed whether motor and sensory responses during PTNS could predict treatment outcome. None of the studies included a control group., Conclusions: Despite the very limited data PTNS seems an effective and safe treatment option in the management of LUTS in patients with MS.

The mechanisms leading to disability and the long-term efficacy and safety of disease modifying drugs (DMDs) in multiple sclerosis (MS) are unclear. We aimed at building a prospective cohort of MS patients with standardized collection of demographic, clinical, MRI data and body fluids that can be used to develop prognostic indicators and biomarkers of disease evolution and therapeutic response. The Swiss MS Cohort (SMSC) is a prospective observational study performed across seven Swiss MS centers including patients with MS, clinically isolated syndrome (CIS), radiologically isolated syndrome or neuromyelitis optica. Neurological and radiological assessments and biological samples are collected every 6-12 months. We recruited 872 patients (clinically isolated syndrome [CIS] 5.5%, relapsing-remitting MS [RRMS] 85.8%, primary progressive MS [PPMS] 3.5%, secondary progressive MS [SPMS] 5.2%) between June 2012 and July 2015. We performed 2,286 visits (median follow-up 398 days) and collected 2,274 serum, plasma and blood samples, 152 cerebrospinal fluid samples and 1,276 brain MRI scans. 158 relapses occurred and expanded disability status scale (EDSS) scores increased in PPMS, SPMS and RRMS patients experiencing relapses. Most RRMS patients were treated with fingolimod (33.4%), natalizumab (24.5%) or injectable DMDs (13.6%). The SMSC will provide relevant information regarding DMDs efficacy and safety and will serve as a comprehensive infrastructure available for nested research projects.

Background: There is a scarcity of reports comparing efficacy and tolerability of the multiple sclerosis (MS) disease-modifying therapies [DMTs; intramuscular interferon-β1a (IM IFNβ-1a), subcutaneous (SC) IFNβ-1a, SC IFNβ-1b, SC glatiramer acetate (GA)] in a real-world setting., Methods: This multicenter, non-interventional, retrospective cohort study analyzed data from 546 patients with clinically isolated or relapsing-remitting MS constantly treated with one DMT for 2 years. Annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) scores, and DMT tolerability were assessed., Results: Demographic data were comparable across DMTs. There were no significant differences between DMT groups in ARR during study year 1 (p = 0.277) or study year 2 (p = 0.670), or in EDSS change between years 1 and 2 (p = 0.624). Adverse events were frequent (39-56%) in all groups. Flu-like symptoms were less frequent with GA treatment (2.3% vs. IM IFNβ-1a, 46.7%; SC IFNβ-1a, 39.8%; SC IFNβ-1b, 25.8%; p < 0.05). Injection site reactions were less often reported with IM IFNβ-1a (10.5% vs. SC IFNβ-1a, 33.9%; SC IFNβ-1b, 38.3%; GA, 26.1%; p < 0.05)., Conclusions: All DMTs showed comparable effects on MS relapse rate and EDSS change, with IM IFNβ-1a and GA being more tolerable with respect to injection site reactions and flu-like symptoms, respectively., (Copyright © 2013 S. Karger AG, Basel.)