Stress and Multiple Sclerosis - Systematic review and meta-analysis of the association with disease onset, relapse risk and disability progression.

OBJECTIVE: This systematic review and meta-analysis address the evidence on the association of psychological stressors with onset of multiple sclerosis, inflammatory disease activity (relapses or new disease activity on magnetic resonance imaging, MRI) and disability progression. METHODS: PubMed was searched from 1946 to 15 July 2022. Studies and certain stressors were selected when they assessed stressors independent from stress elicited by the disease process itself. Risk of bias was assessed by the CASP Case Control Study Checklist and the CASP Cohort Study Checklist. Normal-Normal Hierarchical Model (NNHM) for random-effects meta-analysis was used in the Bayesian framework. RESULTS: 30 studies reporting data from 26 cohorts reporting on 24.781 cases could be identified. Ten studies addressed stressors and MS disease onset showing a weak to modest effect of psychological stressors. A meta-analysis of three studies investigating diagnosed stress disorders and MS risk showed a 1.87-fold (CI 1.061 to 3.429) increased MS risk. Stress and MS relapse risk were addressed in 19 heterogeneous studies. Meta-analyses from two independent cohorts investigating the same military threat of a population showed a threefold increased risk for relapses in association with war (relapse rate: 3.0, CI 1.56 to 5.81). In addition, two studies confirmed an association of stressful life events and MRI activity. Three studies of stressors and disease progression were included indicating some effect on disease progression. CONCLUSIONS: Taken together studies indicate a minor to modest impact of psychological stressors on disease onset, inflammatory activity and progression of MS. Possible case-selection bias and lack of confounder analysis were present in many studies.

Evolution of retinal degeneration and prediction of disease activity in relapsing and progressive multiple sclerosis.

Retinal optical coherence tomography has been identified as biomarker for disease progression in relapsing-remitting multiple sclerosis (RRMS), while the dynamics of retinal atrophy in progressive MS are less clear. We investigated retinal layer thickness changes in RRMS, primary and secondary progressive MS (PPMS, SPMS), and their prognostic value for disease activity. Here, we analyzed 2651 OCT measurements of 195 RRMS, 87 SPMS, 125 PPMS patients, and 98 controls from five German MS centers after quality control. Peripapillary and macular retinal nerve fiber layer (pRNFL, mRNFL) thickness predicted future relapses in all MS and RRMS patients while mRNFL and ganglion cell-inner plexiform layer (GCIPL) thickness predicted future MRI activity in RRMS (mRNFL, GCIPL) and PPMS (GCIPL). mRNFL thickness predicted future disability progression in PPMS. However, thickness change rates were subject to considerable amounts of measurement variability. In conclusion, retinal degeneration, most pronounced of pRNFL and GCIPL, occurs in all subtypes. Using the current state of technology, longitudinal assessments of retinal thickness may not be suitable on a single patient level.

"A second birthday"? Experiences of persons with multiple sclerosis treated with autologous hematopoietic stem cell transplantation-a qualitative interview study.

Introduction and objective: Autologous hematopoietic stem cell transplantation (aHSCT) is a promising treatment option for persons with multiple sclerosis (pwMS). Patients undergoing aHSCT face unique challenges in all aspects of life. In this study, we explored the lived experiences of pwMS undergoing aHSCT. Methods: Semi-structured interviews of 12 pwMS treated with aHSCT were conducted using a maximum variation sampling strategy. Interviews were transcribed verbatim and analyzed thematically using inductive and deductive categories. Results: Three major themes were identified: (1) preparing for aHSCT, (2) experiencing the procedure, and (3) post-treatment time. A difficult decision-making process, organizational effort, and funding difficulties characterized the preparation for transplantation. AHSCT was seen as a life-changing event accompanied by both psychological and physical stress, with an associated feeling of regaining control. The transplantation had a lasting positive effect on the lives of the interviewed pwMS. However, the early post-treatment time was characterized by successes and failures alike. Particularly the independently organized medical aftercare was perceived as challenging. Retrospective revaluation has led most pwMS to wish for earlier information provision about the treatment option of aHSCT during their treatment history. Conclusion: AHSCT had a clear impact on patients' physical and psycho-social health, influencing their perception of life and its quality. Assessing and attending to unmet needs of patients before, during, and after transplantation may positively influence their experience of aHSCT.

Childhood and adolescence factors and multiple sclerosis: results from the German National Cohort (NAKO).

BACKGROUND: Multiple Sclerosis (MS) represents the most common inflammatory neurological disease causing disability in early adulthood. Childhood and adolescence factors might be of relevance in the development of MS. We aimed to investigate the association between various factors (e.g., prematurity, breastfeeding, daycare attendance, weight history) and MS risk. METHODS: Data from the baseline assessment of the German National Cohort (NAKO) were used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the association between childhood and adolescence factors and risk of MS. Analyses stratified by sex were conducted. RESULTS: Among a total of 204,273 participants, 858 reported an MS diagnosis. Male sex was associated with a decreased MS risk (HR 0.48; 95% CI 0.41-0.56), while overweight (HR 2.03; 95% CI 1.41-2.94) and obesity (HR 1.89; 95% CI 1.02-3.48) at 18 years of age compared to normal weight were associated with increased MS risk. Having been breastfed for ≤ 4 months was associated with a decreased MS risk in men (HR 0.59; 95% CI 0.40-0.86) compared to no breastfeeding. No association with MS risk was observed for the remaining factors. CONCLUSIONS: Apart from overweight and obesity at the age of 18 years, we did not observe considerable associations with MS risk. The proportion of cases that can be explained by childhood and adolescence factors examined in this study was low. Further investigations of the association between the onset of overweight and obesity in childhood and adolescence and its interaction with physical activity and MS risk seem worthwhile.

Effectiveness of motivational interviewing on medication adherence for the prevention of recurrent stroke or transient ischemic attack: Systematic review of randomized controlled trials.

BACKGROUND AND PURPOSE: This systematic review examines the effectiveness of motivational interviewing (MI) on medication adherence for preventing recurrent stroke and transient ischemic attack (TIA). METHODS: MEDLINE (via PubMed), CINAHL, PsycINFO, CENTRAL, and ClinicalTrials.gov were searched from inception to 12 June 2023. Randomized controlled trials comparing MI with usual care or interventions without MI in participants with any stroke type were identified and summarized descriptively. Primary outcome was medication adherence. Secondary outcomes were quality of life (QoL) and different clinical outcomes. We assessed risk of bias with RoB 2 (revised Cochrane risk-of-bias tool) and intervention complexity with the iCAT_SR (intervention Complexity Assessment Tool for Systematic Reviews). RESULTS: We screened 691 records for eligibility and included four studies published in five articles. The studies included a total of 2751 participants, and three were multicentric. Three studies had a high risk of bias, and interventions varied in complexity. Two studies found significantly improved medication adherence, one at 9 (96.9% vs. 88.2%, risk ratio = 1.098, 95% confidence interval = 1.03-1.17) and one at 12 months (97.0% vs. 95.0%, p = 0.026), but not at other time points, whereas two other studies reported no significant changes. No significant differences were found in QoL or clinical outcomes. CONCLUSIONS: Evidence on MI appears inconclusive for improving medication adherence for recurrent stroke and TIA prevention, with no benefits on QoL and clinical outcomes. There is a need for robustly designed studies and process evaluations of MI as a complex intervention for people with stroke. REGISTRATION: PROSPERO (CRD42023433284).

Factors affecting driving performance in patients with Multiple Sclerosis - still an open question.

Background and objectives: Research on driving ability in people with multiple sclerosis (MS) suggests that they might be at risk for unsafe driving due to MS-related motor, visual, and cognitive impairment. Our first aim was to investigate differences in driving ability and performance between people with MS (PwMS) and those without any neurologic or psychiatric disease ("controls"). Secondly, we determined disease-related factors influencing driving ability in PwMS. Methods: We prospectively compared standardized performance in a driving simulator between 97 persons with early MS [mean (SD) = 6.4 (7.3) years since diagnosis, mean (SD) Expanded Disability Status Scale (EDSS) = 2.5 (1.4)] and 94 group-matched controls. Participants completed an extensive examination comprising questionnaires and assessments regarding driving, cognitive and psychological factors, as well as demographic and disease-related measures. Between-group comparisons of driving-relevant neuropsychological tests and driving performance were done. Correlations were performed to define demographic and disease-related factors on driving performance in MS. Results: In a driving simulator setting, PwMS had more driving accidents [T(188) = 2.762, p = 0.006], reacted slower to hazardous events [T(188) = 2.561, p = 0.011], made more driving errors [T(188) = 2.883, p = 0.004] and had a worse Driving Safety Score (DSS) [T(188) = 3.058, p = 0.003] than controls. The only disease-related measure to be associated with most driving outcomes was the Wechsler Block-Tapping test (WMS-R) backward: number of accidents (r = 0.28, p = 0.01), number of driving errors (r = 0.23, p = 0.05) and DSS (r = -0.23, p = 0.05). Conclusion: Driving performance in a simulator seems to be reduced in PwMS at an early stage of disease compared to controls, as a result of increased erroneous driving, reduced reaction time and higher accident rate. MS-related impairment in mobility, vision, cognition, and in psychological and demographic aspects showed no or only minimal association to driving ability, but impairment in different areas of cognition such as spatial short-term memory, working memory and selective attention correlated with the number of accidents, and might indicate a higher risk for driving errors and worse performance. These results show that driving ability is a complex skill with involvement of many different domains, which need further research.

CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis.

BACKGROUND: Progressive multiple sclerosis (MS) is characterized by compartmentalized smoldering neuroinflammation caused by the proliferation of immune cells residing in the central nervous system (CNS), including B cells. Although inflammatory activity can be prevented by immunomodulatory therapies during early disease, such therapies typically fail to halt disease progression. CD19 chimeric antigen receptor (CAR)-T cell therapies have revolutionized the field of hematologic malignancies. Although generally considered efficacious, serious adverse events associated with CAR-T cell therapies such as immune effector cell-associated neurotoxicity syndrome (ICANS) have been observed. Successful use of CD19 CAR-T cells in rheumatic diseases like systemic lupus erythematosus and neuroimmunological diseases like myasthenia gravis have recently been observed, suggesting possible application in other autoimmune diseases. METHODS: Here, we report the first individual treatment with a fully human CD19 CAR-T cell therapy (KYV-101) in two patients with progressive MS. FINDINGS: CD19 CAR-T cell administration resulted in acceptable safety profiles for both patients. No ICANS was observed despite detection of CD19 CAR-T cells in the cerebrospinal fluid. In case 1, intrathecal antibody production in the cerebrospinal fluid decreased notably after CAR-T cell infusion and was sustained through day 64. CONCLUSIONS: CD19 CAR-T cell administration in progressive MS resulted in an acceptable safety profile. CAR-T cell presence and expansion were observed in the cerebrospinal fluid without clinical signs of neurotoxicity, which, along with intrathecal antibody reduction, indicates expansion-dependent effects of CAR-T cells on CD19+ target cells in the CNS. Larger clinical studies assessing CD19 CAR-T cells in MS are warranted. FUNDING: Both individual treatments as well the generated data were not based on external funding.

Evaluating Relapse Knowledge in People with Multiple Sclerosis: A Cross-Sectional Study on the Development and Validation of the Relapse Knowledge Questionnaire.

BACKGROUND: Multiple sclerosis (MS) knowledge is a prerequisite for active patient engagement in medical decision-making. Treatment of relapses in MS is a clinical field with many uncertainties and each acute relapse requires decisions regarding possible options for action, indicating the need for patient involvement. However, there is no validated instrument assessing relapse knowledge in people with MS. Our study aims to develop a valid MS relapse questionnaire for use as an outcome instrument for educational interventions. METHODS: A multidisciplinary panel developed the relapse knowledge questionnaire (RKQ) based on a previously developed questionnaire. We tested the RKQ on MS patients for comprehensibility, usability and acceptance in qualitative think-aloud interviews and conducted a cross-sectional quantitative online survey to validate the questionnaire. People with suspected or confirmed relapsing-remitting MS and a recent relapse experience were eligible for inclusion. We checked normal distribution of the RKQ score and determined the item difficulty. Construct validity was analysed using correlational analysis. RESULTS: The final RKQ consists of 10 items. After minor changes of the RKQ during pre-testing (n = 2), pilot testing (n = 10) confirmed the usability and acceptance of the instrument. The subsequent validation study (n = 203) resulted in a mean item difficulty of 0.44, ranging from 0.18 to 0.83. Seven items were particularly difficult and answered incorrectly by more than 50 % of participants. Construct validity of the RKQ was satisfactory. The RKQ score correlated only weakly with participants' degree of education (|rp|>0.1), years since diagnosis (|rp|>0.1), and the intention to receive corticosteroids (|rp|>0.1). CONCLUSION: This study indicates the validity of the RKQ and proposes that the RKQ is a suitable instrument to assess relapse knowledge in people with MS participating in educational interventions.

Benefits of aHSCT over alemtuzumab in patients with multiple sclerosis besides disability and relapses: Sustained improvement in cognition and quality of life.

BACKGROUND: Autologous hematopoietic stem cell transplantation (aHSCT) exhibits promising results for multiple sclerosis (MS) in the short term. We investigated the long-term outcome differences in disease progression and cognitive impairment after aHSCT and alemtuzumab treatment. METHODS: 20 patients receiving aHSCT and 21 patients treated with alemtuzumab between 2007 and 2020 were included in this monocentric observational cohort study. The primary objective was to compare the outcome of both groups with regards to achieving No Evidence of Disease Activity (NEDA-3), defined by the absence of relapses, EDSS progression, and MRI activity. Secondary endpoints in the study included the assessment of neurocognitive functioning, quality of life (QoL), Multiple Sclerosis Functional Composite (MSFC), and EDSS improvement. RESULTS: Baseline characteristics between both groups were comparable, except for a longer disease duration in the alemtuzumab group of 11.3 years compared to 5.4 years in aHSCT-treated patients (p = 0.002) and a longer mean follow-up time in the aHSCT cohort of 9.0 (range 2.8-15.7) years compared to 5.9 years (range 0.9-9.2) in alemtuzumab patients. NEDA-3 was more frequently observed in the aHSCT group with 75.0 % and 55.0 % at five and 10 years, respectively, than in the alemtuzumab group with only 40.0 % at five years (p = 0.012). Relapse free survival was higher in the aHSCT group (p < 0.001). None of the aHSCT-treated patients showed new T2-lesions six months after therapy initiation until the end of the observational period in contrast to 35.0 % of the alemtuzumab-treated patients showing new T2-lesions (95 %CI 14.2-98.9, p = 0.002). aHSCT-treated patients showed significantly improved cognitive performance in five out of 12 cognitive tests whereas alemtuzumab treated patients deteriorated in four out of 12 tests. Quality of life remained on a constant level for up to 10 years in patients receiving aHSCT with improved scores for the subscale fatigue (p = 0.013). CONCLUSION: aHSCT seems to be superior to alemtuzumab in maintaining long-term NEDA-3 status, improving cognition and stabilizing quality of life for up to 10 years.

Acceptability of a digital health application to empower persons with multiple sclerosis with moderate to severe disability: single-arm prospective pilot study.

BACKGROUND: Many persons with multiple sclerosis (pwMS) desire to learn how health behaviour changes (e.g., dietary adjustments, physical activity, improvements in stress management) might help them manage their disease. Previous research has shown that certain health behaviour changes can improve quality of life (QoL), fatigue and other MS outcomes. Digital health applications may be well suited to deliver relevant health behavioural interventions because of their accessibility and flexibility. The digital health application "levidex" was designed to facilitate health behaviour change by offering evidence-based patient information and cognitive-behavioural therapy techniques to pwMS. By doing so, levidex aims to improve QoL and MS symptoms such as fatigue and mental health. OBJECTIVES: A previous study reported on the development of levidex; this non-randomised pilot study examined the feasibility (practicability and acceptability) of levidex in pwMS with moderate to severe disability. Furthermore, the intervention's impact on empowerment, stress management, and relevant health behaviours (e.g., dietary behaviour, physical activity) was explored. METHODS: levidex was originally developed for newly diagnosed pwMS in the first year after diagnosis and eventually modified to offer access to pwMS with moderate to severe disability. Participants (n = 43) with an Expanded Disability Status Scale between 3.5 and 7.5 and a disease duration of more than one year were eligible to participate. The intervention was used over a period of six months with measurement time points at baseline, month 3 and month 6. RESULTS: Out of 38 participants who completed the six-month intervention period, 18 (47.4%) completed all 16 modules and 9 (23.7%) reached modules 13-16, the long-term maintenance part of levidex. Participants rated levidex positively in terms of practicability and acceptability and had only few points of criticism such as to include more physical exercise routine suggestions suitable for participants with severe impairment. Data on secondary endpoints showed no significant changes. CONCLUSION: This pilot study provided evidence for the practicability and acceptability of levidex, a digital health application designed to facilitate health behaviour change in pwMS with moderate to severe disability. Adequately powered randomised controlled studies with longer follow-up periods are needed to clarify the benefit of levidex in pwMS with moderate to severe disability. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) DRKS00032667 (14/09/2023); Retrospectively registered.

The MoXFo initiative - adherence: Exercise adherence, compliance and sustainability among people with multiple sclerosis: An overview and roadmap for research.

We know very little about exercise adherence, compliance and sustainability in multiple sclerosis (MS), yet adherence is seemingly important for yielding immediate and sustained health benefits. This paper is focused on exercise adherence, compliance and sustainability in the context of informing research and practice involving MS. This focus is critical for clarifying terminology for future research and providing a roadmap guiding clinical research and practice. Our objective was accomplished through a narrative summary of the literature by a panel of experts on exercise adherence from the Moving Exercise Research in Multiple Sclerosis Forward (MoXFo) initiative and a concluding summary of the state of the literature and future research directions. The panel of experts identified three overall themes (Background and Importance; Understanding and Promoting Exercise Adherence, Compliance and Sustainability and Challenges to Exercise Adherence, Compliance and Sustainability) that represented a categorization of nine subthemes. These overall themes and subthemes formed the basis of our recommendations regarding future research broadly involving exercise adherence in MS. Overall, there is limited evidence on rates and determinants of exercise adherence and compliance in MS, and little is known about techniques and interventions for immediate and long-term exercise behaviour change.

Mobile health interventions in multiple sclerosis: A systematic review.

BACKGROUND: Persons with multiple sclerosis (pwMS) might be particularly well suited to benefit from digital health applications because they are, on average, younger and less severely disabled than patients with many other chronic diseases. Many digital health applications for pwMS have been developed. OBJECTIVES: Analysis of the evidence of digital health applications to improve health outcomes from a patient perspective. METHODS: A systematic review was performed on all randomized controlled trials (RCTs) that have studied mobile health interventions for pwMS, that is, which can be applied with a smartphone, tablet, or laptop to improve patient-reported outcomes. RESULTS: Of the 1127 articles identified in the literature search, 13 RCTs fit the inclusion criteria. Two trials studied messaging systems, two depression interventions, one addressed MS fatigue, five cognition, and three mobility issues, of which two focused on spasticity management. One trial aimed to enhance physical activity. Most were pilot studies that cannot yield definitive conclusions regarding efficacy. One depression intervention and one fatigue intervention showed significant results across several outcomes. CONCLUSION: Several mobile self-guided digital health applications for pwMS have been tested in RCTs, and two interventions targeting depression and fatigue have demonstrated significant effects. Challenges remain regarding implementation into routine care.

Autologous haematopoietic stem cell transplantation for multiple sclerosis: a position paper and registry outline.

Background: While substantial progress has been made in the development of disease-modifying medications for multiple sclerosis (MS), a high percentage of treated patients still show progression and persistent inflammatory activity. Autologous haematopoietic stem cell transplantation (AHSCT) aims at eliminating a pathogenic immune repertoire through intense short-term immunosuppression that enables subsequent regeneration of a new and healthy immune system to re-establish immune tolerance for a long period of time. A number of mostly open-label, uncontrolled studies conducted over the past 20 years collected about 4000 cases. They uniformly reported high efficacy of AHSCT in controlling MS inflammatory disease activity, more markedly beneficial in relapsing-remitting MS. Immunological studies provided evidence for qualitative immune resetting following AHSCT. These data and improved safety profiles of transplantation procedures spurred interest in using AHSCT as a treatment option for MS. Objective: To develop expert consensus recommendations on AHSCT in Germany and outline a registry study project. Methods: An open call among MS neurologists as well as among experts in stem cell transplantation in Germany started in December 2021 to join a series of virtual meetings. Results: We provide a consensus-based opinion paper authored by 25 experts on the up-to-date optimal use of AHSCT in managing MS based on the Swiss criteria. Current data indicate that patients who are most likely to benefit from AHSCT have relapsing-remitting MS and are young, ambulatory and have high disease activity. Treatment data with AHSCT will be collected within the German REgistry Cohort of autologous haematopoietic stem CeLl trAnsplantation In MS (RECLAIM). Conclusion: Further clinical trials, including registry-based analyses, are urgently needed to better define the patient characteristics, efficacy and safety profile of AHSCT compared with other high-efficacy therapies and to optimally position it as a treatment option in different MS disease stages.

Autologous haematopoietic stem cell transplantation for multiple sclerosis Substantial progress has been made in the development of disease-modifying medications for multiple sclerosis (MS) during the last 20 years. However, in a relevant percentage of patients, the disease cannot completely be contained. Autologous haematopoietic stem cell transplantation (AHSCT) enables rebuilding of a new and healthy immune system and to potentially stop the autoimmune disease process for a long time. A number of studies documenting 4000 cases cumulatively over the past 20 years reported high efficacy of AHSCT in controlling MS inflammatory disease activity. These data and improved safety profiles of the treatment procedures spurred interest in using AHSCT as a treatment option for MS. An open call among MS neurologists as well as among experts in stem cell transplantation in Germany started in December 2021 to join a series of video calls to develop recommendations and outline a registry study project. We provide a consensus-based opinion paper authored by 25 experts on the up-to-date optimal use of AHSCT in managing MS. Current data indicate that patients are most likely to benefit from AHSCT if they are young, ambulatory, with high disease activity, that is, relapses or new magnetic resonance imaging (MRI) lesions. Treatment data with AHSCT will be collected within the German REgistry Cohort of autoLogous haematopoietic stem cell transplantation MS (RECLAIM). Further clinical trials including registry-based analyses and systematic follow-up are urgently needed to better define the optimal patient characteristics as well as the efficacy and safety profile of AHSCT compared with other high-efficacy therapies. These will help to position AHSCT as a treatment option in different MS disease stages.

Health behaviors of people with multiple sclerosis and its associations with MS related outcomes: a German clinical cohort.

Background: Health behaviors in persons with multiple sclerosis (pwMS) have been associated with MS-related disease outcomes. Objective: The aim of the study was to gain knowledge about current patient health behaviors in a convenience sample representative for pwMS presenting to a large university-based outpatient clinic and to investigate associations between modifiable risk factors with physical impairment, quality of life (QoL) and cardiovascular comorbidities. Methods: A questionnaire was administered at the MS Outpatient Clinic of the University Medical Center Hamburg Eppendorf asking for health behaviors regarding dietary habits assessed with the German adaptation of the validated Spanish short Diet Quality Screener (sDQS), level of physical activity assessed with the Godin Leisure Time Questionnaire (GLTEQ) and tobacco smoking. Participants were asked to report cardiovascular comorbidities using items from the Self-Report Comorbidity Questionnaire for Multiple Sclerosis. Additionally, cardiovascular risk factors like blood pressure, height and weight (to calculate BMI) and waist circumference were measured. MS specific clinical data, e.g., disease course, duration, disability and MS-specific QoL were collected from the clinical database. Descriptive analyses were performed and multivariate regression analyses for complete cases were carried out for each of the three outcome variables including all mentioned modifiable risk factors (dietary behavior, smoking, physical activity and BMI) as independent variables. Results: In this sample of 399 pwMS the mean age was 42 years (SD 12.8) with a mean disease duration since diagnosis of 7.4 years (SD 8.4) and a mean EDSS of 2.8 (SD 1.9). 24% were current smokers, 44% were insufficiently physically active and 54% did not follow a healthy dietary pattern. 49% of this relatively young clinical population was overweight and 27% reported one or more cardiovascular comorbidities. Most modifiable risk factors showed no convincing associations with MS-related disease outcomes in the multiple regression analyses. Conclusion: This clinical cohort of pwMS shows a high prevalence of critical health behaviors and comorbidities and emphasizes the need for monitoring, education and assistance for behavior change in this population.

Translation and validation of the multiple sclerosis walking scale 12 for the German population - the MSWS-12/D.

BACKGROUND: Gait impairment is a relevant problem in persons with multiple sclerosis (pwMS). The Multiple Sclerosis Walking Scale 12 (MSWS-12) is a valid Patient Reported Outcome Measure (PROM) to evaluate walking ability in pwMS. The aim of this study was to provide a linguistically valid translation of MSWS-12 into German language (MSWS-12/D) and to evaluate its psychometric properties. METHODS: The MSWS-12 was translated in a process modified from guidelines for the cross-cultural adaption of PROMs, and a pre-test was applied in a small sample of 20 pwMS to evaluate comprehensibility and acceptance. Psychometric properties (floor and ceiling effects, internal consistency, construct validity) were then assessed in 124 pwMS seen at academic MS centers. Construct validity was evaluated against Expanded Disability Status Scale (EDSS) and maximum gait speed in the Timed 25-Foot Walk (T25FW). RESULTS: Although the sample covered a wide spectrum of symptom severity, the majority had rather low levels of disability (EDSS median 2.0) and 6.5% scored EDSS of 0. In this sample, MSWS-12/D showed floor effects (36% with score 0) and for internal consistency, a Cronbach's alpha of 0.98 was calculated. MSWS-12/D score showed a relevant correlation to EDSS (ρ = 0.73) and T25FW speed (r=-0.72). CONCLUSION: We provide MSWS-12/D as a linguistically valid German version of MSWS-12. Psychometric properties (acceptance, floor and ceiling effects, internal consistency and construct validity) in pwMS were similar to those described for the original version. This indicates that MSWS-12/D can be applied as equivalent to the original version in German speaking pwMS. Results support the relevance of PROMs to capture patient perception of walking ability in addition to performance-based assessments such as maximum walking speed or maximum walking distance.

Association of health behaviour and clinical manifestation in early multiple sclerosis in Germany - Baseline characteristics of the POWER@MS1 randomised controlled trial.

BACKGROUND: Receiving a multiple sclerosis (MS) diagnosis is a significant stressor. Therefore, highly individualised counselling is needed, especially in early MS. Modifiable risk factors (e.g. smoking and obesity) are gaining relevance in MS. Despite evidence for worse MS-related health outcomes, prevalence of adverse health behaviours, such as smoking and physical inactivity, is high across all MS stages. However, knowledge regarding health behaviours as well as their association with MS-related health outcomes among newly diagnosed PwMS in Germany is scarce. Currently, the efficacy of an interactive digital lifestyle management application intended to be used as an add-on to standard care among newly diagnosed PwMS in Germany is evaluated in an ongoing multicentre randomised controlled trial (RCT) ('POWER@MS1'). OBJECTIVES: To describe baseline disease characteristics and health behaviours of the POWER@MS1 cohort and investigate associations between MS characteristics, quality of life (QOL), health behaviours and intention to optimise health behaviour habits. METHODS: This study included 234 persons with early MS from 20 study centres located across Germany who participate in the POWER@MS1 RCT. Participants were recruited by treating neurologists from different regions and health-care settings in Germany. Baseline data was obtained using paper-based questionnaires and a web-based healthy diet screener between July 2019 and end of March 2022 and analysed descriptively. RESULTS: In this early MS cohort (mean disease duration 4 months), a screening tool showed severe symptoms of anxiety in 15 % of the participants. Better means for stress management appeared to be particularly relevant for the whole cohort. Moreover, 19 % were current smokers, 15 % were obese and 36 % were insufficiently physically active. On average, participants only moderately adhered to dietary guidelines for recommended intake of key food groups (e.g. vegetables, fruits and fatty marine fish). Higher EDSS scores were associated with approximately 20 % higher T2-lesion burden (rate ratio RR=1.2, p<0.001) and 13 % higher relapse rate (RR=1.13,p=0.02) per EDSS disability level. Moreover, a higher T2-lesion burden was associated with current smoking (RR=0.76, p=0.033), resulting in approximately 24 % less T2-lesions at disease onset among non-smokers. In addition, smoking was associated with unhealthier dietary habits according to lower diet scores (linear regression coefficient ß=-1.27, p<0.001). Higher EDSS scores (ß=0.19,p<0.001) and higher BMI (ß=0.013,p=0.03) were associated with higher HAQUAMS (lower QOL). Further, lower diet scores (ß=-0.044,p=0.039) were associated with lower QOL. Moreover, higher HAQUAMS (lower QOL) indicated a higher intention to optimise stress management (ß=0.98,p<0.001), physical activity (ß=0.74,p=0.046) and sleep behaviour (ß=1.82,p<0.001). Further, higher intention to optimise stress management was accounted for by higher EDSS scores (ß=0.39,p=0.004) and a higher number of T2-lesions (ß=0.029,p=0.015) in this newly diagnosed MS cohort. CONCLUSION: Results indicate a clear need for modifications of health behaviours among newly diagnosed PwMS participating in POWER@MS1. Individualised psychological and health behaviour counselling appears to be an important factor in treatment, also for similar early MS cohorts and particularly in those who demonstrate a more severe disease in clinical and MRI metrics.

Internet-delivered cognitive behavioural therapy programme to reduce depressive symptoms in patients with multiple sclerosis: a multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: Depression is three to four times more prevalent in patients with neurological and inflammatory disorders than in the general population. For example, in patients with multiple sclerosis, the 12-month prevalence of major depressive disorder is around 25% and it is associated with a lower quality of life, faster disease progression, and higher morbidity and mortality. Despite its clinical relevance, there are few treatment options for depression associated with multiple sclerosis and confirmatory trials are scarce. We aimed to evaluate the safety and efficacy of a multiple sclerosis-specific, internet-based cognitive behavioural therapy (iCBT) programme for the treatment of depressive symptoms associated with the disease. METHODS: This parallel-group, randomised, controlled, phase 3 trial of an iCBT programme to reduce depressive symptoms in patients with multiple sclerosis was carried out at five academic centres with large outpatient care units in Germany and the USA. Patients with a neurologist-confirmed diagnosis of multiple sclerosis and depressive symptoms were randomly assigned (1:1:1; automated assignment, concealed allocation, no stratification, no blocking) to receive treatment as usual plus one of two versions of the iCBT programme Amiria (stand-alone or therapist-guided) or to a control condition, in which participants received treatment as usual and were offered access to the iCBT programme after 6 months. Masking of participants to group assignment between active treatment and control was not possible, although raters were masked to group assignment. The predefined primary endpoint, which was analysed in the intention-to-treat population, was severity of depressive symptoms as measured by the Beck Depression Inventory-II (BDI-II) at week 12 after randomisation. This trial is registered at ClinicalTrials.gov, NCT02740361, and is complete. FINDINGS: Between May 3, 2017, and Nov 4, 2020, we screened 485 patients for eligibility. 279 participants were enrolled, of whom 101 were allocated to receive stand-alone iCBT, 85 to receive guided iCBT, and 93 to the control condition. The dropout rate at week 12 was 18% (50 participants). Both versions of the iCBT programme significantly reduced depressive symptoms compared with the control group (BDI-II between-group mean differences: control vs stand-alone iCBT 6·32 points [95% CI 3·37-9·27], p<0·0001, effect size d=0·97 [95% CI 0·64-1·30]; control vs guided iCBT 5·80 points [2·71-8·88], p<0·0001, effect size d=0·96 [0·62-1·30]). Clinically relevant worsening of depressive symptoms was observed in three participants in the control group, one in the stand-alone iCBT group, and none in the guided iCBT group. No occurrences of suicidality were observed during the trial and there were no deaths. INTERPRETATION: This trial provides evidence for the safety and efficacy of a multiple sclerosis-specific iCBT tool to reduce depressive symptoms in patients with the disease. This remote-access, scalable intervention increases the therapeutic options in this patient group and could help to overcome treatment barriers. FUNDING: National Multiple Sclerosis Society (USA).

Visual function resists early neurodegeneration in the visual system in primary progressive multiple sclerosis.

BACKGROUND: Neurodegeneration in multiple sclerosis (MS) affects the visual system but dynamics and pathomechanisms over several years especially in primary progressive MS (PPMS) are not fully understood. METHODS: We assessed longitudinal changes in visual function, retinal neurodegeneration using optical coherence tomography, MRI and serum NfL (sNfL) levels in a prospective PPMS cohort and matched healthy controls. We investigated the changes over time, correlations between outcomes and with loss of visual function. RESULTS: We followed 81 patients with PPMS (mean disease duration 5.9 years) over 2.7 years on average. Retinal nerve fibre layer thickness (RNFL) was reduced in comparison with controls (90.1 vs 97.8 µm; p<0.001). Visual function quantified by the area under the log contrast sensitivity function (AULCSF) remained stable over a continuous loss of RNFL (0.46 µm/year, 95% CI 0.10 to 0.82; p=0.015) up until a mean turning point of 91 µm from which the AULCSF deteriorated. Intereye RNFL asymmetry above 6 µm, suggestive of subclinical optic neuritis, occurred in 15 patients and was related to lower AULCSF but occurred also in 5 out of 44 controls. Patients with an AULCSF progression had a faster increase in Expanded Disability Status Scale (beta=0.17/year, p=0.043). sNfL levels were elevated in patients (12.2 pg/mL vs 8.0 pg/mL, p<0.001), but remained stable during follow-up (beta=-0.14 pg/mL/year, p=0.291) and were not associated with other outcomes. CONCLUSION: Whereas neurodegeneration in the anterior visual system is already present at onset, visual function is not impaired until a certain turning point. sNfL is not correlated with structural or functional impairment in the visual system.