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.

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).

Education for fatigue management in people with multiple sclerosis: Systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Fatigue is a common and disabling symptom in multiple sclerosis (MS). Educational interventions have shown potential to reduce fatigue. The aim was to systematically review the current best evidence on patient education programmes for MS-related fatigue. METHODS: This was a systematic review and meta-analysis following Cochrane methodology. A systematic search was conducted in eight databases (September 2023). Moreover, reference lists and trial registers were searched and experts in the field were contacted. Randomized controlled trials were included evaluating patient education programmes for people with MS with the primary aim of reducing fatigue. RESULTS: In total, 1176 studies were identified and assessed by two independent reviewers; 15 studies (1473 participants) were included. All interventions provided information and education about different aspects of MS-related fatigue with different forms of application, some with components of psychological interventions. Amongst those, the most frequently applied were cognitive behavioural therapy (n = 5) and energy-conservation-based approaches (n = 4). Studies differed considerably concerning mode of intervention delivery, number of participants and length of follow-up. Interventions reduced fatigue severity (eight studies, n = 878, standardized mean difference -0.28; 95% confidence interval -0.53 to -0.03; low certainty) and fatigue impact (nine studies, n = 824, standardized mean difference -0.21; 95% confidence interval -0.42 to 0.00; moderate certainty) directly after the intervention. Mixed results were found for long-term effects on fatigue, for secondary endpoints (depressive symptoms, quality of life, coping) and for subgroup analyses. CONCLUSION: Educational interventions for people with MS-related fatigue may be effective in reducing fatigue in the short term. More research is needed on long-term effects and the importance of specific intervention components, delivery and context.

Exploring the therapeutic potential of autologous hematopoietic stem cell transplantation in progressive multiple sclerosis-a systematic review.

BACKGROUND AND PURPOSE: The aim was to determine the value of autologous haematopoietic stem cell transplantation (aHSCT) as a therapeutic intervention for progressive multiple sclerosis (PMS) based on a systematic review of the current literature. METHODS: All studies from the databases PubMed and Google Scholar published in English before February 2024 which provided individual data for PMS patients were systematically reviewed. PICO was defined as population (P), primary progressive MS and secondary progressive MS patients; intervention (I), treatment with aHSCT; comparison (C), none, disease-modifying therapy treated/relapsing-remitting MS cohorts if available; outcome (O), transplant-related mortality, progression-free survival (PFS) and no evidence of disease activity. RESULTS: A total of 15 studies met the criteria including 665 patients with PMS (74 primary progressive MS, 591 secondary progressive MS) and 801 patients with relapsing-remitting MS as controls. PFS data were available for 647 patients. PMS patients showed more severe disability at baseline than relapsing-remitting MS patients. The average transplant-related mortality for PMS in 10 studies was 1.9%, with 10 deaths in 528 patients. PFS ranged from 0% to 78% in PMS groups 5 years after treatment initiation, demonstrating a high variability. No evidence of disease activity scores at 5 years ranged from 0% to 75%. CONCLUSION: Based on the available data, aHSCT does not halt progression in people with PMS. However, there appears to be evidence of improved outcome in selected patients. Due to the heterogeneity of the available data, more comprehensive clinical trials assessing the efficacy of aHSCT across different patient groups are urgently needed to reduce variability and improve patient stratification.

Effectiveness of a digital lifestyle management intervention (levidex) to improve quality of life in people with multiple sclerosis: results of a randomized controlled trial.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory neurodegenerative disease with diverse symptomatology, significantly impacting patients' quality of life (QoL). While pharmacological therapies focus primarily on reducing inflammation and relapse rates, non-pharmacological interventions, including digital health applications, have shown promise in improving QoL among persons with MS (PwMS). Pilot studies had shown the feasibility and acceptability of levidex, a digital health application based on cognitive behavioral therapy (CBT) principles, a broad set of behavior change techniques, and relevant lifestyle-change advice. This randomized controlled trial aimed to examine the effects of levidex on MS-related QoL over 6 months. METHODS: Participants who were diagnosed with MS for at least one year were recruited via the internet in Germany, using a secure survey software platform, and were randomly assigned to the intervention group (IG), in which they received standard care + levidex, or an active control group (CG), in which they received standard care and were offered web-adapted material on the topic of lifestyle change from the German Multiple Sclerosis Society (DMSG). The primary outcome was MS-related QoL after 6 months, measured by the Hamburg Quality of Life Questionnaire in MS (HAQUAMS); secondary outcomes included QoL subscales, sick days, and health behavior, among others. Analyses of Covariance (ANCOVA) were used to examine intervention effects at 6 months. Participants were recruited between November 2020 and February 2022. RESULTS: A total of 421 adult participants (mean age: 47.5, 78.1% women) were included and randomized (IG, n = 195, CG, n = 226). After 6 months, the IG exhibited significantly higher MS-related QoL, compared to the CG (total score HAQUAMS, adjusted group mean difference = -0.14, 95% CI: [-0.22, -0.06], p = 0.001; Cohen's d = 0.23), with significant effects also observed on the cognitive and mood subscales. At 6 months, IG participants also reported significantly fewer sick days (median = 2 days in IG vs. 6 days in CG; W = 3939, p = 0.012) and significantly higher levels of daily activities, as measured by the Frenchay Activity Index, adjusted group mean difference = 1.37, 95% CI = [0.33, 2.40], p = 0.010; Cohen's d = 0.16. Safety analyses showed no adverse events and good satisfaction. CONCLUSIONS: Compared to the control group, levidex facilitated clinically relevant improvements in MS-related QoL, reduced sick days, and enhanced activity in PwMS over 6 months. These findings suggest that levidex can serve as an effective non-pharmacological adjunctive treatment element to standard care and could help improve QoL among PwMS. TRIAL REGISTRATION: Registered on 22.09.2020 at the German Clinical Trials Register DRKS00023023.

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.

Topological reorganization of brain network might contribute to the resilience of cognitive functioning in mildly disabled relapsing remitting multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory and demyelinating disease which leads to impairment in several functional systems including cognition. Alteration of brain networks is linked to disability and its progression. However, results are mostly cross-sectional and yet contradictory as putative adaptive and maladaptive mechanisms were found. Here, we aimed to explore longitudinal reorganization of brain networks over 2-years by combining diffusion tensor imaging (DTI), resting-state functional MRI (fMRI), magnetoencephalography (MEG), and a comprehensive neuropsychological-battery. In 37 relapsing-remitting MS (RRMS) and 39 healthy-controls, cognition remained stable over-time. We reconstructed network models based on the three modalities and analyzed connectivity in relation to the hierarchical topology and functional subnetworks. Network models were compared across modalities and in their association with cognition using linear-mixed-effect-regression models. Loss of hub connectivity and global reduction was observed on a structural level over-years (p < .010), which was similar for functional MEG-networks but not for fMRI-networks. Structural hub connectivity increased in controls (p = .044), suggesting a physiological mechanism of healthy aging. Despite a general loss in structural connectivity in RRMS, hub connectivity was preserved (p = .002) over-time in default-mode-network (DMN). MEG-networks were similar to DTI and weakly correlated with fMRI in MS (p < .050). Lower structural (ß between .23-.33) and both lower (ß between .40-.59) and higher functional connectivity (ß = -.54) in DMN was associated with poorer performance in attention and memory in RRMS (p < .001). MEG-networks involved no association with cognition. Here, cognitive stability despite ongoing neurodegeneration might indicate a resilience mechanism of DMN hubs mimicking a physiological reorganization observed in healthy aging.

Subcortical Volumes as Early Predictors of Fatigue in Multiple Sclerosis.

OBJECTIVE: Fatigue is a frequent and severe symptom in multiple sclerosis (MS), but its pathophysiological origin remains incompletely understood. We aimed to examine the predictive value of subcortical gray matter volumes for fatigue severity at disease onset and after 4 years by applying structural equation modeling (SEM). METHODS: This multicenter cohort study included 601 treatment-naive patients with MS after the first demyelinating event. All patients underwent a standardized 3T magnetic resonance imaging (MRI) protocol. A subgroup of 230 patients with available clinical follow-up data after 4 years was also analyzed. Associations of subcortical volumes (included into SEM) with MS-related fatigue were studied regarding their predictive value. In addition, subcortical regions that have a central role in the brain network (hubs) were determined through structural covariance network (SCN) analysis. RESULTS: Predictive causal modeling identified volumes of the caudate (s [standardized path coefficient] = 0.763, p = 0.003 [left]; s = 0.755, p = 0.006 [right]), putamen (s = 0.614, p = 0.002 [left]; s = 0.606, p = 0.003 [right]) and pallidum (s = 0.606, p = 0.012 [left]; s = 0.606, p = 0.012 [right]) as prognostic factors for fatigue severity in the cross-sectional cohort. Moreover, the volume of the pons was additionally predictive for fatigue severity in the longitudinal cohort (s = 0.605, p = 0.013). In the SCN analysis, network hubs in patients with fatigue worsening were detected in the putamen (p = 0.008 [left]; p = 0.007 [right]) and pons (p = 0.0001). INTERPRETATION: We unveiled predictive associations of specific subcortical gray matter volumes with fatigue in an early and initially untreated MS cohort. The colocalization of these subcortical structures with network hubs suggests an early role of these brain regions in terms of fatigue evolution. ANN NEUROL 2022;91:192-202.

Postpartum relapse risk in multiple sclerosis: a systematic review and meta-analysis.

The influence of pregnancy on the course of multiple sclerosis (MS) has long been controversial. While historical evidence suggests a substantial decline in relapse rates during pregnancy followed by a rebound in the postpartum period, more recent work yielded equivocal results. We performed a systematic review and meta-analysis on data from cohort studies to determine whether women with MS experience increased relapse rates after delivery. A systematic literature search was conducted in the databases MEDLINE and Epistemonikos on the topic 'motherhood choice in MS' in March 2022. We included cohort studies assessing the association between pregnancy and MS relapse activity defined by the annualised relapse rate after 3, 6, 9 and 12 months post partum. Furthermore, information about disease-modifying therapies (DMT) and breast feeding was considered, if available. 5369 publications were identified. Of these, 93 full-text articles on MS relapse activity during the postpartum period were screened. 11 studies including 2739 pregnancies were eligible. Women with MS showed a significantly increased relapse rate in the first 6 months post partum, compared with preconception with the incidence rate ratio (IRR) almost doubled in the first 3 months post partum (1.87, 95% CI 1.40 to 2.50). However, at 10-12 months post partum, the IRR decreased significantly (0.81, 95% CI 0.67 to 0.98). Subanalysis on influencing parameters suggested that preconceptional DMTs (IRR for highly-effective DMTs 2.76, 95% CI 1.34 to 5.69) and exclusive breast feeding (risk ratio 0.39, 95% CI 0.18 to 0.86) significantly influenced postpartum relapse risk. Increased postpartum annualised relapse rate and possible modifiers should be considered in counselling women with MS who are considering pregnancy.

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.

Association of obesity with disease outcome in multiple sclerosis.

BACKGROUND: Obesity reportedly increases the risk for developing multiple sclerosis (MS), but little is known about its association with disability accumulation. METHODS: This nationwide longitudinal cohort study included 1066 individuals with newly diagnosed MS from the German National MS cohort. Expanded Disability Status Scale (EDSS) scores, relapse rates, MRI findings and choice of immunotherapy were compared at baseline and at years 2, 4 and 6 between obese (body mass index, BMI ≥30 kg/m2) and non-obese (BMI <30 kg/m2) patients and correlated with individual BMI values. RESULTS: Presence of obesity at disease onset was associated with higher disability at baseline and at 2, 4 and 6 years of follow-up (p<0.001). Median time to reach EDSS 3 was 0.99 years for patients with BMI ≥30 kg/m2 and 1.46 years for non-obese patients. Risk to reach EDSS 3 over 6 years was significantly increased in patients with BMI ≥30 kg/m2 compared with patients with BMI <30 kg/m2 after adjustment for sex, age, smoking (HR 1.87; 95% CI 1.3 to 2.6; log-rank test p<0.001) and independent of disease-modifying therapies. Obesity was not significantly associated with higher relapse rates, increased number of contrast-enhancing MRI lesions or higher MRI T2 lesion burden over 6 years of follow-up. CONCLUSIONS: Obesity in newly diagnosed patients with MS is associated with higher disease severity and poorer outcome. Obesity management could improve clinical outcome of MS.

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.

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.

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.

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.

Immune signature of multiple sclerosis-associated depression.

Multiple neurobiological pathways have been implicated in the pathobiology of major depressive disorder (MDD). The identification of reliable biological substrates across the entire MDD spectrum, however, is hampered by a vast heterogeneity in the clinical presentation, presumably as a consequence of heterogeneous pathobiology. One way to overcome this limitation could be to explore disease subtypes based on biological similarity such as "inflammatory depression". As such a subtype may be particularly enriched in depressed patients with an underlying inflammatory condition, multiple sclerosis (MS) could provide an informative disease context for this approach. Few studies have explored immune markers of MS-associated depression and replications are missing. To address this, we analyzed data from two independent case-control studies on immune signatures of MS-associated depression, conducted at two different academic MS centers (overall sample size of n = 132). Using a stepwise data-driven approach, we identified CD4+CCR7lowTCM cell frequencies as a robust correlate of depression in MS. This signature was associated with core symptoms of depression and depression severity (but not MS severity per se) and linked to neuroinflammation as determined by magnetic resonance imaging (MRI). Furthermore, exploratory analyses of T cell polarization revealed this was largely driven by cells with a TH1-like phenotype. Our findings suggest (neuro)immune pathways linked to affective symptoms of autoimmune disorders such as MS, with potential relevance for the understanding of "inflammatory" subtypes of depression.

Breastfeeding and Risk of Multiple Sclerosis: A Systematic Review and Meta-Analysis of Observational Studies.

INTRODUCTION: The causes of multiple sclerosis (MS) are not fully understood, yet. Genetic predisposition, environmental and lifestyle factors as well as an interplay thereof constitute relevant factors in the development of MS. Especially early-life risk factors such as having been breastfed may also be of relevance. Breast milk provides the newborn not only with essential nutrients and vitamins but also with numerous immune-active molecules, metabolites, oligosaccharides, and microbial components that are important for the development of the immune system. We present a systematic review and meta-analysis on the influence of having been breastfed during infancy on the risk of developing MS. METHODS: The databases MEDLINE, Cochrane Library, and Web of Science were systematically searched for studies on breastfeeding and MS published between database inception and May 18, 2022. Observational studies comparing persons with MS to healthy controls with regard to having been breastfed during the first 2 years of life were eligible for inclusion. A random effects meta-analysis was calculated to estimate pooled effect sizes using the Mantel-Haenszel method for dichotomous outcomes. The Newcastle-Ottawa Scale was used for quality analysis. RESULTS: 15 studies (13 case-control, 2 cohort) were included of which 12 were rated as high quality. The meta-analysis of crude odds ratios (ORs) yielded a risk estimate of ORcrude = 0.82 (95% confidence interval [CI]: 0.70-0.96) for MS in breastfed versus non-breastfed individuals with substantial heterogeneity (I2 = 68.2%). Using adjusted OR, when available, reduced heterogeneity (I2 = 48.9%) and resulted in an ORadjusted = 0.86 (95% CI: 0.75-0.99). Restricting the analysis to studies with high-quality scores (i.e., ≥6/9 points) resulted in a combined ORcrude of 0.79 (95% CI: 0.66-0.94) and an ORadjusted = 0.83 (95% CI: 0.71-0.98), respectively. DISCUSSION/CONCLUSION: The meta-analysis showed a small protective effect of having been breastfed on MS risk. This adds to the knowledge that breastfeeding is beneficial for the immunological health of a child. Future studies on the influence of having been breastfed on MS risk should apply a uniform definition of breastfeeding and investigate possible sex-specific aspects.

Brain grey matter perfusion in primary progressive multiple sclerosis: Mild decrease over years and regional associations with cognition and hand function.

BACKGROUND AND PURPOSE: Extent and dynamic of neurodegeneration in progressive multiple sclerosis (MS) might be reflected by global and regional brain perfusion, an outcome at the intercept between structure and function. Here, we provide a first insight into the evolution of brain perfusion and its association with disability in primary progressive MS (PPMS) over several years. METHODS: Seventy-seven persons with PPMS were followed over up to 5 years. Visits included a 3-T magnetic resonance imaging with pulsed arterial spin labelling perfusion, the Timed 25-Foot Walk, 9-Hole Peg Test (NHPT), Symbol Digit Modalities Test (SDMT), and Expanded Disability Status Scale (EDSS). We extracted regional cerebral blood flow surrogates and compared them to 11 controls. Analyses focused on cortical and deep grey matter, the change over time, and associations with disability on the regional and global levels. RESULTS: Baseline brain perfusion of patients and controls was comparable for the cortex (p = 0.716) and deep grey matter (p = 0.095). EDSS disability increased mildly (p = 0.023), whereas brain perfusion decreased during follow-up (p < 0.001) and with disease duration (p = 0.009). Lower global perfusion correlated with higher disability as indicated by EDSS, NHPT, and Timed 25-Foot Walk (p < 0.001). The motor task NHPT showed associations with 20 grey matter regions. In contrast, better SDMT performance correlated with lower perfusion (p < 0.001) in seven predominantly frontal regions, indicating a functional maladaptation. CONCLUSIONS: Decreasing perfusion indicates a putative association with MS disease mechanisms such as neurodegeneration, reduced metabolism, and loss of resilience. A low alteration rate limits its use in clinical practice, but regional association patterns might provide a snapshot of adaptive and maladaptive functional reorganization.

Development and evaluation of a website with patients experiences of multiple sclerosis: a mixed methods study.

BACKGROUND: A variety of management options (e.g., disease-modifying therapy, lifestyle interventions, rehabilitation) are available for persons with relapsing-remitting multiple sclerosis (MS). Besides coping with the diagnosis, persons with MS have to make complex decisions, e.g., regarding disease-modifying therapies. In addition to factual information, reports of patient experiences may support other patients in their decision-making. Therefore, we developed a website presenting patient experiences illustrated by video, audio and text files. This study aimed to test the acceptability and usability of a website with patient experiences with MS. METHODS: A mixed-methods approach was applied. A total of 69 participants visited the German "Patient Experiences with MS (PExMS)" website and among them, 50 persons with MS and 6 experts completed an online survey. In total, 18 participants took part in telephone interviews or focus groups. Data from the survey were analysed using descriptive statistics. Qualitative data were analysed using thematic analysis. RESULTS: Both quantitative and qualitative responses suggest that the PExMS website was viewed positively by patients and experts. 94% of persons with MS agreed that the information was comprehensible and reliable. 54% felt encouraged to share their health problems with others after having studied the website. 74% claimed to use the website if they had to make a decision regarding their health. Qualitative responses deduced from the website fell into 5 key themes: (1) web design, appearance, and functionality, (2) content, (3) usability, (4) satisfaction, and (5) loyalty. The search for persons of similar age and with comparable experiences was a major driving force to navigate the website. The material on the website was perceived as diverse, covering both positive and negative experiences in daily living with MS. All participants greatly appreciated having access to other people's experiences online and judged the material on the website as particularly helpful in decision-making for disease-modifying therapies. CONCLUSIONS: The findings suggest that the PExMS website might have the potential to be a useful source of audio-visual information for persons with MS. Given the lack of websites available to patients with experiential information, health care professionals may be encouraged to routinely inform patients about this website at regular appointments.

Experiences of persons with multiple sclerosis with rehabilitation-a qualitative interview study.

BACKGROUND: Managing multiple sclerosis (MS) includes different treatment approaches. Rehabilitation is a key strategy in MS for improving functioning, activity and participation. As part of a larger study on overall patient experiences with different treatment approaches, this study aims to give an overview of different patients' experiences and perspectives on inpatient rehabilitation in MS. METHODS: We conducted problem-centered interviews in 50 persons with MS in Germany, of whom most had relapsing-remitting MS. We used the maximum variation sampling method during recruitment. Data were analyzed thematically. RESULTS: As a result of the analysis, three major themes were identified: 1) factors contributing to the decision-making concerning rehabilitation, 2) experience with the rehabilitation setting, 3) benefits of rehabilitation treatments. The treating physicians' attitude had a major impact on the decision to either opt for rehabilitation or not. Setting goals prior to rehabilitation was given a high priority. Exchanging experiences with other persons with MS presented a major benefit from rehabilitation while for some being separated from regular daily life resulted in a more ambiguous attitude ranging from appreciation of escaping daily hassles to substantial behavioral change management. CONCLUSION: Patients reported various experiences in the process of decision-making with regard to rehabilitation. Physicians´ advice, goal setting and the selection of the most suitable rehabilitation clinic were considered most relevant.