Search

Objective: Severe fatigue is a prevalent and disabling symptom in multiple sclerosis (MS). This study tested if a fatigue- and physical activity-related attentional bias (AB) and a somatic interpretation bias (IB) are present in severely fatigued patients with MS. Biases were compared to healthy controls and patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)., Method: Severely fatigued patients with MS or ME/CFS and healthy controls completed a Visual Probe Task (VPT) assessing fatigue- and physical activity-related AB and an IB task that assesses the tendency to interpret ambiguous information in either a somatically threatening way or in a more neutral manner. The VPT was completed by 38 MS patients, 44 ME/CFS patients, and 46 healthy controls; the IB task was completed by 156, 40 and 46 participants respectively., Results: ANOVA showed no statistically significant group differences in a fatigue-related AB or physical activity-related AB (omnibus test of interaction between topic × condition: F 2,125  = 1.87; p = .159). Both patient groups showed a tendency to interpret ambiguous information in a somatically threatening way compared to healthy controls (F 1,2  = 27.61, p < .001). This IB was significantly stronger in MS patients compared to ME/CFS patients. IB was significantly correlated with cognitive responses to symptoms in MS patients., Conclusion: MS patients tend to interpret ambiguous information in a somatically threatening way. This may feed into unhelpful ways of dealing with symptoms, possibly contributing to the perpetuation of severe fatigue in MS., (© 2024 The Authors. British Journal of Health Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

Objective: To examine the relationship between perceived and physiological strains of real-time societal participation in people with multiple sclerosis., Design: Observational study., Subjects/patients: 70 people with multiple sclerosis., Methods: Perceived and physiological strain of societal participation (10 participation-at-location and 9 transport domains) were measured in real time using the Whereabouts smartphone app and Fitbit over 7 consecutive days. Longitudinal relationships between perceived (1 not strenuous to 10 most strenuous) and physiological strains (heart rate reserve) were examined using mixed-model analyses. Type of event (participation-at-location or transport) was added as covariate, with further adjustments for fatigue and walking ability., Results: Median perceived strain, summarized for all societal participation domains, varied between 3 and 6 (range: 1-10), whereas physiological strain varied between 18.5% and 33.2% heart rate reserve. Perceived strain (outcome) and physiological strain were not associated (β -0.001, 95%CI -0.008; 0.005, with a 7-day longitudinal correlation coefficient of -0.001). Transport domains were perceived as less strenuous (β -0.80, 95%CI -0.92; -0.68). Higher fatigue levels resulted in higher perceived strain (all societal participation domains) (β 0.05, 95%CI 0.02; 0.08)., Conclusion: Societal participation resulted in low-to-moderate perceived and physiological strain. Perceived and physiological strain of societal participation were unrelated and should be considered different constructs in multiple sclerosis.

Objective: To examine the energy demand of walking relative to aerobic capacity in people with multiple sclerosis., Design: Cross-sectional cohort study., Patients: A total of 45 people with multiple sclerosis (32 females), median disease duration 15 years (interquartile range (IQR) 9; 20), median Expanded Disability Status Scale 4 (min-max range: 2.0; 6.0)., Methods: Aerobic capacity, derived from a cardiopulmonary exercise test and gas exchange measurements, assessed during a 6-min overground walk test at comfortable speed, were analysed. The relative aerobic load of walking was determined as the energy demand of walking relative to oxygen uptake at peak and at the first ventilatory threshold. Healthy reference data were used for clinical inference., Results: People with multiple sclerosis walk at a mean relative aerobic load of 60.0% (standard deviation 12.8%) relative to peak aerobic capacity, and 89.1% (standard deviation 19.9%) relative to the first ventilatory threshold. Fourteen participants walked above the first ventilatory threshold (31%). Peak aerobic capacity was reduced in 45% of participants, and energy demands were increased in 52% of participants., Conclusion: People with multiple sclerosis walk at a relative aerobic load close to their first ventilatory threshold. A high relative aerobic load can guide clinicians to improve aerobic capacity or reduce the energy demands of walking.

Background: Cognitive behavioural therapy (CBT) reduces MS-related fatigue. However, studies on the long-term effects show inconsistent findings., Objective: To evaluate whether a blended booster programme improves the outcome of CBT for MS-related fatigue on fatigue severity at 1-year follow-up., Method: A multicentre randomized clinical trial in which 126 patients with MS were allocated to either a booster programme or no booster programme (control), after following 20-week tailored CBT for MS-related fatigue. Primary outcome was fatigue severity assessed with the Checklist Individual Strength fatigue subscale 1 year after start of treatment (T52). Mixed model analysis was performed by a statistician blinded for treatment-allocation to determine between-group differences in fatigue severity., Results: Fatigue severity at 1-year follow-up did not differ significantly between the booster ( N = 62) and control condition ( N = 64) ( B = -2.01, 95% confidence interval (CI) = -4.76 to 0.75). No significant increase in fatigue severity was found at T52 compared with directly post-treatment (T20) in both conditions ( B = 0.44, 95% CI = -0.97 to 1.85)., Conclusion: Effects of CBT were sustained up to 1 year in both conditions. The booster programme did not significantly improve the long-term outcome of CBT for MS-related fatigue., Trial Registration: Dutch Trial Register (NTR6966), registered 18 January 2018 https://www.trialregister.nl/trial/6782., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Background: Exercise as a subset of physical activity is a cornerstone in the management of multiple sclerosis (MS) based on its pleiotropic effects, but continued progression of the field requires better future designs and methodologies., Objectives: This paper outlines the work of the 'Study design and methodology' group of the MoXFo (moving exercise research forward) initiative, and addresses critical aspects and future directions when defining the research question of interest, and subsequently, designing the study and exercise intervention in MS patients., Methods: The work is based on the formation of an international expert panel formed within the MoXFo initiative. We provide a structured and concise synthesis of exercise-specific MS research challenges and considerations when designing randomized controlled trials (RCTs)., Results: Challenges and considerations are presented using the Patient population, Intervention, Comparator, Outcomes, Timing, Setting (PICOTS) framework, thereby forming a new and specific MS exercise PICOTS framework., Conclusion: We propose that researchers should carefully consider and align all elements of this MS exercise PICOTS framework when developing future research questions and study designs, ultimately improving the quality of new exercise studies in people with MS., 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: U.D. has received research support, travel grants and teaching honorary from Biogen Idec, Merck Serono, Novartis, Bayer Schering and Sanofi Aventis, and honoraria from serving on scientific advisory boards of Biogen Idec and Genzyme. S.M.G. reports honoraria from Celgene and Hexal, and research funding from Biogen. M.R., T.E., L.A.P., V.D.G., H.B., J.F., A.K. and R.D. declare no conflicts of interest related to this work.

Background: Cognitive behavioural therapy (CBT) reduces multiple sclerosis (MS)-related fatigue. Implementation of face-to-face CBT is hindered by limited treatment capacity and traveling distances to treatment locations., Objective: Evaluate whether blended CBT (online treatment modules supported with guidance by a therapist) is non-inferior to face-to-face CBT in reducing fatigue severity in severely fatigued patients with MS., Method: A non-inferiority multicentre randomized clinical trial, in which 166 patients with MS were allocated to either face-to-face or blended CBT. Primary outcome was fatigue severity assessed with the Checklist Individual Strength fatigue subscale directly post-treatment (week 20). Mixed model analysis was used by a statistician blinded for allocation to determine between-group differences post-treatment. The upper limit of the 95% confidence interval (CI) was compared to a pre-specified non-inferiority margin of 5.32., Results: Blended CBT ( N = 82) was non-inferior to face-to-face CBT ( N = 84) (B = 1.70, 95% CI: -1.51 to 4.90). Blended CBT significantly reduced therapist time ( B = -187.1 minutes, 95% CI: 141.0-233.3). Post hoc analysis showed more improvement ( B = -5.35, 95% CI: -9.22 to -1.48) when patients received their preferred treatment. No harm related to treatment was reported., Discussion: Blended CBT is an efficient alternative to face-to-face CBT. Offering the preferred CBT format may optimize treatment outcome.

Background: Neuroinflammation and neurodegeneration are pathological hallmarks of multiple sclerosis (MS). Brain-derived neurotrophic factor (BDNF), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) are blood-based biomarkers for neurogenesis, axonal damage and astrocyte reactivity, respectively. We hypothesize that exercise has a neuroprotective effect on MS reflected by normalization of BDNF, NfL and GFAP levels., Objectives: To investigate the neuroprotective effect of aerobic training (AT) compared to a control intervention on blood-based biomarkers (i.e. BDNF, NfL, GFAP) in people with MS (pwMS)., Methods: In the TREFAMS-AT (Treating Fatigue in Multiple Sclerosis - Aerobic Training) study, 89 pwMS were randomly allocated to either a 16-week AT intervention or a control intervention (3 visits to a MS nurse). In this secondary analysis, blood-based biomarker concentrations were measured in 55 patients using Simoa technology. Changes in pre- and post-intervention concentrations were compared and between-group differences were assessed using analysis of covariance (ANCOVA). Confounding effects of age, sex, MS-related disability assessed using the Expanded Disability Status Scale (EDSS), MS duration, use of disease-modifying medication, and Body Mass Index were considered., Results: Blood samples were available for 30 AT and 25 control group participants (mean age 45.6 years, 71% female, median disease duration 8 years, median EDSS score 2.5). Within-group changes in both study groups were small and non-significant, with the exception of BDNF in the control group (median (interquartile range) -2.1 (-4.7; 0)). No between-group differences were found for any biomarker: BDNF (β = 0.11, 95%CI (-3.78 to 4.00)), NfL (β = -0.04, 95%CI (-0.26 to 0.18)), and GFAP (β = -0.01, 95%CI (-0.16 to 0.15)), adjusted for confounders., Conclusion: Aerobic exercise therapy did not result in statistically significant changes in the tested neuro-specific blood-based biomarkers in people with MS., Trial Registration: this study is registered under number ISRCTN69520623 (https://www.isrctn.com/ISRCTN695206)., Competing Interests: Declaration of Competing Interest HH receives research support from the ZonMW, NWO, ATARA, Biogen, Celgene/BMS, Merck and MedDay and serves as a consultant for Sanofi Genzyme, Merck BV, Biogen Idec, Roche and Novartis, and received honorary from these parties paid to her institution. She serves on the editorial board of Multiple Sclerosis Journal. CT receives research support from the National MS Society (Progressive MS alliance) and Innovative Medicines Initiatives 3TR, has a research contract with Celgene. She serves on editorial boards of Medidact Neurologie/Springer, Neurology: Neuroimmunology & Neuroinflammation. She is editor of a Neuromethods book Springer. VG, HB, AG, EW, BJ declare to have no competing interests., (Copyright © 2022. Published by Elsevier B.V.)

Background: The energy cost of walking (ECw) is an important indicator of walking dysfunction in persons with multiple sclerosis (PwMS). However, its underlying causes and its relation with ankle push-off and walking speed are not well understood., Research Question: What is the contribution of ankle push-off and walking speed to increased ECw in PwMS?, Methods: Ten PwMS with walking limitations and 10 individually gender- and age-matched healthy controls (HC) were included. All participants performed two 6-min walking trials on a treadmill at comfortable walking speed (CWS of PwMS) and fast walking speed (FWS, 130 % of CWS of PwMS). Kinetics and metabolic cost were evaluated. Generalized estimating equations were performed to investigate effects of group and walking speed, and their interaction. Spearman correlations were conducted to examine whether ECw was related to ankle push-off in PwMS, controlling for differences in walking speed in PwMS., Results: ECw at matched walking speed was significantly higher in PwMS compared to HC. Kinetic parameters were not different between the most impaired leg in PwMS and HC at matched walking speed, but asymmetry between both legs of PwMS was observed. At FWS, ECw reduced and ankle push-off increased similarly in both groups. ECw was inversely related to peak ankle power of the most impaired leg in PwMS at CWS., Significance: Slow walking speed is one factor that contributes to increased ECw in PwMS. Furthermore, PwMS who had a higher ECw showed a lower peak ankle power, independent of walking speed. This indicates that ankle push-off could be a contributor to increased ECw., Competing Interests: Conflict of interest The authors have no conflicts of interest to report., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Exercise as a subset of physical activity is a cornerstone in the management of multiple sclerosis (MS) based on its pleotropic effects. There is an exponential increase in the quantity of research on exercise in MS, yet a number of barriers associated with study content and quality hamper rapid progress in the field. To address these barriers and accelerate discovery, a new international partnership of MS-related experts in exercise has emerged with the goal of advancing the research agenda. As a first step, the expert panel met in May 2018 and identified the most urgent areas for moving the field forward, and discussed the framework for such a process. This led to identification of five themes, namely "Definitions and terminology," "Study methodology," "Reporting and outcomes," "Adherence to exercise," and "Mechanisms of action." Based on the identified themes, five expert groups have been formed, that will further (a) outline the challenges per theme and (b) provide recommendations for moving forward. We aim to involve and collaborate with people with MS/MS organizations (e.g. Multiple Sclerosis International Federation (MSIF) and European Multiple Sclerosis Platform (EMSP)) in all of these five themes. The generation of this thematic framework with multi-expert perspectives can bolster the quality and scope of exercise studies in MS that may ultimately improve the daily lives of people with MS.

Fatigue related to Multiple Sclerosis (MS) is considered a multidimensional symptom, manifesting in several dimensions such as physical, cognitive, and psychosocial fatigue. This study investigated in 264 patients with severe primary MS-related fatigue (median MS duration 6.8 years, mean age 48.1 years, 75% women) whether subgroups can be distinguished based on these dimensions. Subsequently, we tested whether MS-related fatigue consists of a single common unidimensional factor. Subscale scores on four self-reported fatigue questionnaires, including the Checklist of Individual Strength, the Modified Fatigue Impact Scale, the Fatigue Severity Scale and the SF36 vitality, were used in a cluster analysis to identify patients with similar fatigue characteristics. Next, all 54 items were included in exploratory factor analysis to test unidimensionality. Study results show that in patients with a treatment indication for primary MS-related fatigue, fatigue profiles are based on severity and not on the various dimensions of fatigue. The three profiles found, suggested one underlying fatigue dimension, but this could not be confirmed. Factor analysis of all 54 items resulted in 8 factors, confirming the multidimensional construct of the included fatigue questionnaires.

Background: This study aimed to examine muscle fatigue in lower leg muscles in of people with multiple sclerosis and healthy controls, and whether muscle fatigue coincided with potential changes in gait., Methods: In this case-control study, people with multiple sclerosis (n = 8; 3male; mean age (SD) = 49.7 (9.6) yr) and age-matched healthy controls (n = 10; 4male; mean age (SD) = 47.4 (8.7) yr) walked on a treadmill for 12-min at self-paced speed. Muscle fatigue was indirectly quantified by a decrease in median frequency and increase in root mean square of surface electromyographic recordings of lower leg muscles. Walking speed, ankle push-off power and net ankle work were calculated from marker positions and force plate data using inverse dynamic calculations., Results: People with multiple sclerosis showed larger decreases in median frequency of soleus (most affected leg: p = 0.003; least affected leg: p = 0.009) and larger increases in root mean square of soleus (most and least affected leg: p = 0.037), gastrocnemius medialis (most affected leg: p = 0.003; least affected leg: p = 0.005) and lateralis (most and least affected leg: p < 0.001) compared to controls. Walking speed (p = 0.001), ankle push-off power (most affected leg: p = 0.018; least affected leg: p = 0.001) and net work around the ankle (most affected leg: p = 0.046; least affected leg: p = 0.001) were lower in people with multiple sclerosis compared to controls, but increased in both groups., Interpretation: The results yield preliminary evidence that soleus muscles of people with multiple sclerosis fatigue during prolonged walking. Changes in electromyography of gastrocnemius muscles could however be related to muscle fatigue, changes in gait or a combination., Competing Interests: Declaration of competing interest None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Cognitive behavioural therapy (CBT) has been found to be effective in reducing fatigue severity in MS patients directly following treatment. However, long-term effects are inconsistent leaving room for improvement. In addition, individual face-to-face CBT draws heavily on limited treatment capacity, and the travel distance to the treatment centre can be burdensome for patients. Therefore, we developed "MS Fit", a blended CBT for MS-related fatigue, based on a face-to-face CBT protocol found effective in a previous study, and "MS Stay Fit", internet-based booster sessions to improve long-term effectiveness of CBT for MS-related fatigue. This article presents the protocol of two randomised clinical trials (RCTs) conducted within one study investigating (1) the non-inferiority of MS Fit compared with evidence-based face-to-face CBT for MS-related fatigue and (2) the effectiveness of MS Stay Fit on the long-term outcome of fatigue compared with no booster sessions., Methods/design: The first part of this study is an observer-blinded non-inferiority multicentre RCT, in which 166 severely fatigued MS patients will be randomly assigned (1:1 ratio, computer-generated sequence) to either face-to-face CBT or blended CBT (MS Fit) for fatigue. The primary endpoint is at 20 weeks after baseline. After this post-treatment assessment, patients will be randomly assigned again (1:1 ratio, computer generated sequence) to either MS Stay Fit consisting of two booster sessions at 2 and 4 months after end of treatment or no booster sessions. The primary endpoint of the second study is 52 weeks after baseline. Primary outcome measure in both studies is fatigue severity assessed with the fatigue severity subscale of the Checklist Individual Strength (CIS20r). Outcomes will be assessed at baseline (T0), at the end of treatment (T20), and after 39 and 52 weeks (T39 and T52)., Discussion: If MS Fit is found to be non-inferior to face-to-face CBT, it will improve the accessibility of this treatment. In addition, the study aims to test whether it is possible to improve long-term effectiveness of CBT for MS-related fatigue with MS Stay Fit., Trial Registration: Dutch Trial Register (NTR6966), registered 18 January 2018 https://www.trialregister.nl/trial/6782 WORLD HEALTH ORGANIZATION (WHO) TRIAL REGISTRATION DATA SET: All items from the WHO Trial Registration Data Set can be found within the protocol.

Objective: We investigated whether demographic, disease-related, or personal baseline determinants can predict a positive response to energy conservation management (ECM)., Method: We conducted a secondary analysis of a single-blind, two-parallel-arms randomized controlled trial that included ambulatory adults with severe MS-related fatigue. Therapy responders and nonresponders were categorized by Checklist Individual Strength fatigue change scores between baseline and end of treatment. Logistic regression analyses were used to assess the determinants of response., Results: Sixty-nine participants were included (ECM group, n = 34; control group, n = 35). In the ECM group, fatigue severity, perception of fatigue, illness cognitions about MS, and social support discrepancies were related to the probability of being a responder., Conclusion: The results suggest that people with MS-related fatigue who had a less negative perception of fatigue and who perceived fewer disease benefits and a higher discrepancy in social support had the best response to ECM treatment., (Copyright © 2019 by the American Occupational Therapy Association, Inc.)

Background: Patients with multiple sclerosis (pwMS) often experience a decline in motor function and performance during prolonged walking, which potentially is associated with reduced ankle push-off power and might be alleviated through structured exercise. The objectives of this pilot study were to assess ankle push-off power and walking performance in pwMS and healthy controls, and the preliminary effectiveness of a sequential exercise program (resistance training followed by walking-specific endurance training) on ankle push-off power and walking performance., Methods: PwMS (N = 10) with self-reported reduced walking performance and healthy controls (N = 10; at baseline only) underwent 3D gait analysis during a self-paced 12-minute walking test to assess walking performance prior to and following a sequential exercise program. Secondary testing paradigms comprised isometric muscle testing (triceps surae), cardiopulmonary exercise testing and self-report measures., Findings: PwMS had a shorter 12-minute walking distance, and lower peak ankle push-off power (most-affected leg) in comparison to healthy controls. There was no minute-to-minute decline in walking performance. The 8-week resistance training significantly improved walking distance. In parallel, higher peak and speed-normalized ankle push-off power were found in the less-affected side. No additional changes were found following the walking-specific endurance training phase., Interpretation: There was no walking-related motor fatigue found during a self-paced 12-minute walking test despite reduced ankle push-off power, and self-reported walking problems. Preliminary effects suggest a positive effect of resistance training on walking performance, potentially associated with increases in ankle push-off power, interestingly, in the less-affected leg. The added effect of the walking-specific endurance training remains unclear., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Walking tests, like the 2-minute fast walk test, are simple, inexpensive performance-based tests, and therefore seem attractive to estimate the aerobic fitness in people with chronic diseases., Objective: To determine the criterion validity of the 2-minute fast walk test for estimating aerobic capacity in patients with Multiple Sclerosis (MS), by comparing it with the peak oxygen uptake (VO2peak in mL/kg/min) as measured by Cardiopulmonary Exercise Testing (CPET) on a cycle ergometer., Methods: The 2 min fast walk test was performed on a marked indoor trajectory, using a static start protocol. Aerobic capacity (VO2peak, in mL/kg/min) was derived from CPET on a cycle ergometer. Criterion validity was tested by means of Pearson's correlation coefficient and should be at least 0.70 for a good criterion validity of the 2 min walk test. Linear regression analysis was applied to more precisely estimate VO2peak., Results: In total 141 people with severe MS-related fatigue (mean age 47.0 years (range 23-68 years), 73% women, median disease duration 7.8 years (range 0.3 - 28.7 years)) performed both tests. The distance walked in two minutes ranged from 52.0 to 290.0 m (mean 175.1 m, sd 44.9 m), while the VO2peak varied between 11.31 and 40.28 mL/kg/min (mean 22.52 mL/kg/min, sd 6.07 mL/kg/min). The correlation between the 2 min walk test and VO2peak was 0.441 (95% CI: 0.309-0.570). The absolute residual error in estimated VO2peak was 5.47 mL/kg/min., Conclusions: Due to the poor correlation found between the 2 min walk test and VO2peak, the 2-min walk test cannot be recommended as a valid alternative for estimating aerobic capacity in persons with MS.

Background: Fatigue affects 80% of persons with multiple sclerosis and is associated with daily physical functioning. Both fatigue and physical behaviour are multidimensional concepts., Objective: To study the association between the dimensions of physical behaviour and multiple sclerosis-related fatigue., Methods: Cross-sectional analysis of 212 persons with multiple sclerosis. Participants were severely fatigued, with a Fatigue Severity Scale median (interquartile range): 5.4 (4.8-5.9) and were minimally to moderately neurologically impaired, based on the Expanded Disability Status Scale: 2.5 (2.0-3.5), 73% had relapsing-remitting multiple sclerosis. Fatigue was measured by questionnaires (i.e. Checklist Individual Strength, Modified Fatigue Impact Scale), and the dimensions subjective, physical, cognitive and psychological fatigue were distinguished. Physical behaviour was measured using an Actigraph GT3X+, and outcomes were categorized into the dimensions of activity amount, activity intensity, day pattern, and distribution of activities., Results: The physical behaviour dimensions were significantly associated with only the physical fatigue dimension (omnibus F-test: 3.96; df1 = 4, df2 = 207; p = 0.004). Additional analysis showed that the amount of activity (unstandardized beta coefficient (β) = -0.16; 95% confidence interval (CI) -0.27 to -0.04; p = 0.007), activity intensity (β = -0.18; 95% CI -0.31 to -0.06; p = 0.004) and day pattern of activity (β = -0.17; 95% CI, -0.28 to -0.06; p = 0.002) were the physical behaviour dimensions that were significantly associated with physical fatigue., Conclusion: Physical behaviour is weakly associated with physical fatigue and is not associated with other dimensions of fatigue.

Objective: To investigate whether aerobic capacity explains the level of self-reported physical activity, physical functioning, and participation and autonomy in daily living in persons with multiple sclerosis-related fatigue., Design: A cross-sectional study., Patients: Sixty-two participants with multiple sclerosis-related fatigue., Methods: Aerobic capacity was measured with a leg ergometer and was expressed as maximal oxygen uptake (VO2max, in ml/kg/min). Physical activity was measured with the Physical Activity Scale for Individuals with Physical Disabilities (PASIPD), physical functioning with the Short Form 36 - physical functioning (SF36-pf), and participation and autonomy in daily living with the Impact on Participation and Autonomy questionnaire (IPA). Multiple regression analyses were performed, adjusted for potential confounders (gender, age, body mass index, educational level, and employment status)., Results: Mean maximal oxygen uptake (VO2max) was 23.9 ml/kg/min (standard deviation (SD) 6.3 ml/kg/min). There was no significant relationship between VO2max and physical activity (PASIPD): β = 0.320, 95% confidence interval (95% CI) = -0.109 to 0.749, R2 = 10.8%. Higher VO2max correlated with better physical functioning (SF36-pf): β = 1.527, 95% CI = 0.820-2.234, R2 = 25.9%, and was significantly related to IPA domains "autonomy indoors" (β = -0.043, 95% CI = -0.067 to -0.020, R2 = 20.6%), "autonomy outdoors" (β = -0.037, 95% CI = -0.062 to -0.012, R2 = 18.2%) and "social life and relationships" (β=-0.033, 95% CI = -0.060 to -0.007, R2 = 21.3%)., Conclusion: Maximum aerobic capacity was severely reduced in persons with multiple sclerosis-related fatigue. This partly explains the limited physical functioning and restrictions in participation and autonomy indoors, outdoors and in social life and relationships in these persons.

Background: Evidence supporting the effectiveness of aerobic training, specific for fatigue, in severely fatigued patients with multiple sclerosis (MS) is lacking., Objective: To estimate the effectiveness of aerobic training on MS-related fatigue and societal participation in ambulant patients with severe MS-related fatigue., Methods: Patients ( N = 90) with severe MS-related fatigue were allocated to 16-week aerobic training or control intervention. Primary outcomes were perceived fatigue (Checklist Individual Strength (CIS20r) fatigue subscale) and societal participation. An improvement of ⩾8 points on the CIS20r fatigue subscale was considered clinically relevant. Outcomes were assessed by a blinded observer at baseline, 2, 4, 6 and 12 months., Results: Of the 89 patients that started treatment (median Expanded Disability Status Scale (interquartile range), 3.0 (2.0-3.6); mean CIS20r fatigue subscale (standard deviation (SD)), 42.6 (8.0)), 43 received aerobic training and 46 received the control intervention. A significant post-intervention between-group mean difference (MD) on the CIS20r fatigue subscale of 4.708 (95% confidence interval (CI) = 1.003-8.412; p  = 0.014) points was found in favour of aerobic training that, however, was not sustained during follow-up. No effect was found on societal participation., Conclusion: Aerobic training in MS patients with severe fatigue does not lead to a clinically meaningful reduction in fatigue or societal participation when compared to a low-intensity control intervention.

Background: Fatigue is a frequently reported and disabling symptom in multiple sclerosis (MS)., Objective: To investigate the effectiveness of an individual energy conservation management (ECM) intervention on fatigue and participation in persons with primary MS-related fatigue., Methods: A total of 86 severely fatigued and ambulatory adults with a definite diagnosis of MS were randomized in a single-blind, two-parallel-arm randomized clinical trial to the ECM group or the information-only control group in outpatient rehabilitation departments. Blinded assessments were carried out at baseline and at 8, 16, 26 and 52 weeks after randomization. Primary outcomes were fatigue (fatigue subscale of Checklist Individual Strength - CIS20r) and participation (Impact on Participation and Autonomy scale - IPA)., Results: Modified intention-to-treat analysis was based on 76 randomized patients (ECM, n = 36; MS nurse, n=40). No significant ECM effects were found for fatigue (overall difference CIS20r between the groups = -0.81; 95% confidence interval (CI), -3.71 to 2.11) or for four out of five IPA domains. An overall unfavourable effect was found in the ECM group for the IPA domain social relations (difference between the groups = 0.19; 95% CI, 0.03 to 0.35)., Conclusion: The individual ECM format used in this study did not reduce MS-related fatigue and restrictions in participation more than an information-only control condition.

Background: Fatigue is a common symptom in multiple sclerosis (MS) and often restricts societal participation. Cognitive behavioral therapy (CBT) may alleviate MS-related fatigue, but evidence in literature is inconclusive., Objective: To evaluate the effectiveness of CBT to improve MS-related fatigue and participation., Methods: In a multi-center, assessor-masked, randomized controlled trial, participants with severe MS-related fatigue were assigned to CBT or control treatment. CBT consisted of 12 individual sessions with a psychologist trained in CBT, the control treatment consisted of three consultations with a MS nurse, both delivered over 16 weeks. Assessments were at baseline, 8, 16 (i.e. post-intervention), 26, and 52 weeks post-baseline. Primary outcomes were the Checklist Individual Strength-fatigue subscale (CIS20r fatigue) and the Impact on Participation and Autonomy questionnaire (IPA). Data were analyzed according to the intention-to-treat principle, using mixed-model analysis., Results: Between 2011 and 2014, 91 patients were randomized (CBT: n = 44; control: n = 47). Between-group analysis showed a positive post-intervention effect for CBT on CIS20r fatigue (T16: -6.7 (95% confidence interval (CI) = -10.7; -2.7) points) that diminished during follow-up (T52: 0.5 (95% CI = -3.6; 4.4)). No clinically relevant effects were found on societal participation., Conclusion: Severe MS-related fatigue can be reduced effectively with CBT in the short term. More research is needed on how to maintain this effect over the long term.

Background: Limited walking ability is an important problem for patients with multiple sclerosis. A better understanding of how gait impairments lead to limited walking ability may help to develop more targeted interventions. Although gait classifications are available in cerebral palsy and stroke, relevant knowledge in MS is scarce., Objective: The aims of this study were: (1) to identify distinctive gait patterns in patients with MS based on a combined evaluation of kinematics, gait features, and muscle activity during walking and (2) to determine the clinical relevance of these gait patterns., Design: This was a cross-sectional study of 81 patients with MS of mild-to-moderate severity (Expanded Disability Status Scale [EDSS] median score=3.0, range=1.0-7.0) and an age range of 28 to 69 years., Method: The patients participated in 2-dimensional video gait analysis, with concurrent measurement of surface electromyography and ground reaction forces. A score chart of 73 gait items was used to rate each gait analysis. A single rater performed the scoring. Latent class analysis was used to identify gait classes., Results: Analysis of the 73 gait variables revealed that 9 variables could distinguish 3 clinically meaningful gait classes. The 9 variables were: (1) heel-rise in terminal stance, (2) push-off, (3) clearance in initial swing, (4) plantar-flexion position in mid-swing, (5) pelvic rotation, (6) arm-trunk movement, (7) activity of the gastrocnemius muscle in pre-swing, (8) M-wave, and (9) propulsive force. The EDSS score and gait speed worsened in ascending classes., Limitations: Most participants had mild-to-moderate limitations in walking ability based on their EDSS scores, and the number of walkers who were severely limited was small., Conclusions: Based on a small set of 9 variables measured with 2-dimensional clinical gait analysis, patients with MS could be divided into 3 different gait classes. The gait variables are suggestive of insufficient ankle push-off., (© 2016 American Physical Therapy Association.)

Background: Fatigue is a frequently occurring symptom of multiple sclerosis (MS) that limits social participation., Objective: To systematically determine the short and long-term effects of cognitive behavioral therapy (CBT) for the treatment of MS-related fatigue., Data Sources: Pubmed, Cochrane, EMBASE, Psychology and Behavioral Sciences Collection, ERIC, PsychINFO, Cinahl, PsycARTICLES, and relevant trial registers were searched up to February 2016. In addition, references from retrieved articles were examined., Study Selection: Studies were included if participants had MS, fatigue was a primary outcome measure, the intervention was CBT, and the design was a randomized controlled trial. The search was performed by two independent reviewers, three CBT experts determined whether interventions were CBT., Data Extraction: Data on patient and study characteristics and fatigue were systematically extracted using a standardized data extraction form. Two independent reviewers assessed risk of bias using the Cochrane Collaboration risk of bias tool. In the event of disagreement, a third reviewer was consulted., Data Synthesis: Of the 994 identified studies, 4 studies were included in the meta-analysis, comprising 193 CBT-treated patients and 210 patients who underwent a control treatment. Meta-analyses of these studies showed that CBT treatment had a positive short-term effect on fatigue (standardized mean difference [SMD]=-0.47; 95% confidence interval [CI]=-0.88; -0.06; I 2 =73%). In addition, three studies showed a long-term positive effect of CBT (SMD=-0.30; CI -0.51; -0.08; I 2 =0%)., Conclusions: This review found that the use of CBT for the treatment of fatigue in patients with MS has a moderately positive short-term effect. However, this effect decreases with cessation of treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

To determine the relationship between appraisal and societal participation in fatigued patients with Multiple Sclerosis (MS), and whether this relation is mediated by coping styles. 265 severely-fatigued MS patients. Appraisal, a latent construct, was created from the General Self-Efficacy Scale and the helplessness and acceptance subscales of the Illness Cognition Questionnaire. Coping styles were assessed using the Coping Inventory Stressful Situations (CISS21) and societal participation was assessed using the Impact on Participation and Autonomy. A multiple mediator model was developed and tested by structural equation modeling on cross-sectional data. We corrected for confounding by disease-related factors. Mediation was determined using a product-of-coefficients approach. A significant relationship existed between appraisal and participation (β = 0.21, 95 % CI 0.04-0.39). The pathways via coping styles were not significant. In patients with severe MS-related fatigue, appraisal and societal participation show a positive relationship that is not mediated by coping styles., Competing Interests: Lizanne Eva van den Akker, Heleen Beckerman, Emma Hubertine Collette, Gijs Bleijenberg, Joost Dekker, Hans Knoop, Vincent de Groot, and TREFAMS-ACE study group declare that they have no conflict of interest. Human and animal rights and Informed consent All procedures followed were in accordance with ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.

Objective: To investigate the feasibility and safety of cardiopulmonary exercise testing (CPET) in patients with multiple sclerosis (MS)., Data Sources: PubMed, EMBASE, CINAHL, SPORTDiscus, PsycINFO, ERIC, and the Psychology and Behavioral Sciences Collection were searched up to October 2014. References from retrieved articles were examined to identify additional relevant studies., Study Selection: Inclusion of original studies was on the basis of performance of maximal CPET, description of the protocol, and participants with definite MS aged ≥18 years. No language restrictions were applied., Data Extraction: The quality of CPET reporting in included studies was scored according to a structured checklist considering 10 feasibility (eg, test abnormalities) and 12 safety quality criteria (eg, adverse events). Structured data extraction was performed for these feasibility and safety features of CPET., Data Synthesis: Forty-six studies were included, comprising 1483 patients with MS, with a mean age ± SD of 42.0±5.8 years and a median Expanded Disability Status Scale (EDSS) score of 2.8 (first quartile=2.1; third quartile=3.9; range of average EDSS scores, .75-5.8). Quality of reporting on CPET varied from 3 to 13 out of a possible 22 quality points. The percentage of test abnormalities (feasibility) was 10.0%, primarily because of an inability to maintain pedaling at a specific resistance. The percentage of adverse events (safety) was 2.1%. All adverse events were temporary., Conclusions: Based on the available data, we conclude that CPET is feasible provided that the CPET modality is tailored to the physical abilities of the patient. Furthermore, CPET is safe when recommended precautions and safety measures are implemented. However, future optimization of CPET will require protocolized testing and the implementation of standard reporting procedures., (Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To study physical behavior in detail in fatigued persons with multiple sclerosis (MS)., Design: Case-control explorative study., Setting: Outpatient rehabilitation department and participants' daily environment., Participants: Fatigued persons with MS (n=23) were selected from a randomized controlled trial. Cases were matched by age and sex to healthy, nonfatigued controls (n=23). Eligible persons with MS were severely fatigued (Checklist Individual Strength fatigue domain mean score, 43.2±6.6) and ambulatory (Expanded Disability Status Scale mean score, 2.5±1.5)., Interventions: Not applicable., Main Outcome Measures: Measurements were performed using an accelerometer over 7 days. Outcomes included the following: amount of physical activity expressed in counts per day, counts per minute (CPM), and counts per day period (morning, afternoon, evening); duration of activity intensity categories (sedentary, light physical activity, moderate-to-vigorous physical activity [MVPA]); and distribution of MVPA and sedentary periods over the day., Results: Persons with MS had fewer counts per day (mean difference, -156×10(3); 95% confidence interval [CI], -273×10(3) to -39×10(3); P=.010), had fewer CPM (mean difference, -135; 95% CI, -256 to -14; P=.030), and were less physically active in the morning (mean difference, -200; 95% CI, -389 to -11; P=.039) and evening (mean difference, -175; 95% CI, -336 to -14; P=.034) than controls. Persons with MS spent a higher percentage of their time sedentary (mean difference, 5.6; 95% CI, .1-11.1; P=.045) and spent less time at the higher MVPA intensity (mean difference, -2.4; 95% CI, -4.7 to -0.09; P=.042). They had fewer MVPA periods (mean difference, 29; 95% CI, -56.2 to -2.6; P=.032) and a different distribution of sedentary (mean difference, .033; 95% CI, .002 to .064; P=.039) and MVPA periods (mean difference, -.08; 95% CI, -.15 to -.01; P=.023)., Conclusions: Detailed analyses of physical behavior showed that ambulatory fatigued persons with MS do differ from healthy controls not only in physical activity level, but also in other physical behavior dimensions (eg, day patterns, intensity, distribution)., (Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the pathophysiological role of pro- and anti-inflammatory cytokines in primary multiple sclerosis-related fatigue., Methods: Fatigued and non-fatigued patients with multiple sclerosis (MS) were recruited and their cytokine profiles compared. Patients with secondary fatigue were excluded. Fatigue was assessed with the self-reported Checklist Individual Strength (CIS20r), subscale fatigue. A CIS20r fatigue cut-off score of 35 was applied to differentiate between non-fatigued (CIS20r fatigue ≤34) and fatigued (CIS20r fatigue ≥35) patients with MS. Blood was collected to determine the serum concentrations of pro-inflammatory cytokines (IL-1β, IL-2, IL-6, IL-8, IL-12p70, IL-17, TNFα, and IFN-γ) and anti-inflammatory cytokines (IL-4, IL-5, IL-10, and IL-13). We controlled for the confounding effect of age, gender, duration of MS, disease severity, type of MS, and use of immunomodulatory drugs., Results: Similar cytokine levels were observed between MS patients with (n = 21) and without fatigue (n = 14). Adjusted multiple regression analyses showed a single significant positive relationship, that of IL-6 with CIS20r fatigue score. The explained variance of the IL-6 model was 21.1%, once adjusted for the confounding effect of age., Conclusion: The pro-inflammatory cytokine interleukin-6 (IL-6) may play a role in the pathophysiology of primary fatigue in patients with MS., Trial Registrations: ISRCTN69520623, ISRCTN58583714, and ISRCTN82353628.

Background: TREFAMS is an acronym for TReating FAtigue in Multiple Sclerosis, while ACE refers to the rehabilitation treatment methods under study, that is, Aerobic training, Cognitive behavioural therapy, and Energy conservation management. The TREFAMS-ACE research programme consists of four studies and has two main objectives: (1) to assess the effectiveness of three different rehabilitation treatment strategies in reducing fatigue and improving societal participation in patients with MS; and (2) to study the neurobiological mechanisms of action that underlie treatment effects and MS-related fatigue in general., Methods/design: Ambulatory patients (n = 270) suffering from MS-related fatigue will be recruited to three single-blinded randomised clinical trials (RCTs). In each RCT, 90 patients will be randomly allocated to the trial-specific intervention or to a low-intensity intervention that is the same for all RCTs. This low-intensity intervention consists of three individual consultations with a specialised MS-nurse. The trial-specific interventions are Aerobic Training, Cognitive Behavioural Therapy, and Energy Conservation Management. These interventions consist of 12 individual therapist-supervised sessions with additional intervention-specific home exercises. The therapy period lasts 16 weeks. All RCTs have the same design and the same primary outcome measures: fatigue - measured with the Checklist Individual Strength, and participation - measured with the Impact on Participation and Autonomy questionnaire. Outcomes will be assessed 1 week prior to, and at 0, 8, 16, 26 and 52 weeks after randomisation. The assessors will be blinded to allocation. Pro- and anti-inflammatory cytokines in serum, salivary cortisol, physical fitness, physical activity, coping, self-efficacy, illness cognitions and other determinants will be longitudinally measured in order to study the neurobiological mechanisms of action., Discussion: The TREFAMS-ACE programme is unique in its aim to assess the effectiveness of three rehabilitation treatments. The programme will provide important insights regarding the most effective treatment for MS-related fatigue and the mechanisms that underlie treatment response. A major strength of the programme is that the design involves three almost identical RCTs, enabling a close comparison of the treatment strategies and a strong overall meta-analysis. The results will also support clinical practice guidelines for the treatment of MS-related fatigue., Trial Registrations: Current Controlled Trials ISRCTN69520623, ISRCTN58583714, and ISRCTN82353628.

Objective: To determine the course of daily functioning in patients with multiple sclerosis in the 10 years after their definite diagnosis., Methods: A long-term prospective follow-up study including an incidence cohort of 156 patients with multiple sclerosis. Participants were examined systematically, beginning immediately after definite diagnosis, then at the following time-points: 6 months, 1, 2, 3, 6 and 10 years. The various domains of daily functioning were assessed with the Expanded Disability Status Scale, the Functional Independence Measure, and the Medical Outcome Study Short Form-36 (SF-36)., Results: Neurological disability and physical functioning worsened significantly, with a time course dependent on whether a patient had multiple sclerosis of the relapse onset type or non-relapse onset type. Cognitive and social functioning worsened significantly over time, but with the same (accelerated) rate of change in both the RO and NRO groups. Scores on SF-36 mental health, SF-36 role physical, and SF-36 general health changed only slightly., Conclusion: In the first 10 years after definite diagnosis, patients with multiple sclerosis showed a more pronounced decline in physical functioning than in cognitive and social functioning. There was no time-related decline in mental health, social role due to physical limitations, or general health.

Objectives: To determine whether there is a relationship between self-reported fatigue and the energy cost of walking (ECw), and how self-reported fatigue and ECw relate to physical functioning in patients with multiple sclerosis (MS)., Design: Cross-sectional cohort study, using structural equation modeling., Setting: Home environment and at a university medical center., Participants: Patients (N=75) were obtained from a longitudinal study on outcome measurement and functional prognosis in early MS. Patients were included if they were able to walk for 6 minutes without being assisted by a person. The age range was between 28.0 and 69.7 years and the median Expanded Disability Status Scale was 2.5 (range, 1.0-6.5)., Interventions: Not applicable., Main Outcome Measures: Self-reported fatigue was measured with the Fatigue Severity Scale, the vitality subscale of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and a visual analog scale. Physical functioning was determined with the physical functioning subscale of the SF-36, fast walking speed, and comfortable walking speed. The ECw (J·kg(-1)·m(-1)) was measured with the energy cost of the walking test., Results: The relationship between ECw and latent variable fatigue had a β=-.188 (P=.236), that between ECw and physical functioning (SF-36 physical functioning) had a β=-.344 (P=.001), and that between fatigue and physical functioning had a β=-.448 (P=.000)., Conclusions: Fatigue and ECw are not related in patients with MS with mild to moderate walking problems. ECw and fatigue are independent determinants of physical functioning., (Copyright © 2012 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Background: People with multiple sclerosis (MS) are less physically active than those without the disease. Understanding the modifiable factors that are related to physical inactivity is important for developing effective physical activity programs., Objective: The objectives of this study were to determine levels of physical activity and to determine factors related to the physical activity behavior of adults with MS by use of the Physical Activity for People With a Disability (PAD) model. The PAD model combines the International Classification of Functioning, Disability and Health framework of disability and theoretical models of physical activity behavior., Design: This investigation was a cross-sectional study., Methods: The study participants were 106 people who had MS and who, since their definite diagnosis, had been participating in a prospective cohort study. Physical activity was assessed with the Short Questionnaire to Assess Health-Enhancing Physical Activity. The independent roles of disease characteristics and demographic, cognitive-behavioral, and environmental factors were determined using questionnaires for which reliability and validity have been established., Results: The median total level of physical activity of participants with MS (mean age=42.8 years, median Expanded Disability Status Scale score=3, disease duration=6 years) was 10.68 metabolic equivalents x h/d (interquartile range=3.69-16.57). On average, participants spent 30 h/wk on activities with metabolic equivalents of 2 or more (interquartile range=10.7-45.0 h/wk). The regression models predicting physical activity behavior on the basis of demographic (29.4%) and disease-related (28.3%) variables explained more variance than the models based on cognitive-behavioral (12.0%) and environmental (9.1%) variables. Combining significant variables yielded a final regression model that explained 37.2% of the variance in physical activity. Significant determinants were disease severity, a disability pension, and having children to care for., Limitations: Changes in physical activity behavior were not measured., Conclusions: Participants with MS were less active if their disease was more severe, if they received a disability pension, or if they had children to care for. The PAD model was helpful in understanding the physical activity behavior of participants with MS.

Objective: To predict functioning after 3 years in patients with recently diagnosed multiple sclerosis (MS)., Design: Inception cohort with 3 years of follow-up. At baseline, predictors were obtained from medical history taking, neurologic examination, and magnetic resonance imaging (MRI)., Setting: Neurology outpatient clinic., Participants: Patients with MS (N=156); 146 with complete follow-up., Interventions: Not applicable., Main Outcome Measures: Inability to walk at least 500 m, impaired dexterity, cognitive impairments, incontinence, inability to drive a car or use public transportation, social dysfunction, and reliance on a disability pension., Results: Clinical prediction rules were constructed for the models that were well calibrated (sufficient agreement between predicted and observed outcomes, based on visual inspection of calibration curves) and that showed sufficient discrimination (area under the receiver operation characteristic curve >.70) after internal bootstrap validation. The models for the inability to walk at least 500 m, impaired dexterity, and cognitive impairments were well calibrated. Discrimination was sufficient for all 7 models, except the one predicting social dysfunction (.67). The inability to walk at least 500 m was predicted by the perceived ability to walk, impairment of the cerebellar tract, and the number of MRI lesions in the spinal cord. Impaired dexterity was predicted by the perceived ability to use the hands, impairments of the pyramidal, cerebellar, and sensory tracts, and the T2-weighted infratentorial lesion load. Cognitive impairment was predicted by age, gender, the perceived ability to concentrate, and the T2-weighted supratentorial lesion load., Conclusions: Inability to walk at least 500 m, impaired dexterity, and cognitive impairments can be predicted with predictors that are derived from medical history taking, neurologic examination, and MRI shortly after a definite diagnosis of MS has been made.

Objective: To study the effect of comorbidity on the course of physical functioning in patients after stroke and with multiple sclerosis., Subjects: Patients after a first-ever supratentorial stroke (n = 198), who had been admitted for inpatient rehabilitaion, and patients with recently diagnosed multiple sclerosis (n =146)., Design: Prospective, observational study over a period of 3 years., Measurements: Physical functioning was measured with the motor score of the Functional Independence Measure at baseline (time of diagnosis), and at 6 months, and 1 and 3 year follow-ups. Cardiovascular, respiratory, musculoskele nottal, diabetes mellitus, and other comorbidities were measured at baseline., Results: Patients after stroke and multiple sclerosis with comorbidity showed a significantly lower level of physical functioning over all 4 measurements. There was no difference in the course of physical functioning between patients after stroke with and without comorbidity. In patients with multiple sclerosis, a greater decrease in physical functioning over the 3-year follow-up was found in patients with comorbidity of the musculoskeletal system compared with patients without., Conclusion: These findings indicate that similar improvements in physical functioning can be expected during rehabilitation of stroke patients with comorbidity compared with patients without these conditions. In patients with multiple sclerosis, musculoskeletal comorbidity requires further attention because of its association with a greater decrease in physical functioning.

Objective: The aim of this study was to identify the principal determinants that are longitudinally associated with the performance of social roles in the first 3 years following a diagnosis of multiple sclerosis., Design: Inception cohort with 5 measurements over 3 years., Patients: A total of 156 patients recently diagnosed with multiple sclerosis., Method: Performance of social roles was measured using the 2 role functioning and the social sub-scales of the Medical Outcome Study Short Form 36. Potential determinants (n = 43) were divided into the following clusters: patient and disease characteristics (n = 12), psychosocial characteristics (n = 10), basic functions (n = 18) and basic activities (n = 3). Multivariate longitudinal regression analyses were performed with generalized estimating equations. A backwards selection procedure for every cluster per outcome reduced the large number of potential determinants. In order to determine whether longitudinal associations are present the selected determinants were entered into an overall regression model., Results: Twenty-three candidate determinants were selected. Vitality, measured with the SF36 sub-scale vitality, the T2-weighted supratentorial lesion load and the perceived amount of social support, measured with the Social Support List Discrepancies, were longitudinally associated with the performance of social roles in 2 or 3 of the models., Conclusion: Vitality, the perceived amount of social support, and disease activity, i.e. the T2-weighted supratentorial lesion load, determine the performance of social roles in the early stages of multiple sclerosis.

Background: Exercise as a subset of physical activity is a cornerstone in the management of multiple sclerosis (MS) based on its pleiotropic effects, but continued progression of the field requires better future designs and methodologies. Objectives: This paper outlines the work of the 'Study design and methodology' group of the MoXFo (moving exercise research forward) initiative, and addresses critical aspects and future directions when defining the research question of interest, and subsequently, designing the study and exercise intervention in MS patients. Methods: The work is based on the formation of an international expert panel formed within the MoXFo initiative. We provide a structured and concise synthesis of exercise-specific MS research challenges and considerations when designing randomized controlled trials (RCTs). Results: Challenges and considerations are presented using the Patient population, Intervention, Comparator, Outcomes, Timing, Setting (PICOTS) framework, thereby forming a new and specific MS exercise PICOTS framework. Conclusion: We propose that researchers should carefully consider and align all elements of this MS exercise PICOTS framework when developing future research questions and study designs, ultimately improving the quality of new exercise studies in people with MS. [ABSTRACT FROM AUTHOR]

• The Whereabouts app creates a unique individual societal participation profile. • The app creates a real-time timeline of specific participation activities. • The app assess participation with ratings of meaningfulness and perceived strain. • The app is a potential valuable tool for patients, clinicians, and researchers. To develop a mobile health app to assess individual-specific meaningful societal participation in real time and to evaluate its usability. Development and usability study. General community. Persons with multiple sclerosis (PwMS) utilized the app for 7 consecutive days. In total, 72 PwMS and smartphone owners were included in the analysis (N=72). Using location tracking, the newly developed Whereabouts app generates an individual-specific timeline of societal participation activities each day, consisting of location and transportation intervals. Subsequently, this timeline is real time enriched by the user with self-reported ratings of meaningfulness and perceived strain of these societal participation activities. The app is based on the International Classification of Functioning, Disability and Health and was developed in an iterative process. Usability of the newly developed Whereabouts app was evaluated by analyzing the effectiveness, efficiency, and user satisfaction. Regarding effectiveness, the app correctly assessed the type, frequency, and duration of different societal participation activities for 96.1% of the participation activities. The self-reported ratings of societal participation varied for meaningfulness (range, 5-8), perceived strain (range, 2-6), and meaningfulness of the perceived strain (range, 5-8). The latter 2 were highly correlated (r =0.857). With regards to efficiency, 3.9% of the generated participation activities had to be excluded due to inaccuracy or incompleteness. Relating to user satisfaction, 57.3% of PwMS reported that they were satisfied with the usability of the app and 59.7% stated that it gave a realistic overview of their daily activities. However, 54.4% PwMS missed the possibility to specify activities at home, to add activities in more detail, and to correct mistakes. The Whereabouts app demonstrates usability in assessing real-time, individual-specific meaningful societal participation. Improvements are recommended, such as the possibility to specify participation activities and to generate a graphic overview. [ABSTRACT FROM AUTHOR]

Background: Patient autonomy is a bioethical principle that was strengthened in the revised Declaration of Geneva. Shared decision making (SDM) is particularly relevant in the management of multiple sclerosis (MS) because many preference-sensitive decisions have to be made during the disease course. We aimed to summarize the available evidence on SDM in the MS field and to inform future research and practice. Methods: We performed a scoping review by searching MEDLINE (past 5 years). Studies were included if they reported primary/secondary research and focused on SDM related to people with MS. Data were grouped into topics, with results presented in narrative form. Results: From 865 references, we included 55 studies conducted mostly in Europe. Half of the studies were observational, followed by qualitative (20%), mixed-methods (17%), randomized controlled trials (RCTs, 5%), quasi-experimental (5%), and reviews (4%). Most studies addressed people with relapsing-remitting MS (85%); the remaining addressed health care professionals, patients' significant others, or a combination. We identified five main topics: decisions on disease-modifying drugs, decisions on chronic cerebrospinal venous insufficiency treatment, information provision and patient education, health literacy, and risk knowledge. Conclusions: The high proportion of included studies on SDM in MS in Europe suggests an earlier adoption of these concepts in this area. Decisions on disease-modifying drugs was the prevalent topic. Only 5% of studies were RCTs, indicating that more research is needed to study the effectiveness of SDM interventions. Studies addressing people with primary and secondary progressive MS are also needed. [ABSTRACT FROM AUTHOR]

With the current rate in growth of evidence in multiple sclerosis (MS) rehabilitation, systematic reviews and clinical guidelines typically lag behind the most currently published research findings. In addition, most health care professionals lack the time, resources, or adequate skills to identify and evaluate new evidence, and hands-on tools to implement the latest evidence into clinical practice are often lacking or not readily available. The Applying Evidence with Confidence (APPECO) platform is a newly developed online tool that addresses these key challenges. APPECO was initiated as a proof-of-concept for the common MS symptoms fatigue and cognitive function. Subsequently, intervention studies about depression, pain, and mobility were added. APPECO currently hosts detailed information from 250 randomized clinical trials, 293 interventions, and 1250 effect sizes on 53 patient outcomes. Few studies with high quality (ie, low risk of bias) are available specifically designed to test the benefits of MS rehabilitation on fatigue (n = 5 [2.4%]), cognitive function (n = 4 [1.6%]), and depression (n = 2 [0.8%]). No high-quality studies were included for pain and mobility. APPECO has the potential to address key challenges in evidence-based rehabilitation medicine for MS and to facilitate swift knowledge translation from evidence into clinical practice. Sustainability of APPECO depends on a continuous resource impulse (eg, financial, time, editorial management, platform maintenance) to ensure up-to-date information across all relevant MS symptoms and activity limitations (≈2-6 randomized controlled trials per month). Ways to optimize knowledge translation in the absence of high-quality evidence in APPECO need to be explored further. [ABSTRACT FROM AUTHOR]

Exercise as a subset of physical activity is a cornerstone in the management of multiple sclerosis (MS) based on its pleotropic effects. There is an exponential increase in the quantity of research on exercise in MS, yet a number of barriers associated with study content and quality hamper rapid progress in the field. To address these barriers and accelerate discovery, a new international partnership of MS-related experts in exercise has emerged with the goal of advancing the research agenda. As a first step, the expert panel met in May 2018 and identified the most urgent areas for moving the field forward, and discussed the framework for such a process. This led to identification of five themes, namely "Definitions and terminology," "Study methodology," "Reporting and outcomes," "Adherence to exercise," and "Mechanisms of action." Based on the identified themes, five expert groups have been formed, that will further (a) outline the challenges per theme and (b) provide recommendations for moving forward. We aim to involve and collaborate with people with MS/MS organizations (e.g. Multiple Sclerosis International Federation (MSIF) and European Multiple Sclerosis Platform (EMSP)) in all of these five themes. The generation of this thematic framework with multi-expert perspectives can bolster the quality and scope of exercise studies in MS that may ultimately improve the daily lives of people with MS. [ABSTRACT FROM AUTHOR]

Some evidence supports the involvement of the hypothalamic–pituitary–adrenal axis (HPA axis) with multiple sclerosis (MS)-related fatigue. In this study, we determined the relation of HPA-axis function with primary fatigue in MS patients in the longitudinal treating fatigue in a MS cohort. MS patients from the TREeating FAtigue in MS (TREFAMS) research program that consists of three randomized controlled trials to study the effects of aerobic training, energy conservation management, and cognitive behavioral therapy on MS-related fatigue were included. The HPA-axis functioning was determined at baseline, the end of treatment (16 weeks) and after 52 weeks. The cortisol awakening response (CAR) and night-time cortisol levels were analyzed. Fatigue was measured with the fatigue subscale of the Checklist Individual Strength (CIS20r fatigue). There was no relationship between CAR and night-time cortisol parameters with CIS20r fatigue scores. Neither of the treatments influenced CAR and night-time cortisol parameters, with the exception of an effect in the energy conservation management treatment group on the CAR surge increase over 52 weeks (β = −114.8, p = 0.007, 95% CI = −197.6, −31.9). Our data suggest that the diurnal cortisol secretion is not associated with MS-related fatigue. This indicates that MS-related fatigue is not attributed to diurnal cortisol secretion and is likely caused by other disease mechanisms. [ABSTRACT FROM AUTHOR]

Background: Evidence supporting the effectiveness of aerobic training, specific for fatigue, in severely fatigued patients with multiple sclerosis (MS) is lacking. Objective: To estimate the effectiveness of aerobic training on MS-related fatigue and societal participation in ambulant patients with severe MS-related fatigue. Methods: Patients (N = 90) with severe MS-related fatigue were allocated to 16-week aerobic training or control intervention. Primary outcomes were perceived fatigue (Checklist Individual Strength (CIS20r) fatigue subscale) and societal participation. An improvement of ⩾8 points on the CIS20r fatigue subscale was considered clinically relevant. Outcomes were assessed by a blinded observer at baseline, 2, 4, 6 and 12 months. Results: Of the 89 patients that started treatment (median Expanded Disability Status Scale (interquartile range), 3.0 (2.0-3.6); mean CIS20r fatigue subscale (standard deviation (SD)), 42.6 (8.0)), 43 received aerobic training and 46 received the control intervention. A significant post-intervention between-group mean difference (MD) on the CIS20r fatigue subscale of 4.708 (95% confidence interval (CI) = 1.003-8.412; p = 0.014) points was found in favour of aerobic training that, however, was not sustained during follow-up. No effect was found on societal participation. Conclusion: Aerobic training in MS patients with severe fatigue does not lead to a clinically meaningful reduction in fatigue or societal participation when compared to a low-intensity control intervention. [ABSTRACT FROM AUTHOR]

Background: Fatigue is a frequently reported and disabling symptom in multiple sclerosis (MS). Objective: To investigate the effectiveness of an individual energy conservation management (ECM) intervention on fatigue and participation in persons with primary MS-related fatigue. Methods: A total of 86 severely fatigued and ambulatory adults with a definite diagnosis of MS were randomized in a single-blind, two-parallel-arm randomized clinical trial to the ECM group or the information-only control group in outpatient rehabilitation departments. Blinded assessments were carried out at baseline and at 8, 16, 26 and 52 weeks after randomization. Primary outcomes were fatigue (fatigue subscale of Checklist Individual Strength - CIS20r) and participation (Impact on Participation and Autonomy scale - IPA). Results: Modified intention-to-treat analysis was based on 76 randomized patients (ECM, n = 36; MS nurse, n=40). No significant ECM effects were found for fatigue (overall difference CIS20r between the groups = -0.81; 95% confidence interval (CI), -3.71 to 2.11) or for four out of five IPA domains. An overall unfavourable effect was found in the ECM group for the IPA domain social relations (difference between the groups = 0.19; 95% CI, 0.03 to 0.35). Conclusion: The individual ECM format used in this study did not reduce MS-related fatigue and restrictions in participation more than an information-only control condition. [ABSTRACT FROM AUTHOR]

Background: Fatigue is a common symptom in multiple sclerosis (MS) and often restricts societal participation. Cognitive behavioral therapy (CBT) may alleviate MS-related fatigue, but evidence in literature is inconclusive. Objective: To evaluate the effectiveness of CBT to improve MS-related fatigue and participation. Methods: In a multi-center, assessor-masked, randomized controlled trial, participants with severe MSrelated fatigue were assigned to CBT or control treatment. CBT consisted of 12 individual sessions with a psychologist trained in CBT, the control treatment consisted of three consultations with a MS nurse, both delivered over 16 weeks. Assessments were at baseline, 8, 16 (i.e. post-intervention), 26, and 52 weeks post-baseline. Primary outcomes were the Checklist Individual Strength-fatigue subscale (CIS20r fatigue) and the Impact on Participation and Autonomy questionnaire (IPA). Data were analyzed according to the intention-to-treat principle, using mixed-model analysis. Results: Between 2011 and 2014, 91 patients were randomized (CBT: n = 44; control: n = 47). Betweengroup analysis showed a positive post-intervention effect for CBT on CIS20r fatigue (T16: -6.7 (95% confidence interval (CI) = -10.7; -2.7) points) that diminished during follow-up (T52: 0.5 (95% CI = -3.6; 4.4)). No clinically relevant effects were found on societal participation. Conclusion: Severe MS-related fatigue can be reduced effectively with CBT in the short term. More research is needed on how to maintain this effect over the long term. [ABSTRACT FROM AUTHOR]

The article discusses a study that determined the relationship between appraisal and societal participation in fatigued patients with Multiple Sclerosis (MS) and whether this relation is mediated by coping styles. Topics include the creation of General Self-Efficacy Scale, the Illiness Cognition Questionnaire and the Coping Inventory Stressful Situations (CISS21). Also mentioned are appraisal and societal participation in patients with severe MS-realted fatigue showing a positive relationship.

Abstract: Pro and anti-inflammatory cytokines are involved in disease onset and pathophysiology of multiple sclerosis, Alzheimer’s disease and Parkinson’s disease. It is likely that panels of multiple cytokines provide a good reflection of disease status and can be used as biological markers in body fluids. Different multi-plex platforms, Luminex-xMAP and Meso Scale Discovery, are able to detect multiple analytes in the same sample at the same time. In this literature based review, we offer an overview of the multi-plex platforms and compare them with the golden standard ELISA in their ability to accurately and sensitively detect cytokines in cerebrospinal fluid (CSF) and blood (serum/plasma). The detectability and levels of cytokines in multiple sclerosis, Alzheimer’s disease and Parkinson’s disease are promising but also show discrepancies between studies. The current immuno-assays lack sensitivity for detection of various cytokines that have low concentrations of cytokines in CSF and blood, and therefore technical improvements are needed. With such improvements the use of large panels of cytokines as inflammatory profiles may offer additional value in diagnosis, prognosis and therapeutic response in neurodegenerative diseases. [Copyright &y& Elsevier]

Around 60% of people with Multiple Sclerosis (PwMS) experience walking difficulties within 10 years of diagnosis1. Walking problems can be caused by diverse and interacting neurological impairments2. Spatiotemporal abnormalities in PwMS have been described clearly3, but the heterogeneity in etiology complicates describing typical gait patterns, including kinematic and kinetic deviations, in PwMS. A recent review showed that, amongst others, knee flexion in swing phase, ankle dorsiflexion at initial contact and ankle plantar flexion during pre-swing are decreased4. In the pediatric cerebral palsy population general gait subtypes have been shown to assist clinical decision making5. In the MS population practice variation in diagnosing and treating gait disorders may hamper (optimal) patient treatment. This practice variation between different physicians, centres and countries could be improved by clearly defined gait patterns in PwMS. To identify key gait patterns that are typical for PwMS, describe their characteristics and identify their underlying causes. A diverse international group of 20 physiotherapists, neurologists, rehabilitation physicians, biomechanical engineers and movement scientists with either clinical or scientifically relevant expertise within MS or gait analysis participated in an online Delphi study, including repeating questionnaires in a structured order6. The results of the current study are based on the first three rounds of our Delphi study, which focused on gathering information about gait patterns in PwMS, and the accompanying impairments and causes. The complete list of answers to the question: "which gait features and impairments contribute to gait disorders in MS patients" were grouped to create the final gait patterns based on common features and underlying impairments. To unify the given answers we used pre-existing kinematic and kinetic gait terminology. After 3 rounds consensus was reached. Six relevant and common gait patterns in MS were identified: 1) drop foot, 2) insufficient push-off, 3) stiff knee during swing, 4) knee hyperextension during stance, 5) flexion in midstance and 6) enhanced gait variability (Fig. 1). For each gait pattern the key characteristics and key potential could be defined. [Display omitted] The identification of gait patterns in MS may support clinical decision making and improves our understanding of disorders that underlie gait problems in PwMS. These gait patterns may help to improve diagnosing gait problems and improve treatment of these problems. Therefore, future Delphi rounds will focus on diagnostic and therapeutic measures for each of the gait patterns and their underlying causes. [ABSTRACT FROM AUTHOR]