The MoXFo initiative - study design: Considerations related to study design and methodology in exercise research for people with 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.

A Thematic Survey on the Reporting Quality of Randomized Controlled Trials in Rehabilitation: The Case of Multiple Sclerosis.

BACKGROUND AND PURPOSE: Optimal reporting is a critical element of scholarly communications. Several initiatives, such as the EQUATOR checklists, have raised authors' awareness about the importance of adequate research reports. On these premises, we aimed at appraising the reporting quality of published randomized controlled trials (RCTs) dealing with rehabilitation interventions. Given the breadth of such literature, we focused on rehabilitation for multiple sclerosis (MS), which was taken as a model of a challenging condition for all the rehabilitation professionals.A thematic methodological survey was performed to critically examine rehabilitative RCTs published in the last 2 decades in MS populations according to 3 main reporting themes: (1) basic methodological and statistical aspects; (2) reproducibility and responsiveness of measurements; and (3) clinical meaningfulness of the change. SUMMARY OF KEY POINTS: Of the initial 526 RCTs retrieved, 370 satisfied the inclusion criteria and were included in the analysis. The survey revealed several sources of weakness affecting all the predefined themes: among these, 25.7% of the studies complemented the P values with the confidence interval of the change; 46.8% reported the effect size of the observed differences; 40.0% conducted power analyses to establish the sample size; 4.3% performed retest procedures to determine the outcomes' reproducibility and responsiveness; and 5.9% appraised the observed differences against thresholds for clinically meaningful change, for example, the minimal important change. RECOMMENDATIONS FOR CLINICAL PRACTICE: The RCTs dealing with MS rehabilitation still suffer from incomplete reporting. Adherence to evidence-based checklists and attention to measurement issues and their impact on data interpretation can improve study design and reporting in order to truly advance the field of rehabilitation in people with MS.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1 available at: http://links.lww.com/JNPT/A424 ).

Physical Activity in Multiple Sclerosis: Meeting the Guidelines at the Time of the COVID-19 Pandemic.

BACKGROUND AND PURPOSE: Regular physical activity (PA) helps to reduce the severity of physical and mental symptoms and improves quality of life in people with multiple sclerosis (PwMS). Based on current evidence and expert opinion, the recent multiple sclerosis guidelines recommend at least 150 minutes/week of PA. This study presents the results of a survey analyzing whether and how PwMS met the guidelines before and during the pandemic. METHODS: We developed and disseminated an international online survey between December 2020 and July 2021, investigating changes in self-reported PA type, duration, frequency, and intensity due to the COVID-19 outbreak in PwMS with differing disability levels. RESULTS: Among respondents (n = 3810), 3725 were eligible. The proportion of those who conducted at least one activity decreased with increasing disability level at both time points (pre and during). Overall 60% of respondents met the guidelines before the pandemic (mild: 64.43%; moderate: 51.53%; severe: 39.34%; χ 2(2) = 109.13, P < 0.01); a reduction of approximately 10% occurred during the pandemic in all disability groups (mild: 54.76%; moderate: 42.47%; severe: 29.48%; χ 2(2) = 109.67, P < 0.01). Respondents with higher disability participated more in physical therapy and less in walking, cycling, and running at both time points. Most respondents reported practicing PA at a moderate intensity at both time points; frequency and duration of sessions decreased as disability level increased. DISCUSSION AND CONCLUSIONS: The percentage of those meeting the guidelines reduced with increasing disability level and during the pandemic. PA type and intensity varied widely across the disability categories. Interventions accounting for disability level are required to enable more PwMS to reap the benefits of PA.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A415 ).

Impact of the COVID-19 Pandemic on Physical Activity and Associated Technology Use in Persons With Multiple Sclerosis: An International RIMS-SIG Mobility Survey Study.

OBJECTIVE: To investigate the impact of the COVID-19 pandemic on physical activity in persons with multiple sclerosis (PwMS). DESIGN: Multicenter international online survey study. SETTING: The survey was conducted within 11 participating countries. Each country launched the survey using online platforms from May to July 2021. PARTICIPANTS: This was an electronic survey study targeting PwMS (N=3725). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: The survey ascertained physical activity performance and its intensity, the nature of the activities conducted, and the use of technology to support home-based physical activity before and during the pandemic. RESULTS: A total of 3725 respondents completed the survey. Prepandemic, the majority (83%) of respondents reported being physically active, and this decreased to 75% during the pandemic. This change was significant for moderate- and high-intensity activity (P<.0001). Activities carried out in physiotherapy centers, gyms, or pools decreased the most. Walking was the most frequently performed activity prepandemic (27%) and increased during the pandemic (33%). A total of 24% of those inactive during the pandemic had no intention of changing their physical activity behavior post pandemic. A total of 58% of the respondents did not use technology to support physical activity during the pandemic. Of those who did use technology, wearables were most used (24%). Of those currently nonactive (25%) expressed a preference for an in-person format to conduct physical activity post pandemic. CONCLUSIONS: Physical activity performance, especially activities at moderate and high intensities, decreased during the pandemic in PwMS compared with prepandemic. Walking and using wearables gained popularity as ways to stay active. As we move toward an endemic COVID-19, a call for action to develop interventions focused on walking programs with specific emphasis on increasing physical activity of PwMS is proposed.

Differential effects and discriminative validity of motor and cognitive tasks varying in difficulty on cognitive-motor interference in persons with multiple sclerosis.

BACKGROUND: Cognitive-motor interference (CMI) has been well recognized in persons with multiple sclerosis (pwMS); however, there are limited data on effects of task difficulty. OBJECTIVE: Examine (1) the effects of motor and cognitive tasks varying in difficulty on the magnitude of CMI and (2) the discriminative validity of CMI between pwMS and healthy controls (HC). METHODS: Nine cognitive-motor dual-task (DT) conditions (combinations of three cognitive and three walking tasks) were examined. Outcome measures were DT-performance and dual-task cost (DTC) of gait parameters and correct answers. Task differences and overall group-effects were analysed by mixed model analysis, plus the Wilcoxon signed-rank tests or multivariate analysis of variances (MANOVAs), respectively. RESULTS: Task effects were examined in 82 pwMS (Expanded Disability Status Scale (EDSS): 3.3 ± 1.0) and discriminative validity in a subsample (35 pwMS and 33 HC). Motor-DTC and DT-performance were affected by difficulty of both the cognitive task (p < 0.001) and the walking condition (p ⩽ 0.002), while cognitive-DTC only varied between cognitive tasks with a large difference in difficulty (p ⩽ 0.005) and not between walking conditions (p ⩾ 0.125). None of the DTCs differed between groups. CONCLUSION: CMI, and especially motor performance, is affected by difficulty of the DT. Although pwMS performed worse on the tasks than HC, none of the DT-conditions showed a discriminative DTC.

Reproducibility and Convergent Validity of the Sitting-Rising Test in People With Multiple Sclerosis.

OBJECTIVE: To evaluate the test-retest reproducibility and convergent validity of the sitting-rising test (SRT) in people with multiple sclerosis (PwMS). DESIGN: Observational study comprising a test-retest design. SETTING: Multiple Sclerosis Center, Rehabilitation Hospital at Sheba Medical Center, Tel-Hashomer, Israel. PARTICIPANTS: A total of 50 PwMS (32 women, 18 men, N=50), mean age 44.8±7.6 years and mean disease duration of 13.8±8.5 years since diagnosis, were enrolled in the study. The median Expanded Disability Status Scale score was 4.5, indicating a mild-moderate neurologic disability. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: SRT, posturography measures, 10-repetion sit-to-stand test (10STS), timed Up and Go (TUG) test, hand grip strength, strength of hip flexion/extension/abduction, knee flexion/extension, and Fall Status Questionnaire. RESULTS: The intraclass correlation coefficient value for the intrarater test-retest reproducibility (7- to 10-day interval between tests) of the SRT test, was 0.931 (95% confidence interval, 0.796-0.977). Strong correlations were found between the SRT, TUG test (ρ=-0.709), and 10STS (ρ=-0.719), and moderate correlations were found between the SRT and postural control measures (ρ∼0.4). Moderate correlations were found between the SRT and the hip and knee strength (combined) of the weaker limb (ρ=0.344). No differences were found in the SRT score between fallers and nonfallers. CONCLUSIONS: The current study supports the convergent validity and test-retest reproducibility of the SRT in PwMS.

Moving exercise research in multiple sclerosis forward (the MoXFo initiative): Developing consensus statements for research.

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.

The immediate effect of stroboscopic visual training on information-processing time in people with multiple sclerosis: an exploratory study.

Stroboscopic visual training (SVT) is a form of training aimed at improving visual and perceptual performance by having individuals perform activities under conditions of intermittent vision. The efficacy of SVT has never been examined in people with multiple sclerosis (PwMS), therefore, our aim was to examine the immediate effect of SVT on cognitive function, gait and static balance performance in PwMS. This assessor-blinded, randomized crossover study included 26 PwMS, 16 females, mean age 47.9 and median EDSS score 4.5. Participants attended two sessions: SVT and control training. Exercises for both the SVT and control sessions were based on ball-catching tasks. Training sessions were identical in length (40-50 min) and type of exercise drills. The difference between the two practice regimes was that the SVT session was performed wearing stroboscopic glasses and the control training was performed with similar glasses without lenses. Cognition was evaluated by a computerized software (Mindstreams®, NeuroTrax Corp., NY). Gait and balance were evaluated via wearable accelerometers (APDM, Oregon, USA). Outcome measures were collected twice during a single session, prior to training and immediately afterward. Information processing speed (p = 0.003) increased at the post-evaluation compared with baseline, solely in the SVT session. No differences between pre-post evaluations were observed for other cognitive scores following the SVT session. No differences between pre-post measurements were noted for gait and balance following the SVT session. The present study's results justify performing future RCT studies to examine the effects of a longer SVT program on cognition in PwMS.

Physical activity participation according to the pyramidal, sensory, and cerebellar functional systems in multiple sclerosis.

The objective of the study was to examine the differences in physical activity participation with the pyramidal, cerebellar, and sensory functional systems in people with multiple sclerosis (PwMS). This cross-sectional study included 289 PwMS with a median EDSS of 2.0 (range 0-6.5) and a mean disease duration of 6.8 (SD = 8.4) years. The Godin leisure-time exercise questionnaire (GLTEQ) assessed physical activity participation. The sample was divided into seven groups according to the pyramidal, cerebellar, and sensory functional system scores derived from the EDSS data. Additionally, PwMS were divided into three physical activity subgroups (active, moderately active, and insufficiently active). Furthermore, PwMS were categorized into four levels of disability based on their global Expanded Disability Status Scale (EDSS) score [very mild (0-1.5), mild (2.0-3.5), moderate (4.0-5.5), and severe (6.0-6.5)]. In the physical activity subgroups, 159 (55.0%) were classified as insufficiently active, 59 (20.4%) as moderately active, and 71 (24.6%) as active. Pyramidal, cerebellar, and sensory impairments were demonstrated in 134 (46.4%), 73 (25.3%), and 85 (29.4%) patients, respectively. No differences were found for the GLTEQ scores for all seven functional system groups (P value = 0.168). As for the EDSS disability subgroups, the percentage of active patients (moderately at least) were 60%, 45.8%, 36.5%, and 15.4%, for the very mild, mild, moderate, and severe subgroups, respectively. This study found that participation in leisure-time physical activity is independent from the pyramidal, cerebellar, and sensory functional systems in PwMS.

Is the dual-task cost of walking and texting unique in people with multiple sclerosis?

The objective of the study was to investigate cognitive-motor interference of walking while texting in people with multiple sclerosis (PwMS). The study included 30 PwMS, mean disease duration 11.8 (SD = 6.8) years, and 15 healthy controls. The investigation included a cognitive assessment; texting assessment based on 100 typed characters; and gait assessment under two different conditions: normal walking and walking while texting. Outcome measures included the Symbol Digit Modalities Test to assess cognition. Texting measures included accuracy (%) and duration(s). Gait was assessed with axial accelerometers to quantify temporal measures. The dual-task cost percentage for the walking tests and texting accuracy was determined by calculating the percentage change from a single task to a double task. The impact of texting while walking on gait measures was significantly higher in PwMS; furthermore, texting was less accurate compared to the healthy controls. The dual-task cost for texting accuracy in the PwMS group was 153.3 (SD = 105.7) compared to 8.9 (SD = 26.6) in the healthy group. A significant association was found solely in the PwMS group between cognition and texting accuracy while in a sitting position (R2 = 0.564) and while walking (R2 = 0.534). The dual-task cost of walking and texting appears to be unique in the MS population.

The relationship between gait variability and cognitive functions differs between fallers and non-fallers in MS.

The objective of the study was to determine if cognitive function is associated with step time variability in people with multiple sclerosis (PwMS). The study included 355 PwMS (218 women), average age 41.1 (SD = 13.5), disease duration 5.9 (SD = 7.3) years, and a median expanded disability status scale score of 2.5. We separately analyzed the sample group of fallers and non-fallers based on their fall history. Gait variability was measured by an electronic walkway and all participants completed a computerized cognitive test battery designed to evaluate multiple cognitive domains. Fallers (43.7%) demonstrated elevated step time variability (%CV), 5.0 (SD = 3.4) vs. 3.5 (SD = 1.6), P < 0.001 compared to the non-faller subjects. According to the regression analysis in the non-fallers' group, step time variability was found significantly associated with the global cognitive score (P = 0.001), executive function subcategory (P = 0.038), and motor skills subcategory (P < 0.001). No relationship between step time variability and any cognitive domain was demonstrated in the faller group. This study illustrated that the association between gait variability and cognition occurs only in PwMS without a fall history. From a clinical standpoint, these findings might help medical professionals to create improved assessment tests and rehabilitation strategies in the MS population.

Gait and cognitive impairments in multiple sclerosis: the specific contribution of falls and fear of falling.

Our goal was to identify the specific contribution of fear of falling (FoF) and falls with quantitative gait impairments and cognition capabilities in multiple sclerosis (MS) patients. Patients were separated into four individual subgroups as to the presence of FoF and falls (i.e., fearless/non-fallers, fearless/fallers, FoF/non-fallers and FoF/fallers). The Falls Efficacy Scale International questionnaire was used to assess the level of concern of falling. Participants were defined as "fallers" and "non-fallers" based on their fall history. Spatio-temporal parameters of gait were analyzed using an electronic mat. Cognitive performance was assessed by a computerized cognitive battery of tests. The study included 540 MS patients, 47% were defined as fallers and 61.9% reported a FoF. Non-significant differences were found between the fearless/non-fallers and fearless/fallers in all clinical, gait and cognitive scores. FoF/non-fallers walked significantly slower compared to fearless MS individuals who had previously fallen. Furthermore, the same patient group exhibited a poorer performance in the motor skills cognitive subdomain. A significant reverse relationship was found between FoF and cognitive motor skills in the fallers and non-fallers groups. FoF characterizes a more disabling symptom than falling in the MS population.

Pilates exercise training vs. physical therapy for improving walking and balance in people with multiple sclerosis: a randomized controlled trial.

OBJECTIVE: Evaluate the effects of a Pilates exercise programme on walking and balance in people with multiple sclerosis and compare this exercise approach to conventional physical therapy sessions. DESIGN: Randomized controlled trial. SETTING: Multiple Sclerosis Center, Sheba Medical Center, Tel-Hashomer, Israel. SUBJECTS: Forty-five people with multiple sclerosis, 29 females, mean age (SD) was 43.2 (11.6) years; mean Expanded Disability Status Scale (S.D) was 4.3 (1.3). INTERVENTIONS: Participants received 12 weekly training sessions of either Pilates ( n=22) or standardized physical therapy ( n=23) in an outpatient basis. MAIN MEASURES: Spatio-temporal parameters of walking and posturography parameters during static stance. Functional tests included the Time Up and Go Test, 2 and 6-minute walk test, Functional Reach Test, Berg Balance Scale and the Four Square Step Test. In addition, the following self-report forms included the Multiple Sclerosis Walking Scale and Modified Fatigue Impact Scale. RESULTS: At the termination, both groups had significantly increased their walking speed ( P=0.021) and mean step length ( P=0.023). According to the 2-minute and 6-minute walking tests, both groups at the end of the intervention program had increased their walking speed. Mean (SD) increase in the Pilates and physical therapy groups were 39.1 (78.3) and 25.3 (67.2) meters, respectively. There was no effect of group X time in all instrumented and clinical balance and gait measures. CONCLUSIONS: Pilates is a possible treatment option for people with multiple sclerosis in order to improve their walking and balance capabilities. However, this approach does not have any significant advantage over standardized physical therapy.

Static posturography across the EDSS scale in people with multiple sclerosis: a cross sectional study.

BACKGROUND: Posturography is considered the gold standard objective measure of standing postural control in people with multiple sclerosis (PwMS). This reliable tool provides quantitative data related to risk of falling and white and gray matter brain damage due to MS. Nevertheless, it remains unclear whether and to what extent, postural control declines throughout the disease process. We therefore examined the impact of disability on posturography measures in PwMS. METHODS: In this cross-sectional study, the data pool was divided into seven levels of disability based on the Expanded Disability Status Scale (EDSS) score. The study group comprised 464 PwMS, mean disease duration was 6.2 (SD = 7.5) years and mean age 42.6 (SD = 14.1). Static postural control parameters were obtained from the Zebris FDM-T instrumented Treadmill (Medical GmbH, Germany). RESULTS: A significant positive correlation between the EDSS and posturography parameters was found. Scores for the ellipse area, center of pressure (CoP) path length and sway rate with eyes open were Spearman's rho =0.512, 0.527, 0.528; (P-value < 0.001), respectively. Non-significant differences were observed between the EDSS subgroups at the lower end of the spectrum (EDSS 0-2.5) in all posturography parameters. In contrast, MS patients with an EDSS score of 3.0-3.5 demonstrated a significant increase in the ellipse area with eyes open (~108 %) and closed (~169 %), CoP path length with eyes open (~83 %) and closed (~88 %) and sway rate with eyes open (~39 %) and closed (~148 %), compared with those who scored within the range of 0-2.5 in the EDSS. Non-significant differences were observed between MS patients with an EDSS score of 3.0-5.5. MS patients with an EDSS score of 6.0-6.5 were significantly poorer in 4 (out of 6) balance measures compared to other disability subgroups. CONCLUSIONS: Posturography CoP trajectories are appropriate outcome measures indicating disability deterioration in PwMS.

Construct Validity of the Four Square Step Test in Multiple Sclerosis.

OBJECTIVE: To expand the construct validity of the Four Square Step Test (FSST) in people with multiple sclerosis (PWMS). DESIGN: Cross-sectional study. SETTING: Multiple sclerosis center. PARTICIPANTS: PWMS (N=218; 133 women, 85 men; mean age, 43.2±13.5y; mean disease duration, 7.5±7.7y since diagnosis) were enrolled in the study. The Expanded Disability Status Scale score was 3.1±1.3, indicating minimal to moderate neurologic disability. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The FSST, posturography measures, 2-minute walk test, timed Up & Go test, timed 25-foot walk, fall status, Falls Efficacy Scale International, Modified Fatigue Impact Scale, instrumented cognitive assessment, and 12-item Multiple Sclerosis Walking Scale. RESULTS: The FSST score of the total sample was 11.0±4.9. Significant differences were observed between the very mild, mild, and moderate disability groups: 8.8±3.4, 11.1±4.9, and 14.1±5.3, respectively. In terms of fall status, the fallers demonstrated a significant slower FSST score than the nonfallers (12.5±5.7 vs 9.0±2.6, respectively). Modest significant correlation scores were found between the FSST and the timed Up & Go test and 2-minute walk test (Pearson ρ=.652 and ρ=-.575, respectively). In terms of posturography, all measures were significantly associated with the FSST scores. A significant positive relation was observed with the visual spatial cognitive domain (Pearson ρ=-.207). CONCLUSIONS: The current study supports and broadens the construct validity of the FSST in PWMS.

The effect of balance training on postural control in people with multiple sclerosis using the CAREN virtual reality system: a pilot randomized controlled trial.

BACKGROUND: Multiple sclerosis (MS) is a multi-focal progressive disorder of the central nervous system often resulting in diverse clinical manifestations. Imbalance appears in most people with multiple sclerosis (PwMS). A popular balance training tool is virtual reality (VR) with several advantages including increased compliance and user satisfaction. Therefore, the aim of this pilot RCT (Trial registration number, date: ISRCTN14425615, 21/01/2016) was to examine the efficacy of a 6-week VR balance training program using the computer assisted rehabilitation environment (CAREN) system (Motek Medical BV, Amsterdam, Netherlands) on balance measures in PwMS. Results were compared with those of a conventional balance exercise group. Secondary aims included the impact of this program on the fear of falling. METHODS: Thirty-two PwMS were equally randomized into the VR intervention group or the control group. Each group received balance training sessions for 6 consecutive weeks, two sessions per week, 30 min sessions. Clinical balance tests and instrumented posturography outcome measures were collected upon initiation of the intervention programs and at termination. RESULTS: Final analysis included 30 patients (19 females, 11 males; mean age, (S.D.) = 45.2 (11.6) years; mean EDSS (S.D.) = 4.1 (1.3), mean disease duration (S.D.) = 11.0 (8.9) years). Both groups showed a main effect of time on the center of pressure (CoP) path length with eyes open (F = 5.278, P = .024), sway rate with eyes open (F = 5.852, P = .035), Functional Reach Test (F = 20.841, P = .001), Four Square Step Test (F = 9.011, P = .031) and the Fear of Falls self-reported questionnaire (F = 17.815, P = .023). In addition, significant differences in favor of the VR program were observed for the group x time interactions of the Functional Reach Test (F = 10.173, P = .009) and fear of falling (F = 6.710, P = .021). CONCLUSIONS: We demonstrated that balance training based on the CAREN device is an effective method of balance training for PwMS.

Effect of Alfacalcidol on multiple sclerosis-related fatigue: A randomized, double-blind placebo-controlled study.

CONTEXT: Fatigue is one of the most common and disabling symptoms of multiple sclerosis (MS); however, there is no medication that has been approved specifically to treat MS-related fatigue. OBJECTIVE: We aimed to evaluate the effect of vitamin D analogue, Alfacalcidol, on MS-related fatigue. DESIGN, SETTINGS, PARTICIPANTS: This was a randomized, double-blind, parallel group, placebo-controlled trial in patients with clinically definite MS by McDonald criteria conducted in a single university-affiliated medical center in Israel. Randomly selected patients from the Sheba MS Registry computerized database (N=600) were assessed using the self-report Fatigue Severity Scale (FSS). Patients with clinically meaningful fatigue (N=259) were further assessed for trial eligibility, and MS patients with significant fatigue (N=158; 61%, 118 females, mean age 41.1 ± 9.2 years and mean disease duration of 6.2 ± 5.5 years) were included in the study and randomized to receive treatment or placebo. INTERVENTION: Alfacalcidol (1 mcg/d, N=80) or placebo (N=78) was administered for six consecutive months. MAIN OUTCOME MEASURE: The primary endpoint of the study was the change between Alfacalcidol and placebo-treated patients in the Fatigue Impact Scale (FIS) score; the cut-off point for improvement was defined as 30% decrease. All analyses followed the intention-to-treat principle and were performed for all participants based on the group they were randomly allocated regardless of whether or not they dropped out. RESULTS: Alfacalcidol decreased the mean relative FIS score as compared with placebo (-41.6% vs. -27.4%, p=0.007, respectively). This advantage was further emphasized when the modified FIS (MFIS) relative change was calculated. Quality of Life (QoL) improved in Alfacalcidol-treated patients as compared with placebo in the RAYS psychological (p=0.033) and social (p=0.043) sub-scales. The Alfacalcidol-treated group had reduced number of relapses (p=0.006) and higher proportion of relapse-free patients (p=0.007). Reduction of relapses by Alfacalcidol became significant at 4 months of treatment, was sustained at 6 months and decayed 2 months after drug discontinuation. Alfacalcidol treatment was safe and no serious adverse events were recorded. CONCLUSION: Alfacalcidol is a safe and effective treatment strategy to decrease fatigue and improve QoL in patients with MS.

A personalized, intense physical rehabilitation program improves walking in people with multiple sclerosis presenting with different levels of disability: a retrospective cohort.

BACKGROUND: People with multiple sclerosis (PwMS) endure walking limitations. To address this restriction, various physical rehabilitation programs have been implemented with no consensus regarding their efficacy. Our objective was to report on the efficacy of an integrated tailored physical rehabilitation program on walking in people with multiple sclerosis categorized according to their level of neurological disability. METHODS: Retrospective data were examined and analyzed. Specifically, data obtained from all patients who participated in the Multiple Sclerosis Center's 3 week rehabilitation program were extracted for in depth exploration. The personalized rehabilitation program included three major components modified according to the patient's specific impairments and functional needs: (a) goal directed physical therapy (b) moderately intense aerobic exercise training on a bicycle ergometer and (c) aquatic therapy chiefly oriented to body structures appropriate to movement. Gait outcome measurements included the 10 meter, 20 meter, Timed up and go and 2 minute walking tests measured pre and post the rehabilitation program. Three hundred and twelve people with relapsing-remitting multiple sclerosis were included in the final analysis. Patients were categorized into mild (n = 87), moderate (n = 104) and severely (n = 121) disabled groups. RESULTS: All clinical walking outcome measurements demonstrated statistically significant improvements, however, only an increase in the 2 minute walking test was above the minimal clinical difference value. The moderate and severe groups considerably improved compared to the mild gait disability group. Mean change scores (%) of the pre-post intervention period of the 2 minute walking test were 19.0 (S.E. = 3.4) in the moderate group, 16.2 (S.E. = 5.4) in the severe group and 10.9 (S.E. = 2.3) in the mild gait disability group. CONCLUSIONS: We presented comprehensive evidence verifying the effects of an intense goal-directed physical rehabilitation program on ambulation in people with multiple sclerosis presenting with different neurological impairment levels.

Association between perceived fatigue and gait parameters measured by an instrumented treadmill in people with multiple sclerosis: a cross-sectional study.

BACKGROUND: Multiple sclerosis (MS) is a multi-focal progressive disorder of the central nervous system often resulting in diverse clinical manifestations. Symptomatic fatigue is quite common in people with MS (PwMS), with prevalence as high as 85%. Nevertheless, it remains poorly understood and its association with walking capabilities unclear. Therefore, the objective of this investigation was to examine the relationship between symptomatic fatigue and spatio-temporal parameters of gait in PwMS based on an instrumented treadmill. METHODS: One hundred and twenty-four relapsing-remitting patients diagnosed with MS, 84 women and 40 men aged 42.6 (S.D = 11.9), participated in this investigation. A convenience sample of 25 apparently healthy subjects, 15 women and 10 men aged 40.3 (S.D = 11.1), served as controls. Gait spatiotemporal parameters were obtained using the Zebris FDM-T Treadmill (Zebris1 Medical GmbH, Germany). The Modified Fatigue Impact Scale (MFIS), a self-reported questionnaire, was used to determine the level of symptomatic fatigue in the MS study group. PwMS were divided into two groups: fatigued and non-fatigued. RESULTS: Forty-four PwMS were classified as suffering from fatigue (mean MFIS = 52.0, S.D = 13.7); 80 were classified as non-fatigued (mean MFIS = 14.5, S.D = 14.5). Individuals in the fatigued group walked slower than those in the non-fatigued group; 1.7 (S.D = 2.4) vs. 2.4 (S.D = 1.0); P < 0.001, respectively. Moreover, fatigued patients took smaller steps, had a shorter stride length, prolonged stance, double support phase and a shorter single support phase compared to the non-fatigued group. In the total group, fatigue was significantly correlated with 10 (out of 14) spatiotemporal parameters of gait, however, correlation scores <0.40 were considered as weak correlations. According to step one of the linear logistic regression analysis, the temporal gait component was found to explain 5.1% of the variance related to symptomatic fatigue, R2 = 0.051, χ2 (1) = 6.511, P = 0.011. Step two of the model added the gait spatial component, thus increasing the explaining variance to 9.3%; R2 = 0.093, χ2 (2) = 12.12, P = 0.002. The asymmetry gait parameter did not contribute to the equation. CONCLUSIONS: Perceived fatigue is related to walking speed in PwMS, nevertheless its contribution to level of fatigue is limited.