Three weeks of rehabilitation improves walking capacity but not daily physical activity in patients with multiple sclerosis with moderate to severe walking disability.

BACKGROUND: Patients with multiple sclerosis have low levels of physical activity. This is of concern because low activity levels are related to cardiovascular disease, poor walking ability, and reduced quality of life. The aim of this study was to evaluate the impact of rehabilitation on daily physical activity and walking capacity in patients with multiple sclerosis who have moderate to severe walking disability.
METHODS: This exploratory, observational study of 24 patients with multiple sclerosis examined daily physical activity, walking capacity and fatigue before and after 3 weeks of inpatient rehabilitation. Inpatient rehabilitation included physiotherapy (30-60 min, 5 times/week), strength and endurance training (30-45 min, 3-5 times/week), occupational therapy (30 min, 2-3 times/week), and neuropsychological training (30 min, 2 times/week). There were no specific interventions to target daily levels of physical activity.
RESULTS: Daily physical activity did not change after rehabilitation (physical activity: effect size = -0.23, 95% confidence interval (95% CI) 0.02‒0.62). There were significant improvements in walking capacity (Two-Minute Walk Test: effect size = 0.74, 95% CI 0.31‒1.16, +17 m, 20.2%) and mobility (Timed Up and Go Test: effect size = 0.65, 95% CI 0.22‒1.07, ‒2.1 s, 14.9%). Motor and cognitive fatigue (Fatigue Scale for Motor: effect size = 0.56, 95% CI 0.14‒0.99 and Cognitive Functions: effect size = 0.44, 95% CI 0.01‒0.86) improved significantly after rehabilitation.
CONCLUSION: Three weeks of rehabilitation improved walking capacity, but not daily physical activity, in patients with multiple sclerosis with moderate to severe walking disability. To increase physical activity, it may be necessary to add specific behavioural interventions to the rehabilitation programme. The intervention plan should include strategies to overcome personal and environmental barriers.

Introduction

Multiple sclerosis (MS) is a disease of the central nervous system that results in heterogeneous symptoms and progressive functional deficits [1]. These symptoms and deficits lead to low levels of physical activity (PA) in most patients with MS (PwMS). A secondary analysis of pooled data from 13 studies indicated that PA, quantified using accelerometry, is lower in PwMS compared with healthy persons, and is below recommended levels [2]. A meta-analysis found a reduction in PA by almost one standard deviation (SD) compared with non-diseased populations [3]. As the disease progresses with worsening of symptoms and functional deficits, PA in daily life declines further [4, 5]. These low and declining levels of PA in PwMS are of concern, because they are associated with cardiovascular disease, poor walking ability, fatigue, depression and low quality of life [6].

PwMS are less physically active than the general population. Several barriers to PA have been identified in this population, which can be grouped into personal or environmental barriers [7]. Personal barriers comprise ambulatory disability, fatigue, and depression, which are frequent symptoms and comorbidities in MS. Environmental barriers comprise a lack of accessible facilities, insufficient advice on PA from healthcare professionals, or feelings of social exclusion [7]. There is good evidence that exercise therapy and rehabilitation have positive effects on MS-related symptoms and functional impairments. For example, several meta-analyses have shown that exercise therapy improves walking disability [8-10] and fatigue [11, 12]. It seems reasonable to assume that this would lead to an increase in PA, as personal barriers to PA are reduced. However, in our experience, some patients report being more physically active after rehabilitation, whereas others report that their daily PA remains unchanged, despite improvements in walking capacity and fatigue. We are unaware of any studies that have prospectively assessed the impact of exercise therapy or rehabilitation on PA in these patients. In a prospective observational study, Ehling et al. found that multidisciplinary inpatient rehabilitation in PwMS with moderate to severe walking impairment resulted in improved walking capacity, but not walking performance, measured in steps per day [13]. However, Ehling et al.’s study did not examine PA.

The World Health Organization (WHO) defines capacity as an individual’s ability to perform a given task or action in a controlled setting, and performance as the activities performed by an individual on a day to day basis in the context of their own life [14].

The objective of this longitudinal study of PwMS was to evaluate the impact of inpatient rehabilitation on PA. It was hypothesised that rehabilitation would increase PA by improving walking capacity and reducing fatigue. Walking capacity, fatigue and mood were secondary outcome parameters, because they have been implicated as barriers to PA in PwMS.

Methods

Design and blinding

An exploratory, observational study was conducted in PwMS referred to the Rehabilitation Centre Valens in Switzerland for inpatient rehabilitation. Sample size calculation found that 22 participants were needed to detect a within-group effect size of 0.6 with a power of 0.8, accepting a type I error probability of 0.05 [15]. Recruitment was between 1 August 2017 and 31 March 2018. Participants were consecutively recruited by telephone 2–4 weeks before rehabilitation. Outcomes were evaluated at five time-points: before rehabilitation (T0), at the beginning (T1) and end (T2) of rehabilitation, one week after rehabilitation (T3), and at follow-up 3 months after inclusion (T4). Participants and clinicians were blinded to the results of accelerometer and clinical measurements throughout the study. The study was approved by the ethics committee (BASEC number 2017–00728), registered at ClinicalTrials.gov (NCT03187847) and conducted in accordance with the principles of the Declaration of Helsinki. All participants were informed about the study procedures and provided informed consent.

Eligibility and recruitment

Eligible subjects were German-speaking PwMS, aged 18 years or older, with moderate to severe disease severity (Expanded Disability Status Scale (EDSS) 3.0–6.5) [16] and a primary rehabilitation goal of improving mobility, as defined by the International Classification of Functioning, Disability and Health (ICF) [14]. Participants were excluded if they were unable to use the accelerometer, had cognitive deficits interfering with study participation, or had comorbidities, such as musculoskeletal or cardiovascular diseases, that reduced walking ability.

The inclusion procedure consisted of two phases. For provisional inclusion, PwMS who were registered for planned rehabilitation were contacted by telephone by a researcher who checked the inclusion criteria and provided verbal information about the study. After provisional inclusion, a letter was sent to patients with written information about the study, an informed consent form, an accelerometer with instructions, and questionnaires regarding fatigue and mood. Definite inclusion was at the start of rehabilitation, when inclusion criteria and patients’ ability to use the sensors were checked.

Rehabilitation

Inpatient rehabilitation was not affected by participation in the study. Therapy generally included physiotherapy to improve balance and walking ability (30–60 min, 5 times/week), strength training (30–45 min, 3 times/week) and endurance training (30–45 min, 2 times/week). Occupational therapy (30 min, 2–3 times/week) focused on energy management and activities of daily living (ADL). Energy management is a form of cognitive behavioural therapy [17] providing information and focusing on coping strategies to tackle fatigue [18, 19]. Neuropsychological training addressed cognitive deficits (30 min, 2 times/week, including training of impaired functions and learning strategies to compensate for deficits). Therapies were individualised according to rehabilitation goals and available therapy resources. There were no specific interventions to target daily levels of PA.

Outcomes

Primary outcome: Physical activity

PA was evaluated with an accelerometer, the Actigraph GT3X (Actigraph, Pensacola, FL, USA), a lightweight device (27 g, 3.8 × 3.7 × 1.8 cm) reported to have good accuracy compared with other devices [20-22]. Participants wore the accelerometer on an elastic belt around their waist above the hip. Patients were asked to wear the accelerometer after getting dressed in the morning and to take it off before going to bed. Because of considerable between-day variation and differences between weekdays and weekend days, participants were instructed to wear the accelerometer for 7 days during waking hours [23]. Datasets with a minimum wear time of 10 h per day for at least 4 days were considered valid, consistent with previous studies [24-26]. Step count and time spent in PA [27] were calculated in Actilife (Actigraph, Pensacola, FL, USA).

Walking capacity and mobility

Waking capacity and mobility were evaluated at the beginning (T1) and end (T2) of inpatient rehabilitation. Walking capacity was evaluated with the Two-Minute Walk Test (2MWT). Participants were asked to walk as fast and as far as possible back and forth along a 30-m hallway, turning around cones at each end, while using their usual walking aids. Mobility was evaluated with the Timed Up and Go Test (TUG) [28]. Patients were seated in a non-armed chair and were asked to sit-up, walk 3 m, turn around a cone at 3-m distance, walk back and sit back down on the chair. The time needed was recorded.

Fatigue and mood

Fatigue and mood were assessed when participants were at home, at the following time-points: T0 (before rehabilitation), T3 (1 week after rehabilitation) and T4 (12 weeks after study inclusion). Fatigue was evaluated with the Fatigue Scale for Motor and Cognitive Functions (FSMC) [29], which comprises 20 items, 10 each for the cognitive and motor subscales. Items are rated on a 5-point Likert scale, ranging from 1 (absolutely disagree) to 5 (absolutely agree). FSMC sub-scores for motor and cognitive fatigue range from 10 to 50, interpreted as “mildly fatigued” if 10‒26, “moderately fatigued” if 27‒31, and “severely fatigued” if >31. Mood was assessed with the depression scale of the Hospital Anxiety and Depression Scale (HADS). Scores between 0 and 7 on HADS are interpreted as “normal”, while scores ≥8 points indicate depression in PwMS [30, 31].

Data analysis

Clinical outcome assessment

SPSS Statistics version 24.0 (SPSS Inc., Chicago, IL, USA) was used for the analyses of patient-reported outcomes of fatigue and mood and measurements of mobility and walking capacity during rehabilitation. Because outcomes did not have a normal distribution, as shown by the Shapiro–Wilk test, Wilcoxon signed-rank tests were used to analyse changes. Effect sizes (ES) r = Z / sqrtN with 95% confidence intervals (95% CIs) = r ± 1.96/sqrt (N–3) were calculated, where Z is the Z-value from the Wilcoxon signed-rank test. ES were considered small if 0.1‒0.3, moderate if 0.3‒0.5, and large if >0.5.

Accelerometer-based measurements

Accelerometer data were analysed using R (v3.6.1) [32]. Due to technical issues, wear-time validation was not available for most recordings in the current study. During recording, all data were previously aggregated at the hourly level. Thus, a custom cut-point-based wear-time validation method was developed. Receiver operating curve (ROC) analysis, theoretical knowledge, visual inspection, and triangulation were used to propose a suitable cut-point. If less than 5 min of wear-time was recorded in a 60 min period, 1 h of the day was considered as non-wear-time. This is consistent with a common non-wear-time definition of 60 min of continuous zeros [33, 34]. Four wear-time validated datasets were available to determine a suitable cut-point, comprising 28 days (648 h) of data (not all days were full days). These data were randomly divided into testing (20%) and training (80%) sets. Ultimately a cut-point of 200 vector magnitude (VM) counts per h was chosen as a theoretically sound option with high specificity (0.99) and sensitivity (0.92). Non-wear-time was filtered from the dataset. Step count and time spent in PA during waking hours (06.00 h to 24.00 h) was aggregated into daily totals. A cut-point of 100 counts per min was used to delineate sedentary behaviour from PA [35]. Distributions and ranges of PA metrics were inspected visually.

Wilcoxon signed-rank test and ES were used to assess the effects of rehabilitation on daily PA, as described for the clinical outcome measures. Mean daily PA was calculated by dividing total time spent in PA by the number of valid days in the measurement period. In a previous study, PA in healthy persons was significantly different on weekdays compared with weekend days [36], but not in PwMS. Differences in PA between weekdays and weekend days were assessed through univariate and adjusted linear regression. Linear regression models were used to adjust for the confounding effects of walking disability severity, weekends, baseline PA, age, and sex. Walking disability severity was defined as a categorial variable describing either mild/moderate disability (EDSS < = 5) or severe disability (EDSS >5). In a sensitivity analysis, multi-level models were used to account for patient-level random effects.

Results

Participants

Participants were recruited between 1 September and 31 October 2017. After the initial telephone contact, 28 PwMS were preliminarily included, of whom 24 were definitely included at the start of rehabilitation. Fig 1 gives an overview of the patient flow in the study and reasons for exclusion.

Fig 1

Study flow chart.

1EDSS: Expanded Disability Status Scale.

Baseline characteristics of the 24 participants are reported in Table 1. Data were complete for baseline and outcome measurements. All participants wore the accelerometer at each of the three time-points. Participants had a broad variety of disease duration and severity, mobility, fatigue and depressive mood. Median cognitive fatigue was moderate, while median motor fatigue was severe. Baseline visits took place in September and October 2017, post-rehabilitation assessments were performed in October and November 2017, and the 3-month follow-up occurred between December 2017 and early February 2018.

Table 1

Baseline characteristics of the 24 participants.

Variables
Age, years, mean (SD)	50.8 (11.1)
Sex (female, %)	12 (50)
MS duration, years, median [IQR]	13.0 [4.8; 17.0]
Disease severity, EDSS, median [ÏQR]	6.0 [4.5; 6.5]
Type of MS (n)
• primary progressive	6
• secondary progressive	8
• relapsing remitting	10
Mobility TUG, s, median [IQR]	14.2 [8.9; 20.0]
Walking capacity 2MWT, m, median [IQR]	84.5 [51.5; 125.0]
Fatigue FSMC, median [IQR]
• total	67 [54; 82]
• motor	38 [33; 43]
• cognitive	26.5 [19; 41]
Depressive mood, HADS subscale, median [IQR]	4.0 [3.0; 11]

MS, multiple sclerosis; EDSS, Expanded Disability Status Scale; TUG, Timed Up and Go test; 2MWT, Two-Minute Walk Test; FSMC, Fatigue Scale for Motor and Cognitive functions; HADS, Hospital Anxiety and Depression Scale.

Outcomes are reported in Table 2. There was no difference in daily PA at home after, compared with before, rehabilitation. Three months after rehabilitation, the PA was reduced, compared with before rehabilitation. In contrast, walking capacity and mobility evaluated at the beginning and end of 3-weeks’ rehabilitation were significantly improved. Self-reported motor and cognitive fatigue and mood were significantly improved at 1 week and at 3 months follow-up after rehabilitation. Fig 2 gives information about interventions and outcome measurements.

Table 2

Physical activity, walking capacity, mobility, and mood before and after rehabilitation and at 3 months’ follow-up.

Outcome measure	T0: before rehabilitation	T1: start of rehabilitation	T2: end of rehabilitation	T3: 1 week after rehabilitation	ES vs first measurement [95% CI], p-valuea	T4: at home at 3 months’ follow-up	ES vs first measurement [95% CI], p-value
Physical Activity	291			267	-0.23	262	-0.44
Min per day, median [IQR]	[183–327]			[202–328]	[0.02; 0.62]	[169–325]	[0.10; 0.81]
					p = 0.23		p = 0.029
Walking capacity		84	101		0.74
2MWT, m, median [IQR]		[51; 125]	[66; 170]		[0.31; 1.16]
					p = 0.002
Mobility		14.1	12.0		0.65
TUG, s, median [IQR]		[8.9; 20.0]	[5.8; 15.3]		[0.22; 1.07]
					p = 0.002
Motor fatigue	38			36	0.56	34	0.49
FSMC (10–50 max.), median [IQR]	[33; 43]			[30; 38]	[0.14; 0.99]	[27; 40]	[0.07; 0.92]
					p = 0.004		p = 0.012
Cognitive fatigue	26			24	0.44	24	0.38
FSMC, (10–50 max.), median [IQR]	[19; 41]			[17; 36]	[0.01; 0.86]	[18; 35]	[–0.05; 0.80]
					p = 0.033		p = 0.065
Depressive mood	4.0			3.5	0.61	3.5	0.50
HADSb, median [IQR4]	[3; 11]			[1; 9]	[0.18; 1.03]	[2; 7]	[0.07–0.93]
					p = 0.003		p = 0.014

ES: effect size; r, Wilcoxon test statistic Z/sqrt(n), positive values indicate improvement; 95% CI, 95% confidence interval; IQR, interquartile range; 2MWT, Two-Minute Walk Test; TUG, Timed Up and Go test; FSMC, Fatigue Scale for Motor and Cognitive functions; HADS, Hospital Anxiety and Depression Scale.

ap-value of the non-parametric Wilcoxon signed-rank test.

bChi-square test.

Fig 2

Time schedule of interventions and outcome measurements.

Abbreviations: PA, physical activity; FSMC, Fatigue Scale for Motor and Cognitive functions; HADS, Hospital Anxiety and Depression; 2MWT, Two-Minute Walk Test; TUG, Timed Up and Go test; T0–4, time point for outcome measurements.

Physical activity

All participants met minimum wear-time requirements at all time-points. Participants wore the devices for a mean of 14.9 h (SD 1.5) on 6.5 days (SD 8.2) during recording periods. At baseline, participants spent a median of 291 min (interquartile range (IQR) 183–327 min) in PA daily (Fig 3). Time spent in PA was 30 min less (95% CI 6–53, p = 0.016) during weekend days compared with weekdays. All except two recordings captured at least one weekend day. Weekends, walking disability severity, age, sex, and baseline PA were treated as potential confounders and adjusted for in subsequent models.

Fig 3

Median daily physical activity before and after rehabilitation.

(A) Participants with mild to moderate walking disability, defined as Expanded Disability Status Scale (EDSS) less than or equal to 5. (B) Participants with severe walking disability, defined as EDSS greater than 5. T0: the week prior to rehabilitation; T3: the week following rehabilitation, T4: 3-month follow-up.

No changes in PA were observed immediately following rehabilitation. However, adjusted linear regression models revealed that participants spent less time in PA at the 3-month follow-up compared with baseline (p = 0.0055), representing a median reduction of 30 min (IQR –41 to +3.8) or 9.2% (IQR –21.1% to +1.1%). In all cases, sensitivity analyses accounting for participant-level random effects yielded similar results. At the individual level, most participants (18 of 24) decreased their PA between baseline and the 3-month follow-up, with 11 exhibiting decreases of 20% or more. These 11 participants had significantly higher EDSS than the rest of the study population (median [Q2‒Q3]: 6 [6‒6.5] vs 4.75 [4‒6], p = 0.011).

Walking capacity, evaluated with the 2MWT, and mobility, evaluated with the TUG, improved significantly from start to end of rehabilitation (Table 2).

Compared with baseline before rehabilitation (T0), participants reported significantly less fatigue and depressive mood 1 week after rehabilitation (T3) and at 3 months’ follow-up (T4), with the exception of cognitive fatigue at T4 (Table 2).

Discussion

Three weeks of multidisciplinary inpatient rehabilitation in PwMS with moderate to severe walking impairment (EDSS median: 6.0, range: 3‒6.5) improved mobility (TUG ‒2.1 s, ‒14.9%, p = 0.002), walking capacity (2MWT +17 m, +20.2%, p = 0.002), fatigue (FSMC ‒4, ‒6.3%) and mood (HADS ‒0.5, ‒12.5%), but not daily PA, immediately after rehabilitation. At 3 months’ follow up, motor fatigue and mood were still improved, but PA had declined, compared with before rehabilitation. The improvements seen in the 2MWT (+17m) and TUG (‒2.1 s) exceed the reported minimum for clinically meaningful changes for the 2MWT (+9.1 m) [37] and the TUG (‒0.75 s) [38] and are in the range of other rehabilitation studies in MS reporting improvements of 14.8 m (35.1%) [13] for the 2MWT and ‒1.2 s (‒7.9%) for the TUG [39]. The improvement in fatigue (FSMC) by ‒6 points (‒9.4%) at the 3-month follow-up is in line with other studies, which showed a decrease in fatigue levels after rehabilitation [40] of ‒6.1 points (‒12.4%) evaluated with the Modified Fatigue Impact Scale. However, the 6 points (95% CI 2‒11) improvement in fatigue on the FSMC 3 months after rehabilitation compared with 1 week before rehabilitation in the current study is below the reported minimum for a clinical meaningful change of 9 points (95% CI ‒6.8‒11.2) reported by Svenningsson et al. [41].

The results of the current study are in line with those of a similar study by Ehling et al. [13], who examined the impact of 28 days of rehabilitation on walking performance, measured in steps per day. The authors reported similar improvements in walking capacity (2MWT +14.8 m) as in the current study, but unchanged steps per day in the subgroup of PwMS with moderate to severe walking impairment, corresponding to an EDSS between 4.0 and 6.5. Although steps per day and PA are different measures of daily life behaviour, the results point in the same direction: rehabilitation resulted in improved walking capacity without altered daily life behaviours, such as steps per day or PA.

This study demonstrates that improvements in mobility and walking capacity do not necessarily translate into increased physical activity behaviour after rehabilitation. One possible explanation is that walking impairment is not the only factor that affects PA in PwMS. Fatigue and depression, which are both common in MS, are further personal barriers to PA [7]. In the current study, the patients reported relatively high levels of fatigue (FSMC 64) and reduced mood (HADS 4.0), and both factors may have prevented higher levels of PA. Both fatigue and mood improved after rehabilitation, but only to a small to moderate degree, which was below clinical relevance [41]. Another explanation might be that environmental factors, such as stairs, uneven surfaces, or ascents/descents, etc., remained unsurmountable barriers for patients with moderate to severe walking deficits, even after improving walking capacity. Such environmental barriers are likely to be more relevant in moderate and severe walking deficits, as in the current study, and less relevant for those with only minor walking deficits. Other environmental barriers, such as inappropriate access for disabled persons, or lack of disabled facilities, cannot be removed by rehabilitation and may have resulted in limitations in PA [7]. Furthermore, the lack of strategies to change behaviour is a barrier to changing PA in PwMS [7].

Further research is warranted to identify strategies and novel components of rehabilitation programmes that will enable the translation of gains in walking capacity into changes in real-world walking behaviours. Although all patients received instructions for an individual home training programme before discharge, the rehabilitation programme in this study did not include a dedicated intervention aimed at increasing PA. Including a dedicated behavioural treatment with the goal of increasing PA as part of the rehabilitation programme might have an effect on PA levels. Behavioural treatment should include goal-setting, patient education, tailored activity planning, addressing self-efficacy, and problem solving [6, 42–44]. Treatment should also identify and address barriers to PA in individual patients, such as fixed personal routines, fatigue, mood, or lack of motivation [45, 46]. Furthermore, internet-based interventions supplemented by video coaching have been proposed for behavioural treatment [46]. The reason why PA decreased slightly, by 10% at 3 months’ follow-up (T4) compared with baseline, is not clear. Seasonal effects may have contributed to this result, as participants were recruited in summer and autumn, and the 3 months’ follow-up occurred during winter [47, 48]. Furthermore, it cannot be excluded that disease progression also played a role, even though the follow-up duration was only 3 months [49].

Study limitations

Since this is an exploratory single-group non-randomised observational study, effect sizes presented in the manuscript do not ascribe causality. Female PwMS were under-represented in the present study (50%) compared with the Swiss population of PwMS (74%) [50]. The patient population was recruited at a single centre, and is of a relatively small sample size, which limits the generalisability of the results. As most patients had moderate to severe disability, the results cannot be generalised to PwMS with mild disability. For technical reasons a non-standard approach to wear time validation was followed, and this may have affected point estimates of time spent in PA. However, we were able to validate our method in a subset of data against traditional wear time validation methods.

Conclusion

Multidisciplinary inpatient rehabilitation that includes physical therapy, fitness and education in energy management significantly improved walking capacity, mobility, fatigue and mood, but not PA. Further research should examine whether adding goal-directed behavioural interventions to inpatient rehabilitation increases PA in PwMS.

Physical activity.

Data is presented as median (min per day). Abbreviations: T0, one week before rehabilitation; T3, one week after rehabilitation; T4, 3-month follow up.

(XLSX)

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SPSS dataset of baseline characteristics and clinical outcomes.

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11 Jul 2022

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The authors have conducted an exploratory, observational study that measured the impact of a 3-week inpatient rehabilitation that included physiotherapy, strength and endurance training, occupational therapy, and neuropsychological training, on daily physical activity levels, walking capacity, and fatigue on 24 patients with moderate to severe Multiple Sclerosis (MS).

It is interesting to note that the standard components of MS rehabilitation when conducted inpatient for 3 weeks improved walking capacity, mobility, and motor and cognitive fatigue. As expected, the inpatient rehabilitation for 3 weeks did not have an effect on the physical activity levels after discharge, as there were no specific interventions to improve daily physical activity levels post-discharge.

I notice that you have adjusted your regression models for disease severity (line 190) (or walking disability severity – line 232), and other potential confounders. Can you pls clarify whether you have used total EDSS scores or any other specific walking disability measure for these analyses?

Some researchers debate that the difference in disability status between EDSS scores are not equal (for e.g., EDSS 3.0 to 3.5 vs 6.0 to 6.5 represent no vs large change in walking disability). I see that the inter-quartile range for EDSS scores at baseline were 4.5 to 6.5. Does this mean that there were participants with no walking impairment (EDSS 3.0 to 3.5) in your study? If so, I am thinking whether such a limitation of EDSS scale could have had a confounding effect on your analyses. Pls acknowledge this as a limitation, and/or if necessary, pls revise your analyses.

It is nice to read that some of your results are in line with the literature, as per your citations in the discussion. Are you able to report a comparison with adequate data/explanation, instead of textual statements (as in lines 256-7)?

Since this is an exploratory single group non-randomized observational study, pls acknowledge that the effect sizes presented in the manuscript do not ascribe causality, in your limitation section.

I see that there were 50% females in your sample (table 1). Pls acknowledge this as a limitation as it does not represent male to female ratio of MS prevalence.

In the introduction, you have mentioned that, in your experience, patients with MS report having either more or no change in physical activity levels after rehabilitation. I notice that the lower end of inter-quartile range for physical activity level has decreased from 202 to 169 min/day between T3 and T4 time points (table 2). Have you considered describing the characteristics of those who had a decrease in their physical activity levels after rehabilitation through a sub-group analysis? Or, you may consider presenting the spread of your individual data points (connected/paired pre-post) using figures with/without error bars.

I acknowledge that relevant statistical analyses were completed to support the conclusions. However, there is no mention of how missing data were handled (other than accelerometer data), if any.

Reviewer #2: Thank you for the opportunity to review this manuscript. I have read it with great interest.

The authors performed a study on the effects of inpatient rehabilitation on physical activity, walking capacity and fatigue in patients with MS.

I have reviewed the well-conducted and well-reported manuscript and would like to make some minor suggestions on how to improve the quality of reporting.

Title & Abstract:

1. Please avoid abbreviations. Especially FSMCc and FSMCm are not explained.

2. Please avoid p values according to recent recommendations. Rather report 95% CIs. Please refer to doi: 10.1016/j.physio.2021.12.003

Introduction/Background:

3. A “question” such as “Why are PwMS less physically active than the general population?” seems uncommon for a scientific report and may be revised. Eg, “PwMS are less physically active than the general population because of xyz”.

Methods:

4. Please give examples for the “comorbidities that reduced walking ability” (exclusion criterium).

5. I suggest to reporting the recruitment and data collection periods in the methods section (if defined a priori before the data collection).

6. Please provide a sample size calculation or justification/rationale.

Results:

7. Well reported.

Discussion:

8. Please state the exact values of the “reported minimum for clinically meaningful changes” used in this study ands exceeded by the participants.

9. Line 264: What is the meaning of the EDSS values (EDSS 4.0–6.5)? Range, IQR?

10. Please avoid questions such as in line 268 and 289.

11. Please explain why the heterogeneous population of PwMS is a limitation.

12. I suggest to discuss the issues with data collection (“Due to technical issues, wear time validation was not available for most recordings in the current study.”) in the limitations section.

13. Since this is an explorative study, generalisability is not the focus and thus, this is not a weakness of the study. The authors may clearly state this and rather discuss future directions for further research and how this study might inform further studies with a bit more passion.

I hope that these comments will help the authors to further improve the manuscript. I would be happy to read a revision of the manuscript.

Sincerely, Tobias Braun

Reviewer #3: The purpose of this study is to assess the effect of rehabilitation on daily physical activity and walking ability in multiple sclerosis patients with moderate to severe walking disability. This study, I believe, is an insightful examination that offers light on an essential problem. However, the author must address a number of critical issues before publication.

I have compiled the following list of criticisms that the authors need to address:

1. Why some exercises were given 5 times per week while others 3-5 or 2-3 times/week?

2. How physiotherapy and strength/endurance training are different? What type of interventions were given in physiotherapy? please clarify

3. What are the activities included under Neuropsychological training?

4. Did you assess the reliability of each outcome measure used in the current study?

5. did you find any variations in test-retest reliability of any outcome measure?

6. Please provide details of sample size estimation.

7. Follow-up periods were inconsistent. For example, in the beginning it was mentioned 3 months, however, in page 11 it was 2 months? please clarify

8. Please include some figures showing interventions and findings for better understanding and interpretation.

Thank You

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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2 Aug 2022

Thank you for your positive feedback on our manuscript, and for the extensive suggestions for improvements, which we have copied in this letter. We have noted our changes and comments in italics below, based on your suggestions. We hope that we have addressed all of the comments to your satisfaction.

The authors.

Submitted filename: response to reviewers.docx

Click here for additional data file.

26 Aug 2022

Three weeks of rehabilitation improves walking capacity but not daily physical activity in patients with multiple sclerosis with moderate to severe walking disability

PONE-D-22-10453R1

Dear Dr. Schallert,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Fatih Özden, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for addressing all of my concerns and suggestions.

The PA_Data.xlsx file is password protected and the supporting information renamed_f3a4d.sav file is not readable.

Reviewer #2: Thanks for the invitation to review this revises manuscript. All my comments have been satisfactorily addressed by the authors and I have no further comments.

Reviewer #3: Authors have revised the manuscript based on the reviewer comments. Manuscript is much improved now. No further comments.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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9 Sep 2022

PONE-D-22-10453R1

Three weeks of rehabilitation improves walking capacity but not daily physical activity in patients with multiple sclerosis with moderate to severe walking disability

Dear Dr. Schallert:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

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on behalf of

Dr. Fatih Özden

Academic Editor

PLOS ONE