Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2014.921147
Vol. 30, No. 9, 2014, 1857–1862
Article ST-0072.R1/921147 All rights reserved: reproduction in whole or part not permitted
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Original article Mobility, walking and physical activity in persons with multiple sclerosis
Christine G. Kohn Craig I. Coleman C. Michael White Department of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, CT, USA
Abstract Objective: The effect of differing levels of mobility and walking disability on level of physical activity (PA) performed in persons with multiple sclerosis (PwMS) is unknown. We aimed to quantify the association between mobility and walking impairment and PA levels in PwMS.
Matthew F. Sidovar Clinical Development and Medical Affairs, Acorda Therapeutics, Ardsley, NY, USA
Diana M. Sobieraj Department of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, CT, USA Address for correspondence: Diana M. Sobieraj PharmD, Assistant Professor, University of Connecticut School of Pharmacy, 69 N Eagleville Road, Unit 3092, Storrs, CT 06269, USA. Tel.: +1 860 545 22429: Fax: +1 860 545 2277; [email protected] Keywords: Exercise – Mobility – Motor activity – Multiple sclerosis – Physical activity – Walking Accepted: 25 April 2014; published online: 29 May 2014 Citation: Curr Med Res Opin 2014; 30:1857–62
Methods: We assessed mobility and walking impairment in43000 North American Research Committee on Multiple Sclerosis registrants using the Patient Determined Disease Steps scale (score of 0–2 ¼ no, 3–6 ¼ moderate, 7 ¼ severe impairment) and 12-Item Multiple Sclerosis Walking Scale (MSWS-12) score (divided into quartiles, score of 0–25 ¼ least walking impairment, 76–100 ¼ most). Level of PA performance (metabolic equivalent [MET] minutes/week) was estimated using the Godin Leisure-Time Exercise Questionnaire. Multivariable regression and general linear models were used to assess the impact of walking and mobility impairment on PA levels. Results: Moderate and severe mobility impairment was associated with performance of 183 and 319 fewer MET minutes/week and a 65% and 90% reduced odds of performing 500 MET minutes/week of PA compared to no impairment (mean SD: 447 413 MET minutes/week) (p50.05 for all). Compared to the first quartile of MSWS-12 score (mean SD: 475 401), the second, third and fourth quartiles were associated with performance of 127, 216 and 268 fewer MET minutes/week and 51%, 71% and 77% reduced odds of achieving 500 MET minutes/week of PA (p50.05 for each). Limitations of our study include possible recall bias, use of a patient-reported rather than objective outcome and assumptions made when calculating MET minutes. Conclusion: Mobility and walking impairment are associated with less physical activity in PwMS.
Introduction The health benefits associated with the general population’s performance of physical activity (PA) have been well elucidated. In 2008, the US Department of Health and Human Services (DHHS) published the guidance document entitled, ‘Physical Activity Guidelines for Americans’ which describes the evidence supporting health benefits from performing PA, and provides recommendations for optimal levels of PA to achieve health benefits including decreased risks of cardio- and cerebro-vascular disease, diabetes, cancer, obesity and depression1. Specifically, these guidelines recommend Americans perform between 500 and 1000 metabolic minutes (MET minutes) of PA per week. ! 2014 Informa UK Ltd www.cmrojournal.com
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Persons with multiple sclerosis (PwMS) often suffer from mobility and walking impairment due to the neurodegenerative nature of their disease2. In fact, prior studies have shown that 40% to 50% of PwMS need assistance walking within 15 years of disease onset3,4, and that patients with MS engage in less PA than matched non-MS controls5. However, the effect of differing levels of mobility and walking disability in PwMS on quantity of PA performed and the achievement of guideline recommended levels of PA are unknown. In addition, it is unknown what other patient-related factors are associated with performance of PA in PwMS. Therefore, we sought to evaluate the association of mobility and walking impairment on achievement of guideline recommended levels of PA in PwMS and to ascertain which patient-related factors modify the likelihood of performing PA.
Methods Study type and inclusion criteria This was a cross-sectional study using all participants who completed the 2010 spring survey and the supplemental semi-annual survey for the North American Research Committee on Multiple Sclerosis (NARCOMS) registry. The NARCOMS registry contains self-reported data on PwMS obtained through a biannual health survey, including demographic factors, disease history, employment, symptoms, functional outcome measures, mobility impairment and quality of life. The supplemental semi-annual questionnaire gathers more specific data on work productivity, mobility and walking impairment and physical activity performance.
Mobility and walking measures In this study we determined a patient’s level of mobility and walking impairment using two validated patientreported outcome scales, the Patient Determined Disease Steps (PDDS) and the 12-item Multiple Sclerosis Walking Scale (MSWS-12), respectively. The PDDS is scored ordinally from 0 (no disability) to 8 (bedbound) and for this study, we categorized responses into three groups: ‘no mobility impairment’ (PDDS score 0–2), ‘moderate mobility impairment’ (PDDS score 3–6), and ‘severe mobility impairment’ (PDDS score 47)6,7. The MSWS-12 includes 12 questions rated on a 5 point scale with total scores ranging from 0–100 with higher scores indicating worsening walking mobility. MSWS-12 scores were categorized into four groups: minimal (total score of 0–25), mild (total score of 26–50), moderate (total score of 51–75), and severe (total score of 76–100) impairment8. 1858
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To calculate a patient’s quantity of PA, expressed in metabolic equivalent minutes (MET minutes), the Godin Leisure-Time Exercise Questionnaire (GLTEQ) was used. The GLTEQ is a validated, two-part, self-administered questionnaire measuring total leisure activity in a 1 week period9. Patients record the number of times per week in which they perform strenuous (heart beats rapidly), moderate (not exhausting) and mild (minimal effort) exercise for periods of at least 15 minutes. Each level of activity contributes a different amount to the total MET minutes, denoted by a multiplication factor within the equation. To convert GLTEQ results to MET minutes, each occurrence of activity was multiplied by 15 minutes, per the initial GLTEQ development research9. For example, if a patient had two strenuous, three moderate, and three light exercise events in a week, the estimated MET minutes would be 630 (630 MET minutes ¼ [(2 strenuous 9) þ (3 moderate 5) þ (3 light 3)] 15 min per metabolic equivalents). MET minutes were evaluated both as a continuous variable based on the actual calculated MET minutes and a dichotomous variable of patients who achieved 500 MET minutes of PA each week which is consistent with the US DHHS PA guidelines.
Statistical analyses Patient characteristics were summarized across mobility and walking impairment categories as previously defined, including the following characteristics: age (545 years, 45–54 years, 55–64 years, 464 years); duration of MS (10 years, 11–20 years, 21–30 years, 430 years); race; gender; employment status; use of disease-modifying drug (DMD) therapy; and use of physical therapy (PT). Chi-square and Mann Whitney tests were used to determine significant differences. In order to evaluate the association of mobility impairment and walking impairment on quantity of PA performed defined as a continuous outcome, general linear models were fitted. To evaluate the association of mobility and walking impairment on quantity of physical activity performed defined as achievement of 500 MET minutes of PA per week, multivariate logistic regression was used. Mobility and walking impairment groups were referent to those with the least impairment; each independent variable was referent to the selection with the fewest patients; exceptions were age 545 years and duration 11–20 years. Results of the general linear model are presented as average change in MET minutes performed and results of multivariable logistic regression are presented as adjusted odds ratios (AOR) with associated 95% confidence intervals (CI). A p-value of 50.05 determined statistical significance for all cases. www.cmrojournal.com ! 2014 Informa UK Ltd
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Analyses were conducted using SPSS (version 20, SPSS Inc., Chicago, IL, USA).
Results
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Demographic evaluation In 2010, 3609 subjects completed the spring NARCOMS survey. Of those, 3307 subjects also completed the PDSS and 3225 had a complete data set and were included in our analyses. For the MSWS-12 analysis, 3338 subjects completed the survey and 3260 had a complete data set and were therefore evaluated in our analysis. Tables 1 and 2 display patient characteristics of the studied population stratified by PDDS and MSWS-12 categories. Included subjects were mostly white, female, 55–64 years of age, and diagnosed with MS for 11–20 years. Close to half of all patients were taking disease modifying drug (DMD) therapy. The median PDDS score was 3, indicating moderate impairment (38% of patients had no impairment; 57% were classified as moderately impaired; 5% were severely impaired). The mean MSWS-12 score was 50 (standard deviation ¼ 34).
Mobility impairment and physical activity levels After adjustment for patient characteristics, presence of moderate or severe mobility impairment determined by PDDS score was associated with exercising for significantly fewer MET minutes each week and a lower likelihood of achieving the target of at least 500 MET minutes per week compared to having no mobility impairment
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(Table 3). Several patient characteristics aside from mobility impairment modified physical activity outcomes. Being over 64 years of age or being female was associated with exercising significantly fewer MET minutes each week and being significantly less likely to achieve the target MET minutes for the week compared to being under 45 years or male. Being employed or receiving physical therapy was associated with exercising significantly more MET minutes each week, but did not significantly impact the likelihood of hitting the target MET minutes for the week. Receiving DMD or duration of MS was not associated with modifications in physical activity level.
Walking impairment and physical activity level After adjusting for patient characteristics, presence of mild, moderate, or severe walking impairment defined by MSWS-12 score was associated with exercising for significantly fewer MET minutes each week and a reduced likelihood of achieving the target of at least 500 MET minutes/week, compared with minimal walking impairment (Table 4). Being over 64 years of age or being female was associated with exercising significantly fewer MET minutes each week and being significantly less likely to achieve their target MET minutes for the week compared to being under 45 years or male, respectively. Receiving physical therapy was associated with exercising significantly more MET minutes each week compared to not receiving physical therapy. Again, receiving DMD or duration of MS was not associated with modifications in physical activity level.
Table 1. Comparison of respondent characteristics stratified by PDDS score. Demographics
Age 545 years 45–54 years 55–64 years 464 years Duration of MS 10 years 11–20 years 21–30 years 430 years White race Female gender Employed Receiving a DMD Receiving physical therapy Mean (SD) MET minutes/week Patients performing 500 MET minutes/week
PDDS No Impairment (N ¼ 1216) n (%)
PDDS Moderate Impairment (N ¼ 1834) n (%)
PDDS Severe Impairment (N ¼ 175) n (%)
226 (19) 389 (32) 441 (36) 160 (13)
115 (6) 440 (24) 784 (43) 495 (27)
3 (2) 34 (19) 78 (45) 60 (34)
336 (28) 609 (50) 195 (16) 76 (6) 1164 (96) 1042 (86) 695 (57) 820 (67) 171 (14) 102 (218) 439 (36)
289 (16) 830 (45) 509 (28) 206 (11) 1760 (96) 1411 (77) 423 (23) 1064 (58) 520 (28) 248 (310) 283 (15)
13 (7) 68 (39) 59 (34) 35 (20) 164 (94) 130 (74) 20 (11) 83 (47) 63 (36) 446 (375) 8 (5)
p-Value
50.001
50.001
0.37 50.001 50.001 50.001 50.001 50.001 50.001
DMD ¼ disease-modifying drug; MS ¼ multiple sclerosis; PDDS ¼ Patient Determined Disease Steps. No impairment ¼ PDDS score of 0–2 (referent); moderate impairment ¼ PDDS score of 3–6; severe impairment ¼ PDDS score of 7.
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Table 2. Comparison of respondent characteristics stratified by 12-item Multiple Sclerosis Walking Scale total score.
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Demographics
Age 545 years 45–54 years 55–64 years 464 years Duration of MS 10 years 11–20 years 21–30 years 430 years White race Female gender Employed Receiving a DMD Receiving physical therapy Mean (SD) MET minutes/week Patients Performing 500 MET minutes/week
MSWS-12 Minimal Impairment (N ¼ 1012) n (%)
MSWS-12 Mild Impairment (N ¼ 616) n (%)
MSWS-12 Moderate Impairment (N ¼ 656) n (%)
MSWS-12 Severe Impairment (N ¼ 976) n (%)
232 (23) 338 (33) 346 (34) 96 (9)
63 (10) 177 (29) 242 (39) 134 (22)
41 (6) 188 (29) 288 (44) 139 (21)
43 (4) 203 (21) 430 (44) 300 (31)
324 (32) 495 (49) 145 (14) 48 (5) 968 (96) 870 (86) 678 (67) 645 (64) 114 (11) 475 (400) 393 (39)
123 (20) 317 (51) 129 (21) 47 (8) 595 (92) 506 (82) 243 (39) 375 (91) 143 (23) 350 (374) 148 (24)
115 (18) 307 (47) 171 (26) 63 (10) 624 (95) 521 (79) 149 (23) 385 (59) 168 (26) 258 (306) 104 (16)
114 (12) 430 (44) 298 (31) 134 (14) 935 (96) 734 (75) 145 (15) 461 (47) 314 (32) 202 (302) 122 (13)
p-Value
50.001
50.001
0.63 50.001 50.001 50.001 50.001 50.001 50.001
DMD ¼ disease-modifying drug; MS ¼ multiple sclerosis; MSWS-12 ¼ 12-Item Multiple Sclerosis Walking Scale. Minimal impairment ¼ total score of 0–25 (least walking impairment, referent); mild impairment ¼ total score of 26–50; moderate impairment ¼ total score of 51–75; severe impairment ¼ total score of 76–100 (most walking impairment).
Table 3. Results of the general linear model and multivariate logistic regression analyses stratified by PDDS scores.
Age 545 years 45–54 years 55–64 years 464 years Duration of MS 10 years 11–20 years 21–30 years 430 years White race Female gender Employed Receiving a DMD Receiving physical therapy PDDS* No impairment Moderate impairment Severe impairment
95% CI
p-Value
500 MET minutes/week AOR
95% CI
Referent 5.7 41.0 84.1
Referent 38.4 to 49.7 84.7 to 2.65 134 to 34.2
Referent 0.89 0.02 0.002
Referent 0.98 0.71 0.52
Referent 0.74 to 1.30 0.53 to 0.95 0.40 to 0.82
0.81 Referent 0.50 0.86 0.38 0.003 0.03 0.62 0.01
3.99 Referent 10.5 3.9 26.8 45.3 32.1 6.3 36.8
36.9 to 28.9 Referent 41.1 to 20.1 48.0 to 40.1 32.5 to 86.2 75.4 to 15.0 3.83 to 60.3 18.8 to 31.5 8.0 to 65.5
0.55 Referent 0.67 0.94 0.87 0.003 0.43 0.90 0.51
0.93 Referent 0.91 0.99 0.97 0.72 1.08 0.99 1.08
0.74 to 1.17 Referent 0.76 to 1.20 0.70 to 1.40 0.63 to 1.48 0.58 to 0.89 0.89 to 1.32 0.82 to 1.19 0.87 to 1.34
Referent 50.001 50.001
Referent 183 319
Referent 210 to 155 376 to 262
Referent 50.001 50.001
Referent 0.35 0.10
Referent 0.29 to 0.42 0.05 to 0.20
p-Value
Adjusted Change in MET minutes/week
Referent 0.80 0.07 0.001
AOR ¼ adjusted odds ratio; CI ¼ confidence interval; DMD ¼ disease-modifying drug; MS ¼ multiple sclerosis; PDDS ¼ Patient Determined Disease Steps. *No impairment ¼ PDDS score of 0–2 (referent); moderate impairment ¼ PDDS score of 3–6; severe impairment ¼ PDDS score of 7.
Discussion The health benefits associated with PA performance in the general US population have been well researched and have been summarized by the US DHHS in their ‘Physical Activity Guidelines for Americans’ document1. This guidance document suggests there is strong evidence to support that regular PA can reduce peoples’ risk of many 1860
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adverse health outcomes including coronary heart disease, stroke, high blood pressure, high cholesterol, obesity, type 2 diabetes, metabolic syndrome, colon and breast cancer and depression. Health benefits related to performance of adequate PA can also occur in people with disabilities such as mobility or walking impairment. Moreover, while the guidelines suggest that some PA is better than none, they highlight the importance of achieving at least 500 MET www.cmrojournal.com ! 2014 Informa UK Ltd
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Table 4. Results of the general linear model and multivariate logistic regression analyses stratified by MSWS-12 scores.
Age 545 years 45–54 years 55–64 years 464 years Duration of MS 10 years 11–20 years 21–30 years 430 years White race Female gender Employed Receiving a DMD Receiving physical therapy MSWS-12 score groups* Group 1 Group 2 Group 3 Group 4
95% CI
p-Value
500 MET minutes/week AOR
95% CI
Referent 17.3 27.0 65.7
Referent 25.4 to 60.0 69.5 to 15.5 155 to 16.2
Referent 0.67 0.13 0.02
Referent 1.06 0.80 0.67
Referent 0.81 to 1.40 0.61 to 1.06 0.47 to 0.95
0.37 Referent 0.39 0.98 0.16 0.002 0.90 0.97 0.003
14.9 Referent 13.6 0.59 42.3 48.0 1.86 0.41 43.7
47.4 to 17.5 Referent 44.7 to 17.4 45.2 to 46.4 17.3 to 102.0 78.8 to 17.3 27.0 to 30.7 24.3 to 25.2 14.5 to 72.9
0.30 Referent 0.58 0.93 0.72 0.001 0.61 40.99 0.44
0.89 Referent 0.94 0.98 1.08 0.70 0.95 1.00 1.09
0.71 to 1.11 Referent 0.75 to 1.18 0.69 to 1.40 0.71 to 1.66 0.56 to 0.86 0.78 to 1.16 0.84 to 1.19 0.88 to 1.35
Referent 50.001 50.001 50.001
Referent 127 216 268
Referent 163 to 90.8 253 to 179 304 to 233
Referent 50.001 50.001 50.001
Referent 0.49 0.29 0.23
Referent 0.39 to 0.62 0.22 to 0.38 0.18 to 0.30
p-Value
Adjusted Change in MET minutes/week
Referent 0.43 0.21 0.009
AOR ¼ adjusted odds ratio; CI ¼ confidence interval; DMD ¼ disease-modifying drug; MS ¼ multiple sclerosis; MSWS-12 ¼ 12-item Multiple Sclerosis Walking Scale. *Group 1 ¼ total score of 0–25 (least walking impairment, referent); group 2 ¼ total score of 26–50; group 3 ¼ total score of 51–75; group 4 ¼ total score of 76–100 (most walking impairment).
minutes of PA per week, since a strong positive correlation has been observed between health benefits and the intensity, frequency and duration of PA1. The results of this study suggest worsening mobility and walking impairment are associated with the performance of less PA and decreased odds of achieving guidelinerecommended PA goals. Our findings suggest a mechanism by which previous investigations have shown PwMS to have an increased prevalence/risk of numerous comorbidities (i.e., myocardial infarction, heart failure, stroke, peripheral vascular disease, venous thromboembolism, anemia, depression rheumatoid arthritis and lupus) compared to people without MS10–11. The results of this study also suggest the impact of mobility and walking impairment on PA levels may be more profound than observed in previous studies of PwMS. In a 2012 study by Sandroff and colleagues, the GLTEQ and International Physical Activity Questionnaire (IPAQ) were used to quantify levels of PA in persons with and without MS12. The investigators found only a modest reduction in PA performed by PwMS compared to matched non-MS controls (mean MET min/ week performed ¼ 537 vs. 680, delta ¼ 143). We observed large reductions in MET minutes of PA performed in our study between PwMS with ‘no’ vs. ‘severe’ mobility impairment (delta ¼ 319) or group 1 (least) vs. 4 (most impaired walkers) using the MSWS-12 (delta ¼ 268). However, the majority of PwMS in Sandroff’s study suffered from mild mobility/walking disability (reported median PDSS of 1 with a range of 0 to 6 and a ! 2014 Informa UK Ltd www.cmrojournal.com
median MSWS-12 of 22.9). Our study enrolled PwMS with a wider representation of mobility and walking impairment scores (median PDDS of 3, range ¼ 0–8; median MSWS-12 of 52; range 0–100), which is more representative of the real-world MS population. There are limitations to our study that should be noted. First, while the NARCOMS registry is a large, well designed and executed registry of PwMS from North America, as with all registries it may not be representative of all PwMS. Moreover, NARCOMS data comes from cross-sectional biannual surveys and, therefore, responses may be subject to reporting or recall bias and only a limited number of variables are available for inclusion into the final statistical models, opening up the potential for residual confounding of our results. Prior research suggests PDSS and MSWS-12 are correlated and therefore may not represent independent measures of ambulation and are likely both impaired to some degree as ambulation in PwMS becomes compromised7. However, it is reassuring that both measures of ambulation were in agreement as to the impact of impairment with performance of PA levels. Although measures of physical activity level in our study are based on patient report rather than objective measurements, data using the latter has also suggested reduced physical activity levels in PwMS13. Use of objective measures may be perceived as superior to patient-reported outcomes although not until recently were cut-points developed for PwMS, limiting the interpretation of such measurements14. Next, although the MSWS-12 and GLTEQ are validated tools, the manner in which we Mobility and physical activity in multiple sclerosis Kohn et al.
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used these tools (categorizing walking impairment by MSWS-12 score quartiles; estimating MET minutes using the GLTEQ) are novel and have not been formally investigated. In particular, our calculation of MET minutes assumed respondents performed exactly 15 minutes of PA at each occurrence, and is likely an underestimation of the level of PA performed. Finally, it was not possible to evaluate the impact of PA on final health outcomes linked to PA performance levels (e.g., development of myocardial infarction, diabetes or cancer) because this data is not collected in the NARCOMS registry. This is of ultimate interest and an area for future research within multiple sclerosis. If proven, development of future multiple sclerosis treatments focusing on improvement of physical activity levels could translate into benefits in final health outcomes.
Conclusions More severe mobility and walking impairment in PwMS, measured by the PDDS and MSWS-12, is associated with the performance of less PA and decreased odds of achieving guideline-recommended goals for PA. These decreases in PA may have deleterious consequences for PwMS patients, since failure to meet recommended PA levels has been linked to increased morbidity and mortality. Future drug development targeting improvement of mobility and walking impairment in PwMS may lead to achievement of PA goals, translating into reduced risk of the aforementioned comorbidities. Future prospective studies would be necessary to confirm such a hypothesis.
Transparency Declaration of funding This work was supported by Acorda Therapeutics Inc., Ardsley, NY, USA. The publication of these study results was not contingent on the sponsor’s approval or censorship of the manuscript.
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Declaration of financial/other relationships M.F.S. has disclosed that he is a paid employee and stockholder of Acorda Therapeutics Inc., Ardsley, NY, USA. C.I.C. has disclosed that he has received research funding from Acorda Therapeutics Inc., Ardsley, NY, USA. C.G.K., C.M.W. and D.M.S. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
References 1. U.S. Dept. of Health and Human Services. 2008 Physical Activity Guidelines for Americans. June 2008. Available at: http://www.health.gov/paguidelines [Last accessed 18 June 2013] 2. Sutliff MH. Contribution of impaired mobility to patient burden in multiple sclerosis. Curr Med Res Opin 2010;26:109-19 3. Weinshenker BG. Natural history of multiple sclerosis. Ann Neurol 1994;36(Suppl):S6-11 4. Myhr KM, Riise T, Vedeler C, et al. Disability and prognosis in multiple sclerosis: demographic and clinical variables important for the ability to walk and awarding of disability pension. Mult Scler 2001;7:59-65 5. Motl RW, McAuley E, Snook EM. Physical activity and multiple sclerosis: a meta-analysis. Mult Scler 2005;11:459-63 6. Marrie RA, Goldman M. Validity of performance scales for disability assessment in multiple sclerosis. Mult Scler 2007;13:1176-82 7. Learmonth YC, Motl RW, Sandroff BM, et al. Validation of patient determined disease steps (PDDS) scale scores in persons with multiple sclerosis. BMC Neurol 2013;13:37 8. Godin G, Shephard RJ. A simple method to assess exercise behavior in the community. Can J Appl Sport Sci 1985;10:141-6 9. Kang JH, Chen YH, Lin HC. Comorbidities amongst patients with multiple sclerosis: a population-based controlled study. Euro J Neurol 2010;17:1215-19 10. Christiansen CR, Christensen S, Farkas DK, et al. Risk of arterial cardiovascular diseases in patients with multiple sclerosis: a population-based cohort study. Neuroepidemiology 2010;35:267-74 11. Christiansen CF. Risk of vascular disease in patients with multiple sclerosis: a review. Neurol Res 2012;34:746-53 12. Sandroff BM, Dlugnski D, Weikert M, et al. Physical activity and multiple sclerosis: new insights regarding inactivity. Acta Neurol Scand 2012;126:256-62 13. Klaren RE, Motl RE, Dlugonski D, et al. Objectively quantified physical activity in persons with multiple sclerosis. Arch Phys Med Rehabil 2013;94:2342-8 14. Sandroff BM, Motl RW, Suh Y. Accelerometer output and its association with energy expenditure in persons with multiple sclerosis. J Rehabil Res Dev 2012;49:467-75
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Vol. 30, No. 9, 2014, 1857–1862
Article ST-0072.R1/921147 All rights reserved: reproduction in whole or part not permitted
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Original article Mobility, walking and physical activity in persons with multiple sclerosis
Christine G. Kohn Craig I. Coleman C. Michael White Department of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, CT, USA
Abstract Objective: The effect of differing levels of mobility and walking disability on level of physical activity (PA) performed in persons with multiple sclerosis (PwMS) is unknown. We aimed to quantify the association between mobility and walking impairment and PA levels in PwMS.
Matthew F. Sidovar Clinical Development and Medical Affairs, Acorda Therapeutics, Ardsley, NY, USA
Diana M. Sobieraj Department of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, CT, USA Address for correspondence: Diana M. Sobieraj PharmD, Assistant Professor, University of Connecticut School of Pharmacy, 69 N Eagleville Road, Unit 3092, Storrs, CT 06269, USA. Tel.: +1 860 545 22429: Fax: +1 860 545 2277; [email protected] Keywords: Exercise – Mobility – Motor activity – Multiple sclerosis – Physical activity – Walking Accepted: 25 April 2014; published online: 29 May 2014 Citation: Curr Med Res Opin 2014; 30:1857–62
Methods: We assessed mobility and walking impairment in43000 North American Research Committee on Multiple Sclerosis registrants using the Patient Determined Disease Steps scale (score of 0–2 ¼ no, 3–6 ¼ moderate, 7 ¼ severe impairment) and 12-Item Multiple Sclerosis Walking Scale (MSWS-12) score (divided into quartiles, score of 0–25 ¼ least walking impairment, 76–100 ¼ most). Level of PA performance (metabolic equivalent [MET] minutes/week) was estimated using the Godin Leisure-Time Exercise Questionnaire. Multivariable regression and general linear models were used to assess the impact of walking and mobility impairment on PA levels. Results: Moderate and severe mobility impairment was associated with performance of 183 and 319 fewer MET minutes/week and a 65% and 90% reduced odds of performing 500 MET minutes/week of PA compared to no impairment (mean SD: 447 413 MET minutes/week) (p50.05 for all). Compared to the first quartile of MSWS-12 score (mean SD: 475 401), the second, third and fourth quartiles were associated with performance of 127, 216 and 268 fewer MET minutes/week and 51%, 71% and 77% reduced odds of achieving 500 MET minutes/week of PA (p50.05 for each). Limitations of our study include possible recall bias, use of a patient-reported rather than objective outcome and assumptions made when calculating MET minutes. Conclusion: Mobility and walking impairment are associated with less physical activity in PwMS.
Introduction The health benefits associated with the general population’s performance of physical activity (PA) have been well elucidated. In 2008, the US Department of Health and Human Services (DHHS) published the guidance document entitled, ‘Physical Activity Guidelines for Americans’ which describes the evidence supporting health benefits from performing PA, and provides recommendations for optimal levels of PA to achieve health benefits including decreased risks of cardio- and cerebro-vascular disease, diabetes, cancer, obesity and depression1. Specifically, these guidelines recommend Americans perform between 500 and 1000 metabolic minutes (MET minutes) of PA per week. ! 2014 Informa UK Ltd www.cmrojournal.com
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Persons with multiple sclerosis (PwMS) often suffer from mobility and walking impairment due to the neurodegenerative nature of their disease2. In fact, prior studies have shown that 40% to 50% of PwMS need assistance walking within 15 years of disease onset3,4, and that patients with MS engage in less PA than matched non-MS controls5. However, the effect of differing levels of mobility and walking disability in PwMS on quantity of PA performed and the achievement of guideline recommended levels of PA are unknown. In addition, it is unknown what other patient-related factors are associated with performance of PA in PwMS. Therefore, we sought to evaluate the association of mobility and walking impairment on achievement of guideline recommended levels of PA in PwMS and to ascertain which patient-related factors modify the likelihood of performing PA.
Methods Study type and inclusion criteria This was a cross-sectional study using all participants who completed the 2010 spring survey and the supplemental semi-annual survey for the North American Research Committee on Multiple Sclerosis (NARCOMS) registry. The NARCOMS registry contains self-reported data on PwMS obtained through a biannual health survey, including demographic factors, disease history, employment, symptoms, functional outcome measures, mobility impairment and quality of life. The supplemental semi-annual questionnaire gathers more specific data on work productivity, mobility and walking impairment and physical activity performance.
Mobility and walking measures In this study we determined a patient’s level of mobility and walking impairment using two validated patientreported outcome scales, the Patient Determined Disease Steps (PDDS) and the 12-item Multiple Sclerosis Walking Scale (MSWS-12), respectively. The PDDS is scored ordinally from 0 (no disability) to 8 (bedbound) and for this study, we categorized responses into three groups: ‘no mobility impairment’ (PDDS score 0–2), ‘moderate mobility impairment’ (PDDS score 3–6), and ‘severe mobility impairment’ (PDDS score 47)6,7. The MSWS-12 includes 12 questions rated on a 5 point scale with total scores ranging from 0–100 with higher scores indicating worsening walking mobility. MSWS-12 scores were categorized into four groups: minimal (total score of 0–25), mild (total score of 26–50), moderate (total score of 51–75), and severe (total score of 76–100) impairment8. 1858
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To calculate a patient’s quantity of PA, expressed in metabolic equivalent minutes (MET minutes), the Godin Leisure-Time Exercise Questionnaire (GLTEQ) was used. The GLTEQ is a validated, two-part, self-administered questionnaire measuring total leisure activity in a 1 week period9. Patients record the number of times per week in which they perform strenuous (heart beats rapidly), moderate (not exhausting) and mild (minimal effort) exercise for periods of at least 15 minutes. Each level of activity contributes a different amount to the total MET minutes, denoted by a multiplication factor within the equation. To convert GLTEQ results to MET minutes, each occurrence of activity was multiplied by 15 minutes, per the initial GLTEQ development research9. For example, if a patient had two strenuous, three moderate, and three light exercise events in a week, the estimated MET minutes would be 630 (630 MET minutes ¼ [(2 strenuous 9) þ (3 moderate 5) þ (3 light 3)] 15 min per metabolic equivalents). MET minutes were evaluated both as a continuous variable based on the actual calculated MET minutes and a dichotomous variable of patients who achieved 500 MET minutes of PA each week which is consistent with the US DHHS PA guidelines.
Statistical analyses Patient characteristics were summarized across mobility and walking impairment categories as previously defined, including the following characteristics: age (545 years, 45–54 years, 55–64 years, 464 years); duration of MS (10 years, 11–20 years, 21–30 years, 430 years); race; gender; employment status; use of disease-modifying drug (DMD) therapy; and use of physical therapy (PT). Chi-square and Mann Whitney tests were used to determine significant differences. In order to evaluate the association of mobility impairment and walking impairment on quantity of PA performed defined as a continuous outcome, general linear models were fitted. To evaluate the association of mobility and walking impairment on quantity of physical activity performed defined as achievement of 500 MET minutes of PA per week, multivariate logistic regression was used. Mobility and walking impairment groups were referent to those with the least impairment; each independent variable was referent to the selection with the fewest patients; exceptions were age 545 years and duration 11–20 years. Results of the general linear model are presented as average change in MET minutes performed and results of multivariable logistic regression are presented as adjusted odds ratios (AOR) with associated 95% confidence intervals (CI). A p-value of 50.05 determined statistical significance for all cases. www.cmrojournal.com ! 2014 Informa UK Ltd
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Analyses were conducted using SPSS (version 20, SPSS Inc., Chicago, IL, USA).
Results
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Demographic evaluation In 2010, 3609 subjects completed the spring NARCOMS survey. Of those, 3307 subjects also completed the PDSS and 3225 had a complete data set and were included in our analyses. For the MSWS-12 analysis, 3338 subjects completed the survey and 3260 had a complete data set and were therefore evaluated in our analysis. Tables 1 and 2 display patient characteristics of the studied population stratified by PDDS and MSWS-12 categories. Included subjects were mostly white, female, 55–64 years of age, and diagnosed with MS for 11–20 years. Close to half of all patients were taking disease modifying drug (DMD) therapy. The median PDDS score was 3, indicating moderate impairment (38% of patients had no impairment; 57% were classified as moderately impaired; 5% were severely impaired). The mean MSWS-12 score was 50 (standard deviation ¼ 34).
Mobility impairment and physical activity levels After adjustment for patient characteristics, presence of moderate or severe mobility impairment determined by PDDS score was associated with exercising for significantly fewer MET minutes each week and a lower likelihood of achieving the target of at least 500 MET minutes per week compared to having no mobility impairment
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(Table 3). Several patient characteristics aside from mobility impairment modified physical activity outcomes. Being over 64 years of age or being female was associated with exercising significantly fewer MET minutes each week and being significantly less likely to achieve the target MET minutes for the week compared to being under 45 years or male. Being employed or receiving physical therapy was associated with exercising significantly more MET minutes each week, but did not significantly impact the likelihood of hitting the target MET minutes for the week. Receiving DMD or duration of MS was not associated with modifications in physical activity level.
Walking impairment and physical activity level After adjusting for patient characteristics, presence of mild, moderate, or severe walking impairment defined by MSWS-12 score was associated with exercising for significantly fewer MET minutes each week and a reduced likelihood of achieving the target of at least 500 MET minutes/week, compared with minimal walking impairment (Table 4). Being over 64 years of age or being female was associated with exercising significantly fewer MET minutes each week and being significantly less likely to achieve their target MET minutes for the week compared to being under 45 years or male, respectively. Receiving physical therapy was associated with exercising significantly more MET minutes each week compared to not receiving physical therapy. Again, receiving DMD or duration of MS was not associated with modifications in physical activity level.
Table 1. Comparison of respondent characteristics stratified by PDDS score. Demographics
Age 545 years 45–54 years 55–64 years 464 years Duration of MS 10 years 11–20 years 21–30 years 430 years White race Female gender Employed Receiving a DMD Receiving physical therapy Mean (SD) MET minutes/week Patients performing 500 MET minutes/week
PDDS No Impairment (N ¼ 1216) n (%)
PDDS Moderate Impairment (N ¼ 1834) n (%)
PDDS Severe Impairment (N ¼ 175) n (%)
226 (19) 389 (32) 441 (36) 160 (13)
115 (6) 440 (24) 784 (43) 495 (27)
3 (2) 34 (19) 78 (45) 60 (34)
336 (28) 609 (50) 195 (16) 76 (6) 1164 (96) 1042 (86) 695 (57) 820 (67) 171 (14) 102 (218) 439 (36)
289 (16) 830 (45) 509 (28) 206 (11) 1760 (96) 1411 (77) 423 (23) 1064 (58) 520 (28) 248 (310) 283 (15)
13 (7) 68 (39) 59 (34) 35 (20) 164 (94) 130 (74) 20 (11) 83 (47) 63 (36) 446 (375) 8 (5)
p-Value
50.001
50.001
0.37 50.001 50.001 50.001 50.001 50.001 50.001
DMD ¼ disease-modifying drug; MS ¼ multiple sclerosis; PDDS ¼ Patient Determined Disease Steps. No impairment ¼ PDDS score of 0–2 (referent); moderate impairment ¼ PDDS score of 3–6; severe impairment ¼ PDDS score of 7.
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Table 2. Comparison of respondent characteristics stratified by 12-item Multiple Sclerosis Walking Scale total score.
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Demographics
Age 545 years 45–54 years 55–64 years 464 years Duration of MS 10 years 11–20 years 21–30 years 430 years White race Female gender Employed Receiving a DMD Receiving physical therapy Mean (SD) MET minutes/week Patients Performing 500 MET minutes/week
MSWS-12 Minimal Impairment (N ¼ 1012) n (%)
MSWS-12 Mild Impairment (N ¼ 616) n (%)
MSWS-12 Moderate Impairment (N ¼ 656) n (%)
MSWS-12 Severe Impairment (N ¼ 976) n (%)
232 (23) 338 (33) 346 (34) 96 (9)
63 (10) 177 (29) 242 (39) 134 (22)
41 (6) 188 (29) 288 (44) 139 (21)
43 (4) 203 (21) 430 (44) 300 (31)
324 (32) 495 (49) 145 (14) 48 (5) 968 (96) 870 (86) 678 (67) 645 (64) 114 (11) 475 (400) 393 (39)
123 (20) 317 (51) 129 (21) 47 (8) 595 (92) 506 (82) 243 (39) 375 (91) 143 (23) 350 (374) 148 (24)
115 (18) 307 (47) 171 (26) 63 (10) 624 (95) 521 (79) 149 (23) 385 (59) 168 (26) 258 (306) 104 (16)
114 (12) 430 (44) 298 (31) 134 (14) 935 (96) 734 (75) 145 (15) 461 (47) 314 (32) 202 (302) 122 (13)
p-Value
50.001
50.001
0.63 50.001 50.001 50.001 50.001 50.001 50.001
DMD ¼ disease-modifying drug; MS ¼ multiple sclerosis; MSWS-12 ¼ 12-Item Multiple Sclerosis Walking Scale. Minimal impairment ¼ total score of 0–25 (least walking impairment, referent); mild impairment ¼ total score of 26–50; moderate impairment ¼ total score of 51–75; severe impairment ¼ total score of 76–100 (most walking impairment).
Table 3. Results of the general linear model and multivariate logistic regression analyses stratified by PDDS scores.
Age 545 years 45–54 years 55–64 years 464 years Duration of MS 10 years 11–20 years 21–30 years 430 years White race Female gender Employed Receiving a DMD Receiving physical therapy PDDS* No impairment Moderate impairment Severe impairment
95% CI
p-Value
500 MET minutes/week AOR
95% CI
Referent 5.7 41.0 84.1
Referent 38.4 to 49.7 84.7 to 2.65 134 to 34.2
Referent 0.89 0.02 0.002
Referent 0.98 0.71 0.52
Referent 0.74 to 1.30 0.53 to 0.95 0.40 to 0.82
0.81 Referent 0.50 0.86 0.38 0.003 0.03 0.62 0.01
3.99 Referent 10.5 3.9 26.8 45.3 32.1 6.3 36.8
36.9 to 28.9 Referent 41.1 to 20.1 48.0 to 40.1 32.5 to 86.2 75.4 to 15.0 3.83 to 60.3 18.8 to 31.5 8.0 to 65.5
0.55 Referent 0.67 0.94 0.87 0.003 0.43 0.90 0.51
0.93 Referent 0.91 0.99 0.97 0.72 1.08 0.99 1.08
0.74 to 1.17 Referent 0.76 to 1.20 0.70 to 1.40 0.63 to 1.48 0.58 to 0.89 0.89 to 1.32 0.82 to 1.19 0.87 to 1.34
Referent 50.001 50.001
Referent 183 319
Referent 210 to 155 376 to 262
Referent 50.001 50.001
Referent 0.35 0.10
Referent 0.29 to 0.42 0.05 to 0.20
p-Value
Adjusted Change in MET minutes/week
Referent 0.80 0.07 0.001
AOR ¼ adjusted odds ratio; CI ¼ confidence interval; DMD ¼ disease-modifying drug; MS ¼ multiple sclerosis; PDDS ¼ Patient Determined Disease Steps. *No impairment ¼ PDDS score of 0–2 (referent); moderate impairment ¼ PDDS score of 3–6; severe impairment ¼ PDDS score of 7.
Discussion The health benefits associated with PA performance in the general US population have been well researched and have been summarized by the US DHHS in their ‘Physical Activity Guidelines for Americans’ document1. This guidance document suggests there is strong evidence to support that regular PA can reduce peoples’ risk of many 1860
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adverse health outcomes including coronary heart disease, stroke, high blood pressure, high cholesterol, obesity, type 2 diabetes, metabolic syndrome, colon and breast cancer and depression. Health benefits related to performance of adequate PA can also occur in people with disabilities such as mobility or walking impairment. Moreover, while the guidelines suggest that some PA is better than none, they highlight the importance of achieving at least 500 MET www.cmrojournal.com ! 2014 Informa UK Ltd
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Table 4. Results of the general linear model and multivariate logistic regression analyses stratified by MSWS-12 scores.
Age 545 years 45–54 years 55–64 years 464 years Duration of MS 10 years 11–20 years 21–30 years 430 years White race Female gender Employed Receiving a DMD Receiving physical therapy MSWS-12 score groups* Group 1 Group 2 Group 3 Group 4
95% CI
p-Value
500 MET minutes/week AOR
95% CI
Referent 17.3 27.0 65.7
Referent 25.4 to 60.0 69.5 to 15.5 155 to 16.2
Referent 0.67 0.13 0.02
Referent 1.06 0.80 0.67
Referent 0.81 to 1.40 0.61 to 1.06 0.47 to 0.95
0.37 Referent 0.39 0.98 0.16 0.002 0.90 0.97 0.003
14.9 Referent 13.6 0.59 42.3 48.0 1.86 0.41 43.7
47.4 to 17.5 Referent 44.7 to 17.4 45.2 to 46.4 17.3 to 102.0 78.8 to 17.3 27.0 to 30.7 24.3 to 25.2 14.5 to 72.9
0.30 Referent 0.58 0.93 0.72 0.001 0.61 40.99 0.44
0.89 Referent 0.94 0.98 1.08 0.70 0.95 1.00 1.09
0.71 to 1.11 Referent 0.75 to 1.18 0.69 to 1.40 0.71 to 1.66 0.56 to 0.86 0.78 to 1.16 0.84 to 1.19 0.88 to 1.35
Referent 50.001 50.001 50.001
Referent 127 216 268
Referent 163 to 90.8 253 to 179 304 to 233
Referent 50.001 50.001 50.001
Referent 0.49 0.29 0.23
Referent 0.39 to 0.62 0.22 to 0.38 0.18 to 0.30
p-Value
Adjusted Change in MET minutes/week
Referent 0.43 0.21 0.009
AOR ¼ adjusted odds ratio; CI ¼ confidence interval; DMD ¼ disease-modifying drug; MS ¼ multiple sclerosis; MSWS-12 ¼ 12-item Multiple Sclerosis Walking Scale. *Group 1 ¼ total score of 0–25 (least walking impairment, referent); group 2 ¼ total score of 26–50; group 3 ¼ total score of 51–75; group 4 ¼ total score of 76–100 (most walking impairment).
minutes of PA per week, since a strong positive correlation has been observed between health benefits and the intensity, frequency and duration of PA1. The results of this study suggest worsening mobility and walking impairment are associated with the performance of less PA and decreased odds of achieving guidelinerecommended PA goals. Our findings suggest a mechanism by which previous investigations have shown PwMS to have an increased prevalence/risk of numerous comorbidities (i.e., myocardial infarction, heart failure, stroke, peripheral vascular disease, venous thromboembolism, anemia, depression rheumatoid arthritis and lupus) compared to people without MS10–11. The results of this study also suggest the impact of mobility and walking impairment on PA levels may be more profound than observed in previous studies of PwMS. In a 2012 study by Sandroff and colleagues, the GLTEQ and International Physical Activity Questionnaire (IPAQ) were used to quantify levels of PA in persons with and without MS12. The investigators found only a modest reduction in PA performed by PwMS compared to matched non-MS controls (mean MET min/ week performed ¼ 537 vs. 680, delta ¼ 143). We observed large reductions in MET minutes of PA performed in our study between PwMS with ‘no’ vs. ‘severe’ mobility impairment (delta ¼ 319) or group 1 (least) vs. 4 (most impaired walkers) using the MSWS-12 (delta ¼ 268). However, the majority of PwMS in Sandroff’s study suffered from mild mobility/walking disability (reported median PDSS of 1 with a range of 0 to 6 and a ! 2014 Informa UK Ltd www.cmrojournal.com
median MSWS-12 of 22.9). Our study enrolled PwMS with a wider representation of mobility and walking impairment scores (median PDDS of 3, range ¼ 0–8; median MSWS-12 of 52; range 0–100), which is more representative of the real-world MS population. There are limitations to our study that should be noted. First, while the NARCOMS registry is a large, well designed and executed registry of PwMS from North America, as with all registries it may not be representative of all PwMS. Moreover, NARCOMS data comes from cross-sectional biannual surveys and, therefore, responses may be subject to reporting or recall bias and only a limited number of variables are available for inclusion into the final statistical models, opening up the potential for residual confounding of our results. Prior research suggests PDSS and MSWS-12 are correlated and therefore may not represent independent measures of ambulation and are likely both impaired to some degree as ambulation in PwMS becomes compromised7. However, it is reassuring that both measures of ambulation were in agreement as to the impact of impairment with performance of PA levels. Although measures of physical activity level in our study are based on patient report rather than objective measurements, data using the latter has also suggested reduced physical activity levels in PwMS13. Use of objective measures may be perceived as superior to patient-reported outcomes although not until recently were cut-points developed for PwMS, limiting the interpretation of such measurements14. Next, although the MSWS-12 and GLTEQ are validated tools, the manner in which we Mobility and physical activity in multiple sclerosis Kohn et al.
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used these tools (categorizing walking impairment by MSWS-12 score quartiles; estimating MET minutes using the GLTEQ) are novel and have not been formally investigated. In particular, our calculation of MET minutes assumed respondents performed exactly 15 minutes of PA at each occurrence, and is likely an underestimation of the level of PA performed. Finally, it was not possible to evaluate the impact of PA on final health outcomes linked to PA performance levels (e.g., development of myocardial infarction, diabetes or cancer) because this data is not collected in the NARCOMS registry. This is of ultimate interest and an area for future research within multiple sclerosis. If proven, development of future multiple sclerosis treatments focusing on improvement of physical activity levels could translate into benefits in final health outcomes.
Conclusions More severe mobility and walking impairment in PwMS, measured by the PDDS and MSWS-12, is associated with the performance of less PA and decreased odds of achieving guideline-recommended goals for PA. These decreases in PA may have deleterious consequences for PwMS patients, since failure to meet recommended PA levels has been linked to increased morbidity and mortality. Future drug development targeting improvement of mobility and walking impairment in PwMS may lead to achievement of PA goals, translating into reduced risk of the aforementioned comorbidities. Future prospective studies would be necessary to confirm such a hypothesis.
Transparency Declaration of funding This work was supported by Acorda Therapeutics Inc., Ardsley, NY, USA. The publication of these study results was not contingent on the sponsor’s approval or censorship of the manuscript.
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Declaration of financial/other relationships M.F.S. has disclosed that he is a paid employee and stockholder of Acorda Therapeutics Inc., Ardsley, NY, USA. C.I.C. has disclosed that he has received research funding from Acorda Therapeutics Inc., Ardsley, NY, USA. C.G.K., C.M.W. and D.M.S. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
References 1. U.S. Dept. of Health and Human Services. 2008 Physical Activity Guidelines for Americans. June 2008. Available at: http://www.health.gov/paguidelines [Last accessed 18 June 2013] 2. Sutliff MH. Contribution of impaired mobility to patient burden in multiple sclerosis. Curr Med Res Opin 2010;26:109-19 3. Weinshenker BG. Natural history of multiple sclerosis. Ann Neurol 1994;36(Suppl):S6-11 4. Myhr KM, Riise T, Vedeler C, et al. Disability and prognosis in multiple sclerosis: demographic and clinical variables important for the ability to walk and awarding of disability pension. Mult Scler 2001;7:59-65 5. Motl RW, McAuley E, Snook EM. Physical activity and multiple sclerosis: a meta-analysis. Mult Scler 2005;11:459-63 6. Marrie RA, Goldman M. Validity of performance scales for disability assessment in multiple sclerosis. Mult Scler 2007;13:1176-82 7. Learmonth YC, Motl RW, Sandroff BM, et al. Validation of patient determined disease steps (PDDS) scale scores in persons with multiple sclerosis. BMC Neurol 2013;13:37 8. Godin G, Shephard RJ. A simple method to assess exercise behavior in the community. Can J Appl Sport Sci 1985;10:141-6 9. Kang JH, Chen YH, Lin HC. Comorbidities amongst patients with multiple sclerosis: a population-based controlled study. Euro J Neurol 2010;17:1215-19 10. Christiansen CR, Christensen S, Farkas DK, et al. Risk of arterial cardiovascular diseases in patients with multiple sclerosis: a population-based cohort study. Neuroepidemiology 2010;35:267-74 11. Christiansen CF. Risk of vascular disease in patients with multiple sclerosis: a review. Neurol Res 2012;34:746-53 12. Sandroff BM, Dlugnski D, Weikert M, et al. Physical activity and multiple sclerosis: new insights regarding inactivity. Acta Neurol Scand 2012;126:256-62 13. Klaren RE, Motl RE, Dlugonski D, et al. Objectively quantified physical activity in persons with multiple sclerosis. Arch Phys Med Rehabil 2013;94:2342-8 14. Sandroff BM, Motl RW, Suh Y. Accelerometer output and its association with energy expenditure in persons with multiple sclerosis. J Rehabil Res Dev 2012;49:467-75
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