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Performed and perceived walking ability in relation to the Expanded Disability Status Scale in persons with multiple sclerosis
Journal of the Neurological Sciences 382 (2017) 131–136
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Performed and perceived walking ability in relation to the Expanded Disability Status Scale in persons with multiple sclerosis
MARK
D. Langeskov-Christensena, P. Feysb, I. Baertb, M. Riemenschneidera, E. Stenagerc,d, U. Dalgasa,⁎ a
Section of Sport Science, Department of Public Health, Aarhus University, Aarhus, Denmark REVAL, BIOMED-Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium c Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark d MS-Clinic of Southern Jutland (Sønderborg, Esbjerg, Kolding), Department of Neurology, Sønderborg, Denmark b
A R T I C L E I N F O
A B S T R A C T
Keywords: Multiple sclerosis EDSS Walking impairment Walking measures 6MWT MSWS-12
Background: The severity of walking impairment in persons with multiple sclerosis (pwMS) at different levels on the expanded disability status scale (EDSS) is unclear. Furthermore, it is unclear if the EDSS is differently related to performed- and perceived walking capacity tests. Aims: To quantify walking impairment and perceived impact of MS on walking according to EDSS scores and to examine the relations between these parameters in pwMS. Methods: EDSS was collected by neurologists and walking was assessed by the timed 25 ft walk test (T25FWT), two minute walk test (2MWT), six minute walk test (6MWT) and the 12-item MS walking scale (MSWS-12) in 474 PwMS with mild (EDSS 1–4: n = 200) to moderate (EDSS 4.5–6.5: n = 274) MS. Magnitude of walking impairment was calculated and related to EDSS. Results: Compared to predicted values in healthy controls, walking speed was reduced by 41.5 ± 25.8% in the 6MWT for the total MS group and by 21.8 ± 20.2% and 55.8 ± 19.1% in the mild and moderate MS subgroups, respectively. The EDSS score showed the strongest relationship to the 2MWT and the 6MWT in the total MS group (r = −0.76, p < 0.0001), to the MSWS-12 score in the mild MS group (r = 0.56, p < 0.0001), and to the 2MWT in the moderate MS group (r = − 0.50, p < 0.0001). Conclusion: In pwMS (EDSS scores 1–6.5), walking speed is on average reduced by ~40% when compared to predicted values in healthy controls, and impairments are already present at early disease stages, suggesting early initiation of rehabilitation. The 2MWT and 6MWT show the strongest relationship to EDSS, but the MSWS12 identify impairments more gradually at low EDSS scores.
1. Introduction
quantification can give insight to the actual reduction in walking capacity throughout the different disease stages, and this has to be investigated and confirmed by a large sample study [6,7]. Furthermore, it is unclear to which extent walking speed is compromised at low disability levels, although changes in muscle coordination and gait kinematics has been documented [9–11]. This could help to clarify the necessity for early rehabilitation interventions aiming at maintaining walking abilities. The expanded disability status scale (EDSS) of Kurtzke [12] is the most widely used instrument to describe the clinical severity in MS. The EDSS score is based on neurological examination and reflects the functional system scores (pyramidal, cerebellar, brain stem, sensory, bowel and bladder, visual, cerebral and other), which may be related to walking capacity, since walking performance is affected by loss of muscle strength, cerebellar damage, ataxia, sensory loss, visual
Multiple sclerosis (MS) is a demyelinating, inflammatory and neurodegenerative disorder of the central nervous system (CNS) that is characterized by progressive neurologic impairment [1]. Ambulatory dysfunction is a common and well-recognized feature of the disease [2] with MS patients perceiving walking as the most valued bodily function independent of disease duration [3]. In persons with MS (pwMS) decreased walking capacity relates to reduced health-related quality of life [4]. Compared to healthy persons, it has been shown that most pwMS walk slower during longer walking tests (e.g. 6 minute walk test, 6MWT) [5–7]. However, only few and small studies have precisely quantified the magnitude of reduced walking speed or distance in PwMS at different disease stages and compared these with reference values from sex and age matched healthy controls [6–8]. Such a
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Corresponding author at: Section of Sport Science, Dep. of Public Health, Aarhus University, Dalgas Avenue 4, 8000 Aarhus C, Denmark. E-mail address: [email protected] (U. Dalgas).
http://dx.doi.org/10.1016/j.jns.2017.09.049 Received 20 June 2017; Received in revised form 6 September 2017; Accepted 30 September 2017 Available online 03 October 2017 0022-510X/ © 2017 Elsevier B.V. All rights reserved.
Journal of the Neurological Sciences 382 (2017) 131–136
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walking speed (m/s). The 2MWT represented either the distance covered after the first 2 min in the 6MWT or the distance walked in an independent 2MWT, which has been shown not to influence the result of the test [18]. The transformed MSWS-12 score (0 −100) was used as a patient-reported measure of the impact of MS on walking [26].
impairment, and cognitive impairment in PwMS [5]. However, previous studies reporting on the relationship between the EDSS score and various walking measures, in terms of the timed 25 foot walk test (T25FWT) [13–17], the 2 min walk test (2MWT) [18], the 6 min walk test (6MWT) [7,16–22], and the 12-item MS walking scale (MSWS-12) [7,16,17,23–26], show heterogeneous results ranging from no to strong correlations. Only few studies [16,17] simultaneously examined the relation between the EDSS score and multiple walking measures, and these studies suggest that the objective 6MWT is most closely related to the EDSS score. However, these studies are either preliminary [16], or are limited in the range of included EDSS scores [17]. Therefore, the relations between different walking measures and the EDSS score still remain to be investigated in a large and representative sample of pwMS. A better understanding of the relationship between EDSS score and different walking measures as well as the magnitude of walking impairments, can help clinicians in the assessment of walking capacity and in optimizing rehabilitation interventions for pwMS. Consequently, the purposes of this study were 1) to quantify the magnitude of reduction in walking speed and perceived impact of MS on walking at various EDSS levels by applying predicted reference values from healthy persons and 2) to examine to which extent several walking measures, including performed and perceived outcome measures, are related to the EDSS. We hypothesized that 1) walking impairment would be present already at disease onset, and that walking impairments are more pronounced at higher EDSS scores, and 2) that the 6MWT and MSWS-12 would relate better to the EDSS than the T25FWT.
2.3. Data processing The subjects were classified as having mild MS if they had an ≤4.0 and moderate MS if they had an EDSS ≥ 4.5 and ≤6.5. This criterion has been used in previous studies as it discriminates relatively mild ambulatory dysfunction (self-sufficient and able to walk without aid for 500 m) and moderate to severe ambulatory dysfunctions [9,27,29,31]. The percent of predicted walking speed in the 2MWT and 6MWT compared to healthy subjects was calculated based on reference values for healthy persons with formulas published by Selman et al. [32] (2MWTpredicted = 252.583 − 1.165 ∗ age + 19.987 ∗ gender, where gender = 1 if male subject and gender = 0 if female subject) and Enright et al. [33] (6MWTpredictedmen = 7.57 ∗ height, cm − 5.02 ∗ age − 1.76 ∗ weight, kg − 309 m; 6MWTpredictedwomen = 2.11 ∗ height,cm − 2.29 ∗ weight, kg − 5.78 ∗ age + 667 m). No good evidence-based reference values could be found for the T25FWT. Subjects were excluded from the analyses if they 1) had an EDSS score below 1 or over 6.5 due to small sample sizes in these subgroups (n = 1 and n = 4, respectively), 2) took > 30 s to complete the T25FWT (n = 12), 3) or if data on crucial variables were missing (EDSS: n = 1, height: n = 3, 6MWT: n = 4, MSWS-12: n = 4). From the total sample of 503 subjects this left 474 subjects for analyses.
2. Methods 2.4. Statistical analysis The current study presents data from two cross-sectional multicentre studies performed within the European Rehabilitation in MS network for best practice and research in MS rehabilitation (www. eurims.org). Detailed description of methodology and study design has been reported elsewhere [27–29] and is only summarized below.
The statistical analysis was performed in Stata version 11.2 and used a 5% limit of significance. The variables that were modelled as continuous were assumed to follow a normal distribution and subsequently the characteristics of the two MS-subgroups were compared by Student's unpaired t-test or Welch's t-test where appropriate for continuous variables and the Chi-squared test for categorical variables. To determine which walking measures had the strongest linear relations to the EDSS score at different disability levels, Pearson correlation coefficients were calculated between EDSS scores and walking measure variables. Pitman's test, which calculates the Pearson correlation between the sum and the difference of the residuals from two linear regressions, was applied in order to determine the ranking of correlations. Linear regressions between walking variables and EDSS scores were used to determine the relationship between level of EDSS scores and walking measure outcomes. Post-hoc, we analyzed which items in the MSWS-12 that were driving the correlations between this walking measure and the EDSS by calculating Pearson correlation coefficients between the individual items in the MSWS-12 questionnaire and the EDSS.
2.1. Subjects A convenience sample of 503 MS patients was recruited at inpatient and outpatient rehabilitation and research centers in Europe (n = 18), Israel (n = 1) and the USA (n = 1). The included subjects had a definite diagnosis of MS and an EDSS ≤ 6.5. The subjects had not experienced an exacerbation in the month prior to testing, and had no other medical conditions that interfered with walking. All participants gave written informed consent. The study was conducted in accordance with the declaration of Helsinki and approved by the Human Ethics Committee of the leading University of Hasselt as well as by the local ethical committees of the participating centers. 2.2. Experimental design, outcome measures and procedure
3. Results
A cross-sectional multicentre study design was applied. The EDSS score was collected by neurologists from the participating sites [12]. The outcome measures in this study were short (T25FWT) and long (2MWT, 6MWT) walking capacity tests, patient reported walking ability (MSWS-12) and disability level (EDSS). Subjects were permitted to use habitual assistive devices during testing. All sites utilized the same standardized instruction booklet. The MSFC guidelines [30] were applied for the T25FWT, meaning that subjects were instructed ‘to walk at fastest but safe speed’ over a 25 ft/7.62 m course using a static start. Subjects also completed the 2MWT and 6MWT ‘at fastest speed’. They were instructed to cover as much distance as possible, albeit safely, according to the script of Goldman et al. [7]. Participants walked back and forth in a 30-metre hallway turning around cones at each end, and were notified, without further encouragement, about each expired minute. Total distance (m) was registered, and was also expressed as
3.1. Patient characteristics The characteristics of the total, mild and moderate MS groups are presented in Table 1. The persons with moderate MS were older, had longer disease duration, and had more primary progressive (p < 0.001) and secondary progressive patients (p < 0.001) when compared to those with mild MS. 3.2. Walking capacity according to EDSS Walking speed was reduced to 61.3 ± 25.4% and 58.5 ± 25.8% of the predicted walking speed of healthy persons, in the total sample of pwMS in the 2MWT and 6MWT, respectively (see Table 1). The 132
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Table 1 Patient characteristics for the total sample, and subgroups with mild or moderate MS (EDSS 1.0–4.0 or 4.5–6.5, respectively).
Age (years) Sex (M/F) Height (cm) EDSS (a.u.) Type of MS (RR/SP/ PP) Disease duration (years) T25FWT (s) T25FWT (m/ s) 2MWT (m) 2MWT (m/s) 2MWT% (%) 6MWT (m) 6MWT (m/s) 6MWT% (%) MSWS-12 (a.u.)
Total sample N = 474
Mild MS N = 200
Moderate MS N = 274
P value (mild vs. moderate)
49.0 ± 10.7 183/291 169.6 ± 8.9 4.5 ± 1.6 250/152/72
45.6 ± 9.9 80/120 170.5 ± 8.1 2.9 ± 1.0 142/36/22
51.5 ± 10.6 103/171 169.0 ± 9.3 5.7 ± 0.7 108/116/50
P < 0.0001 P = 0.6 P = 0.06 P < 0.0001 P < 0.001
11.4 ± 7.9
8.4 ± 6.5
13.6 ± 8.2
P < 0.0001
7.87 ± 4.5 1.21 ± 0.50
5.21 ± 1.9 1.59 ± 0.40
9.82 ± 4.9 0.93 ± 0.36
P < 0.0001 P < 0.0001
125 ± 53 1.04 ± 0.44 61.3 ± 25.4 353 ± 159 0.98 ± 0.44 58.5 ± 25.8 55.8 ± 26.1
167 ± 40 1.39 ± 0.33 80.6 ± 19.4 482 ± 116 1.34 ± 0.32 78.2 ± 20.2 40.1 ± 25.3
94 ± 39 0.78 ± 0.32 47.2 ± 19.2 259 ± 114 0.72 ± 0.32 44.2 ± 19.1 67.4 ± 20.0
P P P P P P P
< < < < < < <
0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001
Data are mean ± standard deviation (SD) or numbers. M = Male, F = Female, a.u. = Arbitrary units, RR = Relapsing remitting MS, SP = Secondary progressive MS, PP = Primary progressive MS, EDSS = Expanded disability status scale, T25FWT = Timed 25 foot walk test, 2MWT = Two minute walk test, 2MWT% = Percent of expected walking speed in the 2MWT compared to healthy controls, 6MWT = Six minute walk test, 6MWT% = Percent of expected walking speed in 6MWT compared to healthy controls, and MSWS-12 = The 12-item MS walking scale.
moderate MS group was significantly more impaired than the mild MS group on all walking measures, but walking impairments were present already at low EDSS scores, as depicted in Fig. 1. Fig. 1A presents outcomes of walking measures according to the continouos EDSS scores in the total sample. The overall pattern was that higher EDSS scores correspond to worse outcomes in all walking measures. There were some small random deviations of this pattern, especially in the 1.0–2.0 range of the EDSS.
Fig. 1. Performed and perceived walking measures according to EDSS, and walking capacity test performance normative to reference values. (A) Mean values of walking speed ((T25FWT (m/s)), (2MWT (m/s)), (6MWT (m/s))) and impact of MS on walking (MSWS-12 (a.u.)) depicted as a function of disability (EDSS score (a.u.)) in the total MS sample. (B) Mean values of percent of expected walking speed ((2MWT% (%)), (6MWT% (%))) depicted as a function of disability (EDSS score (a.u.)) in the total MS sample.
4. Discussion
3.3. Relation between walking measures and the EDSS
The present study shows that walking speed on average was reduced by 40% in PwMS when compared to healthy persons, and importantly, a marked reduction was noted already at low EDSS levels. The 6MWT and 2MWT were the walking measures that showed the strongest relationship to the EDSS across the total sample. However, the MSWS-12 interestingly showed the strongest relationship to the EDSS in the mild MS subgroup.
Pearson correlation coefficients between the EDSS and different walking measures and the results of the Pitman analysis of residuals are reported in Table 2. The EDSS correlations to walking measures ranged from weak to strong, and all correlations were significant (p < 0.0001). In the total MS sample the EDSS score showed the strongest relationship to the 2MWT and 6MWT, while EDSS had the strongest relationship with MSWS-12 in the mild MS group, and to the 2MWT in the moderate MS subgroup. Additionally, Table 3 shows the coefficients of the linear regression analysis' on how EDSS level is related to the different walking measures.
4.1. Walking capacity according to the EDSS Higher EDSS scores were associated with more pronounced walking impairments and walking capacity was already impaired early in the disease stage, as EDSS scores of 1–4 were associated with reductions from 4 to 35% in walking speed in the 2MWT and 6MWT compared to reference values from healthy persons (see Fig. 1B). It should be noted, that comparison with predicted reference values should be interpreted with caution, as such predictive equations are associated with limitations [33]. Our procedure for the 6MWT was the same as in the original study by Enright et al., but with minor modifications in instructions and encouragement. We used the first 2 min of the 6MWT as a measure of the 2MWT, but this has been shown not to influence the result [18]. Taken together, we feel confident that the formulas are applicable in our setting. In support of the present study results, two small-scale
3.4. Exploratory analyses Table 4 presents Pearson correlation coefficients between the individual items of the MSWS-12 and the EDSS. In the total sample, only minor differences were seen between correlations of the EDSS and the different items (approximating 0,5) except for item number 9 (r = 0,73) referring to the need for support when walking outdoors. The relation between the items and the EDSS was obviously lower in the moderate (approximating 0,2) compared to mild MS subgroup, with the relation even being non-significant for items 2 and 5 referring to ability to running and balance. 133
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Table 2 Hierarchic presentation of Pearson correlation coefficients between walking measures and the EDSS score for the total, mild and moderate MS groups. EDSS 1.0–6.5 n = 474
EDSS 1.0–4.0 n = 200
EDSS 4.5–6.5 n = 274
Measure
r
Pitman
Measure
r
Pitman
Measure
r
Pitman
6MWT 2MWT 2MWT% T25FWT 6MWT% MSWS-12
−0.76 −0.76 −0.73 −0.72 −0.71 0.64
A, B, C, D A, B, C, D A, B A A
MSWS-12 6MWT 2MWT 2MWT% T25FWT 6MWT%
0.56 − 0.46 − 0.45 − 0.40 − 0.39 − 0.35
B, C, D, E B, C, D B, D
2MWT 2MWT% T25FWT 6MWT 6MWT% MSWS-12
− 0.50 − 0.50 − 0.47 − 0.46 − 0.42 0.29
A, B, F A, B, F A A, B A
All pearson correlations are significant (p < 0.0001). EDSS = Expanded disability status scale, T25FWT = Timed 25 foot walk test, 2MWT = Two minute walk test, 2MWT% = Percent of expected walking speed in the 2MWT, 6MWT = Six minute walk test, 6MWT% = Percent of expected walking speed in 6MWT and MSWS-12 = The 12-item MS walking scale. Pitman analysis: A: Significantly better related to EDSS-Score than MSWS-12, p ≤ 0.05. B: Significantly better related to EDSS-Score than 6MWT%, p ≤ 0.05. C: Significantly better related to EDSS-Score than T25FWT, p ≤ 0.05. D: Significantly better related to EDSS-Score than 2MWT%, p ≤ 0.05. E: Significantly better related to EDSS-Score than 2MWT, p ≤ 0.05. F: Significantly better related to EDSS-Score than 6MWT, p ≤ 0.05.
ambulatory”. This suggests the need for early rehabilitation interventions aiming to improve walking capacity. The slopes of the linear regressions from the present study (table 3) indicate that a person with a 1 point higher EDSS score walks 0.22 m/s slower in the T25FWT, 24.8 and 74.7 m shorter in the 2MWT and 6MWT respectively, and have a 10.3 points higher score in the MSWS12. Baert et al. [29] reported clinically meaningful changes for pwMS of − 10.4 for the MSWS-12, 9.6 m for the 2MWT, and 21.6 m for the 6MWT. When combining the results of the present cross-sectional study and those reported in Baert et al., 0.5 point increase in the EDSS of our large MS cohort may represent a clinically meaningful change in walking distance reflected by the 2MWT and 6MWT and a 1 point increase in the EDSS may represent a clinically meaningful change in walking ability reflected by the MSWS-12.
Table 3 Slopes of the linear regression analysis' between EDSS and walking measures for the total sample. EDSS 1.0–6.5 (n = 474) Measure
Slope (95% CI)
6MWT (m) 6MWT% 2MWT (m) 2MWT% T25FWT (m/s) MSWS-12
− 74.7 [− 80.4; − 11.2 [− 12.3; − 24.8 [− 26.7; − 11.4 [− 12.4; − 0.22 [− 0.24; 10.3 [9.1; 11.4]
P-value − 69.0] − 10.2] − 22.9] − 10.4] − 0.20]
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
Data are given as slope [95% confidence interval]. EDSS = Expanded disability status scale, 6MWT = Six minute walk test, 6MWT% = Percent of expected walking speed in the 6MWT, 2MWT = Two minute walk test, 2MWT% = Percent of expected walking speed in 2MWT, T25FWT = Timed 25 foot walk test and MSWS-12 = The 12-item MS walking scale.
4.2. Walking speed in long vs. short walking tests in relation to the EDSS In the total sample, walking speed in the 6MWT and 2MWT was slightly better related to the EDSS score (r = − 0.76) than walking speed in the T25FWT (r = −0.72). The same pattern, but with a more pronounced difference, was observed in the mild MS subgroup. In comparison, previous small scale studies have reported a correlation coefficient of 0.60 and −0.70 between the EDSS score and the T25FWT and 6MWT [16], respectively, and the same pattern was observed by Learmonth et al. [17] who reported a correlation coefficient of 0.73 and
studies report reductions in walking speed during the 6MWT of 25–33%, when persons with predominantly mild MS were compared to healthy persons [19,34]. This reduction is considered as meaningful, and related to daily walking activity [31]. The EDSS characterizes PwMS as “fully ambulatory” at EDSS levels < 4, but the observed reduction in walking capacity in the early disease stage of the present study indicate that persons with EDSS < 4 not necessarily are “fully
Table 4 Pearson correlation coefficients between items from the MSWS-12 and the EDSS score. MSWS-12
Question Question Question Question Question Question Question Question Question Question Question Question
1: walking 2: running 3: stair climb 4: standing 5: balance 6: walking distance 7: effort 8: indoor support 9: outdoor support 10: walking speed 11: uniformity 12: concentration
EDSS 1–6,5 (n = 394)
EDSS 1–4 (n = 144)
EDSS 4,5–6,5 (n = 250)
r
P
r
P
r
P
0.51 0.56 0.51 0.47 0.50 0.45 0.44 0.57 0.73 0.51 0.50 0.47
< 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001
0.44 0.61 0.57 0.47 0.50 0.48 0.45 0.31 0.37 0.44 0.49 0.52
< 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001
0.14 0.07 0.21 0.18 0.10 0.13 0.20 0.41 0.46 0.15 0.22 0.16
0.03 0.27 0.001 0.004 0.12 0.04 0.002 < 0.0001 < 0.0001 0.017 0.0004 0.01
Each question from the MSWS-12 has been given a keyword in relation to the subject of the question. EDSS = Expanded disability status scale, and MSWS-12 = The 12-item MS walking scale.
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− 0.81 between the EDSS score and the T25FWT and 6MWT, respectively (the direction of the correlation coefficient is determined by the way walking capacity is expressed in terms of walking time or walking speed). The difference in correlation coefficients between the EDSS score and 6MWT and T25FWT in these studies seems to be slightly overestimated compared to the finding in our large sample size. However, the results from our study confirms the finding that the EDSS score correlates more closely with the 2MWT and 6MWT than with the T25FWT. The fact that the EDSS score partly is defined on a evaluation of walking distance, is a highly likely explaination of this observation. The 2MWT furthermore seems to be more sensitive to changes in disease progression than the T25FWT, as the walking speed is reduced relatively more with increasing EDSS. Some concern could be raised due to the fact that the absolute walking speed in the 2MWT falls just below the one observed in the 6MWT, but as it is depicted in Fig. 1A no difference is observed in the walking speed relative to reference values. Taken together, we do not suspect significant instabilities in this measurement. Lastly, longer walking tests seem to have a lower ceiling effect than the T25FWT, and might be more responsive [35].
at the same time it is less intense and time-consuming for both patients and clinicians. It is furthermore noteworthy, that early in disease stages, the MSWS-12 showed the strongest relationship to EDSS by identifying impairments more gradually than the objective walking capacity tests. This suggests that the MSWS-12 is preferable when assessing walking in pwMS with a low disability status. When applying predicted reference data, walking speed can be compared to walking speed in healthy persons, and thereby provide an expression of the severity of walking impairment in PwMS. Such normalized data show that walking impairments are present already at an early stage of MS. This suggests that rehabilatory efforts aiming at improving and/or preserving walking capacity is of great importance already at an early timepoint of the disease course. Age-sex matched reference data for the T25FWT is warranted. 5. Conclusion PwMS walk on average approximately 40% slower than healthy sex and age matched persons, with reductions in walking speed being present already at low EDSS levels. In a clinical view this suggest the importance of early rehabilatory efforts. The EDSS score is most strongly related to walking speed in the 2MWT and 6MWT, but in the early disease stages the MSWS-12 captured impairments more gradually and showed the strongest relation to EDSS.
4.3. Walking speed vs. MSWS-12 in relation to the EDSS score Walking speed in the 6MWT, 2MWT and T25FWT was better related to the EDSS score in the total and moderate MS sample than the MSWS12 score, while the MSWS-12 score was better related to the EDSS score in the mild MS sample than walking speed in the 6MWT, 2MWT and T25FWT. Previous studies have found moderate to strong correlation coefficients between the EDSS score and the MSWS-12 (0.65 ≤ r ≤ 0.84 (7,16,17,23–26)). Some [7,17] but not all [16] previous studies support the finding from the present study, where EDSS, in general, shows stronger correlation to objective walking tests than to the MSWS-12. Regarding the EDSS relation to the MSWS-12 in mild vs. moderate MS, Motl et al. [23] reported, in accordance to our results, a stronger correlation coefficient between the EDSS score and the MSWS12 score in mild vs. moderate MS (r = 0.71 vs. 0.33). In the present study exploratory analyses of the relations between the questions comprising the MSWS-12 and the EDSS score were performed to better understand these differences. In a subset of 394 patients from the MS sample (all individual questions available in the database), it was found that question 8 (“Made it necessary for you to use support when walking indoors?”) and especially question 9 (“Made it necessary for you to use support when walking outdoors?”) were the primary drivers of the EDSS-MSWS-12 correlation in the total MS sample (r = 0.57 and r = 0.73, respectively) and in the moderate MS group (r = 0.41 and r = 0.46, respectively). In the mild MS group, question 2 (“Limited your ability to run?”) and 3 (“Limited your ability to climb up and down stairs?”) (r = 0.61 and r = 0.57, respectively) showed the strongest relationship. In the moderate subgroup, item number 2 regarding running, and item number 5 regarding balance were not significantly related with the EDSS perhaps due to floor effects in perceived impact. These observations suggest that in the total and moderate MS sample the MSWS-12 probably captures aspects related to walking that are not captured by the EDSS score. Conclusively, in mild MS the MSWS-12 may detect (neurological) impairments affecting performance during running and walking on stairs that is also captured by the EDSS but not by objective walking tests.
Conflicts of interest DLC, MR, ES and IB report no disclosures. PF has received honoraria from serving on scientific advisory boards of Biogen Idec. UD has received research support, travel grants and/or teaching honorary from Biogen Idec, Merck Serono, Novartis, Bayer Schering and Sanofi Aventis as well as honoraria from serving on a scientific advisory board of Biogen Idec and Genzyme. Funding Coordination of this study was partially funded via a unrestricted educational grant from Novartis Pharma AG to the European RIMS network for best research and practice in MS rehabilitation. See www. euRIMS.org. Author contribution Conception or design of the work: DLC, PF, UD. Data collection: UD, PF, IB. Data-analysis: DLC, MR, PF, IB, UD. Interpretation of data: All. Drafting the work and/or revising it: All. Final approval of the version to be published: All. Agreement to be accountable for all aspects of the work: All. Acknowledgements The RIMS network (www.eurims.org) is acknowledged for facilitating inter European consultation and testing. All data-collecting centers REVAL Rehabilitation Research Center, Hasselt; Rehabilitation and MS Center Overpelt, Overpelt; National MS Center, Melsbroek; Centre Neurologique et de Réadaptation Fonctionelle, Fraiture-en-Condroz; Charles University Prague and General Faculty Hospital, Prague; MS Centers of Haslev and Ry, Haslev and Ry; West-Tallinn Central Hospital, Tallinn; Masku Neurological Rehabilitation Center, Masku; School of Health Professions, Plymouth University, Plymouth, United Kingdom; Norwegian Multiple Sclerosis Competence Center, Department of Neurology, and Department of Physiotherapy, Haukeland University Hospital, Bergen, Norway; Poole hospital NHS foundation trust, Dorset, United Kingdom; Eugenia Epalza
4.4. Implications for clinical practice and future research In this large scale study the 2MWT and the 6MWT were the walking measures that provided the best reflection of disease severity in terms of the EDSS score. Differences between 2MWT and 6MWT, in relation to EDSS score, were always small. Despite the fact that the 6MWT is the most common long walking test [17], this suggests that the 2MWT preferably should be included in a core set of walking capacity tests. The 2MWT is just as closely related to the EDSS score as the 6MWT, and 135
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[17] Y.C. Learmonth, R.W. Motl, B.M. Sandroff, J.H. Pula, D. Cadavid, Validation of patient determined disease steps (PDDS) scale scores in persons with multiple sclerosis, BMC Neurol. 13 (1) (Apr 25, 2013) 37. [18] D. Gijbels, B.O. Eijnde, P. Feys, Comparison of the 2- and 6-minute walk test in multiple sclerosis, Mult. Scler. 17 (10) (Oct 2011) 1269–1272. [19] M. Bosnak-Guclu, A.G. Gunduz, B. Nazliel, C. Irkec, Comparison of functional exercise capacity, pulmonary function and respiratory muscle strength in patients with multiple sclerosis with different disability levels and healthy controls, J. Rehabil. Med. 44 (1) (Jan 2012) 80–86. [20] S. Savci, D. Inal-Ince, H. Arikan, A. Guclu-Gunduz, N. Cetisli-Korkmaz, K. Armutlu, et al., Six-minute walk distance as a measure of functional exercise capacity in multiple sclerosis, Disabil. Rehabil. 27 (22) (Nov 30, 2005) 1365–1371. [21] J.L. Wetzel, D.K. Fry, L.A. Pfalzer, Six-minute walk test for persons with mild or moderate disability from multiple sclerosis: performance and explanatory factors, Physiother. Can. 63 (2) (Spring 2011) 166–180. [22] D. Hansen, P. Feys, I. Wens, B.O. Eijnde, Is walking capacity in subjects with multiple sclerosis primarily related to muscle oxidative capacity or maximal muscle strength? A pilot study, Mult. Scler. Int. 2014 (2014) 759030. [23] R.W. Motl, E.M. Snook, Confirmation and extension of the validity of the Multiple Sclerosis Walking Scale-12 (MSWS-12), J. Neurol. Sci. 268 (1–2) (May 15, 2008) 69–73. [24] C. McGuigan, M. Hutchinson, Confirming the validity and responsiveness of the Multiple Sclerosis Walking Scale-12 (MSWS-12), Neurology 62 (11) (Jun 8, 2004) 2103–2105. [25] R.W. Motl, D. Cadavid, B.M. Sandroff, L.A. Pilutti, J.H. Pula, R.H. Benedict, Cognitive processing speed has minimal influence on the construct validity of Multiple Sclerosis Walking Scale-12 scores, J. Neurol. Sci. 335 (1–2) (Dec 15, 2013) 169–173. [26] J.C. Hobart, A. Riazi, D.L. Lamping, R. Fitzpatrick, A.J. Thompson, Measuring the impact of MS on walking ability: the 12-Item MS Walking Scale (MSWS-12), Neurology 60 (1) (Jan 14, 2003) 31–36. [27] D. Gijbels, U. Dalgas, A. Romberg, V. de Groot, F. Bethoux, C. Vaney, et al., Which walking capacity tests to use in multiple sclerosis? A multicentre study providing the basis for a core set, Mult. Scler. 18 (3) (Mar 2012) 364–371. [28] P. Feys, D. Gijbels, A. Romberg, C. Santoyo, B. Gebara, B.M. de Noordhout, et al., Effect of time of day on walking capacity and self-reported fatigue in persons with multiple sclerosis: a multi-center trial, Mult. Scler. 18 (3) (Mar 2012) 351–357. [29] I. Baert, J. Freeman, T. Smedal, U. Dalgas, A. Romberg, A. Kalron, et al., Responsiveness and clinically meaningful improvement, according to disability level, of five walking measures after rehabilitation in multiple sclerosis: a European multicenter study, Neurorehabil. Neural Repair (Feb 6, 2014). [30] J.S. Fischer, R.A. Rudick, G.R. Cutter, S.C. Reingold, The Multiple Sclerosis Functional Composite Measure (MSFC): an integrated approach to MS clinical outcome assessment. National MS Society Clinical Outcomes Assessment Task Force, Mult. Scler. 5 (4) (Aug 1999) 244–250. [31] D. Gijbels, G. Alders, E. Van Hoof, C. Charlier, M. Roelants, T. Broekmans, et al., Predicting habitual walking performance in multiple sclerosis: relevance of capacity and self-report measures, Mult. Scler. 16 (5) (May 2010) 618–626. [32] J.P. Selman, A.A. de Camargo, J. Santos, F.C. Lanza, S. Dal Corso, Reference equation for the two-minute walk test in adults and the elderly, Respir. Care (Aug 6, 2013). [33] P.L. Enright, D.L. Sherrill, Reference equations for the six-minute walk in healthy adults, Am. J. Respir. Crit. Care Med. 158 (5 Pt 1) (Nov 1998) 1384–1387. [34] A. Chetta, A. Rampello, E. Marangio, S. Merlini, F. Dazzi, M. Aiello, et al., Cardiorespiratory response to walk in multiple sclerosis patients, Respir. Med. 98 (6) (Jun 2004) 522–529. [35] R. Phan-Ba, A. Pace, P. Calay, P. Grodent, F. Douchamps, R. Hyde, et al., Comparison of the timed 25-foot and the 100-meter walk as performance measures in multiple sclerosis, Neurorehabil. Neural Repair 25 (7) (Sep 2011) 672–679.
Rehabilitation Center, Bilbao, Spain; Helsinki MS-Neuvola, Finland; MS Center Hakadal AS, Norway; Center for MS, University Medical Center Ljubljana, Slovenia; Kongsgaarden Physiotherapy AS/Nordland Hospital Trust, Bodø, Norway; Hospital de Dia de Barcelona, CEMCat, Spain; Sheba Medical Center, Tel-Hashomer, Israel and The Mellen Center for MS Treatment and Research, Cleveland, USA are thanked for their effort. Domien Gijbels, who coordinated part of the data collection, is acknowledged for his effort during the study. The Research Foundation Flanders is thanked for their Research Grant to PF, the Belgian Charcot Foundation for Equipment Grants. Bo Martin Bibby is thanked for statistical assistance. References [1] H. Beckerman, J.C. Kempen, D.L. Knol, C.H. Polman, G.J. Lankhorst, V. de Groot, The first 10 years with multiple sclerosis: the longitudinal course of daily functioning, J. Rehabil. Med. 45 (1) (Jan 2013) 68–75. [2] N.G. Larocca, Impact of walking impairment in multiple sclerosis: perspectives of patients and care partners, Patient 4 (3) (2011) 189–201. [3] C. Heesen, J. Bohm, C. Reich, J. Kasper, M. Goebel, S.M. Gold, Patient perception of bodily functions in multiple sclerosis: gait and visual function are the most valuable, Mult. Scler. 14 (7) (Aug 2008) 988–991. [4] C.G. Kohn, W.L. Baker, M.F. Sidovar, C.I. Coleman, Walking speed and health-related quality of life in multiple sclerosis, Patient (Sep 28, 2013). [5] F. Bethoux, Gait disorders in multiple sclerosis, Continuum (Minneap Minn) 19 (Aug 2013) 1007–1022 (4 Multiple Sclerosis). [6] J.M. Burschka, P.M. Keune, U. Menge, U. Hofstadt-van Oy, P. Oschmann, O. Hoos, An exploration of impaired walking dynamics and fatigue in multiple sclerosis, BMC Neurol. 12 (Dec 27, 2012) 161-2377-12-161. [7] M.D. Goldman, R.A. Marrie, J.A. Cohen, Evaluation of the six-minute walk in multiple sclerosis subjects and healthy controls, Mult. Scler. 14 (3) (Apr 2008) 383–390. [8] M.L. van der Linden, S.M. Scott, J.E. Hooper, P. Cowan, T.H. Mercer, Gait kinematics of people with multiple sclerosis and the acute application of functional electrical stimulation, Gait Posture 39 (4) (Apr 2014) 1092–1096. [9] A. Kalron, A. Achiron, Z. Dvir, Muscular and gait abnormalities in persons with early onset multiple sclerosis, J. Neurol. Phys. Ther. 35 (4) (Dec 2011) 164–169. [10] K. Novotna, L. Sobisek, D. Horakova, E. Havrdova, J. Lizrova Preiningerova, Quantification of gait abnormalities in healthy-looking multiple sclerosis patients (with expanded disability status scale 0–1.5), Eur. Neurol. 76 (3–4) (2016) 99–104. [11] C.L. Martin, B.A. Phillips, T.J. Kilpatrick, H. Butzkueven, N. Tubridy, E. McDonald, et al., Gait and balance impairment in early multiple sclerosis in the absence of clinical disability, Mult. Scler. 12 (5) (Oct 2006) 620–628. [12] J.F. Kurtzke, Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS), Neurology 33 (11) (Nov 1983) 1444–1452. [13] S.D. Newsome, J.I. Wang, J.Y. Kang, P.A. Calabresi, K.M. Zackowski, Quantitative measures detect sensory and motor impairments in multiple sclerosis, J. Neurol. Sci. 305 (1–2) (Jun 15, 2011) 103–111. [14] C.H. Polman, R.A. Rudick, The multiple sclerosis functional composite: a clinically meaningful measure of disability, Neurology 74 (Suppl. 3) (Apr 27, 2010) S8–15. [15] J.A. Cohen, G.R. Cutter, J.S. Fischer, A.D. Goodman, F.R. Heidenreich, A.J. Jak, et al., Use of the multiple sclerosis functional composite as an outcome measure in a phase 3 clinical trial, Arch. Neurol. 58 (6) (Jun 2001) 961–967. [16] J.T. Cavanaugh, V.O. Gappmaier, L.E. Dibble, E. Gappmaier, Ambulatory activity in individuals with multiple sclerosis, J. Neurol. Phys. Ther. 35 (1) (Mar 2011) 26–33.
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Performed and perceived walking ability in relation to the Expanded Disability Status Scale in persons with multiple sclerosis
MARK
D. Langeskov-Christensena, P. Feysb, I. Baertb, M. Riemenschneidera, E. Stenagerc,d, U. Dalgasa,⁎ a
Section of Sport Science, Department of Public Health, Aarhus University, Aarhus, Denmark REVAL, BIOMED-Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium c Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark d MS-Clinic of Southern Jutland (Sønderborg, Esbjerg, Kolding), Department of Neurology, Sønderborg, Denmark b
A R T I C L E I N F O
A B S T R A C T
Keywords: Multiple sclerosis EDSS Walking impairment Walking measures 6MWT MSWS-12
Background: The severity of walking impairment in persons with multiple sclerosis (pwMS) at different levels on the expanded disability status scale (EDSS) is unclear. Furthermore, it is unclear if the EDSS is differently related to performed- and perceived walking capacity tests. Aims: To quantify walking impairment and perceived impact of MS on walking according to EDSS scores and to examine the relations between these parameters in pwMS. Methods: EDSS was collected by neurologists and walking was assessed by the timed 25 ft walk test (T25FWT), two minute walk test (2MWT), six minute walk test (6MWT) and the 12-item MS walking scale (MSWS-12) in 474 PwMS with mild (EDSS 1–4: n = 200) to moderate (EDSS 4.5–6.5: n = 274) MS. Magnitude of walking impairment was calculated and related to EDSS. Results: Compared to predicted values in healthy controls, walking speed was reduced by 41.5 ± 25.8% in the 6MWT for the total MS group and by 21.8 ± 20.2% and 55.8 ± 19.1% in the mild and moderate MS subgroups, respectively. The EDSS score showed the strongest relationship to the 2MWT and the 6MWT in the total MS group (r = −0.76, p < 0.0001), to the MSWS-12 score in the mild MS group (r = 0.56, p < 0.0001), and to the 2MWT in the moderate MS group (r = − 0.50, p < 0.0001). Conclusion: In pwMS (EDSS scores 1–6.5), walking speed is on average reduced by ~40% when compared to predicted values in healthy controls, and impairments are already present at early disease stages, suggesting early initiation of rehabilitation. The 2MWT and 6MWT show the strongest relationship to EDSS, but the MSWS12 identify impairments more gradually at low EDSS scores.
1. Introduction
quantification can give insight to the actual reduction in walking capacity throughout the different disease stages, and this has to be investigated and confirmed by a large sample study [6,7]. Furthermore, it is unclear to which extent walking speed is compromised at low disability levels, although changes in muscle coordination and gait kinematics has been documented [9–11]. This could help to clarify the necessity for early rehabilitation interventions aiming at maintaining walking abilities. The expanded disability status scale (EDSS) of Kurtzke [12] is the most widely used instrument to describe the clinical severity in MS. The EDSS score is based on neurological examination and reflects the functional system scores (pyramidal, cerebellar, brain stem, sensory, bowel and bladder, visual, cerebral and other), which may be related to walking capacity, since walking performance is affected by loss of muscle strength, cerebellar damage, ataxia, sensory loss, visual
Multiple sclerosis (MS) is a demyelinating, inflammatory and neurodegenerative disorder of the central nervous system (CNS) that is characterized by progressive neurologic impairment [1]. Ambulatory dysfunction is a common and well-recognized feature of the disease [2] with MS patients perceiving walking as the most valued bodily function independent of disease duration [3]. In persons with MS (pwMS) decreased walking capacity relates to reduced health-related quality of life [4]. Compared to healthy persons, it has been shown that most pwMS walk slower during longer walking tests (e.g. 6 minute walk test, 6MWT) [5–7]. However, only few and small studies have precisely quantified the magnitude of reduced walking speed or distance in PwMS at different disease stages and compared these with reference values from sex and age matched healthy controls [6–8]. Such a
⁎
Corresponding author at: Section of Sport Science, Dep. of Public Health, Aarhus University, Dalgas Avenue 4, 8000 Aarhus C, Denmark. E-mail address: [email protected] (U. Dalgas).
http://dx.doi.org/10.1016/j.jns.2017.09.049 Received 20 June 2017; Received in revised form 6 September 2017; Accepted 30 September 2017 Available online 03 October 2017 0022-510X/ © 2017 Elsevier B.V. All rights reserved.
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walking speed (m/s). The 2MWT represented either the distance covered after the first 2 min in the 6MWT or the distance walked in an independent 2MWT, which has been shown not to influence the result of the test [18]. The transformed MSWS-12 score (0 −100) was used as a patient-reported measure of the impact of MS on walking [26].
impairment, and cognitive impairment in PwMS [5]. However, previous studies reporting on the relationship between the EDSS score and various walking measures, in terms of the timed 25 foot walk test (T25FWT) [13–17], the 2 min walk test (2MWT) [18], the 6 min walk test (6MWT) [7,16–22], and the 12-item MS walking scale (MSWS-12) [7,16,17,23–26], show heterogeneous results ranging from no to strong correlations. Only few studies [16,17] simultaneously examined the relation between the EDSS score and multiple walking measures, and these studies suggest that the objective 6MWT is most closely related to the EDSS score. However, these studies are either preliminary [16], or are limited in the range of included EDSS scores [17]. Therefore, the relations between different walking measures and the EDSS score still remain to be investigated in a large and representative sample of pwMS. A better understanding of the relationship between EDSS score and different walking measures as well as the magnitude of walking impairments, can help clinicians in the assessment of walking capacity and in optimizing rehabilitation interventions for pwMS. Consequently, the purposes of this study were 1) to quantify the magnitude of reduction in walking speed and perceived impact of MS on walking at various EDSS levels by applying predicted reference values from healthy persons and 2) to examine to which extent several walking measures, including performed and perceived outcome measures, are related to the EDSS. We hypothesized that 1) walking impairment would be present already at disease onset, and that walking impairments are more pronounced at higher EDSS scores, and 2) that the 6MWT and MSWS-12 would relate better to the EDSS than the T25FWT.
2.3. Data processing The subjects were classified as having mild MS if they had an ≤4.0 and moderate MS if they had an EDSS ≥ 4.5 and ≤6.5. This criterion has been used in previous studies as it discriminates relatively mild ambulatory dysfunction (self-sufficient and able to walk without aid for 500 m) and moderate to severe ambulatory dysfunctions [9,27,29,31]. The percent of predicted walking speed in the 2MWT and 6MWT compared to healthy subjects was calculated based on reference values for healthy persons with formulas published by Selman et al. [32] (2MWTpredicted = 252.583 − 1.165 ∗ age + 19.987 ∗ gender, where gender = 1 if male subject and gender = 0 if female subject) and Enright et al. [33] (6MWTpredictedmen = 7.57 ∗ height, cm − 5.02 ∗ age − 1.76 ∗ weight, kg − 309 m; 6MWTpredictedwomen = 2.11 ∗ height,cm − 2.29 ∗ weight, kg − 5.78 ∗ age + 667 m). No good evidence-based reference values could be found for the T25FWT. Subjects were excluded from the analyses if they 1) had an EDSS score below 1 or over 6.5 due to small sample sizes in these subgroups (n = 1 and n = 4, respectively), 2) took > 30 s to complete the T25FWT (n = 12), 3) or if data on crucial variables were missing (EDSS: n = 1, height: n = 3, 6MWT: n = 4, MSWS-12: n = 4). From the total sample of 503 subjects this left 474 subjects for analyses.
2. Methods 2.4. Statistical analysis The current study presents data from two cross-sectional multicentre studies performed within the European Rehabilitation in MS network for best practice and research in MS rehabilitation (www. eurims.org). Detailed description of methodology and study design has been reported elsewhere [27–29] and is only summarized below.
The statistical analysis was performed in Stata version 11.2 and used a 5% limit of significance. The variables that were modelled as continuous were assumed to follow a normal distribution and subsequently the characteristics of the two MS-subgroups were compared by Student's unpaired t-test or Welch's t-test where appropriate for continuous variables and the Chi-squared test for categorical variables. To determine which walking measures had the strongest linear relations to the EDSS score at different disability levels, Pearson correlation coefficients were calculated between EDSS scores and walking measure variables. Pitman's test, which calculates the Pearson correlation between the sum and the difference of the residuals from two linear regressions, was applied in order to determine the ranking of correlations. Linear regressions between walking variables and EDSS scores were used to determine the relationship between level of EDSS scores and walking measure outcomes. Post-hoc, we analyzed which items in the MSWS-12 that were driving the correlations between this walking measure and the EDSS by calculating Pearson correlation coefficients between the individual items in the MSWS-12 questionnaire and the EDSS.
2.1. Subjects A convenience sample of 503 MS patients was recruited at inpatient and outpatient rehabilitation and research centers in Europe (n = 18), Israel (n = 1) and the USA (n = 1). The included subjects had a definite diagnosis of MS and an EDSS ≤ 6.5. The subjects had not experienced an exacerbation in the month prior to testing, and had no other medical conditions that interfered with walking. All participants gave written informed consent. The study was conducted in accordance with the declaration of Helsinki and approved by the Human Ethics Committee of the leading University of Hasselt as well as by the local ethical committees of the participating centers. 2.2. Experimental design, outcome measures and procedure
3. Results
A cross-sectional multicentre study design was applied. The EDSS score was collected by neurologists from the participating sites [12]. The outcome measures in this study were short (T25FWT) and long (2MWT, 6MWT) walking capacity tests, patient reported walking ability (MSWS-12) and disability level (EDSS). Subjects were permitted to use habitual assistive devices during testing. All sites utilized the same standardized instruction booklet. The MSFC guidelines [30] were applied for the T25FWT, meaning that subjects were instructed ‘to walk at fastest but safe speed’ over a 25 ft/7.62 m course using a static start. Subjects also completed the 2MWT and 6MWT ‘at fastest speed’. They were instructed to cover as much distance as possible, albeit safely, according to the script of Goldman et al. [7]. Participants walked back and forth in a 30-metre hallway turning around cones at each end, and were notified, without further encouragement, about each expired minute. Total distance (m) was registered, and was also expressed as
3.1. Patient characteristics The characteristics of the total, mild and moderate MS groups are presented in Table 1. The persons with moderate MS were older, had longer disease duration, and had more primary progressive (p < 0.001) and secondary progressive patients (p < 0.001) when compared to those with mild MS. 3.2. Walking capacity according to EDSS Walking speed was reduced to 61.3 ± 25.4% and 58.5 ± 25.8% of the predicted walking speed of healthy persons, in the total sample of pwMS in the 2MWT and 6MWT, respectively (see Table 1). The 132
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Table 1 Patient characteristics for the total sample, and subgroups with mild or moderate MS (EDSS 1.0–4.0 or 4.5–6.5, respectively).
Age (years) Sex (M/F) Height (cm) EDSS (a.u.) Type of MS (RR/SP/ PP) Disease duration (years) T25FWT (s) T25FWT (m/ s) 2MWT (m) 2MWT (m/s) 2MWT% (%) 6MWT (m) 6MWT (m/s) 6MWT% (%) MSWS-12 (a.u.)
Total sample N = 474
Mild MS N = 200
Moderate MS N = 274
P value (mild vs. moderate)
49.0 ± 10.7 183/291 169.6 ± 8.9 4.5 ± 1.6 250/152/72
45.6 ± 9.9 80/120 170.5 ± 8.1 2.9 ± 1.0 142/36/22
51.5 ± 10.6 103/171 169.0 ± 9.3 5.7 ± 0.7 108/116/50
P < 0.0001 P = 0.6 P = 0.06 P < 0.0001 P < 0.001
11.4 ± 7.9
8.4 ± 6.5
13.6 ± 8.2
P < 0.0001
7.87 ± 4.5 1.21 ± 0.50
5.21 ± 1.9 1.59 ± 0.40
9.82 ± 4.9 0.93 ± 0.36
P < 0.0001 P < 0.0001
125 ± 53 1.04 ± 0.44 61.3 ± 25.4 353 ± 159 0.98 ± 0.44 58.5 ± 25.8 55.8 ± 26.1
167 ± 40 1.39 ± 0.33 80.6 ± 19.4 482 ± 116 1.34 ± 0.32 78.2 ± 20.2 40.1 ± 25.3
94 ± 39 0.78 ± 0.32 47.2 ± 19.2 259 ± 114 0.72 ± 0.32 44.2 ± 19.1 67.4 ± 20.0
P P P P P P P
< < < < < < <
0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001
Data are mean ± standard deviation (SD) or numbers. M = Male, F = Female, a.u. = Arbitrary units, RR = Relapsing remitting MS, SP = Secondary progressive MS, PP = Primary progressive MS, EDSS = Expanded disability status scale, T25FWT = Timed 25 foot walk test, 2MWT = Two minute walk test, 2MWT% = Percent of expected walking speed in the 2MWT compared to healthy controls, 6MWT = Six minute walk test, 6MWT% = Percent of expected walking speed in 6MWT compared to healthy controls, and MSWS-12 = The 12-item MS walking scale.
moderate MS group was significantly more impaired than the mild MS group on all walking measures, but walking impairments were present already at low EDSS scores, as depicted in Fig. 1. Fig. 1A presents outcomes of walking measures according to the continouos EDSS scores in the total sample. The overall pattern was that higher EDSS scores correspond to worse outcomes in all walking measures. There were some small random deviations of this pattern, especially in the 1.0–2.0 range of the EDSS.
Fig. 1. Performed and perceived walking measures according to EDSS, and walking capacity test performance normative to reference values. (A) Mean values of walking speed ((T25FWT (m/s)), (2MWT (m/s)), (6MWT (m/s))) and impact of MS on walking (MSWS-12 (a.u.)) depicted as a function of disability (EDSS score (a.u.)) in the total MS sample. (B) Mean values of percent of expected walking speed ((2MWT% (%)), (6MWT% (%))) depicted as a function of disability (EDSS score (a.u.)) in the total MS sample.
4. Discussion
3.3. Relation between walking measures and the EDSS
The present study shows that walking speed on average was reduced by 40% in PwMS when compared to healthy persons, and importantly, a marked reduction was noted already at low EDSS levels. The 6MWT and 2MWT were the walking measures that showed the strongest relationship to the EDSS across the total sample. However, the MSWS-12 interestingly showed the strongest relationship to the EDSS in the mild MS subgroup.
Pearson correlation coefficients between the EDSS and different walking measures and the results of the Pitman analysis of residuals are reported in Table 2. The EDSS correlations to walking measures ranged from weak to strong, and all correlations were significant (p < 0.0001). In the total MS sample the EDSS score showed the strongest relationship to the 2MWT and 6MWT, while EDSS had the strongest relationship with MSWS-12 in the mild MS group, and to the 2MWT in the moderate MS subgroup. Additionally, Table 3 shows the coefficients of the linear regression analysis' on how EDSS level is related to the different walking measures.
4.1. Walking capacity according to the EDSS Higher EDSS scores were associated with more pronounced walking impairments and walking capacity was already impaired early in the disease stage, as EDSS scores of 1–4 were associated with reductions from 4 to 35% in walking speed in the 2MWT and 6MWT compared to reference values from healthy persons (see Fig. 1B). It should be noted, that comparison with predicted reference values should be interpreted with caution, as such predictive equations are associated with limitations [33]. Our procedure for the 6MWT was the same as in the original study by Enright et al., but with minor modifications in instructions and encouragement. We used the first 2 min of the 6MWT as a measure of the 2MWT, but this has been shown not to influence the result [18]. Taken together, we feel confident that the formulas are applicable in our setting. In support of the present study results, two small-scale
3.4. Exploratory analyses Table 4 presents Pearson correlation coefficients between the individual items of the MSWS-12 and the EDSS. In the total sample, only minor differences were seen between correlations of the EDSS and the different items (approximating 0,5) except for item number 9 (r = 0,73) referring to the need for support when walking outdoors. The relation between the items and the EDSS was obviously lower in the moderate (approximating 0,2) compared to mild MS subgroup, with the relation even being non-significant for items 2 and 5 referring to ability to running and balance. 133
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Table 2 Hierarchic presentation of Pearson correlation coefficients between walking measures and the EDSS score for the total, mild and moderate MS groups. EDSS 1.0–6.5 n = 474
EDSS 1.0–4.0 n = 200
EDSS 4.5–6.5 n = 274
Measure
r
Pitman
Measure
r
Pitman
Measure
r
Pitman
6MWT 2MWT 2MWT% T25FWT 6MWT% MSWS-12
−0.76 −0.76 −0.73 −0.72 −0.71 0.64
A, B, C, D A, B, C, D A, B A A
MSWS-12 6MWT 2MWT 2MWT% T25FWT 6MWT%
0.56 − 0.46 − 0.45 − 0.40 − 0.39 − 0.35
B, C, D, E B, C, D B, D
2MWT 2MWT% T25FWT 6MWT 6MWT% MSWS-12
− 0.50 − 0.50 − 0.47 − 0.46 − 0.42 0.29
A, B, F A, B, F A A, B A
All pearson correlations are significant (p < 0.0001). EDSS = Expanded disability status scale, T25FWT = Timed 25 foot walk test, 2MWT = Two minute walk test, 2MWT% = Percent of expected walking speed in the 2MWT, 6MWT = Six minute walk test, 6MWT% = Percent of expected walking speed in 6MWT and MSWS-12 = The 12-item MS walking scale. Pitman analysis: A: Significantly better related to EDSS-Score than MSWS-12, p ≤ 0.05. B: Significantly better related to EDSS-Score than 6MWT%, p ≤ 0.05. C: Significantly better related to EDSS-Score than T25FWT, p ≤ 0.05. D: Significantly better related to EDSS-Score than 2MWT%, p ≤ 0.05. E: Significantly better related to EDSS-Score than 2MWT, p ≤ 0.05. F: Significantly better related to EDSS-Score than 6MWT, p ≤ 0.05.
ambulatory”. This suggests the need for early rehabilitation interventions aiming to improve walking capacity. The slopes of the linear regressions from the present study (table 3) indicate that a person with a 1 point higher EDSS score walks 0.22 m/s slower in the T25FWT, 24.8 and 74.7 m shorter in the 2MWT and 6MWT respectively, and have a 10.3 points higher score in the MSWS12. Baert et al. [29] reported clinically meaningful changes for pwMS of − 10.4 for the MSWS-12, 9.6 m for the 2MWT, and 21.6 m for the 6MWT. When combining the results of the present cross-sectional study and those reported in Baert et al., 0.5 point increase in the EDSS of our large MS cohort may represent a clinically meaningful change in walking distance reflected by the 2MWT and 6MWT and a 1 point increase in the EDSS may represent a clinically meaningful change in walking ability reflected by the MSWS-12.
Table 3 Slopes of the linear regression analysis' between EDSS and walking measures for the total sample. EDSS 1.0–6.5 (n = 474) Measure
Slope (95% CI)
6MWT (m) 6MWT% 2MWT (m) 2MWT% T25FWT (m/s) MSWS-12
− 74.7 [− 80.4; − 11.2 [− 12.3; − 24.8 [− 26.7; − 11.4 [− 12.4; − 0.22 [− 0.24; 10.3 [9.1; 11.4]
P-value − 69.0] − 10.2] − 22.9] − 10.4] − 0.20]
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
Data are given as slope [95% confidence interval]. EDSS = Expanded disability status scale, 6MWT = Six minute walk test, 6MWT% = Percent of expected walking speed in the 6MWT, 2MWT = Two minute walk test, 2MWT% = Percent of expected walking speed in 2MWT, T25FWT = Timed 25 foot walk test and MSWS-12 = The 12-item MS walking scale.
4.2. Walking speed in long vs. short walking tests in relation to the EDSS In the total sample, walking speed in the 6MWT and 2MWT was slightly better related to the EDSS score (r = − 0.76) than walking speed in the T25FWT (r = −0.72). The same pattern, but with a more pronounced difference, was observed in the mild MS subgroup. In comparison, previous small scale studies have reported a correlation coefficient of 0.60 and −0.70 between the EDSS score and the T25FWT and 6MWT [16], respectively, and the same pattern was observed by Learmonth et al. [17] who reported a correlation coefficient of 0.73 and
studies report reductions in walking speed during the 6MWT of 25–33%, when persons with predominantly mild MS were compared to healthy persons [19,34]. This reduction is considered as meaningful, and related to daily walking activity [31]. The EDSS characterizes PwMS as “fully ambulatory” at EDSS levels < 4, but the observed reduction in walking capacity in the early disease stage of the present study indicate that persons with EDSS < 4 not necessarily are “fully
Table 4 Pearson correlation coefficients between items from the MSWS-12 and the EDSS score. MSWS-12
Question Question Question Question Question Question Question Question Question Question Question Question
1: walking 2: running 3: stair climb 4: standing 5: balance 6: walking distance 7: effort 8: indoor support 9: outdoor support 10: walking speed 11: uniformity 12: concentration
EDSS 1–6,5 (n = 394)
EDSS 1–4 (n = 144)
EDSS 4,5–6,5 (n = 250)
r
P
r
P
r
P
0.51 0.56 0.51 0.47 0.50 0.45 0.44 0.57 0.73 0.51 0.50 0.47
< 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001
0.44 0.61 0.57 0.47 0.50 0.48 0.45 0.31 0.37 0.44 0.49 0.52
< 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001
0.14 0.07 0.21 0.18 0.10 0.13 0.20 0.41 0.46 0.15 0.22 0.16
0.03 0.27 0.001 0.004 0.12 0.04 0.002 < 0.0001 < 0.0001 0.017 0.0004 0.01
Each question from the MSWS-12 has been given a keyword in relation to the subject of the question. EDSS = Expanded disability status scale, and MSWS-12 = The 12-item MS walking scale.
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− 0.81 between the EDSS score and the T25FWT and 6MWT, respectively (the direction of the correlation coefficient is determined by the way walking capacity is expressed in terms of walking time or walking speed). The difference in correlation coefficients between the EDSS score and 6MWT and T25FWT in these studies seems to be slightly overestimated compared to the finding in our large sample size. However, the results from our study confirms the finding that the EDSS score correlates more closely with the 2MWT and 6MWT than with the T25FWT. The fact that the EDSS score partly is defined on a evaluation of walking distance, is a highly likely explaination of this observation. The 2MWT furthermore seems to be more sensitive to changes in disease progression than the T25FWT, as the walking speed is reduced relatively more with increasing EDSS. Some concern could be raised due to the fact that the absolute walking speed in the 2MWT falls just below the one observed in the 6MWT, but as it is depicted in Fig. 1A no difference is observed in the walking speed relative to reference values. Taken together, we do not suspect significant instabilities in this measurement. Lastly, longer walking tests seem to have a lower ceiling effect than the T25FWT, and might be more responsive [35].
at the same time it is less intense and time-consuming for both patients and clinicians. It is furthermore noteworthy, that early in disease stages, the MSWS-12 showed the strongest relationship to EDSS by identifying impairments more gradually than the objective walking capacity tests. This suggests that the MSWS-12 is preferable when assessing walking in pwMS with a low disability status. When applying predicted reference data, walking speed can be compared to walking speed in healthy persons, and thereby provide an expression of the severity of walking impairment in PwMS. Such normalized data show that walking impairments are present already at an early stage of MS. This suggests that rehabilatory efforts aiming at improving and/or preserving walking capacity is of great importance already at an early timepoint of the disease course. Age-sex matched reference data for the T25FWT is warranted. 5. Conclusion PwMS walk on average approximately 40% slower than healthy sex and age matched persons, with reductions in walking speed being present already at low EDSS levels. In a clinical view this suggest the importance of early rehabilatory efforts. The EDSS score is most strongly related to walking speed in the 2MWT and 6MWT, but in the early disease stages the MSWS-12 captured impairments more gradually and showed the strongest relation to EDSS.
4.3. Walking speed vs. MSWS-12 in relation to the EDSS score Walking speed in the 6MWT, 2MWT and T25FWT was better related to the EDSS score in the total and moderate MS sample than the MSWS12 score, while the MSWS-12 score was better related to the EDSS score in the mild MS sample than walking speed in the 6MWT, 2MWT and T25FWT. Previous studies have found moderate to strong correlation coefficients between the EDSS score and the MSWS-12 (0.65 ≤ r ≤ 0.84 (7,16,17,23–26)). Some [7,17] but not all [16] previous studies support the finding from the present study, where EDSS, in general, shows stronger correlation to objective walking tests than to the MSWS-12. Regarding the EDSS relation to the MSWS-12 in mild vs. moderate MS, Motl et al. [23] reported, in accordance to our results, a stronger correlation coefficient between the EDSS score and the MSWS12 score in mild vs. moderate MS (r = 0.71 vs. 0.33). In the present study exploratory analyses of the relations between the questions comprising the MSWS-12 and the EDSS score were performed to better understand these differences. In a subset of 394 patients from the MS sample (all individual questions available in the database), it was found that question 8 (“Made it necessary for you to use support when walking indoors?”) and especially question 9 (“Made it necessary for you to use support when walking outdoors?”) were the primary drivers of the EDSS-MSWS-12 correlation in the total MS sample (r = 0.57 and r = 0.73, respectively) and in the moderate MS group (r = 0.41 and r = 0.46, respectively). In the mild MS group, question 2 (“Limited your ability to run?”) and 3 (“Limited your ability to climb up and down stairs?”) (r = 0.61 and r = 0.57, respectively) showed the strongest relationship. In the moderate subgroup, item number 2 regarding running, and item number 5 regarding balance were not significantly related with the EDSS perhaps due to floor effects in perceived impact. These observations suggest that in the total and moderate MS sample the MSWS-12 probably captures aspects related to walking that are not captured by the EDSS score. Conclusively, in mild MS the MSWS-12 may detect (neurological) impairments affecting performance during running and walking on stairs that is also captured by the EDSS but not by objective walking tests.
Conflicts of interest DLC, MR, ES and IB report no disclosures. PF has received honoraria from serving on scientific advisory boards of Biogen Idec. UD has received research support, travel grants and/or teaching honorary from Biogen Idec, Merck Serono, Novartis, Bayer Schering and Sanofi Aventis as well as honoraria from serving on a scientific advisory board of Biogen Idec and Genzyme. Funding Coordination of this study was partially funded via a unrestricted educational grant from Novartis Pharma AG to the European RIMS network for best research and practice in MS rehabilitation. See www. euRIMS.org. Author contribution Conception or design of the work: DLC, PF, UD. Data collection: UD, PF, IB. Data-analysis: DLC, MR, PF, IB, UD. Interpretation of data: All. Drafting the work and/or revising it: All. Final approval of the version to be published: All. Agreement to be accountable for all aspects of the work: All. Acknowledgements The RIMS network (www.eurims.org) is acknowledged for facilitating inter European consultation and testing. All data-collecting centers REVAL Rehabilitation Research Center, Hasselt; Rehabilitation and MS Center Overpelt, Overpelt; National MS Center, Melsbroek; Centre Neurologique et de Réadaptation Fonctionelle, Fraiture-en-Condroz; Charles University Prague and General Faculty Hospital, Prague; MS Centers of Haslev and Ry, Haslev and Ry; West-Tallinn Central Hospital, Tallinn; Masku Neurological Rehabilitation Center, Masku; School of Health Professions, Plymouth University, Plymouth, United Kingdom; Norwegian Multiple Sclerosis Competence Center, Department of Neurology, and Department of Physiotherapy, Haukeland University Hospital, Bergen, Norway; Poole hospital NHS foundation trust, Dorset, United Kingdom; Eugenia Epalza
4.4. Implications for clinical practice and future research In this large scale study the 2MWT and the 6MWT were the walking measures that provided the best reflection of disease severity in terms of the EDSS score. Differences between 2MWT and 6MWT, in relation to EDSS score, were always small. Despite the fact that the 6MWT is the most common long walking test [17], this suggests that the 2MWT preferably should be included in a core set of walking capacity tests. The 2MWT is just as closely related to the EDSS score as the 6MWT, and 135
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