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Effects of dalfampridine on multi-dimensional aspects of gait and dexterity in multiple sclerosis among timed walk responders and non-responders
Journal of the Neurological Sciences, In Press, Corrected Proof, Available online 8 June 2015
Dalfampridine extended release 10 mg tablets (D-ER) have demonstrated improvement in walking for ambulatory persons with multiple sclerosis (pwMS), termed “responders.”
This study examined the extent additional aspects of gait and dexterity change for patients prescribed D-ER.
Over 14-weeks, walking endurance, dynamic gait, self-report walking ability andfine and gross dexterity were examined in pwMS prescribed D-ER as a part of routine clinical care.
The final results (n = 39) validate that a subset of pwMS improve walking speed (Time 25-Foot Walk Test, p < 0.0001). Significant improvements in gait and dexterity were observed even among participants who did not improve walking speed. Improvements were evident in gait and dexterity domains including Six Minute Walk Test, p = 0.007, Six-Spot Step Test, p < 0.0001, Multiple Sclerosis Walking Scale-12, p < 0.0001, Nine Hole Peg Test, p < 0.0001 dominant and non-dominant sides, and Box and Blocks Test, p = 0.005 and 0.002, dominant and non-dominant sides, respectively.
These findings suggest that D-ER may be a potential treatment for gait impairments, beyond walking speed and dexterity in pwMS. Further investigation regarding D-ER response is warranted.
- D-ER use improved gait and dexterity functions in addition to walking speed in pwMS
- Function measures are improved after D-ER use even among timed walk non-responders
- We recommend adding SSST, 6 MW, MSWS-12, 9HPT, and BBT to assess individual response
Abbreviations: pwMS - Persons with Multiple Sclerosis, MS - Multiple Sclerosis, CNS - Central Nervous System, D-ER - Dalfampridine-Extended Release, FDA - Food and Drug Administration, T25FW - Timed 25-Foot Walk, Kv - potassium, 4-AP - 4-Aminopyridine, 6 MW - Six Minute Walk, SSST - Six-Spot Step Test, MSWS-12 - 12-item Multiple Sclerosis Walking Scale, 9HPT - Nine-Hole Peg Test, BBT - Box and Blocks Test, OS - Observational Sample, ES - Efficacy Sample, TWR - Timed Walk Responders, TWNR - Timed Walk Non-Responders, EDSS - Expanded Disability Status Scale.
Keywords: Multiple Sclerosis, Dalfampridine, Walking, Gait, Dexterity.
Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that produces axonal damage and loss of myelin  . Loss of myelin leads to delayed or complete blockade of nerve impulse conduction  and . Abnormal nerve conduction plays a significant role in how functional activities such as ambulation are completed in persons with MS (pwMS)  and . In 2010, dalfampridine extended release 10 mg tablets (D-ER; Ampyra Extended Release Tablets, Acorda Therapeutics, Inc.) were approved by the Food and Drug Administration (FDA) for treatment to improve walking in pwMS as demonstrated by an increase in walking speed.
In the pivotal D-ER clinical trials, the primary outcome was walking speed using the Timed 25-Foot Walk Test (T25FW) , , and . Efficacy was based on consistency of walking speed improvement over repeated trials. Specifically, a “responder” was defined as an individual with a faster walking speed for at least three of the four on-drug visits compared to the maximum speed recorded during the five off-drug visits , , and . Using this “responder” definition, the two phase III clinical trials found 35%-43% of pwMS receiving D-ER had significant improvement in walking speed compared to 8-9% in the placebo groups  and .
Pharmacologically, D-ER acts by blocking potassium (Kv) channels exposed through MS-related demyelination, potentially improving conduction  . Kv channels are ubiquitously expressed within the CNS, thus any foci of demyelination which expose Kv channels may be influenced by D-ER. Previous published research on 4-Aminopyridine (4-AP), the active ingredient chemical constituent of D-ER, suggests improvement in more than just walking speed in pwMS , , and . The pharmacokinetics of D-ER compared to the immediate release formulation of 4-AP result in more constant systemic exposure  and . Initial D-ER trials provided evidence of improvement in muscle strength , , and  and these findings should be further explored. The goal of the present study is to evaluate D-ER’s effects on multi-dimensional aspects of gait and dexterity in a real world, clinical setting.
This study was conducted at the Joyce D. and Andrew J. Mandell Center for Comprehensive Multiple Sclerosis Care and Neuroscience Research (Mandell Center) located at the Mount Sinai Rehabilitation Hospital in Hartford, CT and was registered on www.clinicaltrials.gov , NCT01399957. The Saint Francis Hospital Institutional Review Board approved the project. All participants provided written informed consent.
2.1. Study design
This prospective, observational study of pwMS prescribed D-ER by their treating clinician, monitored participants for the outcomes listed in Table 1 at a pre-D-ER baseline, and at 3.5, 7, 10.5, and 14 weeks after starting D-ER. The outcome data presented in this manuscript were collected as part of a larger ongoing study examining the effects of D-ER on multiple domains over 18 months. Participants were enrolled between August 2010 and March 2013. Participants were monitored for the duration of the project regardless of their decision to continue using D-ER. Research visits lasted 1.5 to three hours. Participants were compensated for travel and time for research visits, however, no compensation was provided for medication or routine clinical care.
|Gait Speed||Timed 25-Ft Walk||T25FW|
|Endurance||Six-Minute Walk Test||6 MW|
|Dynamic Gait||Six-Spot Step Test||SSST|
|Self-Perceived Walking Ability||MS Walking Scale-12||MSWS-12|
|Fine Dexterity||Nine-Hole Peg Test||9HPT|
|Gross Dexterity||Box and Blocks Test||BBT|
PwMS prescribed D-ER as a part of routine care were referred to the study by neurology providers at the Mandell Center. Key inclusion criteria were: (1) a clinical diagnosis of MS, (2) receive MS care at the Mandell Center, (3) receive a new D-ER prescription, (4) able to understand directions (score of 22 or greater on the Mini Mental State Examination), and (5) 18 years of age or older. Key exclusion criteria included: prior use of D-ER or 4-AP based medications. Fifty-two participants met study criteria and were enrolled ( Fig. 1 A). Thirteen participants were excluded from analysis: five did not start medication within 30 days of consenting, five withdrew, two were unable to complete the 14 week assessment and one subject’s diagnosis was changed from MS. The final analytic sample included 39 participants followed for 14 weeks.
2.3. Outcome measures
The following gait outcomes ( Table 1 ) were measured at each of the 5 time points. The T25FW assessed walking speed by averaging the time to complete two trials , , and . The Six Minute Walk (6 MW) assessed walking endurance by capturing the total distance traveled while walking laps in a 50 meter hallway over 6 minutes  . The Six-Spot Step Test (SSST) assessed dynamic gait through navigation of a 1 x 5 meter course requiring initiation of gait, changes in direction and weight shifting to kick cylindrical blocks off of targets marked on the floor  . A total of four trials were completed, two with each leg. The time to complete two consecutive trials was averaged for each leg and an overall task average was calculated  . The 12-item Multiple Sclerosis Walking Scale (MSWS-12) and  assessed self-perceived difficulty walking over the past 2 weeks. Each situation was rated on a scale of 1 (no limitation) to 5 (extreme limitation). A score was calculated by subtracting the minimum possible score  from the patient’s score, dividing that number by 48 and then multiplying by 100; thus scores ranged from 0 to 100  . Walking tests were conducted only on ambulatory participants; they were instructed to walk as fast as safely possible utilizing the assistive device typically used, if any, during ambulation.
Fine and gross dexterity measures were also assessed at each of the five time points. The Nine-Hole Peg Test (9HPT) assessed dexterity and fine motor control by averaging the time to complete two non-consecutive trials of each hand  and . The Box and Blocks Test (BBT) assessed gross manual dexterity  and  by capturing the total number of blocks (2.5 x 2.5 x 2.5 cm) moved from one compartment to an adjacent compartment using one hand in one minute. Prior to the first trial for each hand, participants were given 15 seconds of practice. Results were averaged for two trials on each hand separately  . The BBT was added part way through the study and therefore not performed on all participants.
Disease history, subject characteristics, and the subject’s most recent Expanded Disability Status Score (EDSS) from a clinic visit (not research), if performed within the past 3 years, was extracted from the participant’s medical record. Patients completed the Patient Determined Disease Steps (PDDS) for the study. Data presented in this manuscript evaluate change from baseline to 14 weeks. Supplemental data are provided that evaluate the period from baseline to 7 weeks.
2.4. Statistical analyses
Thirty-nine participants completed both baseline and week 14 visits (observational sample; OS). Of the 39, an Efficacy Sample (ES) included the 31 subjects who remained on D-ER for the entire 14-week observational period. In order to investigate whether changes in gait and dexterity outcomes varied by traditional responder status, the 31 persons who remained on drug for 14 weeks were sub-divided based on walking speed. The timed-walk responder (TWR) group (n = 20) included participants who showed improvement in walking speed (T25FW) on three out of four visits while on D-ER compared to their single off-drug baseline T25FW performance; the timed walk non-responder (TWNR) group (n = 8) included participants who failed to meet criteria for gait speed improvement , , and  ( Fig. 1 B). Two persons who were non-ambulatory (defined as unable to complete the T25FW) and 1 person who did not complete enough assessments to classify responder status were excluded from the responder sub-group analyses.
Baseline differences between TWR and TWNR sub-groups were analyzed using chi-squared tests for categorical variables (gender and disease subtype) and Mann-Whitney U test for continuous or ordinal variables (age, disease duration, EDSS, PDDS, and baseline gait and dexterity measures). Changes between baseline and the 14-week visit (and between baseline and the 7-week visit presented in supplemental tables) were analyzed using the Wilcoxon signed-rank test. All data analyses were performed using SPSS version 21 (SPSS, Chicago, IL). A two-tailed p-value less than or equal to 0.05 was considered statistically significant.
3.1. Study enrollment and baseline demographics
Fig. 1 A depicts study enrollment. Reasons for withdrawal are described in the methods. Briefly, 52 individuals were consented of whom 39 were included for analysis in the overall observational sample (OS); a subset of 31 (ES) remained on D-ER throughout the 14 week observation period. Of the 31 participants in the ES group, 20 were classified as a TWR, 8 classified as TWNR, and three (2 non-ambulatory and 1 who did not complete enough assessments) were excluded because they could not be classified.
Demographics for each study group and subgroup are shown in Table 2 . The majority of the cohort was women (79.5%) and had relapsing remitting MS (76.9%). The cohort had a mean age of 54.1 ± 9.9 years, a mean MS disease duration of 13.2 ± 8.7 years and a mean EDSS score of 5.1 ± 1.6. While there were no statistically significant differences in the distribution of demographic variables between the TWR and TWNR subgroups, the TWNR group generally had lower baseline PDDS scores, higher BMI, more males and more PPMS than the TWR group.
n = 39
n = 31
n = 20
n = 8
|Gender, n (%)||0.35|
|Male||8 (20.5)||7 (22.6)||4 (20.0)||3 (37.5)|
|Female||31 (79.5)||24 (77.4)||16 (80.0)||5 (62.5)|
|MS Subtype, n (%)||0.07|
|PPMS||4 (10.3)||2 (6.5)||0 (0.0)||1 (12.5)|
|RRMS||30 (76.9)||25 (80.6)||16 (80.0)||7 (87.5)|
|SPMS||5 (12.8)||4 (12.9)||4 (20.0)||0 (0.0)|
|Age (years), μ ± sd||54.1 ± 9.9||53.7 ± 10.3||53.8 ± 9.6||52.4 ± 13.9||0.94|
|Disease duration (years), μ ± sd||13.2 ± 8.7||13.1 ± 8.8||13.2 ± 9.4||13.8 ± 9.3||0.86|
|Baseline BMI||28.6 + 6.4||28.6 ± 6.1||27.8 ± 6.3||31.2 ± 6.4||0.12|
|PDDS, μ ± sd||4.6 ± 1.4||4.6 ± 1.3||4.7 ± 1.0||3.9 ± 1.5||0.16|
|EDSS b , μ ± sd||5.1 ± 1.6||5.1 ± 1.7||5.1 ± 1.6||4.7 ± 1.7||0.53|
a p-value comparing TWR and TWNR based on Likelihood Ratio chi-squared test for categorical variables (gender, MS subtype) and Mann-Whitney U test for continuous variables (age, disease duration, PDDS, EDSS).
b EDSS obtained from chart review when available; n = 31, 27, 18, and 7 in on-drug, off-drug, TWR and TWNR groups, respectively.
Abbreviations: OS = Observational Sample; ES = Efficacy Sample; TWR = Timed Walk Responder;
TWNR = Timed Walk Non-Responder; PPMS = Primary Progressive Multiple Sclerosis; RRMS = Relapsing Remitting Multiple Sclerosis; SPMS = Secondary Progressive Multiple Sclerosis; PDDS = Patient Determined Disease Steps; EDSS = Expanded Disability Status Scale.
Table 3 shows the baseline measures of gait and dexterity for the OS group, the ES group, and the TWR and TWNR subgroups. Baseline measures of BBT dominant side were significantly different (p = 0.04) between the TWR and TWNR subgroups, with a median of 56.0 and 43.5 blocks, respectively. Trends (p ≤ 0.1) towards worse baseline performances in the TWR compared with the TWNR for the T25FW (11.2 and 6.4 sec, respectively, p = 0.09), the SSST dominant side (21.6 and 13.0 sec, respectively, p = 0.10), the SSST average of both sides combined (23.2 and 13.1 sec, respectively, p = 0.07), and the MSWS-12 (78.1 and 65.6 points, respectively, p = 0.09) were noted. Although not significant, TWR baseline performances were worse than TWNR subgroups for all other measures, except for the 9-hole peg test (dominant and non-dominant sides) and the BBT non-dominant side.
|Observational Sample||Efficacy Sample||Timed Walk Responders||Timed Walk Non-Responders|
|Baseline measure||n||Median||IQR||n||Median||IQR||n||Median||IQR||n||Median||IQR||p-value a|
|T25FW (sec)||36||8.6||6.0, 13.0||29||8.0||5.9, 12.4||20||11.2||6.3, 13.0||8||6.4||5.2, 7.9||0.09|
|6MWalk (m) c||35||300.0||193.2, 363.0||28||303.5||224.6, 391.4||19||285.4||198.9, 336.5||8||367.2||282.4, 425.8||0.12|
|Dominant||36||17.5||12.8, 27.2||29||18.2||12.9, 27.6||20||20.7||14.2, 28.8||8||13.4||11.5, 20.6||0.10|
|Non-dominant d||36||20.8||13.0, 27.5||29||21.1||13.0, 27.4||20||21.6||15.6, 32.2||8||13.0||12.5, 20.4||0.12|
|Combined||36||19.3||13.3, 26.6||29||19.3||13.4, 27.1||20||23.2||14.3, 29.2||8||13.1||11.8, 20.5||0.07|
|MSWS-12 (score)||36||69.8||56.2, 83.3||29||70.8||56.2, 83.3||20||78.1||63.5, 84.4||8||65.6||47.9, 72.9||0.09|
|Dominant d||38||24.5||21.6, 30.3||31||24.7||21.6, 30.2||20||24.6||20.6, 28.9||8||25.9||22.7, 28.9||0.68|
|Non-dominant d||38||28.4||22.0, 35.1||31||28.8||23.8, 34.1||20||29.9||21.7, 35.3||8||25.5||23.1, 28.9||0.40|
|BBT (# blocks) e|
|Dominant||27||49.5||42.5, 56.2||22||51.5||42.5, 56.5||15||56.0||48.2, 57.0||6||43.5||37.5, 50.0||0.04|
|Non-dominant||27||47.0||42.5, 49.8||22||46.2||43.0, 49.5||15||47.0||43.0, 51.5||6||47.0||44.0, 49.0||0.76|
a p-value comparing TWR and TWNR based on Mann-Whitney U test.
b Non-ambulatory participants were excluded from each walking task (reducing OS sample size by three and ES by two).
c One participant refused to perform 6 MW task during their 14-week visit due to fatigue (reducing 6 MW sample size by one: OS, ES and TWR).
d One trial was missing for one participant and the one available score was used for their average score.
e This task was added to the protocol after enrollment started, resulting in missing data for n = 12 in OS, n = 7 in ES, n = 5 in TWR, and n = 2 in TWNR did not complete the BBT test.
Abbreviations: IQR = Inter-quartile Range; T25FW = Timed 25-Foot Walk Test; 6 MW = 6 Minute Walk Test; SSST = Six Spot Step Test; MSWS-12 = Multiple Sclerosis Walking Scale - 12; 9HPT = 9-Hole Peg Test; BBT = Box and Blocks Test.
3.2. Changes in outcomes
Table 4 shows changes observed from baseline to week 14 for the OS group and ES subgroup. Results were divided into gait and dexterity outcomes. Walking assessments were only conducted on ambulatory participants. Both the OS group and ES subgroup show significant improvement on all gait outcomes: -0.7 and -0.7 sec on the T25FW, 21.1 and 25.0 meters for the 6 MW, -2.9 and -2.8 sec for the SSST dominant side, -2.8 and -2.8 sec for the SSST non-dominant side, and -2.3 and -2.4 sec for the SSST combined averages, and -11.4 and -12.5 points for MSWS-12, respectively. Both the OS group and ES subgroup showed significant improvements for all dexterity outcomes: -1.6 and -1.8 sec for 9HPT dominant side and -2.2 and -2.1 sec for non-dominant side, and 3.5 and 3.8 blocks for the BBT dominant side and 3.0 and 2.8 blocks for the non-dominant side, respectively.
|Observational Sample||Efficacy Sub-Sample||Timed Walk Responders||Timed Walk Non-Responders|
|Gait and Dexterity Measures a||Median Δ (IQR)||p b||Median Δ (IQR)||p b||Median Δ (IQR)||p b||Median Δ (IQR)||p b||p c|
|T25FW (sec)||-0.7 (-2.6, -0.3)||< 0.0001||-0.7 (-3.2, -0.4)||< 0.0001||-1.2 (-3.6, -0.4)||< 0.0001||-0.1 (-0.6, 0.3)||0.48||0.02|
|6 MW (m)||21.1 (-1.2, 47.4)||0.007||25.0 (3.8, 49.6)||0.005||34.1 (10.2, 53.4)||0.002||17.7 (-32.2, 30.7)||0.67||0.18|
|Dominant||-2.9 (-6.3, -1.0)||< 0.0001||-2.8 (-6.8, -0.9)||< 0.0001||-4.0 (-10.2, -1.6)||0.003||-1.0 (-2.7, 0.1)||0.16||0.13|
|Non-dominant||-2.8 (-6.0, -1.7)||< 0.0001||-2.8 (-6.0, -1.8)||0.002||-3.6 (-7.0, -1.0)||0.023||-2.4 (-2.7, -1.7)||0.02||0.26|
|Combined||-2.3 (-5.6, -1.6)||< 0.0001||-2.4 (-5.3, -1.7)||0.001||-3.1 (-8.7, -1.7)||0.011||-1.8 (-2.3, -1.6)||0.02||0.22|
|MSWS-12 (score)||-11.4 (-24.0, -2.1)||< 0.0001||-12.5 (-25.0, -4.2)||< 0.0001||-9.4 (-28.1, 0.0)||0.001||-16.7 (-25.0, -13.5)||0.02||0.44|
|Dominant||-1.6 (-3.0, -0.3)||< 0.0001||-1.8 (-3.2, -0.4)||< 0.0001||-1.6 (-3.0, -0.6)||0.002||-2.0 (-3.5, -0.4)||0.02||0.76|
|Non-dominant||-2.2 (-4.6, -0.6)||< 0.0001||-2.1 (-4.2, -0.4)||< 0.0001||-2.0 (-3.7, 0.3)||0.011||-1.6 (-2.4, -0.6)||0.02||0.82|
|BBT (# blocks)|
|Dominant||3.5 (1.0, 6.2)||0.005||3.8 (1.5, 6.5)||0.004||2.5 (-0.2, 7.0)||0.050||5.0 (3.5, 6.5)||0.03||0.48|
|Non-dominant||3.0 (0.0, 4.5)||0.002||2.8 (0.0, 4.5)||0.002||3.0 (-0.2, 4.5)||0.015||1.8 (0.0, 3.5)||0.08||0.72|
a n’s for each outcome in each group and subgroup are as shown in Table 3 .
b p-values for within-group changes from baseline to week 14 are based on Wilcoxon signed rank test.
c p-values for between-group changes (TWR v. TWNR) from baseline to week 14 are based on Mann-Whitney U test.
Abbreviations: Δ = Change; IQR = Inter-quartile Range; T25FW = Timed 25-Foot Walk Test; 6 MW = 6 Minute Walk Test; SSST = Six Spot Step Test; MSWS-12 = Multiple Sclerosis Walking Scale - 12; 9HPT = 9-Hole Peg Test; BBT = Box and Blocks Test.
Table 4 also shows results stratified by responder status subgroups (TWR and TWNR). TWRs had significant improvement on all LE gait outcomes from baseline to week 14: -1.2 sec for T25FW, 34.1 meters on the 6 MW, -4.0, -3.6, and -3.1 sec for the dominant and non-dominant sides and both sides combined for the SSST, respectively and -9.4 points on the MSWS-12. For TWNRs, by definition, there was no significant change on the T25FW. Furthermore, non-significant improvements were seen for TWNRs on the 6 MW and the dominant side for the SSST. The TWNRs did show significant improvement on the non-dominant side and combined sides for the SSST (-2.4 and -1.8 sec, respectively) and the MSWS-12 (-16.7 points). In addition, TWRs had significant improvement on all dexterity outcomes: -1.6 and -2.0 sec for 9HPT dominant and non-dominant sides, and 2.5 and 3.0 blocks for BBT dominant and non-dominant sides, respectively. TWNRs had significant improvement for all dexterity outcomes except for the non-dominant BBT, including: -2.0 and -1.6 sec for 9HPT dominant and non-dominant sides and 5.0 and 1.8 blocks for BBT dominant and non-dominant sides, respectively.
The primary objective of the current study was to determine the effect of D-ER on a variety of gait and dexterity function measures, including walking, over a 14-week period in a clinical setting. Overall, improvements were observed on both gait and dexterity outcomes, and were not limited to those meeting the traditional T25FW “responder” definition , , and . Individuals in the OS group and each subgroup (ES, TWR, TWNR) demonstrated improvement on gait and dexterity outcomes with the exception of the TWNR’s non-dominant side performance on BBT. The clinical significance of this exception is unknown; it may have been a result of the small subgroup sample size. Improvements seen in dexterity are of particular interest. Prior to designing our study, little evidence existed to support the use of D-ER for improvement of dexterity. Since then, one study failed to find improvement on 9HPT after 2 weeks and after 9-12 months of treatment with D-ER  . Our study, however, supports other recent research  showing improvement in 9HPT performance and expands on these findings by also observing gross dexterity performance, lengthening the observation duration, and examining whether performance response varies based on traditional timed walk response.
In the current study, participants in the OS group and ES subgroup showed improved endurance during the 6 MW and improved dynamic gait on the SSST. Although the 6 MW test is longer and likely more sensitive at capturing endurance affected by MS related fatigue, results were consistent with studies  and  utilizing a 2-min walk test. TWRs also improved on all gait measures. By definition, the TWNRs did not improve on walking speed, and further failed to improve endurance on the 6 MW. However, TWNRs did improve on perceived walking ability (MSWS-12) and dynamic gait (SSST) on the non-dominant side and when both sides were combined.
The current study examined dalfampridine’s effectiveness in a clinical practice setting rather than a randomized clinical trial, and may better reflect patients in a typical neurology practice. Other strengths include multiple assessment time points in order to delineate TWR status, and hence the ability to perform analyses on TWR and TWNR sub-groups for multidimensional aspects of gait and dexterity.
D-ER was approved as a treatment to improve walking in pwMS, as demonstrated by an increase in walking speed. As was established by Goodman et al., , , and  we also found that some participants “responded” to D-ER with an improved walking speed and some did not. The demographics of our study population are comparable to those reported by Goodman et al.,  and  particularly for gender and MS subtypes. One potential explanation for the lack of improvement in walking speed among the TWNR, based on our data, is that they are less impaired at baseline than the TWR, and therefore may be less likely to respond to treatment. Although not statistically significant, many of the baseline gait measures were substantially better among TWNR in our population compared to the TWR. The better performances at baseline among the TWNR compared to the TWR, indicating that the TWR subgroup may have had more room for improvement. It is noteworthy, however, that even among the traditional non-responders, participants improved on a number of other gait and dexterity measures, including the SSST, MSWS-12, BBT, and 9HPT.
Another strength of this study is the inclusion of multiple measures of gait, including the SSST. The SSST has been proposed as a more comprehensive gait assessment, having a greater dynamic range, and discriminatory power when compared to the T25FW  and . Jensen et al.  suggested the SSST may be more sensitive than the T25FW, likely due to SSST capturing performance aspects of coordination and balance in addition to walking speed. Therefore, although the SSST does not substitute for endurance testing, the SSST encompasses other essential components of functional ambulation, and assesses the ability to initiate, stop, change directions and navigate objects, all of which are components of functional ambulation. Performance on SSST significantly improved in the OS group and all subgroups for both sides, except for the TWNR’s dominant side. The clinical significance of the exception is not clear but may be a result of the small sample size or influenced by which side was more impaired rather than the side of dominance, a factor which was not captured in this study. The combined SSST scores were assessed as they may be more reflective of functional dynamic gait, which requires the coordination between both limbs. The change observed in the combined SSST scores was significant for the OS group and all subgroups including the TWNRs. Our findings suggest that the SSST may be a more sensitive test than the T25FW when evaluating treatment effects of D-ER on ambulation in pwMS. Furthermore, while taking D-ER, self-perceived walking ability improved in the OS group and all subgroups, which was discordant with quantitative changes in T25FW and 6 MW in the TWNR yet reflective of the changes observed on the SSST.
While the study design allows a treatment-naïve set of participants to act as their own control, limitations include the small sample size and lack of blinding or control group. With frequent assessments, the possibility exists that positive changes could be due to practice effects. The outcome measures performed in this study are routinely used at the Mandell Center, and thus individuals experienced the testing procedure prior to study participation. Nonetheless, the repetition of assessments per the study protocol is more than patients would receive in clinical practice, so we performed several sub-analyses to attempt to clarify the influence of practice effects on our findings. First, we considered the possibility that immediate training effects might be an issue. At each time point, we had subjects complete two trials for some of the measures (SSST, BBT, 9HPT); these trial measurements were averaged in the primary analyses. If there were immediate training effects, we might see differences from one trial to the next. To adjust for potential training effects within each time point, we re-did the analyses with the “best” trial score instead of the average trial score, and the results were very similar to those using the “average” trial score. Next, we looked at changes from baseline to 7 weeks to examine whether there might be a pronounced difference between these changes and changes from baseline to 14 weeks; a large difference might suggest another influence beyond gradual improvement from D-ER, such as a practice effect. The results were similar to those at 14 weeks for the gait measures; results for the dexterity measures suggest a more gradual increase in performance of these measures over time, particularly for the TWNR. (See baseline to 7-week comparisons in Supplemental Table 1 ). Finally, we looked at whether there were changes from 7 weeks to 14 weeks to determine whether there might be continued practice effects (marginal increases over time), which would result in changes between those two later time points. There were no significant changes for any of the measures except for the box and blocks test (BBT) for the dominant hand. While these additional analyses suggest that the effects found in this study were not entirely due to practice effects, we cannot rule out that some practice effects may have affected our findings.
Though we found statistically significant changes in several of the outcome measures in the current study, the minimally clinically important difference (MCID) has yet to be established for the SSST, MSWS-12, BBT or 9HPT in pwMS. A 2014 publication by Baert et al.  on the topic of clinically meaningful improvement of walking measures concluded that the most appropriate gait measures for detecting minimally important changes (MIC) were MSWS-12 and longer walks (e.g., 6 MW); the SSST was not reviewed in this paper. The authors assessed each measure and identified minimally important changes from both the patients’ and therapists’ perspectives. The MIC reported from a patient’s perspective for the MSWS-12 was -10.4 and for the 6 MW was 21.6 m; from a therapist’s perspective, MIC was -11.4 for MSWS-12 and 9.1 m for 6 MW. In our study population, all subgroups reported benefit on the MWSW-12, with changes ranging from -9.4 to -16.7, and 6 MW changes from 17.7 m to 34.1 m. Future studies are warranted to determine if the improvements seen in the identified domains are equal to or greater than the MCID.
Another potential limitation is that we did not have the resources to obtain the EDSS scores at baseline for research participants. While not ideal, we were able to obtain the most recent EDSS score, if available from clinical exams within the past 3 years, and present that information in Table 1 . In addition, we were able to obtain PDDS scores, which are highly correlated with EDSS scores (Spearman’s rho = 0.73, p = 0.000), as part of the research protocol.
The present observational study is supportive of earlier findings from controlled studies suggesting additional benefits in gait and dexterity that could be further explored through randomized controlled trials. We also expand findings, suggesting that traditional TWNR also experience consistent and significant treatment effects on some outcome gait and dexterity measures. Our findings suggest that, in a clinical practice setting, D-ER may have the ability to improve dexterity, endurance, and functional gait even in persons with mild disability and those not showing improvement in walking speed. In addition, although there is considerable attention on ambulation in MS, reduced dexterity is also a source of disability and improving dexterity impairments through D-ER may be equally important  and . Our data indicate, in a manner consistent with MS, that heterogeneity exists in our responses, and that non-response in the T25FW domain is not an inclusive categorization of D-ER response. The results of the current study suggest that use of additional or alternate outcomes such as the SSST, 6 MW, MSWS-12, 9HPT and BBT be utilized when assessing individual needs and functional response to D-ER treatment. Therefore, although not currently indicated, we propose that D-ER be further studied as a potential treatment for gait impairments beyond walking speed and dexterity in pwMS.
Conflict of interest statement
Dr. Albert Lo has served on advisory boards for Acorda Therapeutics, Inc. Dr. Elizabeth Triche serves on the Steering Committee for a pregnancy-related rEVO pharmaceutical trial. No other authors have a disclosure or conflict of interest to report.
The following are the supplementary data related to this article.
The authors would like to thank Peter Wade, MD, Amy Neal, PA-C and the clinical staff at the Mandell Center for Multiple Sclerosis for referring potential participants and for their continued support of MS research. The authors would also like to thank Michele Labas, RN and Tara Patterson, PhD for their contributions to data collection. This investigator-initiated study was partially supported through an investigator-initiated grant (#11-385) from Acorda Therapeutics, Inc. and by Mount Sinai Rehabilitation Hospital, Hartford, CT. Acorda Therapeutics, Inc. did not take part in designing or analyzing results of this study, nor did they provide medication for participants.
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a Mandell Center for Multiple Sclerosis, Mount Sinai Rehabilitation Hospital, Hartford, CT, USA
b Department of Epidemiology, School of Public Health, Brown University, Providence, RI, USA
c Department of Neurology, Brown University, Providence, RI, USA
⁎ Corresponding author at: Mandell Center for Multiple Sclerosis, Mount Sinai Rehabilitation Hospital, A Saint Francis Care Provider, 490 Blue Hills Avenue, Hartford, CT, USA 06112.
1 These authors contributed equally to the manuscript.
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