Multiplehttp://msj.sagepub.com/
Sclerosis Journal
Progressive resistance training did not improve walking but can improve muscle performance, quality
of life and fatigue in adults with multiple sclerosis: a randomized controlled trial
KJ Dodd, NF Taylor, N Shields, D Prasad, E McDonald and A Gillon
Mult Scler published online 15 June 2011
DOI: 10.1177/1352458511409084
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Research Paper
Progressive resistance training did not
improve walking but can improve muscle
performance, quality of life and fatigue
in adults with multiple sclerosis:
a randomized controlled trial
Multiple Sclerosis Journal
0(00) 1–14
! The Author(s) 2011
Reprints and permissions:
sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/1352458511409084
msj.sagepub.com
KJ Dodd1, NF Taylor1, N Shields1, D Prasad2, E McDonald2 and
A Gillon1
Abstract
Background: Few high-quality trials have examined the effects of progressive resistance training (PRT) on people with
multiple sclerosis (MS).
Objective: To determine the effectiveness of PRT for people with MS, focusing on improving the gait deficits common in
this population.
Methods: Using a single blind randomized controlled trial, people with relapsing–remitting MS were randomly allocated
to either a PRT program targeting the lower limb muscles twice a week for 10 weeks (n ¼ 36), or usual care plus an
attention and social program conducted once a week for 10 weeks (n ¼ 35). Outcomes were recorded at baseline, week
10 and week 22.
Results: Participants attended 92% of training sessions, with no serious adverse events. At 10 weeks, no differences
were detected in walking performance. However, compared with the comparison group PRT demonstrated increased leg
press strength (16.8%, SD 4.5), increased reverse leg press strength (29.8%, SD 12.7), and increased muscle endurance of
the reverse leg press (38.7%, SD 32.8). Improvements in favor of PRT were also found for physical fatigue (Mean
difference 3.9 units, 95%CI 6.6 to 1.3), and the physical health domain of quality of life (Mean difference 1.5
units, 95%CI 0.1 to 2.9). At week 22 almost no between-group differences remained.
Conclusion: PRT is a relatively safe intervention that can have short-term effects on reducing physical fatigue, increasing
muscle endurance and can lead to small improvements in muscle strength and quality of life in people with relapsing–
remitting MS. However, no improvements in walking performance were observed and benefits do not appear to persist if
training is completely stopped.
Keywords
fatigue, multiple sclerosis, muscle strength, resistance training, randomized controlled trial, walking performance
Date received: 13th July 2010; revised: 22nd March 2011; accepted: 10th April 2011
Introduction
To date there is no cure for multiple sclerosis (MS) and
little evidence that pharmacological solutions can help
the muscle weakness and gait problems commonly
experienced by people with this condition.1 Research
has shown that there is a direct and primary correlation
between muscle strength and the performance of many
everyday activities, such as walking, in people with
MS.14 For this reason, it has been argued that using
progressive resistance training (PRT) to increase muscle
strength might help improve the performance of physical activities such as walking and thereby increase the
health-related quality of life5,6 of people with MS. The
key principles of PRT in healthy individuals are to perform sets of a small number of exercise repetitions (usually 8–12) with relatively high loads until muscle fatigue
1
Musculoskeletal Research Centre and School of Physiotherapy, Faculty
of Health Sciences, La Trobe University, Victoria, Australia.
2
MS Australia (ACT/NSW/VIC), Blackburn, Victoria, Australia.
Corresponding author:
Professor Karen J Dodd, School of Physiotherapy, Faculty of Health
Sciences, La Trobe University, Victoria, 3086, Australia.
Email: k.dodd@latrobe.edu.au
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2
Multiple Sclerosis Journal 0(00)
is reached, and to increase the load as muscle force
develops over time.7
Although there is a rationale for implementing PRT,
the role of this intervention for people with MS remains
uncertain because relatively few studies of satisfactory
quality have examined its effects in this population. One
of the few available studies8 used a randomized controlled research design to determine the effects of a
home-based program conducted three times a week
for 8 weeks on 19 adults with MS. Compared with a
wait-list control group, the resistance group significantly increased leg extensor muscle power by around
37% without negative effects. However, no changes
were detected in more functional outcomes such as in
the timed up-and-go test. No attempts were made to
determine how long improvements were maintained
after training was finished.
Another randomized controlled trial9,10 investigated
the effects of a supervised resistance training program
conducted twice a week for 12 weeks with 19 participants training in small groups using pin-loaded weight
machines. Results were again compared with a wait-list
control group. Participants in the training group, measured immediately after completing the program, significantly increased muscle performance, functional
outcomes (including walking), improved quality of life
related to physical function, and reduced general fatigue. Reassessment of this group 12 weeks after
completing the supervised program showed all
improvements were maintained. However, because
after finishing the supervised program participants
were encouraged to continue training unsupervised, it
remains unknown if improvements in physical function
persist if participants stop exercising. This is important
to investigate because in reality most people are not
willing to continue high-intensity exercise programs
indefinitely, particularly without evidence available to
support the need to continue. Also, PRT might have a
differential effect on people with MS compared with
people who have no physical impairments. In people
without impairment, muscle strength tends to reduce
to pre-training levels relatively quickly after they stop
exercising. This is probably because their pre-training
strength exceeds that required for everyday functional
activities. However, because muscle weakness in people
with MS can impact on the performance of everyday
activities, increases in muscle strength from PRT might
lead to more permanent changes in everyday physical
activities that in turn might lead to the maintenance of
strength and other beneficial outcomes without the
need to keep exercising. A previous randomized controlled trial of PRT in young people with cerebral
palsy11 provides some support for this idea.
Other studies of lesser quality have reported
improvements in muscle strength1216 and endurance,13
walking speed12,13,15,17,18 and endurance,16 stair climbing speed,15 timed up-and-go15 and chair transfers,17 as
well as general fitness,17 self-reported disability13,15 and
self-reported fatigue.16 However, apart from one,17 all
of these studies used a single-group pre-post research
design and so their results must be interpreted cautiously. The remaining study17 was described as a randomized controlled trial, but analyses were only done
for within-group changes and so, like the single-group
studies, conclusions were not based on comparisons
against control data.
Together this literature provides preliminary evidence that PRT might have physical and psychological
benefits for adults with MS, and that these might persist
for some time after completing a supervised program so
long as people keep exercising independently. However,
due to the use of relatively small samples, non-blinding
of assessors, lack of effective control data, and insufficient control of potentially confounding factors such as
the impact of increased attention and social interaction
during the training programs, the effects of PRT need
further investigation.
Given these considerations, the primary aim of this
randomized controlled trial was to examine the immediate effects of a supervised PRT program on walking
function in people with relapsing–remitting MS who
had difficulty walking. The secondary aims were to
determine the effects of the exercise program on
muscle performance (strength, endurance, stiffness
and spasm), fatigue, and health-related quality of life,
and to determine if any improvements were maintained
12 weeks after a complete break from training. It was
hypothesized that compared with a control group,
people with MS who participated in PRT would:
1. walk further over 2 min, and their maximum walking speed over 10 m would be faster;
2. demonstrate increased leg muscle strength and
increased leg muscle endurance;
3. demonstrate less physical fatigue and greater healthrelated quality of life;
4. demonstrate no change in muscle stiffness and
muscle spasms, and there would be relatively few
adverse events during the exercise program; and,
5. any changes observed in the training group immediately after completing the program would have dissipated if participants had a complete break from
training for 12 weeks.
Methods
Participants
Participants were recruited through a statewide organization providing education and support to people with
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Dodd et al.
3
MS, and a large specialist MS outpatient clinic. To be
included, people had to be aged 18 years or more, have
a confirmed diagnosis of relapsing–remitting MS, have
an Ambulation Index score19 of 2, 3 or 4 (mild to moderate walking disabilities), and have received medical
clearance to participate. Volunteers were excluded if
they had an acute exacerbation of MS within 2
months of starting the program, had benign or progressive/relapsing types of MS, had a serious unstable medical condition, had any concurrent condition, for
example stroke, or had participated in a PRT program
in the 6 months before training started. Recruitment
information flyers were sent by mail to all potential
participants registered on the mailing lists of both organizations. If interested, volunteers were asked to contact one of the researchers (KD) by telephone, during
which volunteers were screened to ensure they satisfied
the inclusion criteria.
The University Human Ethics Committee approved
this trial, and written informed consent was obtained
from each participant. This trial was registered at the
Australian New Zealand Clinical Trials Registry
(ACTRN 12607000101482).
Procedures
Participants were randomly allocated to either the
experimental or the control group. Consistent with
the CONSORT guidelines,20 a separate randomization
procedure was prepared for each stratum (Ambulation
Index 2, 3 or 4) using permuted blocks. For each stratum, the block allocation sequence was generated by
the research coordinator (KD) from a random-numbers
table, and assignments sealed in sequentially numbered
opaque envelopes. After enrolment, participants were
allocated to either ‘progressive resistance training’ or
‘control’ by opening the next envelope in the sequence.
The experimental group completed a 10-week (two
times per week), PRT program in one of four
community gymnasiums in metropolitan and regional
areas. The exercises targeted the key lower limb muscles
for supporting body weight and for generating and
absorbing power during walking (Table 1).21 While
these were the core exercises, they could be individualized. For example, if any exercise caused discomfort,
the starting position was modified or the exercise was
replaced. All exercises were completed on weight
machines. The training intensity was based on recommendations of the American College of Sports
Medicine (2009)7 and consisted of two sets of 10–12
repetitions of each exercise, at a training intensity of
10–12 repetition maximum (that is, only 12 consecutive
repetitions of each exercise could be completed before
muscle fatigue was reached). The weight lifted was
increased when two sets of 12 repetitions of an exercise
could be completed. Two-minute rest periods were
given between each exercise set. Each participant had
a logbook detailing each exercise, the weight lifted, the
number of repetitions, and the number of sets completed. This was filled in at the end of each session.
Each program was attended by a group of up to 12
participants, and they were supervised by up to three
experienced trainers (physiotherapists and registered
personal sports trainers). Each trainer directly supervised a sub-group of three or four participants. Each
exercise session was completed in around 45 min, and
at the end of each session there was a 30-min recovery
period when the participants had refreshments and time
to socialize.
Participants in the control group received ‘usual
care’ plus a social program. ‘Usual care’ could include
habitual exercise participants engaged in, or therapy,
provided it did not include PRT. In addition, to control
for the increased attention and social aspects of the
resistance training program, the control group participated in an attention and social program conducted for
1 h each week for 10 weeks. The program comprised
leisure and social activities not expected to have a
Table 1. Basic Progressive Resistance Training Program
Exercise name
Exercise description
1. Leg press
2. Knee extension
Sitting, hips and knees at a 90 angle, slowly push both feet against resistance plate to fully extend the knees
Sitting, knees flexed 90 , resistance bar positioned over distal anterior shin, extend both knees against
resistance to full extension
Sitting, knee flexed 90 , resistance bar positioned over distal thigh, raise bar by plantar flexing ankles
Lying in prone legs lying on the plinth, resistance bar at mid-calf level, slowly flex the knees toward the
buttocks.
Supine, hips and knees at approximately 30 angle with a pulley machine cuff placed around the forefoot,
dorsiflex the ankle and slowly flex the hips and knees to their full range.
3. Calf raise
4. Leg curl
5. Reverse leg press
Table describes the basic exercise program before any individualization, and in the usual order that exercises were completed.
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4
Multiple Sclerosis Journal 0(00)
fitness or training effect, such as massage, luncheons
and educational sessions, including some that enabled
participants to experience a single session of different
physical therapies such as Bobath therapy and yoga. In
developing the control program careful consideration
was given to optimizing participant attendance. Pilot
work we completed earlier suggested that a program
perceived by participants as being ineffective, such as
simple muscle stretching, or one that required participants allocated to a control intervention to attend several sessions each week, was unlikely to be adhered to.
Therefore, to balance the need to maximize control
group adherence against the need to provide adequate
control for the potentially confounding active ingredient of attention and social interaction, the control program we developed: 1) took into consideration
participant choices about content; 2) included some
minimal exercise attention control activities (e.g.
yoga, Bobath therapy) provided they would not be
expected to provide a sufficient stimulus to increase
muscle strength; and, 3) minimized the total number
of attendances for control participants’ convenience
while matching the approximate total duration (in minutes per week) of attention and social interaction
between the control and experimental programs.
Outcome measures
Outcome measurements were taken three times: at
baseline, after 10 weeks to determine the immediate effects of the intervention, and after a further
12 weeks (week 22) to determine if any benefits from
the program had been sustained. After completing their
10-week intervention programs, participants were
asked to return to their usual activities and not to continue or commence resistance training until after the
follow-up assessment session. Outcome measures were
taken by a registered physiotherapist blinded to group
allocation, and experienced in musculoskeletal
evaluation.
Primary outcome measures. Changes in walking
endurance were measured with the 2-minute walk test
(2MWT).22 Participants were instructed to walk at their
preferred speed using their usual assistive device up and
down a 10-m walkway for 2 min, with the distance
walked measured. Changes in maximal walking speed
were measured by recording the time taken to walk the
middle 10 m of a level 14-m walkway using a stopwatch.22 If relevant, the participant used their normal
assistive device. For both walking performance outcomes, the assessor provided standardized instructions
to each participant and the assessor answered any questions and provided a demonstration of the test.
For both tests, participants’ performed only one trial
with no practice trials.
Secondary outcome measures. Changes in muscle
strength were determined by the amount of weight
that could be lifted in a single seated leg press (1RM,
1 repetition maximum) and a single reverse leg press
(resistance of the combined movement of hip flexion,
knee flexion and ankle dorsiflexion) (1RM). In adults
with MS, a single 1RM leg press has been measured
with high levels of retest reliability (r > 0.93).13
Changes in muscle endurance were measured by
counting the repetitions that could be completed
when the weight on the seated leg press and reverse
leg press was lowered to 50% of 1RM. There is evidence of construct validity for this measure in that this
method detected hypothesized changes in adults with
MS for the leg press.13 The baseline weight lifted
(50% of 1RM at baseline) was used for the 10-week
and 22-week measurement as recommended.23
Changes in muscle performance were measured using
the same equipment that participants used in their exercise training sessions, but to reduce learning effects, the
1RM and muscle endurance assessment protocols were
not practiced during training sessions.
Changes in self-reported fatigue were assessed using
the Modified Fatigue Impact Scale (MFIS).24 The
MFIS consists of 21 items that assess how fatigue
affects an individual’s physical, psychological and psychosocial functioning. It has demonstrated evidence of
validity with moderately high correlations (r ¼ 0.69)
with the vitality subscale of the Short Form-36.25
Participants were categorized as being fatigued if they
scored more than 38 on the MFIS total score.26
Changes in health-related quality of life were quantified using the WHOQoL-Bréf.27 This scale contains 26
items that measure the domains of physical health, psychological health, social relationships, and environment. The scale has been found to have high internal
consistency and test–retest reliability in adults with neurological disabilities.28
Possible adverse changes in muscle stiffness and
spasm were measured with the muscle stiffness and
muscle spasm subscales of the Multiple Sclerosis
Spasticity Scale-88 (MSSS-88).29 This disease-specific
instrument has high internal reliability (coefficient >
0.93), and moderately high concurrent validity with
other scales such as the physical domain of the MSIS29 (Multiple Sclerosis Impact Scale).29 Other possible
adverse events that might occur during training were
recorded at the end and at the start of each exercise
session by the exercise trainers. Any incidents during
the intervention phase of the study, including relapses,
were described in detail and recorded in the participant’s logbook.
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Dodd et al.
5
Data analysis
To determine sample size, power analysis was completed using data from a pilot study.13 Based on the
most conservative of the walking performance effect
sizes from that study (d ¼ 0.75, the 2MWT), with
power of 0.80, a sample size of 35 participants was
required in each group to detect a difference between
groups.
To determine whether the PRT group improved
more than the control group immediately after the 10week program, data were analyzed with analysis of
covariance using the baseline measures as covariates,
a method that has been recommended for the analysis
of continuous data measured at baseline and follow-up
in randomized controlled trials.30,31 Categorical outcome variables were analyzed with relative risk ratios.
To determine if the PRT group improved more than the
control group 12 weeks after the program had finished
and participants had been advised to not train, a separate analysis of covariance was completed on follow-up
data at 22 weeks using baseline measures as covariates.
Standardized mean differences (effect sizes) and 95%
confidence intervals (CI) were calculated from postintervention means and standard deviations (SD).32
To interpret the clinical significance of any statistically
significant between-group differences, half the SD of
the control group at baseline was accepted as representing the minimally important difference.33 Analysis was
completed without Bonferroni adjustment because we
decided that this would have resulted in a risk of missing real effects (type II errors) and the consequences of
any type I errors would not lead to any negative effects
on participants.34 Intention-to-treat analysis was
applied, with all participants who were allocated and
commenced their program included in analysis. Where
data were missing, the carry forward technique was
used.35 Analysis was repeated after a small number of
extreme outliers were omitted. Since omission of these
outliers did not change the outcome of any of the statistical tests, only the results from the complete data
sets are presented.
In addition to the primary analyses and to compare
the results to other previous relevant trials that have
not conducted intention-to-treat analysis, we conducted
a per protocol analysis for participants who completed
more than 18 of the scheduled 20 training sessions. The
relationships between any significant changes in outcomes were explored using Pearson product moment
correlations.
Results
Figure 1 summarizes the flow of participants through
the study. People in the training program attended a
mean of 18.4 (SD 2.9, range 6–20) of their 20 scheduled
sessions, while people in the social program attended a
mean of 6.2 (SD 3.1, range 0–10) of their 10 scheduled
sessions. Baseline data indicated that the groups were
well matched for demographic factors such as age,
gender, height, weight, severity of MS symptoms, gait
aid use and fatigue (Table 2).
Effects of strength training after 10 weeks
Primary outcomes
Walking performance. As Table 3 shows, at the end
of the 10-week program, participants in the PRT group
did not significantly increase the distance they walked
over 2 min (2.6 m, 95% CI -4.0–9.1), or increase their
maximal walking speed (0.04 m s1, 95% CI -0.05–
0.13) compared with the control group. A per protocol
analysis of the 26 participants who attended more than
18 training sessions also demonstrated no significant
increase in the distance they walked over 2 min (5.1
m, 95% CI -2.0–12.1) or increase in their maximal
walking speed (0.05 m s1, 95% CI -0.05–0.14) compared with the control group.
Secondary outcomes
Muscle performance. As Table 4 shows, at the end of
the 10-week program, participants in the PRT group
significantly increased leg press 1RM (10.8 kg, 95%
CI 4.9–16.7) and reverse leg press 1RM (5.7 kg, 95%
CI 1.9–9.5) compared with the control group. These
changes represented average strength increases of
16.8% (SD 4.5) and 29.8% (SD 12.7), respectively.
The increase in reverse leg press strength exceeded the
minimally important difference of 29%, but the
increase in leg press strength was less than the 26%
increase required to be considered a minimally important difference. Participants in the training program
also increased the muscle endurance of the reverse leg
press (8.3 repetitions, 95% CI 3.0–13.6) compared with
the control group, representing an average increase in
muscle endurance of 39.7% (SD 32.8), in excess of the
minimal important difference of 32%. Between-group
changes in leg press muscle endurance approached but
did not reach significance in favor of the PRT group
(26.0 repetitions, 95% CI 1.7–53.8) (F (1,68) ¼ 3.495,
p ¼ 0.07).
Fatigue and quality of life. As Table 4 also shows, at
the end of the 10-week program, participants in the
PRT program had significantly reduced symptoms of
physical fatigue (3.9 units; 95% CI 6.6– 1.3) and
total fatigue (5.9 units; 95% CI –11.3– –0.5), compared with the control group (Table 3). The reduction
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6
Multiple Sclerosis Journal 0(00)
People with multiple sclerosis screened by
telephone (n = 173)
Excluded (n = 97)
• Did not fulfill inclusion criteria (n = 41)
•
Ambulation index <2 or >4 (n = 34)
•
Doing strength training (n = 2)
•
Recent acute exacerbation (n = 5)
• Not available (n = 41)
•
Location of program (n = 26)
•
Times did not suit (n = 12)
•
Not interested in control option (n =
3)
• Other (n = 15)
Baseline assessment
Randomized (n = 76)
Week 0
(n = 39)
Lost to Week 10
follow-up
• withdrew after
allocation (n = 3)
(n = 37)
Experimental Group
• Progressive
resistance strength
training
• 10 weeks
Week 10
Control Group
• Education and low
activity program
• 10 weeks
Week 10 assessment after intervention
(n = 36)
(n = 35)
Lost to Week 22
follow-up (n = 0)
• Experienced a
relapse (n = 2)
but attended
week 22
assessment
Week 22
Lost to Week 10
follow-up
• withdrew after
allocation (n = 2)
Lost to Week 22
follow-up (n = 4)
• Experienced a
relapse and did
not attend(n = 3)
• Did not attend (n
= 1)
Week 22 assessment (12 weeks after end of intervention)
(n = 36)
(n = 31)
Figure 1. Flow of participants through the trial.
in physical fatigue exceeded the minimally important
difference of 3.85 units, but total fatigue reduction
was less than the minimally important difference of
7.9 units. After 10 weeks, nine of 36 participants in
the PRT group were categorized as fatigued, compared
with 16 of 35 participants in the control group (relative
risk ratio ¼ 1.38, 95%CI 0.97–1.98).
At the end of the program, participants in the PRT
program had improved in the physical health domain
of the quality of life scale compared with the control
group (1.5 units; 95% CI 0.1–2.9). The improvement in
the physical functioning domain of quality of life was
less than the minimally important difference of 2.3
units. There were no differences between the two
groups at 10 weeks for cognitive and psychosocial
symptoms of fatigue, or for other measures of quality
of life.
No further significant between-group differences
were identified in any of the per protocol analyses of
the secondary outcomes, and very similar estimates of
the magnitude of any differences were found.
Exploration of the association between change in
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Dodd et al.
7
Table 2. Baseline demographic data
Number (Male/Female)
Age, y
Height, cm
Weight, kg
Ambulation index
2 (mild)
3 (moderate)
4 (severe)
Gait aid use
Yes
No
Fatigue (MFIS total)
Fatigued (MFIS > 38)
Not fatigued (MFIS 38)
Safety and adverse events
Experimental
Control
36 (10/26)
47.7 (10.8)
167.5 (8.0)
78.4 (20.4)
35 (9/26)
50.4 (9.6)
168.2 (10.0)
74.6 (14.6)
17
14
5
19
9
7
12
24
13
22
22
14
19
16
Data presented as mean (standard deviation) or numbers
MFIS, modified fatigue impact scale
muscle performance in completers (n ¼ 26) with change
in fatigue (MFIS total) and change in the primary outcomes of walking performance (2MWT and fast walking speed) demonstrated a moderate positive
correlation between the increase in leg press strength
and the increase in fast walking speed (r ¼ 0.47,
p ¼ 0.015). There was also a positive correlation
between increase in reverse leg press endurance and
the increase in the 2MWT (r ¼ 0.42, p ¼ 0.03), and the
increase in reverse leg press strength 2MWT (r ¼ 0.39,
p ¼ 0.052) approached significance. The increase in
reverse leg press endurance was correlated with a reduction in fatigue (r ¼ 0.40, p ¼ 0.04). None of the
other correlations between muscle performance and
walking performance or muscle fatigue approached
significance.
Effects of strength training after 22 weeks
Twelve weeks after training stopped (week 22), participants in the PRT group had not significantly increased
the distance they walked over 2 min (–3.4 m, 95% CI –
9.5–2.7) or increased their maximum walking speed
(0.03 m s1, 95% CI –0.12–0.06) compared with the
control group (Table 3).
At week 22, there appeared to be a significant
between-group difference in favor of the PRT group
for muscle endurance (reverse leg press endurance 7.3
repetitions, 95% CI 1.9–12.6) (Table 4). However, there
were no between-group differences detected for any of
the other measures of muscle performance, fatigue and
health-related quality of life (Table 4).
No between-group differences were detected after 10
weeks or 22 weeks for symptoms of muscle stiffness
or muscle spasm (Table 4). However, compared with
the control group, participants in the PRT group demonstrated reductions in symptoms of muscle spasm
(2.8 units, 95% CI 5.6–0.3) (F(1,68) ¼ 3.90,
p ¼ 0.052) and muscle stiffness (2.4 units, 95% CI
5.2–0.5) (F(1,68) ¼ 2.651, p ¼ 0.11) that approached
but did not reach significance.
Analysis of the participants’ logbooks showed there
were no reports of increases in any sensory symptoms
characteristic of MS or of any injury that required participants to miss a training session. The only musculoskeletal problems were short-term muscle soreness
reported by most participants (25 out of 36). All cases
of muscle soreness were resolved within a few days. No
relapses were identified in the training group during the
intervention phase of the study serious enough to warrant exclusion of the participant, or for them to miss a
training session.
Discussion
Our results suggest that contrary to our predictions,
PRT did not improve walking performance in adults
with relapsing–remitting MS and mild to moderate
walking disabilities. This finding differs from that of a
previous high-quality randomized controlled trial9
which reported that functional outcomes including
walking speed over 10 m and walking endurance measured over 6 min improved after completing a supervised 12-week PRT program. The reasons for this
disparity in findings are unclear. However, it is possible
that the PRT progression model used in the previous
randomized controlled trial which applied higher training intensities of up to 8RM (compared with 10–
12RM), and larger training volumes of up to four sets
of each exercise (compared with our two sets) over a
slightly longer duration (12 weeks versus our 10 weeks)
than our program could perhaps explain the different
findings. On the other hand, it is possible that our
research design, which included a comparison group
to control for the effects of the increased attention
and social interaction inherent in the training program,
may have resulted in smaller effect sizes from PRT than
that found in the previous trial9 which examined the
effects of PRT simply using a comparison of wait-list
control participants.
This latter idea is supported by our per protocol
analysis of participants who completed the PRT intervention (attended 18 sessions). The per protocol analysis demonstrated moderate positive associations
between measures of muscle strength and fast walking
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0.03
(0.12–0.06)
d ¼ 0.15
(0.32–0.61)
3.4 (-9.5–2.7)
d ¼ 0.12
(0.34–0.59)
Exp, strength training group; Con, education/low activity group; 1RM, one repetition maximum.*p < 0.05
2-minute walk (m)
120.2
(35.8)
112.1
(37.2)
122.9
(35.1)
112.9
(38.5)
118.6
(39.0)
113.7
(40.3)
2.8
(14.4)
0.7
(13.4)
1.6
(15.6)
1.6
(9.0)
0.04
(0.05–0.13)
d ¼ 0.31
(0.16–0.77)
2.6
(4.0–9.1)
d ¼ 0.27
(0.20–0.74)
0.01
(0.18)
0.02
(0.19)
0.01
(0.19)
0.05
(0.17)
1.29
(0.48)
1.36
(0.47)
1.29
(0.49)
1.43
(0.41)
1.28
(0.44)
Exp-Con
Exp-Con
Con
Exp
Con
Exp
Exp
(n ¼ 36)
Exp
(n ¼ 36)
Exp
(n ¼ 36)
1.38
(0.39)
Walking performance
Fast walking speed (ms1)
Outcome
Groups
Con
(n ¼ 35)
Week 10
Week 0
Con
(n ¼ 35)
Week 22
Con
(n ¼ 35)
Week 10 minus
Week 0
Difference within groups
Week 22 minus
Week 0
Week 10 minus
Week 0
Difference between groups
Week 22 minus
Week 0
Multiple Sclerosis Journal 0(00)
Table 3. Primary outcomes: Walking performance. Mean (SD) of groups, mean (SD) difference within groups, and mean difference and effect size (d) (95% CI) between groups
8
speed, and between measures of muscle endurance and
walking endurance. In addition, inspection of the
between-group differences in walking performance suggested a small, non-significant trend in favor of PRT, as
indicated by how close the lower 95% confidence bands
were to zero. In combination, these results suggest that
if the effect sizes of the current study were maintained
and the sample size was larger we may have observed a
statistically significant systematic improvement in walking performance in the PRT group. In other words our
study may have been underpowered to detect the relatively small effects due to the exercise component of the
training program without the added elements of
increased attention and social interaction.
The sample size calculation for our study was based
on an effect size of d ¼ 0.75 reported in a pilot study.13
A recent meta-analysis36 on the effect of exercise on
walking ability in people with MS suggested an overall
effect size of d ¼ 0.19 (95% CI 0.09–0.28), suggesting
our pilot data may have overestimated this effect.
Effect sizes calculated from the current experiment
(fast walking speed d ¼ 0.31, 95% CI 0.16–0.77; 2minute walk distance d ¼ 0.27, 95% CI 0.20–0.74)
are consistent with this meta-analysis. It is reasonable
to expect only small changes in walking ability after a
PRT program, particularly from a relatively short program, because muscle strength is only one component
that contributes to walking. Therefore implementing
PRT to improve walking might be best suited for
patients for whom muscle strength is the primary limitation affecting their walking ability.
Despite not observing any changes in walking performance, our results showed that PRT can lead to
clinically and statistically significant changes in physical
fatigue and in muscle endurance in people with MS.
Further, there was a moderate correlation between
changes in fatigue and muscle endurance. In addition,
PRT can lead to small significant changes in muscle
strength and quality of life. These changes are relevant
as physical fatigue, poor muscle endurance and muscle
weakness are some of the primary symptoms reported
by people with MS. In the current study 58% of our
participants (41/71) were categorized as being fatigued
at baseline. This supports the findings of a previous
study that reported 68% of people with MS rated fatigue as one of their worst symptoms, and 44% said they
experienced fatigue every day.37 Also, compared with
people without impairment, people with MS demonstrate reduced muscle strength of up to 26%, and
have muscles that fatigue about 10% more quickly
with repeated contractions.38
The finding that physical fatigue was improved by
PRT and was associated with changes in muscle endurance is important to people with MS, clinicians, and to
health services. First, there is no other effective
Downloaded from msj.sagepub.com at UNIV OF DELAWARE LIB on September 14, 2011
20.5
(14.1)
Reverse leg press
endurance (repetitions)
Downloaded from msj.sagepub.com at UNIV OF DELAWARE LIB on September 14, 2011
22.2
(6.8)
15.7
(7.6)
MFIS physical (0-36)
MFIS cognitive (0-40)
41.9
(14.0)
30.8
(22.3)
Reverse leg press
1RM (kg)
Fatigue
MFIS total (0–84)
43.4
(32.4)
70.0
(36.0)
15.3
(9.2)
21.7
(7.7)
40.0
(15.8)
18.1
(13.3)
27.4
(18.0)
40.7
(28.2)
62.2
(37.6)
12.5
(6.5)
16.3
(6.0)
31.7
(11.3)
28.5
(14.0)
37.3
(21.2)
80.9
(106.8)
85.8
(46.5)
Exp
(n ¼ 36)
Exp
(n ¼ 36)
Con
(n ¼ 35)
Week 10
Week 0
Groups
Leg press endurance
(repetitions)
Muscle performance
Leg press 1RM (kg)
Outcome
13.6
(9.3)
19.9
(7.7)
37.0
(16.9)
18.6
(12.8)
28.5
(18.1)
49.7
(40.3)
66.0
(41.6)
Con
(n ¼ 35)
15.5
(7.8)
19.6
(6.9)
39.0
(14.7)
27.7
(14.5)
35.8
(20.1)
70.2
(93.7)
80.2
(40.5)
Exp
(n ¼ 36)
Week 22
13.2
(8.6)
19.5
(7.2)
36.2
(16.2)
19.1
(12.5)
32.1
(19.5)
53.1
(52.8)
68.3
(42.5)
Con
(n ¼ 35)
3.2
(5.9)
5.9
(5.9)
10.2
(11.2)
8.0
(15.1)
6.5
(8.7)
37.5
(81.8)
15.9
(15.5)
Exp
1.7
(6.9)
1.8
(6.8)
3.0
(14.1)
0.7
(9.3)
1.1
(7.9)
9.1
(36.9)
3.9
(11.1)
Con
Week 10 minus
Week 0
0.2
(7.0)
2.6
(6.8)
2.9
(12.8)
7.2
(15.3)
5.0
(10.1)
26.7
(69.4)
10.2
(13.7)
Exp
2.1
(6.3)
2.1
(5.4)
4.8
(12.4)
1.0
(9.4)
4.7
(7.9)
12.4
(41.8)
6.2
(11.6)
Con
Week 22 minus
Week 0
Difference within groups
5.9*
(11.3–0.5)
d ¼ .37
(0.83–0.11)
3.9*
(6.6–1.3)
d ¼ 0.52
(0.99–0.04)
1.3
(4.1–1.4)
d ¼ 0.14
(0.60–0.35)
10.8*
(4.9–16.7)
d ¼ 0.44
(0.03–0.91)
26.0
(1.7–53.8)
d ¼ 0.38
(0.09–0.85)
5.7*
(1.9–9.5)
d ¼ 0.44
(0.03–0.91)
8.3*
(3.0–13.6)
d ¼ 0.73
(0.25–1.21)
Exp-Con
Week 10 minus
Week 0
(continued)
2.2
(3.4–7.8)
d ¼ 0.18
(0.29–0.65)
0.2
(2.8–2.4)
d ¼ 0.01
(0.45–0.48)
2.1
(0.8–5.0)
d ¼ 0.28
(0.19–0.74)
3.5
(2.5–9.4)
d ¼ 0.28
(0.18–0.75)
11.9
(12.5–36.2)
d ¼ 0.22
(0.25–0.69)
0.7
(3.5–4.9)
d ¼ 0.18
(0.28–0.65)
7.3*
(1.9–12.6)
d ¼ 0.63
(0.15–1.1)
Exp-Con
Week 22 minus
Week 0
Difference between groups
Table 4. Secondary Outcomes: Muscle performance, fatigue, quality of life, stiffness, and spasm. Mean (SD) of groups, mean (SD) difference within groups, and mean (95% CI)
difference and effect size (d) between groups
Dodd et al.
9
Downloaded from msj.sagepub.com at UNIV OF DELAWARE LIB on September 14, 2011
22.3
(7.7)
MSIS-88 muscle
spasms (14-56)
22.8
(9.2)
25.1
(9.0)
20.3
(6.1)
22.4
(7.8)
24.9
(4.7)
3.3
(0.9)
4.2
(0.9)
2.9
(1.7)
23.3
(7.6)
24.7
(7.9)
22.9
(5.0)
2.9
(1.2)
4.0
(0.9)
3.5
(2.2)
Con
(n ¼ 35)
23.4
(8.5)
26.5
(8.7)
23.4
(5.4)
3.1
(1.0)
3.7
(1.1)
3.9
(1.9)
Exp
(n ¼ 36)
Week 22
21.7
(6.3)
24.2
(8.2)
23.5
(4.6)
3.0
(1.0)
4.0
(1.0)
3.5
(2.3)
Con
(n ¼ 35)
2.0
(6.2)
3.6
(7.6)
1.8
(3.4)
0.3
(1.2)
0.4
(0.9)
1.1
(1.6)
Exp
0.5
(8.9)
0.5
(6.0)
0.3
(2.8)
0.1
(1.0)
0.1
(0.8)
0.4
(2.4)
Con
Week 10 minus
Week 0
1.1
(8.2)
0.5
(7.0)
0.3
(3.3)
0.1
(1.1)
0.1
(1.1)
0.1
(2.0)
Exp
1.1
(7.5)
0.7
(7.7)
0.9
(3.2)
0.1
(1.0)
0.1
(0.8)
0.5
(2.2)
Con
Week 22 minus
Week 0
Difference within groups
2.4
(5.2–0.5)
d ¼ 0.29
(0.76–0.18)
2.8
(5.6–0.03)
d ¼ .43
(0.90–0.04)
0.3
(0.1–0.6)
d ¼ 0.22
(0.25–0.69)
0.4
(0.04–0.9)
d ¼ 0.37
(0.10–0.84)
1.5*
(0.1–2.9)
d ¼ 0.41
(0.06–0.88)
0.7
(1.5 to 0.2)
d ¼ 0.30
(0.77 to 0.17)
Exp-Con
Week 10 minus
Week 0
0.8
(2.3–4.0)
d ¼ 0.27
(0.20–0.74)
1.9
(1.1–5.0)
d ¼ 0.22
(0.24–0.69)
0.2
(0.6–0.3)
d ¼ 0.28
(0.75–0.19)
0.001
(0.4–0.4)
d ¼ 0.10
(0.37–0.56)
0.5
(2.0–1.0)
d ¼ 0.02
(0.49–0.45)
0.4
(0.5 to 1.3)
d ¼ 0.19
(0.28 to 0.65)
Exp-Con
Week 22 minus
Week 0
Difference between groups
Exp, strength training group; Con, education/low activity group; MFIS, modified fatigue impact scale; MSIS-88, multiple sclerosis spasticity scale; WHOQOL-BREF=World Health Organization Quality of Life
– shorter version. * p < 0.05.
27.0
(8.8)
22.6
(4.5)
23.1
(4.8)
WHOQOL-BREF
Physical health
(7-35)
Stiffness & spasm
MSIS-88 muscle
stiffness (12-48)
2.9
(1.0)
3.0
(1.0)
WHOQOL-BREF
overall health (1-5)
3.9
(1.0)
4.0
(2.2)
3.8
(0.9)
4.0
(1.7)
Exp
(n ¼ 36)
Exp
(n ¼ 36)
Con
(n ¼ 35)
Week 10
Week 0
Groups
Quality of life
WHOQOL-BREF
overall quality of life (1-5)
MFIS psychosocial (0-8)
Outcome
Table 4. Continued
10
Multiple Sclerosis Journal 0(00)
Dodd et al.
11
intervention (pharmacological or psychosocial) for fatigue in people with MS. A recent systematic review concluded that the effectiveness of both pharmacological
and psychosocial interventions for the treatment of fatigue in adults with MS were modest at best.39 Our data
confirm the results of a smaller randomized controlled
trial showing that PRT can reduce fatigue,10 and therefore it can be used as a viable treatment option for a
debilitating symptom. Second, fatigue has a negative
effect on the quality of life of people with MS,40 therefore PRT has the potential to make a significant difference to this key aspect in the everyday lives of this
group. Third, people with MS who complain of fatigue
are reported to use more hospital outpatient care and
primary care services, including rehabilitation, compared with people with mild MS with no fatigue,41
therefore reducing fatigue in this group has the potential to also reduce health care costs. It is important to
note there are different aspects to fatigue: lassitude or
feelings of reduced energy, and muscle fatigue or a
decline in motor performance during sustained muscle
activity.42 Our results suggest that PRT reduced physical fatigue but had no effect on psychosocial or cognitive fatigue. Therefore, a PRT program is appropriate if
people with MS have symptoms of physical fatigue.
There were no adverse events from the program,
indicating that it is a relatively safe form of exercise
for adults with MS. Most participants experienced
muscle soreness during the early weeks of training,
but this is expected for participants who had not previously participated in a PRT program. There was no
increase in the symptoms of muscle spasms or muscle
stiffness; in fact, there was a trend for the symptoms of
muscle spasms to improve with training. These findings
are consistent with the conclusions of a previous
study43 that showed PRT was a relatively safe intervention for people with a broad range of health conditions.
The training program conducted in this trial is typical of those that members of the community might
undertake if they attended their local gymnasium.
This is noteworthy because people with disability
(including people with MS) may have restricted opportunities to participate in exercise programs taking place
in community settings.44 The training also took the
form of small group-based training; this is important
because it made exercising a more social activity, and it
was more cost effective and time efficient than individual training. Our results suggest a community-based
group program, as implemented in this trial, is feasible
for people with MS as a therapeutic intervention and as
a recreation option. There was good adherence with the
training program (92%), compared with the control
group’s adherence with the increased attention and
social activities program (62%). No participants withdrew from the experimental group once training had
started, indicating that PRT was an acceptable form
of exercise. However, the follow-up data found that
the benefits of the program declined once the program
was stopped. This suggests that people with MS need to
continue to train to maintain the benefits.
The strengths of our trial were that it was a highquality randomized controlled trial that assessed the
effects of a PRT program conforming to the training
guidelines of the American College of Sports
Medicine.7 We used concealed allocation, blinded
assessment, random allocation and intention-to-treat
analysis to control for many potential sources of bias.
Particularly important is that we controlled for the
increased attention and social component of the exercise program. This is a limitation of previous studies in
this area810 and is a common concern with exercise
programs. This study adds to the small number of
high-quality studies that have investigated if PRT programs are beneficial for adults with MS.810
The limitations of this study include that the study
only included participants with relapsing–remitting MS
who had mild to moderate walking impairment.
Therefore, the results may not be generalizable to
people with other forms of MS and those with more
severe disability. Another limitation is that in designing
the trial, we were conscious of selecting only a reasonable number of outcomes for assessment; therefore it is
possible that there are other positive or negative outcomes from the program that we did not measure. A
further possible limitation is that muscle performance
outcomes were assessed using the same equipment participants trained on, therefore improvements in muscle
strength and endurance are likely to contain a component of learning. For example, a recent study9 that measured the maximal isometric knee extensor muscle
strength of a group of 15 participants with MS using
a dynamometer, and the leg press 1RM using a leg
press machine reported pre–post-intervention percentage changes in strength of around 16% (95%CI 4–27)
for the isometric measures and 37% (95%CI 27–48) for
the 1RM measures. It is possible that learning, together
with other components such as the differences in the
type of muscle strength measured (isometric versus isotonic strength), differences in the number of exercises
that would be expected to influence a composite outcome measure versus a single muscle group outcome
measure, and measurement variability inherent in
each of the measurement procedures may contribute
to these observed differences. Despite this consideration, in the current study a decision was made to use
isotonic measures because they better met the principle
of specificity of measurement than alternative measures
such as dynamometers. In other words isotonic outcome measures better measured the type of strength
and endurance the program was trying to improve – a
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12
Multiple Sclerosis Journal 0(00)
dynamic through-range composite measure of strength
and endurance similar to that needed during functional
activities such as walking – than dynamometric measures. To minimize possible learning effects, the 1RM
and muscle endurance protocols were not practiced
during training sessions. Finally, the intervention program was not individualized to the participants’ primary impairments and all the participants completed
a similar program targeted at strengthening the major
muscles of the lower limbs. It is possible that a program
that targets the specific deficits of an individual might
be more effective.
Conclusion
PRT performed in a community gymnasium did not
lead to improved walking performance, but was effective in the short term in reducing physical fatigue and
increasing muscle endurance in people with relapsing–
remitting MS and mild to moderate walking difficulty.
It also appears to be a feasible and safe fitness option
for people with MS that can also lead to small improvements in muscle strength and quality of life. However,
benefits do not appear to persist if training is completely stopped.
Funding
This work was supported by Multiple Sclerosis Research
Australia.
Conflict of interest statement
The authors declare that they have no conflicts of interest.
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