1. 1
The effect of progressive resistance training in multiple
sclerosis patients: A systematic review
By Daniel Yazbek
Abstract
Aim: This paper reports a systematic review of progressive resistance training (PRT)
interventions for persons with multiple sclerosis (MS). The sum of randomised
controlled trials (RCTs) within this review aims to report outcome measures in quality
of life (QOL), physical function, balance and gait. Background: MS is an auto-
immune disease resulting in the destruction of the myelin sheath and nerve axons of
the brain and spinal cord, severely impacting on a person’s QOL. Numerous studies
have been shown that exercise activity can improve subjective symptoms of fatigue,
mood, depression and functional outcomes. However, few studies of high calibre
have investigated the effects of progressive resistance training in outcome measures
in those with MS. Methods: A comprehensive literature search identified all studies
of those which contained the key words related to multiple sclerosis and progressive
resistance training. It included four electronic database and two internet search
engines. Language was limited to English and was dated from 2000 to 2011. PRT
studies examining the effects on outcome measures were selected for review.
Studies were analysed by the different types of intervention strategies in enhancing
QOL, physical function, balance and gait in MS. Results: Meta-analysis showed a
significant mean difference in leg strength, indicating the positive impact of PRT in
patients with MS. Conclusion: Future studies should aim at recruiting those with
varying levels of disability (QOL, spasticity, gait & fatigue) so that exercise
prescription can be broader in its approach to achieve greater health benefits for a
wider population with MS.
Keywords: Multiple Sclerosis, Progressive resistance training, Meta-analysis

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Introduction
Multiple Sclerosis (MS) involves destruction and demyelination of the myelin sheaths
that surround neurons within the brain and spinal cord (Haines, Inglese, & Casaccia,
2011). There is growing evidence that a catastrophic auto-immune response
targeted at the white matter of the brain and spinal cord has a role in the disease
onset (Lucas et al., 2011). Severe MS is characterised by muscle weakness,
spasticity, systemic fatigue, sensory loss and pathological reflexes (Thompson,
Toosy, & Ciccarelli, 2010).The symptoms of MS have been shown to negatively
impact physical function, quality of life (QOL), balance, central neurophysiologic
responses, gait and general health (Hale, Nukada, Du Plessis, & Peebles, 2009;
Sanya et al., 2005).The inability to ambulate, usually presented during the advanced
stages of the disease, is the most common problem for those suffering from MS
(Wahls, Reese, Kaplan, & Darling, 2010).
In a review of the literature by Thompson et al. (2010), the evidence base for drug
therapy in reducing symptoms of MS such as muscle spasticity is underpowered.
Baclofen, benzodiazepines and tizanidine have shown to reduce stiffness and
spasticity, but their side effects include postural hypotension, fatigue, dizziness and
abnormal liver functioning (Thompson et al., 2010). Invasive interventions such as
deep brain stimulation and stereotactic thalamotomy have shown to be successful
although there have not been enough randomized controlled trials in confirming the
significant reduction of ataxia and tremor in those with MS with these treatments
(Thompson et al., 2010).
Numerous studies investigated the effects of exercise on MS in improving strength,
fatigue, and QOL. Along with the positive benefits that MS patients gain through
exercise treatment, exasperations of fatigue, muscle weakness and pain have not
been reported in the majority of studies (Petajan & White, 1999). Mostert and
Kesselring (2002) investigated the effects of a 4-week aerobic exercise program
consisting 5 bouts of 30 minutes of individualized intensity on a cycle ergometer.
Baseline measures of activity level, fatigue, aerobic threshold and health perception
were recorded. After the intervention, there was an improvement in functional
capacity, along with an improvement in activity levels and perception of fatigue as

3. 3
indicated by questionnaires. Additionally, 19 subjects with MS of mild to moderate
disability were engaged in an 8-week aerobic training program. At post intervention,
scores for walking distances and speed during a self-paced walk test were improved
as well as perceived level of exertion and oxygen pulse reading (Rampello et al.,
2007).
Over the past decade the mainstream rehabilitative exercise management in MS
subjects was primarily consisted of aerobic training rather than strength training
interventions. This may be due to the assumption that resistance training will further
raise core temperature causing a conduction block in demyelinated nerves, thereby
worsening the severity of symptoms associated with MS (Dodd, Taylor, Denisenko,
& Prasad, 2006). As such, researchers have been reluctant to perform randomized
controlled trials involving MS patients undergoing progressive resistance training
(PRT). Most studies examining the effects of PRT used small sample sizes, such as
pilot and single group repeated measure designs, which neglected random sampling
from MS patients and lacked control groups (Ayán Pérez, Martín Sánchez, De Souza
Teixeira, & De Paz Fernández, 2007; Filipi, Kucera, Filipi, Ridpath, & Leuschen,
2011; Sethy, Bajpai, & Kujur, 2010).
On the other hand, insufficient intensity of the training load and levels of disability
might have caused the paucity of PRT interventions. In a study by Ronai, LaFontaine
and Bollinger (2011), MS subjects with mild to moderate walking impairment did not
increase their scores within the 2-minute walk test and maximal walking speed
although subjects underwent an appropriate resistance training program matched by
the ACSM guidelines. There was no relationship between an increase in leg strength
and walking parameters which seem to reflect the training principle of specificity.
Nevertheless patients with higher levels of walking impairment may benefit from
strength training, as muscle strength may be a greater rate limiter in those.
Despite MS patients being in a chronic pathological state, there is a potential for
improvement in strength and functional capacity which shows comparative effect to
those who are healthy (Ogasawara, Yasuda, Sakamaki, Ozaki, & Abe, 2011; White
et al., 2004). This implies that strength reserve or adaptation is not affected by the
disease. This intact neuromuscular adaptation can be explained by exercise-induced

4. 4
neuronal activity which contributes to the production of neutrotrophic factors that
could in turn promote neuroprotection, neuroregeneration and neuroplasticity (White
& Castellano, 2008).
To date, there has been no systematic review on the effects of PRT in MS patients.
Therefore, this paper aims to systematically identify the benefits of PRT interventions
in studies with appropriate methodological quality and randomized controlled
designs.
Methods
Identification and selection of literature
A comprehensive literature search was performed using electronic databases,
including Medline (2000 to Dec 2011); SPORTDiscus (2000 to Dec 2011); Web of
Science (2000 to Dec 2011); and Cinahl (2000 to Dec 2011). The following keywords
were used: ‘Multiple sclerosis’ combined with‘strength training’, ‘weight training’ or
resistance training’. To optimize journal article selection, abstracts and full texts were
selected prior to searching.
A study was included if it met the following criteria:
 Participants: People with MS aged 18 years or over
 MS history: Varying disability levels
 Outcome measures (at least one of the following): muscle strength, quality of
life, functional capacity, mood, subjective fatigue, gait, balance
 Intervention: Progressive resistance exercise/training compared with a control
group
 Study design: Randomized controlled trial (RCT) consisting of qualitative,
quantitative or mixed-methods research design
For a study to be excluded, the intervention must be of any other than resistance
exercise or PRT (e.g. cardiovascular/aerobic exercise, pharmacological treatment,
physical therapy, chiropractic or any other manual medicine, cognitive behavioural
therapy or any other behavioural interventions). Any study that failed to report
outcomes at baseline testing prior to the intervention were also excluded.

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Selection of data and analysis of quality
The quality of each study was determined by internal validity (intention to treat
analysis, blinding study designs, reporting of subject withdrawals within groups and
randomisation), external validity (inclusion/exclusion criteria) and power analysis
(sample size calculation). Assessment of quality was accomplished by the
attainment of a critical appraisal skills programme (CASP) (Guyatt et al., 1995). This
programme tool involves 10 screening questions that determine the quality of RCTs.
Each question will be answered ‘yes’, ‘can’t tell’ and ‘no’ for each RCT, and will be
awarded1 point, zero points or a deduction point respectively, with a total score out
of 10.
Data analysis and synthesis
The most commonly reported outcome measure was leg strength where three of the
four studies reported it as a primary outcome. Therefore, meta-analysis was
undertaken on this variable using MetaEasy Excel add-in (StatAnalysis;
Kontopantelis& Reeves, 2009). A standardised effect size was calculated for each
study and expressed in standard deviation units. An overall effect was calculated
using the DerSimonial-Laird method (DerSimonial& Laird, 1986).
Results
The initial search identified 341 articles, and 157 studies remained after the initial
screening. Applying the exclusion/inclusion criteria to these articles resulted in four
studies (Figure 1). Table 1 summarizes the quality of the five studies included in this
systematic review. Two studies were found to be of moderate quality (score ≥4 & ≤
6), and two of low quality (score ≤ 3).
All of the included studies provided well-defined selection criteria and an extensive
rationale for the use of resistance training as an intervention for MS. Three studies
(Dalgas, et al., 2010; DeBolt & McCubbin, 2004; Dodd et al., 2011) reported both
power and sample size calculations. Subject exclusion criteria showed to be similar
in all the selected studies. An intention to treat analysis was performed in one study
(Dodd et al., 2011).One study (Dodd, et al., 2011) reported adequate concealment of
randomization. Dodd et al. (2011) stated that subjects were blinded during group

6. 6
allocation; however, this study did not mention if subjects or assessor was blinded to
pre-testing results.
All participants in the four studies were accounted for at its conclusion. Only one
study (Fimland et al., 2010) was successful in retaining participant numbers at
baseline throughout the intervention in which outcome measures were completed on
all but one subject in the PRT group. This subject was tested on all but one
dependant variable measure (electrostimulation). Overall, 15 out of 128 participants
(11.7%) from the four studies dropped out (dropout average:3.8 participants/study).
Six out of fifteen (40%) of those who dropped out were attributed to medical reasons,
which involved typical MS exasperations.
Figure1.Flow diagram for literature search.

7. 7
Table 1.Description of the quality of selected studies
Study Design
Rationale
described?
Power/sample
size calculations
presented?
Selection
criteria
described?
Assessor/participants
blinded?
Adequate
concealment of
randomization?
Intention to
treat analysis
performed?
*CASP quality
score
Fimland et al.
(2010)
Matched
RCT
Parallel
Yes No Yes Not reported Not reported No 2 (Low)
Dalgas et al.
(2010)
Matched
RCT
Parallel
Yes Yes Yes Not reported Not reported No 3 (Low)
DeBolt et al.
(2004)
Matched
RCT
Parallel
Yes Yes Yes Not reported Not reported No 4 (moderate)
Dodd et al.
(2011)
Matched
RCT
Parallel
Yes Yes Yes Yes Yes Yes 6 (moderate)
* CASP score out of maximum of 10

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Table 2.Variations and outcomes of selected studies
Study Subjects Resistance training Duration Outcome measures Major findings
Fimland et al.
(2010)
1) 7 PRT MS patients
(33-65 yrs, YSD: 8±1)
2) 7 MS cons (48-60
yrs, YSD: 8±1)
PRT: Unilateral Horizontal leg
press and seated calf raises
4x4 reps (85-90%1RM) 1-2
min rest between sets, load ↑
5% when subjects could
complete 4x4 reps +
concurrent aqua, stretching,
physiotherapy and relaxation
techniques Cons: Aqua,
stretching, physiotherapy,
relaxation techniques
15 sessions
(3 days/wk, 5
weeks)
- Horizontal leg press MVC
Torque
- Seated calf raise MVC
Torque
- Soleus EMG RMS activity
- V/Msup and Hsup/Msup
1) MVC Torque ↑ 20.1±9%
2) Soleus EMG RMS activity
↑ 36±16%
3) V/Msup ↑ 0.17 ± 0.04 -
0.25±0.03
4) No sig change in
Hsup/Msup
Dalgas et al.
(2010)
1) 15 PRT MS patients
(47.7±10.4yrs, YSD:
6.6±5.9yrs)
2) 16 MS Cons
(49.1±8.4yrs, YSD:
8.1±6.0yrs)
PRT: leg press, knee
extension, hip flexion,
hamstring curl & hip extension
wks 1-2 (3x10rep, 15RM)
wks 3-4 (3x12rep, 12RM)
wks 5-6 (4x12rep, 12RM)
wks 7-8 (4x10rep, 10RM)
wks 9-10 (4x8rep, 8RM)
wks 11-12 (3x8rep, 8RM)
2-3 min rest between sets
24 sessions (2
days/wk, 12
weeks)
Muscle CSA, Muscle FT,
TV (Anthropometric
measures), Isokinetic KE at
180°, Isokinetic KF at 90°
and 180°
PRT ↑ mean CSA of all
muscle fibres (7.9±15.4 %
vs -2.6±15.5%, p= 0.02) ↑in
comparison to Cons. ↔ total
TH in PRT. Isokinetic
strength at KE 180°, KF 90 °
and KF 180°↑ sig post PRT
compared to Cons (10.2-
21.3%) p ≤ 0.02

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DeBolt et al.
(2004)
1) 19 PRT MS patients
(50.3-51.1 yrs, YSD:
15.1)
2) 17 MS Cons (50.3-
51.1 yrs, YSD: 15.1)
PRT: Chair raises, step-ups,
heel - toe raises, leg curls, wk
1+3: 2 x 8-12 reps, wk 2+4: 3 x
8-12 reps, wk 5–8: 2 x 8-10
reps. load = 0.5% BWT ↑0.05-
1.5% every 2 wks
4 sessions
2/wk (FMZN) +
24 sessions (3
days/wk, 8
weeks)
-Leg extensor power
- Balance measured by AP,
ML sway and sway velocity
- Mobility assessed by UAG
test
- MAS and EDSS to
measure MS spasticity and
symptoms
1) no sig difference btwn RT
and Con group in AP or ML
sway and sway velocity
2) 18 adults ↓ time by 12.7%
in UAG test 3) RT and Con ↑
leg ext
power by 37.4% and 6.7%
respectively using GBT
analysis
Dodd et al.
(2011)
1) 36 PRT MS patients
(47.7±10.8yrs, YSD:ukn)
2) 35 Cons MS patients
(50±9.6yrs, YSD: ukn)
PRT: Leg press, knee
extension, calf raises, leg curl,
reverse leg press. 2 x 10-12
reps, 2 min rest btwn sets
20 sessions (2
days/wk, 10
wks)
POM: 2MWT, Change in
max walking speed SOM:
Single seated leg press
1RM, Single reverse leg
press 1RM, SSLP 50% 1RM
& SRLP 50% 1RM till
volitional fatigue. Self-
reported fatigue using MFIS
& spasticity symptoms using
MSSS-88
1) no sig ↑in 2MWT or
↑maximal walking speed
compared to Cons
2) Sig ↑1RM leg press &
1RM reverse leg press
compared to Cons
3)PRT ↑ 50% 1RM leg press
& reverse leg press till
fatigue
4) Sig ↓ perceived
symptoms of PF compared
to Cons
MS = Multiple Sclerosis,CON = control group,PRT = Progressive Resistance Training,yrs = years, wk = week, MVC = Maximal voluntary contraction,YSD = Years since
diagnosis,CSA= Cross Sectional Area,ukn = Unknown,KE = Knee extension,KF = Knee flexion, sig = Significant,non sig = N on Significant,FT = Fibre type, TV = Thigh
Volume,↑ = Increase,↓ = Decrease, ↔ = No change,reps = repetitions,EMG = Electromyography, RMS = Root mean square,V = V waves , Hsup = Superimposed H -
Reflexes , Msup = MSuperimposed M waves , 2MWT = two minute walk test, AP = Anterior - posterior,ML = Medio - lateral, RM = repetition maximum,QOL = Quality of
life, FSS = Fatigue severity scale,MFI - 20 = Multidimensional fatigue inventory, MDI = Major depression Inventory, GF = General fatigue, PF = Physical fatigue, MC =
Mental component, SF - 36 = Quality of life questionnaire,POM = Primary outcome measures,SOM = Secondary outcome measures,SSLP = Single seated le g press,
SRLP = SIngle reverse leg press,MFIS = Modified fatigue impactscale ,MSSS = Multiple Sclerosis spasticityscale, GBT = Group by time analysis

10. 10
Participants
The main characteristics and outcomes of the four studies are summarised in Table
2. The minimum participants in a study was 14 (Fimland et al., 2010) and the
maximum 71 (Dodd et al., 2011). Only one of the four studies (Dodd et al., 2011)
failed to provide the years since having the diagnosis. All of the four studies reported
no significant difference in demographic baseline measures between groups.
Two of the four studies (Dalgas et al., 2010; Dodd et al., 2011) reported an extensive
inclusion and exclusion criteria; one study (Fimland et al., 2010) only used an
inclusion criteria of Expanded Disability Status Scale (EDSS)values. Only one of the
four studies (DeBolt & McCubbin, 2004) involved subjects who were more
representative of MS patients from a greater population. This study had only one
inclusion criteria able to ambulate > 20 metres without an assistive device and
recruited participants who varied in weight, height, years since diagnosis, gender,
type of MS and EDSS score except Modified Ashworth scale (MAS spasticity
measure).
Intervention
Only one study (Dalgas, et al., 2010) was based on a strength training periodization
model. The principle of progressive overload was applied to three of the four
selected studies (Dalgas et al., 2010;DeBolt & McCubbin, 2004; Fimland et al.,
2010). Dodd et al. (2011) failed to apply a loading procedure to the strength training
intervention.
Only one out of the four studies (DeBolt & McCubbin., 2004) included 2 week (three
days/week) familiarisation sessions which explained the appropriate and safe
method of lifting execution, prior to the actual strength training intervention. In this
study, participants were able to visually observe an exercise video during or before
exercise sessions.
The most commonly used strengthening exercise within all the four studies of the
training intervention were hamstring (leg) curls. Only one study (DeBolt & McCubbin,
2004) failed to report the rest time interval between sets. Two studies (Dalgas et al.,
2010;DeBolt & McCubbin, 2004) involved 24 weeks of resistance training sessions

11. 11
throughout the intervention.Two studies (Dodd et al., 2011; Fimland et al., 2010)
involved strength training interventions of much less duration, being 20 and 15
weeks respectively.
In regards to resistance training within groups, only two studies (Dodd et al., 2011;
Fimland et al., 2010) explained what activities the control group underwent within the
training intervention. The control groups within these studies received leisure and
social activities not expected to have a fitness effect, such as massage, yoga,
Bobath therapy luncheons, aqua or physiotherapy, stretching and relaxation.
Outcomes
The outcomes for all the studies have been summarised (Table 2) and presented in
narrative form. Most studies differed in their intervention, duration and outcome
measures, yet the most common outcome measures between the threestudies were
leg strength.All studies provided a rationale as to why certain outcome measures
should be examined. However, one study (Fimland et al., 2010) did not explain the
purpose for measuring electromyography of the tibialis anterior after a lower
extremity resistance training intervention, composed of leg presses and seated calf
raises. Additionally this study did not express outcome measures for neural
adaptations (V/Msup or Hsup/Msup) in ratios but rather whole numerical values.
Strength. As can be seen in Figure 2, three out of the four studies measured leg
strength and produced a positive overall effect to suggest that PRT interventions are
most likely to result in improvement in leg strength (standardised mean difference:
0.38; 95% CI: 0.06–0.70). Testing for heterogeneity was not statistically significant
(X² = 0.18, df = 3, p> 0.05).
Only one study (DeBolt & McCubbin, 2004) attempted to produce a reliable pre-
testing measure. DeBolt & McCubbin (2004) appropriately performed an average of
multiple supine single leg extension power tests until plateau. In this study, leg
extensor power was averaged by summing eight to nine trials (or prior plateau) from
the right and left leg and then divided by each participant’s bodyweight. The PRT
group had slightly less lower extremity power than the control group at baseline, but
the main effect for this group implied to be non-significant. Of note is that this study

12. 12
reported one subject from the PRT group to pull out prior to end of training
intervention due to exasperation of MS symptoms.
Figure 2. Overall effect of the three interventions on leg strength
Gait. Only one study (Dodd et al., 2011) reported gait as an outcome measure.
There was no significant improvement in the 2 minute walk test or maximal walking
speed compared to controls.
Physical function. Only one of the fourstudies (DeBolt & McCubbin, 2004) assessed
physical function through the use of the up and go test. There was a significant
reduction (12.7%) in time for the up and go test in the PRT compared to control
group.
Balance. Only one study (DeBolt & McCubbin, 2004) reported balance as an
outcome measure. After 24 PRT sessions, anterior-posterior, medio-lateral sway and
sway velocity did not show to be statistically significant between the PRT and control
group.

13. 13
Quality of life (QOF).Two out of the fourstudies (DeBolt & McCubbin, 2004; Dodd et
al., 2011) examined QOF. Dodd et al. (2011) noted a significant reduction in physical
fatigue in PRT patients compared to controls, using the modified fatigue impact scale
(MFIS). There was no significant difference in spasticity symptoms between groups,
as measured by MSSS-88 (Multiple Sclerosis Spasticity Scale). Similarly, Debolt and
McCubbin (2004) found no significant difference between groups before and after
resistance training intervention in MAS scores. Contrary to Dodd et al. (2011), there
were no significant differences between groups for EDSS scores (p = 0.545) before
and after the intervention.
Discussion
The aim of this systematic review was to analyse and evaluate the effectiveness of
progressive resistance training interventions in randomised controlled trials
undertaken by MS patients. Study design, baseline measures and methodological
quality were below high standard in all four studies. For example, Dalgas et al.
(2010) failed to describe the process of randomization, details about study design
and a flow chart of patient selection. The clinician was blinded to all pre and post
testing outcome measures (thigh volume & muscle biopsies) except during isokinetic
strength testing. Furthermore, a power calculation for this study required at least 29
subjects per group, which exceeded the sample size of each group.
As confirmed by the meta-analysis, there was a significant difference in the mean
effect in leg strength in PRT compared to controls after the resistanceinterventions.
Moderate correlations between muscular strength and subjective measures were
observed, indicating that there are factors other than an increase in maximal
voluntary muscle contraction of the leg which result in the improvement in mood,
QOL and fatigue.
Highly variable results could be seen in the leg strength in Fimland et al. (2010)
(Figure 2). The results may be due to very small sample size of 7 participants per
group, for this study failed to provide power/sample size calculations to quantify
whether there would have been a true mean effect difference. On the other hand,
EDSS scores at baseline indicated that the PRT group had disability levels (4.6 ±

14. 14
0.4) greater than controls (3.5 ± 0.5) (Fimland et al., 2010). The authors of the study
did not report a statistical test to determine if there was non-significance between
groups at baseline. This may have raised the potential for the PRT group to
experience a greater mean significant difference in leg strength due to initial greater
disability levels. Perhaps utilising a cross-over study design may have been
statistically more efficient, reducing cofounding covariates and increasing study
effect size.
A periodised model of progressive resistance training was applied to Dalgas et al.
(2010) (see Table 2) which may influence strength gains and adaptations more
effectively than the typical exercise prescription model set by White and
Dressendorfer (2004) which involved 2–3 sets of 8–15 repetitions. Utilizing the PRT
progression model of Dalgas et al. (2010) should only be applied if an exercise
physiologist understands the disability level of the MS patient. A more conservative
approach would be to work in unison with a neurologist to make any amendments to
current PRT programs for MS patients. Fimland et al. (2010) incorporated a load of
85–90% 1RM with 4 sets of 4 repetitions for the duration of the study. Again, the
load, volume and frequency were greater than those recommended in the MS
guidelines review of White and Dressendorfer (2004).The balance line between
intensity, volume and frequency and the degree of exasperations needs to be
investigated further for effective designing of the PRT protocol.
There were four leg strength variables within the study by Dalgas et al. (2010),
differing in joint actions and execution speeds on the dynamometer. Knee extension
performed at180°/sec was randomly chosen for input into the analysis. Despite a
mean effect difference in the PRT compared to the control group, it would be
interesting to see whether this positive result would apply to the other three strength
variables (knee extension MVC at 90°, knee flexion at MVC at 90°& 180°).
Outcome measures such as muscular endurance till fatigue (50% 1RM leg press &
reverse leg press) increased significantly as a result of the intervention (Dalgas et
al., 2010). It appears from the study that loads aimed at increasing strength also
have a favourable effect on increasing muscular endurance. This challenges the
exercise guidelines of Ehrman,Gordon, Visich, and Keteyian (2003) which

15. 15
recommend loads between 40–50% 1RM to be utilized for achieving enhanced
muscular endurance. More RCTs are needed to evaluate the overall effect of this
outcome.
Conclusion
Overall, PRT should be for part of an overall intervention by any patient who suffers
from MS. Although there were few drop outs within the four studies, the benefits
exceeded those repercussions that resistance training may cause. In implementing
the PRT program for MS patients, professional guidance by an accredited exercise
physiologist is recommended for fine adjustments in the frequency, duration and
intensity of the program. Future RCT studies should aim at recruiting those with
varying levels of disability (QOL, spasticity, gait & fatigue) so that exercise
prescription can be broader in its approach to achievegreater health benefits and
represent a wider population in those with MS.

16. 16
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