NeuroRehabilitation 42 (2018) 131–142 131

DOI:10.3233/NRE-172238
IOS Press

How does strength training and balance

training affect gait and fatigue in patients
with Multiple Sclerosis? A study protocol
of a randomized controlled trial
Jacob Callesena,b,∗ , Davide Cattaneoc , John Brincksa and Ulrik Dalgasb
a Department of Physiotherapy, VIA University College, Faculty of Health Science, Aarhus, Denmark
b Department of Public Health, Aarhus University, Section of Sport Science, Aarhus, Denmark
c Larice Lab, Don Gnocchi Foundation, Gait and Balance Rehabilitation Lab, Milan, Italy

Abstract.
INTRODUCTION: Multiple sclerosis (MS) is characterized by a demyelination that results in reduced conductivity in the
somatosensory nervous system, decreased muscle strength, vestibular alteration, and severe fatigue. Progressive resistance
training (PRT) has proven to be a promising intervention showing a positive effect on muscle strength. Another promising
intervention frequently used in neuro-rehabilitation is task specific training where also Balance and Motor Control Training
(BMCT) are incorporated. Interestingly, the principles of BMCT do fundamentally contrast the principles of PRT in terms of
variation in movement pattern, loading and repetitions. Consequently, knowledge of any diverse effect would be of clinical
relevance.
AIM: To evaluate the effects of PRT and BMCT on gait, balance and fatigue in persons with MS.
METHOD: A three-armed multi-center, single-blinded cluster randomized controlled trial with two intervention groups
(1. PRT of the lower extremities. 2. BMCT that challenges gait function) and a control group that receives usual care
while on a waitlist for a combined PRT + BMCT intervention performed after the two interventions groups have completed
their interventions. The interventions last ten weeks with two sessions per week, in groups of 3–6 participants. Number of
participants is 30 per intervention – 90 in total. Primary outcome measures for gait function are the Timed 25 Foot Walk
(T25FW) and the Six Spot Step Test (SSST). Secondary outcomes are fatigue, perceived gait function, temporo-spatial gait
characteristics, balance and strength.
Inclusion criteria are: EDSS 2–6, SSST >8 sec and T25FW >5 sec. Exclusion: Recent attacks and ongoing intensive
rehabilitation.
ANALYSIS: The effects in the three groups are examined in a mixed effects regression analysis with group and time as fixed
effects and center and patient within center as random effects. Spearman or Pearson correlation analysis will be conducted
on baseline data to determine associations between the primary outcomes on gait function and the secondary outcomes on
fatigue, spatial gait parameters, balance and patient reported measures.
TRIAL REGISTRATION: The study is approved by the Regional ethical committee and registered at clinicaltrials.gov,
NCT02870023.

Keywords: Resistance training, balance training, multiple sclerosis, physiotherapy, gait

∗ Address for correspondence: Jacob Callesen, Department of ence, Hedeager 2, 8200 Aarhus N, Denmark. Tel.: +45 87552330;
Physiotherapy, VIA University College, Faculty of Health Sci- E-mail: jacc@via.dk.

1053-8135/18/$35.00 © 2018 – IOS Press and the authors. All rights reserved
132 J. Callesen et al. / How does strength training and balance training affect gait and fatigue in MS?
1. Background
Multiple sclerosis (MS) is characterized by
demyelination of the sensory and motor axons in the
central nervous system. MS mostly affects women
(women:men ratio: 2–4:1) in the second or third
decade of life (Cameron & Wagner, 2011; Nosewor-
thy, Lucchinetti, Rodriguez, & Weinshenker, 2000),
and approximately 2.3 million people have the dis-
ease world wide (Multiple Sclerosis International
Federation, 2014) The MS disease course is either
characterized by stable phases interrupted by periods
of disease activity (relapsing-remitting MS), or by
a continuous progressive development (primary and
secondary progressive MS).
People with MS experience a wide variety of
symptoms including impaired muscle strength and
balance, fatigue, impaired cognition, depression and
spasticity (Cameron & Wagner, 2011). Of these,
impaired balance (Boes et al., 2012) and severe
fatigue (Claros-Salinas et al., 2013) are described
as two of the most debilitating symptoms leading
to limitations in activities such as upright posture
and gait (Heesen et al., 2008; Penner et al., 2007).
Generally, pharmacological symptomatic treatment
has not proven efficient in the treatment of balance
problems, fatigue and walking impairments, with the
exception that Fampridine has beneficial effects on
gait performance in a subgroup of patients (Lee,
Newell, Ziegler, & Topping, 2008). Consequently,
non-pharmacological interventions that effectively
target these symptoms are warranted.
In the last decade progressive resistance training
(PRT) has proven to be one of the promising interven-
tions in patients with MS showing a consistent and
positive effect on muscle strength (Kjolhede, Viss-
ing, & Dalgas, 2012). However, the effect of PRT
on functional outcomes are heterogeneous but with
promising effects on daily activities such as walking
and chair rise (Kjolhede et al., 2012; Latimer-Cheung
et al., 2013; Motl & Pilutti, 2012). The evidence for
a beneficial effect of PRT on balance and postural
control is divergent and yet inadequately investi-
gated (Kjolhede et al., 2012). Regarding fatigue,
a recent Cochrane review reported that one could
expect improvements in MS fatigue after exercise
interventions, despite methodological flaws in the
existing literature, but only few studies evaluating
PRT were located (Heine, van de Port, Rietberg, van
Wegen, & Kwakkel, 2015).
Another promising intervention is task specific
training of motor function that is widely used by
physiotherapists in neurorehabilitation (Carr & Shep-
herd, 2010). In this study protocol, motor function is
limited to gait related functions with a particular focus
put on balance and motor control, why the term Bal-
ance and Motor Control Training (BMCT) is applied.
There is no universally accepted definition of human
balance, but balance defined as “the inherent ability
of a person to maintain, achieve or restore a spe-
cific state of balance and not to fall, with reference
to the motor and sensory systems and to the physical
properties of the person” (Pollock, Durward, Rowe,
& Paul, 2000), is applied in this study.
Effects obtained from BMCT partly result from
plastic changes in the nervous system (Khan, Amatya,
Galea, Gonzenbach, & Kesselring, 2016). To induce
such effects, repetition of a simple task only has
limited efficiency in order to improve performance.
Once a task has been learned to a certain level,
further practice of the same task will not be accom-
panied by further induction of plasticity and little is
therefore gained by continued practice of the task
(Nielsen, Willerslev-Olsen, Christiansen, Lundbye-
Jensen, & Lorentzen, 2015). To provide challenges
that ensures continued learning, training exercises
have to progress from simple movement trajectories
to more complex movements, that also incorpo-
rates goal setting (Nielsen et al., 2015). Moreover, it
has been shown that shaping and variation of tasks
in combination with feedback on movement qual-
ity is of great importance for the learning outcome
(Homberg, 2013). The underlying concept for per-
forming BMCT is, therefore, that improved motor
control will optimize the movement strategy, which
further leads to improved gait function (Carling, Fors-
berg, Gunnarsson, & Nilsagård, 2016).
Regarding the effects of BMCT on fatigue, there
are diverging results in the literature, but the literature
on BMCT for patients with MS is generally of low
quality with an inadequate description of interven-
tions (Paltamaa, Sjogren, Peurala, & Heinonen, 2012;
Rietberg, Brooks, Uitdehaag, & Kwakkel, 2005),
why further studies are warranted.
Interestingly, the principles of task specific training
do fundamentally contrast the principles of PRT, that
normally consist of monotonous movement patterns
performed under heavy loading for a low number of
repetitions (American College of Sports Medicine,
2009). Consequently, studies comparing the effects of
BMCT and PRT on gait function would add to the cur-
rent literature as no studies doing so could be located.
Such a comparison would help clarify whether
potential effects are overlapping or differentiated
 J. Callesen et al. / How does strength training and balance training affect gait and fatigue in MS?
and would help guiding future rehabilitation inter-
ventions in persons with MS.
The primary objective of this study is, therefore,
to investigate and compare the effects of 10 weeks of
PRT to BMCT on gait function, balance and fatigue
in mobility limited persons with MS.
It is hypothesized that PRT will be superior in
improving maximal straight gait speed, whereas
BMCT will have a greater impact on balance, fatigue,
and more complex walking tasks that include ele-
ments of balance and coordination.
2. Methods/design
2.1. Study design
As depicted in Fig. 1, the study is a three-armed
multi-center, single-blinded cluster randomized con-
trolled trial with two intervention groups (1: PRT;
2: BMCT) and a control group that receives usual
care while on a waitlist followed by an intervention
Fig. 1. Illustration of study design.
133
combining PRT and BMCT. Both interventions last
ten weeks with two sessions per week.
The study protocol conforms to the SPIRIT state-
ment and is registered at www.clinicaltrials.gov
(NCT02870023). The study will be performed in
agreement with the Declaration of Helsinki and
is approved by the Regional ethical committee
(Videnskabsetisk Komite, Region Midt; ID-number:
1-10-72-316-15).
2.2. Recruitment and eligibility
Patients will be invited via regional MS Clinics
in the western part of Denmark. Invitations will be
provided at consultations at the clinics or will be sent
to patients from the registers at the participating MS
clinics. Invitations will also be distributed via social
media and network groups established via the Danish
MS Society.
Patients that reply to an invitation will after-
wards receive a detailed written information along
with a leaflet from the National ethical committee.
134 J. Callesen et al. / How does strength training and balance training affect gait and fatigue in MS?
Eligibility according to inclusion criteria 1–4 (see
below) are determined by a neurologist from either
medical records or from a consultation in case of
insufficient medical record information.
Inclusion criteria are: 1) Expanded Disability Sta-
tus Scale (EDSS) (Kurtzke, 1983) 2.0–6.0 (≥2.0 in
the functional system “pyramidal function”); 2) Age
>18; 3) Able to walk 100 m; 4) Able to manage own
transportation to weekly training sessions as well as
to pre- and post-testing; 5) Six Spot Step Test >8 sec;
and 6) Timed 25 Foot walk >5 sec.
Exclusion criteria are: 1) Co-morbidity in terms
of cognitive disorders or alcohol abuse; 2) Attack
within the last eight weeks; 3) Systematic intensive
rehabilitation/training within the last three months;
4) Adjustment in medication within 2 months before
inclusion (applies for medication that has a disease
modifying effect and/or affects gait performance and
spasticity).
Interventions will be carried out at physiotherapy
clinics located in the community. For a clinic to par-
ticipate it is required that: 1) the responsible staff in
charge of the interventions are experienced in MS
rehabilitation; 2) the clinic has a gym facility that
enables 10 meter of straight walking as well as con-
tain sufficient balance accessories and equipment for
PRT of the lower extremities.
2.3. Random allocation procedures
Group allocation will be determined by cluster
randomization with a concealed allocation. The par-
ticipating clinics are randomly assigned to perform
either PRT, BMCT or Control (and later PRT +
BMCT). To ensure an even distribution of patients
in the intervention groups, allocation is carried out
whenever three groups of 3–6 patients are enrolled.
Three concealed envelopes, each containing the name
of one intervention, is randomly drawn and allocated
to a group/clinic. As the patients will be assigned
to a clinic located close to their home, the alloca-
tion depends on their residential location. A person
with no further involvement in the study manages the
randomized allocation.
An assistant in charge of the test logistics will
assign patients with an ID number and pseudonyms
that will be used during baseline- and follow-
up testing. This procedure is carried out to avoid
that the primary investigator recognizes patients by
their names, which are used during the recruit-
ment procedure, where the primary investigator is
involved. This way the primary investigator can
remain blinded to patient exposure and thus serve as
blinded assessor. Patients will be informed about the
purpose and the procedures regarding blinding. Iden-
tities will be concealed from the primary investigator
until data collection is complete.
3. Study flow
Patients that fulfil the inclusion criteria 1–4 will be
baseline tested by the primary investigator at Section
of Sport Science, Dep. Public Health, Aarhus Uni-
versity. Final allocation to an intervention depends
on the result of the baseline scores for the two pri-
mary outcome measures (SSST & T25FW). If the
scores fall below the predefined limit mentioned in
inclusion criteria 5 or 6, patients are not enrolled in
the study. Results from all baseline testing (includ-
ing those who are not enrolled in the study) will
be recorded and used in a secondary cross sectional
analysis evaluating baseline associations.
When groups are formed and assigned to an inter-
vention, 10 weeks of either BMCT, PRT or Control
intervention will begin. Hereafter a follow-up test
identical to the baseline test procedure will be carried
out. After the intervention period, the control group
start their training consisting of combined PRT and
BMCT for 10 weeks followed by a third identical test
round (Fig. 1).
3.1. Intervention procedures
3.1.1. PRT
Training sessions starts with a 10-minute warm-
up on a stationary bicycle or treadmill. All exercises
will be performed in machines, sitting, lying or
standing adequately supported (Table 1). Varia-
tion in exercise equipment in terms of brand and
types of machines across the different participating
physiotherapy clinics is acceptable as long as the
execution of exercises complies with the description
(Table 1). Training is supervised by a physiothera-
pist to ensure high quality during execution and that
the intended progressive overload model is followed
(Table 2).
3.1.2. BMCT
Each training session starts with a 10-minute
warm-up on a stationary bicycle or treadmill.
The BMCT intervention consists of stations with
exercises that challenges functions related to mobil-
ity. The stations aim at standing, stepping, walking,
 J. Callesen et al. / How does strength training and balance training affect gait and fatigue in MS? 135

Table 1
Description of exercises in the Progressive Resistance Training intervention
Exercises Start position End position
Leg press Sitting or supine
– using both legs – Dorsal flexion in ankle – Plantar flexion
– Flexion in knee and hip – Extension in knee and hip
Knee extension Sitting
– Mid-range knee flexion – Full extension
Hip flexion Standing
– Slight hip extension – Full flexion
Hamstring curl Prone
– Slight knee flexion – Full flexion
Hip extension Standing
– Mid-range hip flexion – Full extension

Table 2
Progression model for the PRT intervention
Week Sets Repetitions Load in RM
1&2 3 10
3&4 3 12
5&6 4 12
7&8 4 10
9 & 10 4 8
RM = Repetitions Maximum.
sit to stand, and vestibular rehabilitation through gaze
control. A detailed framework of the balance inter-
vention is illustrated in appendix 1.
Balance skill is interpreted from the ability to per-
form the exercises while keeping center of mass
(COM) in control within the base of support (BOS).
Multiple failed attempts are interpreted as “an inad-
equate balance for the given task”. Reduced speed,
abnormal fluctuating displacement of COM, exces-
sive corrective upper limb movement and a high
level of concentration with cessation of talking and
head movement is interpreted as “balance being
challenged by the given task”. The exercises are
progressed by altering BOS, loads and speed dur-
ing movements, body and/or head turns, and by
using external tasks (e.g. catching and throwing).
The BMCT framework is defined under inspiration
from already published treatment programs by Coote
et al. (Coote, Garrett, Hogan, Larkin, & Saunders,
2009), Hebert et al. (Hebert, Corboy, Manago, &
Schenkman, 2011) and Nilsagard et al. (Nilsagard,
von Koch, Nilsson, & Forsberg, 2014).
An Error Rate is used to describe intensity of
an exercise and thereby the level of the challenge
(Fig. 2). The therapist adds and adjust tasks aiming
at an adequate level of challenge, corresponding to
an error rate of 20–40%. This means that an exercise
executed at “moderate” intensity is conducted with
approximately 60–80% error free repetitions, cycles
or time depending on the task/exercise.
15
12
12 Fig. 2. Error rate scale with intensities.
10
8
When supervising an exercise, an adequate level of
challenge for a simple exercise is determined. After
several successful executions of the exercise, cog-
nitive and/or motor tasks are added when possible
– in this study defined as “dual task”. Manipula-
tion of sensory conditions by elimination of vision
and performing exercises on a foam will also be
applied. By adding motor or cognitive tasks, per-
formance quality declines, but it should not exceed
an error rate of 40%. In case of a higher error rate,
the motor challenge is reduced, to lower the error
rate.
Due to differences in patients’ level of function,
symptoms, and training experience, the perceived
challenges from the same exercise will differ between
subjects. Hence, the BMCT framework has been
developed in an attempt to standardize the training
protocol in a way that allows the therapist to tailor
and vary the exercises with respect to the patient’s
individual functional level and needs, while ensuring
that all patients receive exercises in the same domains
and at a similar relative intensity.
3.2. Control group
The control group is on a waiting list during the
first 10 weeks where they are encouraged to maintain
usual care and level of physical activity. Hereafter
they will receive an intervention with one weekly ses-
sion of BMCT and one weekly session of PRT. Both
sessions will start out with a 10-minute warm-up on a
stationary bicycle or treadmill. BMCT will be carried
136 J. Callesen et al. / How does strength training and balance training affect gait and fatigue in MS?
out in accordance with the described protocol for the
BMCT-group. PRT consists of the same exercises as
prescribed for the PRT-group but only an intensity of
12 RM is applied during the 10 weeks due to fewer
sessions of PRT.
3.3. Adherence
All interventions are carried out in groups of 3–6
patients. To ensure adherence to the predefined proto-
col, physiotherapists will be instructed by the primary
investigator on how to provide the interventions as
well as receive written guidelines describing the
exercises and the applied progression model. The
therapists will register how training went in terms
of type and execution of exercises, level of intensity
and repetitions. The physiotherapist in charge of the
intervention at the participating physiotherapy clinic
registers symptoms of possible adverse events related
to training. Any adverse event is then reported to the
primary investigator who then reports to the Regional
ethical committee.
3.4. Primary outcomes
Gait will be measured by the Timed 25 Foot
Walk and the Six Spot Step Test. Gait function
is a complex phenomenon where the interpretation
highly dependent on what aspect of function is in
focus – e.g. speed, coordination, duration, gener-
ation of force or task oriented gait. As the two
interventions under investigation may have differ-
ent effects on gait function (cf. the hypotheses),
a design with two primary outcomes was chosen,
that include a simple test of maximal gait speed
(T25FW) and a test of more complex gait that include
elements of balance and coordination (SSST). Per-
spectives on clinical relevant changes are published
for T25FW (Baert et al., 2014) and SSST (H. B.
Jensen, Mamoei, Ravnborg, Dalgas, & Stenager,
2016).
3.5. Timed 25 Foot Walk
Patients complete a T25FW (s) on a 10-meter
walkway at fastest safe walking speed (FWS), respec-
tively. Timed 25-Foot Walk (T25FW) has been
validated in MS as one of the three components of the
Multiple Sclerosis Functional Composite (MSFC)
(Fischer, Rudick, Cutter, & Reingold, 1999). A limi-
tation of the T25FW, is a floor effect seen in patients
with mild disability (Kalkers et al., 2000). This is
explained by the short walking distance, where the
consequences of fatigue, spasticity, and inadequate
coordination and balance will not manifest clearly
(Nieuwenhuis, Van Tongeren, Sorensen, & Ravn-
borg, 2006; Schwid et al., 1999).
3.6. Six Spot Step Test
The SSST involves walking as fast as possible
across a rectangular course, while kicking five blocks
out of their circles marked on the ground. Compared
to the T25FW, which reflects a certain degree of
monotonous and automatized movement pattern, the
SSST can be seen as a more complex task that requires
an ongoing adaptation in terms of orientation, speed
and limb support. As such, the SSST seems to be
a better expression of complex lower-limb function
than maximal straight-line walking.
SSST is superior to T25FW in discriminat-
ing ambulatory function across levels of disability
(Nieuwenhuis et al., 2006), though it still calls for
further validation and evaluation of psychometric
properties such as responsiveness. Some perspectives
on a clinical relevant change have been presented but
more data is required.
3.7. Secondary outcomes
3.7.1. Fatigue
Fatigue is measured by the Danish version of the
modified fatigue impact scale (MFIS). The MFIS is
a multidimensional scale designed to assess the per-
ceived impact of fatigue related to different aspects
of daily life. It consists of 21 standardized questions
where each item has five levels of response. The scale
assesses perceived impact of fatigue on physical, cog-
nitive and psychosocial function (Fisk et al., 1994).
MFIS is reliable in people with MS (Learmonth et al.,
2013)
3.7.2. Endurance and self-reporeted gait
function
The six-minute walk test (6 MW) induces an
endurance component and is therefore more prone to
exhaust patients. The 6 MW has been shown to cap-
ture motor fatigue, as the test might affect gait pattern
and reveal a change in motor strategies after rehabilita-
tion (Leone et al., 2016). Outcome is the distance (m)
walked per minute and total distance covered in 6 min-
utes. Additionally, the distance covered in the first and
the sixth minute is registered (Leone et al., 2016). The
6 MW is a feasible, reproducible, and reliable mea-
 J. Callesen et al. / How does strength training and balance training affect gait and fatigue in MS?
sure (Goldman, Marrie, & Cohen, 2008). To measure
the subjectively experienced impact of MS on walk-
ing ability, the 12-item MS Walking Scale (MSWS)
(Hobart, Riazi, Lamping, Fitzpatrick, & Thompson,
2003) is used. The quality of the questionnaire eval-
uated from a graded response model is found to be
good (Mokkink, Galindo-Garre, & Uitdehaag, 2016)
The current validity of the scale in terms of psychome-
tric properties is primarily based on correlations with
measures of gait speed (T25FW) (Kurtzke, 1983) and
distance (6 MW) (Goldman et al., 2008; Pilutti et al.,
2013), despite these measures would expectedly only
partly explain the MSWS score.
3.7.3. Temporospatial and kinetic measures
Walking at fastest and at self-selected speed is
recorded by a Qualisys system including seven
ProReflex infrared high-speed cameras. The sub-
jects are equipped with 37 retro-reflexive markers
mounted on the skin according to Visual 3D® marker
set guidelines. The tests are performed bare-footed
unless orthosis or other gait assistive devices prevent
this. The system collects kinematic data for a three-
dimensional analysis of gait function and is used for
analysing: step and stride length, step width, time in
swing and stance, gait speed and hip and knee angle
during gait. A thin carpet on the walkway hides the
force plate and patients strike the force plate with
one foot. The test is repeated in order to measure
foot strike on the opposite side. From the force plate
data, a standard three-dimensional inverse-dynamics
method is used to quantify the relevant forces and
moments acting on the lower limb joints (Everett &
Kell, 2010). Combined with angular joint velocity
the peak net joint power, normalized to body mass
(W/kg) can be calculated.
3.8. Balance
Static balance is measured using the “(modified)
Clinical Test for Sensory Interaction and Balance
(CTSIB)” (Shumway-Cook & Horak, 1986). The
somatosensory, visual, vestibular systems and their
interactions are essential for postural control and the
test investigates the organization of sensory inputs for
postural control.
The CTSIB test assesses the influence of sensory
interaction on postural stability. This is done by com-
promising one or more senses during 30 sec stance in
four conditions: 1) eyes open 2) eyes closed 3) eyes
open standing on foam 4) eyes closed standing on
foam. CTSIB is performed at a force plate to regis-
137
ter displacement of COM. Outcome is trajectory path
length and ellipse area (Kalron, Nitzani, & Achiron,
2016).
Mini-BESTest is a 14 item function test that mea-
sures dynamic balance (Franchignoni, Horak, Godi,
Nardone, & Giordano, 2010). The mini BESTest is a
reliable measure of balance and it has shown good
discriminative properties for identifying abnormal
postural response (King, Priest, Salarian, Pierce, &
Horak, 2012) as well as for determining the risk of
fall in patients with Parkinson’s (Ross et al., 2016).
The “Activities-specific Balance Confidence
Scale” (ABC) questionnaire asses balance con-
fidence in 16 different activities from everyday
life (Powell & Myers, 1995) that requires static,
dynamic, proactive and reactive balance. It was
developed as an instrument to detect risk of falling
in elderly people, but has also been used for persons
with MS. It is validated using an Italian translation
(Cattaneo, Regola, & Meotti, 2006). It is believed
that confidence in the bodily abilities is a prerequisite
for bodily actions. Hence, in this study the correlation
between objective and subjective balance-measures
is determined.
3.9. Strength
3.9.1. Maximum isometric and isokinetic muscle
strength
Maximum voluntary contraction (MVC) of the
knee flexors (KF), knee extensors (KE), dorsal flex-
ors (DF) and plantar flexors (PF) are determined by
a Cybex Norm dynamometer (Humac Norm, CSMi,
Stoughton, MA, USA). The individual settings of the
dynamometer are registered and used during the re-
test. Isometric muscle strength in KE and KF is tested
at 70 and 30 degrees flexion, respectively. Isometric
PF and DF are tested with the knee extended and the
ankle in 0◦ and 25◦ flexion, respectively and isoki-
netic (60◦ /sec.) strength is tested in a range of motion
going from 10◦ dorsal flexion to 25◦ plantar flexion.
The patients maximally extend their knee for
approximately 4 seconds followed by a 30 sec. rest.
This sequence is repeated 3 times. The torque signal
is sampled at 100 Hz, and peak torque is determined
as the highest attained torque during a single attempt.
3.10. Health related quality of life
Information on health status is measured by the
Short-Form Health Survey (SF-12) (Jenkinson et al.,
1997; Ware, Kosinski, & Keller, 1996). It is a generic
138 J. Callesen et al. / How does strength training and balance training affect gait and fatigue in MS?
questionnaire evaluating physical and mental health
that was developed to provide a shorter alternative to
the SF-36. Scores on both physical and mental health
is found reliable and valid (Cheak-Zamora, Wyrwich,
& McBride, 2009). The questionnaire is generic and
does not specifically target issues related to MS.
3.11. Sample size
Sample size is estimated from an expected change
in gait speed assessed by Timed 25 foot walk (T25FW)
and the Six Spot Step Test (SSST). The effect
of each intervention are compared to the control
group (effect = 0, Power = 0.80 and level of signif-
icance = 0.05). As two primary outcomes (T25FW
and SSST) are applied the sample size estimation
is based on four different calculations (two for each
intervention):
1. PRT evaluated by T25FW: A study evaluating
a comparable PRT intervention found a 12%
increase in gait speed (Dalgas et al., 2009) with
an SD of 8%. With a similar result 7 participants
in each group are required.
2. PRT evaluated by SSST: In an unpublished
study, a group of comparable patients conducted
30 weeks of PRT (H. Jensen et al., 2015),
showing an increase of 16.8%, SD = 15%. From
this estimate, 13 participants in each group are
needed.
3. BMCT evaluated by T25FW: Studies on elderly
with osteoporosis (Halvarsson, Franzen, &
Stahle, 2015) are used as no relevant studies
in MS could be located. Twelve weeks of bal-
ance training resulted in an 8% increase in gait
speed, SD = 11% (data from Halvorsson et al.
(Halvarsson et al., 2015) and personal com-
munication). Based on this 29 participants are
required in each group.
4. BMCT evaluated by SSST: No publications
usable for the power calculation were found.
In summary, 32 patients in each group (total n = 96)
will be sufficient, when assuming a dropout rate of
10%.
3.12. Statistical analysis
The effects observed from baseline to follow-up on
T25FW, SSST and secondary outcomes in the three
groups is examined in a mixed effects regression anal-
ysis with group and time as fixed effects and center
and patient within center as random effects. This takes
into account that observations on different patients at
the same center are typically better correlated than
what is seen in patients from different centers. Simi-
larly, the stronger correlation among observations on
the same patient compared to different patients at the
same center is accounted for.
It will be checked whether the assumption of equal
variance and a normal distribution of residuals is met
based on the mixed effect model. In case of violation
of assumptions the analyses will be carried out on a
logarithmic scale.
Descriptive statistics will be used to present and
compare characteristics across groups at baseline and
to determine the distributional properties of the data.
Spearman or Pearson correlation analysis will be
conducted on baseline data from all patients that
underwent baseline testing in order to determine
associations between the primary outcomes and the
secondary outcomes on fatigue, spatial gait parame-
ters, balance and self-reported measures.
Analyses will be carried out as intention-to-treat
where all patients that are tested at follow-up are
include regardless of their compliance to the pro-
tocol. In case of low adherence, a supplementary
per-protocol analysis will be performed, where atten-
dance according to the protocol will be defined as
participants having a minimum of 80% attendance
(corresponding to 16 sessions out of 20). Level of
significance is set at 0.05.
4. Discussion
This RCT will expand our understanding of how
different rehabilitation interventions affect gait, bal-
ance and fatigue and the study will thereby help
optimizing future rehabilitation interventions in per-
sons with MS. Moreover, not many studies evaluate
different related rehabilitation interventions in a head
to head design in persons with MS. Expectedly,
BMCT will improve balance (Gandolfi et al., 2015;
Paltamaa et al., 2012), while PRT will improve mus-
cle strength (Kjolhede et al., 2012). However, neither
the size of the effects, nor whether one interven-
tion is superior to the other is clear, when evaluated
by a functional test relying on both strength and
balance.
The amount of high quality literature on PRT is
substantially larger (Kjolhede et al., 2012) than on
BMCT (Paltamaa et al., 2012). This may in part, be
explained by the scientific feasibility of PRT in terms
of standardization, where intensity and exercises
 J. Callesen et al. / How does strength training and balance training affect gait and fatigue in MS?
are easily defined and described and where muscle
strength outcomes can be highly standardised and
easily determined. Despite the extensive use in phys-
iotherapy practise, BMCT is harder to fit into a highly
standardized protocol, as required when causation
is investigated. Moreover, improvement of balance
and motor skills that are transferable to everyday
tasks require BMCT that is tailored with respect
to repetition and variation in the applied exercises
(Carr & Shepherd, 2010). Despite the challenges
when investigating BMCT it may pose elements that
are complementary to PRT, and addition of BMCT
may therefore help optimize motor rehabilitation
in MS.
Execution of gait is the result of a complex
interaction between the environment, physical and
cognitive abilities and the task (Shumway-Cook &
Woollacott, 2017). Hence, manipulation of either sen-
sory input, cognitive requirements or task-oriented
demands affects motor processing and can poten-
tially alter movement pattern during gait. In order
to provide an exercise intervention that transfers into
improved functional ability during complex use in
everyday life, variation in exposure during exercise is
advised (Nielsen et al., 2015). To address this issue,
the framework developed for the BMCT interven-
tion defines training in stations that ensures variation.
Moreover, the BMCT exercises at a given station are
altered and adjusted, as the program progresses, but
the functional aim and duration at a given exercise
station is maintained.
This concept of tailored exercises that varies across
patients, calls for a discussion of the reproducibility
of particularly the BMCT intervention. In this study,
the idea is to standardize the treatment paradigm
rather than the treatment itself. The therapists are
provided reliable rules for the content and progres-
sion, but without specifying the exercises. Intensity
of BMCT is then determined from the level of diffi-
culty (the error rate) interpreted from the quality of
the execution of a particular exercise. When perform-
ing BMCT, the level of function is to a greater extend
dependent on cognitive processing than during PRT.
This is primary explained by increased requirements
in relation to fine motor function, divided attention
and the continuous exposure to new tasks. All though,
muscle strength is still related to performance.
Regarding standardization, two patients with
different clinical characteristics will receive dif-
ferent BMCT interventions, while subjects with
similar characteristics will receive a comparable
intervention. Despite diverse BMCT exposure, the
139
participants are similarly challenged relative to their
motor control ability. Likewise in the PRT interven-
tion, loads differs across patients depending on their
strength level.
For the BMCT, therapists select and adjust exer-
cises aiming at an error rate of approx. 20–40%. It
can be argued, that the dependency of the physiother-
apeutic skill combined with the multi-center design,
where interventions are carried out by different thera-
pists, will pose a threat to the validity of the study. On
the contrary, it can be argued that a BMCT interven-
tion, with only one therapist in charge of all training
sessions, tend to reflect only one person’s handling
of the prescribed intervention. In the present study,
the external validity is thought to be high since the
treatment is performed in a real clinical setting, is
provided by therapists experienced in MS rehabil-
itation, is implemented into the framework of the
national health care system and that the inclusion and
exclusion criteria are quite wide.
The SSST and the T25FW are the primary out-
comes that evaluate function capacity. However, from
the array of secondary measurements it will be pos-
sible gain insight into a potential diverse effect of
PRT and BMCT when looking in mu-scle strength
and balance, fatigue, gait characteristics and the self-
reported level of function. Additionally, as the effects
are results of rehabilitation conducted at different
clinics, data allows for stratification, to determine sys-
temically differences across the participating centers
that provide the same intervention. This might give
rise to future studies of the management of guidelines
in clinical practice.
Authors’ contributions
JC contributed to the conception and design of the
study and drafted the manuscript. UD contributed to
the conception and design of the study and edited
the manuscript. DC contributed to the conception and
design of the study and edited the manuscript. JB con-
tributed to the conception and design of the study and
edited the manuscript. All authors read and approved
the final manuscript.
Conflict of interest
JC, DC and JB declare that they have no con-
flict of interests associated with this paper. UD
has received research support, travel grants and/or
140 J. Callesen et al. / How does strength training and balance training affect gait and fatigue in MS?
teaching honorary from Biogen Idec, Merck Serono,
Novartis, Bayer Schering and Sanofi Aventis as well
as honoraria from serving on scientific advisory
boards of Biogen Idec and Genzyme.
Funding
This work was supported by VIA University Col-
lege - Faculty of Health Sciences and by the Danish
foundation “TrygFonden”, grant number: 108916.
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