Research Report
Effect of Aerobic Training on Walking
Capacity and Maximal Exercise
Tolerance in Patients With Multiple
Sclerosis: A Randomized Crossover
Controlled Study
Anais Rampello, Marco Franceschini, Massimo Piepoli, Roberto Antenucci,
Gabriella Lenti, Dario Olivieri, Alfredo Chetta
Background and Purpose
Physical deconditioning is involved in the impaired exercise tolerance of patients
with multiple sclerosis (MS), but data on the effects of aerobic training (AT) in this
population are scanty. The purpose of this study was to compare the effects of an
8-week AT program on exercise capacity—in terms of walking capacity and maximum exercise tolerance, as well as its effects on fatigue and health-related quality of
life—as compared with neurological rehabilitation (NR) in subjects with MS.
Subjects and Methods
Nineteen subjects (14 female, 5 male; mean age [X⫾SD]⫽41⫾8 years) with mild to
moderate disability secondary to MS participated in a randomized crossover controlled study. Eleven subjects (8 female, 3 male; mean age [X⫾SD]⫽44⫾6 years)
completed the study.
Results
After AT, but not NR, the subjects’ walking distances and speeds during a self-paced
walk were significantly improved, as were their maximum work rate, peak oxygen
uptake, and oxygen pulse during cardiopulmonary exercise tests. The increases in
peak oxygen uptake and maximum work rate, but not in walking capacity, were
significantly higher after AT, as compared with after NR. Additionally, the subjects
who were most disabled tended to benefit more from AT. There were no differences
between AT and NR in effects on fatigue, and the results showed that AT may have
partially affected health-related quality of life.
Discussion and Conclusion
The results suggest that AT is more effective than NR in improving maximum exercise
tolerance and walking capacity in people with mild to moderate disability secondary
to MS.
A Rampello, MD, is Registrar, Department of Geriatrics and Rehabilitation, Unit of Rehabilitation,
University Hospital of Parma,
Parma, Italy.
M Franceschini, MD, is Consultant, Department of Geriatrics and
Rehabilitation, Unit of Rehabilitation, University Hospital of Parma.
M Piepoli, MD, is Consultant,
Heart Failure Unit, Department of
Cardiology, G da Saliceto Hospital, Piacenza, Italy.
R Antenucci, MD, is Registrar, Unit
of Rehabilitation, G da Saliceto
Hospital.
G Lenti, MD, is Consultant, Unit
of Rehabilitation, G da Saliceto
Hospital.
D Olivieri, MD, is Full Professor,
Department of Clinical Sciences,
Section of Respiratory Diseases,
University of Parma, Parma, Italy.
A Chetta, MD, is Associate Professor, Department of Clinical Sciences, Section of Respiratory Diseases, University of Parma, Viale G
Rasori, 10 – 43100, Parma, Italy.
Address all correspondence to
Dr Chetta at: chetta@unipr.it.
[Rampello A, Franceschini M,
Piepoli M, et al. Effect of aerobic
training on walking capacity and
maximal exercise tolerance in patients with multiple sclerosis: a
randomized crossover controlled
study. Phys Ther. 2007;87:545–
555.]
© 2007 American Physical Therapy
Association
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May 2007
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Aerobic Training in Patients With Multiple Sclerosis
M
ultiple sclerosis (MS) is a
chronic demyelinating disease of the central nervous
system characterized by disturbances in nerve conduction and
manifested by various clinical features. People with MS often complain of poor exercise tolerance and
exertion fatigue that limit their daily
living activities.1,2 Peripheral factors3–5 as well as central factors2,6 – 8
may be involved in the pathogenesis
of the reduced exercise tolerance
and fatigue in people with MS. An
abnormally high energy cost of walking has been suggested as an important contributing factor in leg fatigue
during treadmill exercise.3 Respiratory muscle dysfunction also has
been related to the reduction in exercise tolerance in people with MS.4
A recent study by Chetta et al5
showed that subjects with MS who
were mildly disabled had reduced
limb endurance and an impaired cardiorespiratory response to self-paced
walking that might have been related
to deconditioning, cardiovascular autonomic dysfunction, and altered
breathing control. Deconditioning
may play a key role in the impaired
exercise tolerance of people with
MS. In order to minimize fatigue,
people with MS limit their physical
activity.1,2 This limited physical activity, in turn, can lead to deconditioning and disuse that further worsens limb weakness and fatigue.9
Furthermore, fatigue and limitation
of physical activity may reduce the
ability to participate in daily social
and family activities.9
positively affect both maximum exercise capacity12 and daily physical
activities.13 In both the study by Petajan et al12 and the study by Romberg
et al,13 however, the effect of aerobic exercise was compared with that
of no treatment. In addition, in the
study by Romberg et al,13 aerobic
exercise consisted of aquatic training, which was not tailored to meet
the specific exercise capabilities of
the subjects. Only one study14 previously examined the effects of aerobic training (AT) on maximum exercise capacity, as compared with a
physical therapy program. The analysis was restricted to within-group
comparisons, and the results showed
a significant increase in the anaerobic
threshold but no changes in maximum
aerobic capacity.
Therefore, the purpose of this randomized crossover controlled study
was to assess the effects of an 8-week
AT program on exercise capacity—
in terms of walking capacity and
maximum exercise tolerance, as well
as its effects on fatigue and healthrelated quality of life—as compared
with a neurological rehabilitation
(NR) protocol in subjects with mild
to moderate disability secondary to
MS. We considered both the AT program and the NR protocol as 2 effective rehabilitative interventions for
people with MS. Accordingly, we hypothesized that the 2 rehabilitation
protocols could have similar effects
on the functional status of subjects
with MS.
Method
One of the primary aims of rehabilitation in people with MS is to maintain and improve functional independence. Review studies10,11 suggest
that exercise therapy may be beneficial for patients with MS in terms of
physical fitness, activities of daily living, and outcomes related to mood.
In particular, aerobic exercise seems
to be a promising rehabilitative tool
for patients with MS because it could
546
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Volume 87
Subjects and Design
The subjects were screened from a
waiting list for a rehabilitation program in the MS outpatient clinics at
Parma University Hospital and Piacenza Hospital between January and
May 2005. The inclusion criteria
were: a diagnosis of MS according to
the criteria of Poser et al,15 a score of
6 or less on the Expanded Disability
Status Scale (EDSS)16 because indi-
Number 5
viduals with an EDSS score greater
than 6 need constant use of a bilateral aid while walking, and age between 20 and 55 years. Subjects
were excluded if they had a relapse 4
weeks before the study; had a history
of cardiac, pulmonary, orthopedic,
metabolic, or other medical conditions precluding participation; were
currently receiving steroid therapy
or had been treated with steroids
within 2 months prior to the study;
or had engaged in a regular exercise
program within 2 months before the
study.
After screening, the subjects were
randomly assigned, according to a
computer-generated randomization
list, and stratified by sex, age, and
EDSS score to receive either an AT or
NR 8-week parallel crossover intervention. To avoid any interference
between the 2 interventions, all subjects waited 8 weeks before initiating the second intervention. During
the 8-week washout period, the subjects were instructed to stop exercising. Clinical assessments, lung function and respiratory muscle strength
(force-generating capacity) testing,
6-minute walk tests (6MWTs), and cardiopulmonary exercise tests (CPETs)
were administered by the same examiner both prior to and after each
8-week treatment without knowledge
of the subject’s group assignment.
Out of 40 eligible subjects, 21 subjects were excluded because they
did not meet the inclusion criteria or
they declined to be enrolled (Fig. 1).
Accordingly, we studied 19 subjects
with MS (14 female, 5 male). The
subjects’ ages ranged from 22 to 51
years, and their disease duration
ranged from 1 to 15 years. None of
the subjects reported any history of
cardiac or pulmonary disease, and all
subjects had normal physical examinations of the chest, chest radiographs, and resting electrocardiograms. At the time of the study, 10
subjects were being treated with inMay 2007
Aerobic Training in Patients With Multiple Sclerosis
Eligible subjects (n=40)
Excluded (n=21)
Not meeting inclusion criteria (n=17)
Refused to participate (n=4)
Enrollment
Randomization
Allocated to aerobic training group
(n=8)
Received allocated intervention
(n=8)
Allocation
Allocated to neurological rehabilitation
group (n=11)
Received allocated intervention (n=11)
Follow-up
Completed aerobic training (n=8)
Completed neurological rehabilitation
(n=11)
Dropouts (n=2)
MS relapses (n=1)
Did not adhere to
protocol (n=1)
Allocated to aerobic training group
(n=9)
Received allocated intervention (n=9)
Dropouts (n=2)
MS relapses (n=1)
Did not adhere to
protocol (n=1)
Allocated to neurological rehabilitation
group (n=6)
Allocation
Received allocated intervention (n=6)
Dropouts (n=3)
MS relapses (n=1)
Did not adhere to
protocol (n=2)
Completed aerobic training (n=6)
Analyzed (n=6)
Dropouts (n=1)
MS relapses (n=1)
Completed neurological rehabilitation
(n=5)
Follow-up
Analysis
Analyzed (n=5)
Figure 1.
Flow chart of the randomized crossover controlled study. MS⫽multiple sclerosis.
terferon beta, 4 with mitoxantrone,
and 1 with glatiramer acetate. All
subjects gave informed consent to
participate in the study.
Clinical Assessment
The subjects’ neurological impairment and degree of disability were
assessed with the EDSS, which provides a score ranging from 0, indicating normal neurological findings, to
10, indicating death from MS. This
scale is a reliable and valid measure
of impairment and disability in people with MS.17 The EDSS score was
assigned without knowledge of the
May 2007
subjects’ pulmonary function and exercise capacity test results.
The subjects’ perceived effect of fatigue was assessed with the Modified
Fatigue Impact Scale (MFIS),18 which
has been validated in people with
MS.19,20 The MFIS is a structured,
self-report, 21-item questionnaire
that provides an assessment of the
effects of fatigue in terms of physical, cognitive, and psychosocial
functions. Scores on the MFIS range
from 0 to 84, and all items are scaled
so that higher scores indicate a
greater effect of fatigue on a person’s
activities. Fatigue is defined as a selfreported lack of physical or mental
energy that is perceived by the individual to interfere with usual and desired activities.19
The disease-specific Multiple Sclerosis Quality of Life–54 questionnaire
(MSQOL-54) was used to assess
health-related quality of life.21,22 The
54 items are divided into 12 multipleitem scales and 2 single-item scales.
The MSQOL-54 item results are transformed linearly to scores of 0 to 100,
and final scale scores are created by
averaging the scores of items within
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547
Aerobic Training in Patients With Multiple Sclerosis
the scales. A higher score in each
scale indicates a better health-related
quality of life. Physical health composite (PHC) and mental health composite (MHC) scores were calculated
as a weighted sum of selected scale
scores. The reliability and validity of
the MSQOL-54 scores have been confirmed in subjects with MS.23
Lung Function, Respiratory
Muscle Strength, and Exercise
Capacity Assessment
Pulmonary function was measured
with a flow-sensing spirometer (Vmax
22)* and a body plethysmograph
(Vmax 6200)* connected to a computer for data analysis. Baseline total
lung capacity (TLC), forced expiratory
volume in 1 second (FEV1), vital capacity (VC), and FEV1/VC ratio were
recorded. All of these variables are expressed as a percentage of the predicted value.24 The best out of 3 results was used in subsequent
calculations.
Maximum inspiratory pressure and
maximum expiratory pressure were
performed against a valve, which
could be closed by turning a tap.25
Maximum inspiratory pressure and
maximum expiratory pressure were
measured (in centimeters of water)
from TLC and residual volume (RV),
respectively. The highest out of 5
recorded pressures maintained for 1
second were used for analysis.
Walking capacity was assessed with
the 6MWT, according to a standard
protocol.26 The 6MWT is a symptomlimited exercise test, so subjects
were allowed to stop if necessary,
although they were instructed to resume walking as soon as possible. All
subjects performed two 6MWTs, the
second test performed the same as
the first test, following a rest of at
least 60 minutes. The walking distance was recorded in meters and
* SensorMedics Corp, 22705 Savi Ranch Pwy,
Yorba Linda, CA 92667-4609.
548
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Physical Therapy
Volume 87
expressed as a percentage of the predicted value, which accounted for
age, sex, and height.27 Additionally,
the walking speed (in meters per
minute) was calculated. Oxygen uptake (V̇O2, in milliliters per kilogram
per minute) was continuously monitored with a portable lightweight
system (VmaxST)* from 5 minutes
before the walk until test completion, as well as 5 minutes after completion or until the return to the
baseline level. The V̇O2 and the cost
of walking during the walk (expressed as mL O2䡠kg⫺1䡠m⫺1)3 were
considered for analysis. Results from
only the second walk were used for
analysis to allow for any learning
effect.26,28
Each subject performed a physiciansupervised, standard, progressively
increasing work rate CPET to maximum tolerance on an electromagnetically braked cycle ergometer. Gas
exchange measurements (Vmax
229)* were taken for 3 minutes at
rest, for 3 minutes of unloaded cycling at 60 rpm followed by a progressively increasing work rate exercise of 5 to 20 W䡠min⫺1 to maximum
tolerance, and for 2 minutes of recovery. Pulse oximetry, heart rate
(HR), 12-lead electrocardiogram, and
cuff blood pressure were monitored
and recorded. Minute ventilation,
V̇O2, and carbon dioxide production
(V̇CO2) were computer-calculated
breath by breath, interpolated second by second, and averaged over
10-second intervals. The maximum
work rate (in watts), the V̇O2 at the
peak of the exercise (in milliliters
per minute and as a percentage of
the predicted value),29 and the
V̇O2/HR at the peak of the exercise
(in milliliters divided by beats per
minute and as a percentage of the
predicted value)29 were considered
for analysis.
Rehabilitation Program
The AT program partially followed
the protocol proposed by Petajan
Number 5
et al.12 Briefly, the subjects participated in 3 training sessions per week
on a leg cycle ergometer for 8
weeks. Each training session consisted of a 5-minute warm-up at 30%
of maximum work rate, then 30 minutes at 60% of maximum work rate,
which was followed by a 5-minute
cool-down. Subjects then performed
stretching exercises of their lower
limbs and trunk muscles for 15 minutes. Workloads were calculated
from the work rate obtained during
the CPET and were progressively increased every week up to 80% of
maximum work rate. Heart rate,
blood pressure, pulse oximetry, and
the subjects’ perceived exertion, as
assessed with a visual analog scale,
were monitored during exercise.
During the NR program, subjects underwent 3 sessions per week for 8
weeks. Each session lasted 60 minutes and consisted of exercises
aimed at improving respiratorypostural and respiratory-motor synergies and of stretching exercises.
These exercises consisted of active
movements of the trunk and upper
limbs in a standing, sitting, or kneeling position, such as flexion and rotation movements of the trunk; gait
exercises, including tandem gait or
ambulation exercises combining advancement of one lower limb with
raising of the opposite upper limb;
and exercises for stretching the
lower limbs and trunk muscles. During each exercise, much emphasis
was placed on breathing, as the subjects were asked to inspire during
active movements and to expire during relaxation. The exercises were
grouped in 4 parts, separated by
3-minute pauses, and were all proposed with the same temporal
sequence.
Trained physical therapists instructed the subjects individually on
both AT and NR programs and supervised each exercise program session.
Before and immediately after each
May 2007
Aerobic Training in Patients With Multiple Sclerosis
Table 1.
Characteristics of the 19 Subjects With Multiple Sclerosis Enrolled in the Study, of the 11 Subjects Who Completed the Study,
and of the 8 Subjects Who Withdrew From the Studya
Variable
All Subjects
(nⴝ19)
Subjects
Who
Completed
Study
(nⴝ11)
Subjects Who
Withdrew
From Study
(nⴝ8)
Pb
Age (y)
41⫾8
44⫾6
37⫾10
.21
Sex (female/male)
14/5
8/3
6/2
.99
BMI (kg/m2)
22⫾3
23⫾3
21⫾3
.54
8⫾5
6⫾4
10⫾6
.34
8/3
7/1
.74
3.5 (1–4)
3.25 (1.5–6)
.96
Disease duration (y)
Using disease-modifying drugs (yes/no)
EDSS score (0–10)
FEV1/VC (% of predicted value)
15/4
3.5 (1–6)
82⫾8
82⫾8
83⫾8
.99
FEV1 (% of predicted value)
103⫾13
105⫾13
100⫾13
.69
TLC (% of predicted value)
111⫾8
112⫾11
112⫾14
PImax (cm H2O)
83⫾35
75⫾42
95⫾16
.46
.94
PEmax (cm H2O)
93⫾36
91⫾37
96⫾36
.94
a
Values expressed as mean⫾SD, except for Expanded Disability Status Scale (EDSS) scores, which are expressed as median (range). BMI⫽body mass index,
FEV1⫽forced expiratory volume in 1 second, VC⫽vital capacity, TLC⫽total lung capacity, PImax⫽maximum inspiratory pressure, PEmax⫽maximum
expiratory pressure.
b
P values assessed by chi-square test (sex, using disease-modifying drugs), analysis of variance (age, BMI, disease duration, FEV1/VC, FEV1, TLC, PImax,
PEmax), and Kruskal-Wallis test (EDSS score).
exercise program session, subjects
rated the magnitude of their perceived breathlessness and fatigue on
a visual analog scale.
Data Analysis
We considered 2 outcome measures.
The primary outcome measure was
the effect of the rehabilitation programs on exercise capacity. The secondary outcome measure was the effect of the rehabilitation programs
on fatigue and health-related quality
of life.
Values are presented as mean⫾
standard deviation, unless otherwise
specified. Between-group differences
for all enrolled subjects, the subjects
who completed the study, and the
subjects who did not complete the
study were examined using the chisquare test, the analysis of variance,
and the Kruskal-Wallis test, when appropriate. In order to analyze the
between-group and within-group inMay 2007
terventions, the analysis of variance
for repeated measures and the
Newman-Keuls multiple comparison
test were used for analysis of variables
with Gaussian distribution, and the
Friedman test was used for analysis of
nonparametric variables. A P value
ⱕ.05 was taken as significant.
The clinical effect of the interventions on the primary outcomes was
assessed by the effect size statistic,
calculated as the mean change found
in a variable divided by the standard
deviation of that variable.30 We used
the criteria of Cohen31 to interpret
the effect size, where a value of 0.2 is
considered a small effect, a value of
0.5 is considered a moderate effect,
and a value of 0.8 is considered a
large effect.
Results
Fourteen of the 19 subjects recruited
for the investigation completed the
AT program, and 16 subjects com-
pleted the NR program. Only 11 subjects, however, were able to complete the overall crossover controlled
parallel study and were considered for
analysis. Four subjects did not adhere
to the study protocol and dropped out
of the trial. In 2 of those subjects, the
exercise program sessions induced a
perception of breathlessness and fatigue, which persisted up to the beginning of the following session, thereby
precluding the continuation of the rehabilitation program. The other 2 subjects withdrew from the rehabilitation
program because they felt it was too
stressful. Four subjects had a relapse of
MS (2 subjects during the AT program
and 2 subjects during the NR program) and were unable to complete
the study (Fig. 1). Personal details and
pulmonary function test results of the
19 subjects enrolled in the study, of
the 11 subjects who completed the
study, and of the 8 subjects who did
not complete the study are reported in
Table 1. No between-group differ-
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Aerobic Training in Patients With Multiple Sclerosis
Table 2.
Preintervention and Postintervention Values for Lung Function, Respiratory Muscle Strength, 6-Minute Walk Tests, and
Cardiopulmonary Exercise Tests in Subjects With Multiple Sclerosisa
Variable
Aerobic Training Group
Preintervention
FEV1/VC
(% of predicted
value)
Postintervention
Neurological Rehabilitation Group
b
P
Preintervention
Postintervention
Pb
Pc
Pd
84⫾6
83⫾8
.74
82⫾8
84⫾7
.54
.51
.75
FEV1 (% of predicted
value)
110⫾11
108⫾10
.66
105⫾13
109⫾11
.44
.34
.82
TLC (% of predicted
value)
117⫾14
116⫾13
.86
113⫾14
115⫾14
.74
.51
.86
PImax (cm H2O)
78⫾45
80⫾42
.91
75⫾42
77⫾41
.91
.87
.86
PEmax (cm H2O)
88⫾38
90⫾35
.89
91⫾37
92⫾38
.95
.85
.89
308⫾98
332⫾108
.02
298⫾114
308⫾110
.17
.59
.18
Walking distance
(% of predicted
value)
55⫾17
59⫾19
.02
53⫾20
55⫾20
.22
.67
.25
Walking speed
(m/min)
51⫾16
55⫾18
.02
50⫾19
51⫾18
.14
.60
.23
Cost of walking
(mL O2䡠kg⫺1䡠m⫺1)
0.20⫾0.07
0.20⫾0.07
.13
0.23⫾0.1
0.22⫾0.09
.41
.42
.13
Peak V̇O2 (mL/min/kg)
17.1⫾7.0
20.0⫾6.6
.01
16.8⫾6.5
16.9⫾6.1
.88
.66
.02
Peak V̇O2 (% of
predicted value)
58⫾18
68⫾18
.01
57⫾17
57⫾18
.88
.89
.02
Maximum work rate
(W)
82⫾43
103⫾48
.01
79⫾45
82⫾42
.47
.53
.02
Peak V̇O2/HR
(mL/bpm)
7.8⫾3.0
8.7⫾3.2
.04
7.8⫾2.9
8.1⫾3.5
.57
.96
.40
Peak V̇O2/HR (% of
predicted value)
75⫾19
84⫾17
.04
76⫾21
78⫾25
.67
.87
.49
Walking distance (m)
a
Values expressed as mean⫾SD. FEV1⫽forced expiratory volume in 1 second, VC⫽vital capacity, TLC⫽total lung capacity, PImax⫽maximum inspiratory pressure,
PEmax⫽maximum expiratory pressure, V̇O2⫽oxygen uptake, HR⫽heart rate. P values assessed by means of analysis of variance for repeated measures and
Newman-Keuls multiple comparison test.
b
Preintervention vs postintervention.
c
Preintervention vs preintervention.
d
Postintervention vs postintervention.
ences were found. In addition, when
baseline condition measurements of
the 2 interventions were considered,
no difference was found (Tabs. 2, 3,
and 4).
Disease Progression and Exercise
Adherence
No change over time was found in
neurological status, as measured with
the EDSS (P⫽1.0). All subjects who
completed the study adhered very
well to both the AT program and the
NR program. Of 264 exercise sessions
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Physical Therapy
Volume 87
prescribed for either the AT program
or the NR program, 230 and 238 exercise sessions, respectively, were
completed, with an average adherence rate of 87%⫾8% and of 90%⫾6%,
respectively. No exercise-related injuries were reported.
Primary and Secondary
Outcomes
Lung function and respiratory muscle strength were not changed by
participation in the AT program or
the NR program (Tab. 2). All subjects
Number 5
were able to complete a 6MWT without stopping. Due to technical problems, we recorded only preintervention and postintervention values for
the 6MWT in 8 out of 11 subjects.
Within-group analysis showed that
subjects had significant improvements in walking distance (P⫽.02)
and walking speed (P⫽.02) after the
AT program, but not after the NR
program. Cost of walking also did
not change after completion of the
AT program or the NR program
(Tab. 2). When interventions were
May 2007
Aerobic Training in Patients With Multiple Sclerosis
Table 3.
Preintervention and Postintervention Modified Fatigue Impact Scale (MFIS) Scores in Subjects With Muliple Sclerosisa
Variable
Aerobic Training Group
Neurological Rehabilitation Group
Preintervention
Postintervention
P
Preintervention
Postintervention
Pb
Pc
Pd
Total MFIS
score
36 (3–57)
29 (4–56)
.66
30 (6–52)
26 (3–67)
.64
.94
.86
Physical
subscale
17 (3–27)
14 (4–23)
.39
19 (6–33)
13 (3–26)
.55
.79
.89
Cognitive
subscale
11 (0–34)
8 (0–36)
.84
11 (0–31)
10 (0–40)
.97
.00
.71
3 (0–6)
3 (0–7)
.89
4 (0–6)
2 (0–6)
.57
.69
.92
Psychosocial
subscale
b
a
Values are expressed as median (range). P values assessed by means of Friedman test.
Preintervention vs postintervention.
Preintervention vs preintervention.
d
Postintervention vs postintervention.
b
c
analyzed between groups, no difference was found. The effect size for
walking distance and maximum
work rate was small (0.2) in the AT
program and negligible (0.09) in the
NR program.
After the AT program, subjects
showed a significant increase in peak
V̇O2 (P⫽.01), maximum work rate
(P⫽.01), and peak V̇O2/HR at CPET
(P⫽.04) when preintervention and
postintervention values were compared. Moreover, after the AT program, 82% of the subjects had a percent increase in change of maximum
work rate greater than 10% of the
baseline value. After the NR program, subjects showed no significant
increase in any CPET values (Tab. 2,
Fig. 2). When interventions were analyzed between groups, peak V̇O2
and maximum work rate after the AT
program were significantly increased
compared with the corresponding
values after the NR program (P⫽.025
and P⫽.02). The effect size for peak
V̇O2 and maximum work rate was
moderate in the AT program (0.6 and
0.5, respectively) and negligible in
the NR program (0.02 and 0.07,
respectively).
The MFIS and MSQOL-54 scores before and after AT and NR intervenMay 2007
tions are shown in Tables 3 and 4.
After the AT program, the subjects
showed a significant increase in 3
MSQOL-54 scale scores (emotional
well-being, energy, and health distress). After the NR program, the
subjects had significant improvements in health distress and mental
health composite scores and a significant reduction in emotional wellbeing scores.
Discussion
Our study showed that, in subjects
with mild to moderate disability secondary to MS, maximum exercise tolerance improved after completion of
the 8-week AT and NT programs, as
compared with baseline conditions.
The change in walking capacity was
significant after the AT program
when compared with baseline conditions, but not after the NR program. Despite the effect of the AT
program on physical performance,
this rehabilitative approach did not
differ from the NR intervention in
terms of the perceived effect of fatigue and only partially affected the
subjects’ health-related quality of
life.
Walking capacity can be assessed
simply and reliably with the selfpaced 6MWT, which can be consid-
ered to be a measure of limb endurance and reflects the submaximal
functional exercise level of daily
physical activities.26 Restricted walking prevents people with MS from
participating in family and social activities and is a major determinant of
overall impairment in people with
MS who are ambulatory.32 Moreover,
the walking distance covered during
the 6MWT was found to be inversely
related to the EDSS scores.5 In the
present study, we found that the
walking capacity of patients with MS
who were mildly to moderately disabled was substantially reduced, as
expressed as a percentage of the predicted value, and was significantly
increased after the AT program but
not after the NR program. Furthermore, the change in walking capacity induced by AT did not significantly differ from the change
induced by NR.
Previous studies, different in length
and kind of exercise and in outcomes, showed discordant results of
the effects of AT on walking capacity
in subjects with MS. Rodgers et al,33
in an uncontrolled study, found minimal effects on gait abnormalities (ie,
decreased walking speed and cadence) after 6 months of AT. In contrast, Romberg et al13 showed that a
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Table 4.
Preintervention and Postintervention Multiple Sclerosis Quality of Life–54 Questionnaire (MSQOL-54) Scores in Subjects With
Multiple Sclerosisa
Variable
Aerobic Training Group
Preintervention
Postintervention
Neurological Rehabilitation Group
b
P
Preintervention
Postintervention
Pb
Pc
Pd
Physical function
68 (35–95)
60 (25–95)
.59
70 (25–95)
55 (20–95)
.92
.72
.84
Role limitations–
physical
25 (0–100)
75 (0–100)
.69
50 (0–100)
75 (0–100)
.71
.72
.97
Role limitations–
emotional
100 (0–100)
100 (0–100)
.66
100 (0–100)
100 (0–100)
.87
1.00
.76
Pain
63 (23–100)
63 (32–100)
.59
68 (30–100)
77 (38–100)
.79
.77
.41
Emotional wellbeing
52 (4–84)
56 (28–84)
.02
56 (4–76)
52 (28–76)
.04
.59
.62
Energy
36 (8–64)
44 (32–64)
.04
44 (24–56)
40 (20–72)
.86
.67
.14
Health perception
40 (10–70)
35 (10–75)
.84
45 (5–70)
35 (15–65)
.76
.92
.92
Social function
67 (33–100)
75 (50–100)
.45
75 (8–92)
83 (38–100)
.81
.74
.49
Cognitive
function
70 (0–100)
75 (10–100)
.69
70 (5–100)
80 (25–100)
.77
1.00
1.00
Health distress
60 (40–95)
75 (60–95)
.03
65 (15–90)
75 (55–100)
.03
.83
.74
Sexual function
100 (42–100)
100 (33–100)
1.00
100 (50–100)
100 (33–100)
.61
.84
.76
Sexual
satisfaction
75 (50–75)
75 (50–75)
.66
75 (75–100)
75 (0–100)
.87
.97
.92
Change in health
50 (25–75)
50 (25–50)
.96
50 (25–75)
75 (50–75)
.66
.97
.68
Overall quality of
life
36 (5–77)
28 (10–82)
1.00
28 (20–73)
36 (20–82)
.36
.59
.19
Physical health
composite
50 (39–82)
59 (44–81)
.65
53 (43–81)
57 (41–81)
.33
.55
1.00
Mental health
composite
60 (10–86)
66 (24–90)
.41
63 (18–85)
66 (32–87)
.03
.51
.89
a
Values are expressed as median (range). P values assessed by means of Friedman test.
Preintervention vs postintervention.
c
Preintervention vs preintervention.
d
Postintervention vs postintervention.
b
6-month AT program, including
aquatic exercises, induced an increase in walking speed compared
with no therapy. Recently, in an uncontrolled study, Kileff and Ashburn34 found that 24 biweekly sessions of 30 minutes of cycling on a
stationary bicycle improved walking
distance. In that study, the mean improvement in 6MWT walking distance was 32 m.
In the present study, we found that
the AT program induced a significant
change in maximum aerobic capacity and work rate both over the study
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time and as compared with the NR
program. Moreover, if we consider
that a 10% increase in work rate on
the cycle ergometer is indicative of
an improvement in fitness, as suggested by Schapiro and colleagues,35
we found that this outcome was
achieved by most subjects undergoing AT. Our findings are consistent
with those of Petajan et al,12 who
found a significant change in maximum aerobic capacity and work load
in subjects who undertook AT compared with no therapy. Interestingly,
we found a 20% increase in aerobic
capacity, which is comparable to
Number 5
that found by Petajan et al,12 despite
a different duration of training (8 versus 15 weeks) and mode of aerobic
exercise (leg cycle ergometer versus
combined arm and leg cycle ergometer). By contrast, Mostert and Kesselring14 did not find any change in
maximum aerobic capacity in subjects with MS after a 4-week period
of AT, despite findings of significant
increases in V̇O2, anaerobic threshold, and maximum work rate. The
shortness of the training period and
the different degree of disability may
explain the discrepancy between
May 2007
Aerobic Training in Patients With Multiple Sclerosis
showed that the peak oxygen pulse
increased after the AT program, but
not after the NR program. To our
knowledge, no data concerning the
effect of rehabilitation programs on
oxygen pulse have been available until now, except for the study by Mostert and Kesselring,14 which demonstrated significant change in oxygen
pulse measured at anaerobic threshold in subjects with MS who participated in an AT program.
Figure 2.
Mean and standard deviation of peak
oxygen uptake (V̇O2) as percentage of predicted value (upper panel), of maximum
work rate in watts (middle panel), and of
walking distance as percentage of predicted value (lower panel) in 11 subjects
with multiple sclerosis before and after
aerobic training (AT) or neurological rehabilitation (NR). P values assessed by means
of analysis of variance for repeated measures and Newman-Keuls multiple comparison test. *P⬍.05 vs all measurements;
§
P⬍.05 vs baseline measurement.
these results and those of Petajan et
al12 and our study.
In people with MS, the peak oxygen
pulse during maximal incremental
exercise on a cycle ergometer may
be reduced when compared with
subjects who are healthy.36 This finding suggests that people with MS
may have reduced cardiovascular fitness, which, in turn, may be related
to deconditioning. In this study, we
May 2007
Our results showed that both AT and
NR intervention led to no significant
change in the subjects’ MFIS scores.
The poor influence of physical exercise on perception of fatigue may be
related to the multidimensional origin of fatigue, because central factors,2,6 – 8 in addition to peripheral
mechanisms,3–5 are known to play a
key role in the pathogenesis of this
symptom. Furthermore, the MFIS
may not be sensitive enough to detect changes in fatigue over time,
and the duration of the rehabilitative
program was too short to determine
significant changes. Previous studies
have shown discordant results on
the effect of AT on fatigue. Some
studies failed to demonstrate a significant effect of AT on fatigue, when
comparing exercise training versus
no exercise therapy12 or “conventional” physical therapy.14 In contrast,
Surakka et al37 found that 6 months of
aerobic and strength exercises reduced motor fatigue in women, but
not in men.
In this study, we showed that AT
only partly affected the health perception of the subjects, particularly
by significantly inducing increases in
emotional well-being, energy, and
health distress scores. In contrast,
the NR program had a contradictory
effect because it improved health
distress and mental health composite
scores while reducing emotional
well-being. The mechanism of action
of these changes is not completely
clear and may not relate directly to
the AT program or the NR program.
Both intervention programs facilitate
the patient’s socialization, which, in
itself, may have contributed to some
of the beneficial effects. Moreover, it
has been demonstrated that exercise
may enhance psychological wellbeing via a strong placebo effect.38
We found a high rate of participant
loss in this study. Among our subjects, a 26% dropout rate was observed, which was higher than dropout rates reported in previous
studies.13,14 Variations in the type
and duration of the programs can
explain the different adherence rates
of the subjects with MS. Our rehabilitative protocol was an outpatient
program that lasted 6 months, the
study by Mostert and Kesselring14
used a 4-week inpatient program,
and the study by Romberg et al13
used a combined 3-week inpatient
program and a 23-week home-based
rehabilitation program. However,
our findings, together with previous
findings, could imply that people
with MS may have limited tolerance
for traditional exercise training, and
other rehabilitative strategies, such
as pacing and energy conservation
techniques, should be considered to
improve their functional status.
We are aware of the numerous limitations of our study. First, a large
number of subjects did not complete
the study, and we are aware that a
type II error may have occurred in
our analysis of results. Moreover, the
participant loss prevented a full
intention-to-treat analysis being carried out. However, as far as we
know, our study is the first randomized controlled study comparing 2
different rehabilitation interventions
in patients with MS, which was conducted in a crossover way. In addition, we did not find any betweengroup (all subjects versus subjects
who completed the study versus subjects who withdrew from the study)
difference in baseline conditions.
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This finding could likely minimize
the bias due to the effect of attrition
on the study sample.39
Second, it is well known that there is
a learning effect when maximal or
submaximal exercise testing, such as
the 6MWT and the CPET, are performed. Thus, we cannot exclude
the possibility that the positive results of our study might have been
due, in part, to the expected variability in these measures. However, our
subjects performed the 6MWT twice
on the study day to minimize the
learning effect of this exercise test
because
performance
usually
reaches a plateau after 2 tests are
done within a week.26 Moreover, in
the assessment of maximum exercise capacity, we followed the same
method as that applied in previous
clinical trials in which subjects performed the CPET only once.12-14
Third, we arbitrarily choose an
8-week washout period between the
2 interventions. However, previous
studies of subjects with MS showed
beneficial effects on disability and
health-related quality of life after rehabilitation, which lasted for 6
weeks40 to 9 weeks.41 Moreover,
in our study, we can exclude a
carryover effect between interventions because no significant difference was found in baseline measurements of the 2 interventions.
Lastly, we are aware that we compared the AT program with the NR
program by using specific outcomes
for the AT program. We, therefore,
cannot exclude the possibility that
the NR program could be superior to
the AT program with regard to
nonaerobic outcomes (eg, flexibility,
balance) that were not measured in
this study.
Conclusions
The findings demonstrated that 8
weeks of AT may be more effective
than NR in improving maximum ex554
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ercise tolerance and walking capacity in patients with MS and mild to
moderate disability, leading to some
positive effects on health-related
quality of life. Our study supports
the view that AT may be beneficial
for patients with MS who are not
experiencing an exacerbation of
symptoms. However, the high rate of
participant loss that occurred in our
study also indicates that exercise
programs may harm patients with
MS. Further studies are needed to
determine whether a more graded
AT program can improve the adherence of patients with MS.
Dr Rampello, Dr Franceschini, and Dr Chetta
provided concept/idea/research design. Dr
Rampello and Dr Chetta provided writing
and data analysis. Dr Rampello and Dr
Piepoli provided data collection. Dr Franceschini, Dr Olivieri, and Dr Chetta provided
project management. Dr Franceschini and
Dr Olivieri provided fund procurement. Dr
Rampello, Dr Antenucci, and Dr Lenti provided subjects. Dr Piepoli, Dr Olivieri, and Dr
Chetta provided consultation (including review of manuscript before submission).
The study protocol was approved by the ethics committees of University Hospital of
Parma and of G da Saliceto Hospital.
This article was received March 15, 2006, and
was accepted January 9, 2007.
DOI: 10.2522/ptj.20060085
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Invited Commentary
The authors should be congratulated
for proposing this study to investigate the relationship between an aerobic cycling program and a functional activity outcome such as the
cost of walking. As they point out, it
is possible that the physical impairments that occur with the disease
also may lead to a more sedentary
lifestyle and deconditioning, resulting in further limitations in functional ability. For many years, limited
knowledge of the pathophysiology
of multiple sclerosis restricted our
efforts to select the appropriate intensity of intervention and the prevention of accumulation of functional disability. Studies such as this
help us to formulate better hypotheses for future interventions.
In summary, the authors found that
an 8-week program of cycling on a
lower-extremity ergometer with progressive resistance resulted in an increase in walking distance and speed
for individuals with mild to moderate
impairment related to multiple sclerosis. Improvements also were seen
in measures of aerobic capacity. SimMay 2007
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Carol Leiper
ilar changes did not occur when the
subjects performed a “neurological
rehabilitation” exercise program described as emphasizing active movements and gait exercises.
I would like to address 2 very different topics related to the study:
(1) whether reported improvements
represent real change and (2) the
importance of continued physical
activity for people with physical
disability.
Measurement of Change
The measure of walking distance
during the 6-minute walk tests will
be used as the example to discuss
the first question. The authors report
a statistically significant improvement in walking distance of approximately 24 m following the aerobic
training but not after the neurological training. However, the comparison between the 2 groups did not
indicate the superiority of the aerobic training. How do we explain this
discrepancy? One solution is to look
at the size of the standard deviations
of the measurements. The larger the
standard deviation, the less likely the
results will be significant unless the
mean values are greatly different.
The authors have used these variables to calculate the effect size and
show us that for these 2 measures it
is indeed small.
Another way to translate the results
into meaningful values for the clinician would be to ask the question,
“What is the minimal detectable
change (MDC) of the measurements
that would indicate a real change,
indicating either improvement related to the intervention or, perhaps
in a chronic disease, deterioration
over time?” Because all measurements have some error associated
with them, we would like to know
that a reported change exceeded
the likelihood of that due to errors
of measurement. The MDC is frequently reported as the value of the
standard error of measurement
(SEM) multiplied by ⫾1.96 (⫾2
standard deviations) and therefore
should be outside the range of measurement error. For example,
Kennedy and colleagues1 deter-
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