Multiple Sclerosis Journal - October 2017 - 1524

Multiple Sclerosis Journal 23(11)

Figure 2. Change in perceived fatigue according to the CIS20r fatigue subscale in the aerobic training group (blue line)
and control group (orange line). The horizontal reference line at 35 points indicates the value above which participants
had to score in order to be included (i.e. severe fatigue). Asterisk (*) indicates a significant (p = 0.014) mean difference of
4.7 points between the aerobic training group and control group based on the mixed-model analysis.

points; range = 8-56) of change on the CIS20r fatigue
subscale was below the predefined cut-off of eight
points for a clinically relevant difference, did not
result in corresponding changes on the secondary
fatigue measures, and was not sustained during follow-up. The NNT was estimated at 9.
Research into MS-related fatigue is hampered by the
lack of understanding and consensus regarding the
construct and assessment of MS-related fatigue. This
is, for instance, illustrated by the finding that the
decline in MS-related fatigue was only captured
within the CIS20r fatigue subscale and may suggest
some regression to the mean or placebo effect.
However, also according to the cut-off for severe
fatigue on the FSS (>5.0), most patients were severely
fatigued at baseline according to the FSS as well.23 If
we argue that the CIS20r fatigue subscale measures
the severity of fatigue, and the FSS measures the
impact of fatigue (e.g. 'fatigue interferes with my
physical functioning'), this would confirm our conclusion that the small decline in fatigue severity does
not reduce the impact of fatigue and may therefore
explain the absence of improvements in societal participation. Surprisingly, despite low levels of physical
fitness at baseline, markers of physical fitness showed
limited response to the provided training stimulus; a
significant effect on peak power at 8 weeks and a marginal non-significant trend towards an increase in
peak oxygen uptake and greater aerobic capacity.
These results may have been hampered by selective
loss of treatment adherence during the second phase
of the training intervention. However, the magnitude
of change in VO2peak was not out of scope with the
previous literature indicating heterogeneous and

1524

small effects on VO2peak in patients with MS.9 This
may question the trainability of patients with MS or
potential subgroups of patients. Future research
should be conducted to identify predictors of treatment response with respect to aerobic training or
exercise therapy in general and the interaction of
these predictors with the dose of therapy provided.
However, even if we are able to pre-select patients that
are likely to benefit from aerobic training, it is important to recall that the small reduction on the CIS20r
fatigue subscale in this study was not sustained during
follow-up. It has been suggested that incorporating
behavioural change techniques into exercise-based
interventions may improve the long-term effectiveness of exercise interventions.24,25 However, a recent
review showed that behavioural physical activity
interventions also fail to sustain long-term effects.26
A Cochrane systematic review (search date 24
October 2014) on the effects of exercise therapy on
fatigue in patients with MS identified 45 studies, of
which 35 trials were included in a pooled meta-analysis.11 The overall SMD of exercise therapy was −0.53
(95% CI = −0.73 to −0.33) in favour of exercise therapy. For aerobic training in particular, the SMD was
−0.43 (95% CI = −0.69 to −0.17) suggesting that the
outcome on the primary outcome fatigue (SMD = −0.53
(95% CI = −1.0 to −0.06)) was within the pooled 95%
limits of this Cochrane review. However, in contrast
to our study, the trials included in the Cochrane review
suffer from two major limitations. First, none of the
included trials did use fatigue as a primary outcome
measure, and, second, none of these trials did include
specifically participants with a predefined severe
level of fatigue.

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Table of Contents for the Digital Edition of Multiple Sclerosis Journal - October 2017
