Treatment of Fatigue in Multiple Sclerosis: Aerobic Training, Cognitive Behavioural Therapy, Energy Conservation Management

In early multiple sclerosis (MS) fatigue seriously affects social
participation. Aerobic Training (AT), the use of Energy Conservation Management
(ECM), and Cognitive Behavioural Therapy (CBT) may positively influence
fatigue, but evidence is not conclusive. A comprehensive pathophysiological
mechanism explaining fatigue is lacking.

To determine whether rehabilitation treatment strategies effectively reduce
fatigue and improve participation in MS patients with fatigue, and how they
exert their effects.

Research questions
Q1) Does AT result in reduced fatigue and improved participation?
Q2) Does ECM result in reduced fatigue and improved participation?
Q3) Does CBT improve participation and reduce fatigue?
Q4) Which treatment strategy most effectively improves participation?
Q5) Is a reduction in fatigue accompanied by a normalisation in
Hypothalamus-Pituitary-Adrenal (HPA) axis function, a reduction in
pro-inflammatory serum cytokines or an increase in anti-inflammatory serum
cytokines?

270 ambulatory MS patients suffering from fatigue will be recruited for three
Randomized Clinical Trials (RCT). Each treatment protocol will consist of 12
individual therapist-supervised sessions and home assignments during 4 months.
The control treatment consists of written patient information that is discussed
in three 45 minute sessions with an MS nurse. All RCTs use the same design,
with an intervention and a control group, and use the same outcome measures.
Measurements will take place at -1 week, baseline, 8 and 16 weeks, and 6 and 12
months. The primary outcome measures are fatigue (Fatigue subscale of the
Checklist Individual Strength) and participation (Impact on Participation and
Autonomy Questionnaire). The variables age, gender, ethnicity, cytokines in
serum, activation of the HPA-axis, aerobic capacity, Ventilatory Threshold,
vitality, daytime sleepiness, coping, self-efficacy, illness cognitions,
efficiency of energy management, and comorbidity will be used to study the
working mechanisms of the interventions. In order to assure a good
data-quality, a web-based, centrally
managed database will be used. For each RCT the primary analysis will be based
on an intention to treat protocol using longitudinal data-analysis techniques,
including Generalized Estimating Equations and Hierarchical Linear Models, that
will be constructed to detect differences between within-group changes, and
that are corrected for number of exacerbations and ethnicity. Mediation
analyses will be used to examine the working mechanisms, namely changes in
HPA-axis functioning and changes in proand anti-inflammatory cytokine levels,
of the interventions.

1) Aerobic Training consists of 12 individual therapist-supervised 45-minute
physical exercise sessions with an intensity of at least 60%VO2max in a period
of 4 months;[10] in the first 8 weeks one therapist-supervised session will be
given per week, in the subsequent 8 weeks one therapist-supervised session will
be given every other week. The sessions include a warming-up and cooling down.
In addition, patients will perform 2 aerobic training sessions per week at home
of the same duration and at the same intensity as measured by heart rate.[10]
The available treatment protocol has been adapted for this study.

2) Individualized Cognitive Behavioural Therapy (CBT). CBT will focus on the
fatigue maintaining behaviour and cognitions of the patient, which are based on
existing literature and experience in clinical practice. They may involve
insufficient coping with the disease, fear of disease progression,
dysfunctional illness cognitions, dysregulation of sleep, dysregulation of
activity, and low social support and negative social interactions. Because of
the existence of differences between individuals, therapy will be adapted to
each individual. The general aim
of the CBT is to improve daily functioning and to lessen the fatigue by
changing fatigue maintaining cognitions and behavior within the limits of the
disease (MS). We hypothesize that the changedcognitions and changed behaviour
reduce the amount of perceived environmental stressors. This may lead to less
stress and may thus lead to normalization of HPA axis functioning, a reduction
of pro-inflammatory cytokines or an increase in anti-inflammatory cytokines,
which may lead to reduced central fatigue. CBT consists of 12 individual
therapist-supervised 45-minute therapy sessions in a period of 4 months, and an
individualized schedule to gradually expand participation. The time interval
between therapy session will be gradually increased as therapy progresses.

3) The use of Energy Conservation Management (ECM). We hypothesize that
ergonomic advice and coaching towards more efficient use of available energy
leads to a reduction in environmental stressors. This reduction may lead to
less stress and may thus lead to normalization of HPA-axis functioning, a
reduction of pro-inflammatory cytokines or an increase in anti-inflammatory
cytokines, which may lead to reduced central fatigue. A reduction in central
fatigue is expected to improve participation. Individualized ECM consists of 12
individual therapist-supervised 45-minute sessions, in which energy-management
and ergonomic advices are given, in a period of 4 months; in the first 8 weeks
one therapist-supervised session will be given per week, in the subsequent 8
weeks one therapist-supervised session will be given every other week. In
addition, individualized home-assignments are given. The treatment protocol
that has been described by Mathiowetz et
al. has been adapted for this study.

4) Control treatment
The control treatment for each RCT consists of currently available standardized
written patient information and will be provided in a standardized manner by an
MS nurse. Patients receive this information package personally in the first
week. In week 6 and 12, 45-minute appointments with the MS nurse will be
scheduled in order to ask questions about the information package. This control
treatment covers two important aspects that we want to control for: 1) good
information about MS related fatigue, and 2) attention of a professional who
has experience in MS in order to reassure the patient that his concerns or
questions will be taken seriously. The nurses will receive instructions on how
to provide the information without additional therapeutic interventions or
specific personal advises.

Participants in the intervention groups receive 12 treatments over a period of
16 weeks. Participants in the control group receive usual care and information
about MS-related fatigue by an MS nurse (one or more contacts). It also gives
each participant five times to test untill one year after the start of the
study (randomization). These measurements take approximately 2 hours each time.
Questionnaires can be completed by the participants at home. This will cost an
estimated five times for 1 hour. Risks are assessed as low.

Each participant is individually supervised by an experienced therapist or
psychologist. Nevertheless, there may be adverse effects.For each intervention
group these adverse effects may be duifferent. 1) aerobic training: warm-up and
cool down to prevent the participant from sudden excessive physical exercise,
muscle soreness or injuries. 2) cognitive behavioral therapy: possible
confrontational 3) energy management: possible confrontational 4) usual care:
no risks expected.
Cardio-respiratory exercise testing: Risks as described by cycling test
(ergometry): muscle pain, shortness of breath, faint or shaky feeling after
exercise;
Questionnaires: possibly confrontational.