Neurorehabilitation and Neural
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Origin of Fatigue in Multiple Sclerosis: Review of the Literature
D. Kos, E. Kerckhofs, G. Nagels, M.B. D'hooghe and S. Ilsbroukx
Neurorehabil Neural Repair 2008 22: 91 originally published online 4 April 2007
DOI: 10.1177/1545968306298934
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Review Article
Origin of Fatigue in Multiple Sclerosis:
Review of the Literature
D. Kos, MSc, E. Kerckhofs, PhD, G. Nagels, MD, M. B. D’hooghe, MD,
and S. Ilsbroukx, MD
Fatigue is one of the most common and most disabling symptoms of multiple sclerosis (MS). Although numerous studies
have tried to reveal it, no definite pathogenesis factor behind
this fatigue has been identified. Fatigue may be directly related
to the disease mechanisms (primary fatigue) or may be secondary to non–disease-specific factors. Primary fatigue may
be the result of inflammation, demyelination, or axonal loss. A
suggested functional cortical reorganization may result in a
higher energy demand in certain brain areas, culminating in
an increase of fatigue perception. Higher levels of some
immune markers were found in patients with MS-related
fatigue, whereas other studies rejected this hypothesis. There
may be a disturbance in the neuroendocrine system related to
fatigue, but it is not clear whether this is either the result of the
interaction with immune activation or the trigger of this
process. Fatigue may be secondary to sleep problems, which
are frequently present in MS and in their turn result from urinary problems, spasms, pain, or anxiety. Pharmacologic treatment of MS (symptoms) may also provoke fatigue. The
evidence for reduced activity as a cause of secondary fatigue in
MS is inconsistent. Psychological functioning may at least play
a role in the persistence of fatigue. Research did not reach consensus about the association of fatigue with clinical or demographic variables, such as age, gender, disability, type of MS,
education level, and disease duration. In conclusion, it is more
likely to explain fatigue from a multifactor perspective than to
ascribe it to one mechanism. The current evidence on the
pathogenesis of primary and secondary fatigue in MS is limited by inconsistency in defining specific aspects of the concept fatigue, by the lack of appropriate assessment tools, and
by the use of heterogeneous samples. Future research should
overcome these limitations and also include longitudinal designs.
From the Vrije Universiteit Brussel, Department of Rehabilitation
Research, Brussels, Belgium (DK); Vrije Universiteit Brussel, Neurological Rehabilitation, Brussels, Belgium (EK); National MS Centre,
Department of Neurology, Melsbroek, Belgium (GN, MBD); National
MS Centre, Department of Rehabilitation, Melsbroek, Belgium (SI).
Address correspondence to D. Kos, MSc, Vrije Universiteit Brussel,
Department of Rehabilitation Research, Laarbeeklaan 103, B-1090
Brussels, Belgium. E-mail: Daphne.Kos@vub.ac.be.
Kos D, Kerckhofs E, Nagels G, D’hooghe MB, Ilsbroukx S. Origin of
fatigue in multiple sclerosis: review of the literature. Neurorehabil
Neural Repair 2008;22:91-100.
DOI: 10.1177/1545968306298934
Key Words: Fatigue—Multiple sclerosis—Pathophysiology—
Origin—Primary fatigue—Secondary fatigue.
atigue is frequently reported in multiple sclerosis
(MS) and limits performance in daily life, at
home, and in work and leisure activities.1
The MS Council defined fatigue as “a subjective lack
of physical and/or mental energy that is perceived by the
individual or caregiver to interfere with usual and
desired activities”2(p2) Fatigue in MS comes on easily, is
present even with small efforts or after a good night
sleep, is exacerbated with heat, and does often not
decline sufficiently after rest.3 Fatigue is also frequently
reported in other pathological conditions such as
Parkinson’s disease, stroke, rheumatoid arthritis (RA),
systemic lupus erythematosus (SLE), chronic fatigue
syndrome (CFS), and human immunodeficiency virus
(HIV).4,5 As fatigue in these disorders may also be easily
triggered, insufficiently be restored after rest, may limit
physical and mental activity, and may restrict participation, the only distinctive feature of fatigue related to MS
seems to be the heat sensitivity.4
There is still no consensus about the different dimensions of fatigue. Several attempts have been made in this
direction, and the following terms have been mentioned
in the literature: “general fatigue,” “sleepiness,” “lack of
energy,” “consciousness,” “lack of motivation,” “worsening of symptoms,” “mental fatigue,” “cognitive fatigue,”
“physical fatigue,” “fatigability,” “asthenia” (fatigue at
rest), “lassitude,” and “tiredness.”6-11 The different dimensions of MS-related fatigue are also illustrated by the large
variation of self-report instruments used in MS samples
(Table 1).12 The Fatigue Severity Scale (FSS) rates the
agreement with 9 statements concerning the severity, frequency, and impact of fatigue on daily life and has acceptable scientific properties.13 The 40-item Fatigue Impact
Scale (FIS) measures the impact of fatigue on physical,
cognitive, and psychosocial functioning during the past
month; the Modified Fatigue Impact Scale is a shorter
version with 21 items. Both scales have adequate reliability and validity.2,14-16 The Fatigue Descriptive Scale (FDS)
is a reliable and valid 5-item instrument to evaluate the
severity, frequency, quality of fatigue, and the influence of
F
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Table 1. Scales to Assess Multiple Sclerosis–Related Fatigue Dimensions
Scale
Items
Fatigue Severity Scale
Fatigue Impact Scale
Modified Fatigue Impact Scale
Fatigue Descriptive Scale
Epworth Sleepiness Scale
Visual Analogue Scale
9
40
21
5
8
1
Score Range
1-7 (Likert-type)
0-4 (Likert-type)
0-4 (Likert-type)
0-3
0-3 (Likert-type)
0-100 (mm)
heat on fatigue (the so-called Uhthoff phenomenon). An
interview is necessary to consider the spontaneity of
fatigue complaints.8 The Epworth Sleepiness Scale (ESS)
assesses excessive daytime sleepiness by rating the risk to
fall asleep in 8 situations, but it has not been validated in
an MS sample.17 On a 10-cm visual analogue scale (VAS),
patients can indicate their level of fatigue (impact). The
VAS for impact of fatigue is moderately reliable though
valid.18,19 Some studies use a combination of scales to
overcome the multidimensionality of fatigue.
MS-related fatigue can either be primary or secondary to other variables.2 Primary fatigue may result
from centrally mediated processes characterized by the
disease, such as demyelination and axonal loss in the
central nervous system or immune actions. It may also
be the consequence of peripheral mechanisms at muscle
level. Factors that may lead to fatigue include sleep
problems, reduced activity, depression, psychological
functioning, pain, and medication use. This article
reviews the available evidence for the putative pathophysiology of primary and secondary fatigue related to
MS and describes the current treatment options.
PRIMARY FATIGUE
Central Nervous System
Multiple sclerosis is characterized by inflammation,
demyelination, and destruction of the axons in the central nervous system.20 To perform a similar activity,
patients with MS have to recruit more nerve fibers or
innervation areas in the brain than healthy individuals.21
This could provoke fatigue. Following this hypothesis,
one should expect that the increased number and volume
of lesions in the white matter are related to elevated levels
of fatigue. To visualize and quantify brain activity, magnetic resonance imaging (MRI) techniques are used, but
these MRI studies could not confirm this hypothesis.22,23
Bakshi et al partly explained this discrepancy by the limited sensitivity of conventional MRI to detect the pathologic processes in the brain.24 Therefore, more advanced
MRI methods have been used to study the mechanism of
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Dimensions of Fatigue
Modality, severity, frequency, impact on daily life
Physical, cognitive, psychosocial impact
Cognitive, psychosocial, physical impact
Modality, spontaneity, severity, frequency, and influence of heat
Excessive daytime sleepiness
Depends on the question
fatigue, such as proton spectroscopy and magnetization
transfer imaging. A study using proton magnetic resonance spectroscopy found an association between diffuse
axonal damage and fatigue.25 However, the quantitative
estimates of brain lesions provided by magnetization
transfer and diffusion-tensor MRI did not show any differences between 14 fatigued and 14 nonfatigued patients
with MS.26
The relationship between lesion load and fatigue
might also be influenced by concomitant symptoms of
MS, such as depression and physical disability. To exclude
the interference with these variables, Colombo et al studied the MRI findings of nondisabled and nondepressed
individuals with MS.27 The Italian study group did find
higher loads of MS lesions in certain brain regions of
fatigued people than in those who did not complain of
fatigue. Moreover, the lesion load correlated significantly
with the FSS score.27
In a longitudinal study including 134 patients with
relapsing remitting MS, Marrie et al found that an
increase in fatigue during the first 2 years was related to
brain atrophy progression in the subsequent 6 years.28
The results suggest that fatigue predicts the brain atrophy
as opposed to being a consequence of the demyelination
process.
Limited evidence suggests a relationship between
fatigue after stroke and basal ganglia.29
In conclusion, when adjusted for confounding factors
such as physical disability and affective disorders, there
seems to be a relationship between lesion load and fatigue
in MS. However, the exact mechanism of how demyelination and axonal loss influence fatigue (or vice versa) is
not clear.
Fatigue may be induced by functional changes in the
brain. Leocani and colleagues (2001) asked individuals
with MS with and without a fatigue complaint as well as
healthy controls to perform extensions of the thumb,
while brain activity was recorded using an electroencephalogram (EEG). The EEG showed an increased cortical activation and a decreased cortical inhibition in the
MS group complaining of fatigue, compared to nonfatigued patients with MS and healthy controls. At the
onset of the task, more brain areas were recruited than
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Origin of Fatigue in Multiple Sclerosis
necessary, whereas at the end of the task, the needed inhibition process failed. Moreover, the activation/inhibition
pattern correlated moderately with self-reported fatigue.
These results suggest that fatigue is related to a dysfunction in the cortical organization of motor performance,
but it is not clear whether this association is causal.30
Using transcranial magnetic stimulation, Liepert et al
observed a pre- and postexercise reduced inhibition of the
primary motor cortex in fatigued MS patients. The prolonged normalization time after exercise was related with
fatigue severity in this subgroup, suggesting a relationship
between fatigue and membrane excitability of the primary
motor cortex.31 Functional MRI studies also suggest a
cortical functional reorganization in MS. Rocca and
colleagues (2002) examined the brain activations of 30
individuals with primary progressive MS and 15 healthy
controls using functional MRI. Participants had to perform 3 simple motor tasks: a repetitive flexion-extension
of the last 4 fingers of the right hand, a repetitive flexionextension of the right foot, and a simultaneous combination of both. The patients with MS showed an increased
cortical activation of nonmotor areas both ipsi- and contralateral, compared to healthy controls. Moreover, a
strong correlation was present between the changes in
brain activation and the lesion burden demonstrated in
MRI scans. Because in normal circumstances these additional cortical areas are only activated in complex tasks,
the authors hypothesized the cortical functional reorganization to be an adaptive mechanism. To maintain the
functional capacity of the damaged brain, more areas are
recruited.32 Similar results were found in a noncontrolled
study of 9 persons with MS.33 This compensatory mechanism could also explain the limited relationship between
conventional MRI measures of lesion burden and clinically manifest disabilities. However, no correlations with
perceived fatigue have been performed in both studies.
Although this is speculative and needs to be confirmed in
future research, this increased cortical activity might result
in fatigue.
The results of the functional MRI study of Filippi
et al (2002) suggested that fatigue in MS might be
related to the impaired cortico-subcortical interaction,
responsible for motor planning and execution.21 Deep
gray matter involvement—in particular, the thalamus—
in the pathophysiology of fatigue has been further supported by an MRI study using T1 relaxation time.34 In
line with these findings is the reduction of recruited
areas and fatigue after training.21,32,35 The mental fatigue
might be explained by an increased activation of the
cortical area involved in attention tasks (ie, the anterior
cingulate cortex) in people complaining of fatigue.21
Inconsistent with the previous findings, Morris et al
found no changes in gait from morning to afternoon,
despite the self-reported higher fatigue level.36 The authors
suggested that the mechanisms regulating motor performance are different from those responsible for perceived
fatigue. Another explanation may be an increased energy
demand to maintain a similar behavior level.
A reduced energy metabolism in the cortical regions
has been postulated as a possible pathogenesis factor of
fatigue in MS. Roelcke and colleagues (1997) studied
the cerebral glucose metabolism in 47 patients with MS
with F-fluorodeoxyglucose positron emission tomography
(PET). They found a reduced glucose metabolism in the
frontal cortex, white matter, and basal ganglia in individuals with a higher fatigue severity score, independent of
overall disability and depression.37 The brain areas responsible for cognitive and attention tasks showed a higher glucose metabolism in fatigued patients, which is suggested to
be a compensatory mechanism for the impaired motor
performance, although the study could not confirm this
hypothesis.
In a study with individuals with Parkinson’s disease,
fatigue was also related to abnormal glucose metabolism in the supplemental motor areas and putamen.38,39
Despite some inconsistency, there is growing evidence
for the involvement of a functional cortical reorganization
in the origin of fatigue in MS.
Immunological Factors
During the relapse phase of MS, people often complain
of a higher degree of fatigue.5 Besides, immunomodulatory medications such as interferon-alpha and interferonbeta frequently produce fatigue as a side effect in MS and
other diseases.22,40,41 Therefore, an immunological factor in
the etiology of MS-related fatigue is postulated.
During a relapse of MS, the immune activation is
increased, demonstrating higher levels of proinflammatory cytokines such as tumor necrosis factor alpha (TNFalpha), interleukin 1 (IL-1), and IL-6. Cytokines are
involved in the disruption of the blood-brain barrier in
MS, which can be evaluated using MRI techniques.
Mainero et al studied the MRI of 11 patients with relapsing-remitting MS and did not find an association between
fatigue and the action of proinflammatory cytokines
on the central nervous system.22 However, the authors did
not exclude the possible action of cytokines on the
peripheral nervous system. Flachenecker and colleagues
examined the peripheral blood and found higher levels of
TNF-alpha mRNA expression in individuals with fatigue
than in those without symptoms.42 Moreover, the relationship of cytokine levels and fatigue was independent of
disease-related variables or autonomic nervous system
activity, suggesting a role of the MS-related inflammation
process in the fatigue pathogenesis. Similar findings were
reported by Heesen and colleagues.43
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Both the increased interleukin-6 concentrations during a relapse and during treatment with interferon beta
suggest a possible mediating role of interleukin-6 in
fatigue.44-46
In other immune-related diseases with common
fatigue complaints, such as HIV, SLE, and RA, similar
changes in cytokine levels were found.47,48 The immunological role in the pathogenesis of fatigue therefore may
be non–disease-specific.
Neuroendocrine Involvement
Proinflammatory cytokine levels are elevated in
MS.49 These substances may cause an increased activity
of the hypothalamic-pituitary-adrenal (HPA) axis, with
increased secretion of corticotrophin-releasing factor
(CRF), adrenocorticotrophic hormone (ACTH), and
cortisol.5,45 The inverse may also happen, with HPA dysregulation leading to immune activation.5 Whether a disturbed activity of the HPA axis plays a role in MS-related
fatigue, however, remains unclear.39 Gottschalk et al
showed a hyperreactivity of the HPA axis in relapsingremitting MS patients with fatigue, who were not under
MS-specific treatment.50 Heesen et al used a mixed sample of MS types and did not exclude medication use.
However, they could not demonstrate a relation between
fatigue and HPA axis activity.43,51 Tellez and colleagues
found lower serum levels of the adrenal neurohormone
dehydroepiandrosterone and its sulphated ester in progressive MS patients with high fatigue severity, suggesting
a dysregulation of the HPA axis.52 As the hyperactive HPA
axis may be related to the clinical course, future studies
should include homogeneous samples to verify the relationship between fatigue and HPA axis activity.53
Furthermore, the influence of immunomodulatory treatment should be taken into account.
RA-related fatigue was also associated with higher
cortisol levels.48 Opposed to the findings in MS and RA,
CFS is related to a hyporeactivity of the HPA axis, suggesting a dissimilar neuroendocrine-related pathogenesis of fatigue.54 The promising results of modafinil in
MS-related fatigue suggest a hypothalamic involvement
in the pathogenesis of the symptom.55,56 This wake-promoting agent used in narcolepsy is thought to manipulate the brain areas that regulate wakefulness, such as
hypothalamic neurons.57,58 However, in a recent randomized placebo-controlled double-blind clinical trial,
the effect of modafinil on fatigue in patients with MS
was not superior to that of placebo treatment. In a post
hoc analysis, a positive effect was suggested in patients
with excessive daytime sleepiness, suggesting a dissimilar
origin of fatigue and sleepiness.59
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Although some evidence exists on the role of the
endocrine system in the pathophysiology of MS-related
fatigue, there is need to clarify the trigger in the interaction of immune activation and HPA axis dysregulation.
Peripheral Abnormalities
Peripheral mechanisms might be partly involved in
the development of (muscle) fatigue. Although patients
with MS showed decreased isometric and isotonic
strength relative to healthy controls, the recovery of force
after exercise was similar.9 Moreover, the recovery rate did
not correlate with perceived fatigue (FSS and FDS).9,60,61
Several studies reported reduced muscle fibers in patients
with MS, with a higher reliance on anaerobic energy supply than in healthy controls.62,63 De Haan and colleagues
could not confirm these results, however.64
Following stimulation of the peroneal nerve, the
resynthesis of phosphocreatine is delayed in MS, probably due to deconditioning.60,65 During voluntary exercise,
metabolic changes are not related to the development of
muscle fatigue.66
Concluding, in MS, peripheral changes in muscle
performance probably result from disuse or deconditioning and muscle fatigue is induced by impaired central activation rather than peripheral mechanisms.
Muscle fatigue and the symptom fatigue seem to be distinct dimensions.
Conclusion
The origin of primary fatigue in MS is not yet fully
understood. Evidence for the pathological process of
demyelination and axonal loss leading to higher fatigue
levels is available in nondisabled and nondepressed individuals with MS. It remains unclear, however, whether
fatigue is directly influenced by this degenerative process
or a consequence of immunological action in the brain. A
possible functional cortical reorganization may lead to a
higher energy demand, which on its turn may lead to
fatigue. This hypothesis should be confirmed in future
studies. Increased levels of peripheral immunological
markers have been found in fatigued patients. These
agents may trigger a disturbance in the endocrine system;
however, the inverse may also happen. The precise mechanism in this interaction related to fatigue needs to be
clarified. Fatigue seems to have multiple dimensions, such
as “loss of energy,” “sleepy,” “inability to sustain (physical
or mental) activity.” It is likely that the origin of these
dimensions is multiple as well. Future research should
therefore distinguish these various dimensions to examine
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Origin of Fatigue in Multiple Sclerosis
the pathogenesis of fatigue. To initiate good research, a
clear definition of the dimensions of fatigue and appropriate instruments to assess them are needed.
SECONDARY FATIGUE
progresses. However, in a study of 14 individuals with
MS and a similar number of matched controls, no differences in gait pattern were found between morning
and afternoon assessment, whereas fatigue scores
increased in the afternoon. The mechanisms for motor
control and the subjective experience of fatigue are suggested to be dissimilar.36,61,86
Sleep Disorders
Besides the primary fatigue discussed before, fatigue
can also be secondary to sleep disorders. Individuals with
MS have reduced sleep quality twice as often as healthy
controls.67,68 Furthermore, in 2 samples of individuals
with MS, more than 50% reported sleep-related problems as a consequence of pain, spasms, medication, disorders in bladder control, anxiety, or external factors.69,70
However, no evidence was found for a general disturbed
sleep–wake rhythm.71 Patients with MS-related fatigue
had more disturbed sleep by nocturnal activity compared
to nonfatigued individuals with MS.72 Wunderlin et al
found no relation between nocturnal apnoes or oxygen
desaturations and self-reported fatigue or sleepiness in 10
patients with MS.73 Attarian and colleagues studied sleep
disruption in 15 fatigued and 15 nonfatigued MS patients
and 15 healthy controls by means of actigraphs and sleep
logs. In the fatigued patient group, 10 patients had a disrupted sleep pattern, compared to 2 patients of the nonfatigued group and none of the healthy controls.74 In
contrast to difficulties in falling asleep and early wakening, middle insomnia (ie, waking during the night) was
correlated with fatigue severity, although moderately.70
These results suggest a relationship between fatigue and
sleep disruption but do not explain the causality. Several
studies suggested a differentiation between feelings of
fatigue and daytime sleepiness.59,70,75,76
Psychological Factors
Although fatigue in MS does not appear to have a psychological basis, the experience of fatigue can be influenced by psychological factors. Sense of control, often
referred to as self-efficacy, reduces feelings of fatigue,
whereas focusing on bodily sensations aggravates the
symptom.1,87 Cognitive behavior therapy addressing these
attitudes was found to reduce fatigue in CFS and in MS.88,89
Several clinical trials found a large placebo effect
for measures of fatigue.59,90,91 These results suggest a
substantial psychological influence on—at least—the
persistence of fatigue.
Depression
Depression is often reported to be related to fatigue
(impact).67,92-98 Moreover, the treatment of depression
was related to a reduction in the subjective severity
of fatigue.89 The study of Mohr and colleagues used
3 modalities of treatment: an individual cognitive
behavioral therapy, sessions of support groups, and the
antidepressant medication sertraline. The effect of
treatment on fatigue did not differ across the modalities
and could therefore not be explained by a treatmentspecific mechanism.89 The causality of the relationship
between fatigue and depression needs to be elucidated.
Reduced Activity
Persons with MS are less active than healthy controls.77,78 This chronically reduced activity could partly
explain fatigability and change in muscle use; however,
self-reported fatigue was not related to the reduced activity level of individuals with MS.79 In line with these
results, no improvement in fatigue severity scores was
found after a short (3 to 4 weeks) exercise program.80-82
Nevertheless, an aerobic training program of 10 weeks
reduced the subjective fatigue score of the Profile of
Mood States.83 Others found similar results after exercise
training.84 However, no relationship was found between
fatigue impact and spiroergometric parameters.85
When activity and fatigue are related, the observed
higher fatigue scores in the afternoon are expected
to accompany reduced motor performance as the day
Relationship With Other Variables
A number of studies have investigated the relationship
of fatigue with other clinical variables, but they did not
reach consensus. A study with 151 individuals with MS
showed no association between fatigue and age, gender,
disease duration, and clinical activity.99 Other studies
found increased fatigue scores in people with higher age,
lower educational level, longer disease duration, and progressive type of MS.93,100,101 The question remains whether
these variables directly influence fatigue. Post hoc analyses revealed that disability status was mainly responsible
for the differences in fatigue scores between types of
MS,93,97,98 although in other studies no relation was found
between disability and fatigue.23,92,102
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Figure 1. Relationship between fatigue and other variables. Numbers are correlation coefficients, unless otherwise stated.
Numbers in superscript are references. *P < .05; **P < .01.
Figure 1 demonstrates the relationships between
fatigue and clinical variables. The causality and interdependence of the variables still needs to be clarified, however. Strober and Arnett found that sleep disturbance,
disease severity, and depression independently predicted
fatigue in MS.103 Sleep disturbance was the strongest predictor and affected fatigue interactively with depression.
The influence of fatigue on these variables was not examined. The authors used a self-modified version of the
Fatigue Impact Scale, implying a model for fatigue
impact (and not fatigue).
Pain and its treatment can aggravate fatigue.104,105 A
reciprocal relationship between these modalities is possible, though not demonstrated.
The pharmacological management of other MS symptoms may also play a role in the occurrence of fatigue.
Particularly, the use of interferons often induces fatigue.46,106
Current Treatment Options
Fatigue should be approached by a multidisciplinary
team. An elaborate screening of the person with MS
may detect secondary causes of fatigue, which should be
treated appropriately, if possible.2 If fatigue persists, a
nonpharmacological approach can be offered. This
includes a combination of aerobic exercise, a rehabilitation
program, body cooling, energy conservation strategies, and
psychological and dietary interventions.5,107-109 The evidence for the efficacy of aerobic exercise or resistance
training on fatigue perception is inconsistent and insufficient, partly due to lack of trials with large samples and
96
adequate contrast in type of intervention between
experimental and control conditions.81,86,110 Several controlled studies found a reduction of fatigue (impact)
after an in- or outpatient rehabilitation program,110-112
However, a recent randomized controlled trial did not
show any benefits of multidisciplinary inpatient rehabilitation on disability level or perceived fatigue.113
Temperature control can be achieved by cooling the
environment or decreasing the body temperature
directly using cooling vests. No studies investigating the
effect of air temperature control are reported. However,
cooling vests with an active liquid flow significantly
reduced fatigue (impact).114,115 Teaching of energy conservation strategies by an occupational therapist resulted
in higher self-efficacy and lower fatigue impact scores.116
Interventions not specifically developed for fatigue also
showed efficacy: group support, individual cognitive
behavioral interventions, and a professionally guided
self-care management program significantly decreased
subjective feelings of fatigue.89,117 The influence of diet
on fatigue has been poorly studied.118 Recently, one
study found positive results of a low cholesterol diet
supplemented with olive oil capsules.119
Additionally, a pharmacological treatment may
reduce fatigue complaints. The most common agents
are amantadine, modafinil, and pemoline.109 The efficacy of amantadine—an antiviral agent used in
Parkinson’s disease—has been studied in MS by several
research groups, but the clinical importance remains
unclear.109,120-123 Modafinil is a wake-promoting agent
used in narcolepsy and reduced MS-related fatigue.55
However, a double-blind, randomized placebo-controlled
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Origin of Fatigue in Multiple Sclerosis
Table 2. Overview of Evidence for the Origin of Fatigue in Multiple Sclerosis
Support
Primary fatigue
Brain lesions
Axonal damage
Functional cortical reorganization
Immunological factors
Neuroendocrine factors
Peripheral abnormalities
Secondary fatigue
Sleep disorders
Reduced Activity
Psychological factors
Depression
Ref no 27
Ref no 25
Ref nos 21,30,31,35,37,129
Ref nos 42,43
Ref nos 50,52,55,56
Ref nos 70,72,74
Ref no 83
Ref nos 1,87-89
Ref nos 67,89,92-98
trial with parallel groups showed modafinil was not
superior to placebo.59 The efficacy studies with the central
nervous system stimulant pemoline could not demonstrate a significant difference with placebo.121,124 Other
agents may also be used in the treatment of MS-related
fatigue.109 The potassium-channel blocker 4-aminopyridine did not show efficacy in progressive MS, however.91
Although likely treating fatigue secondary to depression,
Mohr et al found a positive effect of the antidepressant
sertraline on fatigue severity in patients with relapsingremitting MS.89 In one study with small sample size and
no long-term follow-up, a beneficial effect of aspirin on
fatigue was found.125
DISCUSSION
Fatigue is a multidimensional, complex and highly
subjective symptom. Due to the heterogeneity of the
symptom, it is likely that several factors or mechanisms
play a role in the origin (see Table 2). Both primary and
secondary fatigue can be present in one individual and
may have an impact on each other. An individual with
primary fatigue (ie, exclusion of secondary causes) may
experience such an impact on his life that he becomes
depressed. This depression in turn may aggravate the
fatigue already present. Similarly, fatigued persons may
reduce their activity level, which in turn may lead to
higher fatigability. Partly because of this interaction, it is
not straightforward to exclude one pathogenesis factor
or the other. Moreover, there is a lack of adequate assessment tools to deal with this problem.
To a great extent, the lack of an accurate and uniform
assessment instrument has led to various results in
the pathogenesis research. The FDS is able to distinguish various dimensions of fatigue.8 In a study using
Reject
Suggest (not related to fatigue)
Ref nos 22,23,26
Ref no 36
Ref no 22
Ref no 51
Ref nos 9,60,61,64,66
Ref nos 32,33
Ref nos 57,58
Ref no 73
Ref nos 36,61,79,85,86
the FDS, asthenia (fatigue at rest) was related to
immunoactivation, whereas fatigability (fatigue with
exercise) was associated with disturbances in the pyramidal functions.126 Using the Epworth Sleepiness Scale,
daytime sleepiness was related to elevated proinflammatory cytokine levels.43 However, higher FSS scores
were also associated with increased levels of immune
activation.42,43 These results suggest multiple mechanisms for the various dimensions of the concept fatigue.
The FSS is widely used as an outcome measure in clinical trials and as an instrument to distinguish fatigued
from nonfatigued persons with MS. However, the FSS
assesses the frequency, severity, and impact of fatigue in
one scale, and therefore no conclusions about distinct
dimensions of the symptom can be drawn based on this
instrument.127
Studies describing the relationship of fatigue with other
variables are often limited by the use of cross-sectional
correlation-based measures (either correlation coefficients
or regression analyses), and therefore no conclusions can
be drawn about the causality of the associations.
Future research should focus on the definition of
fatigue and its dimensions, and on the development of
accurate assessment tools, which can be used in longitudinal studies to investigate what is really behind the complaint of fatigue and the treatment of this impairing
symptom of MS.128 In designing clinical trials, researchers
should be conscious of a potential placebo effect.
ACKNOWLEDGMENT
Daphne Kos was supported by a PhD grant from the
organization Wetenschappelijk Onderzoek in Multiple
Sclerose (WOMS) Belgium. The authors are grateful to
Romain Meeusen for providing useful comments.
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