Central fatigue in multiple sclerosis: a review of the literature

Search method

A detailed literature review addressing fatigue and MS was conducted for this article. The literature search was performed through the databases Ovid HealthStar, Ovid MEDINE, CINAHL, Health and Psychosocial Instruments (HaPI), and PsycINFO. The time frame of the search was from 2009 to 2014, resulting in a total of 164 articles. An initial generic search in PubMed published at any date using the following key words as titles, “Fatigue AND multiple sclerosis,” yielded 101 articles. These common key words/phrases include: (“fatigue” [MeSH Terms] OR “central fatigue” [All Fields]) AND (“circadian rhythm” [MeSH Terms] OR “neurotransmitters” [All Fields] OR “serotonin” [All Fields] OR “suprachiasmatic nucleus (SCN)” [All Fields]). The refined search yielded 30 articles by eliminating inclusion and exclusion criteria. We then incorporated “brain activity” AND “disability.” The search included articles written in English published between the years 2000–2014 and focused on fatigue in patients with MS. Twenty-three publications were included in this review. One article was found by incidental review of the literature.²³ The earliest article was published in 1994²⁴ and the remainder (n = 16) were published from 2004 to the present (Table 2).

Inclusion criteria

All RCTs, quasi-randomized and quasi-experimental designs with comparative controls, and controlled before-and-after studies were included. Whenever RCTs were lacking, a search for relevant observational studies was conducted. Studies involving other medical conditions where data were specifically provided for MS-related fatigue were also included. Descriptive studies and narrative reviews were explored to identify policies, protocols, and gaps in service provision. Systematic reviews and meta-analysis were excluded. No restrictions were set for type of MS, disease severity, level of disability, or demographic characteristics (gender/race/ethnicity) of study participants. Studies were excluded if they targeted non-adults (aged younger than 18 years old), or included populations other than MS. Results and inclusion were discussed until consensus was reached among all three authors. A summary of the publications included in the review is provided in Table 2.

How has fatigue been defined and measured in patients with MS?

A host of assessments have been used to measure MS-related fatigue, many of which have been used in clinical trials (Table 3). Several recent reviews of published MS assessments highlight the strengths and weaknesses of each available assessment.^25,27,43,44 These reviews confirm the Fatigue Task Force by the American Association of Neuroscience Nurses (AANN)²⁷ recommendations that researchers should select the most appropriate instrument to achieve the study goals.

Self-report measures of MS-related fatigue

As a subjective symptom, MS-related fatigue is measured via self-report. Most self-report scales identified in the literature review address both the sensation and impact of fatigue,²⁵ and some scales include additional domains such as reduced motivation, energy or vitality, or diurnal variation.⁷ A brief description of the major self-report fatigue instruments is provided to illustrate variation in measurement.

The Fatigue Severity Scale (FSS) instructs patients to assign a score of between 1 (completely disagree) and 7 (completely agree) for each of the 9 FSS items. The items are designed to rate the extent of fatigue symptoms and their impact on patient functioning (including motivation, exercise, physical functioning, carrying out duties, and interfering with work, family, or social life). Examples of the items include: “exercise brings on my fatigue” and “my fatigue is very debilitating.” A higher score indicates a higher degree of fatigue for all items.¹¹ Scoring of the FSS is performed by dividing the sum of the 9 items to produce an FSS total score that ranges from 1 (no fatigue) to 7 (very severe fatigue).

The MFIS-21 is a modified version of the 40-item Fatigue Impact Scale (FIS), which was originally developed to assess the effects of fatigue on quality of life in patients with chronic diseases, specifically MS.²³ The FIS asks patients to rate the extent to which fatigue has affected their life in the past 4 weeks on a questionnaire consisting of 10 “physical” items, 10 “cognitive” items, and 20 “social” items, with 0 indicating “no problem” and 4 indicating “extreme problem.” The maximum possible score is 160. The MFIS evolved from the FIS during the development of a clinical inventory assessing overall QOL in people with MS (the Multiple Sclerosis Quality of Life Inventory (MSQLI). During the phase 2 field testing of the MSQLI the 40-item FIS was abbreviated into the 21-item MFIS by “eliminating items which appeared both content-redundant and had high inter-item correlations.”^43,44 The maximum possible score is 84, with higher scores indicating a greater impact on QOL.

The Neurological Fatigue Index for MS (NFI-MS) (28) consists of 23 items in four subscales of Physical (8 items), Cognitive (4 items), Relief by diurnal sleep or rest (6 items), and Abnormal nocturnal sleep and sleepiness (5 items). A 10-item Summary Scale derived from physical and cognitive items is also available. Wording of the scales is both simple and concise; the use of the word ‘fatigue’ was deliberately avoided because of its associated semantic ambiguities. All items are worded in such a way as to be scored in the same direction. Each item has a four point Likert response option with headings of ‘strongly disagree,’ ‘disagree,’ ‘agree,’ and ‘strongly agree,’ which progress in the natural reading direction (i.e. left to right), and are scored 0, 1, 2, 3. There is a single sentence instruction at the start of the scale asking respondents to consider their experience over the previous four weeks. The scale has good construct validity across subscales in persons with MS.³⁵

In summary, the publications included in this review used the FSS, MFIS, and NFI-MS to measure fatigue in people with MS. Of the publications identified, almost all used the FSS,^{11,19,28–30,32,37,38,40,41} whereas five ^{20,21,33,35,41,45} used the MFIS and three^33–35 used the NFI-MS. In comparing these commonly used instruments, it is noted that the FSS does not include questions regarding cognitive fatigue whereas the MFIS does include questions of cognitive fatigue as well as the impact of fatigue on social functioning. In contrast, the NFI-MS focuses on measurement of physical and cognitive fatigue as well as the impact of sleep quality, quantity, and sleepiness of levels of fatigue. Because different constructs of fatigue are measured in each instrument, the results cannot be compared across studies. Also, there are no adequate measures for the evaluation of fatigue in control populations to allow for true comparison, as a majority of fatigue scales are disease specific. It is, therefore, reasonable to assume that more research on the various measures described here is needed to identify change in the physical and cognitive domains.⁴⁵

Physiological factors associated with fatigue: neurotransmitter dysfunction

Several studies reviewed investigated the relationships among fatigue and levels of neurochemical modulators. Melamud et al.³² assessed the influence of IFN-β treatment on melatonin secretion, fatigue, and sleep characteristics in a sample of 15 patients with MS compared to healthy controls (HC). Using the Modified Fatigue Impact Scale (MFIS), sleep was assessed by actigraphy, and day/night levels of 6-sulphatoxy-melatonin (6-SMT) in urine were determined using a highly specific ELISA assay. They found that patients with MS had significantly decreased levels of 6-SMT and disrupted circadian regulation of its secretion, which was increased with IFN-β treatment. Furthermore the IFN-β improved fatigue, suggesting dysregulation of melatonin secretion in MS. The results call for further characterization of the role of neuro-hormones, such as melatonin, in MS and their cross-regulation with immune-mediators.

Using an experimental design, Papuć et al.³⁷ found hypocretin system functions may be involved in fatigue levels. The hypocretin system is linked to wakefulness and arousal in the brain. The sample size was small with 25 people diagnosed with relapsing-remitting MS and 13 diagnosed with secondary progressive MS, along with healthy control participants (HCs). All participants completed the Fatigue Severity Scale (FSS), and Epworth Sleepiness Scale (ESS). CSF hypocretin-1 levels did not differ between patients with MS and HCs (P > 0.05), however, a positive correlation between hypocretin-1 level and fatigue level was found in patients with MS who were in the relapse phase (P < 0.05), an effect even stronger in the MS subgroup suffering from fatigue (P = 0.01). The hypocretin system seems to be generally unchanged in MS, but a relationship between hypocretin-1 level and fatigue may indicate involvement of some compensatory mechanisms stimulating the production of the neuropeptide in patients with MS.

In a study by Heesen et al.²¹ there was an altered cytokine response to cognitive stress during MS-related fatigue. Patients (n = 23) and controls (n = /25) participated in a cognitive task lasting 40 minutes in which the heart rate was continuously monitored. Patients scored high on a disease-specific fatigue score compared to controls, whereas baseline cytokine patterns did not differ between the groups. Patients with MS displayed a blunted response of IFN γ (P = / 0.03) whereas TNF α and IL-10 responses did not change. Additionally patients with MS showed a significantly lower heart rate increase after the task (P < / 0.001). Cognitive impairment was associated with a decreased heart rate reactivity (P = /0.02) while depressive symptoms correlated with stronger IL-10 responses (P < /0.05), supporting autonomic dysfunction in the MS group.

In Iriarte et al.²⁸ a sample of 155 patients (105 women, 50 men) with clinically definite MS were studied. Fatigue was measured using the Fatigue Descriptive Scale (FDS) and the Fatigue Severity Scale (FSS). Patients were to report on three clinically different entities (asthenia, fatigability, and worsening of symptoms with effort). Fatigue was a symptom in 118 patients (76.13%.); 26 patients (22.03%) described it as asthenia (fatigue at rest); 85 patients (72.03%) as fatigability (fatigue with exercise), and seven patients (5.9%) as worsening of symptoms. The authors concluded that asthenia (fatigue at rest) and fatigability (fatigue with exercise) may be different clinical entities.

The publications reviewed suggest that there are differences in levels of neurochemical mediators, such as melatonin and hypocretin in people with MS who report fatigue compared to non-fatigued patients with MS and healthy controls. Although inflammatory activation is often cited as a potential mediator of fatigue in people with MS, there is not enough evidence currently available to support this assumption.

Circadian rhythm and timing of fatigue

Several publications reported findings on the relevance of time of day to fatigue severity. In a recent study, Streckis and colleagues³⁹ evaluated the effect of time of day on central and peripheral fatigue during quadriceps exercise in men and women with MS. The sample consisted of age-matched patients with MS (age range 40–50) who completed the FSS to ascertain any difference in men and women with MS in both morning and evening. They found a significant gender difference in central activation ratio (CAR) in the evening. At the end of the 2-min maximal voluntary contraction (MVC), the voluntary torque decreased by about 65% in men and women with MS in both the morning and evening. The most interesting finding of that study was that central fatigue increased, whereas peripheral fatigue decreased markedly in the evening only in women. It remains unclear why women's central fatigue is greater in the evening than in the morning.

In a similar study, Kim et al.³⁰ used the FSS and MFIS in a sample of 49 patients with MS. The authors used a cut-off score of FSS > 4 and had patients wear a wrist-worn device four times a day over 3 weeks. FSS and MFIS were evaluated and compared with real time digital fatigue scores (RDFS). Mean RDFS significantly correlated with FSS (r = 0.55, P < 0.001) and MFIS (r = 0.55, P < 0.001). RDFS captured circadian variations in fatigue, with scores increasing from mean 3.4 at 9 am, to 4.0 at 1 pm, 4.5 at 5 pm, and 5.0 at 9 pm.

Likewise, in a large cross sectional study (n = 635) in the UK, Mills and Young³⁴ reported fatigue was worse in those with progressive disease and clearly worsened once ambulation was started. Fatigue was not related to disease duration or patient age. Fatigue levels were minimum at nocturnal sleep duration of 7.5 hours.

Conversely in a longitudinal study, Johansson and colleagues²⁹ sought to describe variations in fatigue over the course of 2 years in a sample of persons with MS. These authors found that FSS scores varied significantly (P = 0.02); 54% changed FSS category one or several times, 27% were persistently fatigued, and 19% persistently non-fatigued. Furthermore, moderate disease severity predicted increase in fatigue when combined with 10 years since diagnosis, or a progressive course.

In Iran, Najafi et al.³⁶ used a case-control study performed with 120 patients with MS and 60 healthy subjects, who were age-sex matched. Sleep quality, rhythm, and fatigue severity were assessed using PSQI (Pittsburgh Sleep Quality Index) and FSS questionnaires, respectively. They observed that circadian rhythm sleep disorder (CRSD) was more frequent in patients with MS relative to healthy subjects (P = 0.002). Also, CRSD was higher in patients with MS with severe fatigue relative to patients with MS with mild fatigue (P < 0.05). The patients were divided by fatigue severity of 49.9 ± 8.2 and 22.5 ± 7.4 in the first and second group, respectively. The PSQI index was 7.9 ± 4.5 in patients with severe fatigue and 5.9 ± 4.5 in patients with mild fatigue, and 4.5 ± 2.4 in the control group (P = 0.0001). They concluded that distinguishing fatigue and sleep among this population is highly important, as fatigue is difficult to define. Some of the reasons for these findings could be attributed to a shared mechanism between fatigue and sleep.³⁴

In contrast, Vetrugno et al.⁴² reported on sleep-wake and body core temperature (BCT) circadian rhythms in patients with MS associated with chronic fatigue in Italy. They used 48 consecutive hours of polysomnography (PSG) with BCT measurement, followed by a Multiple Sleep Latency Test (MSLT) in six patients with MS and chronic fatigue. Fatigue was also assessed by standardized, self-administered questionnaires that included the FSS and the MFIS. They found normal sleep–wake rhythmicity, sleep structure, and BCT rhythm in six drug-free patients with MS and chronic fatigue, and without sleep-related breathing disorders. However, due to the small sample, the authors concluded that other factors, such as co-occurring sleep symptoms, should be addressed.

It has been documented previously that CRSD may increase fatigue levels.⁴⁵ The possible common mechanisms shared by MS and sleep disturbances may be connected with CRSD combined with compromised melatonin secretion, reducing input to the suprachiasmatic nucleus (SCN) due to increased levels of proinflammatory cytokines.⁴⁶ Najafi et al.³⁶ reported that sleep phase syndrome and irregular sleep wake patterns in patients with MS with mild and severe fatigue were compared with healthy subjects. CRSDs were significantly higher in patients with MS in relation to healthy subjects.^47,48 Furthermore, it is correlated with increased symptoms of tiredness, fatigue, and lack of energy in patients with MS.^40,49

In summary, the literature concerning the impact of circadian rhythm and timing on fatigue suggests that fatigue may worsen over the course of the day,^28,42 with disease severity,^39,50 levels of activity³⁹ and with diagnosis of CRSD.^30,34 A few studies found that the later in the day, the more severe the fatigue for patients with MS.^28,42,44,51 Fatigue has been shown to show noticeable daily cycles, with greater fatigue at the end of the day in some people.⁴⁰ Explanations are unclear, but it is postulated that this may be caused by early neuronal damage in the brain, or influenced by psychological factors, muscle exhaustion,⁴² or an overlap of these factors.²⁸ Particularly in patients with more progressive forms of MS, fatigue may start or intensify with excessive physical activity, emotional stress or cognitive changes.^22,51

Factors related to central fatigue

A recent study²³ found that evoked potential (EP) in EEG may be useful as indicator of neural disruption and not just the subjective nature of fatigue. For example, abnormalities of EP in fatigued patients, independent from MS-related variables, may support the hypothesis of disturbed bioelectrical activity due to CNS damage as the background of fatigue, which contradicts the idea of its purely subjective origin.

While there are differing etiologic theories underlying the pathogenesis of MS-related fatigue, it is clear that damage to the central nervous system is an inciting event. Neuroimaging procedures have demonstrated that select areas of CNS disruption are tied to symptoms of fatigue. Such techniques have shown reduced cerebral blood flow and overall cerebral atrophy in both people with MS and chronic fatigue syndrome,¹⁵ even though the clinical patterns of fatigue differ between these disease states. Other work using fMRI demonstrate impaired functionality of the cortical and subcortical areas in association with increased levels of fatigue as measured by the FSS.¹⁶ In that study, people without fatigue displayed significantly higher activation of the primary somatomotor cortex and several other areas of the brain associated with motor movement and activation. Similarly, those with more severe MS-related fatigue demonstrate increased lesion load, and atrophy of both white and gray matter.³⁶ Other authors conclude that damage to CNS connectivity results in a need for increased activation of other brain areas in order to maintain function, and such increases are tied to resultant fatigue.¹⁹

In summary, it appears that MS-related fatigue is associated with white matter changes in areas associated with motivation and reward processing, in a manner beyond that traditionally associated with the central serotonergic model.⁵² Disease associated damage of the CNS is associated with the manifestation of fatigue in those with MS.

What theoretical models have been used to study fatigue in MS?

Strengths and limitations

The strength of this integrative review is that it provides a current evaluation of the instruments used to measure MS-related fatigue, factors that influence fatigue, and theoretical models⁶⁵ used to understand the phenomenon in patients with MS. Several studies found a link with neurotransmitter dysfunction, CSRD, and the timing of fatigue.⁶⁶ The findings can be useful in the development of intervention programs, and while providing care to patients with MS who experience fatigue. The limitations present in the review include that there were too few randomized control trials (RCT) studies available using large samples to provide a more comprehensive review of central fatigue mechanisms. Likewise, careful classification of well-defined MS subtypes and disability levels is needed for future studies.