Untangling Perception of Fatigue and Fatigability: First Steps ws

Research Article

Austin J Mult Scler & Neuroimmunol. 2015;2(3): 1018.

Untangling Perception of Fatigue and Fatigability: First Steps

Arafah AM1,2,3, Kuspinar A1,3 and Mayo NE1,3,4*

¹School of Physical and Occupational Therapy, McGill University, Canada

²College of Applied Medical Sciences, King Saud University, Saudi Arabia

³McGill University Health Centre Research Institute, Canada

4Department of Medicine, McGill University, Canada

*Corresponding author: Mayo NE, Fellow of the Canadian Academy of Health Sciences, Department of Medicine, School of Physical and Occupational Therapy, McGill University, Division of Clinical Epidemiology, Division of Geriatrics, McGill University Health Center, Royal Victoria Hospital Site, Ross Pavilion R4.29, 687 Pine Ave W, Montreal, QC H3A 1A1, Canada

Received: April 15, 2015; Accepted: June 22, 2015; Published: June 24, 2015


Many terms have been used to distinguish fatigue caused by neuroinflammation and/or neurological damage from fatigue due to disability or side effects of medication (sometimes termed primary vs. secondary or central vs. peripheral fatigue). More recently a unified taxonomy has been proposed to distinguish between perception of fatigue and fatigability and for both physical and mental fatigue. The objective of this study was to estimate the extent to which perception of physical fatigue and perception of mental fatigue correlate with performance on tests that could serve as proxy measures for fatigability. The hypothesis was that perception of physical fatigue would correlate more highly with these proxy tests of physical fatigability than perception of mental fatigue. Data from 189 people with MS were available from a cross sectional study. A perception of physical fatigue latent variable was identified from 5 items that fit a unidimensional and hierarchical measurement model (Rasch model). A single indicator was found to best reflect perception of mental fatigue. Proxy measures for physical fatigability were the Six- Minute Walk Test (6MWT), the slope of the line linking time and oxygen consumption (VO2 slope) and the stages achieved during the step-test of the Modified Canadian Aerobic Fitness Test (mCAFT). The correlations supported the original hypothesis. Physical fatigability correlated with perception of physical fatigue more than with perception of mental fatigue. The information can be used to untangle perception of fatigue and fatigability which will lead to better measurement of the fatigue construct, a prerequisite for developing effective interventions.

Keywords: Perception of fatigue; Fatigability; Physical capacity; Multiple Sclerosis; Six-Minute Walk Test; VO2 peak


CIS: Clinically Isolated Syndrome; CNS: Central Nervous System; EDSS: Expanded Disability Status Scale; FAMS: Functional Assessment of Multiple Sclerosis Quality of Life Instrument; FKS: Fatigue Index Kliniken Schmieder; MFIS: Modified Fatigue Impact Scale; FSS: Fatigue Severity Scale; mCAFT: Modified Canadian Aerobic Fitness Test; MFIS: Multidimensional Fatigue Inventory; MS: Multiple Sclerosis; 6MWT: Six-Minute Walk Test; PRO: Patientreported outcome; QOL: Quality of life; VO2 peak: Peak oxygen consumption; DMT: Disease Modifying Therapies


Fatigue is the most common symptom of MS affecting virtually all [1]. Over 80% of people with MS report having fatigue [2] and 50% to 60% regard fatigue as the most distressing symptom affecting their quality of life (QOL) as it limits one’s capacity to carry out physical and mental activities [3-5]. More than 80% of people with MS state that fatigue is the main problem preventing their ability to work [6,7]. This economic burden not only affects the individual, but also the health care system as outpatient visits and services are more frequent for MS patients with fatigue than for those without fatigue [8].

Though MS-related fatigue has distinct characteristics [9] (e.g., more severe, frequent, persistent and unpredictable), its cause is complex and remains unclear [10]. MS-related fatigue is linked to several factors including: dysregulation of the immune system [11,12], destruction, reorganization and compensation within the central nervous system (CNS) [13-16], and changes in the neuroendocrine [17] and neurotransmitter systems [18]. Secondary factors related to physical deconditioning [19,20], sleep problems [21,22], depression [23] and medication effects [24] also contribute to fatigue in people with MS.

Various definitions of fatigue appear in the literature. One of the most cited is from the Multiple Sclerosis Council for Clinical Practice Guidelines (MS Council), stating that fatigue is “a subjective lack of physical and/or mental energy that is perceived by the individual or the caregiver to interfere with usual or desired activity” [25]. This definition highlights the individualized perception of fatigue and the fact that fatigue can impede not only physical function, but also mental function as expressed by inability to concentrate or think clearly.

Many terms have been also used to distinguish fatigue according to its pathogenesis. Primary fatigue refers to fatigue resulting from the disease process and secondary fatigue is due to disease-related manifestation or side effects of medication [5,20]. Due to the high degree of interdependence among MS symptoms affecting fatigue manifestation, it is difficult to differentiate primary fatigue from secondary fatigue.

Fatigue has also been classified as central or peripheral. Central fatigue is used to describe fatigue caused by reduced force generation triggered by events at or proximal to the anterior horn cells [26]. Peripheral fatigue, in contrast, is related to failure at or beyond the neuromuscular junction [26,27]. However, there is no consensus or strong evidence to anchor the use of these terms. For example, central fatigue was used to refer to multiple aspects of fatigue including the CNS cause of fatigue as manifested by performance changes, perceived changes in attention, and increased level of exhaustion [28].

Without a clear terminology, the measurement and treatment of fatigue remains limited [20]. To overcome these challenges, a unified taxonomy has recently been proposed by Kluger and colleagues to distinguish perception of fatigue from fatigability, and for both physical and mental fatigue [28].

Perception of fatigue is defined as “a subjective sensation of weariness, increasing sense of effort, mismatch between effort expanded and actual performance, or exhaustion” [28]. On the other hand, fatigability is defined as “the magnitude or rate of change in a performance criterion relative to a reference value or a given time of task performance or measure of mechanical output” [28]. Furthermore, perception of fatigue and fatigability can be both further classified to capture mental or physical dimensions.

The measurement of perception of fatigue can only be achieved through patient-reported outcomes (PROs). The most commonly used unidimensional scale of fatigue is the Fatigue Severity Scale (FSS) [29], and the most commonly used multidimensional scales are the Modified Fatigue Impact Scale (MFIS) [30] and the Multidimensional Fatigue Inventory (MFI) [31], although the latter measure was validated on patients with chronic fatigue and not on MS specifically [32]. Fatigue PRO measures vary widely in the way they ascertain perception of fatigue. Some scales capture the frequency, duration, severity, impact, or cause of fatigue, while others measure a mixture of these [33]. The heterogeneity of fatigue poses measurement challenges.

The measurement of fatigability requires testing performance on physical or mental tasks. Within the physical domain, fatigability can be measured through the decline in peak force, power, speed, or accuracy of performance of tasks. For example, electrical stimulations of the quadriceps, adductor pollicis and dorsal interosseous muscles has been applied to induce physiological fatigue and fatigability is measured through the decline in maximal force capacity, rate and speed in people with MS [34-37]. Decline in walking speed or grip strength have also been used as indicators of fatigability [38,39]. Similarly, cognitive fatigability is quantified through decline in processing speed, reaction time or accuracy over time after completing demanding cognitive tasks [40-43]. For example, Moyano and colleagues measured cognitive fatigability in people with MS by computing omissions and mistakes during flexibility and divided attention capacity testing [44].

With existing PROs, it is often difficult to distinguish between physical and mental fatigue and correlations with performance tests are disappointingly weak. Krupp and Elkins reported a decline in the cognitive performance on measures of verbal memory and conceptual planning in people with MS compared to a control group following effortful cognitive tasks. These changes in cognitive performance in the MS group did not correlate with changes in their self-reported level of fatigue [45]. On the same note, a recent study found that the decline of processing speed and working memory of people with MS did not correlate with their self-reported fatigue [40]. Similar findings were reported by studies on the effectiveness of medication in reducing fatigue in MS. In one trial, 3,4 diaminopyridine was found to be effective in reducing performance fatigability as measured by electrophysiological test, however, it failed to produce differences on the perception of fatigue as measured by the FSS [46]. Even scores obtained using the physical domain of the MFIS, one of the most commonly used MS-fatigue scales, failed to correlate with physical capacity as measured through the Six-Minute Walk Test (6MWT) [30]. This discrepancy between fatigability and perception of fatigue (either physical or mental) has been reported by many other studies [47-52]. In fact, studies have called for more clinical research to tackle the association between fatigability and perception of fatigue [20,28].


The global aim of this study is to contribute evidence towards the relationship between perception of fatigue as measured by PROs, and indicators of fatigability. The specific objective of this study is to estimate the extent to which perception of physical fatigue and perception of mental fatigue correlate with performance on tests that could serve as proxy measures for fatigability. The hypothesis is that perception of physical fatigue will correlate more highly with these proxy tests of physical fatigability than perception of mental fatigue.


Study design and subjects

This is a secondary analysis of data arising from a cross-sectional study originally focused on gender differences in the life impact of (the new) MS [53,54]. The details of that study have been reported previously [53,55,56]. Briefly, participants were people with MS diagnosed after 1994 who were registered on clinic databases maintained by the three largest MS clinics in Montreal. A random sample was drawn from each center. Patients were excluded if they had a health condition diagnosed prior to MS that continued to exert an effect on function, if they had a relapse in the preceding month, if they were less than 18 years of age or if they had severe cognitive impairment. Data from 189 people were available (140 women and 49 men; mean age of 43 years). The sample was chosen to be generalizable to people being diagnosed and treated today.

Measurement and procedure

Perception of fatigue: Fatigue was measured in this study using multi-item indexes: the RAND-36 [57,58], MFIS [30], MFI [31] and the Functional Assessment of Multiple Sclerosis Quality of Life Instrument (FAMS) [59] supplemented with 6 items from the FSS. Rasch analysis was applied to this pool of items to create a calibrated item bank supporting a fatigue measure (MS Gender). The wording of some items clearly targeted physical fatigue, while others mental or more general fatigue. To identify items that reflected physical and mental fatigue, a consensus exercise was carried out among fourteen clinical rehabilitation researchers to select items related to these two constructs. Items that were endorsed by ten raters as tapping these separate constructs were then cross-walked to the MFI [31]. The MFI was ideal for this purpose as its 20 items relating to five domains (general fatigue, physical fatigue, reduced activity, reduced motivation and mental fatigue) has been validated on a very large sample (n=783) of people with fatigue symptom and healthy controls [32].

As the sum of ordinal rating scales does not create a legitimate total score [60,61], Rasch analysis was used to test the fit of items that mapped to the physical fatigue domain of the MFI to the Rasch measurement model. The items that fit, generated an MS-specific unidimensional, linear physical fatigue measure (Figure 1). Only two items mapped to the mental fatigue domain of the MFI and an ordinal index was created to tap perception of mental fatigue.