What is the link between fatigue and multiple sclerosis?


Up to 60 percent of patients with multiple sclerosis (MS) report that fatigue is the disease’s most debilitating symptom.

And yet, fatigue remains one of MS’s mysteries – despite its prevalence and significance, the root cause of the symptom remains unclear.

In a study published in Neurology Neuroimmunology & Neuroinflammation, investigators from Brigham and Women’s Hospital used positron emission technology (PET) imaging to look for brain’s immune cells that may become erroneously activated in MS, leading to fatigue.

The team describes a potential link to brain inflammation that may help explain the connection between MS and fatigue.

“Fatigue correlates poorly with the conventional markers of multiple sclerosis – the brain lesions we see using magnetic resonance imaging (MRI) don’t associate well with fatigue,” said corresponding author Tarun Singhal, MD, a neurologist and nuclear medicine physician in the Department of Neurology and director of the PET Imaging Program in Neurologic Diseases at the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital.

“So we went searching for a hidden pathology; something that has gone undetected until now in the context of fatigue in MS.”

Singhal and colleagues used a second-generation radioligand known as [F-18]PBR06 to conduct PET imaging.

Singhal describes this tracer as a “radiolabel detective” that can snoop for clues.

Once injected, the tracer travels to the brain, binds to abnormally activated immune cells called microglia (and to some extent, additionally, to other immune and support cells called astrocytes) and emits gamma rays that can be picked up by a scanner.

The team performed PET scans on 12 MS patients and 10 healthy controls, finding strong correlations between MS patients‘ self-reported fatigue risk scores and activation of immune cells in very specific regions of the brain.

These regions included the substantia nigra – which translates literally to “the dark substance.”

The substantia nigra is the site where dopamine is produced (dopaminergic neurons appear darker on pathology, giving the region its name). Dopamine plays many roles in the body and is required for stimulating attention and wakefulness patterns in the brain.

Several additional areas of the brain also correlated significantly with fatigue scores, but there was no association between fatigue scores and brain atrophy and lesion load in MS patients.

The researchers note that given the study’s small sample size, additional study is needed to validate their findings.

“We detected a widespread network of very specific regions whose inflammation correlates with fatigue scores and all have implications for contributions to fatigue,” said Singhal. “We are now pursuing further study to confirm our findings in a larger sample size and are looking at interactions between neurochemistry and neuroinflammation.”

Multiple sclerosis-related fatigue is a disabling symptom that affects most patients during the neuroprogressive course of the disease1,2,3,4.

MS-related fatigue is a puzzling interplay between multiple genotypic and phenotypic factors5,6. Fatigue can be caused either directly by the MS disease process in the central nervous system (i.e. primary fatigue), initiated by inflammatory processes associated with immune activation, demyelination, axonal loss or neuroendocrine disturbance, or indirectly by other problems (i.e. secondary fatigue) such as insomnia, sleep disturbance due to urge incontinence or spasticity, acute infections, thyroid disorders, physical inactivity and deconditioning, or depression. In all cases, a correct differential diagnosis is required for proper clinical decision making.

There are many definitions of fatigue (see Supplementary Information 1 for references regarding Fatigue Definitions) and over 250 ways to measure fatigue7.

Examples of frequently used definitions of MS-related fatigue include: the reduction in performance following either prolonged or unusual exertion, together with feelings of sensory, motor, cognitive or subjective fatigue8; a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities9; the perception of decreased mental or physical energy that may restrict routines of daily activities10; the failure to initiate and/or sustain attentional tasks (mental or cognitive fatigue) and physical activities (physical fatigue)5.

Dittner et al.11 recognized the wide range of fatigue definitions as a so-called Catch-22 situation: “Before a concept can be measured, it must be defined, and before a definition can be agreed, there must exist an instrument for assessing phenomenology. There is unfortunately no “gold standard” for fatigue, nor is there ever likely to be”.

This Catch-22 situation has caused many researchers to struggle with the assessment, understanding, etiology and classification of fatigue within different patient groups.

To produce a workable solution, proposals were made to distinguish non-pathological or normal physiological fatigue from pathological fatigue, general from disease-specific fatigue, brief or acute periods of fatigue from chronic fatigue, and central from peripheral fatigue, (i.e., muscle fatigability due to disorders of muscle and neuromuscular junctions)5,12,13,14,15.

Furthermore, recent evidence suggests that perceived fatigue and energy should be investigated separately as they seem to be two independent constructs16.

The many elements of fatigue in neurological diseases were included in a proposed unified taxonomy for fatigue, including an assessment approach to addressing distinct aspects of fatigue and fatigability in clinical and research settings6.

In patients with MS, fatigue is considered a multidimensional symptom, manifesting itself in distinct dimensions such as physical, cognitive, and psychosocial fatigue. Assessing perceived fatigue in patients with MS is complex due to its multidimensional and non-objectively verifiable character.

The most commonly used methods in clinical practice and research are self-reported questionnaires, and many valid, reliable, and responsive unidimensional and multidimensional fatigue questionnaires are currently available. See Supplementary Information 2 for references regarding systematic reviews of fatigue instruments.

Fatigue questionnaires vary greatly regarding the factors examined and may include questions on severity or intensity, duration, momentary perceptions, chronic character, dimensions of fatigue (e.g. mental vs. physical), affective meaning and distress (e.g. motivation), impact of fatigue on daily functioning, behavioural interference with activities and ratings of related constructs (e.g. tiredness or sleepiness) (Supplementary Information 2). As in other diagnostic areas, there is currently no consensus regarding the ideal core set of fatigue questions needed to study MS-related fatigue17,18,19,20.

In MS rehabilitation and research, multidimensional fatigue scales are most often used. However, scores on subscales of multidimensional fatigue questionnaires are often presented separately, without showing their mutual relationship in individual patients. On the other hand, the presentation of total scores on multidimensional scales results in the loss of information on the underlying individual dimensions21.

Developing fatigue profiles might help reduce the number of measurement instruments, and might facilitate decision making on which instruments should be used and which qualify as redundant.

More importantly, a patient’s fatigue profile might facilitate clinical decision making with regard to the content and specificity of treatment. Indeed, a clear distinction between different fatigue profiles that show the involvement of a certain domain (e.g. cognitive fatigue or physical activity-induced fatigue) would create opportunities for patient-tailored fatigue treatments.

Differentiation between fatigue profiles might also help to detect specific treatment effects and to explain the underlying mechanisms of treatment interventions such as aerobic training, energy conservation management and cognitive behavioural therapy22.

The objectives of this study were twofold: (1) to investigate whether in patients with a treatment indication for severe primary MS-related fatigue, fatigue profiles are based on the various dimensions of fatigue, and (2) to test whether there is a single common unidimensional factor model of perceived fatigue in patients with MS.


Fatigue related to Multiple Sclerosis (MS) is considered a multidimensional symptom, manifesting in several dimensions such as physical, cognitive, and psychosocial fatigue.

The present cross-sectional study applied cluster analysis to the nine fatigue subscales with the objective of identifying distinct fatigue profiles that might require different rehabilitation treatment approaches in patients with primary MS-related fatigue.

The fatigue profiles discovered did not differentiate between clinically expected dimensions of fatigue. One unidimensional fatigue construct within the 54 fatigue questions could not be confirmed, and the four fatigue instruments CIS20r, MFIS, FSS and SF36 vitality appear to measure different fatigue constructs.

The results of this study imply that for diagnosis and initiation of fatigue treatment, one simple fatigue (sub-)scale, such as the CIS20r fatigue, is sufficient. No currently available study has shown that dimension-specific treatment of fatigue leads to better outcomes. In terms of clinical practice this means that there is as yet no reason to measure multidimensional aspects of fatigue in primary fatigued patients with MS.


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More information: Tarun Singhal et al, Regional microglial activation in the substantia nigra is linked with fatigue in MS, Neurology – Neuroimmunology Neuroinflammation (2020). DOI: 10.1212/NXI.0000000000000854


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