Fatigue is one of the most commonly reported and debilitating symptoms of multiple sclerosis (MS), affecting an estimated 70% to 90% of patients, and is the major contributor to poor health perception.1-3 In a survey of 20 neurologists involving 198 patients with MS, fatigue was reported to be the most common symptom of the disease (Figure 1).4

Despite its prevalence and significant impact on quality of life, MS-related fatigue remains one of the least understood MS symptoms and among the most difficult to diagnose and manage. The complexity of the pathophysiologic mechanisms of fatigue, the subjectivity of its presentation, and the myriad comorbidities that can result in secondary fatigue contribute to significant diagnostic challenges.
Although more than 250 fatigue diagnostic tools have been developed,5 most are not validated for patients with MS or designed to assess multidimensional fatigue related to MS. Understanding the pathophysiologic mechanisms of MS fatigue provides a rational basis for the differential diagnosis of MS fatigue. This article explores current understanding of the pathophysiologic mechanisms of MS fatigue and its differential diagnosis, both of which are critical for individualized fatigue management.
MS-related Fatigue: Pathophysiologic Mechanism
MS-related fatigue is clinically recognized as primary fatigue (associated with the MS disease process) and secondary fatigue (associated with disease complications and comorbidities, such as spasticity, restless legs syndrome, sleep disorders, depression, and pain). The pathophysiology of primary and secondary MS-related fatigue is complex, with each thought to be distinct but interrelated by factors such as musculoskeletal problems, sleep disorders, medication adverse effects, and altered endocrine function (Figure 2).6 Clinicians should recognize that optimal fatigue management requires treating both primary and secondary MS fatigue. Effectively managing MS complications and comorbidities can also manage secondary fatigue; primary fatigue must also be managed, although it is more challenging to diagnose.

The commonly proposed pathophysiology of primary fatigue in MS is thought to involve the thalamus, brain and spinal cord inflammation, cytokine release, and neuroendocrine and autonomic abnormalities associated with gray- and white-matter neuronal lesions.7-9 Brain structural changes and neurodegeneration detected with advanced quantitative magnetic resonance imaging correlate with development of fatigue in patients with MS.10-12 Brain inflammatory activity correlating with waxing and waning of the disease and variation in fatigue symptoms over time also supports inflammation as an essential contributor to primary MS fatigue. For example, disease relapses have been associated with increased fatigue and reduced health-related quality of life, and MS treatment has been associated with reduced fatigue.13,14
However, the link between inflammatory activity and fatigue has not been unequivocally demonstrated. Although some studies have shown correlation between fatigue severity and inflammatory disease activity, others have not.15 Nevertheless, recognizing that fatigue in a patient with MS has a primary and secondary cause should raise clinical suspicion to manage MS complications and comorbidities, and underscores the importance of using tools that can differentially diagnose primary fatigue.
Barriers to a Diagnosis of MS
Diagnosing primary MS fatigue is often difficult for most clinicians. A contributing factor to this challenge is the multidimensional presentation of MS fatigue, which can manifest as physical, cognitive, and psychosocial fatigue. Fatigue symptoms vary from one patient to the next and over time, and a diagnostic tool validated to capture its complexity is lacking.
“Some of the factors that impact the differential diagnosis of MS fatigue [are] the variability of the assessment tools [which is] not directly correlated with clinical outcomes,” said Stacie Hudgens, Chief Executive Officer and Strategic Lead at Clinical Outcomes Solutions. “The lack of correlation to disease severity makes it difficult to predict fatigue outcomes, which then contributes to the challenge of differential diagnosis.”
Also a contributing factor are the criteria by which fatigue is defined, which have included16:

·   Reduction in performance following either prolonged or unusual exertion, together with feelings of sensory, motor, cognitive, or subjective fatigue;
·   Subjective lack of physical or mental energy perceived by the patient or caregiver as interfering with usual and desired activities;
·   Reversible motor and cognitive impairment, with reduced motivation and desire to rest; such impairment can appear spontaneously or be brought on by mental or physical activity, humidity, acute infection, or food ingestion;
·   Perception of decreased mental or physical energy that might restrict routine daily activities; and
·   Failure to initiate or sustain attentional tasks (mental or cognitive fatigue) and physical activities (physical fatigue).

Core elements of these definitions are subjective and difficult to quantify. In the absence of a standardized definition, diagnosing fatigue in patients with MS is complex and challenging. Self-reported fatigue questionnaires are commonly used diagnostic tools in clinical practice and research17; however, MS-related fatigue is considered a multidimensional symptom that includes physical fatigue, cognitive fatigue, and psychosocial fatigue, all of which should be accommodated in the assessment and in treatment decisions. Treatment decisions made from diagnostic evaluations using the Modified Fatigue Impact Scale (MFIS), Fatigue Severity Scale (FSS-9), or Short Form-36 (SF-36) vitality scale appear to be suboptimal because these tools assess fatigue severity but not the multiple dimensions of fatigue.17
Assessing MS fatigue using patient-reported outcomes (PRO) recognizes the subjective nature of fatigue and its unique impact on each patient. A PRO instrument with demonstrated consistency, reliability, and validity was proposed in quality-of-care measures for MS, emphasized by US Food and Drug Administration PRO guidance for outcome measurement in clinical trials, and recommended in Clinical Outcomes Assessments of the International Society for Pharmacoeconomics and Outcomes Research.18-20 However, PRO instruments that have been used to measure fatigue in patients with MS have shortcomings with regard to validity, reliability, and sensitivity. For instance, the 9-item FSS-9 and the 21-item MFIS, tools that are commonly used as outcome measures in MS, have been found to have poor discrimination with bias for variables such as age and cannot be used to generate a single overall fatigue score.21,22

Tools for the Differential Diagnosis of MS Fatigue
Historically, scales used to assess fatigue in patients with MS were developed for other chronic medical conditions, such as chronic fatigue syndrome and systemic lupus erythematosus. Generally, these scales primarily quantified fatigue or assessed its impact on various functions and did not comprehensively assess the multidimensional contributors of MS-related fatigue.9
Existing diagnostic tools, such as the FSS-9 and MFIS, are limited by their multidimensionality and cannot be used to assess fatigue across various forms of MS. A PRO instrument validated in specific MS subtypes will enable a more specific, accurate, and individualized fatigue assessment. A modified PRO instrument, the Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS), was designed to address limitations of existing instruments used to assess MS-specific fatigue. The instrument was evaluated in patients with relapsing-remitting multiple sclerosis (RRMS), progressive relapsing multiple sclerosis (PRMS), and relapsing secondary progressive multiple sclerosis (RSPMS).23 FSIQ-RMS, which includes 7 symptom and 13 impact items (in 3 impacts subdomains: physical, cognitive and emotional, and coping), is an instrument with demonstrated content and measurement validity for MS fatigue.23
“The FSIQ-RMS is a fatigue-specific patient-reported outcome measure, designed with patient input, to cover the full spectrum of mental and physical fatigue severity in patients with MS, including cognitive, emotional, and coping impacts [of fatigue],” Ms Hudgens said. “[The FSIQ-RMS] is a valid and reliable assessment of a patient’s fatigue severity that was developed from direct patient interviews and patient surveys.”
FSIQ-RMS has been assessed only in patients with RRMS, PRMS, and RSPMS subtypes; as such, it might not be applicable in patients with other MS subtypes. However, evidence suggests that the FSIQ-RMS is a tool clinicians can consider to diagnose MS fatigue.
Whether a multidimensional assessment of MS fatigue is essential for diagnostic evaluation and treatment decisions was explored in a study by Beckerman and colleagues.17 The researchers investigated whether treatment indications for severe primary MS fatigue should be based on the various dimensions of fatigue or whether a unidimensional assessment can assess perceived fatigue in patients with MS. The 4 fatigue instruments evaluated were the MFIS, FSS, SF-36, and the Checklist of Individual Strengths (CIS20r) fatigue subscale.17 The CIS20r is a multidimensional questionnaire comprising 20 items in 4 fatigue dimensions and related behavioral aspects, including:
·   The subjective experience of fatigue (8 items);
·   A reduction in motivation (4 items);
·   A reduction of physical activity (3 items); and
·   A reduction in concentration (5 items).
In the analysis conducted by Beckerman et al, those 4 fatigue instruments appear to measure different fatigue constructs. The researchers also argue that no available study has shown that a dimension-specific treatment of fatigue leads to better outcomes. Based on their findings, they suggest that a single simple fatigue scale, such as the CIS20r fatigue subscale, is sufficient for the diagnosis of fatigue, as well as for the initiation of treatment.17 In terms of clinical practice, Beckerman and colleagues suggest that there is, as yet, no reason to measure multidimensional aspects of fatigue in primary MS-related fatigue.

Involving the Patient in the Differential Diagnosis
Fatigue associated with MS is more than the tiredness that accompanies exertion or poor sleep and can be difficult for a patient to describe. Having patients communicate their fatigue is essential to the diagnostic workup, subsequent differential diagnosis, and optimal management. A visual from the MS International Federation (Figure 3) that describes different MS fatigue levels might help a patient describe their fatigue effectively to their healthcare provider.24

Manifestations of MS Fatigue
Manifestations of MS Fatigue
MS fatigue tends to become worse as the day progresses; appears suddenly compared to fatigue due to exertion, such as with exercise, or to poor sleep; and is aggravated by heat and humidity.

Fatigue is one of the most common and debilitating MS symptoms, yet it remains challenging for clinicians to effectively diagnose. Commonly used diagnostic tools such as the MFIS, FSS-9, and SF-36 lack specificity and validity to assess the multiple dimensions of MS fatigue. A patient-reported outcome measure, such as FSIQ-RMS, incorporates patient input in its design. The tool assesses the spectrum of mental and physical fatigue severity in patients with MS. Optimal fatigue diagnosis and management might require clinicians to (1) use visual cues to guide patients with MS to communicate their fatigue symptoms and (2) maintain a high index of suspicion for MS complications and comorbidities often associated with secondary fatigue, which must also be managed.
Stacie Hudgens, MA, is an independent outcomes researcher with a reported affiliation to Clinical Outcomes Solutions.

1. Costello K, Harris C. Differential diagnosis and management of fatigue in multiple sclerosis: considerations for the nurse. J Neurosci Nurs. 2003;35(3):139-148. doi:10.1097/01376517-200306000-00003
2. Bakshi R. Fatigue associated with multiple sclerosis: diagnosis, impact and management. Mult Scler. 2003;9(3):219-227. doi:10.1191/1352458503ms904oa
3. Green R, Cutter G, Friendly M, Kister I. Which symptoms contribute the most to patients’ perception of health in multiple sclerosis? Mult Scler J Exp Transl Clin. 2017;3(3):2055217317728301. doi:10.1177/2055217317728301
4. Ziemssen T, Piani-Meier D, Bennett B, et al. A physician-completed digital tool for evaluating disease progression (multiple sclerosis progression discussion tool): validation study. J Med Internet Res. 2020;22(2):e16932. doi:10.2196/16932
5. Hjollund NH, Andersen JH, Bech P. Assessment of fatigue in chronic disease: a bibliographic study of fatigue measurement scales. Health Qual Life Outcomes. 2007;5:12. doi:10.1186/1477-7525-5-12
6. Carter JL. Fatigue in patients with multiple sclerosis. Practical Neurology. 2018 July/August:43-46. https://practicalneurology.com/articles/2018-july-aug/fatigue-in-patients-with-multiple-sclerosis/pdf. Accessed December 28, 2020.
7. Capone F, Collorone S, Cortese R, Di Lazzaro V, Moccia M. Fatigue in multiple sclerosis: the role of thalamus. Mult Scler. 2020;26(1):6-16. doi:10.1177/1352458519851247
8. Manjaly Z-M, Harrison NA, Critchley HD, et al. Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2019;90(6):642-651. doi:10.1136/jnnp-2018-320050
9. Braley TJ, Chervin RD. Fatigue in multiple sclerosis: mechanisms, evaluation, and treatment. Sleep. 2010;33(8):1061-1067. doi:10.1093/sleep/33.8.1061
10. Arm J, Ribbons K, Lechner-Scott J, Ramadan S. Evaluation of MS related central fatigue using MR neuroimaging methods: scoping review. J Neurol Sci. 2019;400:52-71. doi:10.1016/j.jns.2019.03.007
11. Patejdl R, Penner IK, Noack TK, Zettl UK. Multiple sclerosis and fatigue: a review on the contribution of inflammation and immune-mediated neurodegeneration. Autoimmun Rev. 2016;15(3):210-220. doi:10.1016/j.autrev.2015.11.005
12. Palotai M, Nazeri A, Cavallari M, et al. History of fatigue in multiple sclerosis is associated with grey matter atrophy. Sci Rep. 2019;9(1):14781. doi:10.1038/s41598-019-51110-2
13. Mäurer M, Comi G, Freedman MS, et al. Multiple sclerosis relapses are associated with increased fatigue and reduced health-related quality of life – a post hoc analysis of the TEMSO and TOWER studies. Mult Scler Relat Disord. 2016;7:33-40. doi:10.1016/j.msard.2016.02.012
14. Svenningsson A, Falk E, Celius EG, et al; Tynergy Trial Investigators. Natalizumab treatment reduces fatigue in multiple sclerosis. Results from the TYNERGY trial; a study in the real life setting. PLoS One. 2013;8(3):e58643. doi:10.1371/journal.pone.0058643
15. Chalah MA, Ayache SS. Is there a link between inflammation and fatigue in multiple sclerosis? J Inflamm Res. 2018;11:253-264. doi:10.2147/JIR.S167199
16. Mills RJ, Young CA. A medical definition of fatigue in multiple sclerosis. QJM. 2008;101(1):49-60. doi:10.1093/qjmed/hcm122
17. Beckerman H, Eijssen IC, van Meeteren J, Verhulsdonck MC, de Groot V. Fatigue profiles in patients with multiple sclerosis are based on severity of fatigue and not on dimensions of fatigue. Sci Rep. 2020;10(1):4167. doi:10.1038/s41598-020-61076-1
18. Rae-Grant A, Bennett A, Sanders AE, Phipps M, Cheng E, Bever C. Quality improvement in neurology: multiple sclerosis quality measures: executive summary. Neurology. 2015;85(21):1904-1908. doi:10.1212/WNL.0000000000001965
19. US Food and Drug Administration. Roadmap to patient-focused outcome measurement in clinical trials (text version). https://www.fda.gov/drugs/drug-development-tool-ddt-qualification-programs/roadmap-patient-focused-outcome-measurement-clinical-trials-text-version. October 8, 2015. Accessed January 7, 2021.
20. Walton MK, Powers JH 3rd, Hobart J, et al; International Society for Pharmacoeconomics and Outcomes Research Task Force for Clinical Outcomes Assessment. Clinical outcome assessments: conceptual foundation – report of the ISPOR clinical outcomes assessment – emerging good practices for outcomes research task force. Value Health. 2015;18(6):741-752. doi:10.1016/j.jval.2015.08.006
21. Mills RJ, Young CA, Nicholas RS, Pallant JF, Tennant A. Rasch analysis of the Fatigue Severity Scale in multiple sclerosis. Mult Scler. 2009;15(1):81-87. doi:10.1177/1352458508096215
22. Mills RJ, Young CA, Pallant JF, Tennant A. Rasch analysis of the Modified Fatigue Impact Scale (MFIS) in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2010;81(9):1049-1051. doi:10.1136/jnnp.2008.151340
23. Hudgens S, Schüler R, Stokes J, Eremenco S, Hunsche E, Leist TP. Development and validation of the FSIQ-RMS: a new patient-reported questionnaire to assess symptoms and impacts of fatigue in relapsing multiple sclerosis. Value Health. 2019;22(4):453-466. doi:10.1016/j.jval.2018.11.007
24. Fatigue. London, England: Multiple Sclerosis International Federation. https://www.msif.org/about-ms/symptoms-of-ms/fatigue/.  Accessed December 28, 2020. 

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Neurology Advisor had no role in this content’s preparation.
                                                                                                                       Reviewed January 2021