Fatigue in Multiple Sclerosis: A Comprehensive Approach to Evaluation and Management

Fatigue is a prevalent and debilitating symptom experienced by many people with multiple sclerosis (MS), yet it remains difficult to define and measure. Approximately 80% of people with MS experience fatigue, with 50% to 60% considering it their most disabling symptom.^1,2 Fatigue has far-reaching consequences on quality of life and can affect an individual’s ability to work, often serving as the primary cause of unemployment in people with MS.³ Fatigue also limits participation in leisure activities, hobbies, and social engagement, which has a profound effect on emotional well-being, often leading to isolation and depression. Difficulty in measuring and characterizing fatigue has impeded the ability to understand its underlying mechanisms and develop targeted treatments. For this reason, fatigue remains a challenging symptom for clinicians to address. We review MS-related fatigue and provide an update on evidence-based strategies for evaluation and management.

Types of Fatigue: Primary vs Secondary

To evaluate and address fatigue effectively, clinicians must distinguish between primary and secondary causes. Primary MS fatigue is intricately linked to the disease process itself; secondary MS fatigue is attributed to other factors.

Primary MS fatigue is multifaceted, affecting people with MS both physically and cognitively. This fatigue, termed “lassitude,” signifies a pervasive lack of mental energy unrelated to activity level, mood disorder, or physical strength. The cognitive aspects of lassitude result in slower processing speeds and challenges with word-finding, attention, and organizing thoughts. The physical component includes heightened weakness following prolonged muscle use, often exacerbated by elevated temperatures.

The underlying pathologic mechanisms of primary MS fatigue are poorly understood, with proposed theories including structural damage of white and gray matter, inflammatory processes including elevated cytokines, endocrine dysfunction, and maladaptive network recruitment attributable to distributed lesions or inflammation.² People with MS perceive the need to expend more energy than expected to accomplish everyday tasks, which is supported by evidence including functional MRI scans which reveal elevated demand on functional neural circuits in those with MS compared with those without this diagnosis.⁴

Secondary MS fatigue can originate from various sources, encompassing MS-related complications, comorbid conditions, and lifestyle factors. When addressing MS fatigue, it is crucial to assess how effectively other symptoms related to MS, such as neurogenic bladder, spasticity, depression, and anxiety, are treated, since these can worsen fatigue. Screening for comorbid conditions—particularly sleep-related disorders, such as obstructive sleep apnea, restless legs syndrome, and circadian rhythm disorders—is essential. A comprehensive evaluation, incorporating laboratory studies, sleep studies, and other ancillary testing, is often necessary to explore potential reversible causes of fatigue. Despite the multitude of factors at play, clinicians must not overlook the significant effect of primary fatigue caused directly by MS pathology, as well as secondary causes. Addressing this complex issue medically requires working collaboratively with the individual through extensive, multidisciplinary strategies.

Evaluation

To assess fatigue, clinicians should initiate the evaluation by examining for modifiable causes of secondary fatigue. Secondary MS fatigue is a consequence of a comorbid condition, which may be a sequela of MS. Given the numerous potential secondary causes, the PIANIST mnemonic (Psychiatric, Iatrogenic/Intoxicant, Anemia, Nutrients, Infection, Sleep, Thyroid/hormonal) can be used to aid in identification (Table 1).

Evaluation of primary fatigue should start once secondary causes have been screened for and addressed. Primary MS fatigue is measured in clinical trials using patient-reported outcome measures, but these questionnaires are rarely used in a clinical setting. Although they may appear time-consuming, validated patient-reported outcome measures can help confirm fatigue and provide an objective means of measuring its trajectory. Two commonly used measures are the Fatigue Severity Scale, a 9-item questionnaire, and the Modified Fatigue Impact Scale (MFIS), a 21-item questionnaire. The Fatigue Severity Scale is heavily weighted toward physical aspects of primary MS fatigue, with 8 of 9 questions querying this domain. The MFIS has 3 subscales (physical, cognitive, and psychosocial functioning) with a near-even split of questions regarding physical and cognitive domains. The MFIS is validated in both English and Spanish.

Treatment

Pharmacologic

There are no medications approved by the Food and Drug Administration (FDA) for primary MS fatigue. Clinicians frequently prescribe pharmaceuticals off-label in a trial-and-error approach. Commonly prescribed medications include amantadine, modafinil (Provigil; Teva Pharmaceuticals, Tel Aviv, Israel) amphetamine-like stimulants, and dalfampridine (Ampyra; Acorda Therapeutics, Ardsley, NY). The dosing, mechanism of action, and side effects of these agents are summarized in Table 2.

Amantadine was the first pharmaceutical agent studied for the treatment of fatigue in MS, and several randomized controlled trials (RCTs) have shown that amantadine can reduce fatigue in people with MS.^5,6 Because amantadine does not carry the risk for dependence like stimulant alternatives, off-label amantadine is used to treat fatigue in pediatric patients with MS.⁷ Additionally, it costs considerably less than the other pharmaceutical agents utilized for MS fatigue. When using amantadine to treat fatigue in MS patients who also have chronic kidney disease, kidney function must be monitored, and dose reductions should be considered to avoid unwanted side effects.

Participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry reported modafinil as the most frequently prescribed medication for fatigue.⁸ Modafinil has been studied in RCTs and was associated with improvements in fatigue in people with MS.^9,10 As a moderate CYP3A3 inducer, modafinil can reduce the effectiveness of medications such as oral contraceptives and has been linked to a 13% rate of major congenital malformations when used during pregnancy.¹¹

Amphetamine-like stimulants are approved for attention-deficit/hyperactivity disorder and in some practices are prescribed for primary MS fatigue. The use of amphetamine-like stimulants for MS fatigue remains controversial given their potential for cardiovascular complications as well as abuse and addiction potential. Of the amphetamine-like stimulants, methylphenidate is often preferred for MS fatigue because of its well-known safety profile and relatively lower cost. Whereas more research is needed on the use of amphetamines in MS, a recent small pilot clinical trial demonstrated that methylphenidate improved mental fatigue in people with MS.¹²

In 2010, the FDA approved dalfampridine to improve walking in people with MS. Since that time, people with MS have reported several additional benefits, including a reduction in fatigue. This finding has been supported by a randomized double-blind, placebo-controlled trial.¹³ Clinicians should have a low threshold to trial dalfampridine in their patients because of the potential for dual benefits. Caution or dose reduction should be implemented in people with renal impairment.

The pharmaceuticals described have been tested for effects on fatigue, but limitations in the design, execution, and reporting of the trials have not allowed definite conclusions to be drawn about efficacy. This prompted a randomized double-blind, crossover trial of amantadine, modafinil, and methylphenidate in MS.¹⁴ Using the MFIS as the primary outcome measure, 144 individuals were enrolled and assessed after 5 weeks of medication exposure. The study showed that amantadine, modafinil, and methylphenidate were not superior to placebo in improving fatigue and were associated with a higher risk of adverse events (39% to 40%) compared with placebo (31%). However, according to a post hoc analysis, participants expressed a preference for modafinil or methylphenidate as long-term fatigue treatment compared with placebo. The study had several limitations, including short treatment period and possible nonoptimized dosing of methylphenidate.

Complementary and Alternative Medicine

Between 33% and 80% of people with MS have tried complementary and alternative medicine (CAM): nonconventional therapies used alongside or instead of physician-recommended treatments.¹⁵ Clinicians should inquire about CAM use in their patients, considering their diverse risk–benefit profiles.

Acetyl-L-carnitine (ALCAR), one of the most studied CAMs for MS fatigue, is a form of L-carnitine that transfers long-chain fatty acids into mitochondria to be used for energy production. ALCAR has displayed mixed results in clinical trials. Whereas a crossover trial showed improvement compared with amantadine, a control trial reported no benefit. Typical ALCAR dosing is 1 g twice daily, with potential gastrointestinal side effects. ALCAR should be avoided in people with hypothyroidism, because it can inhibit T3/T4, and in individuals with severe underlying mental health issues, because it can trigger psychosis.^16,17

N-acetylcysteine (NAC), a precursor of the potent antioxidant glutathione, gained popularity during the SARS-CoV-2 pandemic. NAC has long been used as a mucolytic for chronic repository disease and for hepatoprotection in cases of acetaminophen overdose.¹⁸ Mitochondrial dysfunction resulting from oxidative stress is one possible mechanism contributing to the progressive degeneration in people with MS and underlying fatigue. The typical starting dose for NAC is 600 mg twice daily but can be increased up to a total of 3600 mg per day. NAC has the unpleasant smell and taste attributable to the sulfhydryl group. Common side effects, such as insomnia, upset stomach, and nausea, are often dose-dependent. Because of NAC’s anticoagulant and antiplatelet effects, it is contraindicated for individuals with a bleeding disorder or who are on anticoagulants.¹⁹ More data are needed to assess the antifatigue potential of NAC.

Diet

Over the years, various diets have been proposed to manage MS fatigue. However, many of these diets are restrictive or expensive and lack strong clinical evidence to support their benefit. Current recommendations focus on a well-balanced diet that involves eliminating or reducing proinflammatory foods, such as processed foods and noncomplex sugars. Individuals often inquire about specific diets during routine clinic visits. Research has demonstrated that higher adherence to the Mediterranean diet is associated with fatigue reduction in people with MS.²⁰ A recent network meta-analysis of 12 trials comparing 8 dietary interventions showed fatigue reduction only with the Mediterranean and paleolithic diets.²¹ The Mediterranean diet’s nonrestrictive nature makes it more practical to follow.

Exercise

Improving physical strength not only lowers overall energy expenditure, but also enhances mood and alleviates fatigue. A recent meta-analysis validated that physical exercise significantly reduces fatigue in people with MS.²² Using a variety of different modalities, such as walking, stretching, strength training, and high-intensity aerobic activity, is recommended for optimal fatigue reduction. The meta-analysis also demonstrated that aquatic therapy reduces overall fatigue in people with MS.²² Expert consensus suggests encouraging individuals with MS to engage in a minimum of 150 minutes of exercise per week, while accounting for comorbidities and symptom fluctuations.²³

Therapies

Physical therapists (PTs) and occupational therapists (OTs) play a crucial role in managing fatigue. PTs offer tailored interventions, and OTs teach energy conservation techniques, helping individuals allocate energy efficiently.²³ PTs and OTs also assess for specific environmental modifications and assistive devices, such as ankle foot orthoses and nerve stimulators.

Cognitive behavioral therapy (CBT) is a psychotherapeutic approach designed to change negative thought patterns and behaviors, enhancing mental health and emotional well-being. Studies on CBT for MS-related fatigue show positive, but not long-lasting, outcomes after therapy cessation.^24,25 Despite its effectiveness, CBT’s feasibility is limited by the scarcity of specially trained psychotherapists and high costs, often not covered by health insurance.

Conclusion

Fatigue poses a substantial challenge for people with MS, affecting a large majority, with more than 50% of patients considering it their most disabling symptom. The unknown mechanism underlying primary MS fatigue hinders effective treatment development. Primary MS fatigue is intricately linked to the disease process; secondary MS fatigue arises from comorbid conditions and lifestyle factors. Recognizing the distinction between these forms of fatigue is vital, because untreated fatigue can profoundly affect quality of life, mental health, and the individual’s ability to work and engage with society. The management of fatigue involves a holistic approach tailored to the individual.