Clinical manifestations

Presentation and course

Symptoms of fatigue may be constant or intermittent and may fluctuate with clinical disease worsening, such as a multiple sclerosis relapse. Hot environments often trigger or worsen fatigue in heat-sensitive subjects (43). Severity varies between subjects or within the same subject throughout the course of the disease. Due to its subjectivity, the clinical manifestations of fatigue in the context of multiple sclerosis vary widely between subjects and may be interpreted differently depending on cultural or educational backgrounds. Commonly defined as a “lack of energy,” other descriptors that may be used for fatigue in multiple sclerosis include “tiredness, asthenia, lassitude, malaise, lack of motivation, weakness, weariness, or difficulty initiating/sustaining voluntary effort” (46). Other subjects may use the term “sleepiness” as a descriptor (03; 46).

Prognosis and complications

Although fatigue does not correlate with life expectancy or the disease course of multiple sclerosis, its presence increases the risk of several psychosocial and socioeconomic complications. Persistent fatigue adversely affects activities of daily living and social interactions, such as housework, shopping, and engagement in social activities (43). Fatigue also has a profound impact on occupational performance. In a study of multiple sclerosis subjects who had reduced their work hours to part-time status, 90% reported fatigue as a primary reason for work status change (65). As social and occupational functions contribute to quality of life, these aspects should considered when assessing the impact of fatigue.

Clinical vignette

Patient A was a 36-year-old female with a 5-year history of relapsing-remitting multiple sclerosis who had enjoyed clinical and radiographic stability since starting immunomodulatory therapy 2 years ago. During a routine visit, she described an overwhelming lack of energy, as if her “life force was being drained.” She indicated that she had a finite amount of energy to “spend” each day and had to use it wisely because when she exceeded it, the aforementioned symptoms occurred. She denied a change in her mood, feelings of guilt, or anhedonia. She denied an urge to fall asleep in quiet or sedentary situations or the need to nap. Her bed partner denied a history of snoring or apneic episodes. She denied nocturia or difficulty falling asleep or maintaining sleep. She otherwise reported good general health, and a review of systems was negative. Medications included interferon beta-1a and a multivitamin. General examination of the head, neck, heart, lungs, and extremities was unremarkable. Mood and affect were appropriate. Neurologic examination was within normal limits except a right afferent pupillary defect and moderate vibratory loss at the toes. Her Fatigue Severity Scale (FSS) score was 54 (a score greater than 36 is suggestive of fatigue). Amantadine was prescribed, and at a 2-month follow-up visit, the patient reported a moderate improvement in her energy level and had a repeat FSS score of 34.

Patient B was a 42-year-old male with a 10-year history of relapsing-remitting multiple sclerosis, punctuated by two episodes of myelitis. During a routine visit, he described profound fatigue that interfered with his 8-hour workday. He denied any change in his mood. He admitted to taking frequent naps in his car during his lunch hour to get through the afternoon. He reported a bedtime of 10 pm but said he could not fall asleep until 1 am to 2 pm. due to a combination of “aching” legs (relieved by movement) and anxiety over his insomnia. He was able to sleep through the night but was required to rise at 6:30 am for work. He had a history of urinary urgency that was well-controlled with an anticholinergic. He otherwise reported good general health. Neurologic examination was notable for a subtle left intranuclear ophthalmoplegia and bilateral lower extremity hyperreflexia. His Epworth Sleepiness Scale (ESS) score was 12 (a score greater than 10 indicates excessive daytime sleepiness). He was diagnosed with restless legs syndrome and prescribed a dopamine agonist before bedtime. He was also instructed to avoid watching television in the bedroom or going to bed before feeling sleepy. During a follow-up appointment 2 months later, he reported a “50%” improvement in his energy level, which he attributed to improved sleep hygiene and improvement of his restless legs symptoms, which allowed him to fall asleep at 11 pm and avoid napping. A repeat ESS score improved to 8. Despite his improved hypersomnolence, he was still somewhat dissatisfied with his energy level and scored 40 on the FSS. He was prescribed amantadine with little improvement in his symptoms. He was then prescribed modafinil, which substantially improved his energy level.

Biological basis

Anatomic localization

Converging evidence from neurophysiology and neuroimaging research suggests dysfunction in the cortico-subcortical pathway, centered on the thalamus, that is involved in the pathogenesis of fatigue (14). There is also evidence that fatigue in multiple sclerosis has a neuroanatomical correlate. Indirect evidence suggests that fatigue in multiple sclerosis could result from atrophy and altered functional connectivity of interoceptive regions in the hypothalamus, insula, and anterior cingulate cortex (27; 62). This hypothesis needs to be empirically evaluated.

Pathophysiology

Fatigue in persons with multiple sclerosis is often multifactorial. In addition to associated immunologic abnormalities, several other conditions that may be disproportionately prevalent in multiple sclerosis can contribute to fatigue. In general, causes of multiple sclerosis-related fatigue can be divided into two categories: primary and secondary. Primary causes may involve immunologic or hormonal mechanisms and disruption in neural connectivity. Secondary causes include accumulation of disease burden, medication effect, or other conditions frequently associated with multiple sclerosis. The most common primary and secondary causes are reviewed below.

Primary causes. Cytokine fluctuations implicated in the pathophysiology of multiple sclerosis are proposed to contribute to fatigue. Significantly elevated TNF-alpha mRNA expression and elevated TNF-alpha, interferon-gamma, and IL-6 levels have been demonstrated in subjects with multiple sclerosis-related fatigue compared to non-fatigued subjects (50; 28). Unfortunately, these findings have not afforded clinicians a straightforward therapeutic target, as these cytokines are relatively nonspecific and may be elevated in various inflammatory diseases. Moreover, although TNF-alpha antagonists have been shown to reduce sleepiness in patients with obstructive sleep apnea (75), they are contraindicated in multiple sclerosis due to the potential to cause clinical worsening (42).

Associated endocrine abnormalities may also play a role. The hypothalamic-pituitary-adrenal axis and the hormone dehydroepiandrosterone, both implicated in chronic fatigue syndrome, have also been studied in subjects with multiple sclerosis. Studies have demonstrated lower levels of dehydroepiandrosterone and its sulfated compound in multiple sclerosis subjects with sustained fatigue (72), although studies examining ACTH levels after dexamethasone-corticotropin stimulation tests in fatigued multiple sclerosis patients have shown conflicting results (28; 72).

Studies using nonconventional neuroimaging techniques suggest that multiple sclerosis-related fatigue may be partly due to axonal loss and altered cerebral activation patterns in specific brain regions affected by the disease (74). This may particularly apply to regions within the frontal lobes and fronto-striatal circuits. Positron emission tomography studies have demonstrated decreased regional glucose metabolism in the frontal cortex and basal ganglia of fatigued multiple sclerosis subjects (58), and a study using diffusion tensor imaging suggests that fractional anisotropy, a measure of axonal integrity, is decreased in the frontal networks of multiple sclerosis subjects with high levels of fatigue compared to those with lower fatigue levels (52).

Additional brain regions may also be implicated. In a longitudinal study by Yaldizli and colleagues, fatigue was associated with increased corpus callosal atrophy after adjusting for disability status and disease duration (77). Moreover, magnetic resonance spectroscopy imaging has shown significant decreases in N-acetylaspartate/creatine ratios in multiple brain regions among fatigued multiple sclerosis subjects in comparison to nonfatigued subjects, suggesting axonal loss as a contributing factor (70; 71).

In a study by Fuchs and colleagues, fatigue correlated positively with overall lesion burden (22). However, localized white matter damage between the amygdala, temporal pole, insula, and other connected structures was associated with lower severity of fatigue. Other studies have suggested that fatigue in multiple sclerosis is a result of disruptions in autonomic vagal interoceptive mechanisms and from atrophy along with functional changes in the insula, anterior cingulate cortex, and parietal cortex (26; 62; 16; 05). Multiple sclerosis-related fatigue may arise, at least in part, from compensatory reorganization and increased brain recruitment; this hypothesis is based on functional MRI studies that demonstrated altered patterns and increased volume of cerebral activation in the caudate, cingulate gyri, and left primary sensory cortex in fatigued multiple sclerosis subjects compared to nonfatigued subjects (69; 16).

Secondary causes. Sleep disorders have gained recognition as significant contributors to fatigue in persons with multiple sclerosis (03). This is of particular import, as several sleep disorders, including periodic limb movement disorder, restless legs syndrome, chronic insomnia (secondary to pain, spasticity, depression, anxiety, nocturia, medication effects, or other primary sleep disorders), and circadian rhythm disturbances are of increased prevalence in multiple sclerosis compared to the general population and may contribute to fatigue (68; 01; 54; 03; 44; 45). Although sleep disorders are most often thought to contribute to excessive daytime sleepiness as opposed to fatigue, many patients with sleep disorders consider their problems with fatigue, tiredness, or lack of energy to supersede their problems with sleepiness (17). Clinicians must have a low threshold to identify and separately address these potential causes, as poor sleep quality in persons with multiple sclerosis correlates significantly with quality of life (45).

Pharmacologic treatments commonly used to treat symptoms of multiple sclerosis have the potential to cause fatigue. Drowsiness is a common side effect of several antispasmodics, which may be perceived as fatigue. Over-the-counter medications like those containing diphenhydramine are used frequently in persons with multiple sclerosis. There are possible carryover effects to the next day that could contribute to fatigue (08). Various pain medications, including opioids or anticonvulsants for treating neuropathic pain, may have a similar effect. Clinicians should be aware of these potential side effects and review the list of medications in patients presenting with fatigue complaints. Efforts should be made to minimize these medications, if possible.

Depression is a common comorbid condition in persons with multiple sclerosis, with a lifetime prevalence as high as 50% (61). In addition to its independent contributions to quality of life, depression also correlates with fatigue (36; 53). Patients with severe fatigue and no initial depression are at an increased risk of developing depression later in the disease course (24). Discerning between these two conditions is difficult, as depression can manifest with other symptoms that may be mistaken for fatigue (loss of motivation, anhedonia, sleep disturbance). Clinicians should have a low threshold to screen for depression if fatigue is present, and depression should be addressed and treated independently.

Multiple sclerosis severity correlates with fatigue. Several studies, including a review of The New York State Multiple Sclerosis Consortium Database (53) ,show that fatigue correlates with higher expanded disability status scores (31; 73); depression may also contribute to this robust correlation (04; 73). The association between fatigue and multiple sclerosis subtypes is also of interest. Progressive subtypes of multiple sclerosis may have increased fatigue severity (36; 43), although worse disability seen in patients with progressive subtypes may confound this observation (36).

Identification of socioeconomic factors that play a role in fatigue is critical to developing strategies to manage fatigue. In a study by Broch and colleagues, receiving a disability pension, being divorced, having children, low income, current smoking, and the presence of other autoimmune comorbidities were all associated with reported higher levels of fatigue (09). Higher education levels were associated with less fatigue.

Epidemiology

Fatigue is one of the most common and debilitating symptoms affecting persons with multiple sclerosis. It is present in about 50% of persons with clinically isolated syndrome (60) and at least 75% of persons with multiple sclerosis at some point in the disease course (43). Fatigue present during clinically isolated syndrome diagnosis is an independent risk factor for conversion to clinically definite multiple sclerosis (60). Fatigue is more prevalent in patients with progressive multiple sclerosis than in nonprogressive forms of multiple sclerosis (59).

Differential diagnosis

Other symptoms or conditions commonly mistaken for fatigue include hypersomnolence, weakness, motor fatigue, depression, fatigue due to medical illness, and medication effects.

Although some sleep disorders may contribute to fatigue (see “Secondary causes” in the “Pathophysiology” section), they are most commonly associated with excessive daytime sleepiness or hypersomnolence. Several carefully phrased questions regarding the patient’s likelihood of falling asleep in quiet or sedentary situations can often help distinguish hypersomnolence from fatigue (see the “Diagnostic workup” section).

Weakness may also be perceived as fatigue. The distribution of the weakness is an important feature that can help to distinguish between the two symptoms. A thorough examination can typically distinguish this entity from fatigue if focal weakness is reported. More generalized symptoms or a strong diurnal variation in symptoms suggests fatigue instead of weakness. Another symptom associated with weakness is motor fatigue, a loss in the maximal capacity to exert force during exercise (64). Like weakness, motor fatigue is typically focal, involving specific muscle groups utilized in the motor task. This entity is somewhat distinct from classic definitions of fatigue, which are more generalized in their descriptions.

Although depression may cause fatigue in and of itself, it is also associated with other symptoms commonly mistaken for fatigue. This distinction can be difficult. Hypersomnolence and anhedonia, both common consequences of depression, may be perceived as fatigue by patients or clinicians. A careful depression screening and thorough interview may help to distinguish between some of these symptoms.

Other medical entities, including several infectious and metabolic causes, may independently cause fatigue and need to be assessed separately with a thorough review of symptoms and examination. Likewise, medications, including beta-interferons, antispasmodics, anticonvulsants, and pain medications, may contribute to fatigue symptoms (see “Secondary causes” in the “Pathophysiology” section). A thorough review of the medication list is essential.

Multiple sclerosis fatigue and COVID-19 infection. Frequently reported residual symptoms of COVID-19 infection are new or increased fatigue, hyposmia, and dyspnea. Against a multiple sclerosis control cohort matched for age, sex, disability, and disease-modifying therapy, all three symptoms were significantly more frequent at 3 months and still slightly more significant at 6 months after infection (23). Another prospective study looking at non-hospitalized patients with multiple sclerosis and COVID-19 infection showed 30% experienced prolonged COVID symptoms 4 weeks after infection, and 12% experienced symptoms at 12 or more weeks after infection (11). Increasing levels of pre-COVID disability predispose patients with multiple sclerosis to long-term sequelae of COVID-19.

Diagnostic workup

If fatigue is suspected, a thorough history is the first step of the diagnostic workup. Begin with an open-ended question that specifically addresses the patient’s energy level or the presence of tiredness. Patients should be allowed to use their own descriptors. If a classic description of fatigue (exhaustion, tiredness, low energy, lack of stamina) cannot be elucidated, then the patient may be speaking of another symptom, which will necessitate ruling out alternative or concomitant conditions.

Given the overlap in fatigue, sleep disorders, and depression, the phenotypic presentation of patients can be helpful for a more tailored clinical approach to management. For instance, patients can be grouped as those with fatigue only (phenotype 1), those with fatigue and excessive daytime sleepiness (phenotype 2), those with fatigue and depression (phenotype 3), and then those with fatigue, excessive daytime sleepiness, and depression (phenotype 4). Those with phenotype 2 might benefit more from the use of stimulants versus those with phenotype 3, who might benefit from a psychiatric evaluation (66).

If the patient’s symptoms suggest sleepiness or hypersomnolence, using validated instruments to characterize the symptom further may be useful. The Epworth Sleepiness Scale is a validated eight-item questionnaire used in the outpatient setting to evaluate subjective sleepiness. It uses a four-point Likert scale to quantify the patient’s likelihood of falling asleep (dozing) in eight sedentary circumstances (32). A score of 10 or higher indicates sleepiness. Another useful instrument used to quantify sleep quality is the Pittsburgh Sleep Quality Index (PSQI), which is a 19-item instrument that measures sleep quality and disturbances over the preceding month (12). Prior studies have shown that measuring perceived sleep quality using the PSQI may correlate with fatigue in persons with multiple sclerosis (34). The presence of sleepiness, poor sleep quality, or the use of sleep as a recovery mechanism for fatigue necessitates screening for potential sleep disorders, including obstructive sleep apnea, insomnia, narcolepsy, periodic leg movement disorder, and restless legs syndrome. Although restless legs syndrome and insomnia are clinical diagnoses, overnight polysomnography is recommended for symptoms suggestive of obstructive sleep apnea or periodic leg movement disorder. Symptoms suggestive of narcolepsy warrant a nocturnal polysomnogram followed by a daytime multiple sleep latency test. Referral to a sleep specialist for additional workup, including testing for maintenance of wakefulness, can be helpful with diagnosis and assessing the severity of symptoms and treatment response. This testing could help inform whether those in occupations that involve driving can continue working without facing high risk for accidents and injuries.

Symptoms of depressed mood, anhedonia, or psychomotor retardation should alert the clinician to screen for depression. Screening tests for depression are the PHQ-9 or a shortened version, PHQ-2. A combination of depression and anxiety screening with PHQ-4 can also be done. A positive screen warrants prompt treatment or referral to a mental health specialist. Reassessments should be conducted frequently to assess treatment responsiveness. Associated sleep disturbances that may accompany depression, such as insomnia, should be treated separately if they persist following treatment. Alternatively, a formal consultation with psychiatry can be pursued as well.

A retrospective analysis by Diem and colleagues investigated the association of multiple sclerosis fatigue and IgG hypogammaglobulinemia (19). There was a negative association of serum IgG concentration with fatigue in multiple sclerosis. Unclear on what the cause for this might be, the possibility of increased risk of infections in this population was hypothesized to be a potential mediator based on studies in patients with immunodeficiency but not multiple sclerosis. This is interesting, given that a few studies of combined variable immunodeficiency show a connection between immunoglobulin substitution and improvement in reported fatigue.

Anemia, infection, vitamin deficiencies, and thyroid abnormalities should be ruled out with appropriate laboratory testing when appropriate. Medications with known side effects of hypersomnolence should be identified and minimized, if possible.

If fatigue persists after ruling out/addressing other treatable conditions, quantification of its severity may be useful to track treatment progress. Many instruments for quantification are available, including scales designed specifically for persons with multiple sclerosis. Two of the most widely used scales include Krupp’s Fatigue Severity Scale (FSS) (39) and the Modified Fatigue Impact Scale (MFIS), which was derived from the Fatigue Impact Scale (21). Both scales correlate well with each other, have shown acceptable consistency and reliability, and can be easily administered in the clinic. The FSS consists of nine items based on a Likert scale (range 1 to 7). A score of 36 or more suggests fatigue. The MFIS contains 21 items on a Likert scale (range 0 to 4) that cover the physical, cognitive, and psychosocial aspects of fatigue; a general score is obtained by totaling these items. A score of 38 or more suggests fatigue.

Management

Nonpharmacologic treatments. Many clinicians recommend nonpharmacologic treatments, such as aerobic exercise, rehabilitation regimens, energy conservation strategies, and cooling devices, as potential interventions for multiple sclerosis-related fatigue in conjunction with pharmacologic agents. Numerous smaller studies show that several exercise interventions are safe in persons with multiple sclerosis (29; 56). There is a general trend in favor of aerobic exercise (48; 57; 33) except for one study that did not show benefit (30). A systemic review concluded that energy conservation methods had some short-term benefit (06); however, this was followed by a randomized controlled trial that showed no reduction in multiple sclerosis-related fatigue from energy conservation management (07). Neuromodulation therapies have seldom been studied for the management of fatigue in multiple sclerosis. However, one small study showed that transcranial direct current stimulation improved fatigue compared to sham procedure (13). Large-scale randomized controlled studies assessing the benefit of the above-mentioned therapies are lacking.

Pharmacologic treatments. Amantadine is approved by the FDA to treat influenza and Parkinson disease. Its off-label use for multiple sclerosis fatigue is well-studied (38). Although the relatively small scale of these studies and the heterogeneity of outcome measures have not allowed FDA approval, many clinicians advocate its use as a first-line agent for multiple sclerosis-related fatigue. The drug is fairly well-tolerated with a mild side-effect profile, although caution should be used in patients with cardiovascular disease, cardiac arrhythmia, or seizure disorder. It is typically given as a fixed dose of 100 mg twice daily.

Modafinil and its racemic analog armodafinil are wake-promoting agents approved by the FDA for narcolepsy, shift-work sleep disorder, and obstructive sleep apnea with residual excessive sleepiness despite optimal use of continuous positive airway pressure. Modafinil is also widely used in various conditions, including multiple sclerosis-related fatigue. Several studies have demonstrated favorable results regarding improved fatigue, focused attention, dexterity, and enhanced motor cortex excitability at doses lower than those required for narcolepsy patients (55; 40). A case report also suggests that modafinil may have a role in improving primary nocturnal enuresis in multiple sclerosis (15). Nonetheless, modafinil is not FDA-approved for multiple sclerosis-related fatigue, partly due to conflicting results from other studies. Four randomized, double-blind studies found no significant difference or improvement in fatigue when comparing modafinil versus placebo, although significant improvements in the MFIS were seen in both groups at the end of the study compared to baseline (67; 40; 47; 41). Modafinil and armodafinil are generally well-tolerated, and off-label use in some patients anecdotally shows some benefit. Potential side effects include headache, psychiatric disturbance, gastrointestinal irritation, and decreased effectiveness of contraception. For modafinil, a starting dose of 50 to 100 mg every morning, which can be slowly titrated up over several weeks to 200 mg every morning, is recommended. Doses should not exceed 400 mg per day. For armodafinil, a starting dose of 150 mg daily should be used, with a maximum recommended dose of 250 mg daily.

Pemoline is a central nervous system stimulant with dopaminergic effects. It has not been studied as extensively as amantadine, and previous studies have yielded unimpressive results (38). It has also been associated with significant liver toxicity, which may preclude its use. Treatment with an alternative agent, such as amantadine or modafinil, is recommended before considering pemoline, which is available in some countries. Pemoline was withdrawn from the U.S. market in 2005.

Other central nervous system stimulants frequently considered for the treatment of fatigue include methylphenidate and dextroamphetamine. Methylphenidate is a stimulant that is FDA-indicated for attention deficit hyperactivity disorder. Dextroamphetamine is FDA-approved for the treatment of attention deficit hyperactivity disorder and narcolepsy. Although both drugs improve objective and subjective sleepiness in patients with narcolepsy, studies regarding their use for multiple sclerosis-related fatigue are lacking. Moreover, several serious side effects (including tolerance and psychological dependence) and multiple contraindications, including cardiovascular disease, hypertension, history of drug dependence or alcoholism, and concomitant monoamine oxidase inhibitor administration, often preclude their use. As with pemoline, treatment with these and other central nervous system stimulants should not be considered unless other agents are ineffective and should be used with caution and close supervision.

Several other nonstimulant agents have also been studied. 4-Aminopyridine is a voltage-dependent potassium channel blocker used to treat motor fatigue (25). This was initially looked at in smaller studies with variable endpoints that showed suggested benefit but precluded firm conclusions regarding its efficacy in the treatment of generalized multiple sclerosis-related fatigue, but a more recent randomized, placebo-controlled trial looking into effects on cognition and fatigue was positive as well (10). Aspirin has also been studied for its effects on multiple sclerosis-related fatigue. In a small randomized crossover trial of aspirin (1300 mg/day) versus placebo, subjects reported an improvement in the primary efficacy measure (MFIS score) with aspirin (76). This study had several limitations, however. Other fatigue scales used in the study including the FSS (the primary measure used to screen for trial eligibility) did not reflect this benefit. A randomized placebo-controlled crossover study of American ginseng also failed to show any significant benefit in fatigue as measured by the FSS and MFIS, although a significant improvement in the Real-Time Digital Fatigue Score (RDFS)--a novel measurement of real-time fatigue that has been shown by the investigators to correlate with the FSS and MFIS--was noted (35). A randomized placebo-controlled trial of CoQ10 supplementation (500 mg/day) improved fatigue and depression in patients with multiple sclerosis (63).

There are concerns, however, about the possibility that these drugs are not superior to placebo in treating multiple sclerosis-related fatigue. A randomized, placebo-controlled, crossover, double-blind trial testing the safety and efficacy of amantadine, modafinil, and methylphenidate found no superiority of these drugs to placebo (51). However, because fatigue is a debilitating symptom that is common and intrinsic to multiple sclerosis, and given the absence of good pharmacologic targets to treat this fatigue, clinicians are often left with no other choice than to treat with one of these pharmacologic agents. These studies raise interesting questions about the pathogenesis of fatigue and which patients are responders. Further studies are needed to identify better pharmacologic targets.