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 2 categories: primary and secondary. Primary causes involve immunologic or hormonal mechanisms implicated in the disease process or central nervous system changes associated with multiple sclerosis. 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 and interferon-gamma levels have been demonstrated in subjects with multiple sclerosis-related fatigue compared to non-fatigued subjects (Heesen et al 2006). Unfortunately, these findings have not afforded clinicians a straightforward therapeutic target, as these cytokines are relatively nonspecific and may be elevated in a variety of inflammatory diseases. Moreover, although TNF-alpha antagonists have been shown to reduce sleepiness in patients with obstructive sleep apnea (Vgontzas et al 2004), they are contraindicated in multiple sclerosis due to the potential to cause clinical worsening (The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group 1999).
Associated endocrine abnormalities may also play a role. The hypothalamic-pituitary-adrenal axis and the hormone dehydroepiandrosterone, which have both been 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 (Tellez et al 2006), although studies examining ACTH levels after dexamethasone-corticotropin stimulation tests in fatigued multiple sclerosis patients have shown conflicting results (Heesen et al 2006; Tellez et al 2006).
Studies using nonconventional neuroimaging techniques suggest that multiple sclerosis-related fatigue may be due in part to axonal loss and altered cerebral activation patterns in specific brain regions affected by the disease (van der Werf et al 1998). This may be particularly applicable 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 (Roelcke et al 1997), 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 (Pardini et al 2010).
Additional brain regions may also be implicated. In a recent longitudinal study by Yaldizli and colleagues, fatigue was associated with increased corpus callosal atrophy after adjusting for disability status and disease duration (Yaldizli et al 2011). 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 (Tartaglia et al 2004; Tellez et al 2008). Other studies have shown that 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 cingulate gyri and left primary sensory cortex in fatigued multiple sclerosis subjects compared to nonfatigued subjects (Tartaglia et al 2008).
Secondary causes. Sleep disorders have gained recognition as significant contributors to fatigue in persons with multiple sclerosis (Attarian et al 2004). 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 (Tachibana et al 1994; Amarenco et al 1995; Rae-Grant et al 1999; Attarian et al 2004; Manconi et al 2007; Merlino et al 2009). 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 (Chervin 2000). 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 (Merlino et al 2009).
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. Various pain medications, including opioids or anticonvulsants for the treatment of 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 complaint. 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% (Sadovnick et al 1996). In addition to its independent contributions to quality of life, depression also correlates with fatigue (Kroencke et al 2000; Patrick et al 2009). Discerning between these 2 conditions may be difficult, as depression itself can manifest with other symptoms that may be mistaken for fatigue (loss of motivation, anhedonia, sleep disturbance). Nonetheless, clinicians should have a low threshold to screen for depression if fatigue is endorsed, and depression should be addressed and treated independently if identified.
Multiple sclerosis severity also correlates with fatigue. Several studies, including a review of The New York State Multiple Sclerosis Consortium Database (Patrick et al 2009) have demonstrated increased levels of fatigue with higher expanded disability status scores (Iriarte et al 2000; Tellez et al 2005), although depression may also contribute to this robust correlation in some cases (Bakshi et al 2000; Tellez et al 2005). The association between fatigue and multiple sclerosis subtype is also of interest. Some studies suggest that progressive subtypes of multiple sclerosis contribute to fatigue severity (Kroencke et al 2000; Lerdal et al 2007), although increased disability levels seen in patients with progressive subtypes may confound this observation (Kroencke et al 2000).