Medscape Neurology & Neurosurgery 5(2), 2003
Rohit Bakshi, MD
Neurologist, MS specialist, Neuroimager, Director of Clinical MRI/MS Imaging, Partners MS Center, Harvard Medical School, Boston, Massachusetts
Fatigue is the most common symptom of multiple sclerosis (MS), affecting at least two thirds of patients. Furthermore, nearly half of patients describe MS fatigue as the most disabling feature of the disease. Fatigue clearly impairs the quality of life of patients with MS. The cause of MS fatigue is unknown; the phenomenon cannot be adequately explained by physical disability, although it is frequently associated with depression. Factors thought to contribute to MS fatigue include dysfunction of premotor, limbic, basal ganglia, or hypothalamic areas; disturbances of the neuroendocrine axis; changes in serotonin pathways or other neurotransmitters; and dysimmunity. Neuroimaging studies have revealed a correlation between MS fatigue and hypometabolism or reduced activation of frontal and subcortical gray matter areas of the brain. Several pharmacologic and nonpharmacologic measures play a role in the treatment of MS fatigue. A multifactorial approach to treatment is recommended.
Definition, Impact, and Diagnosis
MS is the most common cause of progressive neurologic disability in young adults and affects approximately 350,000 people in the United States. Fatigue associated with MS is an abnormal, generalized lack of energy that significantly limits physical and/or mental ability regardless of the degree of effort or level of neurologic disability.[1-3] Fatigue is the most common symptom of MS and one of the most disabling aspects of the disease. More than two thirds of patients with MS experience significant fatigue,[1-7] and nearly half describe it as the most debilitating feature of the disease.[6-9] Fatigue independently contributes to impairments in quality of life of patients with MS[5, 10-12] through a reduction in energy and endurance, and by adversely affecting mood, outlook, and coping ability.[13,14] Fatigue affects both motor and cognitive ability. Cognitive fatigue is the slowing of mental function while performing repetitive tasks. Additional evidence of the impact of MS fatigue is the negative effect on employment; indeed, the United States Social Security Administration recognizes the impairment resulting from fatigue as a factor contributing to disability in patients with MS.
The diagnosis of MS fatigue includes the presence of fatigue symptoms for at least 50% of days for more than 6 weeks (Multiple Sclerosis Clinical Practice Guideline: Fatigue and Multiple Sclerosis: Evidence-Based Management Strategies for Fatigue in Multiple Sclerosis. Washington, DC: Paralyzed Veterans Association; 1999.). This criterion is useful to distinguish MS fatigue from other MS symptoms. Reduced energy, malaise, motor weakness during sustained activity, and difficulty maintaining concentration are common features of MS fatigue. It is important to question patients about fatigue because the symptom may not be reported voluntarily. This underreporting may occur if the patient has accepted fatigue as an inevitable and untreatable consequence of a chronic disease or if specific physical complaints are more obvious.
The differential diagnosis of MS fatigue includes depression, physical disability, thyroid disorders, and side effects of medications such as antispasmodics and immunosuppressive agents. Self-report questionnaires such as the Fatigue Severity Scale may be useful in the diagnosis of MS fatigue and as a surrogate outcome measure.
The pathogenesis of MS fatigue is poorly understood, but the phenomenon appears to be multifactorial and directly related to the underlying MS disease process. Potential mechanisms include secondary effects of inflammation on neuromodulation, disruption of neural pathways necessary for brain activity, secondary effects of depression, and daytime somnolence due to nocturnal sleep disturbances.[1-3] However, definitive proof implicating these factors is lacking. MS fatigue is not adequately explained by disease duration, gender, psychosomatic mechanisms, physical disability, or sleep dysfunction. Giovannoni and colleagues showed that MS fatigue is not related to systemic inflammation such as interferon-gamma-activated macrophage activity, C-reactive protein, or soluble intercellular adhesion molecule-1 levels.
Patients with benign MS experience the same degree of fatigue as patients with disabling disease. However, MS fatigue may be partially related to depression[4, 18-20]; Bakshi and associates showed a significant relationship between MS fatigue and depression independent of physical disability. Their findings included higher severity of depressive symptoms in fatigued vs nonfatigued patients and a correlation between depressive symptoms and fatigue severity. The association between MS fatigue and depression suggests that common mechanisms such as psychological factors or lesions in specific cerebral pathways link these phenomena.
Neuroimaging studies are beginning to shed light on the pathophysiology of MS fatigue. Functional brain imaging studies using positron emission tomography (PET) and single photon emission computed tomography (SPECT) indicate that MS is associated with widespread hypometabolism.[21-23] Bakshi and associates examined 25 patients with MS and 6 healthy controls and demonstrated a 9% reduction in total brain glucose metabolism on PET scans in patients with MS compared with controls. Hypometabolism was widespread, including in the cerebral cortex, subcortical gray matter nuclei, and periventricular white matter. Roelcke and coworkers showed that hypometabolism in the bilateral prefrontal cortex and basal ganglia was associated with MS fatigue, implicating a role for cortical-subcortical pathways. Filippi and colleagues performed functional MRI (fMRI) during a simple motor task in patients with MS and normal controls. Compared with fatigued patients, nonfatigued patients with MS experienced more significant activations of the ipsilateral cerebellar hemisphere, the ipsilateral rolandic operculum, the ipsilateral precuneus, the contralateral thalamus, and the contralateral middle frontal gyrus. By contrast, patients with MS fatigue demonstrated greater activation of the contralateral cingulate motor area (CMA).
Taken together, these functional imaging studies indicate that MS fatigue is related to impaired interactions between functionally related cortical and subcortical areas. However, structural imaging studies have failed to uncover the pathologic substrate for this cerebral dysfunction. Studies by several groups have shown a consistent lack of association between MS fatigue and a range of MRI metrics, including brain atrophy, lesion load on T1-weighted or T2-weighted images, magnetization transfer ratio, or mean diffusivity.[25-27]
Fatigue or weakness localized to specific muscle groups should not be confused with the generalized fatigue that typifies MS. Fatigue in MS shows a poor relationship to physical disability and each can exist independently. Moreover, some neuromuscular disorders are associated with muscle weakness without generalized fatigue. Rather than being explained by muscle weakness, MS fatigue frequently includes both physical and cognitive fatigue, arguing for a centrally mediated impairment in brain transmission that affects processing and motivation. Although brain injury is likely to play a key role in MS fatigue, other factors, such as the systemic complications of inactivity, psychological effects of a chronic disease, and altered innervation of target muscles, may also contribute.
A comprehensive approach to the treatment of MS fatigue requires a combination of pharmacologic and nonpharmacologic therapies. The treatment plan should take into account the patient's lifestyle, underlying causes, and comorbid conditions. Contributing factors include medications, infections, thyroid disease, depression, cognitive dysfunction, sleep disturbances, bladder dysfunction, spasticity, and exposure to heat. Initial management of MS fatigue typically includes lifestyle changes such as smoking cessation, reducing caffeine intake, and exercising. The patient should schedule strenuous activities earlier in the day, spaced by adequate rest. Mostert and colleagues showed that MS patients participating in a 4-week aerobic exercise program experienced a perception of improved health, an increase in activity, and less fatigue compared with a nonexercising MS group.
An exercise program should be individualized based on the patient's fitness level, physical disability, and heat sensitivity. Reduction of overheating includes simple strategies but also the use of external devices. Flensner and associates studied the use of a cooling-suit in the home setting in 8 patients with MS. All participants reported a reduction in fatigue and improvements in physical, cognitive, and psychosocial function. Further studies are needed to extend and confirm these results.
Drug therapy plays an important role in the management of MS fatigue.[1-3] Several medications have been evaluated for this indication, including the dopaminergic agent amantadine[6, 32-35]; the amphetamine-related stimulant pemoline[33,36,37]; the wake-promoting agent modafinil[38,39]; the potassium channel-blocking aminopyridines[40-42]; and Prokarin, a proprietary blend of histamine and caffeine.
Amantadine has been studied in 5 small-scale, short-term, randomized, placebo-controlled trials[6, 32-35] and has generally shown modest but significant efficacy on some, but not all, measures of MS fatigue. Two randomized, placebo-controlled trials[33,36] demonstrated minimal if any treatment effect from pemoline; furthermore, this agent may possess potentially serious adverse effects, including risk of dependence and hepatic failure. Modafinil has been studied in a single-blind, forced titration, 9-week, controlled crossover trial in 72 patients with MS and was effective on several measures of fatigue. A 3-month, 2-center, open-label trial of 50 patients also showed a benefit of modafinil on fatigue severity. The aminopyridines include 3,4-diaminopyridine and 4-aminopyridine and exert their effect through enhancing conduction in demyelinated nerve fibers. Effects on MS fatigue have been suggested but not definitively demonstrated.[40,41] Finally, in a 12-week, double-blind, placebo-controlled pilot study in 29 patients with MS,Prokarin use led to improved fatigue scores vs placebo. Further evaluation of this agent awaits larger studies.
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