Multiple sclerosis is a chronic, debilitating, inflammatory, and neurodegenerative disease of the central nervous system. There is no cure for the disease, and its management includes use of symptomatic agents and diseasemodifying therapies to reduce and/or prevent relapses and disease progression. Fatigue affects up to 90% of MS patients and can significantly impair function, quality of life, and interaction with family and friends. The common causes of fatigue and effective interventions and treatments are reviewed in this article.
MS is a chronic, debilitating, inflammatory, and neurodegenerative disease of the CNS. There is no cure for the disease, and its management includes use of symptomatic agents and disease-modifying therapies to reduce and/or prevent relapses and disease progression. MS affects approximately 350,000 persons in the United States. Its estimated prevalence is 1/1000 individuals in North America, and it is one of the most common causes of disability in young adults.
The symptoms of MS are numerous and include weakness, paresthesias, visual changes, spasticity, cognitive dysfunction, ataxia, and fatigue. Fatigue remains one of the most common and debilitating symptoms in MS and is quoted as one of the single most disabling symptoms. Forty percent of MS patients state fatigue as their most disabling symptom. It has been reported to cause profound disruption of quality of life in MS patients. Approximately 20% of patients evaluated in primary care clinics experience fatigue. In contrast, 96% of MS patients experience fatigue, 88% of whom report fatigue as a moderate to high problem.
Definition
There is no universally accepted definition of fatigue in MS patients. One common definition describes a “subjective lack of physical and/or mental energy, perceived by the individual or caregiver to interfere with usual and desired activities.” Some other definitions include “pathologic exhaustion,” “reversible motor and cognitive impairment with reduced motivation and desire to rest,” and “difficulty with initiation of or sustaining voluntary activities that does not correlate with muscle weakness, depression, or muscle fatigue.” Researchers in the United Kingdom interviewed MS patients first in face-to-face interviews and then using a questionnaire format to learn about patients’ perceptions of fatigue. Patients described fatigue as a “reversible motor and cognitive impairment, with reduced motivation and desire to rest.”
It is important to differentiate between peripheral and central fatigue, as each has a unique etiology and treatment recommendation. Peripheral fatigue equates to muscle fatigue due to physical exertion and is alleviated with rest and associated with fatigability. Fatigue differs from fatigability, which is a generalized sense of exhaustion, not present at rest, affecting the patient after a few minutes of physical activity, and alleviated with rest. Central fatigue is much more subjective and is associated with difficulty with arousal and attention. The subject reports a feeling of constant exhaustion, which can lead to worsening vision or function. MS patients experience both central and peripheral fatigue. Therefore, differentiation between both types is vital to proper management.
Impact of fatigue
Fatigue in the MS patient can have profound negative effects. Patients frequently need to nap, take frequent breaks, or sleep early. This may interfere with family activities, cause avoidance of the outdoors due to fatiguing effects of heat, or lead to an inability to participate in events that require prolonged physical effort. Social activities with friends and family are difficult to plan, as some days MS patients may awaken with an overwhelming sense of fatigue that cannot be alleviated with rest. Cognitive processing, memory, and concentration are impaired during periods of fatigue. Fatigue can negatively affect vocational performance and maintenance, especially if workplace accommodations are not achievable. The presence of fatigue has significant negative implications on quality of life in MS patients. Interestingly, as disease progresses, the effect of fatigue in MS frequently diminishes due to overall decreased ability of persons to perform previous routine activities.
MS patients often avoid physical activity to avoid fatigue. Additionally, patients may be concerned about thermosensitivity secondary to elevated body temperatures. Therefore, many MS patients engage in minimal physical activity, which may progressively worsen their weakness, fatigue, and other health issues. Limited mobility can play a role in worsening spasticity, constipation, and bone loss. In exercise studies, people with MS were shown to have decreased peak oxygen levels during maximal incremental exercise compared with those of healthy subjects. This finding may suggest that MS patients have reduced cardiovascular fitness related to deconditioning. Insufficient activity in MS patients is linked to muscle changes that occur independently of CNS damage (ie, lowered oxidative capacity, lowered muscle dynamic properties, increased muscle fatigue, impaired metabolic responses to muscles to load, impaired excitation–contraction coupling). Therefore, there may be an imbalance between the increased metabolic need in MS patients and their lowered cardiovascular supply. Rampello and colleagues found that maximum exercise tolerance improved after patients completed 8 weeks of aerobic training, with a significant change in walking capacity. Similar results occurred after a 4-week aerobic treadmill training in MS patients with no worsening of fatigue scores. Several studies have demonstrated clear benefit of regular physical activity in MS patients with improved fitness levels and quality-of-life measures. However, not all results are linked with corresponding decreases in fatigue; conversely, no worsening of fatigue was reported.
In addition to the effect on health, personal life, and vocation, the costs of MS should be considered. Unexpectedly, healthcare costs increase with increasing disability. The MS patient is responsible for the majority of the financial burden. The proportion of costs directly attributable to fatigue is unknown.
Impact of fatigue
Fatigue in the MS patient can have profound negative effects. Patients frequently need to nap, take frequent breaks, or sleep early. This may interfere with family activities, cause avoidance of the outdoors due to fatiguing effects of heat, or lead to an inability to participate in events that require prolonged physical effort. Social activities with friends and family are difficult to plan, as some days MS patients may awaken with an overwhelming sense of fatigue that cannot be alleviated with rest. Cognitive processing, memory, and concentration are impaired during periods of fatigue. Fatigue can negatively affect vocational performance and maintenance, especially if workplace accommodations are not achievable. The presence of fatigue has significant negative implications on quality of life in MS patients. Interestingly, as disease progresses, the effect of fatigue in MS frequently diminishes due to overall decreased ability of persons to perform previous routine activities.
MS patients often avoid physical activity to avoid fatigue. Additionally, patients may be concerned about thermosensitivity secondary to elevated body temperatures. Therefore, many MS patients engage in minimal physical activity, which may progressively worsen their weakness, fatigue, and other health issues. Limited mobility can play a role in worsening spasticity, constipation, and bone loss. In exercise studies, people with MS were shown to have decreased peak oxygen levels during maximal incremental exercise compared with those of healthy subjects. This finding may suggest that MS patients have reduced cardiovascular fitness related to deconditioning. Insufficient activity in MS patients is linked to muscle changes that occur independently of CNS damage (ie, lowered oxidative capacity, lowered muscle dynamic properties, increased muscle fatigue, impaired metabolic responses to muscles to load, impaired excitation–contraction coupling). Therefore, there may be an imbalance between the increased metabolic need in MS patients and their lowered cardiovascular supply. Rampello and colleagues found that maximum exercise tolerance improved after patients completed 8 weeks of aerobic training, with a significant change in walking capacity. Similar results occurred after a 4-week aerobic treadmill training in MS patients with no worsening of fatigue scores. Several studies have demonstrated clear benefit of regular physical activity in MS patients with improved fitness levels and quality-of-life measures. However, not all results are linked with corresponding decreases in fatigue; conversely, no worsening of fatigue was reported.
In addition to the effect on health, personal life, and vocation, the costs of MS should be considered. Unexpectedly, healthcare costs increase with increasing disability. The MS patient is responsible for the majority of the financial burden. The proportion of costs directly attributable to fatigue is unknown.
Assessment tools
The Fatigue Severity Score (FSS), the Fatigue Impact Scale (FIS), and the Modified Fatigue Impact Scale (MFIS) are the most commonly used scales for fatigue assessment in MS patients. The FSS is composed of 9 items that assess perceived fatigue. Subjects are asked to assign a number from 1 (strongly disagree) to 7 (strongly agree) stating their agreement with each statement. Responses are summed and averaged, with a score of 4 or more indicating significant fatigue.
The FIS has been identified by the Multiple Sclerosis Council for Clinical Practice Guidelines “as the most appropriate for assessing the impact of MS-related fatigue on quality of life.” The FIS is a retrospective tool designed to evaluate fatigue during the past month. The FIS has separate subscales for physical, psychosocial, and cognitive functions, which span more than 40 statements. Subjects are asked to score the effect of fatigue on those 4 dimensions using a 5-point scale from 0 (no problem) to 4 (extreme problem). Since the FIS takes approximately 10 to 20 minutes to be administered, followed by 5 minutes to score, shorter versions of the scale have been created. The MFIS is a modified version of the FIS and consists of a long (21-question) and short (5-question) version. The total time to administer and score is about 10 to 15 minutes.
Kos and colleagues developed a Visual Analog Scale that assesses the impact of fatigue on daily life, and they reported reliability and validity comparable to the FSS and MFIS. A score of 59 or more on a 100-mm line signifies individuals with fatigue that has a high impact on daily life. This may be helpful for the clinician to quickly assess fatigue in patients in the context of an office visit.
Although several scales are available for evaluation of fatigue in MS patients, none of them is an objective scale. All currently available scales are self-report questionnaires or surveys. Due to the fluctuating nature of MS, it is possible that patient’s perception of fatigue is highly dependent on the time of day the survey was performed. A study evaluating walking parameters and fatigue in MS patients reported no significant difference in walking speed, stride length, cadence, or double-limb support time from 10 am to 3 pm on the same day, whereas the self-reported fatigue score increased significantly. This study is supported by findings from Krupp and colleagues who found no relation between neurologic disability level and fatigue. This finding supports the need for objective measures in evaluating fatigue. However, the challenge in measuring the biological impact of fatigue is that the mechanisms of fatigue are largely unknown.
Pathogenesis—primary factors
When evaluating the pathogenesis of fatigue in MS, it is important to distinguish primary fatigue from secondary fatigue. Primary fatigue is a result of the disease process, and secondary fatigue results from medications or disease-related manifestations. Due to the multimodal aspect of fatigue in MS, it is difficult to differentiate primary fatigue from secondary fatigue, as several factors contribute to fatigue manifestation.
There are several theories on the pathogenesis of fatigue, with strong evidence for an inflammation mediated process. Giovannoni and Heesen and colleagues state that fatigue is inflammation driven, citing that fatigue caused by viral or bacterial infections can be reproduced by proinflammatory cytokines, such as interferon α or β or interleukin-2. Several MS patients experience fatigue as a side effect of interferon treatment. The potential effect of hypothalamo-pituitary-adrenal (HPA) axis dysfunction on fatigue has been evaluated by multiple researchers with varying results. HPA hypoactivity occurs in chronic fatigue syndrome, and researchers have searched for a connection with MS and fatigue. Some studies report no correlation between fatigue scores and abnormal dexamethasone–corticotropin-releasing hormone scores, whereas others report hyperactivity of the HPA axis. Gadolinium (Gd) enhancing lesions, the quintessential marker for inflammation in MS, failed to demonstrate correlation between fatigue and Gd-enhancing lesions.
Some aspects of fatigue suggest that it may be related to underlying demyelinating pathology, which results in slowing and desynchronization of nerve transmission or partial or complete conduction block. The peripheral causes of fatigue have been investigated using repetitive nerve stimulation (RNS). RNS failed to demonstrate improved impulse conduction along demyelinated nerves. Finally, central motor conduction time is prolonged in MS patients, supporting the use of evoked potential testing in MS patients for diagnostic purposes.
Some researchers correlate hypometabolism detected in positron emission tomography in the bilateral prefrontal cortex, premotor and supplemental motor cortex, putamen, and white matter extending from rostral putamen to the head of the caudate nucleus, with fatigue symptoms. Diffuse axonal damage and brain atrophy are also linked as possibly related to causing fatigue. No correlation between brain atrophy and fatigue has been found. Functional magnetic resonance imaging displays impaired interaction between cortical and subcortical areas, which is inversely related to results on the FSS.
Researchers have raised the question whether MS fatigue is more of a peripheral than central phenomenon. The hallmark of peripheral fatigue is muscle fatigability, frequently due to neuromuscular or myopathic disorders. Sustained muscle fatigue leads to disuse atrophy, thereby limiting endurance in MS patients. This can lead to cardiovascular decline, increased spasticity, contracture development, and overall deconditioning. Central fatigue is characterized by a feeling of constant exhaustion and is associated with several neurologic disorders, including MS. Central fatigue is implicated in MS due to the correlation between fatigue and cognitive dysfunction.
Pathogenesis—secondary factors
There are several additional factors that may worsen fatigue for patients with MS ( Box 1 ). Thermosensitivity is common in people with MS, leading to instability and delay in signal conduction in demyelinated nerves. Increased body temperature induces conduction block, resulting in deterioration of neurologic function, which is known as the Uhthoff phenomenon. MS fatigue secondary to heat sensitivity differs from that in normal healthy adults (NHAs) in that heat intolerance causes difficulty in sustaining physical activities and interferes with physical functions and responsibilities. MS patients should be encouraged to precool with ice water or sit in a cool bath for 20 minutes before engaging in exercise or other forms of physical activity.
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