Multiple sclerosis Fatigue Neurorehabilitation Human Quality of life Treatment of fatigue
MS is a chronic, debilitating, inflammatory, and neurodegenerative disease of theCNS. There is no cure for the disease, and its management includes use of symptom-atic agents and disease-modifying therapies to reduce and/or prevent relapses anddisease progression. MS affects approximately 350,000 persons in the UnitedStates.Its estimated prevalence is 1/1000 individuals in North America, and it isone 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 oneof the most common and debilitating symptoms in MS and is quoted as one of thesingle most disabling symptoms.Forty percent of MS patients state fatigue as theirmost disabling symptom.It has been reported to cause profound disruption of qualityof life in MS patients.Approximately 20% of patients evaluated in primary care clinicsexperience fatigue.In contrast, 96% of MS patients experience fatigue, 88% ofwhom report fatigue as a moderate to high problem.
There is no universally accepted definition of fatigue in MS patients. One commondefinition describes a ‘‘subjective lack of physical and/or mental energy, perceivedby the individual or caregiver to interfere with usual and desired activities.’’ Some otherdefinitions include ‘‘pathologic exhaustion,’’ ‘‘reversible motor and cognitive impair-ment with reduced motivation and desire to rest,’’ and ‘‘difficulty with initiation of orsustaining voluntary activities that does not correlate with muscle weakness, depres-sion, or muscle fatigue.’’ Researchers in the United Kingdom interviewed MS patientsfirst in face-to-face interviews and then using a questionnaire format to learn aboutpatients’ perceptions of fatigue. Patients described fatigue as a ‘‘reversible motorand cognitive impairment, with reduced motivation and desire to
Conflict of Interest: The author is a paid consultant for Biogen Idec, EMD Serono, and TevaPharmaceuticals. Department of Physical Medicine and Rehabilitation, University of Texas Southwestern MedicalCenter, 5323 Harry Hines Blvd, Mail Code 9055, Dallas, TX 75390-9055, USAE-mail address:
Phys Med Rehabil Clin N Am 20 (2009) 363–372doi:10.1016/j.pmr.2008.12.003
1047-9651/08/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
It is important to differentiate between peripheral and central fatigue, as each has
a unique etiology and treatment recommendation. Peripheral fatigue equates tomuscle fatigue due to physical exertion and is alleviated with rest and associatedwith fatigability. Fatigue differs from fatigability, which is a generalized sense ofexhaustion, not present at rest, affecting the patient after a few minutes of physicalactivity, and alleviated with rest. Central fatigue is much more subjective and is asso-ciated with difficulty with arousal and attention. The subject reports a feeling ofconstant exhaustion, which can lead to worsening vision or function. MS patientsexperience both central and peripheral fatigue. Therefore, differentiation betweenboth types is vital to proper management.
Fatigue in the MS patient can have profound negative effects. Patients frequently needto 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 inabilityto participate in events that require prolonged physical effort. Social activities withfriends and family are difficult to plan, as some days MS patients may awaken withan overwhelming sense of fatigue that cannot be alleviated with rest.Cognitive pro-cessing, memory, and concentration are impaired during periods of Fatiguecan negatively affect vocational performance and maintenance, especially if work-place accommodations are not achievable. The presence of fatigue has significantnegative implications on quality of life in MS patients. Interestingly, as disease prog-resses, the effect of fatigue in MS frequently diminishes due to overall decreasedability 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 progres-sively worsen their weakness, fatigue, and other health issues. Limited mobility canplay a role in worsening spasticity, constipation, and bone loss. In exercise studies,people with MS were shown to have decreased peak oxygen levels during maximalincremental exercise compared with those of healthy This finding maysuggest that MS patients have reduced cardiovascular fitness related to decondition-ing. Insufficient activity in MS patients is linked to muscle changes that occur indepen-dently of CNS damage (ie, lowered oxidative capacity, lowered muscle dynamicproperties, increased muscle fatigue, impaired metabolic responses to muscles toload, impaired excitation–contraction Therefore, there may be an imbal-ance between the increased metabolic need in MS patients and their lowered cardio-vascular supply. Rampello and found that maximum exercise toleranceimproved after patients completed 8 weeks of aerobic training, with a significantchange in walking capacity. Similar results occurred after a 4-week aerobic treadmilltraining in MS patients with no worsening of fatigue scores.Several studies havedemonstrated clear benefit of regular physical activity in MS patients with improvedfitness levels and quality-of-life However, not all results arelinked with corresponding decreases in fatigue; conversely, no worsening of fatiguewas reported.
In addition to the effect on health, personal life, and vocation, the costs of MS should
disability.The MS patient is responsible for the majority of the financial burden. The proportion of costs directly attributable to fatigue is unknown.
The Fatigue Severity Score (FSS), the Fatigue Impact Scale (FIS), and the ModifiedFatigue Impact Scale (MFIS) are the most commonly used scales for fatigue assess-ment in MS patients.The FSS is composed of 9 items that assess perceivedSubjects are asked to assign a number from 1 (strongly disagree) to 7(strongly agree) stating their agreement with each statement.Responses aresummed and averaged, with a score of 4 or more indicating significant
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 fatigueon quality of life.The FIS is a retrospective tool designed to evaluate fatigue duringthe past month. The FIS has separate subscales for physical, psychosocial, andcognitive functions, which span more than 40 statements.Subjects are asked toscore the effect of fatigue on those 4 dimensions using a 5-point scale from 0 (noproblem) to 4 (extreme problem). Since the FIS takes approximately 10 to 20 minutesto be administered, followed by 5 minutes to score, shorter versions of the scale havebeen 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 isabout 10 to 15 minutes.
Kos and colleaguesdeveloped a Visual Analog Scale that assesses the impact of
fatigue on daily life, and they reported reliability and validity comparable to the FSSand MFIS. A score of 59 or more on a 100-mm line signifies individuals with fatiguethat has a high impact on daily life. This may be helpful for the clinician to quicklyassess 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 question-naires or surveys. Due to the fluctuating nature of MS, it is possible that patient’sperception 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 signif-icant difference in walking speed, stride length, cadence, or double-limb support timefrom 10 AM to 3 PM on the same day, whereas the self-reported fatigue score increasedsignificantly.This study is supported by findings from Krupp and whofound no relation between neurologic disability level and fatigue. This finding supportsthe need for objective measures in evaluating fatigue. However, the challenge inmeasuring the biological impact of fatigue is that the mechanisms of fatigue are largelyunknown.
When evaluating the pathogenesis of fatigue in MS, it is important to distinguishprimary fatigue from secondary fatigue. Primary fatigue is a result of the diseaseprocess, and secondary fatigue results from medications or disease-related manifes-Due to the multimodal aspect of fatigue in MS, it is difficult to differentiateprimary fatigue from secondary fatigue, as several factors contribute to fatiguemanifestation.
There are several theories on the pathogenesis of fatigue, with strong evidence for
an inflammation mediated process. Giovannoniand Heesen and colleaguesstatethat fatigue is inflammation driven, citing that fatigue caused by viral or bacterial infec-tions can be reproduced by proinflammatory cytokines, such as interferon a or b orinterleukin-2. Several MS patients experience fatigue as a side effect of interferontreatment. The potential effect of hypothalamo-pituitary-adrenal (HPA) axis dysfunc-tion on fatigue has been evaluated by multiple researchers with varying results. HPA
hypoactivity occurs in chronic fatigue syndrome, and researchers have searched fora connection with MS and fatigue. Some studies report no correlation between fatiguescores and abnormal dexamethasone–corticotropin-releasing hormone scores,whereas others report hyperactivity of the HPA axis.Gadolinium (Gd) enhancinglesions, the quintessential marker for inflammation in MS, failed to demonstrate corre-lation 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 orpartial or complete conduction block.The peripheral causes of fatigue havebeen investigated using repetitive nerve stimulation (RNS). RNS failed to demonstrateimproved impulse conduction along demyelinated nerves. Finally, central motorconduction time is prolonged in MS patients, supporting the use of evoked potentialtesting in MS patients for diagnostic purposes.
Some researchers correlate hypometabolism detected in positron emission tomog-
raphy in the bilateral prefrontal cortex, premotor and supplemental motor cortex, puta-men, and white matter extending from rostral putamen to the head of the caudatenucleus, with fatigue Diffuse axonal damage and brain atrophy arealso linked as possibly related to causing No correlation between brainatrophy and fatigue has been found.Functional magnetic resonance imagingdisplays impaired interaction between cortical and subcortical areas, which isinversely related to results on the FSS.
Researchers have raised the question whether MS fatigue is more of a peripheral
than central The hallmark of peripheral fatigue is muscle fatigability,frequently due to neuromuscular or myopathic disorders.Sustained muscle fatigueleads to disuse atrophy, thereby limiting endurance in MS patients. This can lead tocardiovascular decline, increased spasticity, contracture development, and overalldeconditioning. Central fatigue is characterized by a feeling of constant exhaustionand is associated with several neurologic disorders, including MS. Central fatigue isimplicated in MS due to the correlation between fatigue and cognitive dysfunction.
There are several additional factors that may worsen fatigue for patients with MS(). Thermosensitivity is common in people with MS, leading to instability anddelay in signal conduction in demyelinated nerves. Increased body temperatureinduces conduction block, resulting in deterioration of neurologic function, which isknown as the Uhthoff phenomenon. MS fatigue secondary to heat sensitivity differsfrom that in normal healthy adults (NHAs) in that heat intolerance causes difficulty insustaining physical activities and interferes with physical functions and responsibili-MS patients should be encouraged to precool with ice water or sit in a coolbath for 20 minutes before engaging in exercise or other forms of physical
Mood disorders, such as depression and anxiety, are common in MS patients.
Depression occurs in approximately 50% of MS patients.It may either occur asa secondary reaction to living with a chronic, debilitating condition, or it may beembedded in a mood disorder such as bipolar disease. Treatment with the serotoninreuptake inhibitor, fluoxetine, in combination with 4-aminopyridine (4-AP), has demon-strated reduced levels of fatigue in MS patients. A link between fatigue and psychiatricillness, most commonly depression, has been suggested. The results are mixed, withsome reports finding no correlation and some finding strong correlation betweenpsychiatric illness and MS Many researchers strongly support the factthat timely identification and management of mood disorders are vital. Psychiatricillnesses are rarely the sole cause of fatigue.
Many MS patients with fatigue also complain of sleep disturbance. This may be
secondary to neuropathic pain, spasticity, or periodic limb movements. Obstructivesleep apnea should be ruled out as a contributing factor to fatigue. A significant corre-lation has been reported between fatigue and disrupted sleep or abnormal sleepcycles in MS patients.Additionally, a study compared the incidence among FrenchCanadians of restless leg movement (RLM) in 200 MS patients, 100 patients with rheu-matoid arthritis, and 100 NHAs. They reported that 37.5% of MS patients, 31% of RApatients, 16% of NHAs fulfilled criteria for A smaller study of 25 MS patientscompared to 25 normal healthy controls reported RLM in 36% of MS patients. In addi-tion, MS patients had reduced sleep efficiency and increased awakenings on 8-hourpolysomnography Studies in this area remain limited, and further researchis needed to gain a better understanding of the underlying mechanisms associatedwith MS sleep disturbance and fatigue. Surveillance of sleep quality is recommendedin MS patients with fatigue.
Other medical conditions can contribute to fatigue, and that should be evaluated.
Infections, either viral or bacterial, and, most commonly, urinary tract infections orupper respiratory infections can adversely affect energy levels in MS patients andworsen other symptoms such as spasticity and pain. Evaluation and exclusion ofthyroid, liver, and hematologic profile abnormalities are encouraged.
Several of the medications prescribed for symptomatic treatment in MS patients
can worsen fatigue. The clinician is encouraged to regularly review patients’ medica-tion lists for potential offenders. This includes antispasticity agents, antiepileptics,narcotics, or sedatives. Patients may report increased fatigue secondary to interferontreatment. The use of nonsteroidal anti-inflammatory drugs, such as naproxen oribuprofen, has demonstrated efficacy over acetaminophen and is encouraged beforeand after interferon injection for effective management of flu-like effects.
After ruling out primary and/or secondary causes of fatigue and deciding on treatment,it is important that the clinician’s approach to the treatment of fatigue be global,including pharmacologic and nonpharmacologic approaches. Nonpharmacologicapproaches include local cooling devices, energy management strategies (spacingout activities, performing strenuous activities during periods of increased energystores), behavioral/lifestyle modifications (good sleep hygiene, limiting alcohol intake,tobacco cessation), nutrition management, and rehabilitative interventions.
The effect of various neurorehabilitative interventions on fatigue has been investi-gated. Yoga and bicycling demonstrated reduced fatigue and improved quality oflife in MS An aerobic treadmill training program designed for MS patientsof varying degrees of disability, exercising at 55% to 85% of age-predicted maximumheart rate, did not worsen fatigue.Mathiowetz and colleaguesdeveloped anenergy conservation protocol for MS patients based on a model designed by Packerthat was created for patients living with chronic illness. The 6-week, 2 h/wk energyconservation course was taught to 79 MS patients with varying types and degreesof severity of MS and was found to reduce fatigue impact and increase self-efficacyand quality of life. The use of physical and occupational therapists is encouraged tohelp patients with assistive devices for activities of daily living (ADL), using correctbody mechanics, and assist with planning and time management to optimize energylevels.
Several medications have been found to be beneficial for reducing the severity offatigue. Acetyl-L-carnitine (ALC) is a cellular component with a vital role in energymetabolism. ALC has demonstrated effectiveness in fatigue reductions in manychronic fatigue syndrome patients and in cancer patients undergoing chemotherapy. It has also demonstrated decrease in fatigue in MS ALC is believed to havedirect neurotransmitter action in the brain and may play a role in the excitatory andinhibitory pathways.
Amantadine, a tricyclic amine, is more widely known for its antiviral effect. Its mech-
anism of action is not clear, though it has monoaminergic, cholinergic, and glutaminer-gic effects.Typical dosage is about 200 mg/d and is well tolerated. It significantlyreduced fatigue in a placebo-controlled trial in MS patients.When amantadinewas compared with supplemental ALC in a crossover trial, ALC demonstrated superiorefficacy and tolerance to amantadine.Side effects of amantadine include insomnia,ankle edema associated with livedo reticularis, and nervousness.
Potassium channel blockers, such as 3,4-AP and 4-AP, improve synaptic transmis-
sion and increase muscle twitch tension.Titration of the drug is recommended, withdoses ranging from 5 mg daily to 20 mg three times a day. Both 3,4 and 4-AP havedemonstrated improvement in fatigue, weakness, and ambulation.Side effectsinclude vertigo, anxiety, nausea, seizures, confusion, and loss of
The effect of aspirin (acetylsalicylic acid [ASA]) on fatigue has been studied in a small
double-blind, placebo-controlled study revealing modest benefit when dosed at 650mg twice a day.ASA irreversibly inhibits cyclooxygenase and blocks prostaglandinE2 production. Its effect on fatigue is believed to involve the HPA axis. Larger, long-term studies are recommended to further evaluate the benefit–risk profile.
Modafinil is Food and Drug Administration approved for use in persons with narco-
lepsy, obstructive sleep apnea, and shift workers. It is a central a-adrenergic agonist,acting in brain areas to increase wakefulness and increasing frontal lobe corticalactivity.The dosage ranges from 100 to 400 mg/d, and it is recommended that itshould not be given later than lunchtime to avoid symptoms of insomnia. It hasdemonstrated improvement in 1 study over placebo at 200 mg/day, but not at the400 mg/d dosage.Another rigorous study reported no benefit of modafinil overplacebo.Additional trials are warranted, as several patients report significant reliefof fatigue with modafinil. Side effects of modafinil include nervousness, headache,and nausea.
Prokarin is a histamine-caffeine combination in a transdermal cream. Histamine as
a therapeutic agent has been used in the treatment of Bell palsy, vasculitis, and Me-niere disease for several A 12-week, double-blind, placebo-controlled studyof Prokarin demonstrated reduction in the MFIS by 37%. Serum caffeine levels weresimilar in both groups; therefore, the authors conclude that the primary cause offatigue decrease was not caffeine intake alone. The cream was well tolerated, andside effects included skin rash and Calcium supplementation is recom-mended to avoid increased stiffness.
In summary, MS-related fatigue can be a severe problem causing interference withhome and vocational activities. There are multiple factors that can contribute to fatiguein MS, and it is important for the patient, family, and clinician to be aware of potentialconfounders that may worsen fatigue. Clearer understanding about the etiology offatigue is necessary. Additional larger, randomized, clinical trials are needed to eval-uate etiology, pathophysiology, and both pharmacologic and nonpharmacologic inter-ventions. Given the varying nature of fatigue and the limited evidence that fatigue inMS patients is highly dependent on self-perceived scores, additional research intothe effect of psychosocial and psychological interventions is recommended. A multi-disciplinary approach to fatigue is encouraged when treatments are considered formaximum benefit.
The author thanks Dr. Ian B. Maitin for his editorial comments on the manuscript.
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Editorial Introduction Suppose a table of data concerning three variables x , y and z is given, forexample:If we look at the values of x and y we may observe that when x is thesame also y is the same. The converse is not true: y can be the same ona row without x being the same. In the light of this data we say that yfunctionally depends on x but not conversely. If the conc