All About Multiple Sclerosis

More MS news articles for November 2003

Fatigue and Multiple Sclerosis

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.[15] Additional evidence of the impact of MS fatigue is the negative effect on employment[13]; 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[16] 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[17] 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.[17] However, MS fatigue may be partially related to depression[4, 18-20]; Bakshi and associates[4] 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[21] 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[23] 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[24] 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.[4] Moreover, some neuromuscular disorders are associated with muscle weakness without generalized fatigue.[28] 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.[28] 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.

Nonpharmacologic Therapies

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[29] 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.[30] Reduction of overheating includes simple strategies but also the use of external devices. Flensner and associates[31] 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.

Pharmacologic Strategies

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.[43]

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.[37] 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.[38] A 3-month, 2-center, open-label trial of 50 patients also showed a benefit of modafinil on fatigue severity.[39] 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,[43]Prokarin use led to improved fatigue scores vs placebo. Further evaluation of this agent awaits larger studies.


  1. Bakshi R. Fatigue associated with multiple sclerosis: diagnosis, impact and management. Mult Scler. 2003;9:219-227. Abstract
  2. Krupp LB. Fatigue in multiple sclerosis: definition, pathophysiology and treatment. CNS Drugs. 2003;17:225-234. Abstract
  3. Schwid SR, Covington M, Segal BM, Goodman AD. Fatigue in multiple sclerosis: current understanding and future directions. J Rehabil Res Dev. 2002;39:211-224. Abstract
  4. Bakshi R, Shaikh ZA, Miletich RS, et al. Fatigue in multiple sclerosis and its relationship to depression and neurologic disability. Mult Scler. 2000;6:181-185. Abstract
  5. Freal JE, Kraft GH, Coryell JK. Symptomatic fatigue in multiple sclerosis. Arch Phys Med Rehabil. 1984;65:135-138. Abstract
  6. Murray TJ. Amantadine therapy for fatigue in multiple sclerosis. Can J Neurol Sci. 1985;12:251-254. Abstract
  7. Krupp LB, Alvarez LA, LaRocca NG, Scheinberg LC. Fatigue in multiple sclerosis. Arch Neurol. 1988;45:435-437. Abstract
  8. Bergamaschi R, Romani A, Versino M, Poli R, Cosi V. Clinical aspects of fatigue in multiple sclerosis. Funct Neurol. 1997;12:247-251. Abstract
  9. Fisk JD, Pontefract A, Ritvo PG, Archibald CJ, Murray TJ. The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci. 1994;21:9-14. Abstract
  10. Janardhan V, Bakshi R. Quality of life in patients with multiple sclerosis: the impact of fatigue and depression. J Neurol Sci. 2002;205:51-58. Abstract
  11. Merkelbach S, Sittinger H, Koenig J. Is there a differential impact of fatigue and physical disability on quality of life in multiple sclerosis? J Nerv Ment Dis. 2002;190:388-393.
  12. Amato MP, Ponziani G, Rossi F, Liedl CL, Stefanile C, Rossi L. Quality of life in multiple sclerosis: the impact of depression, fatigue and disability. Mult Scler. 2001;7:340-344. Abstract
  13. Schwartz CE, Coultard-Morris L, Zeng Q. Psychosocial correlates of fatigue in multiple sclerosis. Arch Phys Med Rehabil. 1996;77:165-170. Abstract
  14. Ritvo PG, Fisk JD, Archibald CJ, Murray TJ, Field C. Psychosocial and neurologic predictors of mental health in multiple sclerosis patients. J Clin Epidemiol. 1996;49:467-472. Abstract
  15. Krupp LB, Elkins LE. Fatigue and declines in cognitive functioning in multiple sclerosis. Neurology. 2000;55:934-939. Abstract
  16. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale: application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989;46:1121-1123. Abstract
  17. Giovannoni G, Thompson AJ, Miller DH, Thompson EJ Fatigue is not associated with raised inflammatory markers in multiple sclerosis. Neurology. 2001;57:676-681. Abstract
  18. Flachenecker P, Kumpfel T, Kallmann B, et al. Fatigue in multiple sclerosis: a comparison of different rating scales and correlation to clinical parameters. Mult Scler. 2002;8:523-526 . Abstract
  19. van der Werf SP, Evers A, Jongen PJ, Bleijenberg G. The role of helplessness as mediator between neurological disability, emotional instability, experienced fatigue and depression in patients with multiple sclerosis. Mult Scler. 2003;9:89-94. Abstract
  20. Mohr DC, Hart SL, Goldberg A. Effects of treatment for depression on fatigue in multiple sclerosis. Psychosom Med. 2003;65:542-547. Abstract
  21. Bakshi R, Miletich RS, Kinkel PR, Emmet ML, Kinkel WR. High-resolution fluorodeoxyglucose positron emission tomography shows both global and regional cerebral hypometabolism in multiple sclerosis. J Neuroimaging. 1998;8:228-234. Abstract
  22. Blinkenberg M, Rune K, Jensen CV, et al. Cortical cerebral metabolism correlates with MRI lesion load and cognitive dysfunction in MS. Neurology. 2000;54:558-564. Abstract
  23. Roelcke U, Kappos L, Lechner-Scott J, et al. Reduced glucose metabolism in the frontal cortex and basal ganglia of multiple sclerosis patients with fatigue: a 18F-fluorodeoxyglucose positron emission tomography study. Neurology. 1997;48:1566-1571. Abstract
  24. Filippi M, Rocca MA, Colombo B, et al. Functional magnetic resonance imaging correlates of fatigue in multiple sclerosis Neuroimage 2002;15:559-567.
  25. Bakshi R, Miletich RS, Henschel K, et al. Fatigue in multiple sclerosis: cross-sectional correlation with brain MRI findings in 71 patients. Neurology. 1999;53:1151-1153. Abstract
  26. Mainero C, Faroni J, Gasperini C, et al. Fatigue and magnetic resonance imaging activity in multiple sclerosis. J Neurol. 1999;246:454-458. Abstract
  27. Codella M, Rocca MA, Colombo B, Rossi P, Comi G, Filippi M. A preliminary study of magnetization transfer and diffusion tensor MRI of multiple sclerosis patients with fatigue. J Neurol. 2002;249:535-537. Abstract
  28. Chaudhuri A, Behan PO. Fatigue and basal ganglia. J Neurol Sci. 2000;179(suppl 1, pt2):34-42.
  29. Mostert S, Kesselring J. Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis. Mult Scler. 2002;8:161-168. Abstract
  30. Petajan JH, White AT. Recommendations for physical activity in patients with multiple sclerosis. Sports Med. 1999;27:179-191. Abstract
  31. Flensner G, Lindencrona C. The cooling-suit: case studies of its influence on fatigue among eight individuals with multiple sclerosis. J Adv Nurs. 2002;37:541-550. Abstract
  32. The Canadian MS Research Group. A randomized controlled trial of amantadine in fatigue associated with multiple sclerosis. Can J Neurol Sci. 1987;14:273-278. Abstract
  33. Krupp LB, Coyle PK, Doscher C, et al. Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology. 1995;45:1956-1961. Abstract
  34. Cohen RA, Fisher M. Amantadine treatment of fatigue associated with multiple sclerosis. Arch Neurol. 1989;46:676-680. Abstract
  35. Rosenberg GA, Appenzeller O. Amantadine, fatigue, and multiple sclerosis. Arch Neurol. 1988;45:1104-1106. Abstract
  36. Weinshenker BG, Penman M, Bass B, Ebers GC, Rice GPA. A double-blind, randomized crossover trial of pemoline in fatigue associated with multiple sclerosis. Neurology. 1992;42:1468-1471. Abstract
  37. Cylert [package insert]. East Chicago, Illinois: Abbott Laboratories; 1999.
  38. Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two-centre phase 2 study. J Neurol Neurosurg Psychiatry. 2002;72:179-183. Abstract
  39. Zifko UA, Rupp M, Schwarz S, Zipko HT, Maida EM. Modafinil in treatment of fatigue in multiple sclerosis. Results of an open-label study. J Neurol. 2002;249:983-987. Abstract
  40. Rossini PM, Pasqualetti P, Pozzilli C, et al. Fatigue in progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, crossover trial of oral 4-aminopyridine. Mult Scler. 2001;7:354-358. Abstract
  41. Schwid SR, Petrie MD, McDermott MP, Tierney DS, Mason DH, Goodman AD. Quantitative assessment of sustained-release 4-aminopyridine for symptomatic treatment of multiple sclerosis. Neurology. 1997;48:817-821. Abstract
  42. Sheean GL, Murray NM, Rothwell JC, Miller DH, Thompson AJ. An open-labelled clinical and electrophysiological study of 3,4 diaminopyridine in the treatment of fatigue in multiple sclerosis. Brain. 1998;121:967-975. Abstract
  43. Gillson G, Richard TL, Smith RB, Wright JV. A double-blind pilot study of the effect of Prokarin on fatigue in multiple sclerosis. Mult Scler. 2002;8:30-35. Abstract

Copyright © 2003, Medscape