CNS Drugs

, Volume 17, Issue 4, pp 225–234 | Cite as

Fatigue in Multiple Sclerosis

Definition, Pathophysiology and Treatment
  • Lauren B. Krupp
Therapy in Practice


Fatigue is a common disabling symptom of multiple sclerosis (MS). It is often considered a state of exhaustion distinct from depressed mood or physical weakness. Fatigue can be assessed by either self-report scales or performance-based measures; however, neither method captures all features of fatigue. Fatigue in MS frequently leads to unemployment. It is associated with a sense of loss of control over one’s environment, low positive affect, psychological distress and neurological impairment. To date there is no reproducible neuroimaging marker or biological correlate that has been identified.

Proposed pathological mechanisms of fatigue in MS include neuronal factors such as dysfunction of premotor, limbic, basal ganglia or hypothalamic areas; disruption of the neuroendrocrine axis leading to low arousal; alteration in serotoninergic pathways; changes in neurotransmitter levels; and altered CNS functioning caused by a disruption of the immune response.

Treatment of fatigue is best approached in a multidisciplinary fashion that incorporates nonpharmacological interventions as well as medication. Amantadine and modafinil are among the most commonly used medications for fatigue associated with MS. Both medications have been studied with positive results in controlled clinical trials. Additional research towards measurement and pathogenesis of fatigue will hopefully lead to improved therapies.


Multiple Sclerosis Multiple Sclerosis Patient Chronic Fatigue Syndrome Expand Disability Status Scale Amantadine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Parts of this review are based on the chapter ‘Fatigue in MS’ by Dr Krupp, published in the following book: Rudick RA, Cohen J, editors. Multiple sclerosis: experimental and applied therapeutics. 2nd ed. London: Martin Dunitz, 2003. The author received honoraria from Cephalon Inc., TevaNeurosciences, Biogen, Berlex and Serono. No funding was used to assist in the preparation of this manuscript.


  1. 1.
    Freal JE, Kraft GH, Coryell JK. Symptomatic fatigue in multiple sclerosis. Arch Phys Med Rehabil 1984; 65: 135–8PubMedGoogle Scholar
  2. 2.
    Krupp LB, Alvarez LA, LaRocca NG, et al. Fatigue in multiple sclerosis. Arch Neurol 1988; 45(4): 435–7PubMedCrossRefGoogle Scholar
  3. 3.
    Krupp LB, LaRocca NG, Muir-Nash J, et al. The fatigue severity scale: application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989; 46(10): 1121–3PubMedCrossRefGoogle Scholar
  4. 4.
    Monks J. Experiencing symptoms in chronic illness: fatigue in multiple sclerosis. Int Disabil Stud 1989; 11(2): 78–83PubMedCrossRefGoogle Scholar
  5. 5.
    Edgely K, Sullivan MJL, Dehoux E. A survey of multiple sclerosis. Pt 2: determinants of employment status. Can J Rehab 1991; 4: 127–32Google Scholar
  6. 6.
    Fisk JD, Pontefract A, Ritvo PG, et al. The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci 1994; 21: 9–14PubMedGoogle Scholar
  7. 7.
    Kroencke DC, Lynch SG, Denney DR. Fatigue in multiple sclerosis: relationship to depression, disability, and disease pattern. Mult Scler 2000; 6: 131–6PubMedGoogle Scholar
  8. 8.
    Bakshi R, Shaikh ZA, Miletich RS, et al. Fatigue in multiple sclerosis and its relationship to depression and neurologic disability. Mult Scler 2000; 6: 181–5PubMedGoogle Scholar
  9. 9.
    Krupp LB, Elkins LE. Fatigue and declines in cognitive functioning in multiple sclerosis. Neurology 2000; 55: 934–9PubMedCrossRefGoogle Scholar
  10. 10.
    Elkins LE, Krupp LB. The measurement of fatigue and contributing neuropsychiatric factors. Semin Clin Neuropsychiatry 2000; 5: 58–61PubMedGoogle Scholar
  11. 11.
    Schwid SR, Thornton CA, Pandya KL, et al. Quantitative assessment of motor fatigue and strength in MS. Neurology 1999; 53: 743–50PubMedCrossRefGoogle Scholar
  12. 12.
    Comi G, Leocani L, Rossi P, et al. Physiopathology and treatment of fatigue in multiple sclerosis. J Neurol 2001; 248: 174–9PubMedCrossRefGoogle Scholar
  13. 13.
    Giovannoni G, Thompson AJ, Miller DH, et al. Fatigue is not associated with raised inflammatory markers in multiple sclerosis. Neurology 2001; 57: 676–81PubMedCrossRefGoogle Scholar
  14. 14.
    Patten SB, Metz LM. Fatigue and depression in multiple sclerosis. Can J Psychiatry 2000; 45: 84–5PubMedGoogle Scholar
  15. 15.
    Multiple Sclerosis Council for Clinical Practice Guidelines. Fatigue and multiple sclerosis: evidence-based management strategies for fatigue in multiple sclerosis. Washington,DC: Paralyzed Veterans of America, 1998Google Scholar
  16. 16.
    Iriarte J, Katsamakis G, De Castro P. The fatigue descriptive scale (FDS): a useful tool to evaluate fatigue in multiple sclerosis. Mult Scler 1999; 5: 10–6PubMedGoogle Scholar
  17. 17.
    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: 1151–3PubMedCrossRefGoogle Scholar
  18. 18.
    Krupp LB, Soefer MH, Pollina DA, et al. Fatigue measures for clinical trials in multiple sclerosis. Neurology 1998; 126: 50–1Google Scholar
  19. 19.
    Taylor RR, Jason LA, Torres A. Fatigue rating scales: an empirical comparison. Psychol Med 2000; 30: 849–56PubMedCrossRefGoogle Scholar
  20. 20.
    Rammohan KW, Rosenberg JH, Lynn DJ, et al. Efficacy and safety of modafinil (Provigil®) for the treatment of fatigue in multiple sclerosis: a two center phase 2 study. J Neurol Neurosurg Psychiatry 2002; 72: 179–83PubMedCrossRefGoogle Scholar
  21. 21.
    Sheean G, Murray N, Rothwell J, et al. An open labeled clinical and electrophysiological study of 3,4 diaminopyridine in the treatment of fatigue in multiple sclerosis. Brain 1998; 121: 967–75PubMedCrossRefGoogle Scholar
  22. 22.
    Kleinman L, Zodet M, Hakim Z, et al. Psychometric evaluation of the Fatigue Severity Scale for use in chronic hepatitis C. Qual Life Res 2000; 9: 499–508PubMedCrossRefGoogle Scholar
  23. 23.
    Krupp LB. Fatigue in MS. In: Rudick RA, Cohen J, editors. Multiple sclerosis: experimental and applied therapeutics. 2nd ed. London: Martin Dunitz, 2003: 599–608Google Scholar
  24. 24.
    Belza BL, Henke CJ, Yelin EH, et al. Correlates of fatigue in older women with rheumatoid arthritis. Nurs Res 1993; 42: 93–9PubMedCrossRefGoogle Scholar
  25. 25.
    Vercoulen J, Hommes OR, Swanink C, et al. The measurement of fatigue in patients with multiple sclerosis: a multidimensional comparison with patients with chronic fatigue syndrome and healthy subjects. Arch Neurol 1996; 53: 642–9PubMedCrossRefGoogle Scholar
  26. 26.
    Smets EMA, Garssen B, Bonke B, et al. The multidimensional fatigue inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res 1995; 39: 315–25PubMedCrossRefGoogle Scholar
  27. 27.
    Schwartz J, Jandorf L, Krupp LB. The measurement of fatigue: a new scale. J Psychosom Res 1993; 37: 753–62PubMedCrossRefGoogle Scholar
  28. 28.
    Chalder T, Berelowitz G, Pawlikowska T, et al. Development of a fatigue scale. J Psychosom Res 1993; 37: 147–53PubMedCrossRefGoogle Scholar
  29. 29.
    McNair DM, Lorr M, Droppleman LF. Profile of Mood States (POMS). San Diego (CA): Educational and Industrial Testing Service, 1992Google Scholar
  30. 30.
    Cella DF, Dineen K, Arnason B, et al. Validation of the functional assessment of multiple sclerosis (FAMS): quality of life instrument. Neurology 1996; 47: 129–39PubMedCrossRefGoogle Scholar
  31. 31.
    Ware JE, Kosinski M, Keller SD. SF-36 physical and mental health summary scales: a user’s manual. Boston (MA): The Health Institute,New England Medical Center, 1994Google Scholar
  32. 32.
    Djaldetti R, Ziv I, Achiron A, et al. Fatigue in multiple sclerosis compared with chronic fatigue syndrome: a quantitative assessment. Neurology 1996; 46: 632–5PubMedCrossRefGoogle Scholar
  33. 33.
    Kent-Braun JA, Sharma KR, Miller RG, et al. Post exercise phosphocreatine resynthesis is slowed in multiple sclerosis. Muscle Nerve 1994; 17: 835–41PubMedCrossRefGoogle Scholar
  34. 34.
    Kujala P, Portin R, Reconsuo A, et al. Attention related performance in two cognitively different subgroups of patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 1995; 59: 77–82PubMedCrossRefGoogle Scholar
  35. 35.
    Sheean GL, Murray MF, Rothwell SG. An electrophysiologic study of the mechanism of fatigue in MS. Brain 1997; 120: 299–316PubMedCrossRefGoogle Scholar
  36. 36.
    Paul RH, Beatty WW, Schneider R, et al. Cognitive and physical fatigue in multiple sclerosis: relations between self-report and objective performance. Appl Neuropsychol 1998; 5: 143–8PubMedCrossRefGoogle Scholar
  37. 37.
    Colombo B, Martinelli Boneschi F, Rossi P, et al. MRI and motor evoked potential findings in no disabled multiple sclerosis patients with and without symptoms of fatigue. J Neurol 2000; 247: 506–9PubMedCrossRefGoogle Scholar
  38. 38.
    Fuhrer R, Wessely S. The epidemiology of fatigue and depression: a French primary-care study. Psychol Med 1995; 25: 895–905PubMedCrossRefGoogle Scholar
  39. 39.
    Elkins LE, Pollina DA, Scheffer S, et al. Psychological states and neuropsychological performances in chronic Lyme disease. Appl Neuropsychol 1999; 6: 19–26PubMedCrossRefGoogle Scholar
  40. 40.
    Pepper C, Krupp LB, Friedberg F, et al. Comparison of psychiatric characteristics in chronic fatigue syndrome, multiple sclerosis and depression. J Neuropsychiatry Clin Neurosci 1993; 5: 1–7Google Scholar
  41. 41.
    Bergamaschi R, Romani A, Versino M, et al. Clinical aspects of fatigue in multiple sclerosis. Funct Neurol 1997; 12(5): 247–51PubMedGoogle Scholar
  42. 42.
    Ford H, Trigwell P, Johnson M. The nature of fatigue in multiple sclerosis. J Psychosom Res 1998; 45: 33–8PubMedCrossRefGoogle Scholar
  43. 43.
    Schwartz CE, Coulthard-Morris L, Zeng Q. Psychosocial correlates of fatigue in multiple sclerosis. Arch Phys Med Rehabil 1996; 77: 165–70PubMedCrossRefGoogle Scholar
  44. 44.
    Krupp LB, Christodoulou C, Madigan D, et al. The use of interferon-ß-1a (Avonex) and modafinil to evaluate and treat cytokine-induced fatigue in multiple sclerosis [abstract]. Ann Neurol 2002; 52(3 Suppl. 1): S87Google Scholar
  45. 45.
    Marshall PS, Watson D, Steinberg P, et al. An assessment of cognitive function and mood in chronic fatigue syndrome. Biol Psychol 1996; 39: 199–206CrossRefGoogle Scholar
  46. 46.
    Colosimo C, Millefiorini E, Grasso MG, et al. Fatigue in MS is associated with specific clinical features. Acta Neurol Scand 1995; 2: 353–5Google Scholar
  47. 47.
    Janardhan V, Bakshi R. Quality of life and its relationship to brain lesions and atrophy on magnetic resonance images in 60 patients with multiple sclerosis. Arch Neurol 2000; 57: 1485–91PubMedCrossRefGoogle Scholar
  48. 48.
    van der Werf SP, Jongen PJ, Lycklama a Nijeholt GJ, et al. Fatigue in multiple sclerosis: interrelations between fatigue complaints, cerebral MRI abnormalities and neurological disability. J Neurol Sci 1998; 160: 164–70PubMedCrossRefGoogle Scholar
  49. 49.
    Mainero C, Faroni J, Gasperini C, et al. Fatigue and magnetic resonance imaging activity in multiple sclerosis. J Neurol 1999; 246: 454–8PubMedCrossRefGoogle Scholar
  50. 50.
    Geisler MW, Sliwinski M, Coyle PK, et al. The effects of amantadine and pemoline on cognitive functioning in multiple sclerosis. Arch Neurol 1996; 53: 185–8PubMedCrossRefGoogle Scholar
  51. 51.
    Sailer M, Heinze HJ, Schoenfeld MA, et al. Amantadine influences cognitive processing in patients with multiple sclerosis. Pharmacopsychiatry 2000; 33(1): 28–37PubMedCrossRefGoogle Scholar
  52. 52.
    Bohr KC, Haas J. Sleep related breathing disorders do not explain daytime fatigue in multiple sclerosis [abstract]. Mult Scler 1998; 4: 289aCrossRefGoogle Scholar
  53. 53.
    Quesada JR, Talpax M, Rios A, et al. Clinical toxicity of interferons in cancer patients: a review. J Clin Oncol 1986; 4: 234–43PubMedGoogle Scholar
  54. 54.
    Neilly LK, Goodin DS, Goodkin DE, et al. Side effect profile of interferon beta-1b in MS: results of an open label trial. Neurology 1996; 46: 552–4CrossRefGoogle Scholar
  55. 55.
    Iriarte J, Subira ML, Castro P. Modalities of fatigue in multiple sclerosis: correlation with clinical and biological factors. Mult Scler 2000 Apr; 6(2): 124–30PubMedCrossRefGoogle Scholar
  56. 56.
    Wei T, Lightman SL. The neuroendocrine axis in patients with multiple sclerosis. Brain 1997; 120: 1067–76PubMedCrossRefGoogle Scholar
  57. 57.
    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-fluorodeoxyglucosepositron emission tomographic study. Neurology 1997; 48: 1566–71PubMedCrossRefGoogle Scholar
  58. 58.
    Heilman KM, Watson RT. Fatigue. Neurol Network Comment 1997; 1: 283–7Google Scholar
  59. 59.
    Sandroni P, Walker C, Starr A. Fatigue in patients with multiple sclerosis: motor pathway conduction and event-related potentials. Arch Neurol 1992; 49: 517–24PubMedCrossRefGoogle Scholar
  60. 60.
    Brasil-Neto JP, Cohen LG, Hallet M. Central fatigue as revealed by postexercise decrement of motor evoked potentials. Muscle Nerve 1994; 17: 713–9PubMedCrossRefGoogle Scholar
  61. 61.
    Sharma KR, Kent-Braun J, Mynhier MA, et al. Evidence of abnormal intramuscular component of fatigue in multiple sclerosis. Muscle Nerve 1995; 18: 1403–11PubMedCrossRefGoogle Scholar
  62. 62.
    Filippi M, Rocca MA, Colombo B, et al. Functional magnetic resonance imaging correlates of fatigue in multiple sclerosis. Neuroimage 2002; 15: 559–67PubMedCrossRefGoogle Scholar
  63. 63.
    Beck AT, Ward CH, Mendelson M. An inventory for measuring depression. Arch Gen Psych 1961; 4: 561–71CrossRefGoogle Scholar
  64. 64.
    Radloff LS. CES-D scale: a self-report depression scale for research in the general population. Appl Psychol Meas 1977; 1: 385–401CrossRefGoogle Scholar
  65. 65.
    Mohr DC, Goodkin DE, Likosky W, et al. Identification of Beck depression inventory items related to multiple sclerosis. J Behav Med 1997; 20: 407–14PubMedCrossRefGoogle Scholar
  66. 66.
    Petajan JH, Gappmaier E, White AT, et al. Impact of aerobic training on fitness and quality of life in multiple sclerosis. Ann Neurol 1996; 39: 432–41PubMedCrossRefGoogle Scholar
  67. 67.
    Beenakker E, Oparina T, Hartgring A, et al. Cooling garment treatment in ms: clinical improvement and decrease in leukocyte no production. Neurology 2001; 57: 892–4PubMedCrossRefGoogle Scholar
  68. 68.
    Di Fabio RP, Soderberg J, Choi T, et al. Extended outpatient rehabilitation: its influence on symptom frequency, fatigue, and functional status for persons with progressive multiple sclerosis. Arch Phys Med Rehabil 1998; 79: 141–6PubMedCrossRefGoogle Scholar
  69. 69.
    Deale A, Chalder T, Marks I, et al. Cognitive behavior therapy for chronic fatigue syndrome: a randomized controlled trial. Am J Psychiatry 1997; 154: 408–14PubMedGoogle Scholar
  70. 70.
    Friedberg F, Krupp LB. A comparison of cognitive behavioral treatment of chronic fatigue syndrome and primary depression. Clin Infect Dis 1994; 18: 105–10CrossRefGoogle Scholar
  71. 71.
    Butlers,Chalder T, Ron M, et al. Cognitive behaviour therapy in CFS. J Neurol Neurosurg Psychiatry 1991; 54: 153–8CrossRefGoogle Scholar
  72. 72.
    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: 1956–61PubMedCrossRefGoogle Scholar
  73. 73.
    Murray TJ. Amantadine therapy forfatigue in multiple sclerosis. Can J Neurol Sci 1985; 12: 251–4PubMedGoogle Scholar
  74. 74.
    Canadian MS Research Group. A randomized controlled trial of amantadine in fatigue associated with multiple sclerosis. Can J Neurol Sci 1987; 14: 273–8Google Scholar
  75. 75.
    Weinshenker BG, Penman M, Bass B. A double-blind, randomized, crossover trial of pemoline in fatigue associated with multiple sclerosis. Neurology 1992; 42: 1468–71PubMedCrossRefGoogle Scholar
  76. 76.
    Polman CH, Bertelsmann FW, van Loenen AC, et al. 4-Aminopyridine in the treatment of patients with multiple sclerosis. Arch Neurol 1994; 51: 292–6PubMedCrossRefGoogle Scholar
  77. 77.
    Latash M, Kalugina E, Orpett NJ, et al. Myogenic and central neurogenic factors in fatigue in multiple sclerosis. Mult Scler 1996; 1: 236–41PubMedGoogle Scholar
  78. 78.
    Wingerchuk DM, Benarroch EE, O’Brien PC, et al. Aspirin for multiple sclerosis-related fatigue: results of a double-blind, placebo-controlled study [abstract]. Neurology 2002; 58Suppl. 3: A492Google Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  • Lauren B. Krupp
    • 1
  1. 1.Department of NeurologyState University of New York at Stony BrookStony Brook, New YorkUSA

Personalised recommendations