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Fatigue in Multiple Sclerosis

Definition, Pathophysiology and Treatment

  • Therapy in Practice
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Abstract

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.

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References

  1. Freal JE, Kraft GH, Coryell JK. Symptomatic fatigue in multiple sclerosis. Arch Phys Med Rehabil 1984; 65: 135–8

    PubMed  CAS  Google Scholar 

  2. Krupp LB, Alvarez LA, LaRocca NG, et al. Fatigue in multiple sclerosis. Arch Neurol 1988; 45(4): 435–7

    Article  PubMed  CAS  Google Scholar 

  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): 1121–3

    Article  PubMed  CAS  Google Scholar 

  4. Monks J. Experiencing symptoms in chronic illness: fatigue in multiple sclerosis. Int Disabil Stud 1989; 11(2): 78–83

    Article  PubMed  CAS  Google Scholar 

  5. Edgely K, Sullivan MJL, Dehoux E. A survey of multiple sclerosis. Pt 2: determinants of employment status. Can J Rehab 1991; 4: 127–32

    Google Scholar 

  6. Fisk JD, Pontefract A, Ritvo PG, et al. The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci 1994; 21: 9–14

    PubMed  CAS  Google Scholar 

  7. Kroencke DC, Lynch SG, Denney DR. Fatigue in multiple sclerosis: relationship to depression, disability, and disease pattern. Mult Scler 2000; 6: 131–6

    PubMed  CAS  Google Scholar 

  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: 181–5

    PubMed  CAS  Google Scholar 

  9. Krupp LB, Elkins LE. Fatigue and declines in cognitive functioning in multiple sclerosis. Neurology 2000; 55: 934–9

    Article  PubMed  CAS  Google Scholar 

  10. Elkins LE, Krupp LB. The measurement of fatigue and contributing neuropsychiatric factors. Semin Clin Neuropsychiatry 2000; 5: 58–61

    PubMed  CAS  Google Scholar 

  11. Schwid SR, Thornton CA, Pandya KL, et al. Quantitative assessment of motor fatigue and strength in MS. Neurology 1999; 53: 743–50

    Article  PubMed  CAS  Google Scholar 

  12. Comi G, Leocani L, Rossi P, et al. Physiopathology and treatment of fatigue in multiple sclerosis. J Neurol 2001; 248: 174–9

    Article  PubMed  CAS  Google Scholar 

  13. Giovannoni G, Thompson AJ, Miller DH, et al. Fatigue is not associated with raised inflammatory markers in multiple sclerosis. Neurology 2001; 57: 676–81

    Article  PubMed  CAS  Google Scholar 

  14. Patten SB, Metz LM. Fatigue and depression in multiple sclerosis. Can J Psychiatry 2000; 45: 84–5

    PubMed  CAS  Google Scholar 

  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, 1998

    Google Scholar 

  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: 10–6

    PubMed  CAS  Google Scholar 

  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: 1151–3

    Article  PubMed  CAS  Google Scholar 

  18. Krupp LB, Soefer MH, Pollina DA, et al. Fatigue measures for clinical trials in multiple sclerosis. Neurology 1998; 126: 50–1

    Google Scholar 

  19. Taylor RR, Jason LA, Torres A. Fatigue rating scales: an empirical comparison. Psychol Med 2000; 30: 849–56

    Article  PubMed  CAS  Google Scholar 

  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: 179–83

    Article  PubMed  CAS  Google Scholar 

  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: 967–75

    Article  PubMed  Google Scholar 

  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: 499–508

    Article  PubMed  CAS  Google Scholar 

  23. Krupp LB. Fatigue in MS. In: Rudick RA, Cohen J, editors. Multiple sclerosis: experimental and applied therapeutics. 2nd ed. London: Martin Dunitz, 2003: 599–608

    Google Scholar 

  24. Belza BL, Henke CJ, Yelin EH, et al. Correlates of fatigue in older women with rheumatoid arthritis. Nurs Res 1993; 42: 93–9

    Article  PubMed  CAS  Google Scholar 

  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: 642–9

    Article  PubMed  CAS  Google Scholar 

  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: 315–25

    Article  PubMed  CAS  Google Scholar 

  27. Schwartz J, Jandorf L, Krupp LB. The measurement of fatigue: a new scale. J Psychosom Res 1993; 37: 753–62

    Article  PubMed  CAS  Google Scholar 

  28. Chalder T, Berelowitz G, Pawlikowska T, et al. Development of a fatigue scale. J Psychosom Res 1993; 37: 147–53

    Article  PubMed  CAS  Google Scholar 

  29. McNair DM, Lorr M, Droppleman LF. Profile of Mood States (POMS). San Diego (CA): Educational and Industrial Testing Service, 1992

    Google Scholar 

  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: 129–39

    Article  PubMed  CAS  Google Scholar 

  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, 1994

    Google Scholar 

  32. Djaldetti R, Ziv I, Achiron A, et al. Fatigue in multiple sclerosis compared with chronic fatigue syndrome: a quantitative assessment. Neurology 1996; 46: 632–5

    Article  PubMed  CAS  Google Scholar 

  33. Kent-Braun JA, Sharma KR, Miller RG, et al. Post exercise phosphocreatine resynthesis is slowed in multiple sclerosis. Muscle Nerve 1994; 17: 835–41

    Article  PubMed  CAS  Google Scholar 

  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: 77–82

    Article  PubMed  CAS  Google Scholar 

  35. Sheean GL, Murray MF, Rothwell SG. An electrophysiologic study of the mechanism of fatigue in MS. Brain 1997; 120: 299–316

    Article  PubMed  Google Scholar 

  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: 143–8

    Article  PubMed  CAS  Google Scholar 

  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: 506–9

    Article  PubMed  CAS  Google Scholar 

  38. Fuhrer R, Wessely S. The epidemiology of fatigue and depression: a French primary-care study. Psychol Med 1995; 25: 895–905

    Article  PubMed  CAS  Google Scholar 

  39. Elkins LE, Pollina DA, Scheffer S, et al. Psychological states and neuropsychological performances in chronic Lyme disease. Appl Neuropsychol 1999; 6: 19–26

    Article  PubMed  CAS  Google Scholar 

  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: 1–7

    Google Scholar 

  41. Bergamaschi R, Romani A, Versino M, et al. Clinical aspects of fatigue in multiple sclerosis. Funct Neurol 1997; 12(5): 247–51

    PubMed  CAS  Google Scholar 

  42. Ford H, Trigwell P, Johnson M. The nature of fatigue in multiple sclerosis. J Psychosom Res 1998; 45: 33–8

    Article  PubMed  CAS  Google Scholar 

  43. Schwartz CE, Coulthard-Morris L, Zeng Q. Psychosocial correlates of fatigue in multiple sclerosis. Arch Phys Med Rehabil 1996; 77: 165–70

    Article  PubMed  CAS  Google Scholar 

  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): S87

    Google Scholar 

  45. Marshall PS, Watson D, Steinberg P, et al. An assessment of cognitive function and mood in chronic fatigue syndrome. Biol Psychol 1996; 39: 199–206

    Article  CAS  Google Scholar 

  46. Colosimo C, Millefiorini E, Grasso MG, et al. Fatigue in MS is associated with specific clinical features. Acta Neurol Scand 1995; 2: 353–5

    Google Scholar 

  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: 1485–91

    Article  PubMed  CAS  Google Scholar 

  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: 164–70

    Article  PubMed  Google Scholar 

  49. Mainero C, Faroni J, Gasperini C, et al. Fatigue and magnetic resonance imaging activity in multiple sclerosis. J Neurol 1999; 246: 454–8

    Article  PubMed  CAS  Google Scholar 

  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: 185–8

    Article  PubMed  CAS  Google Scholar 

  51. Sailer M, Heinze HJ, Schoenfeld MA, et al. Amantadine influences cognitive processing in patients with multiple sclerosis. Pharmacopsychiatry 2000; 33(1): 28–37

    Article  PubMed  CAS  Google Scholar 

  52. Bohr KC, Haas J. Sleep related breathing disorders do not explain daytime fatigue in multiple sclerosis [abstract]. Mult Scler 1998; 4: 289a

    Article  Google Scholar 

  53. Quesada JR, Talpax M, Rios A, et al. Clinical toxicity of interferons in cancer patients: a review. J Clin Oncol 1986; 4: 234–43

    PubMed  CAS  Google Scholar 

  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: 552–4

    Article  Google Scholar 

  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): 124–30

    Article  PubMed  CAS  Google Scholar 

  56. Wei T, Lightman SL. The neuroendocrine axis in patients with multiple sclerosis. Brain 1997; 120: 1067–76

    Article  PubMed  Google Scholar 

  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: 1566–71

    Article  PubMed  CAS  Google Scholar 

  58. Heilman KM, Watson RT. Fatigue. Neurol Network Comment 1997; 1: 283–7

    Google Scholar 

  59. Sandroni P, Walker C, Starr A. Fatigue in patients with multiple sclerosis: motor pathway conduction and event-related potentials. Arch Neurol 1992; 49: 517–24

    Article  PubMed  CAS  Google Scholar 

  60. Brasil-Neto JP, Cohen LG, Hallet M. Central fatigue as revealed by postexercise decrement of motor evoked potentials. Muscle Nerve 1994; 17: 713–9

    Article  PubMed  CAS  Google Scholar 

  61. Sharma KR, Kent-Braun J, Mynhier MA, et al. Evidence of abnormal intramuscular component of fatigue in multiple sclerosis. Muscle Nerve 1995; 18: 1403–11

    Article  PubMed  CAS  Google Scholar 

  62. Filippi M, Rocca MA, Colombo B, et al. Functional magnetic resonance imaging correlates of fatigue in multiple sclerosis. Neuroimage 2002; 15: 559–67

    Article  PubMed  CAS  Google Scholar 

  63. Beck AT, Ward CH, Mendelson M. An inventory for measuring depression. Arch Gen Psych 1961; 4: 561–71

    Article  CAS  Google Scholar 

  64. Radloff LS. CES-D scale: a self-report depression scale for research in the general population. Appl Psychol Meas 1977; 1: 385–401

    Article  Google Scholar 

  65. Mohr DC, Goodkin DE, Likosky W, et al. Identification of Beck depression inventory items related to multiple sclerosis. J Behav Med 1997; 20: 407–14

    Article  PubMed  CAS  Google Scholar 

  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: 432–41

    Article  PubMed  CAS  Google Scholar 

  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: 892–4

    Article  PubMed  CAS  Google Scholar 

  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: 141–6

    Article  PubMed  Google Scholar 

  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: 408–14

    PubMed  CAS  Google Scholar 

  70. Friedberg F, Krupp LB. A comparison of cognitive behavioral treatment of chronic fatigue syndrome and primary depression. Clin Infect Dis 1994; 18: 105–10

    Article  Google Scholar 

  71. Butlers,Chalder T, Ron M, et al. Cognitive behaviour therapy in CFS. J Neurol Neurosurg Psychiatry 1991; 54: 153–8

    Article  Google Scholar 

  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: 1956–61

    Article  PubMed  CAS  Google Scholar 

  73. Murray TJ. Amantadine therapy forfatigue in multiple sclerosis. Can J Neurol Sci 1985; 12: 251–4

    PubMed  CAS  Google Scholar 

  74. Canadian MS Research Group. A randomized controlled trial of amantadine in fatigue associated with multiple sclerosis. Can J Neurol Sci 1987; 14: 273–8

    Google Scholar 

  75. Weinshenker BG, Penman M, Bass B. A double-blind, randomized, crossover trial of pemoline in fatigue associated with multiple sclerosis. Neurology 1992; 42: 1468–71

    Article  PubMed  CAS  Google Scholar 

  76. Polman CH, Bertelsmann FW, van Loenen AC, et al. 4-Aminopyridine in the treatment of patients with multiple sclerosis. Arch Neurol 1994; 51: 292–6

    Article  PubMed  CAS  Google Scholar 

  77. Latash M, Kalugina E, Orpett NJ, et al. Myogenic and central neurogenic factors in fatigue in multiple sclerosis. Mult Scler 1996; 1: 236–41

    PubMed  CAS  Google Scholar 

  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: A492

    Google Scholar 

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Acknowledgements

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.

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  1. Department of Neurology, State University of New York at Stony Brook, HSC T-12-20, Stony Brook, New York, New York, 11794-8121, USA

    Lauren B. Krupp

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Krupp, L.B. Fatigue in Multiple Sclerosis. CNS Drugs 17, 225–234 (2003). https://doi.org/10.2165/00023210-200317040-00002

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