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Clinical course and classification of multiple sclerosis

Michael J Olek, DO
Section Editor
Francisco Gonzalez-Scarano, MD
Deputy Editor
John F Dashe, MD, PhD


Multiple sclerosis (MS) is most common immune-mediated inflammatory demyelinating disease of the central nervous system. The clinical course and classification of MS will be reviewed here. Other aspects of MS are discussed separately:

(See "Pathogenesis and epidemiology of multiple sclerosis".)

(See "Clinically isolated syndromes suggestive of multiple sclerosis".)

(See "Clinical features of multiple sclerosis in adults".)

(See "Diagnosis of multiple sclerosis in adults".)


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Literature review current through: Sep 2016. | This topic last updated: Aug 22, 2016.
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  1. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014; 83:278.
  2. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996; 46:907.
  3. Weinshenker BG. Natural history of multiple sclerosis. Ann Neurol 1994; 36 Suppl:S6.
  4. Eriksson M, Andersen O, Runmarker B. Long-term follow up of patients with clinically isolated syndromes, relapsing-remitting and secondary progressive multiple sclerosis. Mult Scler 2003; 9:260.
  5. Koch M, Kingwell E, Rieckmann P, Tremlett H. The natural history of primary progressive multiple sclerosis. Neurology 2009; 73:1996.
  6. Rice CM, Cottrell D, Wilkins A, Scolding NJ. Primary progressive multiple sclerosis: progress and challenges. J Neurol Neurosurg Psychiatry 2013; 84:1100.
  7. Khaleeli Z, Ciccarelli O, Mizskiel K, et al. Lesion enhancement diminishes with time in primary progressive multiple sclerosis. Mult Scler 2010; 16:317.
  8. Kremenchutzky M, Rice GP, Baskerville J, et al. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain 2006; 129:584.
  9. Kurtzke JF. Neurologic impairment in multiple sclerosis and the disability status scale. Acta Neurol Scand 1970; 46:493.
  10. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33:1444.
  11. Kister I, Chamot E, Salter AR, et al. Disability in multiple sclerosis: a reference for patients and clinicians. Neurology 2013; 80:1018.
  12. Scalfari A, Neuhaus A, Daumer M, et al. Early relapses, onset of progression, and late outcome in multiple sclerosis. JAMA Neurol 2013; 70:214.
  13. Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000; 343:1430.
  14. Pittock SJ, McClelland RL, Mayr WT, et al. Clinical implications of benign multiple sclerosis: a 20-year population-based follow-up study. Ann Neurol 2004; 56:303.
  15. Tremlett H, Paty D, Devonshire V. Disability progression in multiple sclerosis is slower than previously reported. Neurology 2006; 66:172.
  16. Tremlett H, Zhao Y, Rieckmann P, Hutchinson M. New perspectives in the natural history of multiple sclerosis. Neurology 2010; 74:2004.
  17. Koch M, Kingwell E, Rieckmann P, et al. The natural history of secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 2010; 81:1039.
  18. Confavreux C, Vukusic S. Age at disability milestones in multiple sclerosis. Brain 2006; 129:595.
  19. Runmarker B, Andersen O. Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up. Brain 1993; 116 ( Pt 1):117.
  20. Vollmer T. The natural history of relapses in multiple sclerosis. J Neurol Sci 2007; 256 Suppl 1:S5.
  21. Ebers GC. Prognostic factors for multiple sclerosis: the importance of natural history studies. J Neurol 2005; 252 Suppl 3:iii15.
  22. Scalfari A, Neuhaus A, Degenhardt A, et al. The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability. Brain 2010; 133:1914.
  23. Bejaoui K, Rolak LA. What is the risk of permanent disability from a multiple sclerosis relapse? Neurology 2010; 74:900.
  24. Mohr DC, Hart SL, Julian L, et al. Association between stressful life events and exacerbation in multiple sclerosis: a meta-analysis. BMJ 2004; 328:731.
  25. Goodin DS, Ebers GC, Johnson KP, et al. The relationship of MS to physical trauma and psychological stress: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 1999; 52:1737.
  26. Buljevac D, Hop WC, Reedeker W, et al. Self reported stressful life events and exacerbations in multiple sclerosis: prospective study. BMJ 2003; 327:646.
  27. Scalfari A, Knappertz V, Cutter G, et al. Mortality in patients with multiple sclerosis. Neurology 2013; 81:184.
  28. Manouchehrinia A, Tanasescu R, Tench CR, Constantinescu CS. Mortality in multiple sclerosis: meta-analysis of standardised mortality ratios. J Neurol Neurosurg Psychiatry 2016; 87:324.
  29. GEORGI W. [Multiple sclerosis. Anatomopathological findings of multiple sclerosis in diseases not clinically diagnosed]. Schweiz Med Wochenschr 1961; 91:605.
  30. Mackay RP, Hirano A. Forms of benign multiple sclerosis. Report of two "clinically silent" cases discovered at autopsy. Arch Neurol 1967; 17:588.
  31. Gilbert JJ, Sadler M. Unsuspected multiple sclerosis. Arch Neurol 1983; 40:533.
  32. Phadke JG, Best PV. Atypical and clinically silent multiple sclerosis: a report of 12 cases discovered unexpectedly at necropsy. J Neurol Neurosurg Psychiatry 1983; 46:414.
  33. Engell T. A clinical patho-anatomical study of clinically silent multiple sclerosis. Acta Neurol Scand 1989; 79:428.
  34. Sadovnick AD, Ebers GC. Epidemiology of multiple sclerosis: a critical overview. Can J Neurol Sci 1993; 20:17.
  35. Rovaris M, Barkhof F, Calabrese M, et al. MRI features of benign multiple sclerosis: toward a new definition of this disease phenotype. Neurology 2009; 72:1693.
  36. Sayao AL, Devonshire V, Tremlett H. Longitudinal follow-up of "benign" multiple sclerosis at 20 years. Neurology 2007; 68:496.
  37. Gholipour T, Healy B, Baruch NF, et al. Demographic and clinical characteristics of malignant multiple sclerosis. Neurology 2011; 76:1996.
  38. Menon S, Shirani A, Zhao Y, et al. Characterising aggressive multiple sclerosis. J Neurol Neurosurg Psychiatry 2013; 84:1192.
  39. Swanton J, Fernando K, Miller D. Early prognosis of multiple sclerosis. Handb Clin Neurol 2014; 122:371.
  40. Leibowitz U, Alter M. Clinical factors associated with increased disability in multiple sclerosis. Acta Neurol Scand 1970; 46:53.
  41. Kurtzke JF, Beebe GW, Nagler B, et al. Studies on the natural history of multiple sclerosis--8. Early prognostic features of the later course of the illness. J Chronic Dis 1977; 30:819.
  42. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13:227.
  43. Confavreux C, Aimard G, Devic M. Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients. Brain 1980; 103:281.
  44. Cottrell DA, Kremenchutzky M, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study. 6. Applications to planning and interpretation of clinical therapeutic trials in primary progressive multiple sclerosis. Brain 1999; 122 ( Pt 4):641.
  45. Hawkins SA, McDonnell GV. Benign multiple sclerosis? Clinical course, long term follow up, and assessment of prognostic factors. J Neurol Neurosurg Psychiatry 1999; 67:148.
  46. Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain 2006; 129:606.
  47. Langer-Gould A, Popat RA, Huang SM, et al. Clinical and demographic predictors of long-term disability in patients with relapsing-remitting multiple sclerosis: a systematic review. Arch Neurol 2006; 63:1686.
  48. Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 2003; 126:770.
  49. Filippi M, Rocca MA, De Stefano N, et al. Magnetic resonance techniques in multiple sclerosis: the present and the future. Arch Neurol 2011; 68:1514.
  50. Klawiter EC. Current and new directions in MRI in multiple sclerosis. Continuum (Minneap Minn) 2013; 19:1058.
  51. Schlaeger R, Papinutto N, Zhu AH, et al. Association Between Thoracic Spinal Cord Gray Matter Atrophy and Disability in Multiple Sclerosis. JAMA Neurol 2015; 72:897.
  52. Bernitsas E, Bao F, Seraji-Bozorgzad N, et al. Spinal cord atrophy in multiple sclerosis and relationship with disability across clinical phenotypes. Mult Scler Relat Disord 2015; 4:47.
  53. Schlaeger R, Papinutto N, Panara V, et al. Spinal cord gray matter atrophy correlates with multiple sclerosis disability. Ann Neurol 2014; 76:568.
  54. Brex PA, Ciccarelli O, O'Riordan JI, et al. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 2002; 346:158.
  55. Li DK, Held U, Petkau J, et al. MRI T2 lesion burden in multiple sclerosis: a plateauing relationship with clinical disability. Neurology 2006; 66:1384.
  56. MacKenzie-Graham A, Kurth F, Itoh Y, et al. Disability-Specific Atlases of Gray Matter Loss in Relapsing-Remitting Multiple Sclerosis. JAMA Neurol 2016; 73:944.
  57. Cree BA, Khan O, Bourdette D, et al. Clinical characteristics of African Americans vs Caucasian Americans with multiple sclerosis. Neurology 2004; 63:2039.
  58. Wingerchuk DM, Hogancamp WF, O'Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic's syndrome). Neurology 1999; 53:1107.
  59. Roudbari SA, Ansar MM, Yousefzad A. Smoking as a risk factor for development of Secondary Progressive Multiple Sclerosis: A study in IRAN, Guilan. J Neurol Sci 2013; 330:52.
  60. Titelbaum DS, Degenhardt A, Kinkel RP. Anti-tumor necrosis factor alpha-associated multiple sclerosis. AJNR Am J Neuroradiol 2005; 26:1548.