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Secondary Progressive Multiple Sclerosis: Definition and Measurement

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Abstract

Secondary progressive multiple sclerosis (SPMS) is diagnosed retrospectively and involves a clinical course characterized by a progressive accumulation of neurological disability, independent of relapses, following an initial relapsing–remitting (RR) phase. Our incomplete understanding of the pathological mechanisms underlying neurodegeneration in multiple sclerosis (MS) may explain why, to date, there is no definitive imaging or laboratory test that is able to inform us when the disease is clearly entering into a progressive phase and why the vast majority of clinical trials testing immunosuppressant and immunomodulating drugs in SPMS patients has so far yielded disappointing or mixed results. Here we discuss the definition(s) of SPMS and how it may vary, outcome measurements (current and emerging) and modern trial design.

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References

  1. Charcot J-M. Leçons sur les Maladies du Système Nerveux. Paris A. Delahaye. 1885;26.

  2. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372:1502–17.

    Article  CAS  PubMed  Google Scholar 

  3. Confavreux C, Vukusic S. Age at disability milestones in multiple sclerosis. Brain. 2006;129:595–605.

    Article  PubMed  Google Scholar 

  4. Miller DH, Leary SM. Primary-progressive multiple sclerosis. Lancet Neurol. 2007;6(10):903–12.

    Article  PubMed  Google Scholar 

  5. Leary SM, Thompson AJ. Primary progressive multiple sclerosis : current and future treatment options. CNS Drugs. 2005;19:369–76.

    Article  CAS  PubMed  Google Scholar 

  6. Kremenchutzky M, Rice GPA, Baskerville J, Wingerchuk DM, Ebers GC. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain. 2006;129:584–94.

    Article  CAS  PubMed  Google Scholar 

  7. Koch M, Kingwell E, Rieckmann P, Tremlett H. The natural history of secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2010;81:1039–43.

    Article  PubMed  Google Scholar 

  8. Sand IK, Krieger S, Farrell C, Miller AE. Diagnostic uncertainty during the transition to secondary progressive multiple sclerosis. Mult Scler 2014;20(12):1654–7.

    Article  Google Scholar 

  9. Vukusic S, Confavreux C. Prognostic factors for progression of disability in the secondary progressive phase of multiple sclerosis. J Neurol Sci. 2003;206:135–7.

    Article  PubMed  Google Scholar 

  10. Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83:278–86.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Tremlett H, Yousefi M, Devonshire V, Rieckmann P, Zhao Y. Impact of multiple sclerosis relapses on progression diminishes with time. Neurology. 2009;73:1616–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med. 2000;343:1430–8.

    Article  CAS  PubMed  Google Scholar 

  13. McAlpine D. Multiple Sclerosis. Br Med J. 1957;1:475–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Huijbregts SCJ, Kalkers NF, de Sonneville LMJ, de Groot V, Reuling IEW, Polman CH. Differences in cognitive impairment of relapsing remitting, secondary, and primary progressive MS. Neurology. 2004;63:335–9.

    Article  CAS  PubMed  Google Scholar 

  15. Kidd D, Thorpe JW, Kendall BE, Barker GJ, Miller DH, McDonald WI, et al. MRI dynamics of brain and spinal cord in progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 1996;60:15–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Confavreux C. Natural history of multiple sclerosis: a unifying concept. Brain. 2006;129:606–16.

    Article  PubMed  Google Scholar 

  17. Amato MP, Ponziani G. A prospective study on the prognosis of multiple sclerosis. Neurol Sci. 2000;21:S831–8.

    Article  CAS  PubMed  Google Scholar 

  18. Myhr KM, Riise T, Vedeler C, Nortvedt MW, Gronning R, Midgard R, et al. Disability and prognosis in multiple sclerosis: demographic and clinical variables important for the ability to walk and awarding of disability pension. Mult Scler. 2001;7:59–65.

    Article  CAS  PubMed  Google Scholar 

  19. 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;9:260–74.

    Article  PubMed  Google Scholar 

  20. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis results of an international survey. Neurology. 1996;46:907–11.

    Article  CAS  PubMed  Google Scholar 

  21. Schumacker GA, Beebe G, Kibler RF, Kurland LT, Kurtzke JF, Mcdowell F, et al. Problems of experimental trials of therapy in multiple sclerosis: report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann N Y Acad Sci. 1965;122:552–68.

    Article  Google Scholar 

  22. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983;13:227–31.

    Article  CAS  PubMed  Google Scholar 

  23. Confavreux C, Compston DA, Hommes OR, McDonald WI, Thompson AJ. EDMUS, a European database for multiple sclerosis. J Neurol Neurosurg Psychiatry. 1992;55:671–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rovaris M, Confavreux C, Furlan R, Kappos L, Comi G, Filippi M. Secondary progressive multiple sclerosis: Current knowledge and future challenges. Lancet Neurol. 2006;5:343–54.

    Article  PubMed  Google Scholar 

  25. Ontaneda D, Fox RJ, Chataway J. Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives. Lancet Neurol. 2015;14:208–23.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lassmann H, Brück W, Lucchinetti CF. The immunopathology of multiple sclerosis: an overview. Brain Pathol. 2007;17:210–8.

    Article  PubMed  Google Scholar 

  27. Hochmeister S, Grundtner R, Bauer J, Engelhardt B, Lyck R, Gordon G, et al. Dysferlin is a new marker for leaky brain blood vessels in multiple sclerosis. J Neuropathol Exp Neurol. 2006;65:855–65.

    Article  CAS  PubMed  Google Scholar 

  28. Kutzelnigg A, Lucchinetti CF, Stadelmann C, Brück W, Rauschka H, Bergmann M, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005;128:2705–12.

    Article  PubMed  Google Scholar 

  29. Frisullo G, Plantone D, Marti A, Iorio R, Damato V, Nociti V, et al. Type 1 immune response in progressive multiple sclerosis. J Neuroimmunol. 2012;249:112–6.

    Article  CAS  PubMed  Google Scholar 

  30. Becher B, Giacomini PS, Pelletier D, McCrea E, Prat A, Antel JP. Interferon-gamma secretion by peripheral blood T-cell subsets in multiple sclerosis: correlation with disease phase and interferon-beta therapy. Ann Neurol. 1999;45:247–50.

    Article  CAS  PubMed  Google Scholar 

  31. Soldan SS, Alvarez Retuerto AI, Sicotte NL, Voskuhl RR. Dysregulation of IL-10 and IL-12p40 in secondary progressive multiple sclerosis. J Neuroimmunol. 2004;146:209–15.

    Article  CAS  PubMed  Google Scholar 

  32. Christensen JR, Börnsen L, Ratzer R, Piehl F, Khademi M, Olsson T, et al. Systemic inflammation in progressive multiple sclerosis involves follicular T-Helper, Th17- and activated B-cells and correlates with progression. PLoS One. 2013;8:e57820.

    Article  CAS  PubMed Central  Google Scholar 

  33. Plantone D, Marti A, Frisullo G, Iorio R, Damato V, Nociti V, et al. Circulating CD56dim NK cells expressing perforin are increased in progressive multiple sclerosis. J Neuroimmunol. 2013;265:124–7.

    Article  CAS  PubMed  Google Scholar 

  34. Howell OW, Reeves CA, Nicholas R, Carassiti D, Radotra B, Gentleman SM, et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain. 2011;134:2755–71.

    Article  PubMed  Google Scholar 

  35. Reynolds R, Roncaroli F, Nicholas R, Radotra B, Gveric D, Howell O. The neuropathological basis of clinical progression in multiple sclerosis. Acta Neuropathol. 2011;122:155–70.

    Article  PubMed  Google Scholar 

  36. Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo M, et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain. 2006;130:1089–104.

    Article  Google Scholar 

  37. Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 2004;14:164–74.

    Article  PubMed  Google Scholar 

  38. Lovato L, Willis SN, Rodig SJ, Caron T, Almendinger SE, Howell OW, et al. Related B cell clones populate the meninges and parenchyma of patients with multiple sclerosis. Brain. 2011;134:534–41.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Magliozzi R, Howell OW, Reeves C, Roncaroli F, Nicholas R, Serafini B, et al. A Gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol. 2010;68:477–93.

    Article  CAS  PubMed  Google Scholar 

  40. Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132:1175–89.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Calabrese M, Filippi M, Gallo P. Cortical lesions in multiple sclerosis. Nat Rev Neurol. 2010;6:438–44.

    Article  PubMed  Google Scholar 

  42. Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, Cinque P, et al. Dysregulated epstein-barr virus infection in the multiple sclerosis brain. J Exp Med. 2007;204:2899–912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Su KG, Banker G, Bourdette D, Forte M. Axonal degeneration in multiple sclerosis: the mitochondrial hypothesis. Curr Neurol Neurosci Rep. 2009;9:411–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Craner MJ, Newcombe J, Black JA, Hartle C, Cuzner ML, Waxman SG. Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. Proc Natl Acad Sci USA. 2004;101:8168–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dutta R, McDonough J, Yin X, Peterson J, Chang A, Torres T, et al. Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann. Neurol. 2006;59:478–89.

    Article  CAS  PubMed  Google Scholar 

  46. Stys PK, Waxman SG, Ransom BR. Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+ channels and Na(+)-Ca2+ exchanger. J Neurosci. 1992;12:430–9.

    CAS  PubMed  Google Scholar 

  47. D’haeseleer M, Cambron M, Vanopdenbosch L, De Keyser J. Vascular aspects of multiple sclerosis. Lancet Neurol. 2011;10:657–66.

    Article  PubMed  Google Scholar 

  48. Motl RW, McAuley E, Snook EM. Physical activity and multiple sclerosis: a meta-analysis. Mult Scler. 2005;11:459–63.

    Article  PubMed  Google Scholar 

  49. Russo C, Morabito F, Luise F, Piromalli A, Battaglia L, Vinci A, et al. Hyperhomocysteinemia is associated with cognitive impairment in multiple sclerosis. J Neurol. 2008;255:64–9.

    Article  CAS  PubMed  Google Scholar 

  50. Sahin S, Aksungar FB, Topkaya AE, Yildiz Z, Boru UT, Ayalp S, et al. Increased plasma homocysteine levels in multiple sclerosis. Mult Scler. 2007;13:945–6.

    Article  CAS  PubMed  Google Scholar 

  51. Christiansen CF, Christensen S, Farkas DK, Miret M, Sørensen HT, Pedersen L. Risk of arterial cardiovascular diseases in patients with multiple sclerosis: a population-based cohort study. Neuroepidemiology. 2010;35:267–74.

    Article  PubMed  Google Scholar 

  52. Allen NB, Lichtman JH, Cohen HW, Fang J, Brass LM, Alderman MH. Vascular disease among hospitalized multiple sclerosis patients. Neuroepidemiology. 2008;30:234–8.

    Article  PubMed  Google Scholar 

  53. Lucchinetti CF, Brück W, Rodriguez M, Lassmann H. Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis. Brain Pathol. 1996;6:259–74.

    Article  CAS  PubMed  Google Scholar 

  54. Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000;47:707–17.

    Article  CAS  PubMed  Google Scholar 

  55. Aboul-Enein F, Rauschka H, Kornek B, Stadelmann C, Stefferl A, Brück W, et al. Preferential loss of myelin-associated glycoprotein reflects hypoxia-like white matter damage in stroke and inflammatory brain diseases. J Neuropathol Exp Neurol. 2003;62:25–33.

    Article  CAS  PubMed  Google Scholar 

  56. Alexander JS, Zivadinov R, Maghzi A-H, Ganta VC, Harris MK, Minagar A. Multiple sclerosis and cerebral endothelial dysfunction: mechanisms. Pathophysiology. 2011;18:3–12.

    Article  CAS  PubMed  Google Scholar 

  57. Koudriavtseva T. Thrombotic processes in multiple sclerosis as manifestation of innate immune activation. Front Neurol. 2014;5:119.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Koudriavtseva T, Renna R, Plantone D, Mainero C. Demyelinating and thrombotic diseases of the central nervous system: common pathogenic and triggering factors. Front Neurol. 2015;6:63.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Chataway J, Schuerer N, Alsanousi A, Chan D, MacManus D, Hunter K, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet. 2014;383:2213–21.

    Article  CAS  PubMed  Google Scholar 

  60. Vollmer T, Key L, Durkalski V, Tyor W, Corboy J, Markovic-Plese S, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004;363:1607–8.

    Article  CAS  PubMed  Google Scholar 

  61. Greenwood J, Walters CE, Pryce G, Kanuga N, Beraud E, Baker D, et al. Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. FASEB J. 2003;17:905–7.

    CAS  PubMed  Google Scholar 

  62. van der Most PJ, Dolga AM, Nijholt IM, Luiten PGM, Eisel ULM. Statins: mechanisms of neuroprotection. Prog Neurobiol. 2009;88:64–75.

    Article  PubMed  CAS  Google Scholar 

  63. Schmeer C, Kretz A, Isenmann S. Statin-mediated protective effects in the central nervous system: general mechanisms and putative role of stress proteins. Restor Neurol Neurosci. 2006;24:79–95.

    CAS  PubMed  Google Scholar 

  64. EMA. Guideline on clinical investigation of MPs for the treatment of multiple sclerosis (EMA/CHMP/771815/2011, Rev. 2. Guideline. 2015;44:20.

    Google Scholar 

  65. Khan O. Can clinical outcomes be used to detect neuroprotection in multiple sclerosis? Neurology. 2007;68(S64–71):S91–6.

    Google Scholar 

  66. Barkhof F, Calabresi PA, Miller DH, Reingold SC. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol. 2009;5:256–66.

    Article  PubMed  Google Scholar 

  67. Daumer M, Neuhaus A, Morrissey S, Hintzen R, Ebers GC. MRI as an outcome in multiple sclerosis clinical trials. Neurology. 2009;72:705–11.

    Article  CAS  PubMed  Google Scholar 

  68. Whitaker JN, McFarland HF, Rudge P, Reingold SC. Outcomes assessment in multiple sclerosis trials. Mult Scler. 1995;1:37–47.

    CAS  PubMed  Google Scholar 

  69. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444–52.

    Article  CAS  PubMed  Google Scholar 

  70. Fischer JS, Rudick RA, Cutter GR, Reingold SC. The Multiple sclerosis functional composite measure (MSFC): an integrated approach to MS clinical outcome assessment. National MS Society Clinical Outcomes Assessment Task Force. Mult Scler. 1999;5:244–50.

    Article  CAS  PubMed  Google Scholar 

  71. Cutter GR, Baier ML, Rudick RA, Cookfair DL, Fischer JS, Petkau J, et al. Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain. 1999;122:871–82.

    Article  PubMed  Google Scholar 

  72. Hobart J, Freeman J. Thompson a. Kurtzke scales revisited: the application of psychometric methods to clinical intuition. Brain. 2000;123:1027–40.

    Article  PubMed  Google Scholar 

  73. Amato MP, Ponziani G. Quantification of impairment in MS: discussion of the scales in use. Mult Scler. 1999;5:216–9.

    Article  CAS  PubMed  Google Scholar 

  74. Cohen JA, Reingold SC, Polman CH, Wolinsky JS. Disability outcome measures in multiple sclerosis clinical trials: current status and future prospects. Lancet Neurol. 2012;11:467–76.

    Article  PubMed  Google Scholar 

  75. Cohen JA, Fischer JS, Bolibrush DM, Jak AJ, Kniker JE, Mertz LA, et al. Intrarater and interrater reliability of the MS functional composite outcome measure. Neurology. 2000;54:802–6.

    Article  CAS  PubMed  Google Scholar 

  76. Willoughby EW, Paty DW. Scales for rating impairment in multiple sclerosis: a critique. Neurology. 1988;38:1793–8.

    Article  CAS  PubMed  Google Scholar 

  77. Rudick R, Antel J, Confavreux C, Cutter G, Ellison G, Fischer J, et al. Recommendations from the national multiple sclerosis society clinical outcomes assessment task force. Ann Neurol. 1997;42:379–82.

    Article  CAS  PubMed  Google Scholar 

  78. Rudick R, Cutter G, Reingold S. The multiple sclerosis functional composite: a new clinical outcome measure for multiple sclerosis trials. Mult Scler. 2002;8:359–65.

    Article  CAS  PubMed  Google Scholar 

  79. Miller DM, Rudick RA, Cutter G, Baier M, Fisher JS. Clinical significance of the multiple sclerosis functional composite. Arch Neurol. 2000;57:1319–24.

    CAS  PubMed  Google Scholar 

  80. Kalkers NF, Bergers L, de Groot V, Lazeron RH, van Walderveen MA, Uitdehaag BM, et al. Concurrent validity of the MS Functional composite using MRI as a biological disease marker. Neurology. 2001;56:215–9.

    Article  CAS  PubMed  Google Scholar 

  81. Fisher E, Rudick RA, Cutter G, Baier M, Miller D, Weinstock-Guttman B, et al. Relationship between brain atrophy and disability: an 8-year follow-up study of multiple sclerosis patients. Mult Scler. 2000;6:373–7.

    Article  CAS  PubMed  Google Scholar 

  82. Kragt JJ, van der Linden FAH, Nielsen JM, Uitdehaag BMJ, Polman CH. Clinical impact of 20 % worsening on Timed 25-foot Walk and 9-hole Peg Test in multiple sclerosis. Mult Scler. 2006;12:594–8.

  83. Rudick RA, Polman CH, Cohen JA, Walton MK, Miller AE, Confavreux C, et al. Assessing disability progression with the Multiple Sclerosis Functional Composite. Mult Scler. 2009;15:984–97.

    Article  CAS  PubMed  Google Scholar 

  84. Brochet B, Deloire MSA, Bonnet M, Salort-Campana E, Ouallet JC, Petry KG, et al. Should SDMT substitute for PASAT in MSFC? A 5-year longitudinal study. Mult Scler. 2008;14:1242–9.

    Article  CAS  PubMed  Google Scholar 

  85. Balcer LJ, Baier ML, Cohen JA, Kooijmans MF, Sandrock AW, Nano-Schiavi ML, et al. Contrast letter acuity as a visual component for the multiple sclerosis functional composite. Neurology. 2003;61:1367–73.

  86. Benedict RHB, Cookfair D, Gavett R, Gunther M, Munschauer F, Garg N, et al. Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS). J Int Neuropsychol Soc. 2006;12:549–58.

    Article  PubMed  Google Scholar 

  87. Rao SM, Leo GJ, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology. 1991;41:685–91.

    Article  CAS  PubMed  Google Scholar 

  88. Planche V, Gibelin M, Cregut D, Pereira B, Clavelou P. Cognitive impairment in a population-based study of patients with multiple sclerosis: differences between late relapsing-remitting, secondary progressive and primary progressive multiple sclerosis. Eur J Neurol. 2016;23:282–9.

    Article  CAS  PubMed  Google Scholar 

  89. Strober L, Englert J, Munschauer F, Weinstock-Guttman B, Rao S, Benedict RHB. Sensitivity of conventional memory tests in multiple sclerosis: comparing the Rao Brief repeatable neuropsychological battery and the minimal assessment of cognitive function in MS. Mult Scler. 2009;15:1077–84.

    Article  CAS  PubMed  Google Scholar 

  90. Parmenter BA, Weinstock-Guttman B, Garg N, Munschauer F, Benedict RHB. Screening for cognitive impairment in multiple sclerosis using the symbol digit modalities test. Mult Scler. 2007;13:52–7.

  91. Pardini M, Uccelli A, Grafman J, Yaldizli O, Mancardi G, Roccatagliata L. Isolated cognitive relapses in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry. 2014;85:1035–7.

    Article  PubMed  Google Scholar 

  92. Delis DC, Kramer JH, Kaplan E, Ober BA. California verbal learning test—second edition. Adult Version. Manual. Test. 2000.

  93. Benedict RHB. Revision of the brief visuospatial memory test—revised. Psychol Assess 1997;145–53.

  94. Langdon D, Amato M, Boringa J, Brochet B, Foley F, Fredrikson S, et al. Recommendations for a brief international cognitive assessment for multiple sclerosis (BICAMS). Mult Scler J. 2012;18:891–8.

    Article  CAS  Google Scholar 

  95. Benedict RH, Walton MK. Evaluating cognitive outcome measures for MS clinical trials: what is a clinically meaningful change? Mult Scler J. 2012;18:1673–9.

    Article  Google Scholar 

  96. Doward LC, Mckenna SP, Meads DM, Twiss J, Eckert BJ. The development of patient-reported outcome indices for multiple sclerosis (PRIMUS). 2015;1092–102.

  97. Vickrey BG, Hays RD, Harooni R, Myers LW, Ellison GW. A health-related quality of life measure for multiple sclerosis. Qual Life Res. 1995;4:187–206.

    Article  CAS  PubMed  Google Scholar 

  98. Cella DF, Dineen K, Arnason B, Reder A, Webster KA, Karabatsos G, et al. Validation of the functional assessment of multiple sclerosis quality of life instrument. Neurology. 1996;47(1):129–39.

    Article  CAS  PubMed  Google Scholar 

  99. Hobart J, Lamping D, Fitzpatrick R, Riazi A, Thompson A. The multiple sclerosis impact scale (MSIS-29): a new patient-based outcome measure. Brain. 2001;124:962–73.

    Article  CAS  PubMed  Google Scholar 

  100. Hayton T, Furby J, Smith KJ, Altmann DR, Brenner R, Chataway J, et al. Clinical and imaging correlates of the multiple sclerosis impact scale in secondary progressive multiple sclerosis. J Neurol. 2012;259:237–45.

    Article  CAS  PubMed  Google Scholar 

  101. Simon JH. Brain atrophy in multiple sclerosis: what we know and would like to know. Mult Scler. 2006;12:679–87.

    Article  CAS  PubMed  Google Scholar 

  102. Pelletier D, Garrison K, Henry R. Measurement of whole-brain atrophy in multiple sclerosis. J. neuroimaging. 2004;14:11S–9S.

    Article  PubMed  Google Scholar 

  103. de Bresser J, Portegies MP, Leemans A, Biessels GJ, Kappelle LJ, Viergever MA. A comparison of MR based segmentation methods for measuring brain atrophy progression. Neuroimage. 2011;54:760–8.

    Article  PubMed  Google Scholar 

  104. Vrenken H, Jenkinson M, Horsfield MA, Battaglini M, Van Schijndel RA, Rostrup E, et al. Recommendations to improve imaging and analysis of brain lesion load and atrophy in longitudinal studies of multiple sclerosis. J Neurol. 2013;260:2458–71.

  105. Pirko I, Lucchinetti CF, Sriram S, Bakshi R. Gray matter involvement in multiple sclerosis. Neurology. 2007;68:634–42.

    Article  PubMed  Google Scholar 

  106. Dalton CM, Chard DT, Davies GR, Miszkiel KA, Altmann DR, Fernando K, et al. Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes. Brain. 2004;127:1101–7.

  107. Chard DT, Griffin CM, Parker GJM, Kapoor R. Thompson a J, Miller DH. Brain atrophy in clinically early relapsing-remitting multiple sclerosis. Brain. 2002;125:327–37.

    Article  CAS  PubMed  Google Scholar 

  108. Sastre-Garriga J, Ingle GT, Chard DT, Cercignani M, Ramió-Torrentà L, Miller DH, et al. Grey and white matter volume changes in early primary progressive multiple sclerosis: a longitudinal study. Brain. 2005;128:1454–60.

    Article  PubMed  Google Scholar 

  109. Fisher E, Lee J-C, Nakamura K, Rudick RA. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol. 2008;64:255–65.

    Article  PubMed  Google Scholar 

  110. Fisniku LK, Chard DT, Jackson JS, Anderson VM, Altmann DR, Miszkiel KA, et al. Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol. 2008;64:247–54.

    Article  PubMed  Google Scholar 

  111. Kearney H, Rocca MA, Valsasina P, Balk L, Sastre-Garriga J, Reinhardt J, et al. Magnetic resonance imaging correlates of physical disability in relapse onset multiple sclerosis of long disease duration. Mult Scler. 2014;20:72–80.

  112. De Stefano N, Arnold DL. Towards a better understanding of pseudoatrophy in the brain of multiple sclerosis patients. Mult Scler J. 2015;675–7.

  113. Vidal-Jordana A, Sastre-Garriga J, Pérez-Miralles F, Tur C, Tintoré M, Horga A, et al. Early brain pseudoatrophy while on natalizumab therapy is due to white matter volume changes. Mult Scler. 2013;19:1175–81.

    Article  CAS  PubMed  Google Scholar 

  114. Ashburner J, Friston KJ. Voxel-based morphometry—the methods. Neuroimage. 2000;11:805–21.

    Article  CAS  PubMed  Google Scholar 

  115. Fischl B. Automatically parcellating the human cerebral cortex. Cereb Cortex. 2004;14:11–22.

    Article  PubMed  Google Scholar 

  116. Nakamura K, Guizard N, Fonov VS, Narayanan S, Collins DL, Arnold DL. Jacobian integration method increases the statistical power to measure gray matter atrophy in multiple sclerosis. NeuroImage Clin. 2014;4:10–7.

    Article  PubMed  Google Scholar 

  117. Nakamura K, Fox R, Fisher E. CLADA: cortical longitudinal atrophy detection algorithm. Neuroimage. 2011;54:278–89.

    Article  PubMed  Google Scholar 

  118. van Walderveen MAA, Kamphorst W, Scheltens P, van Waesberghe JHTM, Ravid R, Valk J, et al. Histopathologic correlate of hypointense lesions on T1-weighted spin-echo MRI in multiple sclerosis. Neurology. 1998;50:1282–8.

    Article  PubMed  Google Scholar 

  119. Mallik S, Samson RS, Wheeler-Kingshott CAM, Miller DH. Imaging outcomes for trials of remyelination in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014;85:1396–404.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Kalkers NF, Barkhof F, Bergers E, van Schijndel R, Polman CH. The effect of the neuroprotective agent riluzole on MRI parameters in primary progressive multiple sclerosis: a pilot study. Mult Scler. 2002;8:532–3.

    Article  CAS  PubMed  Google Scholar 

  121. Kearney H, Miller DH, Ciccarelli O. Spinal cord MRI in multiple sclerosis—diagnostic, prognostic and clinical value. Nat Rev Neurol. 2015;11:327–38.

    Article  PubMed  Google Scholar 

  122. Lin X, Tench CR, Turner B, Blumhardt LD, Constantinescu CS. Spinal cord atrophy and disability in multiple sclerosis over four years: application of a reproducible automated technique in monitoring disease progression in a cohort of the interferon beta-1a (Rebif) treatment trial. J Neurol Neurosurg Psychiatry. 2003;74:1090–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Montalban X, Sastre-Garriga J, Tintoré M, Brieva L, Aymerich FX, Río J, et al. A single-center, randomized, double-blind, placebo-controlled study of interferon beta-1b on primary progressive and transitional multiple sclerosis. Mult Scler. 2009;15:1195–205.

    Article  CAS  PubMed  Google Scholar 

  124. Leary SM, Miller DH, Stevenson VL, Brex PA, Chard DT, Thompson AJ. Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial. Neurology. 2003;60:44–51.

    Article  CAS  PubMed  Google Scholar 

  125. Horsfield MA, Sala S, Neema M, Absinta M, Bakshi A, Sormani P, et al. Rapid semi automatic segmentation of spinal cord from Magnetic Resonance Images : application in multiple sclerosis. Neuroimage. 2011;50:446–55.

    Article  Google Scholar 

  126. Rovira A, Alonso J. 1H magnetic resonance spectroscopy in multiple sclerosis and related disorders. Neuroimaging Clin N Am. 2013;23:459–74.

    Article  PubMed  Google Scholar 

  127. Lin A, Ross BD, Harris K, Wong W. Efficacy of proton magnetic resonance spectroscopy in neurological diagnosis and neurotherapeutic decision making. NeuroRx. 2005;2:197–214.

    Article  PubMed  PubMed Central  Google Scholar 

  128. De Stefano N, Filippi M, Miller D, Pouwels PJ, Rovira A, Gass A, et al. Guidelines for using proton MR spectroscopy in multicenter clinical MS studies. Neurology. 2007;69:1942–52.

    Article  PubMed  Google Scholar 

  129. Vavasour IM, Laule C, Li DKB, Traboulsee AL, MacKay AL. Is the magnetization transfer ratio a marker for myelin in multiple sclerosis? J Magn Reson Imaging. 2011;33:713–8.

    Article  PubMed  Google Scholar 

  130. Schmierer K, Scaravilli F, Altmann DR, Barker GJ, Miller DH. Magnetization transfer ratio and myelin in postmortem multiple sclerosis brain. Ann Neurol. 2004;56:407–15.

    Article  PubMed  Google Scholar 

  131. Pierpaoli C, Jezzard P, Basser PJ, Barnett A, Di Chiro G. Diffusion tensor MR imaging of the human brain. Radiology. 1996;201:637–48.

    Article  CAS  PubMed  Google Scholar 

  132. Sbardella E, Tona F, Petsas N, Pantano P. DTI measurements in multiple sclerosis: evaluation of brain damage and clinical implications. Mult Scler Int. 2013;2013:671730.

    PubMed  PubMed Central  Google Scholar 

  133. Petracca M, Fleysher L, Oesingmann N, Inglese M. Sodium MRI of multiple sclerosis. NMR Biomed. 2016;29:153–61.

    Article  CAS  PubMed  Google Scholar 

  134. Zaaraoui W, Konstandin S, Audoin B, Nagel AM, Rico A, Malikova I, et al. Distribution of brain sodium accumulation correlates with disability in multiple sclerosis: a cross-sectional 23Na MR imaging study. Radiology. 2012;264:859–67.

    Article  PubMed  Google Scholar 

  135. Inglese M, Madelin G, Oesingmann N, Babb JS, Wu W, Stoeckel B, et al. Brain tissue sodium concentration in multiple sclerosis: a sodium imaging study at 3 tesla. Brain. 2010;133:847–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Paling D, Solanky BS, Riemer F, Tozer DJ, Wheeler-Kingshott CAM, Kapoor R, et al. Sodium accumulation is associated with disability and a progressive course in multiple sclerosis. Brain. 2013;136:2305–17.

    Article  PubMed  Google Scholar 

  137. Greenberg BM, Frohman E. Optical coherence tomography as a potential readout in clinical trials. Ther Adv Neurol Disord. 2010;3:153–60.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Lamirel C, Newman N, Biousse V. The use of optical coherence tomography in neurology. Rev Neurol Dis. 2009;6:E105–20.

    PubMed  Google Scholar 

  139. Abalo-Lojo JM, Limeres CC, Gómez MA, Baleato-González S, Cadarso-Suárez C, Capeáns-Tomé C, et al. Retinal nerve fiber layer thickness, brain atrophy, and disability in multiple sclerosis patients. J Neuroophthalmol. 2014;34:23–8.

    Article  PubMed  Google Scholar 

  140. Gordon-Lipkin E, Chodkowski B, Reich DS, Smith SA, Pulicken M, Balcer LJ, et al. Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis. Neurology. 2007;69:1603–9.

    Article  CAS  PubMed  Google Scholar 

  141. Sepulcre J, Murie-Fernandez M, Salinas-Alaman A, García-Layana A, Bejarano B, Villoslada P. Diagnostic accuracy of retinal abnormalities in predicting disease activity in MS. Neurology. 2007;68:1488–94.

    Article  PubMed  Google Scholar 

  142. Bielekova B, Martin R. Development of biomarkers in multiple sclerosis. Brain. 2004;127:1463–78.

    Article  PubMed  Google Scholar 

  143. Malmeström C, Haghighi S, Rosengren L, Andersen O, Lycke J. Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS. Neurology. 2003;61:1720–5.

    Article  PubMed  Google Scholar 

  144. Kuhle J, Plattner K, Bestwick JP, Lindberg RL, Ramagopalan SV, Norgren N, et al. A comparative study of CSF neurofilament light and heavy chain protein in MS. Mult Scler. 2013;19:1597–603.

    Article  PubMed  CAS  Google Scholar 

  145. Lycke JN, Karlsson JE, Andersen O, Rosengren LE. Neurofilament protein in cerebrospinal fluid: a potential marker of activity in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1998;64:402–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Teunissen CE, Khalil M. Neurofilaments as biomarkers in multiple sclerosis. Mult Scler J. 2012;18:552–6.

    Article  CAS  Google Scholar 

  147. Madeddu R, Farace C, Tolu P, Solinas G, Asara Y, Sotgiu MA, et al. Cytoskeletal proteins in the cerebrospinal fluid as biomarker of multiple sclerosis. Neurol. Sci. 2013;34:181–6.

    Article  PubMed  Google Scholar 

  148. Katsavos S, Anagnostouli M. Biomarkers in multiple sclerosis: an up-to-date overview. Mult Scler Int. 2013;2013:340508.

    PubMed  PubMed Central  Google Scholar 

  149. Chataway J, Nicholas R, Todd S, Miller DH, Parsons N, Valdés-Márquez E, et al. A novel adaptive design strategy increases the efficiency of clinical trials in secondary progressive multiple sclerosis. Mult Scler. 2011;17:81–8.

    Article  PubMed  Google Scholar 

  150. Koch MW, Cutter G, Stys PK, Yong VW, Metz LM. Treatment trials in progressive MS—current challenges and future directions. Nat Rev Neurol. 2013;9:496–503.

    Article  CAS  PubMed  Google Scholar 

  151. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10:1–10.

    Article  CAS  PubMed  Google Scholar 

  152. Montalban X, Hemmer B, Rammohan K, Giovannoni G, De Seze J, Bar-Or A, et al. Efficacy and safety of ocrelizumab in primary progressive multiple sclerosis: results of the Phase III double-blind, placebo-controlled ORATORIO study. Neurology. 2016;86(Supp.16):S49.001.

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Acknowledgements

JC acknowledges the UK National Institute for Health Research (NIHR) University College London Hospitals/University College London Biomedical Research Centres Funding scheme.

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  1. Department of Neuroinflammation, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK

    Domenico Plantone, Floriana De Angelis, Anisha Doshi & Jeremy Chataway

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  1. Domenico Plantone
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  2. Floriana De Angelis
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  3. Anisha Doshi
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Correspondence to Domenico Plantone.

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Conflict of interest

Jeremy Chataway is local principal investigator for trials in multiple sclerosis funded by Novartis, Biogen and GSK (agents not part of this review); investigator grant from Novartis outside this work; chief investigator of the EME funded MS-SMART trial [NCT01910259]. Domenico Plantone, Floriana De Angelis and Anisha Doshi are investigators of the EME funded MS-SMART trial [NCT01910259].

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Plantone, D., De Angelis, F., Doshi, A. et al. Secondary Progressive Multiple Sclerosis: Definition and Measurement. CNS Drugs 30, 517–526 (2016). https://doi.org/10.1007/s40263-016-0340-9

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