Table of Contents Author Guidelines Submit a Manuscript
Disease Markers
Volume 35, Issue 6, Pages 687–699
http://dx.doi.org/10.1155/2013/484959
Review Article

Clinical, MRI, and CSF Markers of Disability Progression in Multiple Sclerosis

Section of Clinical Neurology, Department of Neurological and Movement Sciences, University of Verona, Neurology Unit, Borgo Roma, Azienda Ospedaliera Universitaria Integrata Verona, Piazzale Ludovico Antonio Scuro 9, 37134 Verona, Italy

Received 30 June 2013; Revised 12 September 2013; Accepted 9 October 2013

Academic Editor: Ralf Lichtinghagen

Copyright © 2013 Alberto Gajofatto et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. B. D. Trapp, J. Peterson, R. M. Ransohoff, R. Rudick, S. Mörk, and L. Bö, “Axonal transection in the lesions of multiple sclerosis,” The New England Journal of Medicine, vol. 338, no. 5, pp. 278–285, 1998. View at Publisher · View at Google Scholar · View at Scopus
  2. J. H. van Waesberghe, W. Kamphorst, C. J. de Groot et al., “Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability,” Annals of Neurology, vol. 46, no. 5, pp. 747–754, 1999. View at Google Scholar
  3. B. Ferguson, M. K. Matyszak, M. M. Esiri, and V. H. Perry, “Axonal damage in acute multiple sclerosis lesions,” Brain, vol. 120, no. 3, pp. 393–399, 1997. View at Publisher · View at Google Scholar · View at Scopus
  4. D. Barnes, P. M. G. Munro, B. D. Youl, J. W. Prineas, and W. I. McDonald, “The longstanding MS lesion. A quantitative MRI and electron microscopic study,” Brain, vol. 114, no. 3, pp. 1271–1280, 1991. View at Google Scholar · View at Scopus
  5. J. van Horssen, B. P. Brink, H. E. de Vries, P. Van der Valk, and L. Bø, “The blood-brain barrier in cortical multiple sclerosis lesions,” Journal of Neuropathology and Experimental Neurology, vol. 66, no. 4, pp. 321–328, 2007. View at Publisher · View at Google Scholar · View at Scopus
  6. J. W. Peterson, L. Bö, S. Mörk, A. Chang, and B. D. Trapp, “Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions,” Annals of Neurology, vol. 50, no. 3, pp. 389–400, 2001. View at Publisher · View at Google Scholar · View at Scopus
  7. C. F. Lucchinetti, B. F. G. Popescu, R. F. Bunyan et al., “Inflammatory cortical demyelination in early multiple sclerosis,” The New England Journal of Medicine, vol. 365, no. 23, pp. 2188–2197, 2011. View at Google Scholar · View at Scopus
  8. A. Charil, A. Dagher, J. P. Lerch, A. P. Zijdenbos, K. J. Worsley, and A. C. Evans, “Focal cortical atrophy in multiple sclerosis: relation to lesion load and disability,” NeuroImage, vol. 34, no. 2, pp. 509–517, 2007. View at Publisher · View at Google Scholar · View at Scopus
  9. R. Reynolds, F. Roncaroli, R. Nicholas, B. Radotra, D. Gveric, and O. Howell, “The neuropathological basis of clinical progression in multiple sclerosis,” Acta Neuropathologica, vol. 122, no. 2, pp. 155–170, 2011. View at Publisher · View at Google Scholar · View at Scopus
  10. J. J. Geurts, M. Calabrese, E. Fisher, and R. A. Rudick, “Measurement and clinical effect of grey matter pathology in multiple sclerosis,” The Lancet Neurology, vol. 11, no. 12, pp. 1082–1192, 2012. View at Publisher · View at Google Scholar
  11. S. Sawcer, “The complex genetics of multiple sclerosis: pitfalls and prospects,” Brain, vol. 131, no. 12, pp. 3118–3131, 2008. View at Publisher · View at Google Scholar · View at Scopus
  12. International Multiple Sclerosis Genetics Consortium, “MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis,” Brain, vol. 136, no. 6, pp. 1778–1782, 2013. View at Publisher · View at Google Scholar
  13. A. Ascherio and K. L. Munger, “Environmental risk factors for multiple sclerosis. Part I: the role of infection,” Annals of Neurology, vol. 61, no. 4, pp. 288–299, 2007. View at Publisher · View at Google Scholar · View at Scopus
  14. A. Ascherio and K. L. Munger, “Environmental risk factors for multiple sclerosis. Part II: noninfectious factors,” Annals of Neurology, vol. 61, no. 6, pp. 504–513, 2007. View at Publisher · View at Google Scholar · View at Scopus
  15. A. Nylander and D. A. Hafler, “Multiple sclerosis,” Journal of Clinical Investigation, vol. 122, no. 4, pp. 1180–1188, 2012. View at Publisher · View at Google Scholar · View at Scopus
  16. C. Confavreux and S. Vukusic, “Natural history of multiple sclerosis: a unifying concept,” Brain, vol. 129, no. 3, pp. 606–616, 2006. View at Publisher · View at Google Scholar · View at Scopus
  17. D. H. Miller and S. M. Leary, “Primary-progressive multiple sclerosis,” The Lancet Neurology, vol. 6, no. 10, pp. 903–912, 2007. View at Publisher · View at Google Scholar · View at Scopus
  18. C. Confavreux, S. Vukusic, T. Moreau, and P. Adeleine, “Relapses and progression of disability in multiple sclerosis,” The New England Journal of Medicine, vol. 343, no. 20, pp. 1430–1438, 2000. View at Publisher · View at Google Scholar · View at Scopus
  19. M. Tintoré, A. Rovira, J. Rio et al., “Is optic neuritis more benign than other first attacks in multiple sclerosis?” Annals of Neurology, vol. 57, no. 2, pp. 210–215, 2005. View at Publisher · View at Google Scholar · View at Scopus
  20. E. M. Mowry, S. Deen, I. Malikova, J. Pelletier, P. Bacchetti, and E. Waubant, “The onset location of multiple sclerosis predicts the location of subsequent relapses,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 80, no. 4, pp. 400–403, 2009. View at Publisher · View at Google Scholar · View at Scopus
  21. M. P. Sormani, M. Tintorè, M. Rovaris et al., “Will Rogers phenomenon in multiple sclerosis,” Annals of Neurology, vol. 64, no. 4, pp. 428–433, 2008. View at Publisher · View at Google Scholar · View at Scopus
  22. M. Eriksson, O. Andersen, and B. Runmarker, “Long-term follow up of patients with clinically isolated syndromes, relapsing-remitting and secondary progressive multiple sclerosis,” Multiple Sclerosis, vol. 9, no. 3, pp. 260–274, 2003. View at Publisher · View at Google Scholar · View at Scopus
  23. C. H. Polman, S. C. Reingold, B. Banwell et al., “Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria,” Annals of Neurology, vol. 69, no. 2, pp. 292–302, 2011. View at Publisher · View at Google Scholar · View at Scopus
  24. B. G. Weinshenker, G. P. A. Rice, J. H. Noseworthy, W. Carriere, J. Baskerville, and G. C. Ebers, “The natural history of multiple sclerosis: a geographically based study. 3. Multivariate analysis of predictive factors and models of outcome,” Brain, vol. 114, no. 2, pp. 1045–1056, 1991. View at Google Scholar · View at Scopus
  25. C. Confavreux, S. Vukusic, and P. Adeleine, “Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process,” Brain, vol. 126, no. 4, pp. 770–782, 2003. View at Publisher · View at Google Scholar · View at Scopus
  26. H. Tremlett, D. Paty, and V. Devonshire, “Disability progression in multiple sclerosis is slower than previously reported,” Neurology, vol. 66, no. 2, pp. 172–177, 2006. View at Publisher · View at Google Scholar · View at Scopus
  27. M. Debouverie, S. Pittion-Vouyovitch, S. Louis, and F. Guillemin, “Natural history of multiple sclerosis in a population-based cohort,” European Journal of Neurology, vol. 15, no. 9, pp. 916–921, 2008. View at Publisher · View at Google Scholar · View at Scopus
  28. H. Tremlett, Y. Zhao, and V. Devonshire, “Natural history of secondary-progressive multiple sclerosis,” Multiple Sclerosis, vol. 14, no. 3, pp. 314–324, 2008. View at Publisher · View at Google Scholar · View at Scopus
  29. S. Vukusic and C. Confavreux, “Prognostic factors for progression of disability in the secondary progressive phase of multiple sclerosis,” Journal of the Neurological Sciences, vol. 206, no. 2, pp. 135–137, 2003. View at Publisher · View at Google Scholar · View at Scopus
  30. B. Runmarker and O. Andersen, “Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up,” Brain, vol. 116, no. 1, pp. 117–134, 1993. View at Google Scholar · View at Scopus
  31. M. W. Koch, M. Uyttenboogaart, A. van Harten, and J. de Keyser, “Factors associated with the risk of secondary progression in multiple sclerosis,” Multiple Sclerosis, vol. 14, no. 6, pp. 799–803, 2008. View at Publisher · View at Google Scholar · View at Scopus
  32. H. Tremlett, M. Yousefi, V. Devonshire, P. Rieckmann, and Y. Zhao, “Impact of multiple sclerosis relapses on progression diminishes with time,” Neurology, vol. 73, no. 20, pp. 1616–1623, 2009. View at Publisher · View at Google Scholar · View at Scopus
  33. M. Filippi, D. W. Paty, L. Kappos et al., “Correlations between changes in disability and T2-weighted brain MRI activity in multiple sclerosis: a follow-up study,” Neurology, vol. 45, no. 2, pp. 255–260, 1995. View at Google Scholar · View at Scopus
  34. L. Kappos, D. Moeri, E. W. Radue et al., “Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis,” The Lancet, vol. 353, no. 9157, pp. 964–969, 1999. View at Publisher · View at Google Scholar · View at Scopus
  35. S. Mesaros, M. A. Rocca, M. P. Sormani, A. Charil, G. Comi, and M. Filippi, “Clinical and conventional MRI predictors of disability and brain atrophy accumulation in RRMS: a large scale, short-term follow-up study,” Journal of Neurology, vol. 255, no. 9, pp. 1378–1383, 2008. View at Publisher · View at Google Scholar · View at Scopus
  36. S. A. Gauthier, M. Mandel, C. R. G. Guttmann et al., “Predicting short-term disability in multiple sclerosis,” Neurology, vol. 68, no. 24, pp. 2059–2065, 2007. View at Publisher · View at Google Scholar · View at Scopus
  37. V. L. Stevenson, G. T. Ingle, D. H. Miller, and A. J. Thompson, “Magnetic resonance imaging predictors of disability in primary progressive multiple sclerosis: a 5-year study,” Multiple Sclerosis, vol. 10, no. 4, pp. 398–401, 2004. View at Publisher · View at Google Scholar · View at Scopus
  38. M. Sailer, N. A. Losseff, L. Wang, M. L. Gawne-Cain, A. J. Thompson, and D. H. Miller, “T1 lesion load and cerebral atrophy as a marker for clinical progression in patients with multiple sclerosis. A prospective 18 months follow-up study,” European Journal of Neurology, vol. 8, no. 1, pp. 37–42, 2001. View at Publisher · View at Google Scholar · View at Scopus
  39. A. Minneboo, B. Jasperse, F. Barkhof et al., “Predicting short-term disability progression in early multiple sclerosis: added value of MRI parameters,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 79, no. 8, pp. 917–923, 2008. View at Publisher · View at Google Scholar · View at Scopus
  40. Z. Khaleeli, O. Ciccatelli, F. Manfredonia et al., “Predicting progression in primary progressive multiple sclerosis: a 10-year multicenter study,” Annals of Neurology, vol. 63, no. 6, pp. 790–793, 2008. View at Publisher · View at Google Scholar · View at Scopus
  41. V. Popescu, F. Agosta, H. E. Hulst et al., “Brain atrophy and lesion load predict long term disability in multiple sclerosis,” Journal of Neurology, Neurosurgery, and Psychiatry, vol. 84, no. 10, pp. 1082–1091, 2013. View at Publisher · View at Google Scholar
  42. B. Jasperse, H. Vrenken, E. Sanz-Arigita et al., “Regional brain atrophy development is related to specific aspects of clinical dysfunction in multiple sclerosis,” NeuroImage, vol. 38, no. 3, pp. 529–537, 2007. View at Publisher · View at Google Scholar · View at Scopus
  43. J. Sepulcre, J. Sastre-Garriga, M. Cercignani, G. T. Ingle, D. H. Miller, and A. J. Thompson, “Regional gray matter atrophy in early primary progressive multiple sclerosis: a voxel-based morphometry study,” Archives of Neurology, vol. 63, no. 8, pp. 1175–1180, 2006. View at Publisher · View at Google Scholar · View at Scopus
  44. J. T. Chen, S. Narayanan, D. L. Collins, S. M. Smith, P. M. Matthews, and D. L. Arnold, “Relating neocortical pathology to disability progression in multiple sclerosis using MRI,” NeuroImage, vol. 23, no. 3, pp. 1168–1175, 2004. View at Publisher · View at Google Scholar · View at Scopus
  45. L. K. Fisniku, D. T. Chard, J. S. Jackson et al., “Gray matter atrophy is related to long-term disability in multiple sclerosis,” Annals of Neurology, vol. 64, no. 3, pp. 247–254, 2008. View at Publisher · View at Google Scholar · View at Scopus
  46. S. D. Roosendaal, K. Bendfeldt, H. Vrenken et al., “Grey matter volume in a large cohort of MS patients: relation to MRI parameters and disability,” Multiple Sclerosis, vol. 17, no. 9, pp. 1098–1106, 2011. View at Publisher · View at Google Scholar · View at Scopus
  47. R. A. Rudick, J.-C. Lee, K. Nakamura, and E. Fisher, “Gray matter atrophy correlates with MS disability progression measured with MSFC but not EDSS,” Journal of the Neurological Sciences, vol. 282, no. 1-2, pp. 106–111, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. M. Calabrese, C. Romualdi, V. Poretto et al., “The changing clinical course of multiple sclerosis: a matter of grey matter,” Annals of Neurology, vol. 74, no. 1, pp. 76–83, 2013. View at Publisher · View at Google Scholar
  49. M. Sailer, B. Fischl, D. Salat et al., “Focal thinning of the cerebral cortex in multiple sclerosis,” Brain, vol. 126, no. 8, pp. 1734–1744, 2003. View at Publisher · View at Google Scholar · View at Scopus
  50. B. Audoin, G. R. Davies, L. Finisku, D. T. Chard, A. J. Thompson, and D. H. Miller, “Localization of grey matter atrophy in early RRMS: a longitudinal study,” Journal of Neurology, vol. 253, no. 11, pp. 1495–1501, 2006. View at Publisher · View at Google Scholar · View at Scopus
  51. M. Calabrese, M. Atzori, V. Bernardi et al., “Cortical atrophy is relevant in multiple sclerosis at clinical onset,” Journal of Neurology, vol. 254, no. 9, pp. 1212–1220, 2007. View at Publisher · View at Google Scholar · View at Scopus
  52. R. H. B. Benedict, D. Ramasamy, F. Munschauer, B. Weinstock-Guttman, and R. Zivadinov, “Memory impairment in multiple sclerosis: correlation with deep grey matter and mesial temporal atrophy,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 80, no. 2, pp. 201–206, 2009. View at Publisher · View at Google Scholar · View at Scopus
  53. N. L. Sicotte, K. C. Kern, B. S. Giesser et al., “Regional hippocampal atrophy in multiple sclerosis,” Brain, vol. 131, no. 4, pp. 1134–1141, 2008. View at Publisher · View at Google Scholar · View at Scopus
  54. M. Calabrese, V. Poretto, A. Favaretto et al., “Cortical lesion load associates with progression of disability in multiple sclerosis,” Brain, vol. 135, no. 10, pp. 2952–2961, 2012. View at Publisher · View at Google Scholar
  55. G. J. Lycklama À Nijeholt, M. A. A. van Walderveen, J. A. Castelijns et al., “Brain and spinal cord abnormalities in multiple sclerosis: correlation between MRI parameters, clinical subtypes and symptoms,” Brain, vol. 121, no. 4, pp. 687–697, 1998. View at Publisher · View at Google Scholar · View at Scopus
  56. N. A. Losseff, S. L. Webb, J. I. O'Riordan et al., “Spinal cord atrophy and disability in multiple sclerosis. A new reproducible and sensitive MRI method with potential to monitor disease progression,” Brain, vol. 119, no. 3, pp. 701–708, 1996. View at Publisher · View at Google Scholar · View at Scopus
  57. M. Rovaris, M. Bozzali, G. Santuccio et al., “Relative contributions of brain and cervical cord pathology to multiple sclerosis disability: a study with magnetisation transfer ratio histogram analysis,” Journal of Neurology Neurosurgery and Psychiatry, vol. 69, no. 6, pp. 723–727, 2000. View at Publisher · View at Google Scholar · View at Scopus
  58. F. Agosta, M. Rovaris, E. Pagani, M. P. Sormani, G. Comi, and M. Filippi, “Magnetization transfer MRI metrics predict the accumulation of disability 8 years later in patients with multiple sclerosis,” Brain, vol. 129, no. 10, pp. 2620–2627, 2006. View at Publisher · View at Google Scholar · View at Scopus
  59. M. Rovaris, E. Judica, A. Gallo et al., “Grey matter damage predicts the evolution of primary progressive multiple sclerosis at 5 years,” Brain, vol. 129, no. 10, pp. 2628–2634, 2006. View at Publisher · View at Google Scholar · View at Scopus
  60. M. Calabrese, F. Rinaldi, D. Seppi et al., “Cortical diffusion-tensor imaging abnormalities in multiple sclerosis: a 3-year longitudinal study,” Radiology, vol. 261, no. 3, pp. 891–898, 2011. View at Publisher · View at Google Scholar · View at Scopus
  61. A. Martínez-Yélamos, A. Rovira, R. Sánchez-Valle et al., “CSF 14-3-3 protein assay and MRI as prognostic markers in patients with a clinically isolated syndrome suggestive of MS,” Journal of Neurology, vol. 251, no. 10, pp. 1278–1279, 2004. View at Publisher · View at Google Scholar · View at Scopus
  62. M. Colucci, L. Roccatagliata, E. Capello et al., “The 14-3-3 protein in multiple sclerosis: a marker of disease severity,” Multiple Sclerosis, vol. 10, no. 5, pp. 477–481, 2004. View at Publisher · View at Google Scholar · View at Scopus
  63. F. G. Joseph, C. L. Hirst, T. P. Pickersgill, Y. Ben-Shlomo, N. P. Robertson, and N. J. Scolding, “CSF oligoclonal band status informs prognosis in multiple sclerosis: a case control study of 100 patients,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 80, no. 3, pp. 292–296, 2009. View at Publisher · View at Google Scholar · View at Scopus
  64. N. Norgren, P. Sundström, A. Svenningsson, L. Rosengren, T. Stigbrand, and M. Gunnarsson, “Neurofilament and glial fibrillary acidic protein in multiple sclerosis,” Neurology, vol. 63, no. 9, pp. 1586–1590, 2004. View at Google Scholar · View at Scopus
  65. J. Salzer, A. Svenningsson, and P. Sundström, “Neurofilament light as a prognostic marker in multiple sclerosis,” Multiple Sclerosis, vol. 16, no. 3, pp. 287–292, 2010. View at Publisher · View at Google Scholar · View at Scopus
  66. A. Petzold, M. J. Eikelenboom, G. Keir et al., “Axonal damage accumulates in the progressive phase of multiple sclerosis: three year follow up study,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 76, no. 2, pp. 206–211, 2005. View at Publisher · View at Google Scholar · View at Scopus
  67. K. Rejdak, A. Petzold, Z. Stelmasiak, and G. Giovannoni, “Cerebrospinal fluid brain specific proteins in relation to nitric oxide metabolites during relapse of multiple sclerosis,” Multiple Sclerosis, vol. 14, no. 1, pp. 59–66, 2008. View at Publisher · View at Google Scholar · View at Scopus
  68. L. M. Villar, N. García-Barragán, M. Espiño et al., “Influence of oligoclonal IgM specificity in multiple sclerosis disease course,” Multiple Sclerosis, vol. 14, no. 2, pp. 183–187, 2008. View at Publisher · View at Google Scholar · View at Scopus
  69. J. Mandrioli, P. Sola, R. Bedin, M. Gambini, and E. Merelli, “A multifactorial prognostic index in multiple sclerosis: cerebrospinal fluid IgM oligoclonal bands and clinical features to predict the evolution of the disease,” Journal of Neurology, vol. 255, no. 7, pp. 1023–1031, 2008. View at Publisher · View at Google Scholar · View at Scopus
  70. M. Comabella, M. Fernández, R. Martin et al., “Cerebrospinal fluid chitinase 3-like 1 levels are associated with conversion to multiple sclerosis,” Brain, vol. 133, no. 4, pp. 1082–1093, 2010. View at Publisher · View at Google Scholar · View at Scopus
  71. A. Gajofatto, S. Monaco, M. Fiorini et al., “Assessment of outcome predictors in first-episode acute myelitis a retrospective study of 53 cases,” Archives of Neurology, vol. 67, no. 6, pp. 724–730, 2010. View at Publisher · View at Google Scholar · View at Scopus
  72. H. Tremlett, Y. Zhao, P. Rieckmann, and M. Hutchinson, “New perspectives in the natural history of multiple sclerosis,” Neurology, vol. 74, no. 24, pp. 2004–2015, 2010. View at Publisher · View at Google Scholar · View at Scopus
  73. A. Gajofatto, M. Bongianni, G. Zanusso et al., “Clinical and biomarker assessment of demyelinating events suggesting multiple sclerosis,” Acta Neurologica Scandinavica, vol. 128, no. 5, pp. 336–344, 2013. View at Publisher · View at Google Scholar
  74. A. E. Hensiek, S. R. Seaman, L. F. Barcellos et al., “Familial effects on the clinical course of multiple sclerosis,” Neurology, vol. 68, no. 5, pp. 376–383, 2007. View at Publisher · View at Google Scholar · View at Scopus
  75. C. Confavreux and S. Vukusic, “Age at disability milestones in multiple sclerosis,” Brain, vol. 129, no. 3, pp. 595–605, 2006. View at Publisher · View at Google Scholar · View at Scopus
  76. C. Renoux, S. Vukusic, Y. Mikaeloff et al., “Natural history of multiple sclerosis with childhood onset,” The New England Journal of Medicine, vol. 356, no. 25, pp. 2603–2613, 2007. View at Publisher · View at Google Scholar · View at Scopus
  77. M. Tutuncu, J. Tang, N. A. Zeid et al., “Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis,” Multiple Sclerosis, vol. 19, no. 2, pp. 188–198, 2013. View at Publisher · View at Google Scholar
  78. A. Scalfari, A. Neuhaus, A. Degenhardt et al., “The natural history of multiple sclerosis, a geographically based study 10: relapses and long-term disability,” Brain, vol. 133, no. 7, pp. 1914–1929, 2010. View at Publisher · View at Google Scholar · View at Scopus
  79. M. Hutchinson, “Truly benign multiple sclerosis is rare: Let's stop fooling ourselves—commentary,” Multiple Sclerosis, vol. 18, no. 1, p. 15, 2012. View at Publisher · View at Google Scholar · View at Scopus
  80. J. F. Kurtzke, “Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS),” Neurology, vol. 33, no. 11, pp. 1444–1452, 1983. View at Google Scholar · View at Scopus
  81. F. D. Lublin and S. C. Reingold, “Defining the clinical course of multiple sclerosis: results of an international survey,” Neurology, vol. 46, no. 4, pp. 907–911, 1996. View at Google Scholar · View at Scopus
  82. S. J. Pittock, R. L. McClelland, W. T. Mayr et al., “Clinical implications of benign multiple sclerosis: a 20-year population-based follow-up study,” Annals of Neurology, vol. 56, no. 2, pp. 303–306, 2004. View at Publisher · View at Google Scholar · View at Scopus
  83. M. P. Amato, E. Portaccio, M. L. Stromillo et al., “Cognitive assessment and quantitative magnetic resonance metrics can help to identify benign multiple sclerosis,” Neurology, vol. 71, no. 9, pp. 632–638, 2008. View at Publisher · View at Google Scholar · View at Scopus
  84. A.-L. Sayao, V. Devonshire, and H. Tremlett, “Longitudinal follow-up of “benign” multiple sclerosis at 20 years,” Neurology, vol. 68, no. 7, pp. 496–500, 2007. View at Publisher · View at Google Scholar · View at Scopus
  85. G. S. M. Ramsaransing and J. de Keyser, “Predictive value of clinical characteristics for “benign” multiple sclerosis,” European Journal of Neurology, vol. 14, no. 8, pp. 885–889, 2007. View at Publisher · View at Google Scholar · View at Scopus
  86. E. Leray, M. Coustans, E. Le Page, J. Yaouanq, J. Oger, and G. Edan, “‘Clinically definite benign multiple sclerosis’, an unwarranted conceptual hodgepodge: evidence from a 30-year observational study,” Multiple Sclerosis, vol. 19, no. 4, pp. 458–465, 2013. View at Publisher · View at Google Scholar
  87. L. Costelloe, A. Thompson, C. Walsh, N. Tubridy, and M. Hutchinson, “Long-term clinical relevance of criteria for designating multiple sclerosis as benign after 10 years of disease,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 79, no. 11, pp. 1245–1248, 2008. View at Publisher · View at Google Scholar · View at Scopus
  88. P. O'Connor, P. Marchetti, L. Lee, and M. Perera, “Evoked potential abnormality scores are a useful measure of disease burden in relapsing-remitting multiple sclerosis,” Annals of Neurology, vol. 44, no. 3, pp. 404–407, 1998. View at Publisher · View at Google Scholar · View at Scopus
  89. P. Fuhr, A. Borggrefe-Chappuis, C. Schindler, and L. Kappos, “Visual and motor evoked potentials in the course of multiple sclerosis,” Brain, vol. 124, no. 11, pp. 2162–2168, 2001. View at Google Scholar · View at Scopus
  90. L. Leocani, M. Rovaris, F. M. Boneschi et al., “Multimodal evoked potentials to assess the evolution of multiple sclerosis: a longitudinal study,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 77, no. 9, pp. 1030–1035, 2006. View at Publisher · View at Google Scholar · View at Scopus
  91. B. A. Kallmann, S. Fackelmann, K. V. Toyka, P. Rieckmann, and K. Reiners, “Early abnormalities of evoked potentials and future disability in patients with multiple sclerosis,” Multiple Sclerosis, vol. 12, no. 1, pp. 58–65, 2006. View at Publisher · View at Google Scholar · View at Scopus
  92. P. Invernizzi, L. Bertolasi, M. R. Bianchi, M. Turatti, A. Gajofatto, and M. D. Benedetti, “Prognostic value of multimodal evoked potentials in multiple sclerosis: the EP score,” Journal of Neurology, vol. 258, no. 11, pp. 1933–1939, 2011. View at Google Scholar · View at Scopus
  93. R. Schlaeger, M. D'Souza, C. Schindler et al., “Prediction of long-term disability in multiple sclerosis,” Multiple Sclerosis, vol. 18, no. 1, pp. 31–38, 2012. View at Publisher · View at Google Scholar · View at Scopus
  94. R. Pelayo, X. Montalban, T. Minoves et al., “Do multimodal evoked potentials add information to MRI in clinically isolated syndromes?” Multiple Sclerosis, vol. 16, no. 1, pp. 55–61, 2010. View at Publisher · View at Google Scholar · View at Scopus
  95. A. Petzold, J. F. de Boer, S. Schippling et al., “Optical coherence tomography in multiple sclerosis: a systematic review and meta-analysis,” The Lancet Neurology, vol. 9, no. 9, pp. 921–932, 2010. View at Publisher · View at Google Scholar · View at Scopus
  96. K. L. Young, A. U. Brandt, A. Petzold et al., “Loss of retinal nerve fibre layer axons indicates white but not grey matter damage in early multiple sclerosis,” European Journal of Neurology, vol. 20, no. 5, pp. 803–811, 2013. View at Publisher · View at Google Scholar
  97. J. N. Ratchford, S. Saidha, E. S. Sotirchos et al., “Active MS is associated with accelerated retinal ganglion cell/inner plexiform layer thinning,” Neurology, vol. 80, no. 1, pp. 47–54, 2013. View at Publisher · View at Google Scholar
  98. S. Saidha, S. B. Syc, M. A. Ibrahim et al., “Primary retinal pathology in multiple sclerosis as detected by optical coherence tomography,” Brain, vol. 134, no. 2, pp. 518–533, 2011. View at Publisher · View at Google Scholar · View at Scopus
  99. P. Albrecht, M. Ringelstein, A. K. Müller et al., “Degeneration of retinal layers in multiple sclerosis subtypes quantified by optical coherence tomography,” Multiple Sclerosis, vol. 18, no. 10, pp. 1422–1429, 2012. View at Publisher · View at Google Scholar
  100. F. Fazekas, P. Soelberg-Sorensen, G. Comi, and M. Filippi, “MRI to monitor treatment efficacy in multiple sclerosis,” Journal of Neuroimaging, vol. 17, supplement s1, pp. 50S–55S, 2007. View at Publisher · View at Google Scholar · View at Scopus
  101. P. A. Brex, O. Ciccarelli, J. I. O'Riordan, M. Sailer, A. J. Thompson, and D. H. Miller, “A longitudinal study of abnormalities on MRI and disability from multiple sclerosis,” The New England Journal of Medicine, vol. 346, no. 3, pp. 158–164, 2002. View at Publisher · View at Google Scholar · View at Scopus
  102. M. Filippi, M. A. Horsfield, S. P. Morrissey et al., “Quantitative brain MRI lesion load predicts the course of clinically isolated syndromes suggestive of multiple sclerosis,” Neurology, vol. 44, no. 4, pp. 635–641, 1994. View at Google Scholar · View at Scopus
  103. F. Pérez-Miralles, J. Sastre-Garriga, M. Tintoré et al., “Clinical impact of early brain atrophy in clinically isolated syndromes,” Multiple Sclerosis, 2013. View at Publisher · View at Google Scholar
  104. M. A. Rocca, S. Mesaros, E. Pagani, M. P. Sormani, G. Comi, and M. Filippi, “Thalamic damage and long-term progression of disability in multiple sclerosis,” Radiology, vol. 257, no. 2, pp. 463–469, 2010. View at Publisher · View at Google Scholar · View at Scopus
  105. A. Kutzelnigg, J. C. Faber-Rod, J. Bauer et al., “Widespread demyelination in the cerebellar cortex in multiple sclerosis,” Brain Pathology, vol. 17, no. 1, pp. 38–44, 2007. View at Publisher · View at Google Scholar · View at Scopus
  106. M. Calabrese, I. Mattisi, F. Rinaldi et al., “Magnetic resonance evidence of cerebellar cortical pathology in multiple sclerosis,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 81, no. 4, pp. 401–404, 2010. View at Publisher · View at Google Scholar · View at Scopus
  107. M. Calabrese, P. Grossi, A. Favaretto et al., “Cortical pathology in multiple sclerosis patients with epilepsy: a 3 year longitudinal study,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 83, no. 1, pp. 49–54, 2012. View at Publisher · View at Google Scholar · View at Scopus
  108. G. Lycklama, A. Thompson, M. Filippi et al., “Spinal-cord MRI in multiple sclerosis,” The Lancet Neurology, vol. 2, no. 9, pp. 555–562, 2003. View at Publisher · View at Google Scholar · View at Scopus
  109. F. Agosta, M. Absinta, M. P. Sormani et al., “In vivo assessment of cervical cord damage in MS patients: a longitudinal diffusion tensor MRI study,” Brain, vol. 130, no. 8, pp. 2211–2219, 2007. View at Publisher · View at Google Scholar · View at Scopus
  110. A. Martínez-Yélamos, A. Saiz, J. Bas, J. J. Hernandez, F. Graus, and T. Arbizu, “Tau protein in cerebrospinal fluid: a possible marker of poor outcome in patients with early relapsing-remitting multiple sclerosis,” Neuroscience Letters, vol. 363, no. 1, pp. 14–17, 2004. View at Publisher · View at Google Scholar · View at Scopus
  111. J. Brettschneider, H. Tumani, U. Kiechle et al., “IgG antibodies against measles, rubella, and varicella zoster virus predict conversion to multiple sclerosis in clinically isolated syndrome,” PLoS ONE, vol. 4, no. 11, Article ID e7638, 2009. View at Publisher · View at Google Scholar · View at Scopus
  112. M. Khademi, I. Kockum, M. L. Andersson et al., “Cerebrospinal fluid CXCL13 in multiple sclerosis: a suggestive prognostic marker for the disease course,” Multiple Sclerosis, vol. 17, no. 3, pp. 335–343, 2011. View at Publisher · View at Google Scholar · View at Scopus
  113. C. E. Teunissen, P. C. Dijkstra, and C. Polman, “Biological markers in CSF and blood for axonal degeneration in multiple sclerosis,” The Lancet Neurology, vol. 4, no. 1, pp. 32–41, 2005. View at Publisher · View at Google Scholar · View at Scopus
  114. A. Gajofatto, M. Bongianni, G. Zanusso, M. D. Benedetti, and S. Monaco, “Are cerebrospinal fluid biomarkers useful in predicting the prognosis of multiple sclerosis patients?” International Journal of Molecular Sciences, vol. 12, no. 11, pp. 7960–7970, 2011. View at Publisher · View at Google Scholar · View at Scopus
  115. E. Kapaki, G. P. Paraskevas, M. Michalopoulou, and K. Kilidireas, “Increased cerebrospinal fluid tau protein in multiple sclerosis,” European Neurology, vol. 43, no. 4, pp. 228–232, 2000. View at Google Scholar · View at Scopus
  116. H. Bartosik-Psujek and J. J. Archelos, “Tau protein and 14-3-3 are elevated in the cerebrospinal fluid of patients with multiple sclerosis and correlate with intrathecal synthesis of IgG,” Journal of Neurology, vol. 251, no. 4, pp. 414–420, 2004. View at Publisher · View at Google Scholar · View at Scopus
  117. J. Brettschneider, M. Maier, S. Arda et al., “Tau protein level in cerebrospinal fluid is increased in patients with early multiple sclerosis,” Multiple Sclerosis, vol. 11, no. 3, pp. 261–265, 2005. View at Publisher · View at Google Scholar · View at Scopus
  118. M. Terzi, A. Birinci, E. Çetinkaya, and M. K. Onar, “Cerebrospinal fluid total tau protein levels in patients with multiple sclerosis,” Acta Neurologica Scandinavica, vol. 115, no. 5, pp. 325–330, 2007. View at Publisher · View at Google Scholar · View at Scopus
  119. J. Frederiksen, K. Kristensen, J. M. C. Bahl, and M. Christiansen, “Tau protein: a possible prognostic factor in optic neuritis and multiple sclerosis,” Multiple Sclerosis, vol. 18, no. 5, pp. 592–599, 2012. View at Publisher · View at Google Scholar · View at Scopus
  120. F. J. Jiménez-Jiménez, J. M. Zurdo, A. Hernanz et al., “Tau protein concentrations in cerebrospinal fluid of patients with multiple sclerosis,” Acta Neurologica Scandinavica, vol. 106, no. 6, pp. 351–354, 2002. View at Publisher · View at Google Scholar · View at Scopus
  121. J. Guimarães, M. J. Cardoso, and M. J. Sá, “Tau protein seems not to be a useful routine clinical marker of axonal damage in multiple sclerosis,” Multiple Sclerosis, vol. 12, no. 3, pp. 354–356, 2006. View at Publisher · View at Google Scholar · View at Scopus
  122. C. E. Teunissen, E. Iacobaeus, M. Khademi et al., “Combination of CSF N-acetylaspartate and neurofilaments in multiple sclerosis,” Neurology, vol. 72, no. 15, pp. 1322–1329, 2009. View at Publisher · View at Google Scholar · View at Scopus
  123. M. Fiorini, G. Zanusso, M. D. Benedetti, P. G. Righetti, and S. Monaco, “Cerebrospinal fluid biomarkers in clinically isolated syndromes and multiple sclerosis,” Proteomics, vol. 1, no. 9, pp. 963–971, 2007. View at Publisher · View at Google Scholar · View at Scopus
  124. J. Jaworski, M. Psujek, M. Janczarek, M. Szczerbo-Trojanowska, and H. Bartosik-Psujek, “Total-tau in cerebrospinal fluid of patients with multiple sclerosis decreases in secondary progressive stage of disease and reflects degree of brain atrophy,” Upsala Journal of Medical Sciences, vol. 117, no. 3, pp. 284–292, 2012. View at Publisher · View at Google Scholar
  125. N. de Stefano, A. Giorgio, M. Battaglini et al., “Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes,” Neurology, vol. 74, no. 23, pp. 1868–1876, 2010. View at Publisher · View at Google Scholar · View at Scopus
  126. J. de Seze, K. Peoc'h, D. Ferriby, T. Stojkovic, J.-L. Laplanche, and P. Vermersch, “14-3-3 protein in the cerebrospinal fluid of patients with acute transverse myelitis and multiple sclerosis,” Journal of Neurology, vol. 249, no. 5, pp. 626–627, 2002. View at Publisher · View at Google Scholar · View at Scopus
  127. K. Hein (née Maier), A. Köhler, R. Diem et al., “Biological markers for axonal degeneration in CSF and blood of patients with the first event indicative for multiple sclerosis,” Neuroscience Letters, vol. 436, no. 1, pp. 72–76, 2008. View at Publisher · View at Google Scholar · View at Scopus
  128. C. Malmeström, S. Haghighi, L. Rosengren, O. Andersen, and J. Lycke, “Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS,” Neurology, vol. 61, no. 12, pp. 1720–1725, 2003. View at Google Scholar · View at Scopus
  129. J. Kuhle, D. Leppert, A. Petzold et al., “Neurofilament heavy chain in CSF correlates with relapses and disability in multiple sclerosis,” Neurology, vol. 76, no. 14, pp. 1206–1213, 2011. View at Publisher · View at Google Scholar · View at Scopus
  130. M. Khalil, C. Enzinger, C. Langkammer et al., “CSF neurofilament and N-acetylaspartate related brain changes in clinically isolated syndrome,” Multiple Sclerosis, vol. 19, no. 4, pp. 436–442, 2013. View at Publisher · View at Google Scholar
  131. B. Bielekova and R. Martin, “Development of biomarkers in multiple sclerosis,” Brain, vol. 127, no. 7, pp. 1463–1478, 2004. View at Publisher · View at Google Scholar · View at Scopus
  132. C. E. Teunissen, A. Petzold, J. L. Bennett et al., “A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking,” Neurology, vol. 73, no. 22, pp. 1914–1922, 2009. View at Publisher · View at Google Scholar · View at Scopus
  133. C. Teunissen, T. Menge, A. Altintas et al., “Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis,” Multiple Sclerosis, 2013. View at Publisher · View at Google Scholar