Sustained progression on the expanded disability status scale (EDSS) is a common outcome measure of disease progression in clinical studies of MS. Unfortunately, this outcome may not accurately measure long-term and irreversible disease progression. To assess the performance of definitions of sustained progression, patients with relapsing-remitting MS (RRMS) or a clinically isolated syndrome with evidence of lesions on a brain MRI were included in our study. Fifteen definitions of sustained progression using both the EDSS and the functional system (FS) scales were investigated. The impact of both relapses and changes in provider on the probability of maintaining progression was also evaluated. Although the provider scoring the EDSS sometimes changed during followup, the provider had access to previous EDSS scores. Between 15.8% and 42.2% of patients experienced sustained progression based on the definitions using EDSS as the outcome, but nearly 50% of these patients failed to maintain sustained progression for the duration of followup. When FS scales were used, progression was most common on the pyramidal and sensory scales. Unfortunately, progression on specific FS scales failed to be more sensitive to irreversible disability. Relapses or changes in provider did not explain the poor performance of the measures. Short-term changes in the EDSS or FS scores may not be an accurate marker of irreversible change in RRMS. 1. Introduction Measurement of disease progression in patients with multiple sclerosis (MS) is complicated by the occurrence of relapses and the potential for recovery, especially early in the disease course in patients with relapsing-remitting MS (RRMS). The most common way to measure disability in MS patients is the expanded disability status scale (EDSS), which is a 0–10 scale with 0.5 point steps based on eight functional system (FS) scales [1]. These FS scales measure seven separate aspects of the disease using five-to seven-step ordinal scales: pyramidal function, cerebellar function, brainstem function, sensory function, bowel/bladder function, mental function, and visual function. The remaining scale is a measure of the presence of other symptoms. In long-term followup studies, EDSS scores of 4, 6, or 7 are considered milestones in terms of disability, and reaching these milestones is a measure of disease progression, especially since patients rarely improve after such milestones are reached [2, 3]. Since the time to these EDSS scores is often long, a short-term indicator of disease progression early in the disease course is an
References
[1]
J. F. Kurtzke, “Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS),” Neurology, vol. 33, no. 11, pp. 1444–1452, 1983.
[2]
B. G. Weinshenker, B. Bass, G. P. A. Rice et al., “The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability,” Brain, vol. 112, no. 1, pp. 133–146, 1989.
[3]
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.
[4]
F. D. Lublin, M. Baier, and G. Cutter, “Effect of relapses on development of residual deficit in multiple sclerosis,” Neurology, vol. 61, no. 11, pp. 1528–1532, 2003.
[5]
H. L. Weiner, “The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease?” Annals of Neurology, vol. 65, no. 3, pp. 239–248, 2009.
[6]
A. J. Coles, D. A. S. Compston, K. W. Selmaj et al., “Alemtuzumab vs. interferon beta-1a in early multiple sclerosis,” The New England Journal of Medicine, vol. 359, no. 17, pp. 1786–1801, 2008.
[7]
R. A. Rudick, W. H. Stuart, P. A. Calabresi et al., “Natalizumab plus interferon beta-1a for relapsing multiple sclerosis,” The New England Journal of Medicine, vol. 354, no. 9, pp. 911–923, 2006.
[8]
G. C. Ebers, L. Heigenhauser, M. Daumer, C. Lederer, and J. H. Noseworthy, “Disability as an outcome in MS clinical trials,” Neurology, vol. 71, no. 9, pp. 624–631, 2008.
[9]
G. W. Ellison, L. W. Myers, B. D. Leake et al., “Design strategies in multiple sclerosis clinical trials,” Annals of Neurology, vol. 36, pp. S108–S112, 1994.
[10]
R. A. Rudick, D. E. Goodkin, L. D. Jacobs et al., “Impact of interferon beta-1a on neurologic disability in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG),” Neurology, vol. 49, no. 2, pp. 358–363, 1997.
[11]
S. A. Gauthier, B. I. Glanz, M. Mandel, and H. L. Weiner, “A model for the comprehensive investigation of a chronic autoimmune disease: the multiple sclerosis CLIMB study,” Autoimmunity Reviews, vol. 5, no. 8, pp. 532–536, 2006.
[12]
J. Hobart, J. Freeman, and A. Thompson, “Kurtzke scales revisited: the application of psychometric methods to clinical intuition,” Brain, vol. 123, no. 5, pp. 1027–1040, 2000.
[13]
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.
[14]
M. Kremenchutzky, G. P. A. Rice, J. Baskerville, D. M. Wingerchuk, and G. C. Ebers, “The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease,” Brain, vol. 129, no. 3, pp. 584–594, 2006.
[15]
S. Martinez-Yelamos, A. Martinez-Yelamos, G. Martin Ozaeta, V. Casado, O. Carmona, and T. Arbizu, “Regression to the mean in multiple sclerosis,” Multiple Sclerosis, vol. 12, no. 6, pp. 826–829, 2006.
[16]
M. J. Hohol, E. J. Orav, and H. L. Weiner, “Disease steps in multiple sclerosis: a simple approach to evaluate disease progression,” Neurology, vol. 45, no. 2, pp. 251–255, 1995.
