Evidence for a two-stage disability progression in multiple sclerosis

Abstract

It is well documented that disability accumulation in multiple sclerosis is correlated with axonal injury and that the extent of axonal injury is correlated with the degree of inflammation. However, the interdependence between focal inflammation, diffuse inflammation and neurodegeneration, and their relative contribution to clinical deficits, remains ambiguous. A hypothesis might be that early focal inflammation could be the pivotal event from which all else follows, suggesting the consideration of multiple sclerosis as a two-stage disease. This prompted us to define two phases in the disease course of multiple sclerosis by using two scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: an early phase, 'Phase 1', from multiple sclerosis clinical onset to irreversible Disability Status Scale 3 and a late phase, 'Phase 2', from irreversible Disability Status Scale 3 to irreversible Disability Status Scale 6. Outcome was assessed through five parameters: Phase 1 duration, age at Disability Status Scale 3, time to Disability Status Scale 6 from multiple sclerosis onset, Phase 2 duration and age at Disability Status Scale 6. The first three were calculated among all patients, while the last two were computed only among patients who had reached Disability Status Scale 3. The possible influence of early clinical markers on these outcomes was studied using Kaplan-Meier estimates and Cox models. The analysis was performed in the Rennes multiple sclerosis database (2054 patients, accounting for 26,273 patient-years) as a whole, and according to phenotype at onset (1609 relapsing/445 progressive onset). Our results indicated that the disability progression during Phase 2 was independent of that during Phase 1. Indeed, the median Phase 2 duration was nearly identical (from 6 to 9 years) irrespective of Phase 1 duration (<3, 3 to <6, 6 to <10, 10 to <15, >or=15 years) in the whole population, and in both phenotypes. In relapsing onset multiple sclerosis, gender, age at onset, residual deficit after the first relapse and relapses during the first 2 years of multiple sclerosis were found to be independent predictive factors of disability progression, but only during Phase 1. Our findings demonstrate that multiple sclerosis disability progression follows a two-stage process, with a first stage probably dependent on focal inflammation and a second stage probably independent of current focal inflammation. This concept has obvious implications for the future therapeutic strategy in multiple sclerosis.

Figure 1

Disability progression during Phase 2 (mean time from DSS 3 to DSS 6) in five subgroups defined according to the duration of Phase 1 (mean time from multiple sclerosis clinical onset to DSS 3) in the 718 multiple sclerosis patients who had reached both DSS 3 and DSS 6.

Figure 2

Kaplan–Meier estimated median age at multiple sclerosis clinical onset and at DSS score of 3 in the 2054 patients with multiple sclerosis, and Kaplan-Meier estimated median age at DSS score of 6 in the 1415 patients who had reached DSS 3, according to (i) disease phenotype at onset, (ii) gender and (iii) gender by disease phenotype at onset. Asterisk denotes the significant comparison (P < 0.05, progressive versus relapsing onset, and females versus males, respectively).

Figure 3

Kaplan–Meier estimated median age at clinical onset of multiple sclerosis and at DSS score of 3 in the 2054 patients with multiple sclerosis, and age at DSS score of 6 in the 1415 patients, who had reached DSS 3, according to age at onset, in the total multiple sclerosis population and in patients with multiple sclerosis classified by disease phenotype at multiple sclerosis onset.