Predictors of Disability in MS
Abstract & Commentary
Source: Confavreux C, et al. Early clinical predictors and progression of irreversible disability in multiple sclerosis: An amnesic process. Brain. 2003;126:770-782.
Confavreux and colleagues studied 1844 multiple sclerosis (MS) patients enrolled in a large European database up until 1997. Clinical variables were identified early in the course of the disease, and their continued prognostic significance was determined after the first stages of irreversible neurological disability. They used 3 scores on the Kurtzke Disability Status Scale as benchmarks of accumulated disability: EDSS 4 (limited walking but without cane); 6 (walking with unilateral aid); 7 (wheelchair restricted). Median times from onset of MS to assignment of a score of 4, 6, and 7 were significantly influenced by gender, age, symptoms, course (relapsing-remitting or progressive), time of onset of disease, degree of recovery after the first relapse, time to a second neurological episode, and the number of relapses in the first 5 years of disease. The median time from onset of MS to assignment of a score of 4, 6, and 7 was 8.4 years, 20.1 years, and 29.9 years, respectively. The median interval to reach landmarks of disability was significantly longer in females than males and inpatients with a younger age of onset. The interval was also longer in those with an initial relapsing-remitting course (85% of the patient cohort) vs a progressive one (15%); those with a complete rather than incomplete recovery; and those with a longer time from onset of MS to a second neurological event.
Times to assignment of a score of 6 or 7 were also influenced by the time interval from onset of MS to a score of 4. Those with a slower progression to 4 showed a delayed progression to 6 or 7. The median intervals to progression were longer in cases presenting initially with isolated optic neuritis, intermediate in cases presenting with isolated brainstem dysfunction, and shorter in patients presenting with dysfunction of long tracts. None of the assessable clinical variables substantially affected the time from a score of 4 to 6 or 7, or from a score of 6 to 7. Thus, the early clinical variables significantly influenced the time from the onset of MS to the assignment of a disability score of 4 but not the subsequent progression of disability to 6 and 7. Similarly, the total number of relapses in the first 5 years did not appear to affect the intervals to later progression to scores of 6 and 7.
Approximately half of the 1844 patients in the cohort received immunosuppressive drugs at some time in their disease course for at least 6 months, usually in the relapsing phase but not before the third relapse (mean of 6.2 years from onset of MS). The most widely used treatment was azathioprine (804 patients), followed by cytoxan (78), interferon beta (72), methotrexate (60), and mitoxantrone (18). Only azathioprine had a minor benefit in increasing the interval from onset of MS to assignment of a score of 4 but not subsequent scores of 6 or 7.
The long-term clinical disability information generated from the large cohort in this MS database is consistent with other studies and our own clinical impressions about disease progression in MS. Thus, Confavreux and colleagues verify prior studies that have consistently shown it takes longer to reach landmarks of irreversible disability in younger female patients with relapsing disease, patients presenting with optic neuritis, and patients with fewer relapses in the first years of disease. Their original contribution is that determining that these same good prognostic clinical variables up to an EDSS of 4 did not seem to remain predictive of the time course of disability past 4 to landmarks of 6 and 7. Their data support the concept that disability progression in MS may be a 2-stage process, the initial phase of variable duration occurring in the relapsing period of the disease that is influenced by the above clinical phenotypes, and a second phase that is more invariant to these baseline parameters at the onset of the disease. The time period from onset to a score of 4 takes place mainly in the relapsing phase, whereas subsequent accumulation of irreversible disability develops during the progressive phase. There is undoubtedly a biological explanation for the invariant course of later disability: Relapses represent recurrent focal inflammation, whereas progression signals a more chronic, diffuse neurodegeneration. One limitation of this study is that all of the data were generated prior to the more widespread use of interferon beta after 1997, which has been shown to favorably modify the natural history of disease. Nonetheless, their findings have implications for the design of future therapies targeting the later stages of disease that may signal progressive cell death in the central nervous system and inexorable disability. — Brian R. Apatoff
Dr. Apatoff is Associate Professor of Neurology, New York Presbyterian Hospital-Cornell Campus.