Eight-year follow-up study of brain atrophy in patients with MS
Fisher E, Rudick RA, Simon JH, Cutter G, Baier M, Lee J-C, Miller D, et al.;
Commented by , 16 Dec 2002
Background
Conventional MRI measurements of pathology in Multiple Sclerosis (MS) do not provide robust correlates of clinical disability, and there has been an increasing demand for more reliable markers of disease activity. In this context, a more global estimate of irreversible focal and diffuse pathological manifestations has been of interest.
Brain white matter consists mainly of axons and myelin, and measurements of atrophy therefore imply loss of these structures. A close relationship between tissue loss and disability would therefore be expected, although previous longitudinal studies have not been able to show this, perhaps due to short follow-up periods.
Aim
To characterize whole-brain atrophy in relapsing-remitting MS patients over an 8-year period. To determine if brain atrophy is related to subsequent disability and to identify MRI correlates of atrophy progression.
Methods
The authors reassessed patients from a phase III interferon beta-1a trial in a follow-up study 8 years after randomization. Clinical MRI data from 172 patients were used as baseline. Follow-up clinical data were obtained in 160 patients, 26 did not have a MRI done. Brain atrophy was estimated by automated calculation of brain parenchymal fraction (BPF).
Subgroup analysis was done if MRI measurements differed according to scanning protocol, MRI data were lost or follow-up data were missing. Data were collected to determine the relation between atrophy and disability (n=138), the progression of atrophy (n=106) and the correlation between lesion measurements from the original trial and BPF at follow-up (n = 134).
Results
Brain atrophy correlated with disability (r = 0.30, p<0,001). Atrophy rate during the original trial was the most significant MRI predictor of disability status at follow-up (r = 0,35, p < 0,0001). Brain atrophy at follow-up was related to lesion volumes measured at the original trail (e.g. T2 lesion load; r = -0,36, p<0,0002).
Discussion
The study showed that atrophy progressed during the 6 years after the original trial. The rate of atrophy was lower in the follow-up study (-0,33% pr. year) than in the original trial (-0,55% per year in the placebo group).
The authors explain these results by (1) the introduction of disease modifying drugs during the interim period, (2) the natural decrease in disease activity over time or (3) due to artifactual technical reasons (implementation of better MR imagers).
Brain atrophy in the initial course of the disease was found to be the most significant predictor of long-term disability, which underlines the necessity of early therapeutic intervention in MS.
The correlation between BPF and disability as well as T2/T1 lesion load was moderate although still statistically significant. Multiple regression analysis showed that the number of enhancing lesions and T2 lesion load were independent predictors of subsequent brain atrophy, which confirms that enhancement and lesion load are relevant markers of inflammation.
The conclusions of the study correborate the notion that atrophy measurements are an indicator of irreversible tissue damage in RRMS, which has a clinical relevance with relation to the individual patient, as well as monitoring effect of new treatments in trials.