Atrophy is detectable within a 3-month period in untreated patients with active relapsing remitting multiple sclerosis
Hardmeier M, Wagenpfeil S, Freitag P, Fisher E, Rudick RA, et al.;
Commented by , 28 Jan 2004
Background
Atrophy of the CNS is the consequence of irreversible tissue damage in MS. Brain and cord volume can accurately be estimated using MRI, providing a reliable secondary outcome measure of disease progression. A long term follow up study (Fisher et al., Neurology, 2002;59:1412-1420), which was earlier commented in CNSforum, showed that brain atrophy in the initial course of the disease, was the most significant predictor of long term disability. Little is known about the short term atrophy changes in MS, which could be of interest with regard to counseling, choice of treatment and clinical trials.
Aim
To determine if significant brain volume changes occur during short time intervals in MS
Methods
138 patients with active relapsing remitting MS and absence of immunomodulatory treatment, were recruited prior to randomization from a study comparing two doses of interferon beta-1a. Three baseline MRI scans were obtained within a mean of 76±20, 2 days and values of T2 lesion load (T2LL) and T1 gadolinium (Gd) load (T1Gd) were calculated. Normalized brain parenchymal fraction (BPF) was used as a measure of brain volume.
Median baseline EDSS score was 3,5 (range 2,0-5,5) and mean disease duration was 7,6±5, 5 years. Ten subjects were treated with intravenous methylprednosolone (IVMP) for acute relapse during the study. Linear regression was used to extrapolate values to an annualized atrophy rate. T-statistic determined if the slope of the regression line differed from zero. Correlation was assessed by Spearman’s test and Wilcoxon rank sum test compared median BPF, T2LL and T1Gd.
Results
BPF at baseline correlated to EDSS and disease duration (p<0,05). Mean relative BPF changed –0,229% during the study. The estimated annualized atrophy rate was –1,06% (95% CI, -1,50% to –0,62%) for complete cases (n= 128). The slope of the regression line differed significantly form zero. Patients had a high number of active scans (65%, 63% and 67% at the three time points).
The T2LL increased significantly between scans, which was not the case for T1Gd. There were no significant longitudinal correlation between BPF and other MRI measures during the study. Exclusion of 10 subjects treated with IVMP did not change the results of the study.
Discussion
The authors illustrate that destructive processes in the CNS of MS patients can be measured during short time intervals. Annualized atrophy rates of app. 1% is a high measure compared with other studies, which could be due to a selection of very active disease cases.
The relationship between atrophy and markers of inflammation was weak, which is interesting, but can be explained by the short duration of the study and high variance in these measures.
The study provides results of considerable short-term destructive pathology in active MS disease, which can easily be measured in clinical practice. In this way, possibilities may be open for reliable evaluation and screening of new therapeutic agents in MS in future short-term phase 2 trials.
In line with other studies, the results argue for aggressive therapeutic intervention in the early course of the disease.