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Although clinical trials in multiple sclerosis are extremely difficult to conduct because of the unpredictable course of the disease and the problem of defining and monitoring disease activity, some controlled and several uncontrolled studies suggest that global immunosuppression may result in a small but beneficial effect. After some methodological considerations the results of recent trials are reviewed especially those concerned with the use of cyclophosphamide, azathioprine and cyclosporine. Major improvements in our ability to slow-down disease progression may develop through the administration of more sophisticated, phase-adapted therapies using combinations of different immunosuppressive and modulating agents which should be applied in earlier phases of the disease. Improved monitoring of disease evolution by the addition of magnetic resonance imaging to current clinical scales and by ameliorated immunological techniques is an indispensable prerequisite of any further therapeutic progress.

To minimize the clinical burden associated with multiple sclerosis (MS), early control of focal and diffuse CNS disease activity is a treatment priority. A post hoc analysis was conducted to evaluate the onset of efficacy of fingolimod treatment in patients with relapsing MS. Data from patients who received fingolimod 0.5 mg or placebo during either of two 24-month, double-blind, randomized, parallel-group clinical trials (FREEDOMS and FREEDOMS II) were pooled for analysis. Efficacy outcomes were: time to first confirmed relapse; annualized relapse rate (ARR); proportions of patients free from T1 gadolinium-enhancing lesions or new/newly enlarged T2 lesions; percentage brain volume loss (BVL); and change in Multiple Sclerosis Functional Composite (MSFC) z-score from baseline to 6 months. An early benefit was seen with fingolimod (N = 783) vs. placebo (N = 773) for ARR at both 3 and 6 months (3 months, 0.32 vs. 0.52, p = 0.0015; 6 months, 0.21 vs. 0.45, p

We measured changes in brain magnetization transfer ratio (MTR) as a potential indicator of myelin density in brain tissue of patients with relapsing-remitting multiple sclerosis (RRMS) treated with delayed-release dimethyl fumarate (DMF) in the Phase 3 DEFINE study. DEFINE was a randomized, double-blind, placebo-controlled study in which patients with RRMS were randomized 1:1:1 to 2 years of treatment with delayed-release DMF 240 mg twice daily (BID) or three times daily (TID) or placebo. MTR was analyzed in whole brain and normal-appearing brain tissue (NABT) at baseline, week 24, 1 year, and 2 years in a subset of patients. MTR data from 392 patients were analyzed. Mean percentage reduction from baseline to 2 years in median whole brain MTR was −0.386 % in the placebo group vs increases of 0.129 % (p = 0.0027) and 0.096 % (p = 0.0051) in the delayed-release DMF BID and TID groups, respectively. Similarly, mean percentage reduction from baseline in median NABT MTR was −0.392 % with placebo vs increases of 0.190 % (p = 0.0006) and 0.115 % (p = 0.0029) with delayed-release DMF BID and TID, respectively. Post hoc analysis of data from patients with no new or enlarging T2 lesions (n = 147), or who experienced no relapses (n = 238), yielded similar results. In this analysis, increases in MTR in brain tissue most likely reflect increases in myelin density in response to delayed-release DMF. These data in patients with RRMS are consistent with preclinical studies that indicate a potential for cytoprotection and remyelination with delayed-release DMF treatment. Electronic supplementary material The online version of this article (doi:10.1007/s00415-014-7504-7) contains supplementary material, which is available to authorized users.

The diagnostic value of magnetic resonance imaging (MRI) in multiple sclerosis (MS) is uncontested. But only little information exists on its usefullness in monitoring disease activity. We describe a method of quantification that can be performed in longitudinal MRI-investigations. We used a standardized method of scanning and determined the area of demyelinating lesions with an interactive planimetric computer system. In order to determine the approximate lesion volumes, the computed area was multiplied by the slice thickness. In 89 patients with clinically definite MS we found an average lesion volume of 11900 mm3. The mean score in Kurtzke's expanded disability scale was 3.0. The correlation between computed lesion volume and neurological deficit was significant, but only weak (rho = 0.3). We conclude, that planimetric evaluation of MRI can be a valuable supplement to clinical rating scales in MS patients. The method described here, used in combination with high spacial resolution and better tissue specificity of latest generation MRI scanners, could be helpful in the evaluation of treatment in many other CNS diseases.

Objective To assess the value of annual serum neurofilament light (NfL) measures in predicting 10‐year clinical and MRI outcomes in multiple sclerosis (MS). Methods We identified patients in our center's Comprehensive Longitudinal Investigations in MS at Brigham and Women's Hospital (CLIMB) study enrolled within 5 years of disease onset, and with annual blood samples up to 10 years (n = 122). Serum NfL was measured using a single molecule array (SIMOA) assay. An automated pipeline quantified brain T2 hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) from year 10 high‐resolution 3T MRI scans. Correlations between averaged annual NfL and 10‐year clinical/MRI outcomes were assessed using Spearman's correlation, univariate, and multivariate linear regression models. Results Averaged annual NfL values were negatively associated with year 10 BPF, which included averaged year 1–5 NfL values (unadjusted P < 0.01; adjusted analysis P < 0.01), and averaged values through year 10. Linear regression analyses of averaged annual NfL values showed multiple associations with T2LV, specifically averaged year 1–5 NfL (unadjusted P < 0.01; adjusted analysis P < 0.01). Approximately 15–20% of the BPF variance and T2LV could be predicted from early averaged annual NfL levels. Also, averaged annual NfL levels with fatigue score worsening between years 1 and 10 showed statistically significant associations. However, averaged NfL measurements were not associated with year 10 EDSS, SDMT or T25FW in this cohort. Interpretation Serum NfL measured during the first few years after the clinical onset of MS contributed to the prediction of 10‐year MRI brain lesion load and atrophy.

Background Previous studies have demonstrated that white matter (WM) lesions bias automated brain tissue classifications and cerebral volume measurements. However, filling WM lesions using the intensity of neighbouring normal-appearing WM has been shown to increase the accuracy of automated volume measurements in the brain. In the present study, we investigate the influence of WM lesions on cortical thickness (CTh) measures and assessed the impact of lesion filling on both cross-sectional/longitudinal and global/regional measurements of CTh in multiple sclerosis (MS) patients. Methods Fifty MS patients were studied at baseline as well as after three and six years of follow-up. CTh was estimated using a fully automated pipeline (CIVET) on T1-weighted magnetic resonance images data acquired at 1.5 Tesla without (original) and with WM lesion filling (filled). WM lesions were semi-automatically segmented and then filled with the mean intensity of the neighbouring voxels. For both original and filled T1 images we investigated and compared the main CIVET’s steps: tissue classification, surfaces generation and CTh measurement. Results On the original T1 images, the majority of WM lesion volume (72%) was wrongly classified as gray matter (GM). After lesion filling the accuracy of WM lesions classification improved significantly (p