Volumetric MRI Markers and Predictors of Disease Activity in Early Multiple Sclerosis: A Longitudinal Cohort Study

<div><h3>Objectives</h3><p>To compare clinical and MRI parameters between patients with clinically isolated syndrome and those converting to clinically definite multiple sclerosis within 2 years, to identify volumetric MRI predictors of this conversion and to assess effect of early relapses.</p> <h3>Methods</h3><p>The SET study comprised 220 patients with clinically isolated syndrome treated with interferon beta (mean age, 29 years; Expanded Disability Status Scale, 1.5). Three patients with missing data were excluded from the analysis. Physical disability, time to clinically definite multiple sclerosis and volumetric MRI data were recorded for 2 years.</p> <h3>Results</h3><p>Patients reaching clinically definite multiple sclerosis showed impaired recovery of neurological function, faster decrease in corpus callosum cross-sectional area, higher T2 lesion volume and more contrast-enhancing lesions. Six-month decrease in corpus callosum cross-sectional area (≥1%) and baseline T2 lesion volume (≥5 cm³) predicted clinically definite multiple sclerosis within 2 years (hazard ratios 2.5 and 1.8, respectively). Of 22 patients fulfilling both predictive criteria, 83% reached clinically definite multiple sclerosis (hazard ratio 6.5). More relapses were associated with poorer recovery of neurological function and accelerated brain atrophy.</p> <h3>Conclusions</h3><p>Neurological impairment is more permanent, brain atrophy is accelerated and focal inflammatory activity is greater in patients converting to clinically definite multiple sclerosis. Six-month corpus callosum atrophy and baseline T2 lesion volume jointly help predict individual risk of clinically definite multiple sclerosis. Early relapses contribute to permanent damage of the central nervous system.</p> </div

An example of automated volumetric assessment.

<p>A, FLAIR image from a patient with the usual extent of T2 hyperintense lesions seen in patients with clinically isolated syndrome. B, T1-weighted image with hypointense T1 lesions (arrows, lesion volume = 0.3 cm³). It is apparent that the T1 lesions were included in calculation of the overall brain volume (red area). C, T1-seighted image segmented by SIENAX. The T1 hypointense lesions (arrows) were misclassified into grey matter.</p

Disability and volumetric MRI parameters in patients with CIS and in those converting to CDMS.

<p>Dashed lines delineate 95% confidence intervals. Statistically significant p-values are shown. CIS, clinically isolated syndrome; CDMS, clinically definite multiple sclerosis; EDSS, Expanded Disability Status Scale; Gd+, gadolinium positive; MSFC, Multiple Sclerosis Functional Composite.</p

Cumulative risk of CDMS by number of volumetric MRI predictors.

<p>The MRI predictors found to be statistically significant by the logistic model were tested. These comprised decrease in corpus callosum area at 6 months ≥1%, and baseline T2 lesion volume ≥5 cm³. Hazard ratios with 95% confidence intervals are shown. CDMS, clinically definite multiple sclerosis, HR, hazard ratio.</p

Demographic, clinical and MRI characteristics of the sample.

*<p>t-test, Mann-Whitney U or χ2 tests; T2 lesion volumes and cumulative number of Gd+lesions were compared after logarithmic transformation.</p><p>CDMS, clinically definite multiple sclerosis; CIS, clinically isolated syndrome; EDSS, Expanded Disability Status Scale; Gd+, gadolinium positive; GM, grey matter; MSFC, Multiple Sclerosis Functional Composite; NS, not significant; SD, standard deviation; WM, white matter.</p

Effect of relapses on disability change and volumetric MRI parameters at 2 years of CIS.

<p>Patients were categorised by the number of relapses during the 2-year follow-up period (0: n = 125, 1: n = 30, 2: n = 35, 3: n = 16, 4+: n = 11). Least-squares regression lines (dashed) and statistically significant p-values are shown. EDSS, Expanded Disability Status Scale; Gd+, gadolinium positive; MSFC, Multiple Sclerosis Functional Composite; T2LV, T2 lesion volume.</p

Relative risk of conversion to CDMS predicted by decrease in CC area at 6 months of CIS.

*<p>reference for the odds ratio estimates.</p><p>CC, corpus callosum; CDMS, clinically definite multiple sclerosis.</p

Environmental Factors Associated with Disease Progression after the First Demyelinating Event: Results from the Multi-Center SET Study

<div><h3>Objectives</h3><p>To investigate the associations of environmental MS risk factors with clinical and MRI measures of progression in high-risk clinically isolated syndromes (CIS) after the first demyelinating event.</p> <h3>Methods</h3><p>We analyzed 211 CIS patients (age: 28.9±7.8 years) enrolled in the SET study, a multi-center study of high-risk CIS patients. Pre-treatment samples were analyzed for IgG antibodies against cytomegalovirus (anti-CMV), Epstein Barr virus (EBV) early nuclear antigen-1 (EBNA-1), viral capsid antigen (VCA), early antigen-diffuse (EA-D), 25 hydroxy-vitamin D3 and cotinine levels and <em>HLA DRB1*1501</em> status. The inclusion criteria required evaluation within 4 months of the initial demyelinating event, 2 or more brain MRI lesions and the presence of two or more oligoclonal bands in cerebrospinal fluid. All patients were treated with interferon-beta. Clinical and MRI assessments were obtained at baseline, 6, 12, and 24 months.</p> <h3>Results</h3><p>The time to first relapse decreased and the number of relapses increased with anti-CMV IgG positivity. Smoking was associated with increased number and volume of contrast-enhancing lesions (CEL) during the 2-year period. The cumulative number of CEL and T2 lesions during the 2-year period was greater for individuals in the highest quartile of anti-EBV VCA IgG antibodies. The percent loss of brain volume was increased for those in the highest quartile of with anti-EBV VCA IgG antibodies.</p> <h3>Conclusions</h3><p>Relapses in CIS patients were associated with CMV positivity whereas anti-EBV VCA positivity was associated with progression on MRI measures, including accumulation of CEL and T2 lesions and development of brain atrophy.</p> </div

Baseline clinical, MRI and other characteristics and changes of patients progressing to CDMS in 2-years.

<p>The continuous variables are expressed as mean ± SD and the categorical variables as frequency (%).</p>*<p>Non-parametric Mann-Whitney test for clinical and MRI variables. Fisher exact test for genetic and environmental variables.</p

Dependence of time to first relapse on demographic, MRI and environmental factors.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053996#pone-0053996-g001" target="_blank">Figure 1A</a> shows the cumulative hazard function for time to first relapse in all subjects. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053996#pone-0053996-g001" target="_blank">Figures 1B-D</a> show the cumulative hazard functions for the age <35 years (red line) vs. age ≥35 years (green line), CEL present as baseline (red line) vs. CEL not present at baseline (green line) and CMV positive (red line) vs. CMV negative sub-groups, respectively. The corresponding covariate <i>p</i>-values from Cox regression are also shown.</p