BackgroundA percent brain volume change (PBVC) cut-off of −0.4% per year has been proposed to distinguish between pathological and physiological changes in multiple sclerosis (MS). Unfortunately, standardized PBVC measurement is not always feasible on scans acquired outside research studies or academic centers. Percent lateral ventricular volume change (PLVVC) is a strong surrogate measure of PBVC, and may be more feasible for atrophy assessment on real-world scans. However, the PLVVC rate corresponding to the established PBVC cut-off of −0.4% is unknown.ObjectiveTo establish a pathological PLVVC expansion rate cut-off analogous to −0.4% PBVC.MethodsWe used three complementary approaches. First, the original follow-up-length-weighted receiver operating characteristic (ROC) analysis method establishing whole brain atrophy rates was adapted to a longitudinal ventricular atrophy dataset of 177 relapsing-remitting MS (RRMS) patients and 48 healthy controls. Second, in the same dataset, SIENA PBVCs were used with non-linear regression to directly predict the PLVVC value corresponding to −0.4% PBVC. Third, in an unstandardized, real world dataset of 590 RRMS patients from 33 centers, the cut-off maximizing correspondence to PBVC was found. Finally, correspondences to clinical outcomes were evaluated in both datasets.ResultsROC analysis suggested a cut-off of 3.09% (AUC = 0.83, p < 0.001). Non-linear regression R2 was 0.71 (p < 0.001) and a − 0.4% PBVC corresponded to a PLVVC of 3.51%. A peak in accuracy in the real-world dataset was found at a 3.51% PLVVC cut-off. Accuracy of a 3.5% cut-off in predicting clinical progression was 0.62 (compared to 0.68 for PBVC).ConclusionsVentricular expansion of between 3.09% and 3.51% on T2-FLAIR corresponds to the pathological whole brain atrophy rate of 0.4% for RRMS. A conservative cut-off of 3.5% performs comparably to PBVC for clinical outcomes.

Background‘No evidence of disease activity’ (NEDA), a composite measure of clinical and magnetic resonance imaging outcomes, provides a comprehensive assessment of disease activity, but is not extensively reported in clinical practice. NEDA-3 is defined as patients with no new/enlarged T2 or gadolinium-enhancing lesions, no relapses, and no disability progression (according to Expanded Disability Status Scale scores). NEDA-4 comprises the components of NEDA-3 and a fourth criterion of ≤ 0.4% annualized brain volume loss.ObjectiveThe objective of this study was to assess NEDA status among patients with relapsing-remitting multiple sclerosis receiving fingolimod in clinical practice.MethodsClinical and magnetic resonance imaging data were retrospectively collected from 590 patients who initiated fingolimod at 33 multiple sclerosis centers in the USA. Patients were required to have a magnetic resonance imaging scan in the 6 months before or 1 month after fingolimod initiation (index period) and in the 9–24 months after fingolimod initiation (post-index period). Magnetic resonance imaging data were systematically quantified at a centralized reading facility. The proportions of patients with NEDA-3 or NEDA-4 status during fingolimod treatment were assessed.ResultsDuring the follow-up period (median: 16 months), data to assess NEDA-3 and NEDA-4 were available for 586 and 325 patients, respectively. In the post-index period, 58.7% of patients achieved NEDA-3 status (no relapses, 85.2%; no new/enlarged T2/gadolinium-enhancing lesions, 76.3%; no disability progression, 87.9%) and 37.2% achieved NEDA-4 status (no relapses, 86.5%; no new/enlarged T2/gadolinium-enhancing lesions, 78.8%; no disability progression, 91.1%; brain volume loss ≤ 0.4, 58.2%).ConclusionAmong patients receiving fingolimod, over half achieved NEDA-3 status and over one-third achieved NEDA-4 status.Electronic supplementary materialThe online version of this article (10.1007/s40263-017-0482-4) contains supplementary material, which is available to authorized users.

The study provides real-world evidence that rate of brain atrophy in MS patients with underlying active disease and NEAD in fingolimod treated patients is below the established pathological cutoff for loss of whole brain volume (>-.4%) or expansion of lateral ventricles (> 3.5%).

BACKGROUND AND PURPOSE Quantitative neuroimaging is an important part of multiple sclerosis research and clinical trials, and measures of lesion volume (LV) and brain atrophy are key clinical trial endpoints. However, translation of these endpoints to heterogeneous historical datasets and nonstandardized clinical routine imaging has been difficult. The NeuroSTREAM technique was recently introduced as a robust and broadly applicable surrogate for brain atrophy measurement, but no such surrogate currently exists for conventional T2‐LV. Therefore, we sought to develop a fully automated proxy for T2‐LV with similar analytic value but increased robustness to common issues arising in clinical routine imaging. METHODS We created an algorithm to identify salient central lesion volume (SCLV), comprised of the subset of lesion voxels within a specific distance to the lateral ventricles (centrality) and with intensity at least a quantitatively‐derived amount brighter than normal appearing tissue (salience). We evaluated this method on four datasets (clinical, inter‐scanner, scan‐rescan, and real‐world multi‐center), including 1.5T, 3T, Philips, Siemens, and GE scanners with heterogeneous protocols, to assess agreement with conventional T2‐LV, comparative relationship with disability, reliability across scanners and between scans, and applicability to real‐world scans. RESULTS SCLV correlated strongly with conventional T2‐LV in both research‐quality (r = .90, P < .001) and real‐world (r = 0.87, P < 0.001) datasets. It also showed similar correlations with Expanded Disability Status Scale, as conventional T2‐LV (r = 0.48 for T2‐LV vs. r = 0.45 for SCLV). Inter‐scanner reproducibility (ICC) was 0.86, p < 0.001 for SCLV compared to 0.84, p < 0.001 for conventional T2‐LV, whereas scan‐rescan ICC was 0.999 for SCLV versus 0.997 for T2‐LV. CONCLUSIONS SCLV is a robust, fully‐automated proxy for T2‐LV in situations where conventional T2‐LV is not easily or reliably calculated.

Background: Lesion location is a prognostic factor of disease progression and disability accrual. Objective: To investigate lesion formation in 11 brain regions, assess correlation between lesion location and physical and cognitive disability measures and investigate treatment effects by region. Methods: In 2355 relapsing-remitting multiple sclerosis patients from the FREEDOMS and FREEDOMS II studies, we extracted T2-weighted lesion number, volume and density for each brain region; we investigated the (Spearman) correlation in lesion formation between brain regions, studied association between location and disability (at baseline and change over 2 years) using linear/logistic regression and assessed the regional effects of fingolimod versus placebo in negative binomial models. Results: At baseline, the majority of lesions were found in the supratentorial brain. New and enlarging lesions over 24 months developed mainly in the frontal and sublobar regions and were substantially correlated to pre-existing lesions at baseline in the supratentorial brain (p ¼ 0.37-0.52), less so infratentorially (p ¼ À0.04-0.23). High sublobar lesion density was consistently and significantly associated with most disability measures at baseline and worsening of physical disability over 24 months. The treatment effect of fingolimod 0.5 mg was consistent across the investigated areas and tracts. Conclusion: These results highlight the role of sublobar lesions for the accrual of disability in relapsingremitting multiple sclerosis.