Diego Silva

An Observational Study to Assess Brain MRI Change and Disease Progression in Multiple Sclerosis Clinical Practice—The MS‐MRIUS Study

To describe methodology, interim baseline, and longitudinal magnetic resonance imaging (MRI) acquisition parameter characteristics of the multiple sclerosis clinical outcome and MRI in the United States (MS‐MRIUS).

Neurological software tool for reliable atrophy measurement (NeuroSTREAM) of the lateral ventricles on clinical-quality T2-FLAIR MRI scans in multiple sclerosis

Background There is a need for a brain volume measure applicable to the clinical routine scans. Nearly every multiple sclerosis (MS) protocol includes low-resolution 2D T2-FLAIR imaging. Objectives To develop and validate cross-sectional and longitudinal brain atrophy measures on clinical-quality T2-FLAIR images in MS patients. Methods A real-world dataset from 109 MS patients from 62 MRI scanners was used to develop a lateral ventricular volume (LVV) algorithm with a longitudinal Jacobian-based extension, called NeuroSTREAM. Gold-standard LVV was calculated on high-resolution T1 1 mm, while NeuroSTREAM LVV was obtained on low-resolution T2-FLAIR 3 mm thick images. Scan-rescan reliability was assessed in 5 subjects. The variability of LVV measurement at different field strengths was tested in 76 healthy controls and 125 MS patients who obtained both 1.5T and 3T scans in 72 hours. Clinical validation of algorithm was performed in 176 MS patients who obtained serial yearly MRI 1.5T scans for 10 years. Results Correlation between gold-standard high-resolution T1 LVV and low-resolution T2-FLAIR LVV was r = 0.99, p < 0.001 and the scan-rescan coefficient of variation was 0.84%. Correlation between low-resolution T2-FLAIR LVV on 1.5T and 3T was r = 0.99, p < 0.001 and the scan-rescan coefficient of variation was 2.69% cross-sectionally and 2.08% via Jacobian integration. NeuroSTREAM showed comparable effect size (d = 0.39–0.71) in separating MS patients with and without confirmed disability progression, compared to SIENA and VIENA. Conclusions Brain atrophy measurement on clinical quality T2-FLAIR scans is feasible, accurate, reliable, and relates to clinical outcomes.

Establishing pathological cut-offs for lateral ventricular volume expansion rates

Background A 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. Objective To establish a pathological PLVVC expansion rate cut-off analogous to −0.4% PBVC. Methods We 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. Results ROC 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). Conclusions Ventricular 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.

Impact of fingolimod on clinical and magnetic resonance imaging outcomes in routine clinical practice: A retrospective analysis of the multiple sclerosis, clinical and MRI outcomes in the USA (MS-MRIUS) study

BACKGROUND The effectiveness of fingolimod on clinical and magnetic resonance imaging (MRI) outcomes in patients with multiple sclerosis (MS) has been well established in trials and, to a lesser extent, in the real world. OBJECTIVE To evaluate clinical and MRI outcomes in patients with relapsing MS receiving fingolimod in US clinical practice. METHODS Clinical and MRI data from 590 patients initiating fingolimod treatment at 33 MS centers in the USA were retrospectively analyzed. Clinical data were obtained from medical records. MRI data were systematically quantified at a centralized imaging facility. Patients had an index (within 6 months before and 1 month after starting fingolimod) and post-index (9-24 months after starting fingolimod) MRI scan; 184 individuals had a pre-index scan (9-24 months before starting fingolimod). RESULTS In the index to post-index period, mean annualized relapse rates decreased from 0.36 to 0.13 and disability progression occurred in 18.5% of patients. Median T2, T1 and gadolinium-enhancing lesion volume changed by 1.15%, 2.36%, and -100% between the index and post-index scans, respectively, and median annualized percentage changes in brain volume and lateral ventricular volume were -0.32% and +0.66%, respectively. For patients with pre-index scans, MRI outcomes were unchanged or improved during treatment. Outcomes were generally comparable with those in fingolimod phase 3 trials. CONCLUSION This real-world study highlights the effectiveness of fingolimod and the feasibility of quantifying clinical and MRI data collected from multiple centers during routine clinical practice on a group level using a systematic, quantitative methodology.

Fingolimod's Impact on MRI Brain Volume Measures in Multiple Sclerosis: Results from MS-MRIUS: Active Disease and Brain Atrophy in MS

Evidence is needed to understand the effect of fingolimod on slowing down brain atrophy progression in multiple sclerosis (MS) patients in clinical practice. We investigated the effect of fingolimod on brain atrophy in MS patients with active disease (clinically and/or magnetic resonance imaging [MRI]) versus no evidence of active disease (NEAD).

No evidence of disease activity in patients receiving fingolimod at private or academic centers in clinical practice: a retrospective analysis of the multiple sclerosis, clinical, and magnetic resonance imaging outcomes in the USA (MS-MRIUS) study

Abstract Objective: The impact of multiple sclerosis (MS) center type on outcomes has not been investigated. This study aimed to evaluate baseline characteristics and clinical and magnetic resonance imaging (MRI) outcomes in patients with MS receiving fingolimod over 16 months’ follow-up at private or academic centers in the USA. Methods: Clinical and MRI data collected in clinical practice from patients initiating fingolimod were stratified by center type and retrospectively analyzed. No evidence of disease activity (NEDA-3) was defined as patients with no new/enlarged T2/gadolinium-enhancing lesions, no relapses, and no disability progression (Expanded Disability Status Scale scores). Results: Data were collected for 398 patients from 25 private centers and 192 patients from eight academic centers. Patients were older (median age = 43 vs 41 years; p = .0047) and had a numerically shorter median disease duration (7.0 vs 8.5 years; p = .0985) at private vs academic centers. Annualized relapse rate (ARR) was higher in patients at private than academic centers in the pre-index (0.40 vs 0.29; p = .0127) and post-index (0.16 vs 0.08; p = .0334) periods. The opposite was true for T2 lesion volume in the pre-index (2.86 vs 5.23 mL; p = .0002) and post-index (2.86 vs 5.11 mL; p = .0016) periods; other MRI outcomes were similar between center types. After initiating fingolimod, ARRs were reduced, disability and most MRI outcomes remained stable, and a similar proportion of patients achieved NEDA-3 at private and academic centers (64.1% vs 56.1%; p = .0659). Conclusion: Patient characteristics differ between private and academic centers. Over 55% of patients achieved NEDA-3 during fingolimod treatment at both center types.