Background

Progressive multifocal leukoencephalopathy (PML) is a serious and potentially fatal complication of some multiple sclerosis (MS) disease-modifying therapies, including fingolimod. Precise estimates and risk stratification tools are not available for fingolimod-related PML.

Objectives

To estimate the global risk of PML in MS patients receiving fingolimod, and to investigate the effect of treatment duration and age on the risk of PML.

Methods

The number of PML cases identified from the manufacturer safety database, attributed to fingolimod by expert adjudication (based on criteria published by Berger et al. in 2014) as of 28 February 2020, was compared with the estimated global number of fingolimod-treated patients at risk (overall, by treatment duration, and by assumed age at fingolimod treatment initiation).

Results

It was estimated that approximately 299,600 patients were treated with fingolimod globally as of 28 February 2020, corresponding to >778,900 patient-years (PYs) of exposure. Of the 188 suspected PML cases reported during fingolimod treatment, 37 confirmed cases were clearly attributed to fingolimod through expert adjudication. In 17 cases, PML was attributed to previous natalizumab treatment. The remaining 134 cases either had inadequate information to confirm the diagnosis of PML or were classified as either possible or not PML. The estimated incidence rate was 4.75 (95% confidence interval [CI]: 3.34; 6.55) per 100,000 PYs. The estimated crude incidence was 0.12 (95% CI: 0.09–0.17) per 1,000 patients. The incidence of PML appears to increase with treatment duration and approach a plateau at approximately 0.13 per 1,000 patients during Year 5, after which data were scarce. Incidence of PML appears to increase between 30 and 50 years of age and then stabilize but the exact shape of the relationship with age is uncertain due to wide CIs, underlying assumptions, and other unknown confounding factors. For both treatment duration and age at treatment initiation, the precision of the incidence estimates was low due to the small number of cases.

Conclusions

PML risk associated with fingolimod is low. Although, the estimated risk of fingolimod-associated PML appears to increase with cumulative exposure, the precise pattern of this relationship remains uncertain. There may be an increase in PML risk with increased age at treatment initiation, although the exact pattern of this possible relationship is also uncertain.

Background

Neuromyelitis optica spectrum disorders (NMOSD) encompasses a group of rare inflammatory diseases which primarily target the optic nerves, spinal cord, and brain. Typically, magnetic resonance imaging (MRI) data from single-center studies comprise 20-50 patients, limiting statistical power for outcomes research. Using retrospective data from the PArallel MRI in NmOsd (PAMRINO) study, a novel prospective NMOSD image repository (NMOsDIR) representing multiple international sites was coordinated by Charité-Universitätsmedizin Berlin and the Medical Image Analysis Center (Basel).

Objectives

The PAMRINO study aimed to investigate and analyze retrospective MRIs collected from NMOSD-specialized centers, potentially for the evaluation of disease-related brain and spinal cord changes. NMOsDIR serves as an international imaging research resource (comprising standardized retinal optical coherence tomography and MRI scans) and clinical data hub for prospective studies in NMOSD. Linking imaging and clinical data, as well as enabling analysis pipelines for each modality, will facilitate multi-centered studies using sufficient data and statistical power to advance outcomes research in this rare disease.

Methods

For clinical data collection in PAMRINO, a Research Electronic Data Capture (REDCap) platform was used, where participating centers entered data relevant for NMOSD patient monitoring. An image database (XNAT) was established for image uploads. This large collection of MRI data is currently being analyzed in a joint international effort of NMOSD clinical neuroradiologists and scientists.

Results

Brain, spinal cord, and optic nerve MRI scans with associated clinical data were collected from 514 NMOSD patients and 56 healthy controls from 17 international centers. Roughly 20,000 individual MRI scans from patients and healthy controls were collected. Of these, 78% had T1-weighted cerebral MRIs (55% with 3D scans), 80% had T2-weighted cerebral MRIs (54% with 3D scans), 86% had T2-weighted spinal cord MRIs (55% with 3D scans), and 35% had optic nerve MRIs.

Conclusions

We successfully established PAMRINO, an international collaborative retrospective MRI and clinical data repository. The knowledge gained during this process provided important new insights, where the initial analysis of the dataset has underscored the large degree of heterogeneity in image and clinical data collection in NMOSD-specialized centers. Thus, calling for more standardized methods of data acquisition and imaging analysis, as not to limit research opportunities. The new longitudinal, prospective NMOsDIR will help us to answer many pressing - yet open - questions regarding patients seropositive for aquaporin-4-IgG+, myelin oligodendrocyte glycoprotein-IgG+ and other autoimmune-related diseases. In turn, such a strategy will strengthen future capabilities in research, diagnosis, monitoring and improving NMOSD patient care.

Background

The central vein sign (CVS) is a proposed MRI diagnostic biomarker for multiple sclerosis (MS). Use of gadolinium (Gd) in the CVS literature has been inconsistent, and it is unknown whether Gd improves detection of CVS when using FLAIR*.

Objectives

To determine if, and to what extent, gadolinium injection improves detection of CVS lesions when using FLAIR* imaging.

Methods

A cross-sectional multicenter study recruited adults clinically and/or radiologically suspected of having MS. High-isotropic-resolution, T2*-weighted segmented echo-planar imaging (T2*-EPI) was acquired pre- and post-injection of Gd-based contrast agent at 3T; pre-Gd 3D FLAIR images were also acquired. T2*-EPI and FLAIR images were processed on the QMENTA platform to generate FLAIR* images. FLAIR* pre-Gd and post-Gd scans from this substudy of 30 patients at 5 sites were analyzed. FLAIR images were used to create T2 lesion masks. Subsequently, FLAIR* images were evaluated in a random order. Lesions were categorized as CVS+, CVS-, or excluded based on the North American Imaging in MS (NAIMS) Criteria by two trained raters blinded to clinical data and Gd use. The proportion of CVS+ lesions was calculated for each scan, and differences in CVS detection based on Gd use were assessed by a Wilcoxon rank-sum test. Diagnostic performance was compared against McDonald 2017 Criteria.

Results

The mean participant age was 45 years (SD: 12); 23 (77%) were women. 14 (47%) met McDonald 2017 Criteria for MS, while 16 (53%) did not (“non-MS”). A total of 487 CVS+ lesions and 976 CVS- lesions were evaluated. The percentage of CVS+ lesions post-Gd in the MS group (median 67% [IQR 30%]) was higher than pre-Gd (41% [47%], p<0.001). There was no apparent difference in percentage of CVS+ lesion in the non-MS group (post-Gd: 10% [23%]; pre-Gd: 5% [29%]; p=0.1). In the MS group, 12/14 (86%) had ≥40% CVS+ lesions on post-Gd imaging, whereas only 8/14 (57%) exceeded that threshold on pre-Gd imaging. When evaluating CVS performance using the 40% CVS+ threshold, the sensitivity and specificity of the CVS post-Gd for MS were 86% and 81%, respectively, compared to 54% and 86% pre-Gd.

Conclusions

The detection of the CVS using FLAIR* at 3T is improved when Gd is used. Based on these results, a multicenter prospective CVS diagnostic study, sponsored by NINDS and NAIMS, will use Gd in the study protocol. Future clinical use of the CVS should balance the increased costs and potential risks of Gd use with the risks of misdiagnosis due to missing CVS on non-contrast imaging.

Background

The central vein sign (CVS) is a proposed diagnostic biomarker for MS that can be identified using FLAIR*. The robustness of 3T FLAIR*, with and without the injection of gadolinium contrast agent (Gd), for imaging the CVS in a multicenter setting has not yet been demonstrated.

Objectives

To assess the conspicuity of the CVS on 3T FLAIR* imaging acquired across different sites with and without the injection of Gd.

Methods

A cross-sectional multicenter study recruited adults with a clinical and/or radiological suspicion of having MS from 10 sites within the North American Imaging in MS (NAIMS) Cooperative. High-isotropic-resolution T2*-weighted segmented echo-planar imaging (T2*-EPI) was acquired at 3T, pre- and post-injection of Gd, along with 3D FLAIR on different scanner brands and models. T2*-EPI and FLAIR images were processed on an online imaging platform (QMENTA) to generate FLAIR* images. To objectively assess the conspicuity of the CVS inside MS lesions, lesions and veins were segmented automatically and used to compute lesion-to-vein contrast-to-noise ratio (CNR) measures. ANOVA was used to compare CNR values across sites with post-hoc Tukey Honest Significant Difference testing. Multiple testing between sites was considered by controlling the false discovery rate. One-sided paired t-testing was used to compare the overall lesion-to-vein CNR values between pre- and post-Gd FLAIR*.

Results

Seventy-eight patients from nine sites were included in the analysis; one site was excluded due to low enrollment. The overall mean(coefficient of variation, CV) lesion-to-vein CNR values across the nine sites were 0.35(14%) and 0.37(12%) for pre- and post-Gd FLAIR*, respectively. Excluding an additional site that used an unharmonized FLAIR acquisition, the resulting mean(CV) CNR values were 0.36(12%) for pre-Gd and 0.37(11%) for post-Gd FLAIR*. Across most sites, there was a significant improvement in lesion-to-vein CNR measures for post-Gd compared to pre-Gd FLAIR* [mean difference = 0.011, p < 0.001, 95% CI: (0.008,0.015)].

Conclusions

Lesion-to-vein CNR measures across sites are in line with values first published for 3T FLAIR* and demonstrate the robustness of 3T FLAIR* for imaging the CVS in a multicenter setting. Moreover, there was an increase in vein conspicuity with improvement in CNR on post-Gd FLAIR*. Based on these results, a prospective multicenter NAIMS CVS diagnostic study, sponsored by NINDS, will use 3T FLAIR* imaging with Gd in the study protocol.

Background

Slowly expanding lesions (SELs) can be detected on conventional in vivo brain magnetic resonance imaging (MRI). Previous studies suggest that SELs reflect chronic tissue loss in the absence of ongoing acute inflammation. Histopathological characterization of SELs are still not fully investigated.

Objectives

To characterize SEL regions using in vivo MRIs and postmortem brain tissue, and compare the difference between SEL and non-SEL regions.

Methods

We identified an autopsy case with secondary progressive MS (male, age=51 years, disease duration=23 years), who had standardized in vivo MRIs. The interval between the last in vivo MRI and death was 7 weeks. From the last two years of in vivo MRIs, T2 lesions were segmented, and the Jacobian determinants of nonlinear registration between baseline and follow-up scans were calculated. SELs were identified as regions with small local constant and concentric expansion from baseline lesions. We identified 11 regions-of-interest (ROI): 10 T2 lesions (3 SELs and 7 non-SEL) and 1 normal-appearing white matter (NAWM). Using a custom brain cutting box with MRI-visible markers, the in vivo ROIs were localized on the corresponding brain slice. The ROIs were blocked and stained for proteolipid protein, SMI-31/32, and MHC class II. We then evaluated myelin status, axonal diameter, axonal loss, and inflammatory activity in ROIs.

Results

The NAWM region was myelinated, the axonal diameter was 0.74 um, and axonal density was 23.4%. In the SEL regions, the mean axonal diameter was 1.11 um, and mean axonal density was 17.5%. In non-SEL regions, the mean axonal diameter was 0.84 um, and mean axonal density was 15.7%.

Two SEL and 4 non-SEL regions were demyelinated. The demyelinated SEL regions had activated microglia at the lesion edge and were compatible with chronic active lesions. Three demyelinated non-SEL regions also had activated microglia at the edge. One demyelinated non-SEL region was a chronic inactive lesion. No microglia activity was observed in any of the myelinated non-SEL regions. In the myelinated SEL region, the density of activated microglia was higher compared to NAWM.

Conclusions

Not all SEL regions in T2 lesions were demyelinated. SEL also had greater axonal diameters suggesting of axonal swelling. In this case report, all of the demyelinated SEL regions had activated microglia at the lesion edge.

Background

Quantitative MRI measures are proposed as biomarkers of disease course and therapeutic response. Understanding the evolution of these metrics is key for interpretation of change in clinical practice.

Objectives

To describe longitudinal changes in T2 lesion volume (T2LV), whole brain (WBF) and gray matter (GMF) fraction, and thalamic volume (TV) over the disease course in a large multiple sclerosis (MS) cohort.

Methods

Demographics, disease history, and MRI were collected from MS patients at a single site. Patients with ≥2 MRI assessments were included. T2LV, WBF, GMF, and TV annualized rate of change and raw values compared to the first available scan were analyzed. Multivariate mixed-effects models were used to evaluate longitudinal MRI changes, adjusting for age at disease onset, sex, and patient-determined disease steps category (PDDS) with a random intercept for patient and an autoregressive covariance structure. For each outcome, three models were generated: a linear model, a second-order B-spline model, and a third-order B-spline model were tested for nonlinearity in the relationship between MRI outcome and disease duration and were compared based on Akaike Information Criterion.

Results

1012 patients were included (69.2% female, 72.9% relapsing-remitting MS, mean ± SD age at disease onset 34.4±10.3, age at baseline MRI 43.8±11.1, disease duration 9.4±5.8 years, mean number of MRIs 3.1±1.2, median [IQR] PDDS 1.0 [0.0-3.0]). Male sex (B=4.9) and PDDS>3 (B=7.0) were associated with greater T2LV accumulation over the disease course (best fit: linear model). T2LV annualized rate of change peaked at 5-6 years of disease duration (rate 9%/year) (best fit: third-order B spline). Male sex, older age, and PDDS>3 were associated with lower WBF, TV (best fit: linear model), and GMF (best fit: second-order B spline), all p<0.05. No non-linear effect of disease duration on WBF, TV, and GMF were observed. There was no statistically significant change in the annualized rate of change of WBF, TV, and GMF over the disease course.

Conclusions

The dynamics of T2LV accumulation are variable throughout the disease course, whereas the rate of change of WBF, TV, and GMF were more stable. These results suggest T2LV accumulation reflecting focal lesion activity predominates early in the disease while WBF, TV, and GMF loss reflecting underlying neurodegeneration is present at disease onset and continues throughout the course.

Background

Cognitive dysfunction is common in multiple sclerosis (MS) and can impair processing speed, episodic memory, and executive function. Magnetic resonance imaging (MRI) studies have demonstrated associations between several MRI metrics and cognitive functioning in MS, including thalamic volume and brain parenchymal fraction. Fingolimod is an MS therapy that demonstrated reduced brain volume loss across several clinical trials.

Objectives

Determine the relationship between cognitive function in fingolimod-treated relapsing-remitting MS patients and 7 tesla (7T) MRI measures.

Methods

We recruited fingolimod-treated MS patients and healthy controls to be followed for 12 months. Participants underwent 7T brain MRI and cognitive testing including the symbol digit modalities test (SDMT), selective reminding test (SRT), and the trail making, color, and verbal subtests of the Delis-Kaplan Executive Function System (DKEFS) at baseline, 6 months, and 12 months. Mixed effects linear regression models were used to determine the relationship between MRI metrics and neurometric test performance, fitting values from all 3 time points. Rates of change in MRI metrics and neurometric test performance were compared between patients and controls using two-sample t-tests.

Results

We enrolled 15 MS patients with mean age 42.4 years (SD=5.6), mean disease duration 8.5 years (SD=4.1), and median expanded disability status scale 3 (IQR=1.5-3.5). Five controls were enrolled with mean age 41.5 (SD=6.6) years. Controls performed better than patients on all psychometric tests, but this was only significant for tests of orthographic knowledge (DKEFS letter fluency) and long-term storage (SRT). When MRI metrics were used to predict neuropsychological test performance over time in patients, thalamic volume was a significant predictor of visuospatial memory (BVMTR), long-term storage (SRT), and inhibitory control (DKEFS Color Inhibition). Thalamic myelin density was a significant predictor of visuospatial memory (BVMTR), long-term storage (SRT), and semantic knowledge (DKEFS Verbal Category Fluency). When changes in neuropsychological testing performance and MRI metrics were compared for patients and controls from 0-6 months, and from 0-12 months, none of the differences between patients and controls were significant.

Conclusions

Thalamic volume and myelin density are associated with measures of cognitive function. 7T MRI of the thalamus may be useful as a clinical trial measure to predict cognitive effects.

Background

Vitamin D deficiency is a known risk factor for multiple sclerosis (MS) and is associated with worsening disease activity and disability.

Objectives

To examine the association between vitamin D with clinical outcomes, patient reported outcomes and quantitative MRI measures in a real-world MS cohort.

Methods

We conducted a retrospective analysis of patients enrolled in the Cleveland Clinic Clinical Practice Data Registry between June 2015 and November 2019. Serum 25-hydroxyvitamin D₃ levels collected within 90 days of the first multiple sclerosis performance test (MSPT) assessment were recorded. Patients were dichotomized as sufficient or insufficient using a cutoff of 30 ng/mL. Baseline demographics, vitamin D supplementation, clinical outcome measures [Processing Speed Test (PST), Manual Dexterity Test (MDT), and Walking Speed Test (WST)], and patient reported outcome measures (PROMs) were collected. Brain/cervical MRIs obtained +/-90-days from the initial MSPT were analyzed via fully-automated methods for spinal cord cross sectional area (SCA), whole brain fraction (WBF), and T2 lesion volume (T2LV). Vitamin D associations were determined using Pearson correlation, quantile regression, and linear regression analysis.

Results

369 patients (median age 47.3 years, 71.0% female, and 79.7% caucasian) were included in the analysis. Median age at diagnosis was 35 (IQR[interquartile range] 29.0-43.0), and median years with MS was 12.3 (IQR 5.49 – 20.6). Median vitamin D levels were 34.1 ng/mL [IQR 24.4;46.7] and 68.6% of patients were on supplementation. 62.3% (n=230) had sufficient vitamin D levels and 37.7% (n=139) had insufficient levels. No statistically significant differences were found between the groups for season at assessment, patient reported relapses, PST, MDT, or any quantitative MRI metrics The vitamin D insufficient [OD1] group had a statistically significantly longer WST (median 7.35 vs 6.56, p-value = 0.028). MDT dominant hand time had a statistically significant inverse relationship with vitamin D levels (ρ = -0.145) (p-value=0.005), which became non-significant after regression adjustment.

Conclusions

Vitamin D levels were found to be sufficient in two-thirds of patients and is likely explained by supplementation. Patients at sufficiency had faster walking speeds, but no other differences were found on clinical/MRI measures. We hypothesize that supplementation obscures the relation between vitamin D levels and clinical/MRI measures.