Evaluation of a self-administered iPad®-based processing speed assessment for people with multiple sclerosis in a clinical routine setting.

BACKGROUND: Limited resources often hinder regular cognitive assessment of people with multiple sclerosis (pwMS) in standard clinical care. A self-administered iPad®-based cognitive screening-tool (Processing Speed Test; PST) might mitigate this problem. OBJECTIVE: To evaluate the PST in clinical routine. METHODS: We investigated the feasibility of the PST in both a quiet and a waiting room setting. We assessed the validity of the PST in comparison with the established Symbol Digit Modalities Test (SDMT). We explored associations between processing speed assessments and the Brief International Cognitive Assessment for MS (BICAMS), magnetic resonance imaging (MRI) parameters, and psychological factors. Additionally, we explored the ability of the PST to detect impairment in processing speed compared to the SDMT. RESULTS: The PST was feasible in the waiting room setting. PST and SDMT correlated comparably with the BICAMS, MRI parameters, and psychological variables. Of 172 pwMS, 50 (30.8%) showed cognitive impairment according to the BICAMS; respective values were 47 (27.3%) for the SDMT and 9 (5.2%) for the PST. CONCLUSIONS: The PST performed in a waiting room setting correlates strongly with established cognitive tests. It thus may be used to assess processing speed in a resource-efficient manner and complement cognitive assessment in clinical routine. Despite comparable validity of the PST and SDMT, we identified more pwMS with impaired processing speed using normative data of the SDMT compared to the PST and advise caution, that the common cut-off score of - 1.5 SD from the current PST is not appropriate in Europe.

A multicenter pilot study evaluating simplified central vein assessment for the diagnosis of multiple sclerosis.

BACKGROUND: The central vein sign (CVS) is a proposed magnetic resonance imaging (MRI) biomarker for multiple sclerosis (MS); the optimal method for abbreviated CVS scoring is not yet established. OBJECTIVE: The aim of this study was to evaluate the performance of a simplified approach to CVS assessment in a multicenter study of patients being evaluated for suspected MS. METHODS: Adults referred for possible MS to 10 sites were recruited. A post-Gd 3D T2*-weighted MRI sequence (FLAIR*) was obtained in each subject. Trained raters at each site identified up to six CVS-positive lesions per FLAIR* scan. Diagnostic performance of CVS was evaluated for a diagnosis of MS which had been confirmed using the 2017 McDonald criteria at thresholds including three positive lesions (Select-3*) and six positive lesions (Select-6*). Inter-rater reliability assessments were performed. RESULTS: Overall, 78 participants were analyzed; 37 (47%) were diagnosed with MS, and 41 (53%) were not. The mean age of participants was 45 (range: 19-64) years, and most were female (n = 55, 71%). The area under the receiver operating characteristic curve (AUROC) for the simplified counting method was 0.83 (95% CI: 0.73-0.93). Select-3* and Select-6* had sensitivity of 81% and 65% and specificity of 68% and 98%, respectively. Inter-rater agreement was 78% for Select-3* and 83% for Select-6*. CONCLUSION: A simplified method for CVS assessment in patients referred for suspected MS demonstrated good diagnostic performance and inter-rater agreement.

Co-assessment of OCT-A and choroidal vascularity index data in multiple sclerosis patients.

OBJECTIVE: To evaluate optical coherence tomography-angiography (OCT-A) findings and choroidal vascular index (CVI) in patients with multiple sclerosis (MS). METHODS: 113 patients, including multiple sclerosis patients with optic neuritis attack (MSON+) and no optic neuritis attack (MSON-) and healthy control group (HCG), participated in this cross-sectional study. OCT-A images of all patients were taken and CVI was calculated. RESULTS: Superior flow (SF), deep flow (DF), foveal, and parafoveal superior vascular density (sVD) were decreased in the MSON+ group compared to HCG (p < 0.05). Optic disk flow (ODF) and optic disk head density (ONHD) values decreased in the MS group (p < 0.05). CVI was decreased in the MSON+ group compared to HCG (p < 0.05). There is a correlation between CVI and foveal and parafoveal sVD. CONCLUSION: Non-invasive diagnostic tools such as OCT-A and CVI can be used for early diagnosis and follow-up of microvascular pathologies in inflammatory diseases such as MS.

Reliability of brain atrophy measurements in multiple sclerosis using MRI: an assessment of six freely available software packages for cross-sectional analyses.

PURPOSE: Volume measurement using MRI is important to assess brain atrophy in multiple sclerosis (MS). However, differences between scanners, acquisition protocols, and analysis software introduce unwanted variability of volumes. To quantify theses effects, we compared within-scanner repeatability and between-scanner reproducibility of three different MR scanners for six brain segmentation methods. METHODS: Twenty-one people with MS underwent scanning and rescanning on three 3 T MR scanners (GE MR750, Philips Ingenuity, Toshiba Vantage Titan) to obtain 3D T1-weighted images. FreeSurfer, FSL, SAMSEG, FastSurfer, CAT-12, and SynthSeg were used to quantify brain, white matter and (deep) gray matter volumes both from lesion-filled and non-lesion-filled 3D T1-weighted images. We used intra-class correlation coefficient (ICC) to quantify agreement; repeated-measures ANOVA to analyze systematic differences; and variance component analysis to quantify the standard error of measurement (SEM) and smallest detectable change (SDC). RESULTS: For all six software, both between-scanner agreement (ICCs ranging 0.4-1) and within-scanner agreement (ICC range: 0.6-1) were typically good, and good to excellent (ICC > 0.7) for large structures. No clear differences were found between filled and non-filled images. However, gray and white matter volumes did differ systematically between scanners for all software (p < 0.05). Variance component analysis yielded within-scanner SDC ranging from 1.02% (SAMSEG, whole-brain) to 14.55% (FreeSurfer, CSF); and between-scanner SDC ranging from 4.83% (SynthSeg, thalamus) to 29.25% (CAT12, thalamus). CONCLUSION: Volume measurements of brain, GM and WM showed high repeatability, and high reproducibility despite substantial differences between scanners. Smallest detectable change was high, especially between different scanners, which hampers the clinical implementation of atrophy measurements.

Genome-wide study of longitudinal brain imaging measures of multiple sclerosis progression across six clinical trials.

While the genetics of MS risk susceptibility are well-described, and recent progress has been made on the genetics of disease severity, the genetics of disease progression remain elusive. We therefore investigated the genetic determinants of MS progression on longitudinal brain MRI: change in brain volume (BV) and change in T2 lesion volume (T2LV), reflecting progressive tissue loss and increasing disease burden, respectively. We performed genome-wide association studies of change in BV (N = 3401) and change in T2LV (N = 3513) across six randomized clinical trials from Biogen and Roche/Genentech: ADVANCE, ASCEND, DECIDE, OPERA I & II, and ORATORIO. Analyses were adjusted for randomized treatment arm, age, sex, and ancestry. Results were pooled in a meta-analysis, and were evaluated for enrichment of MS risk variants. Variant colocalization and cell-specific expression analyses were performed using published cohorts. The strongest peaks were in PTPRD (rs77321193-C/A, p = 3.9 × 10-7) for BV change, and NEDD4L (rs11398377-GC/G, p = 9.3 × 10-8) for T2LV change. Evidence of colocalization was observed for NEDD4L, and both genes showed increased expression in neuronal and/or glial populations. No association between MS risk variants and MRI outcomes was observed. In this unique, precompetitive industry partnership, we report putative regions of interest in the neurodevelopmental gene PTPRD, and the ubiquitin ligase gene NEDD4L. These findings are distinct from known MS risk genetics, indicating an added role for genetic progression analyses and informing drug discovery.

Functional assessment of the dural lymphatic vessels using dynamic contrast MRI in multiple sclerosis.

BACKGROUND AND PURPOSE: The discovery of glymphatic function in the human brain has generated interest in waste clearance mechanisms in neurological disorders such as multiple sclerosis (MS). However, noninvasive in vivo functional assessment is currently lacking. This work studies the feasibility of a novel intravenous dynamic contrast MRI method to assess the dural lymphatics, a purported pathway contributing to glymphatic clearance. METHODS: This prospective study included 20 patients with MS (17 women; age = 46.4 [27, 65] years; disease duration = 13.6 [2.1, 38.0] years, expanded disability status score (EDSS) = 2.0 [0, 6.5]). Patients were scanned on a 3.0T MRI system using intravenous contrast-enhanced fluid-attenuated inversion recovery MRI. Signal in the dural lymphatic vessel along the superior sagittal sinus was measured to calculate peak enhancement, time to maximum enhancement, wash-in and washout slopes, and the area under the time-intensity curve (AUC). Correlation analysis was performed to examine the relationship between the lymphatic dynamic parameters and the demographic and clinical characteristics, including the lesion load and the brain parenchymal fraction (BPF). RESULTS: Contrast enhancement was detected in the dural lymphatics in most patients 2-3 min after contrast administration. BPF had a significant correlation with AUC (p < .03), peak enhancement (p < .01), and wash-in slope (p = .01). Lymphatic dynamic parameters did not correlate with age, BMI, disease duration, EDSS, or lesion load. Moderate trends were observed for correlation between patient age and AUC (p = .062), BMI and peak enhancement (p = .059), and BMI and AUC (p = .093). CONCLUSION: Intravenous dynamic contrast MRI of the dural lymphatics is feasible and may be useful in characterizing its hydrodynamics in neurological diseases.

Clinical and fringe benefits of rituximab in multiple sclerosis treatment in a poor resource setting: Case series and cost analysis.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory demyelinating condition of the central nervous system that leads to neurological disability and a poor quality of life (QoL). Rituximab has been used off-label in many countries to treat MS because of its high efficacy and affordability. However, there is no evidence of its effectiveness in Thailand. Therefore, the objective of this study was to evaluate the efficacy and additional benefits of rituximab in Thai patients with MS. METHODS: This was a prospective cohort study of patients diagnosed with MS who started treatment with rituximab between November 1, 2020, and October 31, 2022. Patients with MS eligible for the study received intravenous rituximab with a starting dose of 1000 mg at the first visit and another 1000 mg dose 2 weeks later. Thereafter, 1000 mg rituximab was administered every 6 months until the end of the study. The primary outcome was the annualized relapse rate (ARR). In addition, magnetic resonance imaging (MRI) activity of the gadolinium-enhancing lesion, QoL, number of hospital visits, and treatment costs were considered secondary outcomes. RESULTS: Ten patients diagnosed with relapsing-remitting multiple sclerosis were included in the study. The median ARR markedly decreased from 2.14 (0-4) to 0 (0-0.5) (p=0.005). The median Expanded Disability Status Scale score improved from 3.25 (1.5-6.0) to 1 (1-4) (p=0.005). The median number of enhancing lesions decreased from 1 (0-7) to 0 (0-3) (p=0.017). In addition, the median EuroQoL 5 Dimension 5 Level score, indicating QoL, improved from 0.7 (0.41-0.85) to 0.88 (0.68-1.00) (p=0.005). The median number of outpatient department visits significantly decreased from 6 (4-12) to 3 (2-5) (p=0.009). Hospitalization or inpatient department visits diminished from 1 (0-2) to 0 (0-1) (p=0.007). The total direct medical cost of rituximab treatment was not significantly different from that of the pre-treatment condition: 70,891 THB (65,391-116,358) VS 66,961 THB (33,927-109,248) or 1,904 USD (1,756-3,125 USD) VS 1,798 USD (911-2,934) (p=0.173). CONCLUSION: Rituximab was effective in the treatment of MS in Thailand. The use of rituximab reduced the number of relapses, reduced disability, decreased the number of active MRI lesions, and improved QoL. Moreover, the benefit of rituximab in treating MS in Thailand surpasses the current cost of treatment.

Longitudinal assessment of cervical spinal cord compartments in multiple sclerosis.

BACKGROUND: Although cervical spinal cord (cSC) area is an established biomarker in MS, there is currently a lack of longitudinal assessments of cSC gray and white matter areas. OBJECTIVE: We conducted an explorative analysis of longitudinal changes of cSC gray and white matter areas in MS patients. METHODS: 65 MS patients (33 relapsing-remitting; 20 secondary progressive and 12 primary progressive) and 20 healthy controls (HC) received clinical and upper cSC MRI assessments over 1.10±0.28 years. cSC compartments were quantified on MRI using the novel averaged magnetization inversion recovery acquisitions sequence (in-plane resolution=0.67 × 0.67mm2), and in-house developed post-processing methods. Patients were stratified regarding clinical progression. RESULTS: Patients with clinical progression showed faster reduction of cSC areas over time at the level of cSC enlargement (approximate vertebral level C4-C5) compared to stable patients (p<0.05). In addition, when compared to the rostral-cSC (approximate vertebral level C2-C3), a preferential reduction of cSC and white matter areas over time at the level of cSC enlargement (p<0.05 and p<0.01, respectively) was demonstrated only in patients with clinical progression, but not in stable MS patients and HC. Compared to HC, MS patients showed comparable changes over time in all cSC compartments. CONCLUSIONS: MS patients with clinical disease progression demonstrate subtle signs of a more pronounced tissue loss at the level of cSC enlargement. Future studies should consider larger sample sizes and more extended observation periods.

Commercial volumetric MRI reporting tools in multiple sclerosis: a systematic review of the evidence.

PURPOSE: MRI is integral to the diagnosis of multiple sclerosis (MS) and is important for clinical prognostication. Quantitative volumetric reporting tools (QReports) can improve the accuracy and objectivity of MRI-based assessments. Several QReports are commercially available; however, validation can be difficult to establish and does not currently follow a common pathway. To aid evidence-based clinical decision-making, we performed a systematic review of commercial QReports for use in MS including technical details and published reports of validation and in-use evaluation. METHODS: We categorized studies into three types of testing: technical validation, for example, comparison to manual segmentation, clinical validation by clinicians or interpretation of results alongside clinician-rated variables, and in-use evaluation, such as health economic assessment. RESULTS: We identified 10 companies, which provide MS lesion and brain segmentation and volume quantification, and 38 relevant publications. Tools received regulatory approval between 2006 and 2020, contextualize results to normative reference populations, ranging from 620 to 8000 subjects, and require T1- and T2-FLAIR-weighted input sequences for longitudinal assessment of whole-brain volume and lesions. In MS, six QReports provided evidence of technical validation, four companies have conducted clinical validation by correlating results with clinical variables, only one has tested their QReport by clinician end-users, and one has performed a simulated in-use socioeconomic evaluation. CONCLUSION: We conclude that there is limited evidence in the literature regarding clinical validation and in-use evaluation of commercial MS QReports with a particular lack of clinician end-user testing. Our systematic review provides clinicians and institutions with the available evidence when considering adopting a quantitative reporting tool for MS.

Preliminary validity of the Draw a Shape Test for upper extremity assessment in multiple sclerosis.

OBJECTIVE: To validate the smartphone sensor-based Draw a Shape Test - a part of the Floodlight Proof-of-Concept app for remotely assessing multiple sclerosis-related upper extremity impairment by tracing six different shapes. METHODS: People with multiple sclerosis, classified functionally normal/abnormal via their Nine-Hole Peg Test time, and healthy controls participated in a 24-week, nonrandomized study. Spatial (trace accuracy), temporal (mean and variability in linear, angular, and radial drawing velocities, and dwell time ratio), and spatiotemporal features (trace celerity) were cross-sectionally analyzed for correlation with standard clinical and brain magnetic resonance imaging (normalized brain volume and total lesion volume) disease burden measures, and for capacity to differentiate people with multiple sclerosis from healthy controls. RESULTS: Data from 69 people with multiple sclerosis and 18 healthy controls were analyzed. Trace accuracy (all shapes), linear velocity variability (circle, figure-of-8, spiral shapes), and radial velocity variability (spiral shape) had a mostly fair/moderate-to-good correlation (|r| = 0.14-0.66) with all disease burden measures. Trace celerity also had mostly fair/moderate-to-good correlation (|r| = 0.18-0.41) with Nine-Hole Peg Test performance, cerebellar functional system score, and brain magnetic resonance imaging. Furthermore, partial correlation analysis related these results to motor impairment. People with multiple sclerosis showed greater drawing velocity variability, though slower mean velocity, than healthy controls. Linear velocity (spiral shape) and angular velocity (circle shape) potentially differentiate functionally normal people with multiple sclerosis from healthy controls. INTERPRETATION: The Draw a Shape Test objectively assesses upper extremity impairment and correlates with all disease burden measures, thus aiding multiple sclerosis-related upper extremity impairment characterization.

Brief international cognitive assessment for MS (BICAMS) and global brain volumes in early stages of MS - A longitudinal correlation study.

BACKGROUND: Cognitive impairment is common in patients with multiple sclerosis, even in the early stages of the disease. The Brief International Cognitive Assessment for multiple sclerosis (BICAMS) is a short screening tool developed to assess cognitive function in everyday clinical practice. OBJECTIVE: To investigate associations between volumetric brain measures derived from a magnetic resonance imaging (MRI) examination and performance on BICAMS subtests in early stages of multiple sclerosis (MS). METHODS: BICAMS was used to assess cognitive function in 49 MS patients at baseline and after one and two years. The patients were separated into two groups (with or without cognitive impairment) based on their performances on BICAMSs subtests. MRI data were analysed by a software tool (MSMetrix), yielding normalized measures of global brain volumes and lesion volumes. Associations between cognitive tests and brain MRI measures were analysed by running correlation analyses, and differences between subgroups and changes over time with independent and paired samples tests, respectively. RESULTS: The strongest baseline correlations were found between the BICAMS subtests and normalized whole brain volume (NBV) and grey matter volume (NGV); processing speed r = 0.54/r = 0.48, verbal memory r = 0.49/ r = 0.42, visual memory r = 0.48 /r = 0.39. Only the verbal memory test had significant correlations with T2 and T1 lesion volumes (LV) at both time points; T2LV r = 0.39, T1LV r = 0.38. There were significant loss of grey matter and white matter volume overall (NGV p<0.001, NWV p = 0.003), as well as an increase in T1LV (p = 0.013). The longitudinally defined confirmed cognitively impaired (CCI) and preserved (CCP) patients showed significant group differences on all MRI volume measures at both time points, except for NWV. Only the CCI subgroup showed significant white matter atrophy (p = 0.006) and increase in T2LV (p = 0.029). CONCLUSIONS: The present study found strong correlations between whole brain and grey matter volumes and performance on the BICAMS subtests as well as significant changes in global volumes from baseline to follow-up with clear differences between patients defined as cognitively impaired and preserved at both baseline and follow-up.

A comparative assessment of myelin-sensitive measures in multiple sclerosis patients and healthy subjects.

INTRODUCTION: Multiple Sclerosis (MS) is a common neurological disease primarily characterized by myelin damage in lesions and in normal - appearing white and gray matter (NAWM, NAGM). Several quantitative MRI (qMRI) methods are sensitive to myelin characteristics by measuring specific tissue biophysical properties. However, there are currently few studies assessing the relative reproducibility and sensitivity of qMRI measures to MS pathology in vivo in patients. METHODS: We performed two studies. The first study assessed of the sensitivity of qMRI measures to MS pathology: in this work, we recruited 150 MS and 100 healthy subjects, who underwent brain MRI at 3 T including quantitative T1 mapping (qT1), quantitative susceptibility mapping (QSM), magnetization transfer saturation imaging (MTsat) and myelin water imaging for myelin water fraction (MWF). The sensitivity of qMRIs to MS focal pathology (MS lesions vs peri-plaque white/gray matter (PPWM/PPGM)) was studied lesion-wise; the sensitivity to diffuse normal appearing (NA) pathology was measured using voxel-wise threshold-free cluster enhancement (TFCE) in NAWM and vertex-wise inflated cortex analysis in NAGM. Furthermore, the sensitivity of qMRI to the identification of lesion tissue was investigated using a voxel-wise logistic regression analysis to distinguish MS lesion and PP voxels. The second study assessed the reproducibility of myelin-sensitive qMRI measures in a single scanner. To evaluate the intra-session and inter-session reproducibility of qMRI measures, we have investigated 10 healthy subjects, who underwent two brain 3 T MRIs within the same day (without repositioning), and one after 1-week interval. Five region of interest (ROIs) in white and deep grey matter areas were segmented, and inter- and intra- session reproducibility was studied using the intra-class correlation coefficient (ICC). Further, we also investigated the voxel-wise reproducibility of qMRI measures in NAWM and NAGM. RESULTS: qT1 and QSM showed the highest sensitivity to distinguish MS focal WM and cortical pathology from peri-plaque WM (P < 0.0001), although QSM also showed the highest variance when applied to lesions. MWF and MTsat exhibited the highest sensitivity to NAWM pathology (P < 0.01). On the other hand, qT1 appeared to be the most sensitive measure to NAGM pathology (P < 0.01). All myelin-sensitive qMRI measures exhibited high inter/intra sessional ICCs in various WM and deep GM ROIs, in NAWM and in NAGM (ICC 0.82 ± 0.12). CONCLUSION: This work shows that the applied qT1, MWF, MTsat and QSM are highly reproducible and exhibit differential sensitivity to focal and diffuse WM and GM pathology in MS patients.

Assessment of T2 lesion-based disease activity volume outcomes in predicting disease progression in multiple sclerosis over 10 years.

BACKGROUND: New/enlarging T2 lesion count and T2-lesion volume (LV) are used as conventional secondary endpoints in clinical trials of patients with multiple sclerosis (PwMS). However, those outcomes may have several limitations, such as inability to account for heterogeneity of lesion formation/enlargement frequency and their dynamic volumetric behavior. Measurement of volume rather than count of new/enlarging lesions may be more representative outcome of dynamic changes over time. OBJECTIVES: To investigate whether new/enlarging T2-LV is more predictive of confirmed disability progression (CDP), compared to total T2-LV or new/enlarging T2 lesion count over long-term follow-up. METHODS: We studied 176 early relapsing-remitting PwMS who were followed with annual MRI examinations over 10 years. T2-LV, new/enlarging T2-LV, and new/enlarging lesion count were determined. Cumulative count/volumes were obtained. 10-year CDP was confirmed after 48-weeks. ANCOVA analysis detected MRI outcome differences in stable (n = 76) and CDP (n = 100) groups at different time points, after correction for multiple comparisons. RESULTS: PwMS with CDP had greater cumulative new/enlarging T2-LV at 4 years (p = 0.049), and enlarging T2-LV at 4- (p = 0.039) and 6-year follow-up (p = 0.032), compared to stable patients. PwMS with CDP did not differ from stable ones in new/enlarging T2 lesion count or total T2-LV at any of the study timepoints. PwMS with Expanded Disability Status Scale change >2.0 had significantly greater enlarging T2 lesion count (p = 0.01) and enlarging T2-LV (p = 0.038) over the 10-year follow-up. CONCLUSION: Enlargement of T2 lesions is more strongly associated with long-term disability progression compared to other conventional T2 lesion-based outcomes.

Stages of brain volume loss and performance in the Brief International Cognitive Assessment for Multiple Sclerosis.

BACKGROUND: Cognitive dysfunction occurs in a substantial proportion of patients with multiple sclerosis (MS), negatively affects their daily activities, and is associated with poor prognosis. Cognitive dysfunction in MS can extend across multiple cognitive domains, depending on the patterns and extent of the brain regions affected. Therefore, a combination of tests, including the Brief International Cognitive Assessment for MS (BICAMS), that assess different aspects of cognition is recommended to capture the full picture of cognitive impairment in each patient. However, the temporal relationships between the progression of the MS brain pathology and the performances in different cognitive tests remain unclear. METHODS: Global and regional brain volume data were obtained based on T1-weighted magnetic resonance imaging from 61 patients with MS, and hierarchical cluster analysis was performed using these brain volume data. Cognitive function was assessed using the three subcomponents of the BICAMS: the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test Second Edition (CVLT2), and Brief Visuospatial Memory Test-Revised (BVMTR). Clinical characteristics, patterns of regional brain volume loss, and cognitive test scores were compared among clusters. RESULTS: Cluster analysis of the global and regional brain volume data classified patients into three clusters (Clusters 1, 2, and 3) in order of decreasing global brain volume. A comparison of the clinical profiles of the patients suggested that those in Clusters 1, 2, and 3 are in the early, intermediate, and advanced stages of MS, respectively. Pair-wise analysis of regional brain volume among the three clusters suggested brain regions where volume loss starts early and continues throughout the disease course, occurs preferentially at the early phase, or evolves relatively slowly. SDMT scores differed significantly among the three clusters, with a decrease from Clusters 1 to 3. BVMTR scores also declined in this order, whereas the CVLT2 was significantly impaired only in Cluster 3. CONCLUSION: Our results suggest that SDMT performance declines in conjunction with brain volume loss throughout the disease course of MS. Performance in the BVMTR also declines in line with the brain volume loss, but impairment in the CVLT2 becomes particularly apparent at the late phase of MS.

Assessment of cervical spinal cord volume in pediatric-onset multiple sclerosis.

PURPOSE: Several studies of adult-onset multiple sclerosis (AOMS) patients have demonstrated that spinal cord volume loss is associated with disease progression and clinical disability. However, complementary studies of young patients with pediatric-onset multiple sclerosis (POMS) are lacking. Our retrospective study aimed to assess spinal cord volume in POMS patients compared with that in healthy controls. METHODS: Cervical spinal cord magnetic resonance images were evaluated for 20 POMS patients and 20 age- and sex-matched controls. Cross-sectional areas (CSAs) were measured at C2 and C7, along with the spinal cord average segmental area (CASA). The POMS group was further subdivided based on the presence or absence of spinal cord lesions, specifically C2 lesions. Pairwise area and volume comparisons were made across the different groups. RESULTS: No significant difference was found in CASA and CSA at C2 and C7 between POMS patients and comparative controls. However, CASA, CSA at C7, and estimated spinal cord volume were significantly lower in a small subset of POMS patients with C2 lesions (3 patients) than in controls (P = 0.001, 0.02, and 0.001, respectively). CONCLUSION: No significant difference was found in spinal cord areas and volumes between POMS patients and controls. This finding contrasts with spinal cord volume measurements in AOMS patients.

EDSS 0 is not normal: Multiple sclerosis disease burden below the clinical threshold.

Little to no above-threshold deficits may be evident in early multiple sclerosis (MS). The Expanded Disability Status Scale (EDSS) is a standard measure of neurologic function, with an EDSS score of 0 defined as "neurologically normal." The topographical model of MS proposes that sub-threshold disease is compensated for by functional reserve. In this short report, we found that physically high-challenge measures of balance and upper extremity coordination reveal sub-threshold deficits in patients with EDSS score of 0 compared with healthy controls. Challenge task performance was correlated with imaging markers of both lesional burden of disease and a volumetric measure of brain reserve.

Assessment of data consistency through cascades of independently recurrent inference machines for fast and robust accelerated MRI reconstruction.

Objective.Machine Learning methods can learn how to reconstruct magnetic resonance images (MRI) and thereby accelerate acquisition, which is of paramount importance to the clinical workflow. Physics-informed networks incorporate the forward model of accelerated MRI reconstruction in the learning process. With increasing network complexity, robustness is not ensured when reconstructing data unseen during training. We aim to embed data consistency (DC) in deep networks while balancing the degree of network complexity. While doing so, we will assess whether either explicit or implicit enforcement of DC in varying network architectures is preferred to optimize performance.Approach.We propose a scheme called Cascades of Independently Recurrent Inference Machines (CIRIM) to assess DC through unrolled optimization. Herein we assess DC both implicitly by gradient descent and explicitly by a designed term. Extensive comparison of the CIRIM to compressed sensing as well as other Machine Learning methods is performed: the End-to-End Variational Network (E2EVN), CascadeNet, KIKINet, LPDNet, RIM, IRIM, and UNet. Models were trained and evaluated on T1-weighted and FLAIR contrast brain data, and T2-weighted knee data. Both 1D and 2D undersampling patterns were evaluated. Robustness was tested by reconstructing 7.5× prospectively undersampled 3D FLAIR MRI data of multiple sclerosis (MS) patients with white matter lesions.Main results.The CIRIM performed best when implicitly enforcing DC, while the E2EVN required an explicit DC formulation. Through its cascades, the CIRIM was able to score higher on structural similarity and PSNR compared to other methods, in particular under heterogeneous imaging conditions. In reconstructing MS patient data, prospectively acquired with a sampling pattern unseen during model training, the CIRIM maintained lesion contrast while efficiently denoising the images.Significance.The CIRIM showed highly promising generalization capabilities maintaining a very fair trade-off between reconstructed image quality and fast reconstruction times, which is crucial in the clinical workflow.

Assessment of 2D conventional and synthetic MRI in multiple sclerosis.

PURPOSE: To qualitatively and quantitatively compare synthetic and conventional MRI sequences acquired on a 1.5-T system for patients with multiple sclerosis (MS). METHODS: Prospective study that involved twenty-seven consecutive relapsing-remitting MS patients scanned on a 1.5-T MRI scanner. The MRI protocol included 2D transverse conventional spin-echo sequences: proton density-weighted (PD), T2-weighted, T2-FLAIR, and T1-weighted. Synthetic images were generated using 2D transverse QRAPMASTER and SyMRI software with the same voxel size, repetition, echo, and inversion times as the conventional sequences. Four raters performed a crosstab qualitative analysis that involved evaluating global image quality, contrast, flow artefacts, and confidence in lesion assessment introducing the concepts of predominance, agreement, and disagreement. A quantitative analysis was also performed and included evaluating the number of lesions (periventricular, juxtacortical, brainstem, and cerebellum) and the contrast-to-noise ratio between regions (CSF, white matter, grey matter, lesions). RESULTS: The global image quality assessment showed predominance for better scores for conventional sequences over synthetic sequences, whereas contrast, confidence in lesion assessment, and flow artefacts showed predominance for agreement between sequences. There was predominance for disagreement between all pairs of raters in most of the evaluated qualitative parameters. Synthetic PD and T2-FLAIR images showed higher contrast-to-noise ratios than the corresponding conventional images for most comparison between regions. There were no significant differences in the number of lesions detected for most of the study regions between conventional and synthetic images. CONCLUSION: Synthetic MRI can be potentially used as an alternative to conventional brain MRI sequences in the assessment of MS.

Quantitative assessment of myelin density using [11C]MeDAS PET in patients with multiple sclerosis: a first-in-human study.

PURPOSE: Multiple sclerosis (MS) is a disease characterized by inflammatory demyelinated lesions. New treatment strategies are being developed to stimulate myelin repair. Quantitative myelin imaging could facilitate these developments. This first-in-man study aimed to evaluate [11C]MeDAS as a PET tracer for myelin imaging in humans. METHODS: Six healthy controls and 11 MS patients underwent MRI and dynamic [11C]MeDAS PET scanning with arterial sampling. Lesion detection and classification were performed on MRI. [11C]MeDAS time-activity curves of brain regions and MS lesions were fitted with various compartment models for the identification of the best model to describe [11C]MeDAS kinetics. Several simplified methods were compared to the optimal compartment model. RESULTS: Visual analysis of the fits of [11C]MeDAS time-activity curves showed no preference for irreversible (2T3k) or reversible (2T4k) two-tissue compartment model. Both volume of distribution and binding potential estimates showed a high degree of variability. As this was not the case for 2T3k-derived net influx rate (Ki), the 2T3k model was selected as the model of choice. Simplified methods, such as SUV and MLAIR2 correlated well with 2T3k-derived Ki, but SUV showed subject-dependent bias when compared to 2T3k. Both the 2T3k model and the simplified methods were able to differentiate not only between gray and white matter, but also between lesions with different myelin densities. CONCLUSION: [11C]MeDAS PET can be used for quantification of myelin density in MS patients and is able to distinguish differences in myelin density within MS lesions. The 2T3k model is the optimal compartment model and MLAIR2 is the best simplified method for quantification. TRIAL REGISTRATION: NL7262. Registered 18 September 2018.

Economic impact of selective use of contrast for routine follow-up MRI of patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Imaging and autopsy studies show intracranial gadolinium deposition in patients who have undergone serial contrast-enhanced MRIs. This observation has raised concerns when using contrast administration in patients who receive frequent MRIs. To address this, we implemented a contrast-conditional protocol wherein gadolinium is administered only for multiple sclerosis (MS) patients with imaging evidence of new disease activity on precontrast imaging. In this study, we explore the economic impact of our new MRI protocol. METHODS: We compared scanner time and Medicare reimbursement using our contrast-conditional methodology versus that of prior protocols where all patients received gadolinium. RESULTS: For 422 patients over 4 months, the contrast-conditional protocol amounted to 60% decrease in contrast injection and savings of approximately 20% of MRI scanner time. If the extra scanner time was used for performing MS follow-up MRIs in additional patients, the contrast-conditional protocol would amount to net revenue loss of $21,707 (∼3.7%). CONCLUSIONS: Implementation of a new protocol to limit contrast in MS follow-up MRIs led to a minimal decrease in revenue when controlled for scanner time utilized and is outweighed by other benefits, including substantial decreased gadolinium administration, increased patient comfort, and increased availability of scanner time, which depending on type of studies performed could result in additional financial benefit.