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Introduction Myeloablative and immunoablative therapy followed by autologous hematopoietic stem cell transplantation (AHSCT) has been shown to be effective in patients with highly active relapsing multiple sclerosis (RMS) with continued activity despite treatment with approved disease-modifying therapies (DMTs). However, AHSCT has not been formally compared to the contemporary high efficacy biologic DMTs in a clinical trial. Objective To implement a trial to compare efficacy, safety, and cost-effectiveness of AHSCT to best available medical therapy (BAT) in treatment-resistant RMS. Methods The BEAT-MS trial was developed by a collaborative study team including academic neurology and transplant protocol chairs, a health economist, neuroradiologist and patient-reported outcome measure expert. The trial will be conducted by the Immune Tolerance Network (ITN) in collaboration with the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), and sponsored by the National Institute of Allergy and Infectious Diseases (UM1AI109565). The trial will be conducted at 18 paired MS and transplant centers in the United States and 1 in the United Kingdom. Results BEAT-MS will be a multi-center prospective rater-blinded randomized controlled trial of 156 participants comparing AHSCT versus BAT. Participants with highly active treatment-resistant relapsing MS and mild to moderate disability will be randomized at a 1:1 ratio. Eligible participants will be age 18-55. Co-morbid medical conditions that increase the risk of AHSCT will be excluded. For participants randomized to the AHSCT arm, peripheral blood stem cells (PBSC) will be mobilized with cyclophosphamide, dexamethasone, and filgrastim, collected by leukapheresis, and cryopreserved. Participants will receive conditioning with carmustine, etoposide, cytarabine, and melphalan (BEAM) and rabbit anti-thymocyte globulin prior to re-infusion of the unmanipulated autologous PBSC. Participants randomized to the BAT arm will be treated with either natalizumab, alemtuzumab, ocrelizumab, or rituximab. All participants will be followed for 72 months. The primary endpoint will be MS relapse-free survival. The primary statistical analysis will be performed when all randomized participants active in the study have completed the Month 36 evaluation. Secondary and exploratory endpoints will compare MS disease activity assessed clinically and by magnetic resonance imaging, and include neurodegeneration, safety outcomes, quality of life, cost-effectiveness, and immune signatures. Conclusion BEAT-MS will be a large scale prospective multi-center randomized clinical trial comparing AHSCT to contemporary high efficacy DMTs, with the goal of determining whether AHSCT is an appropriate treatment option for patients with highly active RMS for whom BAT would be prescribed in current clinical neurology practice.

Noise-based quality evaluation of MRI images is highly desired in noise-dominant environments. Current noise-based MRI quality evaluation methods have drawbacks which limit their effective performance. Traditional full-reference methods such as SNR and most of the model-based techniques cannot provide perceptual quality metrics required for accurate diagnosis, treatment and monitoring of diseases. Although techniques based on the Moran coefficients are perceptual quality metrics, they are full-reference methods and will be ineffective in applications where the reference image is not available. Furthermore, the predicted quality scores are difficult to interpret because their quality indices are not standardized. In this paper, we propose a new no-reference perceptual quality evaluation method for grayscale images such as MRI images. Our approach is formulated to mimic how humans perceive an image. It transforms noise level into a standardized perceptual quality score. Global Moran statistics is combined with local indicators of spatial autocorrelation in the form of local Moran statistics. Quality score is predicted from perceptually weighted combination of clustered and random pixels. Performance evaluation, comparative performance evaluation and validation by human observers, shows that the proposed method will be a useful tool in the evaluation of retrospectively acquired MRI images and the evaluation of noise reduction algorithms. © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

We present an improved image analysis pipeline to detect the percent brain volume change (PBVC) using SIENA (Structural Image Evaluation, using Normalization, of Atrophy) in populations with Alzheimer's dementia. Our proposed approach uses the improved brain extraction mask from BEaST (Brain Extraction based on nonlocal Segmentation Technique) instead of the conventional BET (Brain Extraction Tool) for SIENA. We compared four varying options of BET as well as BEaST and applied these five methods to analyze scan-rescan MRIs in ADNI from 332 subjects, longitudinal ADNI MRIs from the same 332 subjects, their repeat scans over time, and OASIS longitudinal MRIs from 123 subjects. The results showed that BEaST brain masks were consistent in scan-rescan reproducibility. The cross-sectional scan-rescan error in the absolute percent brain volume difference measured by SIENA was smallest (p≤0.0187) with the proposed BEaST-SIENA. We evaluated the statistical power in terms of effect size, and the best performance was achieved with BEaST-SIENA (1.2789 for ADNI and 1.095 for OASIS). The absolute difference in PBVC between scan-dataset (volume change from baseline to year-1) and rescan-dataset (volume change from baseline repeat scan to year-1 repeat scan) was also the smallest with BEaST-SIENA compared to the BET-based SIENA and had the highest correlation when compared to the BET-based SIENA variants. In conclusion, our study shows that BEaST was robust in terms of reproducibility and consistency and that SIENA's reproducibility and statistical power are improved in multiple datasets when used in combination with BEaST.

ObjectiveTo assess the association between daily moderate-to-vigorous physical activity (MVPA) and dentate gyrus volume (DGv) in pediatric patients with acquired demyelinating syndromes (ADSs) of the CNS.MethodsCross-sectional analysis of accelerometry (7 days) and research protocol MRI data from 12 pediatric MS and 18 children with monophasic ADS (monoADS). Total brain and DGv were quantified using standardized methods. The association of daily minutes of MVPA with normalized DGv (nDGv) was assessed using multivariable generalized linear models.ResultsMedian (interquartile range) MVPA was lower in MS patients [9.5 (14)] and exhibited less variation than in monoADS patients [24.5 (47)]. nDGv did not differ significantly between groups [mean nDGv (SD) [cm3]: MS 0.34 (0.1); monoADS 0.4 (0.1); p = 0.100]. In the monoADS group, every 1-minute increase in MVPA was associated with a 2.4-mm3 increase in nDGv (p = 0.0017), an association that was independent of age at incident demyelination, time from incident demyelination, sex, and brain white matter T2 lesion volume. No significant association was found between MVPA and nDGv (−2.6 mm3/min, p = 0.16) in the MS group.ConclusionsHigher MVPA associates with greater nDGv in children who have recovered from monophasic demyelination. Larger studies are required to determine whether MVPA can promote regional brain development, or limit tissue damage, in youth with MS.

In conventional non-quantitative magnetic resonance imaging, image contrast is consistent within images, but absolute intensity can vary arbitrarily between scans. For quantitative analysis of intensity data, images are typically normalized to a consistent reference. The most convenient reference is a tissue that is always present in the image, and is unlikely to be affected by pathological processes. In multiple sclerosis neuroimaging, both the white and gray matter are affected, so normalization techniques that depend on brain tissue may introduce bias or remove biological changes of interest. We introduce a complementary procedure, image “calibration,” the goal of which is to remove technical intensity artifacts while preserving biological differences. We demonstrate a deep learning approach to segmenting fat from within the orbit of the eyes on T1-weighted images at 1.5 and 3 ​T to use as a reference tissue, and use it to calibrate 1018 scans from 256 participants in a study of pediatric-onset multiple sclerosis. The machine segmentations agreed with the adjudicating expert (DF) segmentations better than did those of other expert humans, and calibration resulted in better agreement with semi-quantitative magnetization transfer ratio imaging than did normalization with the WhiteStripe1 algorithm. We suggest that our method addresses two key priorities in the field: (1) it provides a robust option for serial calibration of conventional scans, allowing comparison of disease change in persons imaged at multiple time points in their disease; and (ii) the technique is fast, as the deep learning segmentation takes only 0.5 ​s/scan, which is feasible for both large and small datasets.

ObjectiveTo assess functional changes in lymphocyte repertoire and subsequent clinical implications during delayed-release dimethyl fumarate (DMF) treatment in patients with multiple sclerosis.MethodsUsing peripheral blood from several clinical trials of DMF, immune cell subsets were quantified using flow cytometry. For some patients, lymphocyte counts were assessed after DMF discontinuation. Incidence of adverse events, including serious and opportunistic infections, was assessed.ResultsIn DMF-treated patients, absolute lymphocyte counts (ALCs) demonstrated a pattern of decline followed by stabilization, which also was reflected in the global reduction in numbers of circulating functional lymphocyte subsets. The relative frequencies of circulating memory T- and B-cell populations declined and naive cells increased. No increased incidence of serious infection or malignancy was observed for patients treated with DMF, even when stratified by ALC or T-cell subset frequencies. For patients who discontinued DMF due to lymphopenia, ALCs increased after DMF discontinuation; recovery time varied by ALC level at discontinuation. T-cell subsets closely correlated with ALCs in both longitudinal and cross-sectional analyses.ConclusionsDMF shifted the immunophenotype of circulating lymphocyte subsets. ALCs were closely correlated with CD4+ and CD8+ T-cell counts, indicating that lymphocyte subset monitoring is not required for safety vigilance. No increased risk of serious infection was observed in patients with low T-cell subset counts. Monitoring ALC remains the most effective way of identifying patients at risk of subsequently developing prolonged moderate to severe lymphopenia, a risk factor for progressive multifocal leukoencephalopathy in DMF-treated patients.Trial registration numbersEUDRA CT 2015-001973-42, NCT00168701, NCT00420212, NCT00451451, and NCT00835770.

Background: No evidence of disease activity (NEDA) is a composite measurement, incorporating clinical and magnetic resonance imaging (MRI) elements of disease activity to sensitively evaluate the therapeutic efficacy of treatments for relapsing–remitting multiple sclerosis (RRMS). Objective: To assess the NEDA status of patients treated with peginterferon β-1a in the ADVANCE and ATTAIN studies and explore its predictive value on longer-term clinical outcomes. Methods: ATTAIN was a 2-year extension of the pivotal 2-year ADVANCE study of peginterferon β-1a for RRMS. Achievement of clinical NEDA, MRI NEDA, or overall NEDA was calculated cumulatively and by year over 4 years. Clinical outcomes during ATTAIN were analyzed based on NEDA status at the end of ADVANCE. Results: Significantly more patients treated with peginterferon β-1a every 2 weeks than every 4 weeks achieved clinical NEDA (60.6% versus 50.6%, p = 0.0063) and MRI NEDA (28.3% versus 15.8%, p = 0.0005) through year 4 and overall NEDA through year 3 (20.9% versus 13.9%, p = 0.0160). Over 4 years, 15.8% of patients in the every 2 weeks group and 10.7% of patients in the every 4 weeks group maintained overall NEDA ( p = 0.0584). Achievement of clinical NEDA, MRI NEDA, or overall NEDA in ADVANCE was predictive of annualized relapse rate in ATTAIN; achievement of clinical NEDA in ADVANCE was also predictive of NEDA achievement and confirmed disability worsening in ATTAIN. Conclusions: Peginterferon β-1a every 2 weeks is associated with higher levels of NEDA compared with placebo in year 1 or peginterferon β-1a every 4 weeks in years 2–4. Overall NEDA within the first 2 years of treatment may be prognostic of long-term clinical outcomes. Clinicaltrials.gov : NCT01332019

Background: ADVANCE was a phase III trial of the efficacy and safety of subcutaneous peginterferon beta-1a 125 µg every 2 or 4 weeks in patients with relapsing-remitting multiple sclerosis (RRMS). ATTAIN was a 2-year extension study of ADVANCE. The aim was to evaluate the long-term safety, tolerability, and efficacy of peginterferon beta-1a 125 µg every 2 or 4 weeks in ATTAIN. Methods: ADVANCE dosing schedules were maintained in ATTAIN, except that every-4-weeks dosing patients were switched to every-2-weeks dosing after conversion of the study to an open-label protocol. ATTAIN was considered complete when the last patient completed the 96-week extension study. Primary endpoints included adverse event (AE) and serious AE (SAE) incidence. Secondary endpoints included relapse, magnetic resonance imaging, and disability outcomes. Results: Of the 1512 patients randomized in ADVANCE, 1076 (71%) continued treatment in ATTAIN; of these, 842 (78%) completed the open-label extension study. During ATTAIN, 478 patients (87%) in the every-2-weeks group and 471 patients (89%) in the every-4-weeks group experienced an AE; SAEs were reported in 90 patients (16%) in the every-2-weeks group and 113 patients (21%) in the every-4-weeks group. The most frequent AEs reported were injection site reactions and flu-like symptoms, both of which numerically decreased over time. Peginterferon beta-1a every 2 weeks versus every 4 weeks significantly reduced the adjusted annualized relapse rate over 6 years (0.188 versus 0.263, p = 0.0052) and the risk of relapse over 5 years (36% versus 49%, p = 0.0018). Fewer new T1, new/newly enlarging T2, and gadolinium-enhancing magnetic resonance imaging lesions were observed with every-2-weeks dosing than every-4-weeks dosing over 4 years. Conclusions: Results from the ADVANCE extension study, ATTAIN, confirm the favorable long-term safety and tolerability profile of peginterferon beta-1a in patients with RRMS and provide additional evidence for the clinical and radiological benefits associated with this therapy.

Background: Ozanimod, an oral immunomodulator, selectively targets sphingosine 1-phosphate receptors 1 and 5. Objective: Evaluate efficacy, safety, and tolerability of ozanimod in relapsing multiple sclerosis. Methods: In the RADIANCE Part A phase II study (NCT01628393), participants with relapsing multiple sclerosis were randomized (1:1:1) to once-daily ozanimod hydrochloride (0.5 or 1 mg) or placebo. After 24 weeks, participants could enter a 2-year, dose-blinded extension. Ozanimod-treated participants continued their assigned dose; placebo participants were re-randomized (1:1) to ozanimod hydrochloride 0.5 or 1 mg (equivalent to ozanimod 0.46 and 0.92 mg). Results: A total of 223 (89.6%) of the 249 participants completed the blinded extension. At 2 years of the extension, the percentage of participants who were gadolinium-enhancing lesion-free ranged from 86.5% to 94.6%. Unadjusted annualized relapse rate during the blinded extension (week 24—end of treatment) was 0.32 for ozanimod hydrochloride 0.5 mg → ozanimod hydrochloride 0.5 mg, 0.18 for ozanimod hydrochloride 1 mg → ozanimod hydrochloride 1 mg, 0.30 for placebo → ozanimod hydrochloride 0.5 mg, and 0.18 for placebo → ozanimod hydrochloride 1 mg. No second-degree or higher atrioventricular block or serious opportunistic infection was reported. Conclusion: Ozanimod demonstrated sustained efficacy in participants continuing treatment up to 2 years and reached similar efficacy in participants who switched from placebo; no unexpected safety signals emerged.

Elucidation of distinct T-cell subsets involved in multiple sclerosis immune-pathophysiology continues to be of considerable interest since an ultimate goal is to more selectively target the aberrant immune response operating in individual patients. While abnormalities of both effector (Teff) and regulatory (Treg) T cells have been reported in patients with multiple sclerosis, prior studies have mostly assessed average abnormalities in either limb of the immune response, rather than both at the same time, which limits the ability to evaluate the balance between effectors and regulators operating in the same patient. Assessing both phenotypic and functional responses of Teffs and Tregs has also proven important. In studies of adults with multiple sclerosis, in whom biological disease onset likely started many years prior to the immune assessments, an added challenge for any reported abnormality is whether the abnormality indeed contributes to the disease (and hence of interest to target therapeutically) or merely develops consequent to inflammatory injury (in which case efforts to develop targeted therapies are unlikely to be beneficial). Paediatric-onset multiple sclerosis, though rare, offers a unique window into early disease mechanisms. Here, we carried out a comprehensive integrated study, simultaneously assessing phenotype and functional responses of both effector and regulatory T cells in the same children with multiple sclerosis, monophasic inflammatory CNS disorders, and healthy controls, recruited as part of the multicentre prospective Canadian Pediatric Demyelinating Disease Study (CPDDS). Stringent standard operating procedures were developed and uniformly applied to procure, process and subsequently analyse peripheral blood cells using rigorously applied multi-parametric flow cytometry panels and miniaturized functional assays validated for use with cryopreserved cells. We found abnormally increased frequencies and exaggerated pro-inflammatory responses of CD8(+)CD161(high)TCR-Vα7.2(+ )MAIT T cells and CD4(+)CCR2(+)CCR5(+) Teffs in paediatric-onset multiple sclerosis, compared to both control groups. CD4(+)CD25(hi)CD127(low)FOXP3(+) Tregs of children with multiple sclerosis exhibited deficient suppressive capacity, including diminished capacity to suppress disease-implicated Teffs. In turn, the implicated Teffs of multiple sclerosis patients were relatively resistant to suppression by normal Tregs. An abnormal Teff/Treg ratio at the individual child level best distinguished multiple sclerosis children from controls. We implicate abnormalities in both frequencies and functional responses of distinct pro-inflammatory CD4 and CD8 T cell subsets, as well as Treg function, in paediatric-onset multiple sclerosis, and suggest that mechanisms contributing to early multiple sclerosis development differ across individuals, reflecting an excess abnormality in either Teff or Treg limbs of the T cell response, or a combination of lesser abnormalities in both limbs.

Objective: In relapsing–remitting multiple sclerosis (RRMS), suboptimal adherence to injectable disease-modifying therapies (iDMTs; interferon β-1a/b, glatiramer acetate) is common, reducing their effectiveness. Patient retention on oral fingolimod and iDMTs was evaluated in PREFER MS , a randomized, parallel-group, active-controlled, open-label, 48-week study. Methods: Patients were included if they had RRMS, were aged 18–65 years and had Expanded Disability Status Scale score up to 6, enrolled at 117 US study sites, were treatment naïve or had received only one iDMT class. Patients were randomized 1:1 (fingolimod 0.5 mg/day; preselected iDMT) by interactive voice-and-web-response system without blinding, followed up quarterly, and allowed one study-approved treatment switch after 12 weeks, or earlier for efficacy or safety reasons. The primary outcome was patient retention on randomized treatment over 48 weeks. Secondary endpoints included patient-reported outcomes, brain volume loss (BVL), and cognitive function. Results: Analysis of 433/436 patients receiving fingolimod and 428/439 receiving iDMTs showed that patient retention rate was significantly higher with fingolimod than with iDMTs [352 (81.3%) versus 125 (29.2%); 95% confidence interval 46.4–57.8%; p < 0.0001]. The most common treatment switch was from iDMT to fingolimod for injection-related reasons. Patient satisfaction was greater and BVL less with fingolimod than with iDMTs, with no difference in cognitive function. Adverse events were consistent with established tolerability profiles for each treatment. Conclusions: In RRMS, fingolimod was associated with better treatment retention, patient satisfaction and BVL outcomes than iDMTs. Patients may persist with iDMTs, but many may switch treatment if permitted. Treatment satisfaction fosters adherence, a prerequisite for optimal outcomes.

BACKGROUND: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses.METHODS: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18-58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0-6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0-5·5 vs 6·0-6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181.FINDINGS: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66-1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74-1·53; nominal p=0·753) or the T25FW (0·98, 0·74-1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40-0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108-221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred.INTERPRETATION: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components.FUNDING: Biogen.

Background No evidence of disease activity (NEDA; defined as no 12-week confirmed disability progression, no protocol-defined relapses, no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions) using a fixed-study entry baseline is commonly used as a treatment outcome in multiple sclerosis (MS). Objective The objective of this paper is to assess the effect of ocrelizumab on NEDA using re-baselining analysis, and the predictive value of NEDA status. Methods NEDA was assessed in a modified intent-to-treat population ( n = 1520) from the pooled OPERA I and OPERA II studies over various epochs in patients with relapsing MS receiving ocrelizumab (600 mg) or interferon beta-1a (IFN β‐1a; 44 μg). Results NEDA was increased with ocrelizumab vs IFN β-1a over 96 weeks by 75% ( p Conclusion Superior efficacy with ocrelizumab compared with IFN β-1a was consistently seen in maintaining NEDA status in all epochs evaluated. By contrast with IFN β-1a, the majority of patients with disease activity early in the study subsequently attained NEDA status with ocrelizumab.

Background: Pediatric acquired demyelinating syndromes (ADSs) are monophasic (mono-ADS) in 70% of cases and represent the first attack of multiple sclerosis (MS) in 30%. Secondhand tobacco smoke (SHS) exposure has been implicated as a risk factor for adult-onset MS. Little is known about whether SHS presents an additive risk beyond genetic factors and other environmental exposures associated with pediatric MS. Methods: This study examined SHS exposure in 216 children with mono-ADS and 81 children with MS. Interactions between SHS, HLA-DRB1*15 alleles, serum 25-hydroxyvitamin D concentrations, and serological evidence of remote Epstein–Barr virus (EBV) exposure were evaluated. Results: SHS exposure was more common in children with MS (37% exposed) compared to mono-ADS (29.5% exposed). Compared to mono-ADS, SHS exposure was not an independent risk factor for MS. When both SHS exposure and HLA-DRB1*15 were present, the odds for MS increased (odds ratio (OR) = 3.7; 95% confidence interval (CI): 1.17–11.9) compared to mono-ADS. Interactions between SHS and vitamin D or EBV did not associate with MS. Conclusion: Exposure to SHS is a risk factor for central nervous system (CNS) demyelination. Results suggest that SHS exposure and HLA-DRB1*15 interact to increase risk for MS in children diagnosed with mono-ADS.

Summary Background MRI and laboratory features have been incorporated into international diagnostic criteria for multiple sclerosis. We assessed the pattern of MRI lesions and contributions of cerebrospinal fluid (CSF) and serum antibody findings that best identifies children with multiple sclerosis, and the applicability of international diagnostic criteria in the paediatric context. Methods In this prospective cohort study, detailed clinical assessments, serum and CSF studies, and MRI scans were done in youth (aged 0·46–17·87 years) with incidental acquired demyelinating syndrome. Participants were examined prospectively to identify relapsing disease. All MRI scans were assessed using a validated scoring method. A random forest classifier identified imaging and laboratory features that best predicted a multiple sclerosis or monophasic outcome. Performance of the 2001, 2010, and 2017 international McDonald criteria for the diagnosis of multiple sclerosis, the 2016 MRI in multiple sclerosis (MAGNIMS) criteria, and our 2011 proposed (Verhey) criteria were determined; performance was adjudicated with generalised linear models. Findings Between Sept 1, 2004, and June 30, 2017, we included 324 participants with median follow-up of 72 months (range 6–150), 71 (22%) participants with multiple sclerosis, 237 (73%) with monophasic acquired demyelinating syndrome, 14 (4%) with relapsing non-multiple sclerosis, and two (1%) with alternative diagnoses. We scored 2391 brain, 444 spinal, and 67 dedicated orbital MRI scans. One or more T1 hypointense lesions plus one or more periventricular lesions (Verhey criteria) best predicted multiple sclerosis outcome. Performance of the 2017 McDonald criteria was comparable to the 2010 McDonald criteria and was easier to adjudicate. The ability of CSF oligoclonal bands to substitute for the requirement for both enhancing and non-enhancing lesions in the 2017 McDonald criteria improved its performance compared with the 2010 criteria. Myelin oligodendrocyte testing at baseline did not improve performance of the 2017 McDonald criteria. Interpretation The 2017 McDonald criteria for the diagnosis of multiple sclerosis, as applied at the time of incident attack, perform well in identifying children and youth with multiple sclerosis, indicating that the same diagnostic criteria for multiple sclerosis apply across the age span. The presence of so-called black holes on MRI and periventricular lesions at baseline (Verhey criteria) also effectively distinguish children with multiple sclerosis from children with monophasic demyelination. The presence of CSF oligoclonal bands improve diagnostic accuracy. Myelin oligodendrocyte glycoprotein antibodies identify children with acute disseminated encephalomyelitis, and those with relapsing non-multiple sclerosis, most of whom do not meet 2017 McDonald criteria at onset. Funding The Multiple Sclerosis Scientific Research Foundation and The Children's Hospital of Philadelphia.

Background: Rician noise, bias felds and blur are the common distortions that degrade MRI images during acquisition. Blur is unique in comparison to Rician noise and bias felds because it can be introduced into an image beyond the acquisition stage such as postacquisition processing and the manifestation of pathological condi tions. Most current blur assessment algorithms are designed and validated on con sumer electronics such as television, video and mobile appliances. The few algorithms dedicated to medical images either requires a reference image or incorporate manual approach. For these reasons it is difcult to compare quality measures from diferent images and images with diferent contents. Furthermore, they will not be suitable in environments where large volumes of images are processed. In this report we propose a new blind blur assessment method for diferent types of MRI images and for diferent applications including automated environments. Methods: Two copies of the test image are generated. Edge map is extracted by sepa rately convolving each copy of the test image with two parallel diference of Gaussian flters. At the start of the multiscale representation, the initial output of the flters are equal. In subsequent scales of the multiscale representation, each flter is tuned to diferent operating parameters over the same fxed range of Gaussian scales. The flters are termed low and high energy flters based on their characteristics to successively attenuate and highlight edges over the range of multiscale representation. Quality score is predicted from the distance between the normalized mean of the edge maps at the fnal output of the flters. Results: The proposed method was evaluated on cardiac and brain MRI images. Performance evaluation shows that the quality index has very good correlation with human perception and will be suitable for application in routine clinical practice and clinical research. © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)

Magnetic resonance imaging (MRI) system images are important components in the development of drugs because it can reveal the underlying pathology in diseases. Unfortunately, the processes of image acquisition, storage, transmission, processing, and analysis can influence image quality with the risk of compromising the reliability of MRI-based data. Therefore, it is necessary to monitor image quality throughout the different stages of the imaging workflow. This report describes a new approach to evaluate the quality of an MRI slice in multi-center clinical trials. The design philosophy assumes that an MRI slice, such as all natural images, possess statistical properties that can describe different levels of contrast degradation. A unique set of pixel configuration is assigned to each possible level of contrast-distorted MRI slice. Invocation of the central limit theorem results in two separate Gaussian distributions. The central limit theorem says that the mean and standard deviation of pixel configuration assigned to each possible level of contrast degradation will follow a normal distribution. The mean of each normal distribution corresponds to the mean and standard deviation of the underlying ideal image. Quality prediction processes for a test image can be summarized into four steps. The first step extracts local contrast feature image from the test image. The second step computes the mean and standard deviation of the feature image. The third step separately standardizes each normal distribution using the mean and standard deviation computed from the feature image. This gives two separate z-scores. The fourth step predicts the lightness contrast quality score and the texture contrast quality score from cumulative distribution function of the appropriate normal distribution. The proposed method was evaluated objectively on brain and cardiac MRI volume data using four different types and levels of degradation. The four types of degradation are Rician noise, circular blur, motion blur, and intensity nonuniformity also known as bias fields. Objective evaluation was validated using a proposed variation of difference of mean opinion scores. Results from performance evaluation show that the proposed method will be suitable to monitor and standardize image quality throughout the different stages of imaging workflow in large clinical trials. MATLAB implementation of the proposed objective quality evaluation method can be downloaded from (https://github.com/ezimic/Image-Quality-Evaluation)., This report describes a new approach to evaluate the quality of an MRI cardiac or brain slice in multi-center clinical trials.

Deep learning (DL) networks have recently been shown to outperform other segmentation methods on various public, medical-image challenge datasets [3, 11, 16], especially for large pathologies. However, in the context of diseases such as Multiple Sclerosis (MS), monitoring all the focal lesions visible on MRI sequences, even very small ones, is essential for disease staging, prognosis, and evaluating treatment efficacy. Moreover, producing deterministic outputs hinders DL adoption into clinical routines. Uncertainty estimates for the predictions would permit subsequent revision by clinicians. We present the first exploration of multiple uncertainty estimates based on Monte Carlo (MC) dropout [4] in the context of deep networks for lesion detection and segmentation in medical images. Specifically, we develop a 3D MS lesion segmentation CNN, augmented to provide four different voxel-based uncertainty measures based on MC dropout. We train the network on a proprietary, large-scale, multi-site, multi-scanner, clinical MS dataset, and compute lesion-wise uncertainties by accumulating evidence from voxel-wise uncertainties within detected lesions. We analyze the performance of voxel-based segmentation and lesion-level detection by choosing operating points based on the uncertainty. Empirical evidence suggests that uncertainty measures consistently allow us to choose superior operating points compared only using the network’s sigmoid output as a probability.

A variety of automatic segmentation techniques have been successfully applied to the delineation of larger T2 lesions in patient MRI in the context of Multiple Sclerosis (MS), assisting in the estimation of lesion volume, a common clinical measure of disease activity and stage. In the context of clinical trials, however, a wider number of metrics are required to determine the “burden of disease” and activity in order to measure treatment efficacy. These include: (1) the number and volume of T2 lesions in MRI, (2) the number of new and enlarging T2 volumes in longitudinal MRI, and (3) the number of gadolinium enhancing lesions in T1 MRI, the portion of lesions that enhance in T1w MRI after injection with a contrast agent, often associated with active inflammations. In this context, accurate lesion detection must ensure that even small lesions (e.g. 3 to 10 voxels) are detected as they are prevalent in trials. Manual or semi-manual approaches are too time-consuming, inconsistent and expensive to be practical in large clinical trials. To this end, we present a series of fully-automatic, probabilistic machine learning frameworks to detect and segment all lesions in patient MRI, and show their accuracy and robustness in large multi-center, multi-scanner, clinical trial datasets. Several of these algorithms have been placed into a commercial software analysis pipeline, where they have assisted in improving the efficiency and precision of the development of most new MS treatments worldwide. Recent work has shown how a new Bag-of-Lesions brain representation can be used in the context of clinical trials to automatically predict the probability of future disease activity and potential treatment responders, leading to the possibility of personalized medicine.

Daclizumab high-yield process (HYP) is a humanized monoclonal antibody that binds to CD25 (alpha subunit of the interleukin-2 receptor) and modulates interleukin-2 signaling. Abnormalities in interleukin-2 signaling have been implicated in the pathogenesis of multiple sclerosis and other autoimmune disorders.We conducted a randomized, double-blind, active-controlled, phase 3 study involving 1841 patients with relapsing-remitting multiple sclerosis to compare daclizumab HYP, administered subcutaneously at a dose of 150 mg every 4 weeks, with interferon beta-1a, administered intramuscularly at a dose of 30 μg once weekly, for up to 144 weeks. The primary end point was the annualized relapse rate.The annualized relapse rate was lower with daclizumab HYP than with interferon beta-1a (0.22 vs. 0.39; 45% lower rate with daclizumab HYP; P0.001). The number of new or newly enlarged hyperintense lesions on T2-weighted magnetic resonance imaging (MRI) over a period of 96 weeks was lower with daclizumab HYP than with interferon beta-1a (4.3 vs. 9.4; 54% lower number of lesions with daclizumab HYP; P0.001). At week 144, the estimated incidence of disability progression confirmed at 12 weeks was 16% with daclizumab HYP and 20% with interferon beta-1a (P=0.16). Serious adverse events, excluding relapse of multiple sclerosis, were reported in 15% of the patients in the daclizumab HYP group and in 10% of those in the interferon beta-1a group. Infections were more common in the daclizumab HYP group than in the interferon beta-1a group (in 65% vs. 57% of the patients, including serious infection in 4% vs. 2%), as were cutaneous events such as rash or eczema (in 37% vs. 19%, including serious events in 2% vs.1%) and elevations in liver aminotransferase levels that were more than 5 times the upper limit of the normal range (in 6% vs. 3%).Among patients with relapsing-remitting multiple sclerosis, daclizumab HYP showed efficacy superior to that of interferon beta-1a with regard to the annualized relapse rate and lesions, as assessed by means of MRI, but was not associated with a significantly lower risk of disability progression confirmed at 12 weeks. The rates of infection, rash, and abnormalities on liver-function testing were higher with daclizumab HYP than with interferon beta-1a. (Funded by Biogen and AbbVie Biotherapeutics; DECIDE ClinicalTrials.gov number, NCT01064401.).

Objective: To evaluate resting-state functional connectivity (FC) and relationship to brain volumes and cognition in a sample of cognitively preserved pediatric-onset multiple sclerosis (MS) patients. Methods: Sixteen cognitively intact pediatric-onset MS patients and 15 healthy age- and sex-matched controls underwent cognitive testing and 3T anatomical and functional MRI. Resting-state FC patterns were examined using region-of-interest-based timeseries correlations. Results: Compared to controls, pediatric-onset MS patients demonstrated higher FC of the precuneus, particularly with the anterior cingulate cortex ( z=4.21, p2 lesion volume and lower normalized thalamic volume were associated with reduced FC of the thalamus, especially for FC with the right superior occipital region ( t=−2.87, p=.0123 and t=2.27, p=.04 respectively). FC of the left frontal medial cortex was negatively correlated with composite cognitive z-score in the pediatric-onset MS group ( pConclusions: Greater resting-state FC between posterior and anterior brain regions is present in pediatric-onset MS. With greater disease-related structural pathology, there is a disruption of thalamo-cortical FC. In the absence of actual cognitive impairment, heightened FC of the frontal medial cortex was associated with lower cognitive performance, suggesting that greater functional resources are recruited during resting-state in patients with reduced cognitive efficiency.

Quantitative magnetization transfer imaging (qMTI) increases specificity to macromolecular content in tissue by modeling the exchange process between the liquid and the macromolecular pool. However, its use has been mostly restricted to researchers that have developed these methods, in part due to the need to write complicated in-house software for modeling and data analysis. We have developed a software package (qMTLab) with a simple and easy to use graphical user interface that unifies three of the most widely used qMTI methods: MT spoiled gradient echo (MT-SPGR), MT balanced steady-state free precession (MT-bSSFP), and selective inversion recovery with fast spin echo (SIR-FSE). qMTLab is free open-source software that allows anyone interested in using these methods to easily simulate qMTI data, compare the performance of the methods under various experimental conditions, define new acquisition protocols, fit acquired data, and visualize the fitted parameters maps. By providing free software that gives end users a simple and easy to use graphical interface, we hope to make qMTI accessible to a greater number of investigators and facilitate the development, evaluation, and optimization of acquisition protocols and models. © 2016 Wiley Periodicals, Inc. Concepts Magn Reson Part A, 2016.

Background: Posterior fossa lesions are common in pediatric-onset multiple sclerosis (MS), which is of concern, given the known role of the cerebellum in cognition. Objectives: To investigate the relationship between cerebellar pathology and cognitive function in youth with pediatric-onset MS. Methods: Twenty-eight pediatric-onset relapsing–remitting MS patients (21 girls; mean age 16.2 years; mean disease duration 4.3 years, median Expanded Disability Status Scale 1.25) were compared to 33 age- and sex-matched healthy controls. Participants underwent structural magnetic resonance imaging (MRI) and neuropsychological evaluation to assess intelligence, attention, processing speed, language, visuo-motor integration, and fine-motor dexterity. Associations between cognitive outcomes and cerebellar volume independent of cerebral volume were examined. Results: Cognitive and motor performance of the MS group was reduced relative to controls (all p2=0.43; p=0.02) and vocabulary ( R2=0.56; p=0.04) in patients (controlling for cerebral volume and sex), but not in controls. Conclusion: Smaller cerebellar posterior lobe volume, a known region for cognitive processing, and increased lesion burden in the posterior fossa adversely impact cognitive function, an important functional consequence of MS onset during childhood.

Objectives: Active myelination during childhood may influence the impact of multiple sclerosis (MS) on brain structural integrity. We studied normal-appearing white matter (NAWM) in children with MS onset before age 12 years using diffusion tensor (DT) magnetic resonance imaging (MRI). Methods: DT MRI scans were obtained from 22 MS children with their first attack before age 12 years, and 31 healthy controls from two referral centers. Using probabilistic tractography, brain tissue integrity within interhemispheric, intrahemispheric, and projection tracts was compared between patients and site-matched controls. The impact of disease and age at MRI on tract NAWM fractional anisotropy (FA) and mean diffusivity (MD) values was evaluated using linear models. Results: Compared to controls, pediatric MS patients had reduced FA and increased MD of the bilateral superior longitudinal fasciculus and corpus callosum (CC), without center-by-group interaction. CC NAWM average FA was correlated with brain T2 lesion volume. In controls, the majority of the tracts analyzed showed a significant increase of FA and decrease of MD with age. Such a linear correlation was lost in patients. Conclusions: In very young pediatric MS patients, DT MRI abnormalities affect brain WM tracts differentially, and are only partially correlated with focal WM lesions. Impaired maturation of WM tracts with age may be an additional factor contributing to these findings.

Objective: To evaluate the efficacy and safety of subcutaneous peginterferon beta-1a over 2 years in patients with relapsing–remitting multiple sclerosis in the ADVANCE study. Methods: Patients were randomized to placebo or 125 µg peginterferon beta-1a every 2 or 4 weeks. For Year 2 (Y2), patients originally randomized to placebo were re-randomized to peginterferon beta-1a every 2 weeks or every 4 weeks. Patients randomized to peginterferon beta-1a in Year 1 (Y1) remained on the same dosing regimen in Y2. Results: Compared with Y1, annualized relapse rate (ARR) was further reduced in Y2 with every 2 week dosing (Y1: 0.230 [95% CI 0.183–0.291], Y2: 0.178 [0.136–0.233]) and maintained with every 4 week dosing (Y1: 0.286 [0.231–0.355], Y2: 0.291 [0.231–0.368]). Patients starting peginterferon beta-1a from Y1 displayed improved efficacy versus patients initially assigned placebo, with reductions in ARR (every 2 weeks: 37%, pConclusions: Peginterferon beta-1a efficacy is maintained beyond 1 year, with greater effects observed with every 2 week versus every 4 week dosing, and a similar safety profile to Y1. Clinicaltrials.gov Registration Number: NCT00906399.

Objective: In relapsing–remitting multiple sclerosis (RRMS), suboptimal adherence to injectable disease-modifying therapies (iDMTs; interferon β-1a/b, glatiramer acetate) is common, reducing their effectiveness. Patient retention on oral fingolimod and iDMTs was evaluated in PREFERMS, a randomized, parallel-group, active-controlled, open-label, 48-week study. Methods: Patients were included if they had RRMS, were aged 18–65 years and had Expanded Disability Status Scale score up to 6, enrolled at 117 US study sites, were treatment naïve or had received only one iDMT class. Patients were randomized 1:1 (fingolimod 0.5 mg/day; preselected iDMT) by interactive voice-and-web-response system without blinding, followed up quarterly, and allowed one study-approved treatment switch after 12 weeks, or earlier for efficacy or safety reasons. The primary outcome was patient retention on randomized treatment over 48 weeks. Secondary endpoints included patient-reported outcomes, brain volume loss (BVL), and cognitive function. Results: Analysis of 433/436 patients receiving fingolimod and 428/439 receiving iDMTs showed that patient retention rate was significantly higher with fingolimod than with iDMTs [352 (81.3%) versus 125 (29.2%); 95% confidence interval 46.4–57.8%; p < 0.0001]. The most common treatment switch was from iDMT to fingolimod for injection-related reasons. Patient satisfaction was greater and BVL less with fingolimod than with iDMTs, with no difference in cognitive function. Adverse events were consistent with established tolerability profiles for each treatment. Conclusions: In RRMS, fingolimod was associated with better treatment retention, patient satisfaction and BVL outcomes than iDMTs. Patients may persist with iDMTs, but many may switch treatment if permitted. Treatment satisfaction fosters adherence, a prerequisite for optimal outcomes.

Objective The objective of this paper is to assess, in individuals with clinically stable multiple sclerosis (MS), the safety, tolerability, pharmacokinetics (PK) and exploratory pharmacodynamics of the monoclonal recombinant human antibody IgM22 (rHIgM22). Methods Seventy-two adults with stable MS were enrolled in a double-blind, randomized, placebo-controlled, single ascending-dose, Phase 1 trial examining rHIgM22 from 0.025 to 2.0 mg/kg. Assessments included MRI, MR spectroscopy, plasma PK, and changes in clinical status, laboratory values and adverse events for three months. The final cohort had additional clinical, ophthalmologic, CSF collection and exploratory biomarker evaluations. Participants were monitored for six months. Results rHIgM22 was well tolerated with no clinically significant safety signals. Noncompartmental PK modeling demonstrated linear dose-proportionality both of Cmax and AUC0–Last. The steady-state apparent volume of distribution of approximately 58 ml/kg suggested primarily vascular compartmentalization. CSF:plasma rHIgM22 concentration increased from 0.003% on Day 2 for both 1.0 and 2.0 mg/kg to 0.056% and 0.586% for 1.0 and 2.0 mg/kg, respectively, on Day 29. No statistically significant treatment-related changes were observed in exploratory pharmacodynamic outcome measures included for the 21 participants of the extension cohort. Conclusions Single doses of rHIgM22 were well tolerated and exhibited linear PK, and antibody was detected in the CSF.

Background: Amiselimod, an oral selective sphingosine-1-phosphate 1 receptor modulator, suppressed disease activity dose-dependently without clinically relevant bradyarrhythmia in a 24-week phase 2, placebo-controlled study in relapsing-remitting multiple sclerosis. Objective: To assess safety and efficacy of amiselimod over 96 weeks. Methods: After completing the core study, patients on amiselimod continued at the same dose, whereas those on placebo were randomised 1:1:1 to amiselimod 0.1, 0.2 or 0.4 mg for another 72 weeks. Most patients receiving 0.1 mg were re-randomised to 0.2 or 0.4 mg upon availability of the core study results. Results: Of 415 patients randomised in the core study, 367 (88.4%) entered and 322 (77.6%) completed the extension. One or more adverse events were reported in 303 (82.6%) of 367 patients: ‘headache’, ‘lymphocyte count decreased’, ‘nasopharyngitis’ and ‘MS relapse’ were most common (14.7%–16.9%). No serious opportunistic infection, macular oedema or malignancy was reported and no bradyarrhythmia of clinical concern was observed by Holter or 12-lead electrocardiogram. The dose-dependent effect of amiselimod on clinical and magnetic resonance imaging-related outcomes from the core study was sustained in those continuing on amiselimod and similarly observed after switching to active drug. Conclusion: For up to 2 years of treatment, amiselimod was well tolerated and dose-dependently effective in controlling disease activity.

The effect of delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on the Multiple Sclerosis Functional Composite (MSFC) was assessed using integrated Phase 3 DEFINE and CONFIRM data. Patients treated with DMF ( n = 769) demonstrated significant superiority on the MSFC, and each component, compared with placebo ( n = 771) over two years: mean change for DMF vs placebo was 0.054 vs −0.053 on MSFC; −0.088 vs −0.286 on Timed 25-Foot Walk, 0.047 vs 0.003 on 9-Hole Peg Test and 0.178 vs 0.123 on Paced Auditory Serial Addition Test. DMF was an efficacious treatment for patients with MS.

Background Subcutaneous peginterferon beta-1a has previously been shown to reduce the number of T2-hyperintense and gadolinium-enhancing (Gd+) lesions over 2 years in patients with relapsing-remitting multiple sclerosis (RRMS), and to reduce T1-hypointense lesion formation and the proportion of patients showing evidence of disease activity, based on both clinical and radiological measures, compared with placebo over 1 year of treatment. The objectives of the current analyses were to evaluate T1 lesions and other magnetic resonance imaging (MRI) measures, including whole brain volume and magnetization transfer ratio (MTR) of normal appearing brain tissue (NABT), and the proportions of patients with no evidence of disease activity (NEDA), over 2 years. Methods Patients enrolled in the ADVANCE study received continuous peginterferon beta-1a every 2 or 4 weeks for 2 years, or delayed treatment (placebo in Year 1; peginterferon beta-1a every 2 or 4 weeks in Year 2). MRI scans were performed at baseline and Weeks 24, 48, and 96. Proportions of patients with NEDA were calculated based on radiological criteria (absence of Gd + and new/newly-enlarging T2 lesions) and clinical criteria (no relapse or confirmed disability progression) separately and overall. Results Peginterferon beta-1a every 2 weeks significantly reduced the number and volume of T1-hypointense lesions compared with delayed treatment over 2 years. Changes in whole brain volume and MTR of NABT were suggestive of pseudoatrophy during the first 6 months of peginterferon beta-1a treatment, which subsequently began to resolve. Significantly more patients in the peginterferon beta-1a every 2 weeks group compared with the delayed treatment group met MRI-NEDA criteria (41% vs 21%; odds ratio [OR] 2.56; p

See Hacohen et al. (doi:10.1093/awx075) for a scientific commentary on this article. Most children who experience an acquired demyelinating syndrome of the central nervous system will have a monophasic disease course, with no further clinical or radiological symptoms. A subset will be diagnosed with multiple sclerosis, a life-long disorder. Using linear mixed effects models we examined longitudinal diffusion properties of normal-appearing white matter in 505 serial scans of 132 paediatric participants with acquired demyelinating syndromes followed for a median of 4.4 years, many from first clinical presentation, and 106 scans of 80 healthy paediatric participants. Fifty-three participants with demyelinating syndromes eventually received a diagnosis of paediatric-onset multiple sclerosis. Diffusion tensor imaging measures properties of water diffusion through tissue, which normally becomes increasingly restricted and anisotropic in the brain during childhood and adolescence, as fibre bundles develop and myelinate. In the healthy paediatric participants, our data demonstrate the expected trajectory of more restricted and anisotropic white matter diffusivity with increasing age. However, in participants with multiple sclerosis, fractional anisotropy decreased and mean diffusivity of non-lesional, normal-appearing white matter progressively increased after clinical presentation, suggesting not only a failure of age-expected white matter development but also a progressive loss of tissue integrity. Surprisingly, patients with monophasic disease failed to show age-expected changes in diffusion parameters in normal-appearing white matter, although they did not show progressive loss of integrity over time. Further analysis demonstrated that participants with monophasic disease experienced different post-onset trajectories in normal-appearing white matter depending on their presenting phenotype: those with acute disseminated encephalomyelitis demonstrated abnormal trajectories of diffusion parameters compared to healthy paediatric participants, as did patients with non-acute disseminated encephalomyelitis presentations associated with lesions in the brain at onset. Patients with monofocal syndromes such as optic neuritis, transverse myelitis, or isolated brainstem syndromes in whom multifocal brain lesions were absent, showed trajectories more closely approximating normal-appearing white matter development. Our findings also suggest the existence of sexual dimorphism in the effects of demyelinating syndromes on normal-appearing white matter development. Overall, we demonstrate failure of white matter maturational changes and progressive loss of white matter integrity in paediatric-onset multiple sclerosis, but also show that even a single demyelinating attack-when associated with white matter lesions in the brain-negatively impacts subsequent normal-appearing white matter development.

The growth of lesions and the development of new lesions in MRI are markers of new disease activity in Multiple Sclerosis (MS) patients. Successfully predicting future lesion activity could lead to a better understanding of disease worsening, as well as prediction of treatment efficacy. We introduce the first, fully automatic, probabilistic framework for the prediction of future lesion activity in relapsing-remitting MS patients, based only on baseline multi-modal MRI, and use it to successfully identify responders to two different treatments. We develop a new Bag-of-Lesions (BoL) representation for patient images based on a variety of features extracted from lesions. A probabilistic codebook of lesion types is created by clustering features using Gaussian mixture models. Patients are represented as a probabilistic histogram of lesion-types. A Random Forest classifier is trained to automatically predict future MS activity up to two years ahead based on the patient’s baseline BoL representation. The framework is trained and tested on a large, proprietary, multi-centre, multi-modal clinical trial dataset consisting of 1048 patients. Testing based on 50-fold cross validation shows that our framework compares favourably to several other classifiers. Automated identification of responders in two different treated groups of patients leads to sensitivity of 82% and 84% and specificity of 92% and 94% respectively, showing that this is a very promising approach towards personalized treatment for MS patients.

The authors propose a new application-specific, post-acquisition quality evaluation method for brain magnetic resonance imaging (MRI) images. The domain of a MRI slice is regarded as universal set. Four feature images; greyscale, local entropy, local contrast and local standard deviation are extracted from the slice and transformed into the binary domain. Each feature image is regarded as a set enclosed by the universal set. Four qualities attribute; lightness, contrast, sharpness and texture details are described by four different combinations of feature sets. In an ideal MRI slice, the four feature sets are identically equal. Degree of distortion in real MRI slice is quantified by fidelity between the sets that describe a quality attribute. Noise is the fifth quality attribute and is described by the slice Euler number region property. Total quality score is the weighted sum of the five quality scores. The authors' proposed method addresses current challenges in image quality evaluation. It is simple, easy-to-use and easy-to-understand. Incorporation of binary transformation in the proposed method reduces computational and operational complexity of the algorithm. They provide experimental results that demonstrate efficacy of their proposed method on good quality images and on common distortions in MRI images of the brain. © The Institution of Engineering and Technology 2017. This is the authors’ accepted and refereed manuscript to the article.

Objective Obtain a more precise estimate of the efficacy of delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) in relapsing multiple sclerosis (MS) and examine the consistency of DMF's effects across patient subgroups stratified by baseline demographic and disease characteristics. Methods A prespecified integrated analysis of the randomized, double-blind, placebo-controlled, Phase 3 DEFINE and CONFIRM trials was conducted. Results The intent-to-treat population comprised 2301 patients randomized to receive placebo (n = 771) or DMF 240 mg twice daily (BID; n = 769) or three times daily (TID; n = 761). At 2 years, DMF BID and TID reduced the annualized relapse rate by 49% and 49% (both P

Objective: To determine the impact of pediatric-onset multiple sclerosis (MS) on age-expected brain growth. Methods: Whole brain and regional volumes of 36 patients with relapsing-remitting MS onset prior to 18 years of age were segmented in 185 longitudinal MRI scans (2–11 scans per participant, 3-month to 2-year scan intervals). MRI scans of 25 age- and sex-matched healthy normal controls (NC) were also acquired at baseline and 2 years later on the same scanner as the MS group. A total of 874 scans from 339 participants from the NIH-funded MRI study of normal brain development acquired at 2-year intervals were used as an age-expected healthy growth reference. All data were analyzed with an automatic image processing pipeline to estimate the volume of brain and brain substructures. Mixed-effect models were built using age, sex, and group as fixed effects. Results: Significant group and age interactions were found with the adjusted models fitting brain volumes and normalized thalamus volumes ( p −4 ). These findings indicate a failure of age-normative brain growth for the MS group, and an even greater failure of thalamic growth. In patients with MS, T2 lesion volume correlated with a greater reduction in age-expected thalamic volume. To exclude any scanner-related influence on our data, we confirmed no significant interaction of group in the adjusted models between the NC and NIH MRI Study of Normal Brain Development groups. Conclusions: Our results provide evidence that the onset of MS during childhood and adolescence limits age-expected primary brain growth and leads to subsequent brain atrophy, implicating an early onset of the neurodegenerative aspect of MS.

Children and adolescents diagnosed with multiple sclerosis rarely accrue physical disability early in their disease. This could be explained by greater remyelination in children, a capacity that may be lost in adolescence or early adulthood. Magnetization transfer ratio (MTR) MRI can be used to quantify changes in myelin in MS. We used serial MTR imaging and longitudinal random effects analysis to quantify recovery of MTR in acute lesions and to evaluate MTR changes in normal-appearing tissue in 19 adolescent MS patients. Our objective was to determine whether younger adolescents have a greater capacity for remyelination and whether this decreases as patients approach adulthood. We detected a significant decrease in MTR recovery between ages 16 and 20 years (p = 0.023), with older subjects approaching typical recovery levels for adult-onset MS. MTR recovery in acute MS lesions decreases with age in adolescents, suggesting loss of remyelination capacity. This may be related to the conclusion of primary myelination or other developmental factors., Highlights • Decrease and recovery of MTR in multiple sclerosis suggest demyelination and remyelination. • We quantified MTR recovery in lesions in adolescents and modeled age related changes. • Recovery decreased (p = 0.023) between ages 16 and 20. • Older subjects approached adult-typical recovery values. • This suggests a loss of remyelination capacity during adolescence.

Several algorithms have been proposed in the literature for image denoising but none exhibit optimal performance for all range and types of noise and for all image acquisition modes. We describe a new general framework, built from four-neighborhood clique system, for denoising medical images. The kernel quantifies smoothness energy of spatially continuous anatomical structures. Scalar and vector valued quantification of smoothness energy configures images for Bayesian and variational denoising modes, respectively. Within variational mode, the choice of norm adapts images for either total variation or Tikhonov technique. Our proposal has three significant contributions. First, it demonstrates that the four-neighborhood clique kernel is a basic filter, in same class as Gaussian and wavelet filters, from which state-of-the-art denoising algorithms are derived. Second, we formulate theoretical analysis, which connects and integrates Bayesian and variational techniques into a two-layer structured denoising system. Third, our proposal reveals that the first layer of the new denoising system is a hitherto unknown form of Markov random field model referred to as single-layer Markov random field (SLMRF). The new model denoises a specific type of medical image by minimizing energy subject to knowledge of mathematical model that describes relationship between the image smoothness energy and noise level but without reference to a classical prior model. SLMRF was applied to and evaluated on two real brain magnetic resonance imaging datasets acquired with different protocols. Comparative performance evaluation shows that our proposal is comparable to state-of-the-art algorithms. SLMRF is simple and computationally efficient because it does not incorporate a regularization parameter. Furthermore, it preserves edges and its output is devoid of blurring and ringing artifacts associated with Gaussian-based and wavelet-based algorithms. The denoising system is potentially applicable to speckle reduction in ultrasound images and extendable to three-layer structure that account for texture features in medical images. © 2014 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 24, 224–238, 2014

In the Phase 3 DEFINE study, delayed-release dimethyl fumarate (DMF) 240 mg twice (BID) and three times daily (TID) significantly reduced the mean number of new or enlarging T2-hyperintense lesions and gadolinium-enhancing (Gd+) lesion activity at 2 years in patients (MRI cohort; n = 540) with relapsing–remitting MS. The analyses described here expand on these results by considering additional MRI measures (number of T1-hypointense lesions; volume of T2-hyperintense, Gd+, and T1-hypointense lesions; brain atrophy), delineating the time course of the effects, and examining the generality of the effects across a diverse patient population. Reductions in lesion counts with delayed-release DMF BID and TID, respectively, vs. placebo were apparent by the first MRI assessment at 6 months [T2-hyperintense: 80 and 69 % reduction (both P

BACKGROUND Intensity variation between magnetic resonance images (MRI) hinders comparison of tissue intensity distributions in multicenter MRI studies of brain diseases. The available intensity normalization techniques generally work well in healthy subjects but not in the presence of pathologies that affect tissue intensity. One such disease is multiple sclerosis (MS), which is associated with lesions that prominently affect white matter (WM). OBJECTIVE To develop a T1-weighted (T1w) image intensity normalization method that is independent of WM intensity, and to quantitatively evaluate its performance. METHODS AND SUBJECTS We calculated median intensity of grey matter and intraconal orbital fat on T1w images. Using these two reference tissue intensities we calculated a linear normalization function and applied this to the T1w images to produce normalized T1w (NT1) images. We assessed performance of our normalization method for interscanner, interprotocol, and longitudinal normalization variability, and calculated the utility of the normalization method for lesion analyses in clinical trials. RESULTS Statistical modeling showed marked decreases in T1w intensity differences after normalization (P < .0001). CONCLUSIONS We developed a WM-independent T1w MRI normalization method and tested its performance. This method is suitable for longitudinal multicenter clinical studies for the assessment of the recovery or progression of disease affecting WM.

Multiple sclerosis (MS) is characterized by the formation of demyelinating lesions in the white matter (WM). However, the timecourse of the evolution of healthy white matter into fully demyelinated lesions in MS is not well understood. We use a recently proposed technique to examine magnetization transfer ratio (MTR) timecourses in lesions segmented from MTR images in patients with relapsing–remitting MS (RRMS) and secondary progressive MS (SPMS). In both groups we found MTR lesions forming both in previously normal appearing WM (de novo lesions) as well as in previously lesional tissue that appears to be experiencing a second round of inflammatory demyelination (repeat lesions). Both de novo and repeat lesions exhibited significant, but incomplete MTR recovery, suggesting partial remyelination; post-lesion MTR values in de novo lesions were similar to pre-lesion values in repeat lesions. Both de novo and repeat lesions were found in subjects in relapsing–remitting and secondary progressive stages of MS, and repeat lesions appeared relatively more common in the secondary progressive phase. These observations support the hypothesis that entirely demyelinated lesions found on histopathology are the result of multiple episodes of demyelination and incomplete remyelination, and may have implications for MS treatment development efforts aimed at neuroprotection and enhancing remyelination., Highlights • We imaged multiple sclerosis lesions with magnetization transfer ratio (MTR) MRI. • MTR is sensitive and reasonably specific to changes in myelin in MS. • MTR decrease and recovery (de- and re-myelination) occurred in new and old lesions. • Fully demyelinated lesions may not be the result of complete failure to remyelinate. • MS lesions may undergo multiple episodes of demyelination and partial remyelination.

Objective To evaluate the extent to which treatment effect on brain atrophy is able to mediate, at the trial level, the treatment effect on disability progression in relapsing–remitting multiple sclerosis (RRMS). Methods We collected all published randomized clinical trials in RRMS lasting at least 2 years and including as endpoints disability progression (defined as 6 or 3 months confirmed 1-point increase on the Expanded Disability Status Scale), active magnetic resonance imaging (MRI) lesions (defined as new/enlarging T2 lesions), and brain atrophy (defined as change in brain volume between month 24 and month 6–12). Treatment effects were expressed as relative reductions. A linear regression, weighted for trial size and duration, was used to assess the relationship between the treatment effects on MRI markers and on disability progression. Results Thirteen trials including >13,500 RRMS patients were included in the meta-analysis. Treatment effects on disability progression were correlated with treatment effects both on brain atrophy (R2 = 0.48, p = 0.001) and on active MRI lesions (R2 = 0.61, p

Gray matter atrophy provides important insights into neurodegeneration in multiple sclerosis (MS) and can be used as a marker of neuroprotection in clinical trials. Jacobian integration is a method for measuring volume change that uses integration of the local Jacobian determinants of the nonlinear deformation field registering two images, and is a promising tool for measuring gray matter atrophy. Our main objective was to compare the statistical power of the Jacobian integration method to commonly used methods in terms of the sample size required to detect a treatment effect on gray matter atrophy. We used multi-center longitudinal data from relapsing–remitting MS patients and evaluated combinations of cross-sectional and longitudinal pre-processing with SIENAX/FSL, SPM, and FreeSurfer, as well as the Jacobian integration method. The Jacobian integration method outperformed these other commonly used methods, reducing the required sample size by a factor of 4–5. The results demonstrate the advantage of using the Jacobian integration method to assess neuroprotection in MS clinical trials., Highlights • We compared sample sizes to detect a treatment effect on gray matter atrophy. • Jacobian integration method outperformed SIENAX, SPM, and FreeSurfer. • Sample sizes were reduced by 4 to 5 fold with Jacobian integration method. • Use of Jacobian integration may be advantageous for assessing neuroprotection.

IntroductionOpicinumab is a human monoclonal antibody against LINGO-1, a negative regulator of oligodendrocyte differentiation and axonal regeneration. The phase 2 SYNERGY study identified a patient subpopulation with a potentially enhanced response to opicinumab treatment.MethodsAFFINITY (NCT03222973) is an ongoing, randomised, double-blind, placebo-controlled phase 2 study to evaluate the efficacy/safety of opicinumab vs placebo as an add-on to disease-modifying therapies in a targeted population. Inclusion criteria include: age 18–58; relapsing multiple sclerosis (MS) with ≤20-year duration; Expanded Disability Status Scale (EDSS) score 2.0–6.0; evidence of disease activity within 24 months prior to enrolment; brain MRI criteria suggestive of low myelin content but preserved tissue integrity in pre-existing T2 lesions; stably treated ≥24 weeks with interferon-beta, dimethyl fumarate, or natalizumab. Primary endpoint is the multicomponent Overall Response Score (based on EDSS, Timed 25-Foot Walk, and 9-Hole Peg Test). Secondary endpoints will evaluate confirmed improvement in disability measures.ResultsEnrolment began in September 2017 and was completed in September 2018. Participant baseline demographic, disease, and MRI characteristics will be presented.ConclusionsAFFINITY will further investigate the efficacy and safety of opicinumab in a subpopulation of MS patients.Support: Biogen. Disclosures to be included on poster.

ObjectiveTo evaluate neurofilament light chain (NfL) levels in serum and CSF of patients with aggressive MS pre- and post-treatment with immunoablation followed by autologous hematopoietic stem cell transplantation (IAHSCT) and examine associations with clinical and MRI outcomes.MethodsPaired serum and CSF in addition to MRI and clinical measures were collected on 23 patients with MS at baseline and 1 and 3 years post-IAHSCT. An additional 33 sera and CSF pairs were taken from noninflammatory neurologic controls. NfL levels were quantitated using the Simoa platform (Quanterix).ResultsBaseline MS NfL levels were significantly elevated relative to controls in serum (p = 0.001) and CSF (p = 0.001). Following IAHSCT, high pretreatment NfL levels significantly reduced in serum (p = 0.0023) and CSF (p = 0.0068) and were not significantly different from controls. Serum and CSF NfL levels highly correlated (r = 0.81, p < 0.0001). Baseline NfL levels were associated with worse pretreatment disease measures (Expanded Disability Status Scale [EDSS], relapses, MRI lesions, and MR spectroscopy (MRS) N-acetylaspartate/creatine). Elevated baseline NfL levels were associated with persistently worse indices of disease burden post-IAHSCT (sustained EDSS progression, cognition, quality of life, T1 and T2 lesion volumes, MRS, and brain atrophy).ConclusionThese data substantiate that serum and CSF NfL levels reflect disease severity and treatment response in patients with MS and may therefore be a useful biomarker. Baseline serum levels associated with markers of pretreatment disease severity and post-treatment outcomes.Classification of evidenceThis study provides Class II evidence that for patients with aggressive MS, serum NfL levels are associated with disease severity.

IntroductionEvobrutinib (M2951) is a highly specific oral inhibitor of Bruton’s tyrosine kinase, a key regulator of B cell and macrophage functions implicated in MS.MethodsIn this double-blind, phase 2 study (NCT02975349), adult patients (≤65 years) with relapsing MS (RMS) were randomized to evobrutinib 25 mgQD, 75 mgQD, 75 mgBID, placebo, or open-label dimethyl fumarate (240 mgBID; reference arm) for 48 weeks; placebo-treated patients switched to evobrutinib 25 mgQD after 24 weeks. The primary endpoint was the total number of T1 gadolinium-enhancing (T1Gd+) lesions at Weeks 12, 16, 20, and 24. Secondary endpoints included annualized relapse rate (ARR), MRI measures at Weeks 24 and 48, and safety.ResultsAmong 261 patients, the sum of T1Gd+ lesions over Weeks 12–24 was reduced with evobrutinib 75 mgQD (p=0.002) and 75 mgBID (p=0.03); a dose response was observed (p=0.001). There was no evidence of change in effect on T1Gd+ lesions (mean±SD; Wilcoxon signed-rank test) between Weeks 24 and 48 with evobrutinib 75 mgQD (0.28±0.91 to 0.85±2.87; p=0.57) or 75 mgBID (0.24±0.88 to 0.49±1.22; p=0.23). ARR (unadjusted [95%CI]) was 0.25 (0.12–0.44) for evobrutinib 75 mgQD and 0.11 (0.04–0.25) for 75 mgBID over 48 weeks, and 0.37 (0.17–0.70) for placebo over 24 weeks. Evobrutinib appeared well-tolerated. Shifts to Grade 3–4 ALT and AST elevations from normal (grade 0) occurred in 8 (5.4%) and 6 (3.9%) evobrutinib-treated patients respectively, driven by events with onset within the first 24 weeks.ConclusionsEvobrutinib is the first BTK inhibitor to demonstrate disease activity reduction in RMS. The observed benefit-risk profile supports further clinical development.

Introduction Chronic black holes (BHs) indicate severe tissue injury and are used as a biomarker of therapeutic outcomes in relapsing-remitting multiple sclerosis (RRMS). Objectives Evaluate the effect of peginterferon beta-1a every 2 weeks on the number of chronic BHs that evolve from acute lesions over 2 years. Patients and methods ADVANCE was a 2-year, double-blind phase 3 trial of peginterferon beta-1a in 1512 patients with RRMS. The number of BHs at week 96 that evolved from new/enlarging T2-weighted (NET2) lesions at 24 or 48 weeks or gadolinium-enhancing (Gd + ) lesions (at baseline, 24 weeks, or 48 weeks) were compared. The adjusted annualized relapse rate (ARR) by BH conversion status was also assessed. Results ADVANCE included 231 newly diagnosed and 281 non-newly diagnosed patients in the continuous-treatment group and 229 newly diagnosed and 271 non-newly diagnosed patients in the delayed-treatment group. At week 96, the continuous-treatment ITT patients had fewer BHs that evolved from NET2 lesions at week 24 or week 48 than the delayed-treatment ITT patients in both newly diagnosed (P Discussion The results are similar for the BHs that evolved from the Gd+ lesions detected at baseline, week 24 or week 48 in newly diagnosed (P Conclusion The lower risk of chronic BHs with peginterferon beta-1a therapy suggests the potential to provide treatment benefits to patients with RRMS by reducing long-term disability.