Treating to target in multiple sclerosis: Do we know how to measure whether we hit it?

BACKGROUND AND PURPOSE: The rapidly evolving landscape of effective treatment options in multiple sclerosis has led to a shift of treatment objectives towards a treat-to-target approach aiming to suppress disease activity below the level of detectability early during the disease. To enable treat-to-target, a thorough reappraisal of available outcome measures with respect to their ability in this regard is required. METHODS: To that end, we conducted a comprehensive systematic literature review of more than 1000 studies using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 methodology focusing on underlying evidence as well as utility and implementability in clinical practice. RESULTS: From there, we propose a set of measurable outcomes for everyday routine clinical practice as well as advanced/aspirational measurables requiring additional resources. We also outline remaining knowledge/technology gaps that need to be overcome to enable a treat-to-target approach. CONCLUSIONS: This work provides the basis for an evidence-based definition of outcome targets for relevant stakeholders and regulatory authorities.

MS becomes a treatable disease: 30 years later.

30 years ago the first disease-modifying therapy for relapsing multiple sclerosis was approved for use in the United States and soon thereafter across the globe. Since then the field of MS therapeutics, and studies of immunopathogenesis and genetics, have advanced our understanding of the disease and raised the hope of better addressing the next challenges of treating progressive disease, enhancing repair of the damaged nervous system and, hopefully, of a cure. Thirty years into the MS treatment era, the field continues to debate fundamental aspects of MS, and there exists a widening chasm between the triumphs in relapsing disease and the desolation of MS progression, which remains the principal unmet need. In this Personal Viewpoint, we outline lessons learned from the first era of great therapeutic development, as we look to the future of MS research and therapeutics.

The impact of relapse definition and measures of durability on MS clinical trial outcomes.

BACKGROUND: Definitions of trial measures are consequential to accurately capturing outcomes and cross-trial comparability, particularly for derivative measures. OBJECTIVE: Using CombiRx, examine the impact of relapse definition on endpoints and evaluate the durability of progression measures in Relapsing Remitting Multiple Sclerosis (RRMS). METHODS: CombiRx relapse types were distinguished by the presence or timing of Expanded Disability Status Scale (EDSS) increase. Using the broadest definition of relapse, progression endpoints were assessed in patients without relapses on trial. Durability compared EDSS at study end and time of worsening. RESULTS: Broadening relapse definition to the most inclusive definition increased annualized relapse rate (ARR) threefold in all arms and decreased progression independent of relapse activity (PIRA), defined as 6-month confirmed disability worsening (6M CDW) without relapse, by 44%. Neither PIRA nor PIA (progression independent of any inflammatory activity) guaranteed durable worsening, with 43% and 40%, respectively, improving by end of study. Multivariate analysis showed two CDW events, not relapse, predicted durability among patients meeting 6M CDW. CONCLUSIONS: The stringency of relapse definition impacted absolute ARR and composite endpoints in RRMS. Despite the most generous relapse definition, 43% of patients meeting PIRA on trial did not have durable worsening suggesting that relapse definition and durability should be considered to avoid overestimating progression in RRMS trials.

Relapse recovery in relapsing-remitting multiple sclerosis: An analysis of the CombiRx dataset.

BACKGROUND: Clinical relapses are the defining feature of relapsing forms of multiple sclerosis (MS), but relatively little is known about the time course of relapse recovery. OBJECTIVE: The aim of this study was to investigate the time course of and patient factors associated with the speed and success of relapse recovery in people with relapsing-remitting MS (RRMS). METHODS: Using data from CombiRx, a large RRMS trial (clinicaltrials.gov identifier NCT00211887), we measured the time to recovery from the first on-trial relapse. We used Kaplan-Meier survival analyses and Cox regression models to investigate the association of patient factors with the time to unconfirmed and confirmed relapse recovery. RESULTS: CombiRx included 1008 participants. We investigated 240 relapses. Median time to relapse recovery was 111 days. Most recovery events took place within 1 year of relapse onset: 202 of 240 (84%) individuals recovered during follow-up, 161 of 202 (80%) by 180 days, and 189 of 202 (94%) by 365 days. Relapse severity was the only factor associated with relapse recovery. CONCLUSION: Recovery from relapses takes place up to approximately 1 year after the event. Relapse severity, but no other patient factors, was associated with the speed of relapse recovery. Our findings inform clinical practice and trial design in RRMS.

Do the current MS clinical course descriptors need to change and if so how? A survey of the MS community.

BACKGROUND AND OBJECTIVES: The current clinical course descriptors of multiple sclerosis (MS) include a combination of clinical and magnetic resonance imaging (MRI) features. Recently there has been a growing call to base these descriptors more firmly on biological mechanisms. We investigated the implications of proposing a new mechanism-driven framework for describing MS. METHODS: In a web-based survey, multiple stakeholders rated the need to change current MS clinical course descriptors, the definitions of disease course and their value in clinical practice and related topics. RESULTS: We received 502 responses across 49 countries. In all, 77% of the survey respondents supported changing the current MS clinical course descriptors. They preferred a framework that informs treatment decisions, aids the design and conduct of clinical trials, allows patients to understand their disease, and links disease mechanisms and clinical expression of disease. Clinical validation before dissemination and ease of communication to patients were rated as the most important aspects to consider when developing any new framework for describing MS. CONCLUSION: A majority of MS stakeholders agreed that the current MS clinical course descriptors need to change. Any change process will need to engage a wide range of affected stakeholders and be guided by foundational principles.

Evaluation of neurotrophic factor secreting mesenchymal stem cells in progressive multiple sclerosis.

BACKGROUND: Autologous mesenchymal stem cell neurotrophic factor-secreting cells (NurOwn®) have the potential to modify underlying disease mechanisms in progressive multiple sclerosis (PMS). OBJECTIVE: This open-label phase II study was conducted to evaluate safety/efficacy of three intrathecal cell treatments. METHODS: Eighteen participants with non-relapsing PMS were treated. The primary endpoint was safety. Secondary endpoints included: cerebrospinal fluid (CSF) biomarkers; timed 25-foot walk speed, nine-hole peg test (9-HPT), low-contrast letter acuity, symbol digit modalities test, and 12-item multiple sclerosis (MS) walking scale. Seventeen participants received all treatments. RESULTS: No deaths/adverse events related to worsening of MS, clinical/magnetic resonance imaging (MRI) evidence of disease activation, and clinically significant changes in safety lab results were reported. Two participants developed symptoms of low back and leg pain, consistent with a diagnosis of arachnoiditis, occurring in one of three intrathecal treatments in both participants. Nineteen percent of treated participants achieved pre-specified ⩾ 25% improvements in timed 25-foot walk speed/nine-HPT at 28 weeks compared to baseline, along with consistent efficacy signals for pre-specified response criteria across other secondary efficacy outcomes. CSF neuroprotective factors increased, and inflammatory biomarkers decreased after treatment, consistent with the proposed mechanism of action. CONCLUSION: Based on these encouraging preliminary findings, further confirmation in a randomized study is warranted.

How patients with multiple sclerosis acquire disability.

Patients with multiple sclerosis acquire disability either through relapse-associated worsening (RAW) or progression independent of relapse activity (PIRA). This study addresses the relative contribution of relapses to disability worsening over the course of the disease, how early progression begins and the extent to which multiple sclerosis therapies delay disability accumulation. Using the Novartis-Oxford multiple sclerosis (NO.MS) data pool spanning all multiple sclerosis phenotypes and paediatric multiple sclerosis, we evaluated ∼200 000 Expanded Disability Status Scale (EDSS) transitions from >27 000 patients with ≤15 years follow-up. We analysed three datasets: (i) A full analysis dataset containing all observational and randomized controlled clinical trials in which disability and relapses were assessed (n = 27 328); (ii) all phase 3 clinical trials (n = 8346); and (iii) all placebo-controlled phase 3 clinical trials (n = 4970). We determined the relative importance of RAW and PIRA, investigated the role of relapses on all-cause disability worsening using Andersen-Gill models and observed the impact of the mechanism of worsening and disease-modifying therapies on the time to reach milestone disability levels using time continuous Markov models. PIRA started early in the disease process, occurred in all phenotypes and became the principal driver of disability accumulation in the progressive phase of the disease. Relapses significantly increased the hazard of all-cause disability worsening events; following a year in which relapses occurred (versus a year without relapses), the hazard increased by 31-48% (all P < 0.001). Pre-existing disability and older age were the principal risk factors for incomplete relapse recovery. For placebo-treated patients with minimal disability (EDSS 1), it took 8.95 years until increased limitation in walking ability (EDSS 4) and 18.48 years to require walking assistance (EDSS 6). Treating patients with disease-modifying therapies delayed these times significantly by 3.51 years (95% confidence limit: 3.19, 3.96) and 3.09 years (2.60, 3.72), respectively. In patients with relapsing-remitting multiple sclerosis, those who worsened exclusively due to RAW events took a similar length of time to reach milestone EDSS values compared with those with PIRA events; the fastest transitions were observed in patients with PIRA and superimposed relapses. Our data confirm that relapses contribute to the accumulation of disability, primarily early in multiple sclerosis. PIRA begins in relapsing-remitting multiple sclerosis and becomes the dominant driver of disability accumulation as the disease evolves. Pre-existing disability and older age are the principal risk factors for further disability accumulation. The use of disease-modifying therapies delays disability accrual by years, with the potential to gain time being highest in the earliest stages of multiple sclerosis.

Bacterial neurotoxic metabolites in multiple sclerosis cerebrospinal fluid and plasma.

The identification of intestinal dysbiosis in patients with neurological and psychiatric disorders has highlighted the importance of gut-brain communication, and yet the question regarding the identity of the components responsible for this cross-talk remains open. We previously reported that relapsing remitting multiple sclerosis patients treated with dimethyl fumarate have a prominent depletion of the gut microbiota, thereby suggesting that studying the composition of plasma and CSF samples from these patients may help to identify microbially derived metabolites. We used a functional xenogeneic assay consisting of cultured rat neurons exposed to CSF samples collected from multiple sclerosis patients before and after dimethyl fumarate treatment to assess neurotoxicity and then conducted a metabolomic analysis of plasma and CSF samples to identify metabolites with differential abundance. A weighted correlation network analysis allowed us to identify groups of metabolites, present in plasma and CSF samples, whose abundance correlated with the neurotoxic potential of the CSF. This analysis identified the presence of phenol and indole group metabolites of bacterial origin (e.g. p-cresol sulphate, indoxyl sulphate and N-phenylacetylglutamine) as potentially neurotoxic and decreased by treatment. Chronic exposure of cultured neurons to these metabolites impaired their firing rate and induced axonal damage, independent from mitochondrial dysfunction and oxidative stress, thereby identifying a novel pathway of neurotoxicity. Clinical, radiological and cognitive test metrics were also collected in treated patients at follow-up visits. Improved MRI metrics, disability and cognition were only detected in dimethyl fumarate-treated relapsing remitting multiple sclerosis patients. The levels of the identified metabolites of bacterial origin (p-cresol sulphate, indoxyl sulphate and N-phenylacetylglutamine) were inversely correlated to MRI measurements of cortical volume and directly correlated to the levels of neurofilament light chain, an established biomarker of neurodegeneration. Our data suggest that phenol and indole derivatives from the catabolism of tryptophan and phenylalanine are microbially derived metabolites, which may mediate gut-brain communication and induce neurotoxicity in multiple sclerosis.

CONCERTO: A randomized, placebo-controlled trial of oral laquinimod in relapsing-remitting multiple sclerosis.

BACKGROUND: Interventions targeting the adaptive immune response are needed in multiple sclerosis (MS). OBJECTIVE: Evaluate laquinimod's efficacy, safety, and tolerability in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: CONCERTO was a randomized, double-blind, placebo-controlled, phase-3 study. RRMS patients were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 or 1.2 mg or placebo for ⩽24 months (n = 727, n = 732, and n = 740, respectively). Primary endpoint was time to 3-month confirmed disability progression (CDP). The laquinimod 1.2-mg dose arm was discontinued (1 January 2016) due to cardiovascular events at high doses. Safety was monitored throughout the study. RESULTS: CONCERTO did not meet the primary endpoint of significant effect with laquinimod 0.6-mg versus placebo on 3-month CDP (hazard ratio: 0.94; 95% confidence interval: 0.67-1.31; p = 0.706). Secondary endpoint p values were nominal and non-inferential. Laquinimod 0.6 mg demonstrated 40% reduction in percent brain volume change from baseline to Month 15 versus placebo (p < 0.0001). The other secondary endpoint, time to first relapse, and annualized relapse rate (an exploratory endpoint) were numerically lower (both, p = 0.0001). No unexpected safety findings were reported with laquinimod 0.6 mg. CONCLUSION: Laquinimod 0.6 mg demonstrated only nominally significant effects on clinical relapses and magnetic resonance imaging (MRI) outcomes and was generally well tolerated. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT01707992).

Early first-line treatment response and subsequent disability worsening in relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: Treatment success in relapsing-remitting multiple sclerosis (RRMS) is generally determined using relapse frequency and magnetic resonance imaging (MRI) activity in the first 6 or 12 months on treatment. The association of these definitions of short-term treatment success with disability worsening and disease activity in the longer term is unclear. In this study, we investigated risk factors associated with early first-line treatment failure in RRMS, and the association of early treatment failure with subsequent disability worsening or "no evidence of disease activity" (NEDA-3) status. METHODS: We used data from CombiRx (clinicaltrials.gov identifier NCT00211887) to investigate risk factors associated with early treatment failure, and the association of early treatment failure at 6 and 12 months with subsequent disability worsening or NEDA-3 at 36 months. RESULTS: CombiRx included 1008 treatment-naïve participants with RRMS, who were randomly assigned to treatment with glatiramer acetate, interferon beta, or the combination of both. Early treatment failure at 6 or 12 months by several definitions was associated with NEDA-3 failure at 36 months, but not with subsequent disability worsening at 36 months. Expanded Disability Status Scale (EDSS) was the only baseline characteristic associated with the risk of disability worsening at 36 months. Approximately 70% of NEDA-3 failures occurred due to MRI activity, and <10% occurred due to EDSS worsening. CONCLUSIONS: Our investigation shows that current definitions of early treatment failure in RRMS are unrelated to patient-relevant disability worsening at 36 months of follow-up. Further research into useful definitions of treatment success and failure in RRMS is needed.

Cerebellar pathology and disability worsening in relapsing-remitting multiple sclerosis: A retrospective analysis from the CombiRx trial.

BACKGROUND AND PURPOSE: Cerebellar damage is a valuable predictor of disability, particularly in progressive multiple sclerosis. It is not clear if it could be an equally useful predictor of motor disability worsening in the relapsing-remitting phenotype. AIM: We aimed to determine whether cerebellar damage is an equally useful predictor of motor disability worsening in the relapsing-remitting phenotype. METHODS: Cerebellar lesion loads and volumes were estimated using baseline magnetic resonance imaging from the CombiRx trial (n = 838). The relationship between cerebellar damage and time to disability worsening (confirmed disability progression [CDP], timed 25-foot walk test [T25FWT] score worsening, nine-hole peg test [9HPT] score worsening) was tested in stagewise and stepwise Cox proportional hazards models, accounting for demographics and supratentorial damage. RESULTS: Shorter time to 9HPT score worsening was associated with higher baseline Expanded Disability Status Scale (EDSS) score (hazard ratio [HR] 1.408, p = 0.0042) and higher volume of supratentorial and cerebellar T2 lesions (HR 1.005 p = 0.0196 and HR 2.211, p = 0.0002, respectively). Shorter time to T25FWT score worsening was associated with higher baseline EDSS (HR 1.232, p = 0.0006). Shorter time to CDP was associated with older age (HR 1.026, p = 0.0010), lower baseline EDSS score (HR 0.428, p < 0.0001) and higher volume of supratentorial T2 lesions (HR 1.024, p < 0.0001). CONCLUSION: Among the explored outcomes, single time-point evaluation of cerebellar damage only allows the prediction of manual dexterity worsening. In clinical studies the selection of imaging biomarkers should be informed by the outcome of interest.

Hippocampal volume is more related to patient-reported memory than objective memory performance in early multiple sclerosis.

BACKGROUND: When persons with multiple sclerosis (MS) report memory decline but objective memory performance is normal, there is a bias toward believing objective test results. OBJECTIVE: Investigate whether subjective memory decline or objective memory performance is more related to hippocampal and hippocampal subfield volumes in early MS. METHODS: Persons with early MS (n = 185; ⩽5.0 years diagnosed) completed a subjective memory questionnaire; an objective memory composite was derived from four memory tests. Total hippocampal and subfield volumes were derived from high-resolution 3.0 T magnetic resonance images (MRIs). Partial correlations assessed links between hippocampal volumes and both subjective and objective memory, controlling for age, sex, mood, and pre-morbid intelligence quotient (IQ). RESULTS: Lower total hippocampal and CA1 volumes were related to worse subjective memory but not objective memory (controlling for multiple comparisons). Correlations between subjective memory and both CA1 and subiculum were significantly stronger than were correlations between objective memory and these subfields. Patients in the worst tertile of subjective memory complaints (but not objective memory) had lower hippocampal volumes than 35 demographically similar healthy controls. CONCLUSION: Patient-report is inherently a longitudinal assessment of within-person memory change in everyday life, which may be more sensitive to subtle disease-related changes than cross-sectional objective tests. Findings align with the aging literature.

Depression and cognitive function in early multiple sclerosis: Multitasking is more sensitive than traditional assessments.

BACKGROUND: Persons with multiple sclerosis (MS) and depression symptoms report real-world cognitive difficulties that may be missed by laboratory cognitive tests. OBJECTIVE: To examine the relationship of depressive symptoms to cognitive monotasking versus multitasking in early MS. METHOD: Persons with early MS (n = 185; ⩽5 years diagnosed) reported mood, completed monotasking and multitasking cognitive tests, and received high-resolution 3.0 T magnetic resonance imaging (MRI). Partial correlations analyzed associations between mood and cognition, controlling for age, sex, estimated premorbid IQ, T2 lesion volume, and normalized gray matter volume. RESULTS: Depression symptoms were more related to worse cognitive multitasking (-0.353, p < 0.001) than monotasking (r = -0.189, p = 0.011). There was a significant albeit weaker link to cognitive efficiency composite score (r = -0.281, p < 0.001), but not composite memory (r = -0.036, p > 0.50). Findings were replicated with a second depression measure. Multitasking was worse in patients with at least mild depression than both patients with no/minimal depression and healthy controls. Multitasking was not related to mood in healthy controls. CONCLUSIONS: Depression symptoms are linked to cognitive multitasking in early MS; standard monotasking cognitive assessments appear less sensitive to depression-related cognition. Further investigation should determine directionality and mechanisms of this relationship, with the goal of enhancing treatment for cognitive dysfunction and depression in MS.

Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial.

BACKGROUND: No approved therapies exist for neuromyelitis optica spectrum disorder (NMOSD), a rare, relapsing, autoimmune, inflammatory disease of the CNS that causes blindness and paralysis. We aimed to assess the efficacy and safety of inebilizumab, an anti-CD19, B cell-depleting antibody, in reducing the risk of attacks and disability in NMOSD. METHODS: We did a multicentre, double-blind, randomised placebo-controlled phase 2/3 study at 99 outpatient specialty clinics or hospitals in 25 countries. Eligible participants were adults (≥18 years old) with a diagnosis of NMOSD, an Expanded Disability Status Scale score of 8·0 or less, and a history of at least one attack requiring rescue therapy in the year before screening or at least two attacks requiring rescue therapy in the 2 years before screening. Participants were randomly allocated (3:1) to 300 mg intravenous inebilizumab or placebo with a central interactive voice response system or interactive web response system and permuted block randomisation. Inebilizumab or placebo was administered on days 1 and 15. Participants, investigators, and all clinical staff were masked to the treatments, and inebilizumab and placebo were indistinguishable in appearance. The primary endpoint was time to onset of an NMOSD attack, as determined by the adjudication committee. Efficacy endpoints were assessed in all randomly allocated patients who received at least one dose of study intervention, and safety endpoints were assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT02200770. FINDINGS: Between Jan 6, 2015, and Sept 24, 2018, 230 participants were randomly assigned to treatment and dosed, with 174 participants receiving inebilizumab and 56 receiving placebo. The randomised controlled period was stopped before complete enrolment, as recommended by the independent data-monitoring committee, because of a clear demonstration of efficacy. 21 (12%) of 174 participants receiving inebilizumab had an attack versus 22 (39%) of 56 participants receiving placebo (hazard ratio 0·272 [95% CI 0·150-0·496]; p<0·0001). Adverse events occurred in 125 (72%) of 174 participants receiving inebilizumab and 41 (73%) of 56 participants receiving placebo. Serious adverse events occurred in eight (5%) of 174 participants receiving inebilizumab and five (9%) of 56 participants receiving placebo. INTERPRETATION: Compared with placebo, inebilizumab reduced the risk of an NMOSD attack. Inebilizumab has potential application as an evidence-based treatment for patients with NMOSD. FUNDING: MedImmune and Viela Bio.

Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis.

BACKGROUND: B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. METHODS: In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 µg three times weekly for 96 weeks. The primary end point was the annualized relapse rate. RESULTS: The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a. CONCLUSIONS: Among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann-La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333 , respectively.).

Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis.

BACKGROUND: An evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primary progressive form of the disease. METHODS: In this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. RESULTS: The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). There was no significant difference in the change in the Physical Component Summary score of the 36-Item Short-Form Health Survey. Infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections. CONCLUSIONS: Among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. Extended observation is required to determine the long-term safety and efficacy of ocrelizumab. (Funded by F. Hoffmann-La Roche; ORATORIO ClinicalTrials.gov number, NCT01194570 .).

Deep Learning for Predicting Enhancing Lesions in Multiple Sclerosis from Noncontrast MRI.

Background Enhancing lesions on MRI scans obtained after contrast material administration are commonly thought to represent disease activity in multiple sclerosis (MS); it is desirable to develop methods that can predict enhancing lesions without the use of contrast material. Purpose To evaluate whether deep learning can predict enhancing lesions on MRI scans obtained without the use of contrast material. Materials and Methods This study involved prospective analysis of existing MRI data. A convolutional neural network was used for classification of enhancing lesions on unenhanced MRI scans. This classification was performed for each slice, and the slice scores were combined by using a fully connected network to produce participant-wise predictions. The network input consisted of 1970 multiparametric MRI scans from 1008 patients recruited from 2005 to 2009. Enhanced lesions on postcontrast T1-weighted images served as the ground truth. The network performance was assessed by using fivefold cross-validation. Statistical analysis of the network performance included calculation of lesion detection rates and areas under the receiver operating characteristic curve (AUCs). Results MRI scans from 1008 participants (mean age, 37.7 years ± 9.7; 730 women) were analyzed. At least one enhancing lesion was observed in 519 participants. The sensitivity and specificity averaged across the five test sets were 78% ± 4.3 and 73% ± 2.7, respectively, for slice-wise prediction. The corresponding participant-wise values were 72% ± 9.0 and 70% ± 6.3. The diagnostic performances (AUCs) were 0.82 ± 0.02 and 0.75 ± 0.03 for slice-wise and participant-wise enhancement prediction, respectively. Conclusion Deep learning used with conventional MRI identified enhanced lesions in multiple sclerosis from images from unenhanced multiparametric MRI with moderate to high accuracy. © RSNA, 2019.

Deep-Learning-Based Neural Tissue Segmentation of MRI in Multiple Sclerosis: Effect of Training Set Size.

BACKGROUND: The dependence of deep-learning (DL)-based segmentation accuracy of brain MRI on the training size is not known. PURPOSE: To determine the required training size for a desired accuracy in brain MRI segmentation in multiple sclerosis (MS) using DL. STUDY TYPE: Retrospective analysis of MRI data acquired as part of a multicenter clinical trial. STUDY POPULATION: In all, 1008 patients with clinically definite MS. FIELD STRENGTH/SEQUENCE: MRIs were acquired at 1.5T and 3T scanners manufactured by GE, Philips, and Siemens with dual turbo spin echo, FLAIR, and T1 -weighted turbo spin echo sequences. ASSESSMENT: Segmentation results using an automated analysis pipeline and validated by two neuroimaging experts served as the ground truth. A DL model, based on a fully convolutional neural network, was trained separately using 16 different training sizes. The segmentation accuracy as a function of the training size was determined. These data were fitted to the learning curve for estimating the required training size for desired accuracy. STATISTICAL TESTS: The performance of the network was evaluated by calculating the Dice similarity coefficient (DSC), and lesion true-positive and false-positive rates. RESULTS: The DSC for lesions showed much stronger dependency on the sample size than gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). When the training size was increased from 10 to 800 the DSC values varied from 0.00 to 0.86 ± 0.016 for T2 lesions, 0.87 ± 009 to 0.94 ± 0.004 for GM, 0.86 ± 0.08 to 0.94 ± 0.005 for WM, and 0.91 ± 0.009 to 0.96 ± 0.003 for CSF. DATA CONCLUSION: Excellent segmentation was achieved with a training size as small as 10 image volumes for GM, WM, and CSF. In contrast, a training size of at least 50 image volumes was necessary for adequate lesion segmentation. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2020;51:1487-1496.

Brain and lesion segmentation in multiple sclerosis using fully convolutional neural networks: A large-scale study.

OBJECTIVE: To investigate the performance of deep learning (DL) based on fully convolutional neural network (FCNN) in segmenting brain tissues in a large cohort of multiple sclerosis (MS) patients. METHODS: We developed a FCNN model to segment brain tissues, including T2-hyperintense MS lesions. The training, validation, and testing of FCNN were based on ~1000 magnetic resonance imaging (MRI) datasets acquired on relapsing-remitting MS patients, as a part of a phase 3 randomized clinical trial. Multimodal MRI data (dual-echo, FLAIR, and T1-weighted images) served as input to the network. Expert validated segmentation was used as the target for training the FCNN. We cross-validated our results using the leave-one-center-out approach. RESULTS: We observed a high average (95% confidence limits) Dice similarity coefficient for all the segmented tissues: 0.95 (0.92-0.98) for white matter, 0.96 (0.93-0.98) for gray matter, 0.99 (0.98-0.99) for cerebrospinal fluid, and 0.82 (0.63-1.0) for T2 lesions. High correlations between the DL segmented tissue volumes and ground truth were observed (R2 > 0.92 for all tissues). The cross validation showed consistent results across the centers for all tissues. CONCLUSION: The results from this large-scale study suggest that deep FCNN can automatically segment MS brain tissues, including lesions, with high accuracy.

Psychological resilience is linked to motor strength and gait endurance in early multiple sclerosis.

BACKGROUND: Psychologically resilient persons persist despite obstacles and bounce back after adversity, leading to better outcomes in non-neurologic populations. It is unknown whether psychological resilience relates to objective functional outcomes in multiple sclerosis (MS). OBJECTIVE: To determine whether psychological resilience explains differential objective cognitive and motor functioning in persons with early MS. METHODS: Psychological resilience was assessed in 185 patients with early MS and 50 matched healthy controls with the Connors-Davidson Resilience Scale (CDRS-10). Subjects completed the MS Functional Composite (MSFC) and a comprehensive neurobehavioral evaluation. Correlations assessed links between CDRS-10 and MSFC, motor indices (Total, Fine Motor, Gross Motor), and cognitive indices (Total, Cognitive Efficiency, Memory). RESULTS: Higher CDRS-10 among patients was linked to better MSFC and motor outcomes (but not cognition), with the most robust relationships for gross motor function (grip strength, gait endurance). Findings were independent of mood and fatigue. CDRS-10 was unrelated to MS disease burden. CDRS-10 was also specifically linked to motor outcomes in healthy controls. CONCLUSION: Functional outcomes vary across persons with MS, even when disease burden and neurologic disability are low. These findings identify high psychological resilience as a non-disease-specific contributor to motor strength and endurance, which may explain differential outcomes across patients.