Search

The radiologically isolated syndrome (RIS) represents the earliest detectable pre-clinical phase of multiple sclerosis (MS). This study evaluated the impact of therapeutic intervention in preventing first symptom manifestation at this stage in the disease spectrum.We conducted a multi-center, randomized, double-blinded, placebo-controlled study involving people with RIS. Individuals without clinical symptoms typical of MS but with incidental brain MRI anomalies consistent with CNS demyelination were included. Within 12 MS centers in the U.S., participants were randomly assigned 1:1 to oral dimethyl fumarate (DMF) 240mg twice daily or placebo. The primary endpoint was the time to onset of clinical symptoms attributable to a CNS demyelinating event within a follow-up period of 96 weeks. An intention-to-treat analysis was applied to all participating individuals in the primary and safety investigations. The study is registered at ClinicalTrials.gov, NCT02739542 (ARISE).Participants from 12 centers were recruited from March 9, 2016 to October 31, 2019 with 44 people randomized to dimethyl fumarate and 43 to placebo. Following DMF treatment, the risk of a first clinical demyelinating event during the 96-week study period was highly reduced in the unadjusted Cox proportional-hazards regression model (hazard ratio (HR)=0.18, 95% confidence interval (CI)=0.05-0.63, p=0.007). More moderate adverse reactions were present in the DMF (34 (32%)) than placebo groups (19 (21%)) but severe events were similar (DMF, 3 (5%); placebo, 4 (9%)).This is the first randomized clinical trial demonstrating the benefit of a disease-modifying therapy in preventing a first acute clinical event in people with RIS. This article is protected by copyright. All rights reserved.

Esclerosi múltiple; Cadena lleugera de neurofilaments sèrics Esclerosis múltiple; Cadena ligera de neurofilamentos séricos Multiple sclerosis; Serum neurofilament light chain Objective Evaluation of serum neurofilament light chain (sNfL), measured using high-throughput assays on widely accessible platforms in large, real-world MS populations, is a critical step for sNfL to be utilized in clinical practice. Methods Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is a network of healthcare institutions in the United States and Europe collecting standardized clinical/imaging data and biospecimens during routine clinic visits. sNfL was measured in 6974 MS and 201 healthy control (HC) participants, using a high-throughput, scalable immunoassay. Results Elevated sNfL levels for age (sNfL-E) were found in 1238 MS participants (17.8%). Factors associated with sNfL-E included male sex, younger age, progressive disease subtype, diabetes mellitus, impaired renal function, and active smoking. Higher body mass index (BMI) was associated with lower odds of elevated sNfL. Active treatment with disease-modifying therapy was associated with lower odds of sNfL-E. MS participants with sNfL-E exhibited worse neurological function (patient-reported disability, walking speed, manual dexterity, and cognitive processing speed), lower brain parenchymal fraction, and higher T2 lesion volume. Longitudinal analyses revealed accelerated short-term rates of whole brain atrophy in sNfL-E participants and higher odds of new T2 lesion development, although both MS participants with or without sNfL-E exhibited faster rates of whole brain atrophy compared to HC. Findings were consistent in analyses examining age-normative sNfL Z-scores as a continuous variable. Interpretation Elevated sNfL is associated with clinical disability, inflammatory disease activity, and whole brain atrophy in MS, but interpretation needs to account for comorbidities including impaired renal function, diabetes, and smoking. Study funding was provided from the National Institutes of Health (K23NS117883 to E.S.S.; K01MH121582 to K.C.F.; U01NS111678 to P.A.C.), National Multiple Sclerosis Society (RG-1904-33834 to E.S.S.; RG-1904-33800 to P.A.C.), and Biogen.

ObjectiveTo compare clinical and imaging features of multiple sclerosis (MS) severity between Black Americans (BAs) and White Americans (WAs) and to evaluate the role of socioeconomic status.MethodsWe compared BA and WA participants in the Multiple Sclerosis Partners Advancing Technology Health Solutions (MS PATHS) cohort with respect to MS characteristics, including self-reported disability, objective neurologic function assessments, and quantitative brain MRI measurements, after covariate adjustment (including education level, employment, or insurance as socioeconomic indicators). In a subgroup, we evaluated within-race, neighborhood-level indicators of socioeconomic status (SES) using 9-digit zip codes.ResultsOf 1,214 BAs and 7,530 WAs with MS, BAs were younger, had lower education level, and were more likely to have Medicaid insurance or to be disabled or unemployed than WAs. BAs had worse self-reported disability (1.47-fold greater odds of severe vs mild disability, 95% confidence interval [CI] 1.18, 1.86) and worse performances on tests of cognitive processing speed (−5.06 fewer correct, 95% CI −5.72, −4.41), walking (0.66 seconds slower, 95% CI 0.36, 0.96), and manual dexterity (2.11 seconds slower, 95% CI 1.69, 2.54). BAs had more brain MRI lesions and lower overall and gray matter brain volumes, including reduced thalamic (−0.77 mL, 95% CI −0.91, −0.64), cortical (−30.63 mL, 95% CI −35.93, −25.33), and deep (−1.58 mL, 95% CI −1.92, −1.23) gray matter volumes. While lower SES correlated with worse neuroperformance scores in WAs, this association was less clear in BAs.ConclusionWe observed a greater burden of disease in BAs with MS relative to WAs with MS, despite adjustment for SES indicators. Beyond SES, future longitudinal studies should also consider roles of other societal constructs (e.g., systemic racism). Such studies will be important for identifying prognostic factors; developing optimal treatment strategies among BAs with MS is warranted.

Background: Sensitive and specific biomarkers for use in progressive multiple sclerosis (MS) have not been established. We investigate neurofilament light (NfL) as a treatment response biomarker in progressive MS. Objective: To evaluate whether ibudilast 100 mg/day alters serum and cerebrospinal fluid (CSF) levels of NfL in progressive MS. Methods: In a protocol-defined exploratory analysis from a 2-year, phase 2 clinical trial of ibudilast in progressive MS (NCT01982942), serum samples were collected from 239 subjects and a subset contributed CSF and assayed using single-molecule assay (SIMOA) immunoassay. A mixed model for repeated measurements yielded log(NfL) as the response variable. Results: The geometric mean baseline serum NfL was 31.9 and 28.8 pg/mL in placebo and ibudilast groups, respectively. The geometric mean baseline CSF NfL was 1150.8 and 1290.3 pg/mL in placebo and ibudilast groups, respectively. Serum and CSF NfL correlations were r = 0.52 and r = 0.78 at weeks 48 and 96, respectively. Over 96 weeks, there was no between-group difference in NfL in either serum ( p = 0.76) or CSF ( p = 0.46). After controlling for factors that may affect NfL, no effect of ibudilast on NfL in either serum or CSF was observed. Conclusion: Ibudilast treatment was not associated with a change in either serum or CSF NfL.

Objective Determine whether a treatment effect of ibudilast on brain atrophy rate differs between participants with primary (PPMS) and secondary (SPMS) progressive multiple sclerosis. Background Progressive forms of MS are both associated with continuous disability progression. Whether PPMS and SPMS differ in treatment response remains unknown. Design/Methods SPRINT‐MS was a randomized, placebo‐controlled 96‐week phase 2 trial in both PPMS (n = 134) and SPMS (n = 121) patients. The effect of PPMS and SPMS phenotype on the rate of change of brain atrophy measured by brain parenchymal fraction (BPF) was examined by fitting a three‐way interaction linear‐mixed model. Adjustment for differences in baseline demographics, disease measures, and brain size was explored. Results Analysis showed that there was a three‐way interaction between the time, treatment effect, and disease phenotype (P

Objective Multiple sclerosis (MS) lesions are heterogeneous with regard to inflammation, demyelination, axonal injury, and neuronal loss. We previously developed a diffusion basis spectrum imaging (DBSI) technique to better address MS lesion heterogeneity. We hypothesized that the profiles of multiple DBSI metrics can identify lesion‐defining patterns. Here we test this hypothesis by combining a deep learning algorithm using deep neural network (DNN) with DBSI and other imaging methods. Methods Thirty‐eight MS patients were scanned with diffusion‐weighted imaging, magnetization transfer imaging, and standard conventional MRI sequences (cMRI). A total of 499 regions of interest were identified on standard MRI and labeled as persistent black holes (PBH), persistent gray holes (PGH), acute black holes (ABH), acute gray holes (AGH), nonblack or gray holes (NBH), and normal appearing white matter (NAWM). DBSI, diffusion tensor imaging (DTI), and magnetization transfer ratio (MTR) were applied to the 43,261 imaging voxels extracted from these ROIs. The optimized DNN with 10 fully connected hidden layers was trained using the imaging metrics of the lesion subtypes and NAWM. Results Concordance, sensitivity, specificity, and accuracy were determined for the different imaging methods. DBSI‐DNN derived lesion classification achieved 93.4% overall concordance with predetermined lesion types, compared with 80.2% for DTI‐DNN model, 78.3% for MTR‐DNN model, and 74.2% for cMRI‐DNN model. DBSI‐DNN also produced the highest specificity, sensitivity, and accuracy. Conclusions DBSI‐DNN improves the classification of different MS lesion subtypes, which could aid clinical decision making. The efficacy and efficiency of DBSI‐DNN shows great promise for clinical applications in automatic MS lesion detection and classification.

Diroximel fumarate (DRF) is an oral fumarate for relapsing multiple sclerosis (MS) with the same active metabolite as dimethyl fumarate (DMF). DRF has a safety/efficacy profile similar to DMF but with improved gastrointestinal (GI) tolerability and low ( 1%) treatment discontinuation due to GI adverse events (AEs). Efficacy and safety outcomes in patients who switched to DRF from other disease-modifying therapies (DMTs) have not been evaluated.EVOLVE-MS-1 is an ongoing, 2-year, open-label, phase 3 study of DRF in adults with relapsing-remitting MS. Patients either entered as newly enrolled to DRF trials, or from the 5-week, randomized, head-to-head, phase 3 EVOLVE-MS-2 study of DRF and DMF. This analysis evaluated safety and GI tolerability in patients continuing on DRF (DRF-rollover) or switching from DMF (DMF-rollover) following EVOLVE-MS-2. Safety and efficacy were evaluated in a subset of newly enrolled patients who had received prior glatiramer acetate (GA; GA/DRF) or interferons (IFN; IFN/DRF) as their most recent DMT, prior to switching to DRF in EVOLVE-MS-1.As of September 1, 2020, 1057 patients were enrolled in EVOLVE-MS-1, including 166, 182, 239, and 225 patients in the GA/DRF, IFN/DRF, DRF-rollover, and DMF-rollover groups, respectively. Treatment discontinuation due to GI AEs was 1% in all groups. GA/DRF and IFN/DRF patients experienced improvements from baseline in clinical and radiological efficacy outcomes, including significantly reduced annualized relapse rates. Rollover patients had low rates of new or recurrent GI AEs (DRF-rollover, 26.8%/4.2%; DMF-rollover, 27.1%/4.9%).After 2 years of DRF exposure, patients with prior GA, IFN, or fumarate treatment had safety outcomes consistent with previous fumarate studies. Efficacy in patients with prior GA or IFN treatment was consistent with previous fumarate studies. The data suggest that transition to DRF from GA, IFN, or DMF is a reasonable treatment strategy, with low rates of discontinuation due to GI AEs.ClinicalTrials.gov (NCT02634307). INFOGRAPHIC.

Assessment of intrinsic tissue integrity is commonly accomplished via quantitative relaxometry or other specialized imaging, which requires sequences and analysis procedures not routinely available in clinical settings. We detail an alternative technique for extraction of quantitative tissue biomarkers based on intensity normalization of T1- and T2-weighted images. We develop the theoretical underpinnings of this approach and demonstrate its utility in imaging of multiple sclerosis.

Background: Few studies have addressed the results of educational efforts concerning proper use of McDonald criteria (MC) revisions outside multiple sclerosis (MS) subspecialty centers. Neurology residents and MS subspecialist neurologists demonstrated knowledge gaps for core elements of the MC in a recent prior study. Objective: To assess comprehension and application of MC core elements by non-MS specialist neurologists in the United States who routinely diagnose MS. Methods: Through a cross-sectional study design, a previously developed survey instrument was distributed online. Results: A total of 222 neurologists completed the study survey. Syndromes atypical for MS were frequently incorrectly considered “typical” MS presentations. Fourteen percent correctly identified definitions of both “periventricular” and “juxtacortical” lesions and 2% correctly applied these terms to 9/9 images. Twenty-four percent correctly identified all four central nervous system (CNS) regions for satisfaction of magnetic resonance imaging (MRI) dissemination in space. In two presented cases, 61% and 71% correctly identified dissemination in time (DIT) was not fulfilled, and 85% and 86% subsequently accepted nonspecific historical symptoms without objective evidence for DIT fulfillment. Conclusion: The high rate of knowledge deficiencies and application errors of core elements of the MC demonstrated by participants in this study raise pressing questions concerning adequacy of dissemination and educational efforts upon publication of revisions to MC.

Objective No available assessment tool offers a brief and psychometrically sound way for clinicians to quantify assessment of MS in a typical office visit. The objective of this study was to develop a brief clinician-reported outcome measure of MS signs and symptoms to standardize and quantify assessments that occur during a typical neurology office visit. Methods A questionnaire, called the Clinician Rating of Multiple Sclerosis (CRoMS), was developed in the following steps: literature review; concept elicitation interviews (to generate questionnaire themes and content) with patients with MS (n=14); concept elicitation interviews with neurologists (n=9); online qualitative survey with neurologists in the US, UK, Germany, and Sweden (n=72); online survey with neurologists to evaluate the first draft of the ClinRO (n=26); an in-person meeting with neurologists to discuss and revise the draft ClinRO (n=9); and interviews with neurologists and MS nurses to further refine and finalize the ClinRO (n=16). Results Across all steps of this research, several signs and symptoms consistently emerged as important for assessment in a typical office visit: walking, balance, upper limb function, coordination, weakness, fatigue, pain, sensory symptoms, bladder function, visual function, cognition, spasticity, spasms, and mood. The importance of these signs and symptoms was supported by neurologists during the online surveys and the in-person meeting. Neurologists were generally able to complete the draft ClinRO measure without difficulty, although minor revisions were suggested to refine the ClinRO for future use. Conclusion The CRoMS may be a useful tool for efficiently assessing the severity of MS symptoms. This brief clinician-reported measure could help standardize and quantify assessments in clinical studies and clinical settings.

Extended interval dosing (EID; average dosing interval approximately every 6 weeks) of natalizumab is associated with significantly lower risk of progressive multifocal leukoencephalopathy than standard interval dosing (SID; every 4 weeks) in patients with relapsing-remitting multiple sclerosis (MS). Real-world studies, though limited, suggest that natalizumab effectiveness is generally maintained in patients who switch to EID after initiation of stable treatment with SID. MS PATHS (Multiple Sclerosis Partners Advancing Technology and Health Solutions) is a collaborative, multicenter learning health system that generates real-world clinical and MRI data using highly standardized acquisition protocols. We compared MRI outcomes in MS PATHS patients treated with natalizumab EID versus SID. We also compared MRI outcomes in patients treated with natalizumab (EID and/or SID) versus injectable MS platform therapy.Natalizumab infusion data from the TOUCH Prescribing Program database and MS PATHS MRI assessment data from seven US sites as of July 23, 2020, were used to identify patients with relapsing-remitting MS who had received natalizumab EID or SID in the interval between two MRI scans (an MRI segment). Patients who received injectable platform MS therapy between two MRI scans were also identified. MRI data were used to determine the incidence rate and odds of developing new or enlarging T2 lesions, annualized percentage change in T2 lesion volume (T2LV), and annualized percentage change in brain parenchymal fraction (BPF). MRI outcomes were compared for 1) natalizumab EID treatment versus natalizumab SID treatment, 2) natalizumab treatment (EID + SID) versus platform therapy, and 3) natalizumab EID versus platform therapy. Propensity score-based weighting or matching were used to balance covariates at the start of MRI segments for all comparisons.The MRI outcomes observed with natalizumab EID treatment did not differ significantly from those observed with natalizumab SID treatment. The odds ratio for any new or enlarging T2 lesion was 1.07 (95% confidence interval [CI]: 0.93, 1.24; p = 0.355), and the rate ratio (95% CI) for new or enlarging T2 lesions was 1.62 (0.93, 2.82; p = 0.090). Differences (95% CI) between EID and SID patients in mean annualized percentage change in T2LV and BPF were 1.56% (-3.77%, 6.90%; p = 0.566) and -0.11% (-0.25%, -0.10%; p = 0.096), respectively. Conversely, when MRI outcomes in natalizumab and platform therapy patients were compared, there were significant differences favoring natalizumab in all assessments: the odds of any new or enlarging T2 lesion (odds ratio: 0.69 [95% CI: 0.64, 0.75]; p0.001), the incidence rate of new or enlarging T2 lesions (rate ratio: 0.47 [95% CI: 0.37, 0.61]; p0.001), annualized percentage change (decrease) in T2LV (difference: -3.68% [95% CI: -7.06%, -0.30%]; p = 0.033), and annualized percentage change (increase) in BPF (difference: 0.22% [95% CI: 0.16%, 0.29%]; p0.001). Results of the subgroup comparison of natalizumab EID patients with platform therapy patients were similar to those of the overall-natalizumab-group-versus-platform-therapy comparison.The results indicate that natalizumab EID and SID provide comparable real-world effectiveness on quantitative MRI metrics. These data further demonstrate that natalizumab EID can provide superior real-world effectiveness to injectable platform therapy on quantitative MRI metrics.

This scientific commentary refers to ‘Disease-modifying drugs can reduce disability progression in paediatric, adult and late-onset relapsing multiple sclerosis’, by Amato etal. (doi:10.1093/brain/awaa251).

OBJECTIVES Gadolinium deposition is widely believed to occur, but questions regarding accumulation pattern and permanence remain. We conducted a retrospective study of intracranial signal changes on monthly triple-dose contrast-enhanced magnetic resonance imaging (MRI) examinations from the previously published Betaseron vs. Copaxone in Multiple Sclerosis With Triple-Dose Gadolinium and 3-Tesla MRI Endpoints Trial (N = 67) to characterize the dynamics of gadolinium deposition in several deep brain nuclei and track persistence versus washout of gadolinium deposition on long-term follow-up (LTFU) examinations (N = 28) obtained approximately 10 years after enrollment in the Betaseron vs. Copaxone in Multiple Sclerosis With Triple-Dose Gadolinium and 3-Tesla MRI Endpoints Trial. MATERIALS AND METHODS Using T2 and proton density images and using image analysis software (ITK-SNAP), manual regions of interest were created ascribing boundaries of the caudate nucleus, dentate nucleus, globus pallidus, pulvinar, putamen, white matter, and air. Intensity analysis was conducted on T1-weighted fat-saturated (fat-sat) images using the FSL package. A linear rigid-body transform was calculated from the fat-sat image at each target time point to the region of interest segmentation reference time point fat-sat image. Serial MRI signal was analyzed using linear mixed regression modeling with random intercept. Annual MRI signal changes including LTFU scans were assessed with t test. RESULTS During monthly scanning, all gray matter structures demonstrated a significant (P < 0.0001) increase in contrast-to-noise ratio. Yearly changes in deposition showed distinctive patterns for the specific nucleus: globus pallidus showed complete retention, pulvinar showed partial washout, while dentate, caudate, and putamen returned to baseline (ie, complete washout). CONCLUSIONS Monthly increased contrast-to-noise ratio in gray matter nuclei is consistent with gadolinium deposition over time. The study also suggests that some deep gray matter nuclei permanently retain gadolinium, whereas others demonstrate washout of soluble gadolinium.

Gait impairments in persons with multiple sclerosis (pwMS) leading to decreased ambulation and reduced walking endurance remain poorly understood. Our objective was to assess gait asymmetry (GA) and bilateral coordination of gait (BCG), among pwMS during the six-minute walk test (6MWT), and determine their association with disease severity. We recruited 92 pwMS (age: 46.6 ± 7.9; 83% females) with a range of clinical disability, who completed the 6MWT wearing gait analysis system. GA was assessed by comparing left and right swing times, and BCG was assessed by the phase coordination index (PCI). Several functional and subjective gait assessments were performed. Results show that gait is more asymmetric and less coordinated as the disease progresses (p

Gait impairments in persons with multiple sclerosis (pwMS) underlying reduced walking endurance are still poorly understood. Thus, our objective was to assessed gait asymmetry (GA) and bilateral coordination of gait (BCG), among pwMS during the six-minute walk test (6MWT) and their association with disease severity. For this aim, we recruited ninety-two pwMS (age: 46.6 ± 7.9; 83% females) with a broad range of clinical disability who completed the 6MWT wearing gait analysis system. GA was assessed by comparing left and right swing times, and BCG by using the phase coordination index (PCI). Several functional and subjective gait assessments were performed. Results show that gait is more asymmetric and less coordinated as the disease progresses (p

OBJECTIVES We retrospectively analyzed data of the BECOME trial to investigate whether serial administration of triple-dose (3-dose) gadopentetate dimeglumine would result in the development of T1 signal-to-noise (S/N) changes in the cranial diploic space and whether S/N changes correlated with on-study hypophosphatemia. METHODS Signal intensity analysis was performed on the first year's data of the BECOME trial using 3-dose Gd (14 months, maximum number of doses, 39, mean: 36). Routine blood and urine tests were obtained each month for safety monitoring. Linear mixed regression modeling with random intercept was used to analyze monthly signal-to-noise ratio (S/N = Bone/Air) using an ROI of the diploic space created from T2W images and overlaid on T1FS (T1 fat-saturated) images. Incidence of phosphate abnormalities was analyzed using the general estimation equation; correlation of phosphate and S/N change was achieved with type 3 test of fixed effects. RESULTS Cranial diploic space T1FS S/N increased over 14 months: S/N = 0.039 mean monthly increase (S.E. 0.008; p

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

Objective: To assess comprehension and application of the McDonald criteria. Background: Studies suggest that knowledge gaps for specific core elements of the McDonald criteria may contribute to multiple sclerosis (MS) misdiagnosis. Methods: Neurology residents (NR) and multiple sclerosis specialists (MSS) in North America completed a web-based survey. Results: A total of 160 participants were included: 72 NR and 88 MSS. Syndromes incorrectly identified as typical of MS included: complete transverse myelopathy (35% NR and 15% MSS), intractable vomiting/nausea/hiccoughs (20% NR and 5% MSS), and bilateral optic neuritis/unilateral optic neuritis with poor visual recovery (17% NR and 10% MSS). Periventricular magnetic resonance imaging (MRI) lesions were correctly identified by 39% NR and 52% MSS, and juxtacortical lesions were correctly identified by 28% NR and 53% MSS. The correct definition of “periventricular” was chosen by 38% NR and 61% MSS, and that of “juxtacortical” was chosen by 19% NR and 54% MSS. Regions incorrectly identified for MRI dissemination in space fulfillment included the optic nerve (31% NR and 26% MSS) and the subcortical white matter (11% NR and 18% MSS). The majority of participants assessed previous non-specific neurological symptoms without objective evidence of a central nervous system (CNS) lesion as sufficient for clinical dissemination in time. Conclusion: The McDonald criteria are often misunderstood and misapplied. Concerted educational efforts may prevent MS misdiagnosis.

Misdiagnosis of multiple sclerosis (MS) (the incorrect assignment of a diagnosis of MS) remains a problem in contemporary clinical practice. Studies indicate that misdiagnosed patients are often exposed to prolonged unnecessary health care risks and morbidity. The recently published 2017 revision of the McDonald criteria for the diagnosis of MS provides an opportunity to consider the effect of these revisions on the problem of MS misdiagnosis. The 2017 McDonald criteria include several new recommendations to reduce potential for misdiagnoses. The criteria should be used for the types of patients in which validation studies were performed, specifically those patients who present with typical demyelinating syndromes. MRI lesion characteristics were defined for which McDonald criteria would be expected to perform with accuracy. However, 2017 revisions, which now include assessment for cortical lesions, and the inclusion of symptomatic lesions and positive oligoclonal bands for the fulfillment of diagnostic criteria, may have the potential to lead to misdiagnosis of MS if not applied appropriately. While the 2017 McDonald criteria integrate issues relating to MS misdiagnosis and incorporate specific recommendations for its prevention more prominently than prior criteria, the interpretation of clinical and radiologic assessments upon which these criteria depend will continue to allow misdiagnoses. In patients with atypical clinical presentations, the revised McDonald criteria may not be readily applied. In those situations, further evaluation or monitoring rather than immediate diagnosis of MS is prudent.

BackgroundThere are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis.MethodsWe enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis.ResultsOf 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.ConclusionsIn a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Diffusion basis spectrum imaging (DBSI) models diffusion-weighted magnetic resonance imaging (MRI) signals as a combination of discrete anisotropic diffusion tensors and a spectrum of isotropic diffusion tensors. Here, we report the histopathological correlates of DBSI in the biopsied brain tissue of a patient with an inflammatory demyelinating lesion typical of multiple sclerosis (MS). Increased radial diffusivity (marker of demyelination), decreased fiber fraction (apparent axonal density), elevated nonrestricted isotropic fraction (marker of vasogenic edema), but unchanged axial diffusivity (marker of integrity of residual axons) seen in the lesion appeared consistent with histopathological findings of inflammatory demyelination with relative axonal sparing. Our report supports the application of DBSI as a biomarker in human studies of MS.

BACKGROUND AND PURPOSE Evidence is needed to understand the effect of fingolimod on slowing down brain atrophy progression in multiple sclerosis (MS) patients in clinical practice. We investigated the effect of fingolimod on brain atrophy in MS patients with active disease (clinically and/or magnetic resonance imaging [MRI]) versus no evidence of active disease (NEAD). METHODS MS and clinical outcome and MRI in the United States (MS-MRIUS) is a multicenter, retrospective study that included 590 relapsing-remitting MS patients, who initiated fingolimod, and were followed for a median of 16 months. Patients with active disease at baseline (245, 41.5%) were defined as those who had one or more relapses in the year previous starting fingolimod, and/or displayed gadolinium enhancing lesions(s) at baseline MRI scan, whereas patients with NEAD at baseline (345, 58.5%) did not fulfill these criteria. Annualized percentage brain volume change (PBVC) and percentage lateral ventricle volume change (PLVVC) over the follow-up were analyzed in both groups. RESULTS Over the follow-up, the rate of PBVC was -.38% in active disease and -.25% in NEAD patients (P = .076), whereas PLLVC was 1.76% in active disease and .28% in NEAD patients (P = .046). No changes in timed 25-foot walk (P = .619) and Expanded Disability Status Scale (P = .275) scores or MRI lesion accumulation (P > 0.08) were detected, although the active disease group had a higher proportion of relapses during the follow-up period (P = .02). CONCLUSIONS The study provides real-world evidence that rate of brain atrophy in MS patients with underlying active disease and NEAD in fingolimod treated patients is below the established pathological cutoff for loss of whole brain volume (>-.4%) or expansion of lateral ventricles (> 3.5%).

Background People with MS may have unique perspectives on COVID-19 vaccines due to their condition and/or medications. Objective Assess perspectives and experiences with COVID-19 vaccination, and quantify variables impacting COVID-19 vaccine willingness in people with MS. Methods A survey captured demographics, MS characteristics, and COVID-19 infection and exposures data; opinions on COVID-19 vaccine safety, side effects, and efficacy; and experiences following vaccination. Chi-square tests and a logistic regression model were used to denote between-group differences and variables predicting vaccine willingness, respectively. Results Most (87.8%) of the 237 participants were willing to receive the vaccine. Fifteen percent held or delayed a DMT dose for vaccination. MS symptoms worsened in a minority (7.6% first/only dose; 14.7% second dose), and most side effects were mild (80.0%; 55.3%). Those not planning to receive the vaccine were primarily concerned with long-term safety (70.4%). Medical comorbidities (adjusted odds ratio [aOR]=5.222; p=0.04) and following infection prevention precautions (aOR=6.330; p=0.008) were associated with vaccine willingness. Conclusion Most individuals with MS surveyed plan to receive the COVID-19 vaccine. People with MS experience similar side effects to the general population, and few experience transient MS symptom worsening. These results can inform conversations on vaccination between providers and people with MS.

Background Improved imaging methods are critical to assess neurodegeneration and remyelination in multiple sclerosis. Chronic hypointensities observed on T1-weighted brain MRI, "persistent black holes," reflect severe focal tissue damage. Present measures consist of determining persistent black holes numbers and volumes, but do not quantitate severity of individual lesions. Objective Develop a method to differentiate black and gray holes and estimate the severity of individual multiple sclerosis lesions using standard magnetic resonance imaging. Methods 38 multiple sclerosis patients contributed images. Intensities of lesions on T1-weighted scans were assessed relative to cerebrospinal fluid intensity using commercial software. Magnetization transfer imaging, diffusion tensor imaging and clinical testing were performed to assess associations with T1w intensity-based measures. Results Intensity-based assessments of T1w hypointensities were reproducible and achieved > 90% concordance with expert rater determinations of "black" and "gray" holes. Intensity ratio values correlated with magnetization transfer ratios (R = 0.473) and diffusion tensor imaging metrics (R values ranging from 0.283 to −0.531) that have been associated with demyelination and axon loss. Intensity ratio values incorporated into T1w hypointensity volumes correlated with clinical measures of cognition. Conclusions This method of determining the degree of hypointensity within multiple sclerosis lesions can add information to conventional imaging.

Background: The Expanded Disability Status Scale (EDSS) is the standard measure of disability in multiple sclerosis clinical trials. The EDSS has limited application in the clinical setting due to required completion time and scoring complexity. Systematically recording an objective, simplified, less time-intensive, and neurologist-derived disability score would be beneficial for patient care. Objective: To develop and validate a streamlined version of the Expanded Disability Status Scale (sEDSS) for clinical monitoring. Methods: The EDSS was modified by eliminating maneuvers with no impact on function, consolidating redundancies, and simplifying scoring. This sEDSS was refined and preliminarily validated using a pilot cohort of 102 patients. Subsequently, the sEDSS was retrospectively validated using 968 patients from the CombiRx trial. We evaluated correlation and agreement between each functional system as well as the overall sEDSS and EDSS. Results: The sEDSS correlated strongly with the EDSS, both overall (Spearman’s rho = 0.93) and for each functional system (Spearman’s rho 0.65–0.97). Correlation was slightly lower for functional systems where scoring was modified for consolidation and simplification. Conclusion: The sEDSS had strong agreement and correlation with the existing EDSS and can provide a useful measure of disability in clinical practice.

ObjectiveTo determine whether ibudilast has an effect on brain volume and new lesions in progressive forms of multiple sclerosis (MS).MethodsA randomized, placebo-controlled, blinded study evaluated ibudilast at a dose of up to 100 mg over 96 weeks in primary and secondary progressive MS. In this secondary analysis of a previously reported trial, secondary and tertiary endpoints included gray matter atrophy, new or enlarging T2 lesions as measured every 24 weeks, and new T1 hypointensities at 96 weeks. Whole brain atrophy measured by structural image evaluation, using normalization, of atrophy (SIENA) was a sensitivity analysis.ResultsA total of 129 participants were assigned to ibudilast and 126 to placebo. New or enlarging T2 lesions were observed in 37.2% on ibudilast and 29.0% on placebo (p = 0.82). New T1 hypointense lesions at 96 weeks were observed in 33.3% on ibudilast and 23.5% on placebo (p = 0.11). Gray matter atrophy was reduced by 35% for those on ibudilast vs placebo (p = 0.038). Progression of whole brain atrophy by SIENA was slowed by 20% in the ibudilast group compared with placebo (p = 0.08).ConclusionIbudilast treatment was associated with a reduction in gray matter atrophy. Ibudilast treatment was not associated with a reduction in new or enlarging T2 lesions or new T1 lesions. An effect on brain volume contributes to prior data that ibudilast appears to affect markers associated with neurodegenerative processes, but not inflammatory processes.Classification of EvidenceThis study provides Class II evidence that for people with MS, ibudilast does not significantly reduce new or enlarging T2 lesions or new T1 lesions.

ObjectiveTo use diffusion basis spectrum imaging (DBSI) to assess how damage to normal-appearing white matter (NAWM) in the corpus callosum (CC) influences neurologic impairment in people with MS (pwMS).MethodsUsing standard MRI, the primary pathologies in MS of axonal injury/loss, demyelination, and inflammation are not differentiated well. DBSI has been shown in animal models, phantoms, and in biopsied and autopsied human CNS tissues to distinguish these pathologies. Fifty-five pwMS (22 relapsing-remitting, 17 primary progressive, and 16 secondary progressive) and 13 healthy subjects underwent DBSI analyses of NAWM of the CC, the main WM tract connecting the cerebral hemispheres. Tract-based spatial statistics were used to minimize misalignment. Results were correlated with scores from a battery of clinical tests focused on deficits typical of MS.ResultsNormal-appearing CC in pwMS showed reduced fiber fraction and increased nonrestricted isotropic fraction, with the most extensive abnormalities in secondary progressive MS (SPMS). Reduced DBSI-derived fiber fraction and increased DBSI-derived nonrestricted isotropic fraction of the CC correlated with worse cognitive scores in pwMS. Increased nonrestricted isotropic fraction in the body of the CC correlated with impaired hand function in the SPMS cohort.ConclusionsDBSI fiber fraction and nonrestricted isotropic fraction were the most useful markers of injury in the NAWM CC. These 2 DBSI measures reflect axon loss in animal models. Because of its ability to reveal axonal loss, as well as demyelination, DBSI may be a useful outcome measure for trials of CNS reparative treatments.

Introduction Natalizumab en EID presente un moindre risque de leucoencephalopathie multifocale progressive qu’en SID. Les donnees en vie reelle de patients EID peuvent faciliter la determination du profil benefice–risque de l’EID. Objectifs Comparer l’efficacite du natalizumab en SID et en EID a l’aide de mesures quantitatives d’imagerie par resonance magnetique (IRM) a partir d’images en vie reelle hautement standardisees dans MS PATHS. Patients et methodes Un segment IRM est defini comme 2 acquisitions a duree d’intervalle associee. Les patients inclus avaient ≥ 1 segment, ≥ 2 cycles de perfusion (> 21 ≤ 84 jours) et information covariee complete. Les segments IRM avec un cycle moyen de perfusion (AIC) ≤ 35 jours et > 35 jours sont definis comme SID/EID, respectivement. Les nouvelles lesions T2, les variations du volume des lesions T2 (T2LV) et la fraction parenchymale cerebrale (BPF) ont ete comparees pour les segments IRM SID/EID. Resultats L’analyse portait sur 327 patients SID (596 segments) et 67 patients EID (85 segments). L’AIC moyen etait de 29,5 jours (ET : 1,8) en SID et 40,8 jours (4,9) en EID. La proportion de patients sans nouvelles lesions T2 etait semblable entre SID et EID (75,6 %/75,3 % ; p = 0,921). Aucune difference significative n’a ete montree entre groupe en variation ajustee de T2LV (−0,070 mL/0,022 mL ; p = 0,233) ou variation de BPF (−0,1222 %/−0,1442 % ; p = 0,617). Discussion/Conclusion L’activite IRM etait faible entre les deux groupes ; aucune difference significative dans les resultats d’IRM n’a ete montree. NOVA, essai de phase 3b, permettra d’approfondir sur l’efficacite de l’EID.

Aim: The objective of this Delphi analysis was to obtain consensus on injection-site reaction (ISR) experience and mitigation strategies for patients with relapsing-remitting multiple sclerosis switching from nonpegylated interferons (IFNs) to peginterferon β-1a in the ALLOW Phase IIIb trial using a three-step approach. Methods: Study investigators and coordinators from investigative sites enrolling four or more patients in ALLOW participated in three rounds of questionnaires and interviews. Results: Respondents (n = 37) agreed that the most common ISR, erythema, was not disruptive to daily activities. Patient education, as a conversation with a clinician about ISR potential, was recommended. Conclusion: The consensus of Delphi respondents on ISR experience and ISR management after switching from nonpegylated IFNs to peginterferon β-1a can help inform treatment decisions and manage patient expectations.

Visual dysfunction in MS can be quantified using a variety of tests. Many vision tests have not been formally evaluated among MS patients with existing visual dysfunction.Evaluate several versions of visual acuity and contrast sensitivity tests, measures of central and peripheral vision, retina structure, electrophysiologic function, and quality of life among MS patients with moderate/severe visual dysfunction.Cross-sectional study of 46 patients with stable, incompletely recovered optic neuritis. Testing included Snellen eye charts, several Sloan low contrast charts, Pelli Robson (PR) contrast sensitivity charts, optical coherence tomography, visual fields, Farnsworth Munsell 100-hue test, visual evoked potentials (VEP), and visual function quality of life (VFQ-25) testing.98% of eyes could read two lines of the PR chart, while only 43% read the 2.5% contrast chart. Low contrast tests correlated strongly with each other and with retinal nerve fiber layer (RNFL) thickness, visual fields, and color vision but not with VEPs. For patients with RNFL75µm, VFQ-25 scores dropped by approximately 2 points for every 1µm decrease in RNFL.Among MS patients with visual impairment due to optic neuritis, PR contrast sensitivity could be utilized as a single chart. Visual quality of life was associated with RNFL thinning below 75µm.

Background Antibodies to myelin oligodendrocyte glycoprotein (MOG) are associated with a CNS inflammatory disorder distinct from multiple sclerosis (MS) and aquaporin-4 antibody-positive neuromyelitis optica (NMO). Knowledge of the clinical spectrum of MOG antibody disease (MOGAD) remains incomplete, particularly in comparison to two related inflammatory demyelinating diseases, MS and NMO. Objective Compare demographics, clinical characteristics, estimated disability, laboratory results, and treatment responses of a U.S. MOGAD cohort with age- and sex-matched MS and NMO patients. Design, setting, and participants This observational, case-control, single-center study identified each group via ICD-10 diagnosis code searches through the electronic medical records of adult patients seen at the John L. Trotter MS Center between January 1, 2019 and January 1, 2020. MOGAD and NMO patients were confirmed to have at least one positive antibody test; those in the MS group had a confirmed diagnosis by a physician with MS subspecialty training. Data were collected after IRB approval. Results Twenty-six patients were included in each group. MOGAD patients were predominantly Caucasian (88.5%) with mean onset age of 43.9 years. MOGAD patients had no comorbid other autoimmune diseases and comparatively lower rates of family members with autoimmune disease (20.0%) than either MS (40.0%) or NMO (34.6%) matched cohorts. 91% of MOGAD attacks were monofocal, and over 70% presented with optic neuritis. Severity of MOGAD attacks was similar to that of seropositive NMO, but the robust degree of recovery was more similar to MS. Four MOGAD patients converted to negative antibody status, with no attacks occurring after conversion. Serum ANA and ENA were less frequently elevated in MOGAD (21.7%, 5.0%) than in seropositive NMO patients (66.7%, 42.9%). Elevated IgG synthesis rate and positive CSF-restricted oligoclonal bands were not seen in our MOGAD cohort, and only one MOGAD patient had an elevated IgG index. Despite anti-CD20 therapy, 28.6% of MOGAD patients continued to suffer relapses. Conclusions MOGAD was characterized by a predominantly monofocal presentation (typically optic neuritis) and severe attacks with better recovery than seen with seropositive NMO attacks. Lack of CSF-restricted oligoclonal bands distinguished MOGAD from MS.

Objective: Investigate the relationship between socioeconomic status (SES) and race with self-reported fatigue, depression, and anxiety levels in multiple sclerosis (MS). Methods: Cross-sectional review of the MS Partners Advancing Technology and Health Solutions (MS PATHS) database for adults with MS in the United States. We evaluated race and socioeconomic status (available markers: insurance, employment status, or level of education) as predictors of fatigue, depression, and anxiety sub-scores of the Neuro-QoL (Quality of life in neurological disorders), with particular interest between Caucasians/whites (CA) and African Americans/blacks (AA). Multivariate linear regression models included as covariates age, sex, disability status, smoking status, body mass index, and disease-modifying therapy. Results: 7,430 individuals were included; compared to CA, AA tended to be younger, more female-predominant, and had a higher level of disability. AA had completed slightly less education, had a higher level of Medicaid coverage or uninsured status, and had higher rates of unemployed or disabled status. In the univariate model, markers of lower SES, by whichever definition we used, correlated with worse affective symptoms. In the multivariate model stratified by race, CA showed similar trends. In contrast, in AA, only lower SES by employment status was correlated with worse affective symptoms. In both CA and AA, moderate and severe level of disability correlated with worse affective symptoms. Conclusion: SES and race may influence affective symptoms reported by individuals with MS. The reasons for the correlation are likely multifactorial. Longitudinal studies should strive to identify factors associated with risk of affective symptoms in MS that may be modifiable.

In vivo human optic nerve diffusion magnetic resonance imaging (dMRI) is technically challenging with two outstanding issues not yet well addressed: (i) non-linear optic nerve movement, independent of head motion, and (ii) effect from partial-volumed cerebrospinal fluid or interstitial fluid such as in edema. In this work, we developed a non-linear optic nerve registration algorithm for improved volume alignment in axial high resolution optic nerve dMRI. During eyes-closed dMRI data acquisition, optic nerve dMRI measurements by diffusion tensor imaging (DTI) with and without free water elimination (FWE), and by diffusion basis spectrum imaging (DBSI), as well as optic nerve motion, were characterized in healthy adults at various locations along the posterior-to-anterior dimension. Optic nerve DTI results showed consistent trends in microstructural parametric measurements along the posterior-to-anterior direction of the entire intraorbital optic nerve, while the anterior portion of the intraorbital optic nerve exhibited the largest spatial displacement. Multi-compartmental dMRI modeling, such as DTI with FWE or DBSI, was less subject to spatially dependent biases in diffusivity and anisotropy measurements in the optic nerve which corresponded to similar spatial distributions of the estimated fraction of isotropic diffusion components. DBSI results derived from our clinically feasible (∼10 min) optic nerve dMRI protocol in this study are consistent with those from small animal studies, which provides the basis for evaluating the utility of multi-compartmental dMRI modeling in characterizing coexisting pathophysiology in human optic neuropathies.

Barry Hendin,1 Robert T Naismith,2 Sibyl E Wray,3 Deren Huang,4 Qunming Dong,5 Terrie Livingston,6 Daniel L Jones,6 Crystal Watson,7 Mehul Jhaveri6 1Phoenix Neurological Associates, Phoenix, AZ, USA; 2Department of Neurology, Washington University School of Medicine, St Louis, MO, USA; 3Hope Neurology MS Center, Knoxville, TN, USA; 4Mount Carmel Neuroscience and MDH Research, Westerville, OH, USA; 5Biostatistics, Biogen, Cambridge, MA, USA; 6US Medical, Biogen, Cambridge, MA, USA; 7Global Value and Access, Biogen, Cambridge, MA, USA Objectives: Posthoc analysis of treatment satisfaction in patients switching to subcutaneous (SC) peginterferon beta-1a in the ALLOW study.Patients and methods: Patients with relapsing multiple sclerosis treated with intramuscular interferon (IFN) beta-1a or SC IFN beta-1a or beta-1b remained on their current therapy for a 4-week run-in period, followed by a switch to SC peginterferon beta-1a 125 mcg every 2 weeks for 48 weeks. Treatment satisfaction was measured using the Treatment Satisfaction Questionnaire for Medication (TSQM), which covers effectiveness, side effects, convenience, and global satisfaction. Patients completed the TSQM at baseline (prior to starting the 4-week run-in period) and 4, 12, 24, 36, and 48 weeks after switching, and scores were analyzed for the overall population and compared to baseline. Patients reported the severity of flu-like symptoms (FLS) at baseline and with each peginterferon beta-1a injection; clinicians evaluated the occurrence of injection-site reactions (ISRs) after the first dose of peginterferon beta-1a and every 12 weeks thereafter. TSQM scores were stratified by the presence of FLS or ISRs during the study period and by prior IFN therapy use.Results: For the overall population (n=194), convenience and global satisfaction scores significantly improved from baseline at all time points, and side effect satisfaction scores significantly improved up to week 36. Convenience scores significantly improved regardless of FLS, ISRs, or prior IFN therapy. Patients without FLS during the study period showed significant improvements in global satisfaction, but not side effect satisfaction, versus those with FLS. Patients switching from SC IFN therapies achieved greater improvements in treatment satisfaction than patients who switched from intramuscular IFN beta-1a.Conclusions: Switching relapsing multiple sclerosis patients to SC peginterferon beta-1a from other IFN therapies significantly improved treatment satisfaction and convenience. Keywords: interferon beta-1a, interferon beta-1b, peginterferon beta-1a, relapsing multiple sclerosis, treatmentsatisfaction, Treatment Satisfaction Questionnaire for Medication, TSQM, quality of life, patient-reported outcomes

Background Flu-like symptoms are common adverse events associated with interferon beta relapsing multiple sclerosis therapies. Objectives To evaluate the incidence and severity of flu-like symptoms after transitioning from non-pegylated interferons to peginterferon beta-1a and assess flu-like symptom mitigation using naproxen. Methods ALLOW was a phase 3b open-label study in relapsing multiple sclerosis patients. Patients had received non-pegylated interferon for 4 or more months immediately before beginning a 4-week screening period. At baseline, patients switched to peginterferon beta-1a and were randomly assigned (1:1) to continue their current flu-like symptoms management regimen or start twice-daily naproxen 500 mg for 8 weeks. Patients then switched to their preferred regimen and were followed for 48 weeks in total. Results Of 201 patients, 89.6% did not experience new/worsening flu-like symptoms during their first 8 weeks on peginterferon beta-1a. Flu-like symptom severity remained low in current-regimen and naproxen patients, with no significant between-group differences. Median flu-like symptom duration per injection was 3.2 hours longer with peginterferon beta-1a versus prior interferon, but the 4-week cumulative duration was reduced 49–78%. No new safety signals were identified. Conclusion Most patients who switched from non-pegylated interferon to peginterferon beta-1a did not experience new/worsening flu-like symptoms. Flu-like symptom duration per injection increased, but the cumulative duration significantly decreased. These data may inform flu-like symptom management guidance.

OBJECTIVE: Frequent administration of gadolinium-based contrast agents in multiple sclerosis (MS) may increase signal intensity (SI) unenhanced T1-weighted imaging MRI throughout the brain. We evaluated the association between lifetime cumulative doses of gadodiamide administration and increased SI within the dentate nucleus (DN), globus pallidus (GP), and thalamus in patients with early MS. METHODS: A total of 203 patients with MS (107 with baseline and follow-up MRI assessments) and 262 age- and sex-matched controls were included in this retrospective, longitudinal, 3T MRI-reader-blinded study. Patients with MS had disease duration

Evidence is needed to understand the effect of fingolimod on slowing down brain atrophy progression in multiple sclerosis (MS) patients in clinical practice. We investigated the effect of fingolimod on brain atrophy in MS patients with active disease (clinically and/or magnetic resonance imaging [MRI]) versus no evidence of active disease (NEAD).MS and clinical outcome and MRI in the United States (MS-MRIUS) is a multicenter, retrospective study that included 590 relapsing-remitting MS patients, who initiated fingolimod, and were followed for a median of 16 months. Patients with active disease at baseline (245, 41.5%) were defined as those who had one or more relapses in the year previous starting fingolimod, and/or displayed gadolinium enhancing lesions(s) at baseline MRI scan, whereas patients with NEAD at baseline (345, 58.5%) did not fulfill these criteria. Annualized percentage brain volume change (PBVC) and percentage lateral ventricle volume change (PLVVC) over the follow-up were analyzed in both groups.Over the follow-up, the rate of PBVC was -.38% in active disease and -.25% in NEAD patients (P = .076), whereas PLLVC was 1.76% in active disease and .28% in NEAD patients (P = .046). No changes in timed 25-foot walk (P = .619) and Expanded Disability Status Scale (P = .275) scores or MRI lesion accumulation (P0.08) were detected, although the active disease group had a higher proportion of relapses during the follow-up period (P = .02).The study provides real-world evidence that rate of brain atrophy in MS patients with underlying active disease and NEAD in fingolimod treated patients is below the established pathological cutoff for loss of whole brain volume (-.4%) or expansion of lateral ventricles (3.5%).

Axon injury/loss, demyelination and inflammation are the primary pathologies in multiple sclerosis lesions. Despite the prevailing notion that axon/neuron loss is the substrate of clinical progression of multiple sclerosis, the roles that these individual pathological processes play in multiple sclerosis progression remain to be defined. An imaging modality capable to effectively detect, differentiate and individually quantify axon injury/loss, demyelination and inflammation, would not only facilitate the understanding of the pathophysiology underlying multiple sclerosis progression, but also the assessment of treatments at the clinical trial and individual patient levels. In this report, the newly developed diffusion basis spectrum imaging was used to discriminate and quantify the underlying pathological components in multiple sclerosis white matter. Through the multiple-tensor modelling of diffusion weighted magnetic resonance imaging signals, diffusion basis spectrum imaging resolves inflammation-associated cellularity and vasogenic oedema in addition to accounting for partial volume effects resulting from cerebrospinal fluid contamination, and crossing fibres. Quantitative histological analysis of autopsied multiple sclerosis spinal cord specimens supported that diffusion basis spectrum imaging-determined cellularity, axon and myelin injury metrics closely correlated with those pathologies identified and quantified by conventional histological staining. We demonstrated in healthy control subjects that diffusion basis spectrum imaging rectified inaccurate assessments of diffusion properties of white matter tracts by diffusion tensor imaging in the presence of cerebrospinal fluid contamination and/or crossing fibres. In multiple sclerosis patients, we report that diffusion basis spectrum imaging quantitatively characterized the distinct pathologies underlying gadolinium-enhanced lesions, persistent black holes, non-enhanced lesions and non-black hole lesions, a task yet to be demonstrated by other neuroimaging approaches. Diffusion basis spectrum imaging-derived radial diffusivity (myelin integrity marker) and non-restricted isotropic diffusion fraction (oedema marker) correlated with magnetization transfer ratio, supporting previous reports that magnetization transfer ratio is sensitive not only to myelin integrity, but also to inflammation-associated oedema. Our results suggested that diffusion basis spectrum imaging-derived quantitative biomarkers are highly consistent with histology findings and hold promise to accurately characterize the heterogeneous white matter pathology in multiple sclerosis patients. Thus, diffusion basis spectrum imaging can potentially serve as a non-invasive outcome measure to assess treatment effects on the specific components of underlying pathology targeted by new multiple sclerosis therapies.