Brain atrophy has emerged as a clinically relevant component of disease progression in multiple sclerosis. Progressive loss of brain tissue bulk can be detected in vivo in a sensitive and ...reproducible manner by MRI. Clinical studies have shown that brain atrophy begins early in the disease course. The increasing amount of data linking brain atrophy to clinical impairments suggest that irreversible tissue destruction is an important determinant of disease progression to a greater extent than can be explained by conventional lesion assessments. In this review, we will summarise the proposed mechanisms contributing to brain atrophy in patients with multiple sclerosis. We will critically discuss the wide range of MRI-based methods used to quantify regional and whole-brain-volume loss. Based on a review of current information, we will summarise the rate of atrophy among phenotypes for multiple sclerosis, the clinical relevance of brain atrophy, and the effect of disease-modifying treatments on its progression.
The antiinflammatory small molecule ibudilast was tested in a phase 2 trial in patients with progressive multiple sclerosis. The rate of brain atrophy over 96 weeks was lower with ibudilast than with ...placebo. Side effects with ibudilast included GI symptoms and depression.
Patients with multiple sclerosis acquire disability either through: (1) Relapse-associated worsening (RAW), or (2) 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 MS (NO.MS) data pool spanning all multiple sclerosis phenotypes and pediatric multiple sclerosis, we evaluated ∼200,000 EDSS transitions from >27,000 patients with ≤15 years follow-up. We analyzed three datasets: (A) A full analysis dataset containing all observational and randomized controlled clinical trials in which disability and relapses were assessed (N = 27,328); (B) All phase 3 clinical trials (N = 8364); and (C) 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 (DMTs) on the time to reach milestone disability levels using time continuous Markov models. PIRA started early in multiple sclerosis, 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 (vs 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 DMTs delayed these times significantly by 3.51 years (95% confidence limit: 3.19, 3.96) and by 3.09 years (2.60, 3.72), respectively. In relapsing-remitting multiple sclerosis (RRMS), patients who worsened exclusively due to RAW events took a similar 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 relapses contribute to the accumulation of disability, primarily early in multiple sclerosis. PIRA starts already in RRMS 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. Using DMTs delays disability accrual by years, with the potential to gain time being highest in the earliest stages of multiple sclerosis.
...the meta-analysis confirms that the macular ganglion cell layer (GCL), home to the first-order sensory neurons of the visual pathway, the axons of which form the pRNFL, is prominently affected by ...multiple sclerosis. ...thickening of the inner nuclear layer is reported, which appears to be a consistent finding in multiple sclerosis and is thought to be related to inflammatory disease activity. ...this work highlights the power of collaborative efforts such as the International MS Visual System Consortium to accelerate discovery in neurological disease through the development of quality standards for data acquisition and reporting5,6 and creation of large datasets from which key insights are derived. 7 Control of both inflammatory and neurodegenerative aspects of multiple sclerosis pathophysiology will probably be required to effectively stop multiple sclerosis in its progressive stages.
Optical coherence tomography (OCT) has emerged as a fast, non-invasive, inexpensive, high-resolution imaging technique in multiple sclerosis (MS). Retinal layer quantification by OCT facilitates a ...‘window’ into not only local retinal pathology but also global neurodegenerative processes, recognised to be the principal substrates of disability accumulation in MS. While OCT measures in MS have been demonstrated to reflect visual function, inflammatory activity outside of the visual pathways, disability measures including the prediction of disability progression, whole brain atrophy, and the differential neuroprotective effects of disease-modifying therapies, debate continues regarding the clinical utility of OCT in everyday practice. This review presents an overview of the evidence supporting OCT, with particular focus on its application in the MS clinic. We will also discuss the role of OCT in MS clinical trials to develop novel neuroprotective and potential remyelinating therapies.
Objective:
To identify early predictors of long‐term outcomes in patients with relapsing–remitting multiple sclerosis (RRMS) treated with intramuscular (IM) interferon beta‐1a (IFNβ‐1a).
Methods:
A ...multicenter, observational, 15‐year follow‐up study of patients who completed ≥2 years in the pivotal trial of IM IFNβ‐1a for RRMS was conducted. One hundred thirty‐six patients participated in the 15‐year follow‐up (69 originally randomized to IM IFNβ‐1a and 67 to placebo). After the 2‐year clinical trial, treatment was not regulated by study protocol. Disease activity during the 2‐year trial was defined as: ≥2 gadolinium‐enhancing lesions (cumulative) on year 1 and/or year 2 magnetic resonance imaging (MRI); ≥3 new T2 lesions on year 2 MRI compared to baseline; and ≥2 relapses over 2 years. Odds ratios were calculated for early disease activity predicting severe Expanded Disability Status Scale (EDSS) worsening (worst quartile of change, ≥4.5 EDSS points) during the 15‐year interval.
Results:
The proportion of patients experiencing early disease activity was lower in patients on IM IFNβ‐1a than placebo for all disease activity markers (range, 23.5–29.0% vs 41.0–45.5%). In the IM IFNβ‐1a group, persistent disease activity predicted severe EDSS worsening: gadolinium‐enhancing lesions (odds ratio OR, 8.96; p < 0.001); relapses (OR, 4.44; p = 0.010); and new T2 lesions (OR, 2.90; p = 0.080). In placebo patients, early disease activity was not as strongly associated with long‐term outcomes (OR range, 1.53–2.62; p = 0.069–0.408).
Interpretation:
Disease activity despite treatment with IFNβ is associated with unfavorable long‐term outcomes. Particular attention should be paid to gadolinium‐enhancing lesions on IFNβ therapy, as their presence strongly correlates with severe disability 15 years later. The results provide rationale for monitoring IFNβ‐treated patients with MRI, and for changing therapy in patients with active disease. ANN NEUROL 2013.
Background:
Cognitive dysfunction is common in multiple sclerosis (MS) patients and has important consequences for daily activities, yet, unlike motor function, is not routinely assessed in the ...clinic setting. We developed the Processing Speed Test (PST), a self-administered iPad®-based tool to measure MS-related deficits in processing speed.
Objective:
To determine whether the PST is valid for screening cognitive dysfunction by comparing it to the paper-and-pencil Symbol Digit Modalities Test (SDMT).
Methods:
We assessed PST test–retest reliability, sensitivity of PST and SDMT in discriminating MS patients from healthy controls (HC), convergent validity between PST and SDMT, correlations between T2 lesion load and PST and SDMT, and PST performance with and without technician present during administration.
Results:
PST had excellent test–retest reliability, was highly correlated with SDMT, was slightly more sensitive than SDMT in discriminating MS from HC groups, and correlated better with cerebral T2 lesion load than did SDMT. Finally, PST performance was no different with or without a technician in the testing environment.
Conclusion:
PST has advantages over SDMT because of its efficient administration, scoring, and potential for medical record or research database integration. PST is a practical tool for routine screening of processing speed deficits in the MS clinic.
The C-type lectin receptor Mincle is known for its important role in innate immune cells in recognizing pathogen and damage associated molecular patterns. Here we report a T cell-intrinsic role for ...Mincle in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). Genomic deletion of Mincle in T cells impairs TH17, but not TH1 cell-mediated EAE, in alignment with significantly higher expression of Mincle in TH17 cells than in TH1 cells. Mechanistically, dying cells release β-glucosylceramide during inflammation, which serves as natural ligand for Mincle. Ligand engagement induces activation of the ASC-NLRP3 inflammasome, which leads to Caspase8-dependent IL-1β production and consequentially TH17 cell proliferation via an autocrine regulatory loop. Chemical inhibition of β-glucosylceramide synthesis greatly reduces inflammatory CD4+ T cells in the central nervous system and inhibits EAE progression in mice. Taken together, this study indicates that sensing of danger signals by Mincle on TH17 cells plays a critical role in promoting CNS inflammation.
Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is the first example of a learning health system in multiple sclerosis (MS). This paper describes the initial ...implementation of MS PATHS and initial patient characteristics.
MS PATHS is an ongoing initiative conducted in 10 healthcare institutions in three countries, each contributing standardized information acquired during routine care. Institutional participation required the following: active MS patient census of ≥500, at least one Siemens 3T magnetic resonance imaging scanner, and willingness to standardize patient assessments, share standardized data for research, and offer universal enrolment to capture a representative sample. The eligible participants have diagnosis of MS, including clinically isolated syndrome, and consent for sharing pseudonymized data for research. MS PATHS incorporates a self-administered patient assessment tool, the Multiple Sclerosis Performance Test, to collect a structured history, patient-reported outcomes, and quantitative testing of cognition, vision, dexterity, and walking speed. Brain magnetic resonance imaging is acquired using standardized acquisition sequences on Siemens 3T scanners. Quantitative measures of brain volume and lesion load are obtained. Using a separate consent, the patients contribute DNA, RNA, and serum for future research. The clinicians retain complete autonomy in using MS PATHS data in patient care. A shared governance model ensures transparent data and sample access for research.
As of August 5, 2019, MS PATHS enrolment included participants (
= 16,568) with broad ranges of disease subtypes, duration, and severity. Overall, 14,643 (88.4%) participants contributed data at one or more time points. The average patient contributed 15.6 person-months of follow-up (95% CI: 15.5-15.8); overall, 166,158 person-months of follow-up have been accumulated. Those with relapsing-remitting MS demonstrated more demographic heterogeneity than the participants in six randomized phase 3 MS treatment trials. Across sites, a significant variation was observed in the follow-up frequency and the patterns of disease-modifying therapy use.
Through digital health technology, it is feasible to collect standardized, quantitative, and interpretable data from each patient in busy MS practices, facilitating the merger of research and patient care. This approach holds promise for data-driven clinical decisions and accelerated systematic learning.
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