Multiple Sclerosis Functional Composite Score Research Articles

The effect of ibudilast on thalamic volume in progressive multiple sclerosis

Background: Thalamic volume loss is known to be associated with clinical and cognitive disability in progressive multiple sclerosis (PMS). Objective: To investigate the treatment effect of ibudilast on thalamic atrophy more than 96 weeks in the phase 2 trial in progressive(MS Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis [SPRINT-MS]). Methods: A total of 231 participants were randomized to either ibudilast (n = 114) or placebo (n = 117). Thalamic volume change was computed using Bayesian Sequence Adaptive Multimodal Segmentation tool (SAMseg) incorporating T1, fluid-attenuated inversion recovery (FLAIR), and fractional anisotropy maps and analyzed with a mixed-effects repeated-measures model. Results: There was no significant difference in thalamic volumes between treatment groups. On exploratory analysis, participants with primary progressive multiple sclerosis (PPMS) on placebo had a 0.004% greater rate of thalamic atrophy than PPMS participants on ibudilast (p = 0.058, 95% confidence interval (CI) = −0.008 to <0.001). Greater reductions in thalamic volumes at more than 96 weeks were associated with worsening multiple sclerosis functional composite (MSFC-4) scores (p = 0.002) and worsening performance on the symbol digit modality test (SDMT) (p < 0.001). Conclusion: In a phase 2 trial evaluating ibudilast in PMS, no treatment effect was demonstrated in preventing thalamic atrophy. Participants with PPMS exhibited a treatment effect that trended toward significance. Longitudinal changes in thalamic volume were related to worsening of physical and cognitive disability, highlighting this outcome’s clinical importance.

Diet-induced changes in functional disability are mediated by fatigue in relapsing-remitting multiple sclerosis: A secondary analysis of the WAVES randomized parallel-arm trial.

People with multiple sclerosis (MS) often report dietary modifications; however, evidence on functional outcomes remains sparse. Evaluate the impact of the low-saturated fat (Swank) and modified Paleolithic elimination (Wahls) diets on functional disability among people with relapsing-remitting MS. Baseline-referenced MS functional composite (MSFC) scores were calculated from nine-hole peg-test (NHPT), timed 25-foot walk, and oral symbol digit modalities test (SDMT-O) collected at four study visits: (a) run-in, (b) baseline, (c) 12 weeks, and (d) 24 weeks. Participants were observed at run-in and then randomized at baseline to either the Swank (n = 44) or Wahls (n = 43) diets. Among the Swank group, MSFC scores significantly increased from -0.13 ± 0.14 at baseline to 0.10 ± 0.11 at 12 weeks (p = 0.04) and 0.14 ± 0.11 at 24 weeks (p = 0.02). Among the Wahls group, no change in MSFC scores was observed at 12 weeks from 0.10 ± 0.11 at baseline but increased to 0.28 ± 0.13 at 24 weeks (p = 0.002). In both groups, NHPT and SDMT-O z-scores increased at 24 weeks. Changes in MSFC and NHPT were mediated by fatigue. Both diets reduced functional disability as mediated by fatigue. Clinicaltrials.gov Identifier: NCT02914964.

Multimodal MRI study on the relation between WM integrity and connected GM atrophy and its effect on disability in early multiple sclerosis

BackgroundMultiple sclerosis (MS) is characterized by pathology in white matter (WM) and atrophy of grey matter (GM), but it remains unclear how these processes are related, or how they influence clinical progression.ObjectiveTo study the spatial and temporal relationship between GM atrophy and damage in connected WM in relapsing–remitting (RR) MS in relation to clinical progression.MethodsHealthy control (HC) and early RRMS subjects visited our center twice with a 1-year interval for MRI and clinical examinations, including the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores. RRMS subjects were categorized as MSFC decliners or non-decliners based on ΔMSFC over time. Ten deep (D)GM and 62 cortical (C) GM structures were segmented and probabilistic tractography was performed to identify the connected WM. WM integrity was determined per tract with, amongst others, fractional anisotropy (FA), mean diffusivity (MD), neurite density index (NDI), and myelin water fraction (MWF). Linear mixed models (LMMs) were used to investigate GM and WM differences between HC and RRMS, and between MSFC decliners and non-decliners. LMM was also used to test associations between baseline WM z-scores and changes in connected GM z-scores, and between baseline GM z-scores and changes in connected WM z-scores, in HC/RRMS subjects and in MSFC decliners/non-decliners.ResultsWe included 13 HCs and 31 RRMS subjects with an average disease duration of 3.5 years and a median EDSS of 3.0. Fifteen RRMS subjects showed declining MSFC scores over time, and they showed higher atrophy rates and greater WM integrity loss compared to non-decliners. Lower baseline WM integrity was associated with increased CGM atrophy over time in RRMS, but not in HC subjects. This effect was only seen in MSFC decliners, especially when an extended WM z-score was used, which included FA, MD, NDI and MWF. Baseline GM measures were not significantly related to WM integrity changes over time in any of the groups.DiscussionLower baseline WM integrity was related to more cortical atrophy in RRMS subjects that showed clinical progression over a 1-year follow-up, while baseline GM did not affect WM integrity changes over time. WM damage, therefore, seems to drive atrophy more than conversely.

Ublituximab Efficacy in Treatment-Naive Participants With Relapsing Multiple Sclerosis in the Phase 3 ULTIMATE I and II Studies (P6-3.015)

Ublituximab Efficacy in Treatment-Naive Participants With Relapsing Multiple Sclerosis in the Phase 3 ULTIMATE I and II Studies (P6-3.015)

Application of Rasch Analysis for Measurement of Disability in Multiple Sclerosis (P9-3.018)

<h3>Objective:</h3> To use Rasch analysis to create a linear, validated scale of patient-reported outcomes to measure disability in multiple sclerosis (MS). <h3>Background:</h3> Measuring disability progression in MS is vital to patient management and clinical research. The gold-standard in MS is the Expanded Disability Status Scale (EDSS). However, it has significant limitations. Patient-reported outcomes (PROs) are a promising additional measurement of MS disability progression. Data on validity are lacking. We aim to create a linear, validated scale measuring MS disability by analyzing patient responses to a preliminary PRO using Rasch analysis. We compare our findings to the EDSS and MS functional composite (MSFC). <h3>Design/Methods:</h3> Participants aged 18 – 65 with all MS subtypes are recruited from the Atlanta VA and Emory MS Clinics. A preliminary questionnaire with 140 questions, EDSS, and MSFC are administered. Participants complete a post-visit questionnaire within 7 days for test-retest reliability. Rasch analysis will be performed on questionnaire data and items will be removed based on fit. Correlational analyses with EDSS and MSFC are performed. We will recruit 250 participants. <h3>Results:</h3> 44 participants have completed the preliminary questionnaire. The mean (SD) age is 50.1 (10.2) with 68.2% females and 31.8% males. 54.6% of participants self-identified as black, 43.2% white and 2.3% mixed. 50% receive anti-CD20 therapy. Median EDSS score is 3.75 with a range of 1.0–7.0 and mean MSFC score is −1.75 (2.7). Total questionnaire score correlated moderately with EDSS (r=0.69) and less with MSFC (r=−0.34). Test-retest reliability studies strongly correlate (n=27, r= 0.95). Rasch analysis data will follow. <h3>Conclusions:</h3> Our sample represents a wide range of demographics, disability, and treatments and is similar to published MS cohorts. Preliminary analysis demonstrated good construct validity compared to EDSS and reliable test-retest. This linear scale may aid in monitoring disability progression in MS patients. <b>Disclosure:</b> Ms. Azad has nothing to disclose. Dr. Tarr has nothing to disclose. Dr. Fournier has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Journals. The institution of Dr. Fournier has received research support from Veterans Affairs. The institution of Dr. Fournier has received research support from Department of Defense. The institution of Dr. Fournier has received research support from Amylyx. The institution of Dr. Fournier has received research support from Biogen. The institution of Dr. Fournier has received research support from MT Pharma. The institution of Dr. Tyor has received research support from NIH. The institution of Dr. Tyor has received research support from VHA. The institution of Dr. Tyor has received research support from NIH. The institution of Dr. Tyor has received research support from VHA. The institution of Dr. Tyor has received research support from NIH.

Improvement in the multiple sclerosis functional composite score by multi-function swing suspension training program

BackgroundPhysical activity has been considered as a promising approach to slow down the disease process in Multiple Sclerosis (MS) patients. The functional impairments of MS have been studied in detail, while evidence of the efficacy of exercise training interventions on the Multiple Sclerosis functional composite (MSFC) score in these patients is limited. The aim of this study was to investigate the improvement in MSFC score by multi-function swing suspension training program (MFSST) in the women with MS. MethodsThe patients were divided into two groups as the intervention and control groups. A total of 47 MS patients completed the MSFC components at baseline and after the intervention: the timed 25-foot walk (T25FW); the 9-hole peg test (9HPT); and paced auditory serial addition test (PASAT). Z scores were created for each test based on control means. ResultsThe MSFC score, 9HPT, T25FW, and PASAT showed a significant increment in comparison with the baseline levels in the four, six, and eight weeks following the first exercise session (all p<0.05). These differences in the control group were not significant. The improvement in the MSFC score and the component Z-scores in the intervention groups was found from the fourth week onwards. ConclusionsThe study findings highlight that the progression of MS disability can be partially compensated by physical exercise. Overall, these results indicate that MFSST can be used as an effective treatment method in patients suffering from MS. Longer (years) exercise studies with larger samples of MS patients, with different MS subtypes, and of different sex, are needed to evaluate the effect of other types of exercise interventions on the MSFC score in MS patients with different disabilities.

Immunotherapy for people with clinically isolated syndrome or relapsing-remitting multiple sclerosis: treatment response by demographic, clinical, and biomarker subgroups (PROMISE)—a systematic review protocol

BackgroundMultiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system with an increasing worldwide prevalence. Since 1993, more than 15 disease-modifying immunotherapies (DMTs) have been licenced and have shown moderate efficacy in clinical trials. Based on the heterogeneity of the disease and the partial effectiveness of therapies, a personalised medicine approach would be valuable taking individual prognosis and suitability of a chosen therapy into account to gain the best possible treatment effect.The primary objective of this review is to assess the differential treatment effects of all approved DMTs in subgroups of adults with clinically isolated syndrome or relapsing forms of MS. We will analyse possible treatment effect modifiers (TEM) defined by baseline demographic characteristics (gender, age), and diagnostic (i.e. MRI measures) and clinical (i.e. relapses, disability level) measures of MS disease activity.MethodsWe will include all published and accessible unpublished primary and secondary analyses of randomised controlled trials (RCTs) with a follow-up of at least 12 months investigating the efficacy of at least one approved DMT, with placebo or other approved DMTs as control intervention(s) in subgroups of trial participants. As the primary outcome, we will address disability as defined by the Expanded Disability Status Scale or multiple sclerosis functional composite scores followed by relapse frequency, quality of life measures, and side effects. MRI data will be analysed as secondary outcomes.MEDLINE, EMBASE, CINAHL, LILACS, CENTRAL and major trial registers will be searched for suitable studies. Titles and abstracts and full texts will be screened by two persons independently using Covidence. The risk of bias will be analysed based on the Cochrane “Risk of Bias 2” tool, and the certainty of evidence will be assessed using GRADE.Treatment effects will be reported as rate ratio or odds ratio. Primary analyses will follow the intention-to-treat principle. Meta-analyses will be carried out using random-effects models.DiscussionGiven that individual patient data from clinical studies are often not available, the review will allow to analyse the evidence on TEM in MS immunotherapy and thus support clinical decision making in individual cases.Systematic review registrationPROSPERO CRD42021279665.

Effects of Vibration Training on Cognition and Quality of Life in Individuals With Multiple Sclerosis.

Multiple sclerosis (MS) detrimentally affects cognition and quality of life (QOL). Interventions that can improve cognitive deficit and QOL in individuals with MS are desired. This pilot study investigated the possible effects of vibration training on improving cognition and QOL in individuals with MS. Eighteen adults with MS were randomized into 2 groups: training and control. The training group underwent 6 weeks of vibration training, and the control group maintained their normal lifestyle throughout the study. In both groups, before and after the training course, the disability status was evaluated by the Patient Determined Disease Steps scale and the Multiple Sclerosis Functional Composite (MSFC), cognitive function was assessed by the Behavior Rating Inventory of Executive Function-Adults (BRIEF-A) and the Buschke Selective Reminding Test (SRT), and QOL was gauged by the 36-item Short Form Health Survey (SF-36). The training was well accepted by the participants, and no major adverse event was reported. All participants finished the entire protocol. Compared with the control group, the training group showed greater improvements in MSFC score, Metacognition Index score of the BRIEF, SRT score, and physical domain score of the SF-36. These results suggest that vibration training could be an effective alternative training paradigm to enhance cognition and QOL in individuals with MS, and they provide an encouraging base to conduct a large-scale clinical trial.

Efficacy and safety of Kinezia (fampridine) in the complex therapy of multiple sclerosis

To analyze the efficacy and safety of fampridine** (Valenta Pharm, Russia) in the complex therapy of multiple sclerosis (MS). One hundred and twenty-six patients with MS were double blind randomized to receive fampridine (n=60) or placebo (n=66). Fampridine was administered in prolonged-release form (film-coated tablets, 10 mg) at a dose of 10 mg (1 tablet) 2 times a day, for 24 weeks. The placebo group was treated in the same way. From the 12th week, all patients in the placebo group were transferred to therapy with fampridine, 10 mg 2 times a day, for another 12 weeks. Concomitant standard therapy for MS was allowed in both groups (concomitant disease-modifying medications and other treatment). The primary outcome in the study was the proportion of patients with reduced t25fw test time (determining walking speed on a 25-foot path) on at least two out of three visits compared to baseline. The mean change in Multiple Sclerosis Functional Composite (MSFC) scores from baseline was assessed at visits 4-7 (8-24 weeks). The proportion of patients with reduced t25fw test time compared to the baseline level was 31.7% in the fampridine group, which is higher than in the placebo group - 3.0% (p<0.001). The overall result of the Multiple Sclerosis Functional Composite (MSFC) reflected a gradual improvement in the patient's condition during treatment period. The dynamics of MSFC result relative to the baseline level significantly differed (p<0.05) between the fampridine and placebo groups in favor of the fampridine group during all treatment periods. In the fampridine group, adverse events (AE) associated with disorders of the nervous system were more common: headache, dizziness, and coordination disorders. Fampridine improves walking performance in MS patients. The Russian product fampridine has demonstrated a favorable safety profile.

Machine learning in secondary progressive multiple sclerosis: an improved predictive model for short-term disability progression.

BackgroundEnhanced prediction of progression in secondary progressive multiple sclerosis (SPMS) could improve clinical trial design. Machine learning (ML) algorithms are methods for training predictive models with minimal human intervention.ObjectiveTo evaluate individual and ensemble model performance built using decision tree (DT)-based algorithms compared to logistic regression (LR) and support vector machines (SVMs) for predicting SPMS disability progression.MethodsSPMS participants (n = 485) enrolled in a 2-year placebo-controlled (negative) trial assessing the efficacy of MBP8298 were classified as progressors if a 6-month sustained increase in Expanded Disability Status Scale (EDSS) (≥1.0 or ≥0.5 for a baseline of ≤5.5 or ≥6.0 respectively) was observed. Variables included EDSS, Multiple Sclerosis Functional Composite component scores, T2 lesion volume, brain parenchymal fraction, disease duration, age, and sex. Area under the receiver operating characteristic curve (AUC) was the primary outcome for model evaluation.ResultsThree DT-based models had greater AUCs (61.8%, 60.7%, and 60.2%) than independent and ensemble SVM (52.4% and 51.0%) and LR (49.5% and 51.1%).ConclusionSPMS disability progression was best predicted by non-parametric ML. If confirmed, ML could select those with highest progression risk for inclusion in SPMS trial cohorts and reduce the number of low-risk individuals exposed to experimental therapies.

Alterations in the retinal vasculature occur in multiple sclerosis and exhibit novel correlations with disability and visual function measures

Background: The retinal vasculature may be altered in multiple sclerosis (MS), potentially acting as a biomarker of disease processes. Objective: To compare retinal vascular plexus densities in people with MS (PwMS) and healthy controls (HCs), and examine correlations with visual function and global disability. Methods: In this cross-sectional study, 111 PwMS (201 eyes) and 50 HCs (97 eyes) underwent optical coherence tomography angiography (OCTA). Macular superficial vascular plexus (SVP) and deep vascular plexus (DVP) densities were quantified, and poor quality images were excluded according to an artifact-rating protocol. Results: Mean SVP density was 24.1% (SD = 5.5) in MS eyes (26.0% (SD = 4.7) in non-optic neuritis (ON) eyes vs. 21.7% (SD = 5.5) in ON eyes, p < 0.001), as compared to 29.2% (SD = 3.3) in HC eyes (p < 0.001 for all MS eyes and multiple sclerosis optic neuritis (MSON) eyes vs. HC eyes, p = 0.03 for MS non-ON eyes vs. HC eyes). DVP density did not differ between groups. In PwMS, lower SVP density was associated with higher levels of disability (expanded disability status scale (EDSS): R2 = 0.26, p = 0.004; multiple sclerosis functional composite (MSFC): R2 = 0.27, p = 0.03) and lower letter acuity scores (100% contrast: R2 = 0.29; 2.5% contrast: R2 = 0.40; 1.25% contrast: R2 = 0.31; p < 0.001 for all). Conclusions: Retinal SVP density measured by OCTA is reduced across MS eyes, and correlates with visual function, EDSS, and MSFC scores.

Ballroom dance for persons with multiple sclerosis: a pilot feasibility study

Purpose: The purpose of this study was to evaluate the exercise intensity and feasibility of recreational ballroom dance for persons with multiple sclerosis (MS).Methods: Seven persons with MS participated in 2 one-hour dance sessions per week for 6 weeks. Dance types included rumba, foxtrot, waltz, and push-pull. Six other persons with MS comprised a control group that did not dance. Heart rate and ratings of perceived exertion (RPE) were monitored during the sessions. Outcomes included: quality of life, fatigue, depression, self-efficacy, timed up and go, Berg Balance Scale, Dynamic Gait Index and the Multiple Sclerosis Functional Composite comprising 9-hole peg test, 25-ft walk test, and Paced Auditory Serial Addition Test (PASAT), a cognitive test.Results: Heart rates and RPE indicated that ballroom dance for persons with MS can provide a light to moderate exercise intensity. After the dance program, quality of life and PASAT improved as did the MS Functional Composite Score. No changes were noted in the control group.Conclusions: Recreational ballroom dance is feasible and can provide an exercise stimulus sufficient to help meet exercise recommendations for persons with multiple sclerosis as well as improve quality of life and cognition in persons with MS.Implications for rehabilitationExercise or physical activity is important for the health and wellness of persons with multiple sclerosis.Persons with multiple sclerosis often seek information about non-traditional low-impact physical activity.In a small controlled sample, partnered recreational ballroom or social dance for persons with multiple sclerosis has been shown to be feasible and of recommended exercise intensity.Further, partnered recreational ballroom dance for persons with multiple sclerosis can improve measures of quality of life and cognitive function.

Disruption of neurite morphology parallels MS progression.

ObjectivesTo apply advanced diffusion MRI methods to the study of normal-appearing brain tissue in MS and examine their correlation with measures of clinical disability.MethodsA multi-compartment model of diffusion MRI called neurite orientation dispersion and density imaging (NODDI) was used to study 20 patients with relapsing-remitting MS (RRMS), 15 with secondary progressive MS (SPMS), and 20 healthy controls. Maps of NODDI were analyzed voxel-wise to assess the presence of abnormalities within the normal-appearing brain tissue and the association with disease severity. Standard diffusion tensor imaging (DTI) parameters were also computed for comparing the 2 techniques.ResultsPatients with MS showed reduced neurite density index (NDI) and increased orientation dispersion index (ODI) compared with controls in several brain areas (p < 0.05), with patients with SPMS having more widespread abnormalities. DTI indices were also sensitive to some changes. In addition, patients with SPMS showed reduced ODI in the thalamus and caudate nucleus. These abnormalities were associated with scores of disease severity (p < 0.05). The association with the MS functional composite score was higher in patients with SPMS compared with patients with RRMS.ConclusionsNODDI and DTI findings are largely overlapping. Nevertheless, NODDI helps interpret previous findings of increased anisotropy in the thalamus of patients with MS and are consistent with the degeneration of selective axon populations.

Heart rate variability analysis in patients with multiple sclerosis

BackgroundMultiple sclerosis can cause cardiovascular autonomic dysfunction. It is assumed that is caused by multiple demyelinating plaques localized in the brain stem and spinal cord. Previous studies have determined this using tilt table test, heart rate responses to Valsalva maneuver and deep breathing and heart rate variability analysis with 24 h Holter monitoring. However there is not a consensus regarding the presence of the relationship between autonomic dysfunction and severity of multiple sclerosis, type of multiple sclerosis and expanded disability status scale.The aim of the study is comparison of heart rate variability between recently diagnosed patients with relapsing-remitting multiple sclerosis and healthy controls by using 24 h Holter monitoring. Also we intended to investigate relationship between Expanded Disability Status Scale score, Multiple Sclerosis Functional Composite scores and cranial and spinal magnetic resonance imaging findings and hearth rate variability. MethodFifty-one patients with newly diagnosed relapsing-remitting multiple sclerosis and 44 age- and sex-matched healthy controls were compared in this study. Patients with multiple sclerosis, who were already under immunomodulatory or immunosuppressive treatment, were excluded from the study. Echocardiography and hearth rate variability analysis using 24 h period Holter monitoring were performed in all of the subjects. Echocardiography was used to detect the presence of cardiac pathology. One multiple sclerosis patient with right ventricular dilatation and mobile intratrial septum was excluded from the study. All the patients underwent cranial and cervical spinal magnetic resonance imaging to determine the relationship between autonomic abnormalities and magnetic resonance imaging. ResultsOur results showed that hearth rate variability values were significantly lower in patients with multiple sclerosis when compared with healthy controls: SDNN index (the mean of all the 5 min standard deviations of normal RR intervals during the 24 h period) (59.80 ± 17.33 vs. 67.20 ± 21.28, p = 0,044), the root-mean-square successive difference (rMSSD) (34.40 ± 17.50 vs. 38.25 ± 12.95, p = 0,042), spectral hearth rat variability total power (3738.84 ± 2085.51 vs. 4427.44 ± 1965.71, p = 0,037), spectral hearth rate variability low frequency (852.03 ± 450.54 vs. 1011.75 ± 370.06, p = 0,018). Ten patients (20%) had brainstem lesion, 25 patients (50%) had cervical lesions and 10 patients (20%) had thoracic spinal lesions on magnetic resonance imaging. There was no significant relationship between location of the lesions and heart rate variability analyses. Also there was no significant relationship between hearth rate variability values and Expanded Disability Status Scale score, Multiple Sclerosis Functional Composite scores or number of multiple sclerosis attack (p > 0,05). ConclusionThese findings reveals that our study population with multiple sclerosis had decreased heart rate variability compared to healthy controls. This was reflected by dysfunction of both parasympathetic and sympathetic parameters of hearth rate variability analysis. However, there is no significant relationship between hearth rate variability analysis and the findings on cranial, cervical, thoracic spinal magnetic resonance imaging findings, number of attack, Expanded Disability Status Scale score or Multiple Sclerosis Functional Composite scores in patients with multiple sclerosis.

Disability Outcome Measures in Phase III Clinical Trials in Multiple Sclerosis.

Accumulating neurological disability has a substantial impact on the lives of patients with multiple sclerosis (MS). As well as the established Expanded Disability Status Scale (EDSS), several other outcome measures are now available for assessing disability progression in MS. This review extends the findings of a previous analysis of relapsing-remitting MS (RRMS) trials published up to 2012, to determine whether there has been a shift in outcome measures used to assess disability in phase III clinical trials in RRMS and progressive MS. Forty relevant trials were identified (RRMS, n = 16; progressive MS, n = 18; other/mixed phenotypes, n = 6). Sustained EDSS worsening, particularly over 3 months, was included as an endpoint in almost all identified trials. Other disability-related endpoints included the Multiple Sclerosis Functional Composite z-score and scores for the physical component summary of the Multiple Sclerosis Impact Scale and Medical Outcomes Study Short-Form (36-item) Health Survey. Tests assessing manual dexterity, ambulation, vision and cognition were also employed, and in some trials, composite endpoints were used. However, there was no obvious trend in choice of disability outcome measures over time. Sustained EDSS worsening over short time periods continues to be the most widely used measure of disability progression in pivotal MS trials, despite its well-recognised limitations. A new tool set is needed for use in MS clinical trials that detects the benefit of potential treatments that slow (or reverse) progressive disability.Electronic supplementary materialThe online version of this article (10.1007/s40263-018-0530-8) contains supplementary material, which is available to authorized users.

Long-term follow-up of a randomized study of combination interferon and glatiramer acetate in multiple sclerosis: Efficacy and safety results up to 7 years

BackgroundTo report the long-term results of the blinded extension phase of the randomized, controlled study of the combined use of interferon beta-1a (IFN) 30μg IM weekly and glatiramer acetate (GA) 20mg daily compared to each agent alone in relapsing-remitting multiple sclerosis (RRMS). Methods1008 RRMS patients were followed on protocol until the last participant enrolled completed 3 years, allowing some subjects to be followed for up to 7 years. The primary endpoint was reduction in annualized relapse rate. Secondary outcomes included time to confirmed disability, Multiple Sclerosis Functional Composite (MSFC) score and MRI metrics. ResultsSimilar to the core study, combination IFN + GA was not superior to the better of the single agents (GA) in risk of relapse. Both the combination therapy and GA were significantly better than IFN in reducing the risk of relapse. The combination was not better than either agent alone in lessening confirmed EDSS worsening or change in MSFC. Also similar to the core result, the combination was superior to either agent alone in reducing new lesion activity, but the 3 year MRI result did not presage a clinical benefit over the extended observation interval. ConclusionCombining GA & IFN did not produce a significant clinical benefit over the entire study duration. The earlier effect on reducing MRI activity did not result in a later clinical advantage. The combination showed a sustained advantage in reducing disease activity free status.

Can resistance training impact MRI outcomes in relapsing-remitting multiple sclerosis?

Background: Multiple sclerosis (MS) is characterised by accelerated brain atrophy, which relates to disease progression. Previous research shows that progressive resistance training (PRT) can counteract brain atrophy in other populations. Objective: To evaluate the effects of PRT by magnetic resonance imaging (MRI) and clinical measures of disease progression in people with MS. Methods: This study was a 24-week randomised controlled cross-over trial, including a Training (n = 18, 24 weeks of PRT followed by self-guided physical activity) and Waitlist group (n = 17, 24 weeks of habitual lifestyle followed by PRT). Assessments included disability measures and MRI (lesion load, global brain volume, percentage brain volume change (PBVC) and cortical thickness). Results: While the MS Functional Composite score improved, Expanded Disability Status Scale, lesion load and global brain volumes did not differ between groups. PBVC tended to differ between groups and higher absolute cortical thickness values were observed in 19 of 74 investigated cortical regions after PRT. Observed changes were confirmed and reproduced when comparing relative cortical thickness changes between groups for four areas: anterior cingulate gyrus, temporal pole, orbital sulcus and inferior temporal sulcus. Conclusion: PRT seem to induce an increase in cortical thickness, indicating that PRT have a neuroprotective or even neuroregenerative effect in relapsing-remitting MS.

Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis

BackgroundB cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells.MethodsIn 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.ResultsThe 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.ConclusionsAmong 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.)

Hypoperfusion of the thalamus is associated with disability in relapsing remitting multiple sclerosis

While gray matter (GM) perfusion abnormalities have been evidenced in multiple sclerosis (MS) patients, the relationships with disability still remain unclear. Considering that atrophy is known to impact on perfusion, we aimed to assess perfusion abnormalities in GM of MS patients, outside atrophic regions and investigate relationships with disability. Brain perfusion of 23 relapsing remitting MS patients and 16 matched healthy subjects were assessed at 3T using the pseudo-continuous arterial spin labeling magnetic resonance imaging technique. In order to locate potential GM perfusion abnormalities in regions spared by atrophy, we combined voxelwise comparisons of GM cerebral blood flow (CBF) maps (cortex and deep GM) (P<0.005, FWE-corrected) and voxel-based-morphometry analysis (P<0.005, FDR-corrected) to exclude atrophic regions. Disability was assessed using the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite score (MSFC). In patients, significant GM hypoperfusion outside atrophic regions was depicted only in bilateral thalami. No other cluster was found to be hypoperfused compared to controls. Perfusion of thalami was correlated to MSFC (P=0.011, rho=0.523). A trend of correlation was found between perfusion of thalami and EDSS (P=0.061, rho=-0.396). In relapsing remitting MS, perfusion abnormalities in thalamic regions contribute to disability. These findings suggest that functional impairments of thalami, representing a major brain hub, may disturb various cerebral functions even before structural damage.

The association between retinal nerve fibre layer thickness and N-acetyl aspartate levels in multiple sclerosis brain normal-appearing white matter: a longitudinal study using magnetic resonance spectroscopy and optical coherence tomography.

N-acetyl aspartate (NAA) assessed using proton magnetic resonance spectroscopy (1 H MRS) has a high pathological specificity for axonal density. Retinal nerve fibre layer thickness (RNFLT) measured by using optical coherence tomography is increasingly used as a surrogate marker of neurodegeneration in multiple sclerosis (MS). Our aim was to investigate the relation between RNFLT and NAA/creatine in brain normal-appearing white matter (NAWM), their dynamics over time and the association with clinical outcome measures in relapsing MS. T2 WM lesions served as control tissue. Forty-three MS patients underwent standardized neurological examination including the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC) score, optical coherence tomography and magnetic resonance imaging including 1 H MRS at baseline and after 1 year. At baseline, NAA/creatine level was lower in T2 WM lesions than in NAWM (1.64 ± 0.16 vs. 1.88 ± 0.24, P < 0.001). Lowest levels were found in secondary progressive MS (SPMS). Mean RNFLT was higher in clinically isolated syndrome than in the combined group of relapsing-remitting MS and SPMS (99.8 ± 12.3 μm vs. 92.4 ± 12.8 μm, P = 0.038). In all patients, mean RNFLT decreased by 1.4% during follow-up. At baseline, MSFC z-scores correlated with NAA/creatine levels both in NAWM (r = 0.42; P = 0.008) and T2 WM lesions (r = 0.52, P = 0.004). NAWM NAA/creatine variation correlated with the RNFLT change over 1 year (ρ = 0.43, P = 0.046). N-acetyl aspartate/creatine level reduction correlated with RNFLT thinning over 1 year in an EDSS stable MS cohort suggesting that these techniques might be sensitive to detect subclinical disease progression.