Disability In Relapsing-remitting Multiple Sclerosis Research Articles

Altered Cerebrospinal Fluid Neurofilament Light Chain but Not Neurogranin Levels Are Associated with Response to Ocrelizumab Treatment in Relapsing-Remitting Multiple Sclerosis: A Preliminary Study.

Ocrelizumab is a CD20-targeting monoclonal antibody used for treatment of multiple sclerosis (MS). Serum and cerebrospinal fluid (CSF) neurofilament light (NFL) chain levels are reduced in MS patients under ocrelizumab treatment indicating a preventive action against neuro-axonal degeneration. Our aim, in this preliminary study, was to explore the impact of ocrelizumab treatment on synaptic integrity through assessment of neurogranin levels. Thirteen relapsing-remitting multiple sclerosis (RRMS) patients resistant to first-line immunomodulating agents were enrolled and followed up for 24 months under ocrelizumab treatment. Disease activity was monitored by periodic EDSS, MSSS, and cranial-spinal MRI assessments. No evidence of disease activity (NEDA)-3 was determined, and CSF levels of NFL (marker of neuro-axonal integrity) and neurogranin (marker of synaptic integrity) were measured by ELISA at baseline and 12-month ocrelizumab treatment. Seven RRMS patients, who preserved NEDA-3 status during 24-month follow-up, showed ≥30% NFL level decrease, whereas 6 patients with stable/increased NFL levels displayed relapse, MRI lesion, or disability progression. Although most RRMS patients exhibited increased CSF levels of neurogranin under ocrelizumab treatment, patients with and without neurogranin level increase did not differ in terms of clinical features and NEDA-3 status. Baseline neurogranin levels negatively correlated with baseline EDSS scores. Our results confirm that NFL effectively monitors treatment response of RRMS patients under ocrelizumab treatment. Neurogranin does not appear to exhibit a similar benefit in screening of RRMS disease activity. Nevertheless, lower neurogranin levels are associated with increased disability in RRMS indicating a potential disease activity biomarker function.

Interpretable and Intuitive Machine Learning Approaches for Predicting Disability Progression in Relapsing-Remitting Multiple Sclerosis Based on Clinical and Gray Matter Atrophy Indicators

Rationale and objectivesTo investigate whether clinical and grey matter (GM) atrophy indicators can predict disability in relapsing-remitting multiple sclerosis (RRMS) and to enhance the interpretability and intuitiveness of a predictive machine learning model. Materials and methodsOne hundred forty-five and 50 RRMS patients with structural MRI and at least 1-year follow-up Expanded Disability Status Scale (EDSS) results were retrospectively enrolled and placed in the discovery and external test cohorts, respectively. Six clinical and radiomics feature-based machine learning classifiers were trained and tested to predict disability progression in the discovery cohort and validated in the external test set. Partial dependence plot (PDP) analysis and a Shiny web application were conducted to enhance the interpretability and intuitiveness. ResultsIn the discovery cohort, 98 patients had disability stability, and 47 patients were classified as having disability progression. In the external test set, 35 patients were disability stable, and 15 patients had disability progression. Models trained with both clinical and radiomics features (area under the curve (AUC), 0.725-0.950) outperformed those trained with clinical (AUC, 0.600-0.740) or radiomics features only (AUC, 0.615-0.945). Among clinical + radiomics feature models, the logistic regression (LR) classifier-based model performed best, with an AUC of 0.950. Only the radiomics feature-only models were applied in the external test set due to the data collection problem and showed fair performance, with AUCs ranging from 0.617 to 0.753. PDP analysis showed that female patients and those with lower volume, surface area, and symbol digit modalities test (SDMT) scores; greater mean curvature and age; and no disease modifying therapy (DMT) had increased probabilities of disease progression. Finally, a Shiny web application (https://lauralin1104.shinyapps.io/LRshiny/) was developed to calculate the risk of disability progression. ConclusionsInterpretable and intuitive machine learning approaches based on clinical and GM atrophy indicators can help physicians predict disability progression in RRMS patients for clinical decision-making and patient management.

Contemporary Patterns of High-Efficacy Disease Modifying Therapy Use in Korean Patients with Relapsing-Remitting Multiple Sclerosis

Background: Despite the compelling evidence indicating that early initiation of high-efficacy disease modifying therapies (DMTs) is more effective in controlling disease activity and preventing long-term disability in relapsing-remitting multiple sclerosis (RRMS), there is a scarcity of data regarding the implementation of such treatments in Korea. This study aimed to investigate the actual proportion of patients requiring high-efficacy DMT when disease activity is closely monitored.Methods: We conducted a retrospective analysis of medical records of 104 patients with RRMS who developed their disease after 2015 at the National Cancer Center in Korea. The status of no evidence of disease activity-3 (NEDA-3) was defined as no relapse, disability progression, or active lesions in annual magnetic resonance imaging evaluations.Results: Among 104 RRMS patients, 95 started with moderate-efficacy DMT, and nine with high-efficacy DMT. Of patients, 51% showed disease activity despite moderate-efficacy DMT, and prompting 41% to escalate high-efficacy DMT with a median time to switch of 20 months. Following the switch to a high-efficacy DMT, NEDA-3 was maintained in 82% of patients for a median of 27 months (interquartile range: 22, 45). Among the nine patients initially on high-efficacy DMT, no patient exhibited any signs of disease activity after median 34 months of treatment. The majority of patients experienced no significant side effects of high-efficacy DMT.Conclusion: The study showed a significant number of patients requiring escalation to high-efficacy DMT within a few years of treatment initiation with moderate-efficacy DMT, emphasizing the importance of early intervention strategies in managing the patients.

Contemporary Patterns of High-Efficacy Disease Modifying Therapy Use in Korean Patients with Relapsing-Remitting Multiple Sclerosis

Background: Despite the compelling evidence indicating that early initiation of high-efficacy disease modifying therapies (DMTs) is more effective in controlling disease activity and preventing long-term disability in relapsing-remitting multiple sclerosis (RRMS), there is a scarcity of data regarding the implementation of such treatments in Korea. This study aimed to investigate the actual proportion of patients requiring high-efficacy DMT when disease activity is closely monitored.Methods: We conducted a retrospective analysis of medical records of 104 patients with RRMS who developed their disease after 2015 at the National Cancer Center in Korea. The status of no evidence of disease activity-3 (NEDA-3) was defined as no relapse, disability progression, or active lesions in annual magnetic resonance imaging evaluations.Results: Among 104 RRMS patients, 95 started with moderate-efficacy DMT, and nine with high-efficacy DMT. Of patients, 51% showed disease activity despite moderate-efficacy DMT, and prompting 41% to escalate high-efficacy DMT with a median time to switch of 20 months. Following the switch to a high-efficacy DMT, NEDA-3 was maintained in 82% of patients for a median of 27 months (interquartile range: 22, 45). Among the nine patients initially on high-efficacy DMT, no patient exhibited any signs of disease activity after median 34 months of treatment. The majority of patients experienced no significant side effects of high-efficacy DMT.Conclusion: The study showed a significant number of patients requiring escalation to high-efficacy DMT within a few years of treatment initiation with moderate-efficacy DMT, emphasizing the importance of early intervention strategies in managing the patients.

Leukocyte Telomere Length Predicts Severe Disability in Relapsing-Remitting Multiple Sclerosis and Correlates with Mitochondrial DNA Copy Number.

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease that affects the nervous system. Peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNA-CN) are potential biomarkers of neurological disability and neural damage. Our objective was to assess the LTL and mtDNA-CN in relapsing-remitting MS (RRMS). We included 10 healthy controls, 75 patients with RRMS, 50 of whom had an Expanded Disability Status Scale (EDSS) from 0 to 3 (mild to moderate disability), and 25 had an EDSS of 3.5 to 7 (severe disability). We use the Real-Time Polymerase Chain Reaction (qPCR) technique to quantify absolute LTL and absolute mtDNA-CN. ANOVA test show differences between healthy control vs. severe disability RRMS and mild-moderate RRMS vs. severe disability RRMS (p = 0.0130). LTL and mtDNA-CN showed a linear correlation in mild-moderate disability RRMS (r = 0.378, p = 0.007). Furthermore, we analyzed LTL between RRMS groups with a ROC curve, and LTL can predict severe disability (AUC = 0.702, p = 0.0018, cut-off < 3.0875 Kb, sensitivity = 75%, specificity = 62%), whereas the prediction is improved with a logistic regression model including LTL plus age (AUC = 0.762, p = 0.0001, sensitivity = 79.17%, specificity = 80%). These results show that LTL is a biomarker of disability in RRMS and is correlated with mtDNA-CN in mild-moderate RRMS patients.

Increased intrathecal neurofilament light and immunoglobulin M predict severe disability in relapsing-remitting multiple sclerosis.

BackgroundEmerging evidence supports that determination of intrathecal immunoglobulin M (IgM) synthesis (ITMS) and neurofilament light (NfL) concentration in cerebrospinal fluid (CSF) may be clinically useful as disease severity biomarkers in relapsing-remitting multiple sclerosis (RRMS).MethodsMonocentric observational longitudinal cohort study in which prospectively collected data were retrospectively retrieved. Included were patients with RRMS (n=457) who had a diagnostic investigation including analysis of ITMS and CSF neurofilament light (cNfL). ITMS was calculated with the linear index formula, the intrathecal fraction of IgM according to Reiber (IgMIF), and by qualitative determination of oligoclonal IgM bands (OCMB). Univariable and multivariable models were performed to predict Evidence of Disease Activity-3 (EDA-3) status within 24 months from onset, and the risk of Expanded Disability Status Score (EDSS) ≥3 and ≥6.ResultsAll investigated methods to calculate ITMS significantly predicted evidence of disease activity (EDA-3) within 24 months. IgMIF>0% showed the strongest association with EDA-3 status (adjusted hazard ratio [aHR] 3.7, 95%CI 2.7-5, p<0.001). Combining IgM-index>0.1 or OCMB with increased cNfL were strong predictors of EDSS≥3 (for cNfL + /IgM-index + : aHR 4.6, 95%CI 2.6-8.2, p<0.001) and EDSS≥6 (aHR 8.2, 95%CI 2.3-30, p<0.001).ConclusionsIn a real-world setting, ITMS was a useful biomarker in early RRMS to predict disabling MS and its prognostic value was even stronger in combination with cNfL. Our data suggest that determination of ITMS and cNfL should be included in the diagnostic work-up of RRMS for prognostic purposes and in decisions of disease-modifying therapy.

Red cell distribution width as a predictor of disability in relapsing-remitting multiple sclerosis

BackgroundRed blood cell distribution width (RDW) reflects the variability of circulating red blood cells. The relationship between multiple sclerosis (MS) and RDW is not well studied. The main objective of this work was to compare baseline RDW to EDSS at 5 years of diagnosis and verify if RDW predicts worse disability.MethodsWe conduct a retrospective observational study of relapsing-remitting MS (RRMS) patients followed in the Neuroimmunology Clinic that had at least one measuring of RDW at baseline.ResultsWe included 82 patients with RRMS meeting inclusion criteria, 73,2% female with a mean age of 33,56 years old. Median EDSS score at baseline was 1.5.9,8% patients had new T2 lesions in MRI at 5 years and 4,9% showed lesions capturing contrast at 5 years. Regarding DMT, 75,6% were treated with interferon, glatiramer acetate, teriflunomide, or dimethyl fumarate, and 21,9% were under fingolimod, natalizumab, rituximab, and cladribine, and the remaining 2,4% were without treatment at 5 years.A multiple linear regression model confirmed increased disability (EDSS at 5 years) for patients undergoing second-line treatment (β=0,86;p=,003) and higher RDW at baseline (β=0,47;p=,007). Presenting RDW results for quartiles, it was statistically significant for quartile 4 [13,5;16,4[(β=0,74;p=,039), suggesting that a very increased RDW at baseline is strongly associated with higher EDSS at 5 years.ConclusionHigher RDW at baseline was correlated with a worse disability at 5 years in RRMS patients. Furthermore, RDW equal to or higher than 13,5% may be useful in identifying patients that will have a worse disability at 5 years.

Quantitative magnetization transfer imaging in relapsing-remitting multiple sclerosis: a systematic review and meta-analysis.

Myelin-sensitive MRI such as magnetization transfer imaging has been widely used in multiple sclerosis. The influence of methodology and differences in disease subtype on imaging findings is, however, not well established. Here, we systematically review magnetization transfer brain imaging findings in relapsing-remitting multiple sclerosis. We examine how methodological differences, disease effects and their interaction influence magnetization transfer imaging measures. Articles published before 06/01/2021 were retrieved from online databases (PubMed, EMBASE and Web of Science) with search terms including ‘magnetization transfer’ and ‘brain’ for systematic review, according to a pre-defined protocol. Only studies that used human in vivo quantitative magnetization transfer imaging in adults with relapsing-remitting multiple sclerosis (with or without healthy controls) were included. Additional data from relapsing-remitting multiple sclerosis subjects acquired in other studies comprising mixed disease subtypes were included in meta-analyses.Data including sample size, MRI acquisition protocol parameters, treatments and clinical findings were extracted and qualitatively synthesized. Where possible, effect sizes were calculated for meta-analyses to determine magnetization transfer (i) differences between patients and healthy controls; (ii) longitudinal change and (iii) relationships with clinical disability in relapsing-remitting multiple sclerosis. Eighty-six studies met inclusion criteria. MRI acquisition parameters varied widely, and were also underreported. The majority of studies examined the magnetization transfer ratio in white matter, but magnetization transfer metrics, brain regions examined and results were heterogeneous. The analysis demonstrated a risk of bias due to selective reporting and small sample sizes. The pooled random-effects meta-analysis across all brain compartments revealed magnetization transfer ratio was 1.17 per cent units (95% CI −1.42 to −0.91) lower in relapsing-remitting multiple sclerosis than healthy controls (z-value: −8.99, P < 0.001, 46 studies). Linear mixed-model analysis did not show a significant longitudinal change in magnetization transfer ratio across all brain regions [β = 0.12 (−0.56 to 0.80), t-value = 0.35, P = 0.724, 14 studies] or normal-appearing white matter alone [β = 0.037 (−0.14 to 0.22), t-value = 0.41, P = 0.68, eight studies]. There was a significant negative association between the magnetization transfer ratio and clinical disability, as assessed by the Expanded Disability Status Scale [r = −0.32 (95% CI −0.46 to −0.17); z-value = −4.33, P < 0.001, 13 studies]. Evidence suggests that magnetization transfer imaging metrics are sensitive to pathological brain changes in relapsing-remitting multiple sclerosis, although effect sizes were small in comparison to inter-study variability. Recommendations include: better harmonized magnetization transfer acquisition protocols with detailed methodological reporting standards; larger, well-phenotyped cohorts, including healthy controls; and, further exploration of techniques such as magnetization transfer saturation or inhomogeneous magnetization transfer ratio.

Effect of Disease-Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years.

To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled disability outcomes in 14,717 patients. We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity. A total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 0.43-0.82, p = 0.0016), worsening of disability (0.56, 0.38-0.82, p = 0.0026), and progress to EDSS step 6 (0.33, 0.19-0.59, p = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50-0.70, p = 10-9) and worsening of disability (0.81, 0.67-0.99, p = 0.043). Continued treatment with MS immunotherapies reduces disability accrual by 19%-44% (95% CI 1%-62%), the risk of need of a walking aid by 67% (95% CI 41%-81%), and the frequency of relapses by 40-41% (95% CI 18%-57%) over 15 years. This study provides evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term. This study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.

Voxel-based analysis of gray matter relaxation rates shows different correlation patterns for cognitive impairment and physical disability in relapsing-remitting multiple sclerosis.

Regional analyses of markers of microstructural gray matter (GM) changes, including relaxation rates, have shown inconsistent correlations with physical and cognitive impairment in MS. To assess voxelwise the correlation of the R1 and R2 relaxation rates with the physical and cognitive impairment in MS. GM R1 and R2 relaxation rate maps were obtained in 241 relapsing-remitting MS patients by relaxometric segmentation of MRI studies. Correlations with the Expanded Disability Status Scale (EDSS) and the percentage of impaired cognitive test (Brief Repeatable Battery and Stroop Test, available in 186 patients) were assessed voxelwise, including voxel GM content as nuisance covariate to remove the effect of atrophy on the correlations. Extensive clusters of inverse correlation between EDSS and R2 were detected throughout the brain, while inverse correlations with R1 were mostly limited to perirolandic and supramarginal cortices. Cognitive impairment correlated negatively with R1, and to a lesser extent with R2, in the middle frontal, mesial temporal, midcingulate and medial parieto-occipital cortices. In relapsing-remitting MS patients, GM microstructural changes correlate diffusely with physical disability, independent of atrophy, with a preferential role of the sensorimotor cortices. Neuronal damage in the limbic system and dorsolateral prefrontal cortices correlates with cognitive dysfunction.

White matter lesion location correlates with disability in relapsing multiple sclerosis.

BackgroundLesion location is a prognostic factor of disease progression and disability accrual.ObjectiveTo investigate lesion formation in 11 brain regions, assess correlation between lesion location and physical and cognitive disability measures and investigate treatment effects by region.MethodsIn 2355 relapsing–remitting multiple sclerosis patients from the FREEDOMS and FREEDOMS II studies, we extracted T2-weighted lesion number, volume and density for each brain region; we investigated the (Spearman) correlation in lesion formation between brain regions, studied association between location and disability (at baseline and change over 2 years) using linear/logistic regression and assessed the regional effects of fingolimod versus placebo in negative binomial models.ResultsAt baseline, the majority of lesions were found in the supratentorial brain. New and enlarging lesions over 24 months developed mainly in the frontal and sublobar regions and were substantially correlated to pre-existing lesions at baseline in the supratentorial brain (p = 0.37–0.52), less so infratentorially (p = −0.04–0.23). High sublobar lesion density was consistently and significantly associated with most disability measures at baseline and worsening of physical disability over 24 months. The treatment effect of fingolimod 0.5 mg was consistent across the investigated areas and tracts.ConclusionThese results highlight the role of sublobar lesions for the accrual of disability in relapsing–remitting multiple sclerosis.

A Pilot Cross-Sectional Study to Investigate the Biomarker Potential of Phosphorylated Neurofilament-H and Immune Mediators of Disability in Patients With 5 Year Relapsing-Remitting Multiple Sclerosis.

Objective: To test the feasibility of conducting a full-scale project evaluating the potential value of the phosphorylated neurofilament H (pNF-H) and several cytokines as disability markers in relapsing-remitting multiple sclerosis (RRMS).Methods: Twenty-four patients with 5-year RRMS evolution and eleven healthy control subjects entered the study. None of the participants had an inflammatory systemic or metabolic disease. Disability progression was evaluated using the Expanded Disability Status Scale. Serum level of pNF-H, the anti-inflammatory cytokine transforming growth factor-β 1 (TGF-β1), and the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-17A (IL-17A), monocyte chemotactic protein-1 (MCP-1), and soluble intercellular cell-adhesion molecule 1 (sICAM-1) were quantified using enzyme-linked immunosorbent assay (ELISA).Results: The patients had higher serum level of TGF-β1, IL-6, sICAM-1, and pNF-H. Based on these findings, a sample of at least 49 controls and 89 recent-onset RRMS patients is required to find an at least 1-point between-group difference in pNF-H with a power of 80% and an α error = 0.05. The progression of the disease was correlated with the level of pNF-H (Spearman rho = 0.624, p = 0.006), but not with the cytokines'.Conclusions: The serum level of pNF-H, EDSS score-correlated, might stand for a potential biomarker of disability in RRMS reflecting progressive axonal damage and cumulative neurological deterioration. The novelty of these results warrants conducting a larger confirmatory trial.

Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis

Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS). To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression. Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018. Patients were randomized to receive HSCT along with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55). The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios. Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference, -1.7; 95% CI, -2.03 to -1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events). In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety. ClinicalTrials.gov Identifier: NCT00273364.

MRI features suggestive of gadolinium retention do not correlate with Expanded Disability Status Scale worsening in Multiple Sclerosis.

Different studies showed correlations between gadolinium-based contrast agent (GBCA) administrations and dentate nucleus (DN) T1-weighted hyperintensity. The clinical impact of gadolinium retention, however, is still largely unknown. The aim of this study was to investigate relations between MRI and clinical disability in relapsing-remitting multiple sclerosis (RR-MS) patients. In this retrospective study, clinical data were obtained from 74 RR-MS patients at baseline and after a mean follow-up time of 3.6years, including the expanded disability status scale (EDSS) score and its change (ΔEDSS). Patients were considered showing clinical worsening if they score a ΔEDSS ≥ 1 (for baseline EDSS ≤ 5.5) or ΔEDSS ≥ 0.5 (for baseline EDSS > 5.5). From the MRI data, the presence of bilateral DN hyperintensity was recorded along with the calculation of longitudinal relaxation rate (R1) maps. Patients with DN hyperintensity showed similar ΔEDSS change compared to those without visible changes on T1-weighted images (p = 0.32). Similarly, no DN-R1 difference was found comparing stable patients with those showing a significant clinical worsening (p = 0.54). Finally, no significant effect of DN-R1 values explained the variance in ΔEDSS (p = 0.76), thus suggesting their independence from the clinical outcome. MS patients with DN hyperintensity show similar EDSS changes compared to subjects without DN high-signal intensity. Furthermore, mean DN-R1 values of patients with significant clinical worsening were comparable to those of stable subjects and were unrelated to clinical disability. Taken together, these findings suggest that gadolinium retention in the brain of MS patients does not affect their clinical worsening, expressed by the EDSS change.

Peripapillary retinal nerve fibre layer as measured by optical coherence tomography is a prognostic biomarker not only for physical but also for cognitive disability progression in multiple sclerosis

Background: Peripapillary retinal nerve fibre layer (pRNFL) thickness is emerging as a marker of axonal degeneration in multiple sclerosis (MS). Objective: We aimed to prospectively assess the predictive value of pRNFL for progression of physical and cognitive disability in relapsing-remitting MS (RRMS). Methods: In this 3-year longitudinal study on 151 RRMS patients, pRNFL was measured by spectral-domain optical coherence tomography (OCT). We used proportional hazard models, correcting for age, sex, disease duration, Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT) at baseline, to test a pRNFL thickness ≤88 µm at baseline for prediction of EDSS progression and cognitive decline. We also evaluated the decrease in pRNFL thickness from baseline to year 3 in a multivariate linear regression model. Results: pRNFL thickness ≤88 µm was independently associated with a threefold increased risk of EDSS progression (p < 0.001) and a 2.7-fold increased risk of cognitive decline within the subsequent 3 years (p < 0.001). Mean pRNFL delta was −5.3 µm (SD, 4.2). It was significantly negatively impacted by EDSS progression, cognitive decline, higher age and disease duration, while positively impacted by disease-modifying therapy (DMT). Conclusion: Cross-sectional and longitudinal monitoring of pRNFL is useful as a biomarker for prediction of physical and cognitive disability progression in patients with RRMS in everyday clinical practice.

Injectable multiple sclerosis disease modifying drugs: Analysis of patient compliance in the Tomsk region

Background: Compliance with multiple sclerosis disease modifying drugs (MSDMD) is associated with reduced relapse rate and accumulation of disability in relapsing-remitting multiple sclerosis (RRMS). Low compliance dramatically reduces treatment efficacy, thus it should be analyzed.

Predictors of Disability in Relapsing-Remitting Multiple Sclerosis (RRMS) During the Glatiramer Acetate Low-frequency Administration (GALA) Study (P6.357)

Predictors of Disability in Relapsing-Remitting Multiple Sclerosis (RRMS) During the Glatiramer Acetate Low-frequency Administration (GALA) Study (P6.357)

BRAIN AND SPINE ATROPHY IN RELAPSING REMITTING MULTIPLE SCLEROSIS: A 3-YEAR FOLLOWUP STUDY

Nowadays neurodegeneration in multiple sclerosis is closely associated with irreversible disability progression. However, the involvement sequence of different regions in atrophy is still unclear. The aim of our study was to determine the relationship between brain and spine atrophy and neurological disability in relapsing-remitting multiple sclerosis (RRMS) patients. 45 RRMS patients underwent brain and spine MRI with voxel based morphometry and neurological examination with EDSS and were compared to 20 healthy controls. As a result we determined a distinct patterns of atrophy distribution in MS patients and the sequence of involvement of different central nervous system regions. A strong correlation between disability progression rate and gray matter atrophy rate was detected.

Multimodal quantitative MRI assessment of cortical damage in relapsing-remitting multiple sclerosis.

To investigate magnetization transfer ratio (MTR), T1 relaxation time, and proton density (PD) as indicators of gray matter damage in relapsing-remitting multiple sclerosis (RRMS), reflecting different aspects of microstructural damage and as imaging correlates of clinical disability. We aimed to determine which of these parameters may optimally quantify cortical damage, and serve as an imaging surrogate of clinical disability. In this study, cortical values of MTR, a surrogate for demyelination in MS, of PD, reflecting replacement of neural tissue by water, and of T1 , indicating a complex array of microstructural changes, were assessed in a group of RRMS patients in comparison to healthy controls (HC). 22 RRMS patients with varying disease duration (4.0 ± 6.54 years) and 10 HC received quantitative 3T magnetic resonance imaging (MRI) with MTR, T1 , and PD mapping. We tested for differences in cortical measurements between patients and HC. Additionally, correlation with disability as quantified by the Expanded Disability Status Scale was investigated. Cortical parameter values were significantly altered in the RRMS group, with increased values of T1 (P = 0.008) and PD (P = 0.028) and reduced values of MTR (P = 0.043). Only cortical T1 was correlated with clinical disability measurements (P = 0.001, r = 0.65). Receiver operating characteristic analysis demonstrated the best discriminatory power for T1 (area under the curve 0.79, PD: 0.75, MTR 0.73). Out of the parameters studied, cortical T1 is best suited to detect cortical damage as an imaging surrogate of clinical disability in RRMS. J. Magn. Reson. Imaging 2016;44:1600-1607.

Clinical and experimental studies of multiple sclerosis in Russia: experience of the leading national research centers.

Mechanisms of axonal damage and adaptive capacity in multiple sclerosis (MS), including cortical reorganization, have been actively studied in recent years. The lack of regenerative capabilities and the irreversibility of neurodegeneration in MS are critical factors for the optimization of MS treatment. In this study, we present the results of clinical and basic studies in the field of MS by two leading Russian centers. Clinical and neuroimaging correlations show that spinal damage in MS is accompanied by functional reorganization of the cerebral cortex, which is determined not only by the efferent component but also by the afferent component. Comparative analysis of MS treatment with both interferon β1b (IFN-β1b) and IFN-β1a at a dosage of 22 µg for 3 years through subcutaneous administration and glatiramer acetate showed equally high efficiency in reducing the number of exacerbations in relapsing-remitting MS and secondary-progressive MS. We demonstrate a reduced risk of disability in relapsing-remitting MS and secondary-progressive MS patients in all groups treated with IFN-β1 and glatiramer acetate. MS appears to be a disease that would greatly benefit from the development of personalized therapy; thus, adequate molecular predictors of myelin degradation are greatly needed. Therefore, novel ideas related to the viral hypothesis of the etiology of MS and new targets for therapeutic intervention are currently being developed. In this manuscript, we discuss findings of both clinical practice and fundamental research reflecting challenges and future directions of MS treatment in the Russian Federation.