Secondary Progressive Multiple Sclerosis Research Articles

Characteristics and management of multiple sclerosis patients during the Omicron era: is there a concern about the MS course in the face of the new variant of COVID-19?

IntroductionThe Omicron variant of COVID-19 is highly transmissible, triggering unprecedented infection rates. The present study aimed to investigate the course of multiple sclerosis (MS) in the Omicron era among Iranian patients with MS. MethodsThis observational study was designed on MS patients of the national MS registry of Iran through a self-designed online questionnaire. A questionnaire was prepared as a Google Form for MS patients during the Omicron outbreak from 1 March to 30 April 2022.ResultsOne hundred seventy-four patients with a mean age of 37.3 ± 9.04 were enrolled. Of the patients, 95.97% used DMT, the most common of which were rituximab and fingolimod. Of the patients, 77.58% were fully vaccinated for COVID-19. Regardless of the COVID-19 vaccination status, 76 patients developed COVID-19, which was mild to moderate. Except for recent corticosteroid therapy and secondary progressive MS (SPMS), other demographic and MS characteristics were not significantly associated with the severity of COVID-19. There was also a marginal association between the Expanded Disability Status Scale (EDSS) and the severity of COVID-19. In addition, 17.10% of patients reported MS relapse following COVID-19 leading to escalation therapy in eight patients.ConclusionOur study demonstrated that in the Omicron era, most patients developed mild COVID-19. Although the predominant COVID-19 variant in this period was Omicron, we could not separate the pathogenic variants. The risk factors for COVID-19 during the Omicron era were not different from other pandemic waves. Our preliminary results revealed that the MS relapse following COVID-19 was higher than in previous waves.

Serious infections in patients with relapsing and progressive forms of multiple sclerosis: A German claims data study

BackgroundPeople with multiple sclerosis (pwMS) have a higher risk of serious infection (i.e., infection-related hospitalizations) than people without MS. Few studies have explored the risk of serious infections by MS phenotype in a real-world setting. This retrospective study compared the incidence of serious infections among people with relapse remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS). MethodsAdult pwMS were selected from a German claims database, based on one inpatient or two outpatient diagnoses of MS (ICD-10 G35) by a neurologist from 01/01/2016 to 12/31/2018. Three cohorts (RRMS, PPMS, SPMS) were identified based on codes for MS subtypes included in the German Modification of the ICD-10 system. A fourth cohort of unspecified MS patients combined those with conflicting MS subtype diagnoses and multiple unspecified codes for MS. Serious infections were defined as hospitalizations for which infections were selected as the primary inpatient diagnosis. Infections were identified from a basket of ICD-10 codes distributed across 11 main categories, according to possible pathogen (e.g., other bacterial diseases [A30-A49]) or anatomical location (e.g., urinary tract infection [N39.0]). Multiple infections were counted if an interval of at least 60 days was recorded between episodes. Serious infections were counted from index (i.e., first recorded MS code) until the end of the study period or death. Incidence rates (IRs) were reported per 100 patient years (PY). ResultsA total of 4,250 pwMS (RRMS: 2,307, PPMS: 282, SPMS: 558, unspecified MS: 1,135) were included; 32 patients progressed from RRMS to SPMS during the follow-up period. Mean (SD) age at baseline was 46.6 (13.6), 61.9 (12.4), and 62.5 (11.8) years in patients with RRMS, PPMS, and SPMS, respectively. Most pwMS were female (RRMS 74.8%, PPMS 62.1%, SPMS 67.4%). Progressive pwMS were more likely to have at least 1 comorbidity (PPMS 87.2%, SPMS 87.5%) compared to those with relapsing MS (61.9%). Most RRMS patients received disease-modifying therapy during follow-up (82.1%), while less than half of progressive MS patients did (PPMS 23.8%, SPMS 31.4%). Over a mean (SD) follow-up period of 3.5 (0.8) years, the IR of serious infections per 100 PY was higher in progressive MS cohorts (PPMS 13.5 [11.3–16.1], SPMS 13.6 [12.0–15.3]) than in the RRMS group (3.4 [3.0–3.7]). Yearly IRs remained stable over time in each cohort. Where anatomical location was specified, respiratory (2.0 per 100 PY) and genitourinary (1.9 per 100 PY) infections were most common. Across all subtypes, higher rates of serious infections were observed in men and older patients. ConclusionProgressive MS, older age and male sex are associated with an increased risk of serious infections. Overall, respiratory and genitourinary infections were the most commonly reported serious infections.

Identification of potential regulatory long non-coding RNA-associated competing endogenous RNA axes in periplaque regions in multiple sclerosis.

Slow-burning inflammation at the lesion rim is connected to the expansion of chronic multiple sclerosis (MS) lesions. However, the underlying processes causing expansion are not clearly realized. In this context, the current study used a bioinformatics approach to identify the expression profiles and related lncRNA-associated ceRNA regulatory axes in the periplaque region in MS patients. Expression data (GSE52139) from periplaque regions in the secondary progressive MS spinal cord and controls were downloaded from the Gene Expression Omnibus database (GEO), which has details on mRNAs and lncRNAs. Using the R software's limma package, the differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) were found. The RNA interactions were also found using the DIANA-LncBase, miRTarBase, and HMDD databases. The Pearson correlation coefficient was used to determine whether there were any positive correlations between DEmRNAs and DElncRNAs in the ceRNA network. Finally, lncRNA-associated ceRNA axes were created based on co-expression and connections between DElncRNA, miRNA, and DEmRNA. We used the Enrichr tool to enrich the biological process, molecular function, and pathways for DEmRNAs and DElncRNAs. A network of DEmRNAs' protein-protein interactions was developed, and the top five hub genes were found using Cytoscape and STRING. The current study indicates that 15 DEmRNAs, including FOS, GJA1, NTRK2, CTNND1, and SP3, are connected to the MS ceRNA network. Additionally, four DElncRNAs (such as TUG1, ASB16-AS1, and LINC01094) that regulated the aforementioned mRNAs by sponging 14 MS-related miRNAs (e.g., hsa-miR-145-5p, hsa-miR-200a-3p, hsa-miR-20a-5p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-27a-3p, hsa-miR-29b-3p, hsa-miR-29c-3p, hsa-miR-34a-5p) were found. In addition, the analysis of pathway enrichment revealed that DEmRNAs were enriched in the pathways for the "MAPK signaling pathway", "Kaposi sarcoma-associated herpesvirus infection", "Human immunodeficiency virus one infection", "Lipid and atherosclerosis", and "Amphetamine addiction". Even though the function of these ceRNA axes needs to be investigated further, this study provides research targets for studying ceRNA-mediated molecular mechanisms related to periplaque demyelination in MS.

Rate of Retinal Layer Thinning as a Biomarker for Conversion to Progressive Disease in Multiple Sclerosis.

Background and ObjectivesThe diagnosis of secondary progressive multiple sclerosis (SPMS) is often delayed because of the lack of objective clinical tools, which increases the diagnostic uncertainty and hampers the therapeutic development in progressive multiple sclerosis (MS). Optical coherence tomography (OCT) has been proposed as a promising biomarker of progressive neurodegeneration. To explore longitudinal changes in the thicknesses of retinal layers on OCT in individuals with relapsing-remitting MS (RRMS) who converted to SPMS vs matched patients with RRMS who did not convert to SPMS. Our hypothesis is that the 2 cohorts exhibit different rates of retinal thinning.MethodsFrom our prospective observational cohort of patients with MS at the American University of Beirut, we selected patients with RRMS who converted to SPMS during the observation period and patients with RRMS, matched by age, disease duration, and Expanded Disability Status Scale (EDSS) at the first visit. Baseline retinal measurements were obtained using spectral domain OCT, and all patients underwent clinical and OCT evaluation every 6–12 months on average throughout the study period (mean = 4 years). Mixed-effect regression models were used to assess the annualized rates of retinal changes and the differences between the 2 groups and between converters to SPMS before and after their conversion.ResultsA total of 61 participants were selected (21 SPMS and 40 RRMS). There were no differences in baseline characteristics and retinal measurements between the 2 groups. The annualized rates of thinning of all retinal layers, except for macular volume, were greater in converters before conversion compared with nonconverters by 112% for peripapillary retinal nerve fiber layer (p = 0.008), 344% for tRNFL (p < 0.0001), and 82% for cell-inner plexiform layer (GCIPL) (p = 0.002). When comparing the annualized rate of thinning for the same patients with SPMS before and after conversion, no significant differences were found except for tRNFL and GCIPL with slower thinning rates postconversion (46% and 68%, respectively).DiscussionPatients who converted to SPMS exhibited faster retinal thinning as reflected on OCT. Longitudinal assessment of retinal thinning could confirm the transition to SPMS and help with the therapeutic decision making for patients with MS with clinical suspicion of disease progression.

Classification of multiple sclerosis clinical profiles using machine learning and grey matter connectome.

Purpose: The main goal of this study is to investigate the discrimination power of Grey Matter (GM) thickness connectome data between Multiple Sclerosis (MS) clinical profiles using statistical and Machine Learning (ML) methods. Materials and Methods: A dataset composed of 90 MS patients acquired at the MS clinic of Lyon Neurological Hospital was used for the analysis. Four MS profiles were considered, corresponding to Clinical Isolated Syndrome (CIS), Relapsing-Remitting MS (RRMS), Secondary Progressive MS (SPMS), and Primary Progressive MS (PPMS). Each patient was classified in one of these profiles by our neurologist and underwent longitudinal MRI examinations including T1-weighted image acquisition at each examination, from which the GM tissue was segmented and the cortical GM thickness measured. Following the GM parcellation using two different atlases (FSAverage and Glasser 2016), the morphological connectome was built and six global metrics (Betweenness Centrality (BC), Assortativity (r), Transitivity (T), Efficiency (E g ), Modularity (Q) and Density (D)) were extracted. Based on their connectivity metrics, MS profiles were first statistically compared and second, classified using four different learning machines (Logistic Regression, Random Forest, Support Vector Machine and AdaBoost), combined in a higher level ensemble model by majority voting. Finally, the impact of the GM spatial resolution on the MS clinical profiles classification was analyzed. Results: Using binary comparisons between the four MS clinical profiles, statistical differences and classification performances higher than 0.7 were observed. Good performances were obtained when comparing the two early clinical forms, RRMS and PPMS (F1 score of 0.86), and the two neurodegenerative profiles, PPMS and SPMS (F1 score of 0.72). When comparing the two atlases, slightly better performances were obtained with the Glasser 2016 atlas, especially between RRMS with PPMS (F1 score of 0.83), compared to the FSAverage atlas (F1 score of 0.69). Also, the thresholding value for graph binarization was investigated suggesting more informative graph properties in the percentile range between 0.6 and 0.8. Conclusion: An automated pipeline was proposed for the classification of MS clinical profiles using six global graph metrics extracted from the GM morphological connectome of MS patients. This work demonstrated that GM morphological connectivity data could provide good classification performances by combining four simple ML models, without the cost of long and complex MR techniques, such as MR diffusion, and/or deep learning architectures.

B-lymphocyte-guided retreatment contributes to establish good effectiveness and safety profile in MS patients treated with rituximab

BackgroundRituximab is extensively used for multiple sclerosis (MS) treatment. However, the best dosage remains to be established. It has been proposed that retreatment could be guided by B lymphocyte (BL) percentages. ObjectiveTo establish the best BL value for retreatment with rituximab in MS and to confirm the safety and efficacy of this approach. MethodsA prospective study was done with an exploratory cohort and a confirmatory cohort of MS patients treated with rituximab between 2017 and 2021. The first one comprised 10 MS patients with BL assessed every 3 months after rituximab infusion and retreatment done when BL values were ≥0.5%. The confirmatory cohort included 41 MS patients (41.5% women, 87.8% with secondary progressive MS, median age = 46.3 (interquartile range: 41.3–52.1) years, disease duration = 14.1 (9–19.6) years, EDSS score = 5.5 (4.0–6.5)). The confirmatory cohort was treated with rituximab following the pattern established in the exploratory cohort. ResultsIn the exploratory cohort, ≥0.2% BL was established as the best value for retreatment because in most cases, a substantial increase of BL counts was preceded by initial values of 0.2–0.3%. In the confirmatory cohort, rituximab reduced the annualized relapse rate (ARR 0.56 vs. 0.125, p < 0.001), proportion of patients with appearance of new/enlarged T2 lesions (63.4% vs. 12.2%, p < 0.001), gadolinium-enhancing lesions (39% vs. 0%, p < 0.001), and confirmed disability progression (55% vs. 27.5%, p = 0.037). There were 22 patients (53.7%) who achieved NEDA-3. No patients had severe infections, and 10.7% cases had reduced IgG levels. ConclusionRituximab treatment guided by BL showed high effectiveness and a good safety profile for MS patients after one year of treatment.

Effectiveness of first generation disease-modifying therapy to prevent conversion to secondary progressive multiple sclerosis

BackgroundThe use of disease-modifying therapies (DMTs) in multiple sclerosis (MS) has been associated with reduced relapse rates and accumulation of disability. However, studies examining impact of DMT on risk of transition to secondary progressive MS (SPMS) leveraging population-based nationwide data are still rare. Here, we determine the population incidence of conversion to SPMS using two consecutive nation-wide cohorts, one immediately before and one after the introduction of DMT in Sweden. MethodsWe included two consecutive population cohorts of relapsing-remitting MS (RRMS) from the Swedish national MS register for the periods 1975–1994 (n = 2161), before DMT availability, and 1995–2011 (n = 3510), in which DMTs, mainly first generation DMT (injectables), became available and eventually were used by 70% of patients. We explored the risk of transition to SPMS as a calendar year function encompassing the two cohorts. In addition, we determined the incidence of transition to SPMS through age strata below and above 50 years in untreated and treated patient subgroups. ResultsThe risk of conversion to SPMS (adjusted for current age, current time since onset, calendar year and sex) was significantly lower in the second compared with the first population cohort (hazard ratio 0.58; CI 0.48, 0.70). The risk of SPMS conversion per calendar year decreased by 2.6% annually (p < 0.001) after 1995. The risk of SPMS conversion increased with age until age 50. Thereafter, it was unchanged or decreased among those with early MS onset age (<35 years), but continued to increase with onset at higher age, with similar trends in treated and untreated subgroups. ConclusionThe incidence of SPMS conversion significantly decreased at the population level after introduction of first generation DMTs by 1995. DMT efficiency was confirmed by a downward turn of the annual trajectory of the risk of SPMS conversion after 1995. An onset age determined pattern of variable SPMS incidence in higher age appeared in both treated and untreated strata. While first generation DMT delayed conversion to SPMS, their long-term effect was only moderate.

Editors' Note: Blood Neurofilament Light in Progressive Multiple Sclerosis: Post Hoc Analysis of 2 Randomized Controlled Trials.

In a post hoc blinded analysis of 2 placebo-controlled, phase 3 trials, Dr. Leppert and colleagues investigated the association of plasma neurofilament light (pNfL) levels with disability progression, cognitive decline, and brain atrophy in 1,452 patients with secondary progressive multiple sclerosis (SPMS; EXPAND trial of siponimod) and 378 patients with primary progressive multiple sclerosis (PPMS; INFORMS trial of fingolimod). They found that higher pNfL levels were independently associated with higher risks of confirmed 3- and 6-month disability progression, earlier wheelchair dependence, cognitive decline (in SPMS), and higher rates of 24-month brain atrophy. pNfL levels were lower in patients treated with siponimod or fingolimod vs placebo, and the authors concluded that pNfL may be a meaningful outcome measure in PMS studies. In response, Dr. Barro raises concerns about whether the pNfL quantification in the 2 trials were performed with the same batches of reagents, given the potential for batch-to-batch variability, and questions the use of a fixed threshold for high vs low pNfL levels in the analyses instead of age-adjusted thresholds, given the association of older age with both higher pNfL levels and disability progression. Responding to these comments, the authors agree that batch-to-batch variability may be an important assay confounder, but note that the coefficient of variation was less than 15% for each of the 3 native serum control samples with high, medium, and low pNfL used in the study. They argue that whereas the assay used in their study did not allow direct application of the age-adjusted cutoffs, age was included as a covariable in all statistical models, so the higher risk of progression in patients with a higher baseline pNfL in their study cannot be attributed to age differences. They also agree that z scores or percentiles would be preferable to fixed cutoffs. This exchange indicates the difficulties of standardization of assays for pNfL measurement. Although pNfL measurements now permeate the literature on numerous neurologic conditions, harmonization of study methods continues to be a challenge. In a post hoc blinded analysis of 2 placebo-controlled, phase 3 trials, Dr. Leppert and colleagues investigated the association of plasma neurofilament light (pNfL) levels with disability progression, cognitive decline, and brain atrophy in 1,452 patients with secondary progressive multiple sclerosis (SPMS; EXPAND trial of siponimod) and 378 patients with primary progressive multiple sclerosis (PPMS; INFORMS trial of fingolimod). They found that higher pNfL levels were independently associated with higher risks of confirmed 3- and 6-month disability progression, earlier wheelchair dependence, cognitive decline (in SPMS), and higher rates of 24-month brain atrophy. pNfL levels were lower in patients treated with siponimod or fingolimod vs placebo, and the authors concluded that pNfL may be a meaningful outcome measure in PMS studies. In response, Dr. Barro raises concerns about whether the pNfL quantification in the 2 trials were performed with the same batches of reagents, given the potential for batch-to-batch variability, and questions the use of a fixed threshold for high vs low pNfL levels in the analyses instead of age-adjusted thresholds, given the association of older age with both higher pNfL levels and disability progression. Responding to these comments, the authors agree that batch-to-batch variability may be an important assay confounder, but note that the coefficient of variation was less than 15% for each of the 3 native serum control samples with high, medium, and low pNfL used in the study. They argue that whereas the assay used in their study did not allow direct application of the age-adjusted cutoffs, age was included as a covariable in all statistical models, so the higher risk of progression in patients with a higher baseline pNfL in their study cannot be attributed to age differences. They also agree that z scores or percentiles would be preferable to fixed cutoffs. This exchange indicates the difficulties of standardization of assays for pNfL measurement. Although pNfL measurements now permeate the literature on numerous neurologic conditions, harmonization of study methods continues to be a challenge.

Disease activity after discontinuation of disease-modifying therapies in patients with multiple sclerosis in Argentina: data from the nationwide registry RelevarEM

ABSTRACT Introduction The discontinuation of disease-modifying therapies (DMTs) in multiple sclerosis (MS) is commonly seen in real-world settings due to several factors. Area cover The aim of this study is to describe the frequency of disease activity after discontinuation of DMTs in MS patients included in the Argentinean MS and NMOSD registry. Discusion Patients with relapsing remitting MS (RRMS) and active secondary progressive MS (SPMS) were included based on the following criteria: they discontinued treatment for more than 6 months, they had been treated with a DMT for ≥2 years, and they had at least 6 months of follow-up in the registry after discontinuation. Demographic and clinical data were collected. Disease activity during follow-up was defined as the presence of a clinical relapse or a new magnetic resonance (MRI) lesion (either new lesions on T2-weighted sequence and/or contrast enhancement). Bivariate analysis was applied to identify clinical and demographic factors related to disease activity. Conclusion We included 377 patients (75.5% RRMS, 22.5% SPMS) who had discontinued DMTs. The mean (SD) follow-up after discontinuation was 15.7 (7.9) months. After discontinuation, the presence of relapse was detected in 18.8% and 3.5% in RRMS and SPMS, respectively; and new MRI activity in 22% and 3.5%, respectively. We found that higher risk of relapse and MRI activity was associated with younger age (p < 0.001), shorter disease duration (p < 0.001), and RRMS phenotype (p = 0.006). Males showed higher MRI activity (p 0.011). This study provides real-world data that can guide physicians when considering discontinuation of DMTs.

Association of spinal cord lesions with cognition in multiple sclerosis

Amaç: Çalışmamızda, multipl skleroz (MS)da fiziksel özürlülük ve prognozla yakın ilişkisi olan spinal kord tutulumunun, kognitif işlevler üzerine olası etkisi incelenmiştir.&#x0D; Gereç ve Yöntem: Çalışmaya 29 MS hastası (2 klinik izole sendrom, 23 relaps ve remisyonlarla seyreden MS, 2 sekonder progresif MS, 2 primer progresif MS) alındı. Demografik özellikleri, genişletilmiş özürlülük durum skalası (EDSS) skoru, Rao’nun kısa tekrarlanabilir nöropsikolojik test bataryası ile değerlendirilen kognitif durumu, beyin ve spinal kord T2 lezyon sayısı değerlendirildi. Benzer demografik özelliklere sahip 17 sağlıklı kontrol ile kognitif test sonuçları karşılaştırıldı. &#x0D; Bulgular: İleri yaş, hastalık başlangıç yaşının ileri olması, kısa eğitim süresi kognitif test sonuçlarını olumsuz etkileyen özelliklerdir. Beyin ve spinal kord lezyon sayılarının kognitif testler üzerine anlamlı etkisi saptanmamıştır. Spinal kord lezyonu olan hastalar olmayanlara göre daha yüksek EDSS’ye sahiptir, ancak iki grup arasında kognitif test sonuçları açısından anlamlı farklılık saptanmamıştır. &#x0D; Sonuç: Spinal kord lezyonları, EDSS ile değerlendirilen fiziksel özürlülük ile ilişkilidir. Kord plak varlığının ya da sayısının kognitif test sonuçları üzerine etkisini, servikal kord atrofisi ile birlikte değerlendirecek, daha geniş örneklemli boylamsal çalışmalara ihtiyaç vardır.

Heterogeneity on long-term disability trajectories in patients with secondary progressive MS: a latent class analysis from Big MS Data network

BackgroundOver the decades, several natural history studies on patients with primary (PPMS) or secondary progressive multiple sclerosis (SPMS) were reported from international registries. In PPMS, a consistent heterogeneity on long-term...

Secondary progressive multiple sclerosis: A national consensus paper on diagnostic criteria

BackgroundIn clinical practice, the diagnosis of secondary progressive multiple sclerosis (SPMS) is often delayed, retrospective and non-reproducible, as there are no consensus criteria that define the advent of SPMS. Early identification of SPMS is essential to improve patient care. MethodsEight regional board meetings in France involving 56 multiple sclerosis (MS) experts (neurologists) were convened to discuss diagnostic criteria for SPMS. Subsequently, a national board meeting of 13 neurologists (with an expert representing each geographical region) was held to review points of convergence or divergence between regions and to develop a national consensus document. ResultsBased on the discussions from the regional boards, the MS experts at the national board retained the worsening of the EDSS score, with compatible clinical features, as the only consensus criterion for the diagnosis of SPMS in clinical practice. The patient should have experienced during at least the previous 6 months and in the absence of any relapse, a worsening in the EDSS score of +1.0 point (if the previous EDSS was≤5.0) or of +0.5 point (if the previous EDSS was≥5.5), with a pyramidal or cerebellar functional system score≥2 and without setting a minimum EDSS score; or, in case of a stable EDSS score≥4.0, a worsening of a functional score. This worsening should be confirmed within 3 to 6 months. According to the MS experts, the patient's age, duration of illness and a minimal threshold EDSS score are only risk factors for transition to SPMS. Patient reports during consultation and cognitive impairment are important warning signs, which should trigger an objective assessment with specific tests or closer monitoring. Clinical relapse and/or MRI activities are non-discriminatory for making the diagnosis of SPMS. ConclusionsThe experts defined precise diagnostic criteria adapted to clinical practice for earlier identification of SPMS, paving the way for better management of this stage of the disease.

Spinal cord lesions and brain grey matter atrophy independently predict clinical worsening in definite multiple sclerosis: a 5-year, multicentre study

ObjectivesTo evaluate the combined contribution of brain and cervical cord damage in predicting 5-year clinical worsening in a multicentre cohort of definite multiple sclerosis (MS) patients.MethodsBaseline 3.0T brain and cervical...

Correlation between patient-reported manual ability and three objective measures of upper limb function in people with multiple sclerosis.

Upper limb (UL) function is often affected in people with multiple sclerosis (PwMS) and is typically assessed through objective measures, including the Nine Hole Peg Test (9-HPT), Box and Block Test (BBT), and Hand Grip Strength (HGS). It is important to include the subjective perspective of PwMS in the assessment. This study aims to evaluate associations between Manual Ability Measure-36 (MAM-36) and 9-HPT, BBT, and HGS in MS. The cross-sectional study included five Italian centers. Inclusion criteria were age ≥ 18 years, MS diagnosis, and stable disease course. Exclusion criteria were bilateral UL paralysis, and concomitant orthopedic or neurological diseases. A total of 199 PwMS were included: 128 female, mean age=50.7± 13.0 years, 119 relapsing-remitting MS (RRMS), 31 primary and 49 secondary progressive MS, mean disease duration=14.0± 10.4, years, mean Expanded Disability Status Scale (EDSS)=4.6± 2.0. The MAM-36 showed small correlations with 9-HPT, BBT, and HGS. Correlations between MAM-36 and 9-HPT and BBT were highest among subjects with EDSS ≥ 6 and progressive MS. MAM-36 and HGS showed the highest correlations in subjects with EDSS ≤ 5 and RRMS. Combining 9-HPT and HGS provided the strongest predictive power over the MAM-36. Correlations between objective measures and MAM-36 were small to moderate, meaning that objective measures do not match subjects' perception of UL function. The combination of 9-HPT and HGS measures can help improve the assessment of UL function in activities of daily living.

Siponimod ameliorates metabolic oligodendrocyte injury via the sphingosine-1 phosphate receptor 5

Multiple sclerosis (MS), an autoimmune-driven, inflammatory demyelinating disease of the central nervous system (CNS), causes irreversible accumulation of neurological deficits to a variable extent. Although there are potent disease-modifying agents for its initial relapsing-remitting phase, immunosuppressive therapies show limited efficacy in secondary progressive MS (SPMS). Although modulation of sphingosine-1 phosphate receptors has proven beneficial during SPMS, the underlying mechanisms are poorly understood. In this project, we followed the hypothesis that siponimod, a sphingosine-1 phosphate receptor modulator, exerts protective effects by direct modulation of glia cell function (i.e., either astrocytes, microglia, or oligodendrocytes). To this end, we used the toxin-mediated, nonautoimmune MS animal model of cuprizone (Cup) intoxication. On the histological level, siponimod ameliorated cuprizone-induced oligodendrocyte degeneration, demyelination, and axonal injury. Protective effects were evident as well using GE180 translocator protein 18-kDa (TSPO) imaging with positron emission tomography (PET)/computed tomography (CT) imaging or next generation sequencing (NGS). Siponimod also ameliorated the cuprizone-induced pathologies in Rag1-deficient mice, demonstrating that the protection is independent of T and B cell modulation. Proinflammatory responses in primary mixed astrocytes/microglia cell cultures were not modulated by siponimod, suggesting that other cell types than microglia and astrocytes are targeted. Of note, siponimod completely lost its protective effects in S1pr5-deficient mice, suggesting direct protection of degenerating oligodendrocytes. Our study demonstrates that siponimod exerts protective effects in the brain in a S1PR5-dependent manner. This finding is not just relevant in the context of MS but in other neuropathologies as well, characterized by a degeneration of the axon-myelin unit.

Quantitative Changes in Gait Parameters after Cycling among Multiple Sclerosis Patients withAtaxia:APilot Study

Introduction: Cerebellar ataxia is a common symptom of multiple sclerosis (MS), particularly in progressive forms, where gait and balance problems are the most debilitating symptoms. Exercise training is a critical component of rehabilitation in managing equilibrium dysfunction, and stationary bicycling is a safe, feasible, and effective method to reduce the symptom. Clinical walking performance tests are typically used to assess gait in these patients. However, gait analysis technologies are more sensitive and accurate at detecting subtle and subclinical changes. The purpose of this study was to determine the changes in gait parameters in MS patients with ataxic gait after using a stationary bicycle.&#x0D; Materials and Methods: Ten secondary progressive MS patients with ataxic gait and a mean expanded disability status scale (EDSS) of four were recruited. The participants cycled on a stationary bike. Gait analysis was performed before and after 12 sessions of cycling. It included spatiotemporal and balance parameter measurements.&#x0D; Results: Gait analysis showed statistically significant changes in spatiotemporal parameters, including speed (P=0.02, r=-0.51), and stride length (P=0.01, r=-0.63). Of balance-related indices, the mediolateral (ML) center of pressure (COP) displacement, anterior and posterior COP overshoot, and COP velocity changes were statistically remarkable after the intervention respectively. (P=0.01, r=-0.63), (P=0.02, r=-0.51), (P=0.03, r=-0.49), (P=0.01, r=-0.54).&#x0D; Conclusion: Gait analysis is applicable to track changes following rehabilitation in individuals with MS. The results indicate that using a stationary bicycle can improve some spatiotemporal and COP-related parameters.

Overall Disability Response Score: An integrated endpoint to assess disability improvement and worsening over time in patients with multiple sclerosis

Background: Overall Disability Response Score (ODRS) is a composite endpoint including Expanded Disability Status Scale, Timed 25-foot Walk, and 9-Hole Peg Test, designed to quantify both disability improvement and worsening in multiple sclerosis (MS). Objective: To assess the sensitivity and clinical meaningfulness of ODRS using natalizumab Phase 3 data sets (AFFIRM in relapsing-remitting MS and ASCEND in secondary progressive MS). Methods: Differences in ODRS over 96 weeks, ODRS at Week 96, and slope of ODRS change per year between natalizumab and placebo groups were analyzed. Correlation between ODRS and changes in patient-reported outcomes was also analyzed. Results: The difference (95% confidence interval (CI)) in the ODRS over 96 weeks between natalizumab and placebo groups was 0.34 (0.21–0.46) in AFFIRM (p < 0.001), and 0.18 (0.03–0.34) in ASCEND (p = 0.021). Significant differences between treatment arms were also observed in ODRS at Week 96 and in the slope of change per year in both studies. There was a significant linear correlation between ODRS at Week 96 and the change from baseline in both the physical and mental components of the 36-item Short Form Survey (SF-36) in both studies. Conclusion: This analysis supports ODRS as a sensitive and potentially clinically meaningful disability outcome measure in MS.

MiR-181a-5p is a potential candidate epigenetic biomarker in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal degeneration. Abnormal expression of microRNAs (miRNAs) plays an important role in MS pathology. In this cohort study, differential expression of the four miRNAs (hsa-miR-155-5p,hsa-miR-9-5p,hsa-miR-181a-5p, and hsa-miR-125b-5p) was investigated in 69 individuals, including 39 MS patients (relapsing-remitting MS (RRMS), n=27; secondary progressive MS (SPMS), n=12) and 30 healthy controls. In silico analyses revealed possible genes and pathways specific to miRNAs. Peripheral blood miRNA expressions were detected by quantitative real-time PCR (qPCR). hsa-miR-181a-5p was downregulated and associated with increased MS risk (P=0.012). The other three miRNAs were upregulated and not associated with MS (P<0.05). The area under the curve (AUC) is 0.779. In silico analyses showed that hsa-miR-181a-5p may participate in MS pathology by targeting MAP2K1,CREB1,ATXN1, and ATXN3 genes in inflammation and neurodegeneration pathways. The circulatory hsa-miR-181a-5p can regulate target genes, reversing the mechanisms involved in MS pathologies such as protein uptake and processing, cell proliferation and survival, inflammation, and neurodegeneration. Thus, this miRNA could be used as an epigenomic-guided diagnostic tool and for therapeutic purpose.

Self-assessment of people with relapsing-remitting and progressive multiple sclerosis towards burden of disease, progression, and treatment utilization—Results of a large-scale cross-sectional online survey (MS Perspectives)

BackgroundAssessment of the disease course by people with multiple sclerosis (pwMS) themselves is important for a better understanding of the complex disease, patient counseling and treatment decisions. This may also facilitate identifying the often-unnoticed transition from relapsing-remitting (RRMS) to secondary progressive multiple sclerosis (SPMS). ObjectiveMS Perspectives was designed to collect data on patients' self-assessment of multiple sclerosis (MS) symptoms, relapse-independent progression, and impact on everyday life. MethodsMS Perspectives is a cross-sectional online survey conducted among adult pwMS in Germany. The questionnaire included 36 items on sociodemographic and clinical characteristics as well as pharmacological and non-pharmacological treatment. ResultsIn total, 4555 pwMS completed the survey between December 2021 and February 2022, 69.2% had RRMS, 15.1% had SPMS. Relapse-independent worsening of symptoms was reported by 88.9% of RRMS patients with marked to severe and by 61.8% with no or mild to moderate disability. Problems with walking were most frequently (32.1%) mentioned as most bothersome by RRMS patients with marked to severe disability, fatigue, and cognitive impairment by RRMS patients with no or mild to moderate disability. ConclusionMS Perspectives gives an important insight in the self-assessed disease course and impact on daily life in a large-scale cohort of pwMS.

TU-187. Blood pressure variability changes are more pronounced in secondary progressive Multiple Sclerosis

TU-187. Blood pressure variability changes are more pronounced in secondary progressive Multiple Sclerosis