Early Stages Of Multiple Sclerosis Research Articles

High-Efficacy Therapies for Treatment-Naïve Individuals with Relapsing-Remitting Multiple Sclerosis.

There are >18 distinct disease-modifying therapy (DMT) options covering 10 mechanisms of action currently approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis (RRMS). Given the multitude of available treatment options, and recent international consensus guidelines offering differing recommendations, there is broad heterogeneity in how the DMTs are used in clinical practice. Choosing a DMT for newly diagnosed patients with MS is currently a topic of significant debate in MS care. Historically, an escalation approach to DMT was used for newly diagnosed patients with RRMS. However, the evidence for clinical benefits of early treatment with high-efficacy therapies (HETs) in this population is emerging. In this review, we provide an overview of the DMT options and MS treatment strategies, and discuss the clinical benefits of HETs (including ofatumumab, ocrelizumab, natalizumab, alemtuzumab, and cladribine) in the early stages of MS, along with safety concerns associated with these DMTs. By minimizing the accumulation of neurological damage early in the disease course, early treatment with HETs may enhance long-term clinical outcomes over the lifetime of the patient.

Brief international cognitive assessment for MS (BICAMS) and global brain volumes in early stages of MS – A longitudinal correlation study

BackgroundCognitive impairment is common in patients with multiple sclerosis, even in the early stages of the disease. The Brief International Cognitive Assessment for multiple sclerosis (BICAMS) is a short screening tool developed to assess cognitive function in everyday clinical practice. ObjectiveTo investigate associations between volumetric brain measures derived from a magnetic resonance imaging (MRI) examination and performance on BICAMS subtests in early stages of multiple sclerosis (MS). MethodsBICAMS was used to assess cognitive function in 49 MS patients at baseline and after one and two years. The patients were separated into two groups (with or without cognitive impairment) based on their performances on BICAMSs subtests. MRI data were analysed by a software tool (MSMetrix), yielding normalized measures of global brain volumes and lesion volumes. Associations between cognitive tests and brain MRI measures were analysed by running correlation analyses, and differences between subgroups and changes over time with independent and paired samples tests, respectively. ResultsThe strongest baseline correlations were found between the BICAMS subtests and normalized whole brain volume (NBV) and grey matter volume (NGV); processing speed r = 0.54/r = 0.48, verbal memory r = 0.49/ r = 0.42, visual memory r = 0.48 /r = 0.39. Only the verbal memory test had significant correlations with T2 and T1 lesion volumes (LV) at both time points; T2LV r = 0.39, T1LV r = 0.38. There were significant loss of grey matter and white matter volume overall (NGV p<0.001, NWV p = 0.003), as well as an increase in T1LV (p = 0.013). The longitudinally defined confirmed cognitively impaired (CCI) and preserved (CCP) patients showed significant group differences on all MRI volume measures at both time points, except for NWV. Only the CCI subgroup showed significant white matter atrophy (p = 0.006) and increase in T2LV (p = 0.029). ConclusionsThe present study found strong correlations between whole brain and grey matter volumes and performance on the BICAMS subtests as well as significant changes in global volumes from baseline to follow-up with clear differences between patients defined as cognitively impaired and preserved at both baseline and follow-up.

An investigation of the effect of brain atrophy on brain injury in multiple sclerosis

Multiple sclerosis (MS) is a disease of the central nervous system (CNS) that affects the brain and spinal cord. It is estimated that the average prevalence of MS is 35.9 cases per 100,000 and a total of 2.8 million people worldwide have MS. Brain atrophy is usually seen in the early stages of MS, and its progress is faster than healthy people. The present study was a numerical study that uses the Fluid–structure interaction (FSI) model to investigate the effect of brain atrophy on brain injury in MS. Firstly, a healthy model was constructed from MRI images and validated by experimental data. Then three models with different degrees of brain atrophy, which showed the rate of brain atrophy in different years in MS patients, were developed to model the brain atrophy in MS. The models were subjected to two different types of impact conditions. Type I, which only produced a translational motion and the HIC value of 744, was applied to each model. Type II produced both translational and rotational motion. In this type of impact, the experimental kinematics, with peaks of 450 g for the translational acceleration and 26.2 krad/s2 for the rotational acceleration, were applied to the nodes that located in the center of gravity of the head models and the results were extracted from each one. According to the results of impact type I, the pressure of the frontal lobe of the brain is 149,647 Pa in the health model and 137,690 Pa in the model with severe atrophy.

The contribution of spinal dorsal horn astrocytes in neuropathic pain at the early stage of EAE

Reactive astrocytes play a complex role in multiple sclerosis, and the astrocytes reactivity is an important factor in the pathogenesis of pain. It is of great significance to explore the genesis and development mechanism of pain in the early stage of multiple sclerosis (MS) for early intervention of the disease. This study aims to explore astrocyte reactivity at different stages of the experimental autoimmune encephalomyelitis (EAE) model, a mouse model of MS, and the role of astrocytes in the pain in the early stage of the EAE. In this study, we demonstrated that spinal dorsal horn astrocytes were activated in the pre-clinical stage of EAE mice, and the inhibition of spinal cord astrocyte reactivity effectively alleviates pain symptoms in EAE mice. On the other hand, spinal cord microglia were not directly participated in the early EAE pain. Moreover, the ion channel LRRC8A mediated the reactivity of spinal dorsal horn astrocytes by regulating the STAT3 pathway, therefore playing a role in the early pain of EAE.

Imaging Characteristics of Choroid Plexuses in Presymptomatic Multiple Sclerosis: A Retrospective Study.

Background and ObjectivesRecent imaging studies have suggested a possible involvement of the choroid plexus (CP) in multiple sclerosis (MS). Here, we investigated whether CP changes are already detectable at the earliest stage of MS, preceding symptom onset.MethodsThis study is a retrospective analysis of 27 patients with presymptomatic MS, 97 patients with clinically definite MS (CDMS), and 53 healthy controls (HCs) who underwent a cross-sectional 3T-MRI acquisition; of which, 22 MS, 19 HCs, and 1 presymptomatic MS (evaluated 8 months before conversion to CDMS) also underwent translocator protein (TSPO) 18F-DPA-714 PET and were included in the analysis. CPs were manually segmented on 3D T1-weighted images for volumetric analysis. CP 18F-DPA-714 uptake, reflecting inflammation, was calculated as the average standardized uptake value (SUV). Multivariable regressions adjusted for age, sex, and ventricular and brain volume were fitted to test CP volume differences between presymptomatic patients and MS or HCs. For the presymptomatic case who also had 18F-DPA-714 PET, CP SUV differences with MS and HCs were assessed through Crawford-Howell tests. To provide further insight into the interpretation of 18F-DPA-714-PET uptake at the CP level, a postmortem analysis of CPs in MS vs HCs was performed to characterize the cellular localization of TSPO expression.ResultsCompared with HCs, patients with presymptomatic MS had 32% larger CPs (β = 0.38, p = 0.001), which were not dissimilar to MS CPs (p = 0.69). Moreover, in the baseline scan of the presymptomatic case who later on developed MS, TSPO PET showed 33% greater CP inflammation vs HCs (p = 0.04), although no differences in 18F-DPA-714 uptake were found in parenchymal regions vs controls. CP postmortem analysis identified a population of CD163+ mononuclear phagocytes expressing TSPO in MS, possibly contributing to the increased 18F-DPA-714 uptake.DiscussionWe identified an imaging signature in CPs at the presymptomatic MS stage using MRI; in addition, we found an increased CP inflammation with PET in a single presymptomatic patient. These findings suggest a role of CP imaging as an early biomarker and argue for the involvement of the blood-CSF barrier dysfunction in disease development.Trial Registration InformationAPHP-20210727144630, EudraCT-Number: 2008-004174-40; ClinicalTrials.gov: NCT02305264, NCT01651520, and NCT02319382.

Preventive exercise in people with early-stage Multiple Sclerosis: preliminary results on walking

People with Multiple Sclerosis (PwMS) suffer from mild impairments of balance and gait since the very early stages of the disease [1,2]. Nonetheless, it has been recently suggested that the prompt administration of preventive rehabilitation at the beginning of the pathology can potentially slow the MS- related functional decline [3]. The present multi-center pilot randomized controlled trial (RCT) aims at preliminarily analyze the effects of a treadmill-based exercise program on walking characteristics in early-stage non-disabled PwMS. The study was supported by FISM (grant N16/17/F14). Twenty-six PwMS (age: 39.4±10.4 years, Expanded Disability Status Scale <=2.5, disease duration<=5 years), not involved in regular physical activity during daily life, were randomized to experimental (EG, N=15) and control group (CG, N=11). Participants allocated to EG underwent sixteen 35-minute sessions (2-3 sessions/week) of a training based on published guidelines [4] and previous study [5]. In particular, the training included 10 minutes of aerobic exercises to increase fitness (e.g. walking at different speed and slopes) and15 minutes of task-oriented balance exercises (e.g. walking with feet in tandem). Participants in the CG were asked to continue their daily-life activity. Both groups were assessed pre- and post-training with the 6-minute Walk test (6MWT) instrumented with 3 inertial sensors (MTw, XSens, NL) on trunk and ankles. Distance walked in 6 minutes at maximum speed was provided as a clinical measure of walking endurance, while a set of instrumented metrics were computed from the inertial sensors to describe the temporal aspects (cadence, stance and double support duration) and the quality of walking (gait regularity, symmetry and local dynamic instability, see [2]). In this preliminary analysis, post-training values were compared between EG and CG using ANCOVA with pre-training scores as covariates. For each variable, the effect size (ES) was provided by computing Cohen’s d . Pre-training demographic, clinical and instrumented data were comparable between groups. After adjusting for pre-treatment score, no between-group difference was found in post-training 6MWT (mean ± SE; EG: 573 ± 8 m; CG: 571 ± 9 m, p=0.896, ES: 0.07). Instrumented metrics showed that, after the treatment, EG was characterized by lower double support time (EG: 6.1±0.6%stride; CG: 8.5±0.6%stride, p=0.008, ES: -1.14), increased antero-posterior gait symmetry (EG: 88.4±2.3 a.u.; CG: 81.1±2.6 a.u., p=0.049, ES: 0.86), and reduced vertical local dynamic instability (EG: 0.80±0.02 a.u.; CG: 0.88±0.03 a.u., p=0.04, ES: -0.89) compared to CG. No statistically significant difference between groups were found in the other variables. The preliminary results of this pilot RCT on early-stage PwMS suggested that the proposed treadmill training seems to be efficacious (at least in the short term) in improving gait quality rather than walking endurance. In particular, compared to CG, EG showed after the training increased gait symmetry and improved dynamic balance, as shown by the reduction of double support time and the decrease of local dynamic instability, the latter indicating an improved ability of the locomotor system to cope with small perturbations naturally occurring during walking. Importantly, the large effect sizes (|ES|>0.8) in instrumented metrics suggested their high sensitivity in detecting subtle improvements not easily measurable with clinical scales. Future studies on larger samples should be performed to confirm the present findings and assess the long-term effects of the proposed training.

Dysregulated Sulfide Metabolism in Multiple Sclerosis: Serum and Vascular Endothelial Inflammatory Responses.

Multiple sclerosis (MS) is a leading cause of neurodegenerative disability in younger individuals. When diagnosed early, MS can be managed more effectively, stabilizing clinical symptoms and delaying disease progression. The identification of specific serum biomarkers for early-stage MS could facilitate more successful treatment of this condition. Because MS is an inflammatory disease, we assessed changes in enzymes of the endothelial hydrogen sulfide (H2S) pathway in response to inflammatory cytokines. Blotting analysis was conducted to detect Cystathionine γ-lyase (CSE), Cystathionine beta synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (MST) in human brain microvascular endothelial apical and basolateral microparticles (MPs) and cells following exposure to tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). CSE was increased in MPs and cells by exposure to TNF-α/IFN-γ; CBS was elevated in apical MPs but not in cells or basolateral MPs; MST was not significantly affected by cytokine exposure. To test how our findings relate to MS patients, we evaluated levels of CSE, CBS, and MST in serum samples from healthy control and MS patients. We found significantly decreased levels of CBS and MST (p = 0.0004, 0.009) in MS serum samples, whereas serum levels of CSE were marginally increased (p = 0.06). These observations support increased CSE and lower CBS and MST expression being associated with the vascular inflammation in MS. These changes in endothelial-derived sulfide enzymes at sites of inflammation in the brain may help to explain sulfide-dependent changes in vascular dysfunction/neuroinflammation underlying MS. These findings further support the use of serum samples to assess enzymatic biomarkers derived from circulating MPs. For example, “liquid biopsy” can be an important tool for allowing early diagnosis of MS, prior to the advanced progression of neurodegeneration associated with this disease.

Better cognitive function predicts maintenance of dual-task walking ability over time among people with relapsing-remitting MS.

Physical fitness and preserved cognitive function may provide neuroprotection in multiple sclerosis (MS), but few studies have examined their role in symptom progression over time. Dual-task paradigms can be useful to detect subtle impairment among people with MS in early stages of the disease. The present study investigated whether higher aerobic fitness or greater cognitive function could predict performance in dual-task walking 1-2 years later among people with mild or no MS-related walking impairment. Participants (n = 50) performed dual-task walking (walking while serially subtracting 7's from 100), completed the Montreal Cognitive Assessment (MoCA), the Symbol Digit Modalities Test (SDMT), and a fitness test (VO2max). They were tested at two time points (T1 and T2), approximately 1 year apart. Walking speed, MoCA, SDMT, and VO2max at baseline (T1) were examined as predictors of dual-task walking speed at T2. MoCA (higher score), but not SDMT or fitness, was significantly correlated with percentage decrease in dual-task walking and was a significant predictor of dual-task-walking speed at T2, accounting for additional 6.1% of its variance. Cognitive impairment (MoCA < 26) at baseline corresponded to a 12 cm/s unit decrease in dual-task-walking speed at T2. Our results provide longitudinal evidence that better cognitive function, specifically global MoCA score, may protect against decline in dual-task walking ability over the years. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The use of functional near infrared spectroscopy and gait analysis to characterize cognitive and motor processing in early-stage patients with multiple sclerosis.

BackgroundDual-task paradigms are a known tool to evaluate possible impairments in the motor and cognitive function in patients with multiple sclerosis (MS). A technique to evaluate the cortical function during movement is functional near-infrared spectroscopy (fNIRS). The evaluation of the MS course or its treatment by associating fNIRS with gait measurements may be flexible and low-cost; however, there are no feasibility studies in the literature using these combined techniques in early-stage patients with MS.ObjectiveTo evaluate cortical hemodynamics using fNIRS and gait parameters in patients at early stages of MS and in healthy controls during a dual-task paradigm.MethodsParticipants performed cognitive tasks while walking to simulate daily activities. Cortical activation maps and gait variability were used to evaluate differences between 19 healthy controls and 20 patients with MS.Results and conclusionThe results suggest an enhanced cortical activation in the motor planning areas already at the early stages of MS when compared to controls. We have also shown that a systematic analysis of the spatiotemporal gait variability parameters indicates differences in the patient population. The association of cortical and gait parameters may reveal possible compensatory mechanisms related to gait during dual tasking at the early stages of the disease.

Delayed cognitive processing and treatment status quo bias in early-stage multiple sclerosis

BackgroundThe evolving therapeutic landscape requires more participation of patients with relapsing remitting multiple sclerosis (RRMS) in treatment decisions. The aim of this study was to assess the association between patient's self-perception, cognitive impairment and behavioral factors in treatment choices in a cohort of patients at an early stage of RRMS. MethodsWe conducted a multicenter, non-interventional study including adult patients with a diagnosis of RRMS, a disease duration ≤18 months and receiving care at one of the 21 participating MS centers from across Spain. We used patient-reported measures to gather information on fatigue, mood, quality of life, and perception of severity of their MS. Functional metrics (Expanded Disability Status Scale [EDSS], cognitive function by the Symbol Digit Modalities Test [SDMT], 25-foot walk test) and clinical and radiological data were provided by the treating neurologist. The primary outcome of the study was status quo (SQ) bias, defined as participant's tendency to continue taking a previously selected but inferior treatment when intensification was warranted. SQ bias was assessed based on participants treatment preference in six simulated RRMS case scenarios with evidence of clinical relapses and radiological disease progression. ResultsOf 189 participants who met the inclusion criteria, 188 (99.5%) fully completed the study. The mean age was 36.6 ± 9.5 years, 70.7% female, mean disease duration: 1.2 ± 0.8 years, median EDSS score: 1.0 [IQR=0.0–2.0]). Overall, 43.1% patients (n = 81/188) had an abnormal SDMT (≤49 correct answers). SQ bias was observed in at least one case scenario in 72.3% (137/188). Participant's perception of their MS severity was associated with higher SQ bias (β coeff 0.042; 95% CI 0.0074–0.076) among those with delayed cognitive processing. Higher baseline EDSS and number of T2 lesions were predictors of delayed processing speed (OR EDSS=1.57, 95% CI: 1.11–2.21, p = 0.011; OR T2 lesions=1.50, 95% CI: 1.11–2.03, p<0.01). Bayesian multilevel model accounting for clustering showed that delayed cognitive processing (exp coeff 1.06; 95% CI 1.04–1.09) and MS symptoms severity (exp coeff 1.28; 95% CI 1.22–1.33) were associated with SQ bias. ConclusionOver 40% of patients in earlier stages of RRMS experience delays in cognitive processing that might affect their decision-making ability. Our findings suggest that patients' self-perception of disease severity combined with a delay in cognitive processing would affect treatment choices leading to status quo bias early in the course of their disease.

High leukocyte-to-lymphocyte ratio is associated with acute relapse in multiple sclerosis patients

ABSTRACT Background Multiple sclerosis (MS) is an immune-mediated chronic disease characterized by inflammatory demyelination in the central nervous system (CNS). As there is limited evidence on whether leukocyte-to-lymphocyte ratios (LLRs) are associated with MS, we carried out an investigation on the association between LLRs and MS as favorable markers and aimed to determine the cut-off LLR for the identification of early-stage MS patients. Methods A matched case-control study enrolled a total of 120 MS inpatients and 120 age- and sex-matched non-MS inpatients from January 2013 to June 2018. LLRs were tested from peripheral venous blood routinely during hospitalization. Conditional logistic regression analyses were used to explore differences in LLRs between cases and controls. Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic ability of LLRs and determine the best cut-off value. Disease disability was assessed using the Expanded Disability Status Scale (EDSS). Results The LLR was significantly associated with MS in hospitalized patients (OR: 2.372, 95% CI: 1.282 to 4.387, p < 0.001) after adjusting for potential confounders. The area under the curve (AUC) value was 0.793 (95% CI: 0.736 to 0.851). The cut-off value for LLR was 3.18, with sensitivity and specificity values of 62.5% (95% CI: 53.2% to 71.2%) and 88.3% (95% CI: 81.2% to 93.5%), respectively. The EDSS scores of the higher LLR group were significantly higher than the lower group. Conclusion Systemic inflammation measured using LLRs may be an inflammatory marker among MS inpatients. LLRs may serve as favorable inflammatory markers with which to discriminate MS among Chinese subjects.

CTGF/CCN2 has a possible detrimental role in the inflammation and the remyelination failure in the early stages of multiple sclerosis

Connective tissue growth factor (CTGF/CCN2) is a proinflammatory and an oligodendrocyte-differentiating blocking agent. It is found in MS lesions, which raises the possibility of involvement in MS pathogenesis. We found that its CSF and serum levels were higher in RR-MS patients than in controls and for serum compared to PP and SP-MS. Immune cells of both RR-MS and controls secreted CTGF/CCN2, which was enhanced by CD3/CD28 stimulation or by LPS. Anti-CTGF treatment of mice with experimental autoimmune encephalitis ameliorated its clinical severity. CTGF/CCN2 may play a role in the immune pathogenesis of MS and in remyelination failure in early stages of MS.

Involvement of the Intestinal Microbiota in the Appearance of Multiple Sclerosis: Aloe vera and Citrus bergamia as Potential Candidates for Intestinal Health.

Multiple sclerosis (MS) is a neurological and inflammatory autoimmune disease of the Central Nervous System in which selective activation of T and B lymphocytes prompts a reaction against myelin, inducing demyelination and axonal loss. Although MS is recognized to be an autoimmune pathology, the specific causes are many; thus, to date, it has been considered a disorder resulting from environmental factors in genetically susceptible individuals. Among the environmental factors hypothetically involved in MS, nutrition seems to be well related, although the role of nutritional factors is still unclear. The gut of mammals is home to a bacterial community of about 2000 species known as the “microbiota”, whose composition changes throughout the life of each individual. There are five bacterial phylas that make up the microbiota in healthy adults: Firmicutes (79.4%), Bacteroidetes (16.9%), Actinobacteria (2.5%), Proteobacteria (1%) and Verrucomicrobia (0.1%). The diversity and abundance of microbial populations justifies a condition known as eubiosis. On the contrary, the state of dysbiosis refers to altered diversity and abundance of the microbiota. Many studies carried out in the last few years have demonstrated that there is a relationship between the intestinal microflora and the progression of multiple sclerosis. This correlation was also demonstrated by the discovery that patients with MS, treated with specific prebiotics and probiotics, have greatly increased bacterial diversity in the intestinal microbiota, which might be otherwise reduced or absent. In particular, natural extracts of Aloe vera and bergamot fruits, rich in polyphenols and with a high percentage of polysaccharides (mostly found in indigestible and fermentable fibers), appear to be potential candidates to re-equilibrate the gut microbiota in MS patients. The present review article aims to assess the pathophysiological mechanisms that reveal the role of the microbiota in the development of MS. In addition, the potential for supplementing patients undergoing early stages of MS with Aloe vera as well as bergamot fibers, on top of conventional drug treatments, is discussed.

Altered functional brain states predict cognitive decline 5 years after a clinically isolated syndrome

Background: Cognitive impairment occurs in the earliest stages of multiple sclerosis (MS) together with altered functional connectivity (FC). Objective: The aim of this study was to investigate the evolution of dynamic FC states in early MS and their role in shaping cognitive decline. Methods: Overall, 32 patients were enrolled after their first neurological episode suggestive of MS and underwent cognitive evaluation and resting-state functional MRI (fMRI) over 5 years. In addition, 28 healthy controls were included at baseline. Results: Cognitive performance was stable during the first year and declined after 5 years. At baseline, the number of transitions between states was lower in MS compared to controls (p = 0.01). Over time, frequency of high FC states decreased in patients (p = 0.047) and increased in state with low FC (p = 0.035). Cognitive performance at Year 5 was best predicted by the mean connectivity of high FC state at Year 1. Conclusion: Patients with early MS showed reduced functional network dynamics at baseline. Longitudinal changes showed longer time spent in a state of low FC but less time spent and more connectivity disturbance in more integrative states with high within- and between-network FC. Disturbed FC within this more integrative state was predictive of future cognitive decline.

Treatment Status and Healthcare Cost Trends for Patients with Multiple Sclerosis in Japan: A Claims Database Analysis.

IntroductionThe healthcare situation of multiple sclerosis (MS) and its course are not being thoroughly investigated in Japan. We aimed to examine the current healthcare situation, including treatment and healthcare costs, of MS according to duration since its first diagnosis using Japanese real-world data to determine unidentified healthcare issues at each disease stage.MethodsThis retrospective, non-comparative, non-interventional study used a Japanese nationwide claims database (April 2008–August 2018) comprising 20 million patients from 329 acute care hospitals (as of June 2018). Treatment patterns, comorbidities, healthcare resource utilization, and healthcare costs were analyzed using longitudinal analyses of patients with MS according to duration since the first diagnosis. The time from diagnosis to first treatment was examined using Kaplan–Meier analysis.ResultsWe identified 7067 patients with MS [mean (standard deviation) age at first diagnosis 45.0 (16.2) years]. About 70% of the patients did not receive disease-modifying therapy (DMT) within the first year of diagnosis. The frequency of DMT use decreased in patients with a longer duration since the first diagnosis. MS treatment costs tended to increase with a longer duration from the first diagnosis until 9 years, followed by a tendency to decrease; contrastingly, other healthcare costs tended to increase with duration after decreasing from the year of the first diagnosis to the next year. The frequencies of hospitalizations and hospital visits, healthcare costs—excluding those for MS treatment and tests—and prevalence of comorbidities tended to be higher in patients with a longer duration since the first diagnosis.ConclusionA considerable proportion of patients did not receive DMT, suggesting that patients with early-stage MS may lose the opportunity to improve their prognosis through early intervention with DMT. Among patients with a longer duration since the first diagnosis, fewer treatment choices may be available despite the larger clinical and treatment burden.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-022-00374-4.

Gait stability reflects motor tracts damage at early stages of multiple sclerosis

Background: Gait in people with multiple sclerosis (PwMS) is affected even when no changes can be observed on clinical examination. A sensitive measure of gait deterioration is stability; however, its correlation with motor tract damage has not yet been established. Objective: To compare stability between PwMS and healthy controls (HCs) and determine associations between stability and diffusion magnetic resonance image (MRI) measures of axonal damage in selected sensorimotor tracts. Methods: Twenty-five PwMS (Expanded Disability Status Scale (EDSS) < 2.5) and 15 HCs walked on a treadmill. Stability from sacrum (LDESAC), shoulder (LDESHO) and cervical (LDECER) was calculated using the local divergence exponent (LDE). Participants underwent a 7T-MRI brain scan to obtain fibre-specific measures of axonal loss within the corticospinal tract (CST), interhemispheric sensorimotor tract (IHST) and cerebellothalamic tract (CTT). Correlation analyses between LDE and fibre density (FD) within tracts, fibre cross-section (FC) and FD modulated by FC (FDC) were conducted. Between-groups LDE differences were analysed using analysis of variance (ANOVA). Results: Correlations between all stability measures with CSTFD, between CSTFDC with LDESAC and LDECER, and LDECER with IHSTFD and IHSTFDC were significant yet moderate (R < −0.4). Stability was significantly different between groups. Conclusions: Poorer gait stability is associated with corticospinal tract (CST) axonal loss in PwMS with no-to-low disability and is a sensitive indicator of neurodegeneration.

Serum-Based Biomarkers in Neurodegeneration and Multiple Sclerosis.

Multiple Sclerosis (MS) is a debilitating disease with typical onset between 20 and 40 years of age, so the disability associated with this disease, unfortunately, occurs in the prime of life. At a very early stage of MS, the relapsing-remitting mobility impairment occurs in parallel with a progressive decline in cognition, which is subclinical. This stage of the disease is considered the beginning of progressive MS. Understanding where a patient is along such a subclinical phase could be critical for therapeutic efficacy and enrollment in clinical trials to test drugs targeted at neurodegeneration. Since the disease course is uneven among patients, biomarkers are needed to provide insights into pathogenesis, diagnosis, and prognosis of events that affect neurons during this subclinical phase that shapes neurodegeneration and disability. Thus, subclinical cognitive decline must be better understood. One approach to this problem is to follow known biomarkers of neurodegeneration over time. These biomarkers include Neurofilament, Tau and phosphotau protein, amyloid-peptide-β, Brl2 and Brl2-23, N-Acetylaspartate, and 14-3-3 family proteins. A composite set of these serum-based biomarkers of neurodegeneration might provide a distinct signature in early vs. late subclinical cognitive decline, thus offering additional diagnostic criteria for progressive neurodegeneration and response to treatment. Studies on serum-based biomarkers are described together with selective studies on CSF-based biomarkers and MRI-based biomarkers.

Outcome of short‐term physiotherapy intervention program on early stage of multiple sclerosis ‐ A case report

INTRODUCTIONMultiple sclerosis is a chronic autoimmune progressive disease of demyelination of central nervous system with subsequent axonal damage. The symptoms are due to central nervous system lesions resulting from loss of oligodendrocytes, which myelinates CNS leading to tingling and numbness of limbs and reactive gliosis with no cure for the disease. But CNS diseased effects are often controlled through rehabilitation.OBJECTIVE OF THE STUDYThe aim of this study is to observe the importance of early physiotherapy rehabilitation along with immunosuppressants to suppress and reduce the symptoms and slows down the disease process beginning from the initial day of hospitalization to six weeks which causes progression in the patient reducing the incapacity and improves functional measures and quality of life in multiple sclerosis patients. Muscle weakness, and spasticity, balance and coordination can be improved through stretching and strengthening exercises.METHODPatient strictly followed intervention for a period of six weeks under the supervision of Physiotherapist. Intervention includes strengthening, aerobic conditioning, flexibility exercises, coordination exercise, balance exercises, gait training using assistive devices, sensory, functional, bowel and bladder control training. Interventions were gradually progressed up to the patient every week according to their symptoms. Patient was assessed in 1st and 7th week using the outcome measures namely Functional independence measure (FIM) and Short Form survey‐12 (SF‐12) assessing the impact of health on patient’s everyday quality of life.RESULTSAfter the 7th week re‐assessment, it has been shown there is a difference in the value of outcome measures. FIM level has improved from 3‐moderate assistance with helper to 6‐modified independence without helper. SF‐12 physical score showed marked improvement from 48.020307 to 56.57706 while SF‐12 mental score change showed very minor change.CONCLUSIONMultiple sclerosis disease impairment is primarily a consequence of disease progress, but it can be aggravated by reduced physical activity leading to muscle weakness, decreased ROM, spasticity. Exercise and training have been shown to improve the above said deteriorations in multiple sclerosis patients and certainly can be alleviated.Score through FIM and Health survey scale are tabulated as follows Outcome measure Preintervention Postintervention FIM, Functional Independent Measure (in scales) 3‐‐ Moderate Assistance(&gt;= 50%): Helper‐Modified Dependance 6‐‐ Modified, Independence (Device): No Helper SF‐12, Quality of life measure PCS‐12 (Physical Score): 48.020307 MCS‐12 (Mental Score): 59.04606 PCS‐12 (Physical Score): 56.57706 MCS‐12 (Mental Score): 60.75781

Multimodal Evoked Potentials as Potential Biomarkers of Disease Activity in Patients With Clinically Isolated Syndrome.

ObjectiveThere is an ongoing search for markers useful in monitoring and predicting disease activity at the early stage of multiple sclerosis (MS). The goals of this study were to prospectively evaluate the changes in parameters of multimodal evoked potentials (EP) and cognition within a 3-year follow-up period in patients with clinically isolated syndrome (CIS), and to assess the prognostic value of baseline findings with regard to the disease outcomes.MethodsIn 29 patients (20 women, nine men, mean age 31.1) multimodal (visual, brainstem auditory, somatosensory, event-related) EP and neuropsychological tests (NT) were performed at baseline (T0) and after 1 (T1) and 3 (T3) years. Their results were compared longitudinally between baseline, T1, and T3. Baseline results confirmed conversion of CIS into multiple sclerosis (MS) and disability level at T1 and T3 using multiple comparisons and a logistic regression model.ResultsApart from mean N13/P16 SEP (somatosensory evoked potentials) amplitude (lower at T1 and T3 than at baseline (T0 1.02 ± 0.37 μV, T1 0.90 ± 0.26 μV, T3 0.74 ± 0.32 μV, p < 0.05 for both comparisons), no significant changes of EP or NT parameters were found in longitudinal assessment. Baseline P300 Pz latency was longer for the patients with MS than for those with CIS at T1 (352.69 vs. 325.56 ms). No predictive value was shown for any of the analyzed baseline variables with regard to conversion from CIS into MS.SignificanceBaseline ERP abnormalities were associated with their short-term conversion into MS. ERP are worth considering in multimodal EP evaluation at the early stage of MS.

How patients with multiple sclerosis acquire disability.

Patients with multiple sclerosis acquire disability either through relapse-associated worsening (RAW) or progression independent of relapse activity (PIRA). This study addresses the relative contribution of relapses to disability worsening over the course of the disease, how early progression begins and the extent to which multiple sclerosis therapies delay disability accumulation.Using the Novartis-Oxford multiple sclerosis (NO.MS) data pool spanning all multiple sclerosis phenotypes and paediatric multiple sclerosis, we evaluated ∼200 000 Expanded Disability Status Scale (EDSS) transitions from >27 000 patients with ≤15 years follow-up. We analysed three datasets: (i) A full analysis dataset containing all observational and randomized controlled clinical trials in which disability and relapses were assessed (n = 27 328); (ii) all phase 3 clinical trials (n = 8346); and (iii) all placebo-controlled phase 3 clinical trials (n = 4970). We determined the relative importance of RAW and PIRA, investigated the role of relapses on all-cause disability worsening using Andersen-Gill models and observed the impact of the mechanism of worsening and disease-modifying therapies on the time to reach milestone disability levels using time continuous Markov models.PIRA started early in the disease process, occurred in all phenotypes and became the principal driver of disability accumulation in the progressive phase of the disease. Relapses significantly increased the hazard of all-cause disability worsening events; following a year in which relapses occurred (versus a year without relapses), the hazard increased by 31–48% (all P < 0.001). Pre-existing disability and older age were the principal risk factors for incomplete relapse recovery. For placebo-treated patients with minimal disability (EDSS 1), it took 8.95 years until increased limitation in walking ability (EDSS 4) and 18.48 years to require walking assistance (EDSS 6). Treating patients with disease-modifying therapies delayed these times significantly by 3.51 years (95% confidence limit: 3.19, 3.96) and 3.09 years (2.60, 3.72), respectively. In patients with relapsing-remitting multiple sclerosis, those who worsened exclusively due to RAW events took a similar length of time to reach milestone EDSS values compared with those with PIRA events; the fastest transitions were observed in patients with PIRA and superimposed relapses.Our data confirm that relapses contribute to the accumulation of disability, primarily early in multiple sclerosis. PIRA begins in relapsing-remitting multiple sclerosis and becomes the dominant driver of disability accumulation as the disease evolves. Pre-existing disability and older age are the principal risk factors for further disability accumulation. The use of disease-modifying therapies delays disability accrual by years, with the potential to gain time being highest in the earliest stages of multiple sclerosis.