Progressive Multiple Sclerosis Patients Research Articles

Loss of miR-145 promotes remyelination and functional recovery in a model of chronic central demyelination

Strategies for treating progressive multiple sclerosis (MS) remain limited. Here, we found that miR-145-5p is overabundant uniquely in chronic lesion tissues from secondary progressive MS patients. We induced both acute and chronic demyelination in miR-145 knockout mice to determine its contributions to remyelination failure. Following acute demyelination, no advantage to miR-145 loss could be detected. However, after chronic demyelination, animals with miR-145 loss demonstrated increased remyelination and functional recovery, coincident with altered presence of astrocytes and microglia within the corpus callosum relative to wild-type animals. This improved response in miR-145 knockout animals coincided with a pathological upregulation of miR-145-5p in wild-type animals with chronic cuprizone exposure, paralleling human chronic lesions. Furthermore, miR-145 overexpression specifically in oligodendrocytes (OLs) severely stunted differentiation and negatively impacted survival. RNAseq analysis showed altered transcriptome in these cells with downregulated major pathways involved in myelination. Our data suggest that pathological accumulation of miR-145-5p is a distinctive feature of chronic demyelination and is strongly implicated in the failure of remyelination, possibly due to the inhibition of OL differentiation together with alterations in other glial cells. This is mirrored in chronic MS lesions, and thus miR-145-5p serves as a potential relevant therapeutic target in progressive forms of MS.

Co-supplementation of synbiotics and anti-inflammatory-antioxidant rich diet in patients with progressive forms of multiple sclerosis: A single-center, randomized clinical trial

BACKGROUND: The relationship between dietary modification and Multiple Sclerosis (MS)-related disability has been emphasized in several researches. AIMS: To determine whether a co-administration of anti-inflammatory-antioxidant rich diet and synbiotics might improve clinical manifestations in progressive MS patients. METHODS: The study involved 70 patients with progressive MS (primary-progressive, secondary-progressive, and progressive-relapsing) who were randomized to receive either intervention (synbiotics capsule plus an anti-inflammatory-antioxidant-rich diet) or placebo. Quality of Life (QOL), Expanded Disability Status Scale (EDSS), and depression-anxiety scores were evaluated before and after the follow-up. Analysis of covariance was performed for final analysis (SPSS v.14). RESULTS: Significant reductions were seen in EDSS (2.6±1.1 to 2.4±1.0, P < 0.001), State Anxiety Inventory (53.7±10.3 to 47.8±10.6, P < 0.001), and QOL scores after four months of intervention. No significant difference was seen across the depression severity (Δ for intervention = –2.2±5.5 vs. Δ for control = –0.6±5.7; P = 0.264). CONCLUSION: This study demonstrates that a combination of synbiotics and diet could be a promising strategy to improve severity and clinical manifestations of progressive MS.

The Cognitive Reserve May Influence Fatigue after Rehabilitation in Progressive Multiple Sclerosis: A Secondary Analysis of the RAGTIME Trial

Cognitive reserve (CR) seems to be an ability to adapt cognitive processes in response to brain disease and may influence rehabilitation outcomes. This is a secondary analysis of the “Robot-Assisted Gait Training versus conventional therapy on mobility in severely disabled progressive MultiplE sclerosis patients” (RAGTIME) trial to investigate the influence of CR on the outcomes after gait rehabilitation in people with multiple sclerosis (PwMS). We included 53 PwMS and severe gait disability (EDSS 6–7). The participants were randomized into two groups to receive either robot-assisted gait training or overground walking (three times/week over four weeks). CR was evaluated by the Cognitive Reserve Index questionnaire (CRIq), which encompasses three sections (CRI Education, CRI Working Activity, and CRI Leisure Time). We stratified the patients using the 115 cut-off CRIq total score of at least a medium-high CR. The outcome measures were Timed 25-Foot Walk, 6 min walking test, Berg Balance Scale, Multiple Sclerosis Impact Scale—29, Multiple Sclerosis Walking Scale—12, Patient Health Questionnaire—9, and Fatigue Severity Scale (FSS). After gait rehabilitation, the FSS was significantly improved in those patients with higher CR compared with the others (F = 4.757, p = 0.015). In our study, CR did not affect the gait, balance, disability perception, and depression. Conversely, it positively influenced the fatigue after gait rehabilitation.

Analysis of potential microRNA biomarkers for multiple sclerosis

Multiple sclerosis (MS) is a chronic demyelinating autoimmune neurodegenerative disorder for which no specific blood biomarker is available. MicroRNAs (miRNAs) have been investigated for their diagnostic potential in MS. However, MS-associated miRNAs are rarely replicated in different MS populations, thus impeding their use in clinical testing. Here, we evaluated the fold expression of seven reported MS miRNAs associated with MS incidence and clinical characteristics in 76 MS patients and 75 healthy control plasma samples. We found miR-23a-3p to be upregulated in relapsing-remitting MS (RRMS), while miR-326 was downregulated. MiR-150-5p and -320a-3p were significantly downregulated in secondary progressive MS (SPMS) patients compared to RRMS. High disability was associated with low miR-320a-3p, whereas low BDNF levels were associated with upregulation of miR-150-5p and downregulation of miR-326 expression in the total cohort. MiR-23a-3p and miR-326 showed significant diagnostic sensitivity, specificity, and accuracy for RRMS diagnosis. In addition, miR-150-5p and miR-320a-3p had comparable significant diagnostic test performance metrics distinguishing SPMS from RRMS. Therefore, there is potential for including miR-23a-3p and miR-326 in an RRMS diagnostic miRNA panel. Moreover, we have shown that miR-150-5p and miR-320a-3p could be novel RRMS conversion to SPMS biomarkers. The use of these miRNAs in MS diagnosis and prognosis warrants further investigation.

A clinical case of a severe course of the COVID-­19 in a patient with primary progressive multiple sclerosis

Coronavirus disease-2019 (COVID-19), despite the emergence of new pathogen variants, remains the leading cause of acute respiratory viral infections and can be severe in patients with concomitant chronic diseases, including multiple sclerosis (MS). Increased risks of complicated COVID-19 were more often observed in elderly MS patients, males, those with significant physical activity limitations, and progressive disease. While the majority of patients in this category, according to the literature, were characterised by a mild course of COVID-19, even compared to the general population. There are reports that the prolonged quarantine that accompanied the coronavirus pandemic had a negative impact on patients with progressive MS by reducing patients’ physical activity, increasing body weight, and increasing the incidence of depression. Primary progressive MS patients account for about 15 % of all MS patients. They are characterised by a relatively rapid increase in disability and limitation of motor activity. The article presents a clinical case of severe coronavirus disease in an elderly patient with primary progressive MS. The authors note the wave-like course of the immunopathological stage of COVID-19, which was characterised by both the increase in signs of intoxication, fever and respiratory failure, and the prolonged preservation of elevated markers of the inflammatory process (C-reactive protein). Positive dynamics was obtained after prescribing intravenous immunoglobulins, but the patient’s motor activity was significantly limited, general weakness and fatigue increased, and the ability to care for oneself in bed remained. The patient lost the ability to independently move from the bed to the wheelchair.

The Prevalence and Impact of Urinary Incontinence on Multiple Sclerosis Patients in Taif City, Saudi Arabia.

Introduction Multiple sclerosis (MS) is a chronic inflammatory diseasethat results in demyelination and progressive loss of nerve cells within the central nervous system. Multiple sclerosis, as well as other neurological diseases that impact brain structures and spinal pathways involved in sphincter control, may cause lower urinary tract symptoms (LUTS) Our aims are to determine the prevalence, severity, and impact on the quality of life of urinary incontinence among MS patients in Taif, Saudi Arabia, as well as its potential association with demographics and clinical features. Method A cross-sectional study included 150 of MS patients aged 18 yearsand older who completed the validated Arabic versions of both the International Consultation on Incontinence Questionnaire Overactive Bladder (ICIQ-OAB) and the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form(ICIQ-UI SF).In addition, other clinical parameters were collected from the medical records of patients. The data were analyzed using Statistical Package for the Social Sciences (SPSS) version 26 (IBM Inc., Armonk, New York). Qualitative data were expressed as numbers and percentages, and the Chi-squared test (χ2) was employed. Quantitative data were expressed as means with standard deviation (mean ± SD). Result 67.3% of the participants were female; the mean ICIQ UI and ICIQ OAB scores in these MS patients were found to be 6.30 ± 6.26 and 5.32 ± 3.76, respectively. They were significantly higher in progressive MS patients compared to relapsing-remitting MS patients (p<0.05). There was a high positive correlation obtained between ICIQ UI and ICIQ OAB scores (rho=0.801, p<0.001). Conclusion The findings of this study showed that urinary incontinence was a common and distressing symptom experienced by individuals with MS. The severity of UI symptoms was significantly more in progressive multiple sclerosis compared to relapsing-remitting multiple sclerosis.

Symbol Digit Modalities Test in progressive multiple sclerosis.

The Symbol Digit Modalities Test (SDMT) is a highly sensitive neuropsychological tool used for the assessment of information processing speed (IPS) in various neurological disorders. In this review, we have focused on the current knowledge regarding the use of SDMT selectively in the evaluation of progressive multiple sclerosis (PMS) patients. A literature review was performed regarding the application of SDMT in PMS, with a focus on the primary progressive and secondary progressive subtypes. Relationships of diverse disease-associated factors with SDMT have been described, including disease course, imaging findings, molecular biomarkers, treatment and others. SDMT is a very useful and easily applicable instrument in the diagnostic armamentarium of neurologists and neuropsychologists. It is especially valuable in the evaluation of PMS patients, in whom the prevalence of IPS deficits is higher than in relapsing-remitting multiple sclerosis subjects or in healthy individuals. An emphasis should be laid on larger study groups and differentiating between individual PMS subtypes and their separate analysis in the context of cognitive assessment.

Prevalence and Associated Clinical Characteristics of Walking-Related Motor, Cognitive, and Fatigability in Progressive Multiple Sclerosis: Baseline Results From the CogEx Study

Background: People with progressive multiple sclerosis (PMS) present motor (eg, walking) and cognitive impairments, and report fatigue. Fatigue encompasses fatigability which is objectively measured by the capacity to sustain a motor or cognitive task. Objective: To investigate the prevalence of walking and cognitive fatigability (CF) and the associated clinical characteristics in a large sample of PMS patients. Methods: PMS patients (25-65 years old) were included from 11 sites (Europe and North America), having cognitive impairment (1.28 standard deviation below normative data for the symbol digit modality test [SDMT]). Walking fatigability (WF) was assessed using the distance walk index (DWI) and CF using the SDMT (scores from the last 30 seconds compared to the first 30 seconds). Additional measures were: cognitive assessment—Brief International Cognitive Assessment for multiple sclerosis (MS), cardiorespiratory fitness, 6-minute walk, physical activity, depressive symptoms, perceived fatigue—Modified Fatigue Impact Scale (MFIS), MS impact—MSIS-29, and walking ability. Results: Of 298 participants, 153 (51%) presented WF (DWI = −28.9 ± 22.1%) and 196 (66%) presented CF (−29.7 ± 15%). Clinical characteristics (EDSS, disease duration, and use of assistive device) were worse in patients with versus without WF. They also presented worse scores on MSIS-29 physical, MFIS total and physical and reduced physical capacity. CF patients scored better in the MSIS-29 physical and MFIS psychosocial, compared to non-CF group. Magnitude of CF and WF were not related. Conclusions: Half of the cognitively-impaired PMS population presented WF which was associated with higher disability, physical functions, and fatigue. There was a high prevalence of CF but without strong associations with clinical, cognitive, and physical functions. Trial Registration Number: The “CogEx-study,” www.clinicaltrial.gov identifier number: NCT03679468.

Progressive Multiple Sclerosis Patients Requiring Special Attention as a Group at Risk for Coronavirus Infection

In January 2020, a novel coronavirus was identified by the Chinese Center for Disease Control and Prevention (CDC) and was subsequently named 2019­nCoV (Li et al., 2020). Coronavirus disease 2019 (COVID-19) has spread to many countries in 2020.

Potential Metabolite Biomarkers of Multiple Sclerosis from Multiple Biofluids.

Multiple sclerosis (MS) is a chronic and progressive neurological disorder without a cure, but early intervention can slow disease progression and improve the quality of life for MS patients. Obtaining an accurate diagnosis for MS is an arduous and error-prone task that requires a combination of a detailed medical history, a comprehensive neurological exam, clinical tests such as magnetic resonance imaging, and the exclusion of other possible diseases. A simple and definitive biofluid test for MS does not exist, but is highly desirable. To address this need, we employed NMR-based metabolomics to identify potentially unique metabolite biomarkers of MS from a cohort of age and sex-matched samples of cerebrospinal fluid (CSF), serum, and urine from 206 progressive MS (PMS) patients, 46 relapsing-remitting MS (RRMS) patients, and 99 healthy volunteers without a MS diagnosis. We identified 32 metabolites in CSF that varied between the control and PMS patients. Utilizing patient-matched serum samples, we were able to further identify 31 serum metabolites that may serve as biomarkers for PMS patients. Lastly, we identified 14 urine metabolites associated with PMS. All potential biomarkers are associated with metabolic processes linked to the pathology of MS, such as demyelination and neuronal damage. Four metabolites with identical profiles across all three biofluids were discovered, which demonstrate their potential value as cross-biofluid markers of PMS. We further present a case for using metabolic profiles from PMS patients to delineate biomarkers of RRMS. Specifically, three metabolites exhibited a variation from healthy volunteers without MS through RRMS and PMS patients. The consistency of metabolite changes across multiple biofluids, combined with the reliability of a receiver operating characteristic classification, may provide a rapid diagnostic test for MS.

Sex-driven variability in TSPO-expressing microglia in MS patients and healthy individuals.

Males with multiple sclerosis (MS) have a higher risk for disability progression than females, but the reasons for this are unclear. We hypothesized that potential differences in TSPO-expressing microglia between female and male MS patients could contribute to sex differences in clinical disease progression. The study cohort consisted of 102 MS patients (mean (SD) age 45.3 (9.7) years, median (IQR) disease duration 12.1 (7.0-17.2) years, 72% females, 74% relapsing-remitting MS) and 76 age- and sex-matched healthy controls. TSPO-expressing microglia were measured using the TSPO-binding radioligand [11C](R)-PK11195 and brain positron emission tomography (PET). TSPO-binding was quantified as distribution volume ratio (DVR) in normal-appearing white matter (NAWM), thalamus, whole brain and cortical gray matter (cGM). Male MS patients had higher DVRs compared to female patients in the whole brain [1.22 (0.04) vs. 1.20 (0.02), p = 0.002], NAWM [1.24 (0.06) vs. 1.21 (0.05), p = 0.006], thalamus [1.37 (0.08) vs. 1.32 (0.02), p = 0.008] and cGM [1.25 (0.04) vs. 1.23 (0.04), p = 0.028]. Similarly, healthy men had higher DVRs compared to healthy women except for cGM. Of the studied subgroups, secondary progressive male MS patients had the highest DVRs in all regions, while female controls had the lowest DVRs. We observed higher TSPO-binding in males compared to females among people with MS and in healthy individuals. This sex-driven inherent variability in TSPO-expressing microglia may predispose male MS patients to greater likelihood of disease progression.

Clinical impact of gender and age at onset on disease trajectory in primary progressive multiple sclerosis patients

Background and Objectives: Primary-progressive multiple sclerosis (PPMS) is characterized by gradual neurological deterioration without relapses. This study aimed to investigate the clinical impact of gender and age at disease onset on disease progression and disability accumulation in patients with this disease phenotype. Methods: Secondary data from the RelevarEM registry, a longitudinal database in Argentina, were analyzed. The cohort comprised patients with PPMS who met inclusion criteria. Statistical analysis with multilevel Bayesian robust regression modeling was conducted to assess the associations between gender, age at onset, and Expanded Disability Status Scale (EDSS) score trajectories. Results: We identified 125 patients with a confirmed diagnosis of PPMS encompassing a total of 464 observations. We found no significant differences in EDSS scores after 10 years of disease progression between genders (−0.08; credible interval (CI): −0.60, 0.42). A 20-year difference in age at onset did not show significant differences in EDSS score after 10 years of disease progression (0.281; CI: −0.251, 0.814). Finally, we also did not find any clinically relevant difference between gender EDSS score with a difference of 20 years in age at onset (−0.021; CI: −0.371, 0.319). Conclusion: Biological plausibility of gender and age effects does not correlate with clinical impact measured by EDSS score.

The significance of miRNA-191-5P and miRNA-24-3P as novel biomarkers for multiple sclerosis: a case–control study

BackgroundMultiple sclerosis (MS) is a long-term disease that can lead to disability. microRNAs (miRNA) can provide noninvasive markers allowing more frequent and easy testing in MS. Treatment methods based on manipulating miRNA activity can be innovative. The purpose of this work is to measure the serum expression of miRNA-191-5P and miRNA-24-3P in MS patients. The investigation was carried out on 80 patients with MS (68 patients with Relapsing–remitting multiple sclerosis (RRMS), 12 patients with Progressive MS) and 40 healthy controls. The serum expression of miRNA-191-5P and miRNA-24-3P was measured using real-time quantitative PCR. The expression of the studied miRNAs was relatively calculated using the Eq. 2−ΔΔCt.ResultsSerum levels of miRNA-191 and miRNA-24 showed no difference between MS patients and healthy controls, and neither between RRMS and progressive MS groups. A negative correlation was detected between miRNA-191 and disease duration. Also, a positive correlation was detected between miRNA-191 and miRNA-24 expression. RRMS patients were significantly different from progressive MS patients regarding disease duration (p value 0.001) as well as expanded disability status scale score (p value < 0.001).ConclusionThe study uniquely analyzed the correlation between the miRNA-191 and miRNA-24, being expressed in all MS patients, and being positively correlated means they are influenced by the same factors and they can be therapeutically targeted in the same way, so further studies are required. The impact of disease duration on miRNA-191 expression encourages regular monitoring of miRNA-191.

Evaluation of willingness to obtain of Covid 19 vaccine in patients with multiple sclerosis.

Assessing vaccine willingness and understanding sources of vaccine hesitancy in individuals with multiple sclerosis (MS) helps healthcare providers approach patients more effectively while respecting their autonomy to encourage coronavirus disease 2019 (COVID-19) vaccination. A descriptive-analytical cross-sectional study using a researcher-made checklist was conducted on MS patients referred to Neshat Clinic of Hamadan during the years 2020-2021. The checklist contained questions about demographic information, MS phenotype, duration of illness, expanded disability status scale (EDSS) score, and COVID-19 vaccination status. The expanded disability status scale (EDSS) is the most commonly used instrument for measuring disability in patients with multiple sclerosis (MS). The EDSS scale ranges from 0 to 10 in increments of 0.5 units, denoting advanced points of disability. Based on the results, 20 individuals (10%) were in the vaccine non-acceptance group, while 181 individuals (90%) were in the vaccine acceptance group. A significant number of relapsing and remitting (RR) type MS patients (90.7%) and all primary progressive (PP) type MS patients (100%) accepted the vaccine. In comparison, vaccine non-acceptance in the secondary progressive (SP) group was relatively higher (20.7%) compared to other types of MS, and this difference was significant (P < 0.05). Additionally, there was a statistically significant relationship between the history of COVID-19 and vaccine acceptance (P < 0.05). The study results demonstrated a high rate of COVID-19 vaccine acceptance among MS patients. MS phenotype, previous infection experiences, and other influences allow for COVID-19 vaccine acceptance among MS patients. This information can improve health programs and communication strategies for COVID-19 and future possible infectious disease vaccination in individuals with MS.

Onboarding of siponimod in secondary progressive multiple sclerosis patients in Australia: Novel, real-world evidence from the MSGo digital support programme.

Siponimod is approved for use in people with secondary progressive multiple sclerosis (pwSPMS). An integrated digital platform, MSGo, was developed for pwSPMS and clinicians to help navigate the multiple steps of the pre-siponimod work-up. To explore real-world onboarding experiences of siponimod amongst pwSPMS in Australia. Retrospective, non-interventional, longitudinal, secondary analysis of data extracted from MSGo (20 April 2022). The primary endpoint was the average time for siponimod onboarding; secondary endpoints were adherence and sub-group analyses of variables influencing onboarding. Mixed-cure modelling estimated that 58% of participants (N = 368, females 71%, median age of 59 years) registered in MSGo would ever initiate siponimod. The median time to initiation was 56 days (95% CI [47-59] days). Half of the participants cited 'waiting for vaccination' as the reason for initiation delay. Cox regression analyses found participants with a nominated care partner had faster onboarding (HR 2.1, 95% CI [1.5-3.0]) and were more likely to continue self-reporting daily siponimod dosing than were those without a care partner (HR 2.2, 95% CI [1.3-3.7]). Despite the limitations of self-reported data and the challenges of the COVID-19 pandemic, this study provides insights into siponimod onboarding in Australia and demonstrates the positive impact of care partner support.

Longitudinal fibre-specific white matter damage predicts cognitive decline in multiple sclerosis.

During the course of multiple sclerosis, many patients experience cognitive deficits which are not simply driven by lesion number or location. By considering the full complexity of white matter structure at macro- and microstructural levels, our understanding of cognitive impairment in multiple sclerosis may increase substantially. Accordingly, this study aimed to investigate specific patterns of white matter degeneration, the evolution over time, the manifestation across different stages of the disease and their role in cognitive impairment using a novel fixel-based approach. Neuropsychological test scores and MRI scans including 30-direction diffusion-weighted images were collected from 327 multiple sclerosis patients (mean age = 48.34 years, 221 female) and 95 healthy controls (mean age = 45.70 years, 55 female). Of those, 233 patients and 61 healthy controls had similar follow-up assessments 5 years after. Patients scoring 1.5 or 2 standard deviations below healthy controls on at least two out of seven cognitive domains (from the Brief Repeatable Battery of Neuropsychological Tests, BRB-N) were classified as mildly cognitively impaired or cognitively impaired, respectively, or otherwise cognitively preserved. Fixel-based analysis of diffusion data was used to calculate fibre-specific measures (fibre density, reflecting microstructural diffuse axonal damage; fibre cross-section, reflecting macrostructural tract atrophy) within atlas-based white matter tracts at each visit. At baseline, all fixel-based measures were significantly worse in multiple sclerosis compared with healthy controls (P < 0.05). For both fibre density and fibre cross-section, a similar pattern was observed, with secondary progressive multiple sclerosis patients having the most severe damage, followed by primary progressive and relapsing-remitting multiple sclerosis. Similarly, damage was least severe in cognitively preserved (n = 177), more severe in mildly cognitively impaired (n = 63) and worst in cognitively impaired (n = 87; P < 0.05). Microstructural damage was most pronounced in the cingulum, while macrostructural alterations were most pronounced in the corticospinal tract, cingulum and superior longitudinal fasciculus. Over time, white matter alterations worsened most severely in progressive multiple sclerosis (P < 0.05), with white matter atrophy progression mainly seen in the corticospinal tract and microstructural axonal damage worsening in cingulum and superior longitudinal fasciculus. Cognitive decline at follow-up could be predicted by baseline fixel-based measures (R2 = 0.45, P < 0.001). Fixel-based approaches are sensitive to white matter degeneration patterns in multiple sclerosis and can have strong predictive value for cognitive impairment. Longitudinal deterioration was most marked in progressive multiple sclerosis, indicating that degeneration in white matter remains important to characterize further in this phenotype.

Association of Spinal Cord Atrophy and Brain Paramagnetic Rim Lesions With Progression Independent of Relapse Activity in People With MS.

Progression independent of relapse activity (PIRA) is a crucial determinant of overall disability accumulation in multiple sclerosis (MS). Accelerated brain atrophy has been shown in patients experiencing PIRA. In this study, we assessed the relation between PIRA and neurodegenerative processes reflected by (1) longitudinal spinal cord atrophy and (2) brain paramagnetic rim lesions (PRLs). Besides, the same relationship was investigated in progressive MS (PMS). Last, we explored the value of cross-sectional brain and spinal cord volumetric measurements in predicting PIRA. From an ongoing multicentric cohort study, we selected patients with MS with (1) availability of a susceptibility-based MRI scan and (2) regular clinical and conventional MRI follow-up in the 4 years before the susceptibility-based MRI. Comparisons in spinal cord atrophy rates (explored with linear mixed-effect models) and PRL count (explored with negative binomial regression models) were performed between: (1) relapsing-remitting (RRMS) and PMS phenotypes and (2) patients experiencing PIRA and patients without confirmed disability accumulation (CDA) during follow-up (both considering the entire cohort and the subgroup of patients with RRMS). Associations between baseline MRI volumetric measurements and time to PIRA were explored with multivariable Cox regression analyses. In total, 445 patients with MS (64.9% female; mean [SD] age at baseline 45.0 [11.4] years; 11.2% with PMS) were enrolled. Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change [MD-APC] -1.41; p = 0.004) and higher PRL load (incidence rate ratio [IRR] 1.93; p = 0.005). Increased spinal cord atrophy (MD-APC -1.39; p = 0.0008) and PRL burden (IRR 1.95; p = 0.0008) were measured in patients with PIRA compared with patients without CDA; such differences were also confirmed when restricting the analysis to patients with RRMS. Baseline volumetric measurements of the cervical cord, whole brain, and cerebral cortex significantly predicted time to PIRA (all p ≤ 0.002). Our results show that PIRA is associated with both increased spinal cord atrophy and PRL burden, and this association is evident also in patients with RRMS. These findings further point to the need to develop targeted treatment strategies for PIRA to prevent irreversible neuroaxonal loss and optimize long-term outcomes of patients with MS.

Ocrelizumab in highly disabled progressive multiple sclerosis patients

BackgroundOcrelizumab is a commonly used anti-CD20 monoclonal antibody with efficacy in the treatment of both relapsing-remitting (RRMS) and primary progressive (PPMS) multiple sclerosis. Real world use of ocrelizumab in MS patients with higher levels of motor disability requiring a walker or a wheelchair is not well characterized as these populations were excluded from initial studies. Higher levels of disability may be a barrier to treatment access. This study aimed to describe the access to, and tolerability and therapeutic outcomes of ocrelizumab in highly disabled MS patients in a real-world setting. MethodsAs part of an ongoing study of ocrelizumab treatment access, barriers, and outcomes in MS patients at the Brigham MS Center, we retrospectively reviewed all patients with an Expanded Disability Status Scale (EDSS) of 6.5 or greater at the time of ocrelizumab initiation. All patients were started on ocrelizumab by their treating providers prior to this study initiation. Patients were excluded for recent rituximab exposure, co-treatment with more than one immunosuppressant, or alternative diagnoses contributing to high EDSS. Data was collected on incidence and severity of side effects while on ocrelizumab, persistence of treatment beyond one year, and MS stabilization versus progression while on this treatment. ResultsOf the 1219 patients on ocrelizumab between 2017 and 2021, 113 (9.3 %) had EDSS of 6.5 or greater at the time of ocrelizumab initiation. Of the 113, 51 (45.1 %) were excluded: 6 (5.3 %) because they were duplicates or didn't receive ocrelizumab at our center, 25 (22.1 %) due to rituximab treatment in the previous year, 16 (14.2 %) due to lack of at least 1 year of follow up, and 4 (3.5 %) due to relevant comorbidities/treatment with other immunosuppressants. 62 patients were included in the final analysis. At ocrelizumab start, mean age was 62.1 +/- 8.7 years and median EDSS was 7.0 (range 6.5 to 9.5). Ocrelizumab was started in 26 of the included 62 patients (41.9 %) because of objective clinical disease worsening, in 17 (27.4 %) because of subjective worsening, in 8 (12.9 %) to prevent future progression. 32 patients (51.6 %) continued ocrelizumab throughout the study period, with average length of ocrelizumab use of 36.5 +/- 17.0 months. 29 patients (46.8 %) experienced no side effects during the study period. 29 (46.7 %) patients discontinued treatment, and of those, 9 (31.0 %) cited more than one reason for discontinuation: 17 (58.6 %) cited side effects, 12 (41.4 %) cited progression/lack of benefit, 6 (20.7 %) cited the Covid19 pandemic, and 1 (3.4 %) cited financial issues as a reason for discontinuation. Over the course of the study, 16 (25.8 %) patients had disability worsening by EDSS, 5 (8.1 %) had disability improvement, and 41 (66.1 %) remained stable, with a median end EDSS of 7.0 (range 6.5 to 9.5). Importantly, 18 patients (29.0 %) reported subjective disease stability while on ocrelizumab. ConclusionsOcrelizumab may lead to disease stabilization in a subset of highly disabled MS patients, but possible benefits need to be carefully balanced against the incidence of adverse events in this high-risk patient population.

MSC therapy followed by adoptive cell therapy in progressive multiple sclerosis patients, a case series study

MSC therapy followed by adoptive cell therapy in progressive multiple sclerosis patients, a case series study

Endurance Exercise Attenuates Established Progressive Experimental Autoimmune Encephalomyelitis and Is Associated with an Amelioration of Innate Immune Responses in NOD Mice

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease causing axonal degeneration and demyelination. Exercise in mice with active monophasic experimental autoimmune encephalomyelitis (EAE) attenuates disease severity associated with diverse impacts on T cell-mediated immunity. However, studies have so far focused on preventive approaches. In this study, we investigated the impact of endurance exercise on established EAE disease in a model of secondary progressive MS. When the exercise program on motorized running wheels was started at disease manifestation, the disease course was significantly ameliorated. This was associated with a significant decrease in B cell, dendritic cell, and neutrophil cell counts in the central nervous system (CNS). Furthermore, we observed an increased expression of major histocompatibility complex class II (MHC-II) as well as alterations in costimulatory molecule expression in CNS B cells and dendritic cells. In contrast, T cell responses were not altered in the CNS or periphery. Thus, exercise training is capable of attenuating the disease course even in established secondary progressive EAE, potentially via modulation of the innate immune compartment. Further studies are warranted to corroborate our findings and assess the potential of this lifestyle intervention as a complementary therapeutic strategy in secondary progressive MS patients.