12-week melatonin supplementation improved dynamic postural stability and walking performance in persons living with multiple sclerosis: A randomized controlled trial.

BACKGROUND: Persons with multiple sclerosis (PwMS) suffer from sleep disturbances, fatigue and pain, which can be due, at least in part, to decreased levels of endogenous melatonin. These alterations could exacerbate postural instability, gait disorders and fall risk. Acute effects of exogenous melatonin on physical disorders have been studied in PwMS but its long-term effects on these parameters have not been explored yet in this population. This study aimed to determine the impact of chronic melatonin intake on dynamic postural stability, walking performance and fall risk in PwMS. METHODS: This randomized placebo-controlled study included 27 PwMS who were assigned to either melatonin group (MG, n=15) or placebo group (PG, n=12) (3 mg/night for 12 weeks). Dynamic postural balance (force platform), walking performance (locometer) and fall risk (Four Square Step Test) were evaluated pre (T0)- and post (T1)-intervention. Sleep quality (Pittsburgh Sleep Quality Index (PSQI)), fatigue perception (Fatigue Severity Scale (FSS)), neuropathic pain (Neuropathic Pain Questionnaire 4 (DN4)) and quality of life (International Multiple Sclerosis (MS) Quality of Life Questionnaire) were also assessed at T0 and T1. RESULTS: The center of pressure mean velocity decreased in MG compared with PG in the frontal plane (22.98 %, p=0.028). Stride length and walking speed increased in MG comparatively with PG (18.09 %, p=0.036; 9.65 %, p=0.025, respectively). The PSQI (55.89 %, p<0.001), FSS (32.38 %, p=0.003) and DN4 (32.41 %, p=0.035) scores decreased in MG compared with PG. CONCLUSION: 12-week melatonin supplementation can be recommended for managing MS-related gait disorders and dynamic postural imbalance. This therapy may also be prescribed for PwMS due to its anti-fatigue and analgesic effects as well as its benefits on sleep quality. CLINICAL REGISTRATION: This study was prospectively recorded in the Pan African Clinical Trial Registry database (PACTR202007465309582) (https://pactr.samrc.ac.za/.).

Multiple sclerosis treatments a review of current biomedical engineering approaches.

Multiple Sclerosis (MS) is an autoimmune condition targeting the central nervous system (CNS) characterized by focal demyelination with inflammation, causing neurodegeneration and gliosis. This is accompanied by a refractory period in relapsing MS or chronic progression in primary progressive MS. Current MS treatments target disease relapses and aim to reduce further demyelination and disability. These include the treatment of acute exacerbations through global immunomodulation upon corticosteroid administration, which are accompanied by adverse reactions. Disease modifying therapies (DMTs) which provide targeted immunosuppression of T and B cells, and sequestration of leukocytes out of CNS, have led to further improvements in demyelination prevention and disease burden reduction. Despite their efficacy, DMTs are ineffective in remyelination, pathology reversal and have minimal effects in progressive MS. The advent of modern biomedical engineering approaches in combination with a better understanding of MS pathology, has led to the development of novel, regenerative approaches to treatment. Such treatments utilize neural stem cells (NSCs) and can reduce disease relapses and reverse damage caused by the disease through localized tissue regeneration. While at initial stages, pre-clinical and clinical studies utilizing NSCs and immune modulation have shown promising outcomes in tissue regeneration, creating a potential new era in MS therapy.

Corrigendum: Relationship between gut microbiota and multiple sclerosis: a scientometric visual analysis from 2010 to 2023.

[This corrects the article DOI: 10.3389/fimmu.2024.1451742.].

Exploring Spinal Cord Changes in Multiple Sclerosis Patients Using MRI.

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS). The diagnosis of MS is based on clinical signs and symptoms as well as findings in magnetic resonance imaging (MRI) sequences by demonstrating the spatial and temporal dispersion of white matter lesions, which are thought to be typical of MS in distribution, shape, extent, and signal abnormalities. Spinal cord MRI can identify asymptomatic lesions and rule out malignancies or spinal stenosis in patients for whom brain imaging is not helpful in making an MS diagnosis. This study examines the MRI features of Saudi Arabian patients clinically proven to have MS with typical lesions exclusively evident in the spinal cord. This retrospective cross-sectional study was carried out in 151 patients who are confirmed cases of MS based on clinical findings and MRI results. Patients' MRI data were reviewed from the picture archiving and communication system (PACS). The study revealed that MS incidence was higher in females than males and that the number of people diagnosed with MS increased in middle age. Cervical cord plaques and cervical cord curve straightening were the most frequent changes (67% and 56%, respectively), indicating that MRI can complement and even replace clinical data in MS diagnosis, leading to earlier, more precise diagnoses and speedier starts to treatment.

Comorbidities and their association with outcomes in the multiple sclerosis population: A rapid review.

INTRODUCTION: Multiple sclerosis (MS) has a high comorbidity burden. Despite known associations with adverse outcomes, a comprehensive evaluation of the specific associations between individual comorbidities and disability, treatment initiation, and mortality remains underexplored. This study aimed to review and summarize existing evidence on the association between comorbidities and these three MS outcomes. METHODS: A rapid review spanning the period from January 2002 to October 2023 was conducted following the Cochrane Rapid Review Methods Group recommendations. MEDLINE, Embase, and the grey literature were searched to identify studies examining the effects of comorbidities on disability, treatment initiation, and mortality among individuals with MS. Data extraction and risk of bias assessments were systematically performed, with the Newcastle-Ottawa scale and A MeaSurement Tool to Assess systematic Reviews (AMSTAR-2) criteria for observational studies and systematic reviews respectively. RESULTS: The review included 100 primary studies, encompassing 88 different comorbidities. Most study populations were between 60-80% female, with an average age of 30-45 years at study start. The majority of included studies were conducted in Europe, North America, and Asia (specifically the Middle East). Over half (66%) of specific comorbidity-outcome relationships were examined within a single study only, and just two studies examined treatment initiation as an outcome. Methods used to assess comorbidities and outcomes varied widely and included self-report measures, medical records and diagnostic codes, and standardized clinical assessments. Depression was consistently associated with greater disability (adjusted hazard ratio (aHR): 1.50-3.59) and mortality (aHR: 1.62-3.55). Epilepsy was similarly associated with increased disability (aOR: 1.13-1.77) and increased mortality (aHR: 2.23-3.85). Diabetes was generally associated with increased mortality (aHR: 1.39-1.47), but results for disability were inconsistent. Most other conditions were examined in one or two studies only or findings varied across studies, unable to collectively indicate a clear association. Although the anxiety-disability relationship was assessed by 24 studies, the findings varied in terms of the presence, direction, and strength of a possible association, requiring nuanced interpretation. CONCLUSIONS: This study identifies relationships between various comorbidities and three outcomes in MS, providing a foundation for future research and clinical guidelines. People with psychiatric, metabolic, and neurological conditions may be at a higher risk of MS disease progression and may therefore benefit from the targeted treatment of their comorbidities. Overall, comorbidities have varying associations with MS outcomes and individual associations require further exploration. However, there is evidence that some comorbidities indicate worse disability and higher mortality risk, and present barriers to initiating MS treatment, making the prevention and management of comorbidities an integral piece of MS patient care. PROTOCOL: The protocol for this rapid review was registered on PROSPERO (ID: CRD42023475565) and published on Protocol Exchange (https://doi.org/10.21203/rs.3.pex-2438/v1).

Implementing a multidisciplinary approach for older adults with multiple sclerosis: Geriatric neurology in practice.

BACKGROUND: Older adults with multiple sclerosis (MS) face unique challenges arising from age-related changes in MS pathophysiology and overlapping geriatric syndromes. There is a need for geriatrics-focused multidisciplinary care for the rapidly growing older MS population. OBJECTIVE: To design and implement a geriatric multidisciplinary clinic for older adults with MS. METHODS: We describe the development of a multidisciplinary approach to geriatric MS care within a single institution through the implementation of the Aging with MS Clinic. The clinic model was conceived through collaboration between neurology and geriatric medicine to provide comprehensive care for older adults with MS who are uniquely affected by overlapping symptoms of aging and MS (e.g., frailty, falls, functional decline, multiple comorbidities, polypharmacy, cognitive impairment, nutritional deficits, barriers to access healthcare). Multidisciplinary specialists were recruited to staff the clinic, and initial patient satisfaction outcomes were collected. RESULTS: The team of multidisciplinary specialists staffing the clinic consists of a MS advanced practice practitioner, MS pharmacist, physical therapist, neuropsychologist, dietitian, and social worker. A clinic template was devised where 4 patients with MS over age 60 are seen by each specialist during each half-day clinic session. Initial patient satisfaction surveys from 25 participants showed overwhelmingly positive feedback. A majority of participants (92%) agreed that the clinic was well-organized, while 92% felt they benefitted from attending. Additionally, 80% of participants reported that the clinic improved their overall quality of care. CONCLUSION: The Aging with MS clinic outlines a model for comprehensive geriatric assessment and care in older adults with MS by a team of multidisciplinary specialists. Initial feedback from patients who attended the clinic conveyed improved quality of care.

Preferences and attitudes regarding early intervention in multiple sclerosis: A systematic literature review.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disorder affecting the brain and spinal cord, characterized by immune-mediated myelin damage. Early intervention and detection programs have emerged as promising strategies to improve patient outcomes by identifying and treating MS in its earliest stages. OBJECTIVE: This systematic literature review aims to provide an overview of the preferences, attitudes, and opinions of both patients and healthcare professionals regarding early intervention or early detection programs for MS. METHODS: A comprehensive search strategy was employed in March 2023 across multiple databases (MEDLINE, Scopus, PsyInfo, PubMed), from 1990 to 2023. A total of 38 articles were selected for analysis based on predefined inclusion and exclusion criteria. RESULTS: The majority of articles were published in recent years and represented different methods from case reports to randomized controlled trials, with fewer systematic literature reviews. Data collection approaches included patients, healthcare workers, or mixed samples with varying age ranges and gender ratios, frequently preferring women. These samples represented different preference study methods. The included studies were primarily conducted in the USA and the UK. Thematic analysis revealed several key themes : 1) differences emerged between healthcare professionals' and patients' perspectives 2) interventions for MS outside Disease-Modifying Therapies (DMTs) 3) severe side effects 4) communication, information, and knowledge 5) psychological and emotional aspects. CONCLUSIONS: Understanding these diverse factors and subgroups within the MS population can inform more effective, personalized approaches to MS prevention and treatment.

Accelerated remyelination and immune modulation by the EBI2 agonist 7α,25-dihydroxycholesterol analogue in the cuprizone model.

Research indicates a role for EBI2 receptor in remyelination, demonstrating that its deficiency or antagonism inhibits this process. However, activation of EBI2 with its endogenous ligand, oxysterol 7α,25-dihydroxycholesterol (7α,25OHC), does not enhance remyelination beyond the levels observed in spontaneously remyelinating tissue. We hypothesized that the short half-life of the natural ligand might explain this lack of beneficial effects and tested a synthetic analogue, CF3-7α,25OHC, in the cuprizone model. The data showed that extending the bioavailability of 7α,25OHC is sufficient to accelerate remyelination in vivo. Moreover, the analogue, in contrast to the endogenous ligand, upregulated brain expression of Ebi2 and the synthesis of 15 lipids in the mouse corpus callosum. Mechanistically, the increased concentration of oxysterol likely disrupted its gradient in demyelinated areas of the brain, leading to the dispersion of infiltrating EBI2-expressing immune cells rather than their accumulation in demyelinated regions. Remarkably, the analogue CF3-7α,25OHC markedly decreased the lymphocyte and monocyte counts mimicking the key mechanism of action of some of the most effective disease-modifying therapies for multiple sclerosis. Furthermore, the Cd4+ transcripts in the cerebellum and CD4+ cell number in the corpus callosum were reduced compared to vehicle-treated mice. These findings suggest a mechanism by which EBI2/7α,25OHC signalling modulates the immune response and accelerates remyelination in vivo.

Effect of Telerehabilitation-Based Motor Imagery Training on Pain and Related Factors in People with Multiple Sclerosis: Randomized Controlled Pilot Trial.

OBJECTIVES: To investigate the effect of telerehabilitation-based graded motor imagery (MI,GMI) training on pain and pain-related factors in people with multiple sclerosis (MS). DESIGN: Randomized controlled, assessor-blind pilot trial with repeated measure design. SETTING: Neurology outpatient clinic. PARTICIPANTS: Thirty-two people with MS were randomly allocated to intervention (n=16) and control (n=16) groups. INTERVENTIONS: During 8-week GMI training period, the first 2-weeks involved implicit MI training while 6-weeks explicit MI training were conducted. MAIN OUTCOME: The primary outcome was the general pain intensity over the past two days, assessed with Visual Analogue Scale, with a minimum clinically important difference (MCID) of 23 mm. Secondary outcomes included general pain and specific body parts' pain intensity over the past seven days, neuropathic pain intensity, MI ability, fatigue, depression, anxiety, quality of life, sleep quality, daytime sleepiness and cognitive functions scores. Assessments were conducted at baseline, at weeks 8 (post-treatment) and 12 (follow-up). RESULTS: The intervention group demonstrated a significant reduction in pain intensity over the past two days compared to control group (p<0.05). Furthermore, at the 8-week assessment, the intervention group surpassed the MCID in pain intensity over the past 2 and 7 days (p<0.05), whereas no significant change was observed in the control group (p>0.05). Significant effects were observed post-treatment on general pain over the past seven days, neuropathic pain, MI ability, fatigue, depression, quality of life, processing speed, and visuospatial memory within intervention group compared to control group (p<0.05). However, the impact on anxiety, sleep quality, daytime sleepiness, and verbal memory between groups were not significant (p>0.05). CONCLUSION: Telerehabilitation-based GMI training stands out as viable for management of chronic pain and pain-related psychosocial symptoms for people with MS.

The role of alemtuzumab in the development of secondary autoimmunity in multiple Sclerosis: a systematic review.

BACKGROUND: Secondary autoimmune disease (SAID) in the context of alemtuzumab treatment is one of the main safety concerns that may arise following administration in people with multiple sclerosis (pwMS). Contributing factors underlying this adverse event are not well understood. The purpose of this systematic review was to appraise the literature investigating the role of alemtuzumab in the development of SAID in pwMS following treatment and identify potential biomarkers/ risk factors that may be predictive of onset of this manifestation. METHODS: Relevant publications were retrieved from PubMed, Embase, and Web of Science using a three-pronged search strategy containing the following keywords: "multiple sclerosis"; "alemtuzumab"; and "autoimmunity". Studies that fulfilled the specified eligibility criteria and investigated SAID development after alemtuzumab in pwMS were included in the final analysis. RESULTS: 19 papers were included in the final review. Approximately, 47.92% of pwMS treated with alemtuzumab experienced SAID. A variety of biomarkers and risk factors were noted in the development of SAID, with a focus on immunological changes, including: increased homeostatic proliferation and T cell cycling, along with consistently elevated baseline serum IL-21 levels and thyroid autoantibodies. There was no significant association between known human leukocyte antigen (HLA) risk alleles, lymphocyte profile or dynamics and SAID development. CONCLUSIONS: While the mechanism underlying SAID following alemtuzumab is not fully understood, potential biomarkers and risk factors that may assist in elucidating mechanisms underlying this phenomenon have been documented in several independent studies. Following immunodepletion from alemtuzumab, an IL-21 driven increase in homeostatic proliferation and T cell cycling may disrupt tolerance mechanisms leading to an increase in the propensity toward alemtuzumab-induced autoimmunity. Further research is necessary to clarify the physiological changes after alemtuzumab therapy that trigger SAID in pwMS.

Senolytic treatment diminishes microglia and decreases severity of experimental autoimmune encephalomyelitis.

BACKGROUND: The role of senescence in disease contexts is complex, however there is considerable evidence that depletion of senescent cells improves outcomes in a variety of contexts particularly related to aging, cognition, and neurodegeneration. Much research has shown previously that inflammation can promote cellular senescence. Microglia are a central nervous system innate immune cell that undergo senescence with aging and during neurodegeneration. The contribution of senescent microglia to multiple sclerosis, an inflammatory neurodegenerative disease, is not clear, but microglia are strongly implicated in chronic active lesion pathology, tissue injury, and disease progression. Drugs that could specifically eliminate dysregulated microglia in multiple sclerosis are therefore of great interest to the field. RESULTS: A single-cell analysis of brain tissue from mice subjected to experimental autoimmune encephalomyelitis (EAE), a mouse model of CNS inflammation that models aspects of multiple sclerosis (MS), identified microglia with a strong transcriptional signature of senescence including the presence of BCL2-family gene transcripts. Microglia expressing Bcl2l1 had higher expression of pro-inflammatory and senescence associated genes than their Bcl2l1 negative counterparts in EAE, suggesting they may exacerbate inflammation. Notably, in human single-nucleus sequencing from MS, BCL2L1 positive microglia were enriched in lesions with active inflammatory pathology, and likewise demonstrated increased expression of immune genes suggesting they may be proinflammatory and contribute to disease processes in chronic active lesions. Employing a small molecule BCL2-family inhibitor, Navitoclax (ABT-263), significantly reduced the presence of microglia and macrophages in the EAE spinal cord, suggesting that these cells can be targeted by senolytic treatment. ABT-263 treatment had a profound effect on EAE mice: decreasing motor symptom severity, improving visual acuity, promoting neuronal survival, and decreasing white matter inflammation. CONCLUSION: These results support the hypothesis that microglia and macrophages exhibit transcriptional features of cellular senescence in EAE and MS, and that microglia expressing Bcl2l1 demonstrate a proinflammatory signature that may exacerbate inflammation resulting in negative outcomes in neuroinflammatory disease. Depleting microglia and macrophages using a senolytic results in robust improvement in EAE disease severity, including across measures of neurodegeneration, inflammation, and demyelination, and may therefore represent a novel strategy to address disease progression in multiple sclerosis.

Effect of Fingolimod on Lymphocyte Subsets in Patients With Relapsing Multiple Sclerosis.

Background and aim Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the central nervous system (CNS). This study aims to evaluate the effect of fingolimod on T and B lymphocytes in relapsing-remitting multiple sclerosis (RRMS) patients. Method Multiple sclerosis patients were selected from patients who were scheduled to start medication at the outpatient clinic of Kocaeli University, Kocaeli, Turkey, between February 2019 and February 2022. Venous blood samples were obtained before starting medication from the patients who agreed to participate in the study and who were to start treatment, simultaneous clinical and neurologic examinations were performed and the Expanded Disability Status Scale (EDSS) was calculated. After the six-month treatment, venous blood samples were taken again. Lymphocyte subgroup analyses were performed in the flow cytometry laboratory.  Results The study included 48 patients in the fingolimod group and 33 patients as controls. Flow cytometry analyses showed there was no significant difference between the two groups in the numbers and percentages of CD19+, CD20+, and CD22+ cells at baseline, while a significant decrease was observed in all of these parameters in the fingolimod group after the six-month treatment. Discussion Our findings support that the fingolimod treatment has significant effects on both lymphocyte counts and lymphocyte subgroup ratios. The results show the mechanism of action of fingolimod is unaccountable only through T lymphocytes, and it is effective in both B lymphocyte subgroups and T lymphocytes.

Treatment effect modifiers of immunotherapies for relapsing-remitting multiple sclerosis-A systematic review and meta-analysis.

Background: This meta-analysis aimed to assess the treatment effects of immunotherapies in subgroups of adults with clinically isolated syndrome or relapsing forms of multiple sclerosis (MS) and the effect of potential treatment effect modifiers (TEMs). Methods: Phase 2 and 3 RCTs with a placebo comparator were analyzed. Risk of bias was assessed. Random-effects meta-analyses were conducted to summarize treatment effects within subgroups and differences in treatment effects between subgroups. Results: Thirty-one studies were included. Age < 40 years was the strongest TEM for relapse rate across DMTs with a ratio of rate ratios (RRR) of 1.44 (95% CI 1.09-1.90; 7 studies). Disability progression was influenced by age (ratio of hazard ratios, RHR 1.59, 95% CI 1.11-2.29; 4 studies). Dichotomizing patients based on EDSS cut-offs (EDSS 2.0 and 3.0) also showed a significantly higher benefit for those less disabled for relapse rate (RRR 1.35, CI 1.03-1.76; 8 studies). Sex, baseline MRI parameters, previous immunotherapy, and clinical presentation showed no effect in this meta-analysis. Conclusion: Age < 40 is a robust TEM for a lower relapse rate as well as less disability progression across six MS immunotherapies. Additionally, a lower baseline EDSS was predictive of the relapse rate.

May Glymphatic Drainage Improve Life Quality in Progressive Multiple Sclerosis Outpatients?

Background: The cerebral fluid-dynamic system plays a critical role in maintaining brain health and function. Recent studies identify the glymphatic system as primarily responsible for removing waste products and toxins from brain tissue. In recent years, we have achieved beneficial improvements in MS patients' symptoms and lifestyle using a specific Fluid Dynamic Intensive MAM (FD-MAM) protocol. Methods: We treated 40 outpatients with progressive MS, aged 45-55 years and with EDSS scores from 6 to 9. We applied FD-MAM in 10 daily sessions over two weeks. Before and after glymphatic drainage by FD-MAM, we assessed each patient's clinical status and quality of life using six validated questionnaires. Results: Data from the six validated questionnaires administered to the 40 MS patients show an improvement in 83% of the scores. At the same time, we observed a shift from pathological to physiological values in 50% of the pathological scores after 10 sessions of FD-MAM protocol. Conclusion: This study confirms the positive improvements on life quality in outpatients with progressive multiple sclerosis after one cycle of Fluid Dynamic Intensive MAM (FD-MAM) protocol. Initial follow-up on few patients treated with the FD-MAM protocol suggests that the results persist for six to ten months post-treatment. Future detailed studies, on MS outpatients' larger cohort, are essential to assess the duration of results and its effect on glymphatic system.

Multiple sclerosis and COVID-19: a bidirectional Mendelian randomization study.

This study aimed to investigate the potential relationship between multiple sclerosis (MS) and coronavirus disease 2019 (COVID-19) outcomes using Mendelian randomization analysis. Specifically, it evaluates whether genetic factors, including the single-nucleotide polymorphism (SNP) rs10191329, influence the susceptibility of MS patients to three COVID-19 outcomes [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hospitalized COVID-19, and severe COVID-19]. This study utilized genome-wide association study summary statistics from the International Multiple Sclerosis Genetics Consortium to conduct a Mendelian randomization analysis. SNPs strongly associated with MS were selected to examine their impact on COVID-19 outcomes. The analysis focused on identifying any causal associations between MS and COVID-19 severity, as well as assessing the role of interferon beta (IFNß) treatment in modifying these outcomes. The results suggest a potential association between MS and an increased risk of COVID-19, but individuals carrying the rs10191329 SNP appeared less likely to develop severe COVID-19. This SNP, located within the DYSF-ZNF638 locus, may influence immune responses and MS severity, highlighting its relevance for personalized treatment strategies. Importantly, no significant causal relationship was found between IFNß treatment and the three COVID-19 outcomes, indicating that the findings in treated patients differ from those observed in untreated patients. This suggests that IFNß may offer protective effects against SARS-CoV-2 in MS patients. These findings underscore the importance of genetic factors, such as rs10191329, in shaping the clinical outcomes of MS patients in the context of COVID-19. Further research should explore targeted therapies and personalized approaches for managing MS during the ongoing pandemic.

The impact of different lifestyle factors on disability in multiple sclerosis at older ages: a monocentric retrospective study.

Background: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system affecting approximately 2.8 million people worldwide. In addition to genetic and environmental factors, various lifestyle factors contribute to disease development and progression. Objectives: We performed a monocentric retrospective study and investigated the effect of lifestyle factors such as obesity, smoking, alcohol consumption, physical activity, and dietary habits on the degree of disability in a cohort of people with MS (pwMS) with an average onset of disease after the age of 55. Design: This late-onset MS (LOMS) study group (n = 47) was characterized by a mean age of 60.9 years and a mean duration of disease of 5.0 years. The LOMS study group was compared with two control groups. The study participants in the "old control group" (Cold) were on average as old and in the "young control group" (Cyoung) as long suffering from MS as the pwMS in the LOMS group. Methods: Data from medical documentation and a questionnaire were analyzed using descriptive frequency analyses and testing for correlation between different variables also by generalized estimating equations. The Expanded Disabilty Status Scale (EDSS) score and the progression index were used as a measure of disability. Results: We found a significant association between smoking history and the current EDSS score in the Cyoung group, but not in the two older study groups. For physical activity, there was a significant negative correlation with EDSS score in the study group and the Cold group, alcoholic beverage consumption correlated with decreased EDSS in the Cold group. The intake of meat negatively correlated with the progression index in the LOMS group. Conclusion: In summary, different life-style factors correlated with disability depending on patient age and disease duration. These life-style factors may be considered in the future counseling of pwMS at older ages.

Identification of alemtuzumab-suitable multiple sclerosis patients in Slovakia and sequencing of post-alemtuzumab immunomodulatory treatment.

Background: Alemtuzumab (ALEM) is a humanised monoclonal antibody that depletes circulating lymphocytes by selectively targeting CD52, which is expressed in high levels on T- and B-lymphocytes. This depletion is followed by lymphocyte repopulation and a cytokine expression shift towards a lesser inflammatory profile, both of which may contribute to prolonged efficacy. National recommendations for enrolling and treating multiple sclerosis (MS) patients with ALEM have been established. However, there are no recommendations in place for the treatment of MS reactivation after the ALEM treatment. Objectives: To evaluate the effectiveness and safety of the use of ALEM and to analyse subsequent disease-modifying treatments (DMTs). A multidimensional prediction model was developed to make a patient-specific prognosis regarding the response to ALEM. Design: A multicentre, prospective, non-controlled, non-interventional, observational cohort study. Methods: Relapsing multiple sclerosis patients (RMSp) who received ⩾1 dose of ALEM were enrolled. In each treatment year, the following baseline and prospective data were collected: age, MS history, number, type and duration of previous disease-modifying treatment (PDMT), relapse rate (REL), expanded disability status scale (EDSS), magnetic resonance imaging and serious adverse events (AE). In cases of reactivation of MS, all data about the subsequent DMT were collected. Results: A total of 142 RMSp from 10 MS Slovak Centres fulfilled the inclusion criteria. The average age was 35 years (standard error 8.56). The overall average EDSS was 3.87 (1.46) when ALEM was started. The average duration of PDMT was 6.0 (4.04) years, and the median number of PDMTs was 3 (0-5), while the patients were mostly treated with 2 or 3 DMTs (>65.00%). Post-ALEM treatment was needed in 39 cases (27.46%). The most frequent post-ALEM treatment indicated was ocrelizumab, followed by natalizumab (NAT), siponimod and cladribine. The ocrelizumab and NAT treatment bring little benefit to patients. Siponimod showed less EDSS increase in contrast to ocrelizumab and NAT. Another repopulation therapy, cladribine, may also be an effective option. Statistically significant predictors for the expected EDSS are age (p-value <0.0001), number of ALEM cycles (0.0066), high number of PDMT (0.0459) and the occurrence of relapses (<0.0001). There was no statistically significant effect on the patient's gender (0.6038), duration of disease-modifying treatment before alemtuzumab (0.4466), or the occurrence of AE (0.6668). Conclusion: The study confirms the positive effect of ALEM on clinical and radiological outcomes. We need more data from long-term sequencing studies.

Early regional cerebral grey matter damage predicts long-term cognitive impairment phenotypes in multiple sclerosis: a 20-year study.

Despite grey matter atrophy in cortical and subcortical regions has been related to cognitive impairment in multiple sclerosis, only a few studies evaluated its predictive value for alterations in the long-term. We aimed to determine early predictors of cognitive status after 20 years of multiple sclerosis. In this longitudinal retrospective study, participants underwent a 1.5 T MRI scanning at diagnosis (T0) and after two years (T2), which included the evaluation of regional grey matter volume loss patterns. All individuals with multiple sclerosis underwent a comprehensive neuropsychological assessment at the end of the study and were classified considering their global and specific cognitive domains status (memory, attention/information processing speed, executive functioning). Clinical and MRI characteristics were assessed as predictors of long-term cognitive impairment. Analysis of covariance, t-test, unadjusted and adjusted (for age, sex, disease duration, volume of white matter lesions, volume of cortical lesions) logistic regression were conducted. One hundred seventy-five people with multiple sclerosis (118 females; mean ± SD age at the end of study = 47.7 ± 9.4 years) clinically followed for 20 years from onset (mean ± SD = 19.9 ± 5.1) were evaluated. At the end of the study, 81 (47%) were classified as cognitively impaired: 38 as mildly impaired (22%), and 43 as severely impaired (25%). In particular, 46 were impaired in memory (27%), 66 were impaired in attention/information processing speed (38%), and 71 were impaired in executive functioning (41%). Regression models identified precuneus (adjusted odds ratio = 3.37; P < 0.001), insula (adjusted odds ratio = 2.33; P = 0.036), parahippocampal gyrus (adjusted odds ratio = 2.07; P < 0.001) and cingulate (adjusted odds ratio = 1.81; P = 0.009) as the most associated regions with global cognitive impairment and domains-specific cognitive alterations after a mean of 20 years of multiple sclerosis, after adjusting for demographic and clinical variables as well as for focal white matter and grey matter damage. Early grey matter volume loss of specific cortical and deep grey matter regions predicts global and domain cognitive alterations after 20 years from multiple sclerosis diagnosis.

Flow cytometry identifies changes in peripheral and intrathecal lymphocyte patterns in CNS autoimmune disorders and primary CNS malignancies.

BACKGROUND: Immune dysregulation is a hallmark of autoimmune diseases of the central nervous system (CNS), characterized by an excessive immune response, and primary CNS tumors (pCNS-tumors) showing a highly immunosuppressive parenchymal microenvironment. METHODS: Aiming to provide novel insights into the pathogenesis of CNS autoimmunity and cerebral tumor immunity, we analyzed the peripheral blood (PB) and cerebrospinal fluid (CSF) of 81 autoimmune limbic encephalitis (ALE), 148 relapsing-remitting multiple sclerosis (RRMS), 33 IDH-wildtype glioma, 9 primary diffuse large B cell lymphoma of the CNS (CNS-DLBCL), and 110 controls by flow cytometry (FC). Additionally, an in-depth immunophenotyping of the PB from an independent cohort of 20 RRMS and 18 IDH-wildtype glioblastoma patients compared to 19 controls was performed by FC combined with unsupervised computational approaches. RESULTS: We identified alterations in peripheral and intrathecal adaptive immunity, mainly affecting the T cell (Tc) but also the B cell (Bc) compartment in ALE, RRMS, and pCNS-tumors compared to controls. ALE, RRMS, and pCNS-tumors featured higher expression of the T cell activation marker HLA-DR, which was even more pronounced in pCNS-tumors than in ALE or RRMS. Glioblastoma patients showed signs of T cell exhaustion that were not visible in RRMS patients. In-depth characterization of the PB revealed differences mainly in the T effector and memory compartment between RRMS and glioblastoma patients and similar alterations in the Bc compartment, including atypical Bc, CD19+CD20- double negative Bc, and plasma cells. PB and CSF mFC together with CSF routine parameters could reliably differentiate ALE and RRMS from pCNS-tumors facilitating early diagnosis and treatment. CONCLUSIONS: ALE, RRMS, and pCNS-tumors show distinct but partially overlapping changes mainly in HLA-DR+ Tc, memory Tc, exhausted Tc, and Bc subsets providing insights into disease pathogenesis. Moreover, mFC shows diagnostic potential facilitating early diagnosis and treatment.