Course Of Multiple Sclerosis Research Articles

Epilepsy as a predictor of disease progression in multiple sclerosis

Background: Epilepsy development during the course of multiple sclerosis (MS) is considered to be the result of cortical pathology. However, no long-term data exist on whether epilepsy in MS also leads to increasing disability over time. Objective: To examine if epilepsy leads to more rapid disease progression. Methods: We analyzed the data of 31,052 patients on the German Multiple Sclerosis Register in a case–control study. Results: Secondary progressive disease course (odds ratio (OR) = 2.23), age (OR = 1.12 per 10 years), and disability (OR = 1.29 per Expanded Disability Status Scale (EDSS) point) were associated with the 5-year prevalence of epilepsy. Patients who developed epilepsy during the course of the disease had a higher EDSS score at disease onset compared to matched control patients (EDSS 2.0 vs 1.5), progressed faster in each dimension, and consequently showed higher disability (EDSS 4.4 vs 3.4) and lower employment status (40% vs 65%) at final follow-up. After 15 years of MS, 64% of patients without compared to 54% of patients with epilepsy were not severely limited in walking distance. Conclusion: This work highlights the association of epilepsy on disability progression in MS, and the need for additional data to further clarify the underlying mechanisms.

Clinical predictors of the benign course of multiple sclerosis in a medically underserved population

Benign multiple sclerosis (MS) is characterized by little disability accumulation over the disease course. The majority of contributions to understanding the predictors of benign MS come from high-income areas; it is unknown whether the same predictors can be derived from the resource-limited populations that have limited access to proper diagnostics and management. We aimed to study clinical predictors of benign MS in individuals with relapsing-remitting (RR) course coming from underserved areas.

S3354 Impact of Multiple Sclerosis on the Outcomes of Patients Hospitalized With Inflammatory Bowel Disease

Introduction: It has been reported that there is a possible association between inflammatory bowel disease (IBD) and multiple sclerosis (MS). Some studies suggest that there are familial links and shared genetic factors between two diseases, and MS course appears to be milder in patients with concomitant IBD. On the other hand, there is a lack of studies on how the outcomes of IBD are affected by MS. Thus, we aim to assess the outcomes of IBD in patients with concomitant MS. METHODS: Patients hospitalized with IBD from the National Inpatient Sample, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality 2014 were selected. Diagnoses were identified by using ICD-9 CM codes. Outcomes of IBD were compared between the groups with and without MS. The outcomes of interest were inpatient mortality, length of stay, total hospital charge, and IBD complications including malnutrition, penetrating disease, stricturing disease/bowel obstruction, colectomy, and ileostomy. Chi-squared tests and independent t-tests were used to compare proportions and means respectively. Multivariate logistic regression analysis was performed to determine if MS is an independent predictor for the outcomes, adjusting for age, sex, race, and the Charlson Comorbidity Index. RESULTS: Among 34,374 patients with IBD identified in the study, 132 patients had MS. There were no statistically significant differences in inpatient mortality (0% vs 0.23%, p = 0.58), length of stay (4.4 days vs 4.6 days, p = 0.72), and total hospital charge ($33,730 vs $36,727, p = 0.48). After adjusting for age, sex, race, and the Charlson Comorbidity Index, there were no statistically significant differences in IBD complications including malnutrition (aOR 0.92, 95% CI: 0.38-2.27, p = 0.86), penetrating disease (aOR 0.43, 95% CI: 0.14-1.35, p = 0.15), stricturing disease/bowel obstruction (aOR 1.12, 95% CI: 0.70-1.79, p = 0.63), colectomy (aOR 0.63, 95% CI: 0.23-1.71, p = 0.36), and ileostomy (aOR 0.86, 95% CI: 0.32-2.33, p = 0.76). CONCLUSION: There were no differences in inpatient mortality, length of stay, total hospital charge, and IBD complications between groups with and without MS. Despite possible genetic links between IBD and MS, our study suggests that outcomes of IBD are not affected by the presence of MS.

Manifestation of Susac syndrome during interferon beta-1a and glatiramer acetate treatment for misdiagnosed multiple sclerosis: a case report

BackgroundSusac syndrome (SS) is characterized by the triad of encephalopathy, branch retinal artery occlusion, and sensorineural hearing loss. However, the diagnosis of SS remains difficult because the clinical triad rarely occurs at disease onset, and symptom severity varies. SS symptoms often suggest other diseases, in particular multiple sclerosis (MS), which is more common. Misdiagnosing SS as MS may cause serious complications because MS drugs, such as interferon beta-1a, can worsen the course of SS. This case report confirms previous reports that the use of interferon beta-1a in the course of misdiagnosed MS may lead to exacerbation of SS. Moreover, our case report shows that glatiramer acetate may also exacerbate the course of SS. To the best of our knowledge, this is the first reported case of exacerbation of SS by glatiramer acetate.Case presentationWe present a case report of a patient with a primary diagnosis of MS who developed symptoms of SS during interferon beta-1a treatment for MS; these symptoms were resolved after the discontinuation of the treatment. Upon initiation of glatiramer acetate treatment, the patient developed the full clinical triad of SS. The diagnosis of MS was excluded, and glatiramer acetate therapy was discontinued. The patient’s neurological state improved only after the use of a combination of corticosteroids, intravenous immunoglobulins, and azathioprine.ConclusionsThe coincidence of SS signs and symptoms with treatment for MS, first with interferon beta-1a and then with glatiramer acetate, suggests that these drugs may influence the course of SS. This case report indicates that treatment with glatiramer acetate may modulate or even exacerbate the course of SS.

Значение морфометрических характеристик заднего сегмента глаза при использовании ПИТРС-терапии

It is known that, along with other manifestations of multiple sclerosis (MS), the neurodegenerative process is manifested by optic neuropathy. Therefore, there is no doubt about the importance of analyzing changes in the thickness of the peripapillary nerve fibers, the ganglionic and internal plexiform layers of the retina, and the choroid during the dynamic observation and treatment of patients with MS with disease modifying therapy (DMT). Purpose. To assess the condition of the posterior segment of the eye in patients with optic neuropathy in MS during therapy with 1st and 2nd generation drugs of DMT with the combined use of neuroimaging methods of examination. Material and methods. The retina and optic nerve were examined by optical coherence tomography (OCT) in 68 patients with multiple sclerosis, divided depending on the type of therapy received. Results. Significant differences in the morphometric characteristics of the structures of the posterior segment of the eye were obtained against the background of DMT of the 1st and 2nd generations. Conclusion. The analysis of the parameters of the structures of the posterior segment of the eye, obtained using OCT, is a clinically important and informative approach for dynamic observation, determination of the effectiveness of drugs that change the course of multiple sclerosis and the choice of treatment regimens. Key words: disease modifying therapy (DMT), optical coherence tomography, multiple sclerosis.

Clinical presentation and course of multiple sclerosis in patients with herpesvirus infection

To date, the features of clinical presentation, course, and the effectiveness of therapy for multiple sclerosis (MS) in the presence of persistent herpesvirus infection (PHVI) remain poorly understood.Objective: to evaluate the features of clinical presentation and course of MS in patients with PHVI to optimize patient management.Patients and methods. We examined 122 patients with a clinically definite diagnosis of MS according to McDonald criteria (2010) (82 women and 40 men, age: 18–50 years, mean age – 37.74±11.04 years). MS duration at the time of examination was from 6 months to 20 years (mean – 8.53±7.47 years), mean Expanded Disability Status Scale (EDSS) score – 2.91±1.67. 86% of patients had relapsing-remitting MS; 14% – secondary progressive MS. 98 (80%) patients received disease modifying therapies (DMTs). All patients underwent a comprehensive clinical and neurological examination, magnetic resonance imaging (MRI). 30 healthy donors (20 women and 10 men, age: 19–62 years, mean age: 39.1±12.1 years) were included in the control group. Serum levels of type-specific IgM and IgG antibodies to herpes simplex virus (HSV) 1, 2, 6, Varicella zoster virus (VVZ), Epstein–Barr virus (EBV), cytomegalovirus (CMV) were detected, in some patients – blood and cerebrospinal fluid (CSF) polymerase chain reaction, serum and CSF oligoclonal IgG.Results and discussion. We identified two sub-groups of MS patients: with PHVI reactivation (main group, n=29) and without it (comparison group, n=93). There were a significantly higher VZV (72%) and EBV infection rate (100%) in MS patients compared to the control group (50% and 83%, respectively). Mixed herpesvirus infection prevailed over mono-infection in MS patients. In contrast to controls, the most common viral pattern in MS group was a combination of 4 herpes viruses: HSV 1, 2 + VZV + EBV + CMV (χ2=3.9; p<0.05). Patients in the main group had an unfavorable disease course: earlier MS onset, predominantly polysymptomatic onset, significantly higher relapse rate, faster disease progression, and higher EDSS and Functional Systems Scale (FSS) scores (p <0.05). MRI activity was also associated with EBV infection: new T1Gd+ and T2 foci were associated with an increase in VCA-IgM to EBV level. We also observed decreased DMTs effectiveness (χ2=4,6; p=0,033) and worse DMTs tolerability (χ2=5,3; p=0,022) in the main group.Conclusion. MS patients with PHVI reactivation, have a more unfavorable course of the demyelinating process and, therefore, a greater degree of disability, compared with age-adjusted patients without a viral infection and the same disease duration.

Clinical and epidemiological characteristics of multiple sclerosis in students in the Republic of Bashkortostan

An expansion of the age range of multiple sclerosis (MS) manifestation has been reported recently. Considering the multifactorial etiology, high heterogeneity of the clinical symptoms, and the difficulties of early MS diagnosis in young people, the onset and course of this disease in students can be considered as one of the significant medical and social problems.Objective: to analyze the clinical and epidemiological characteristics of MS in university and secondary specialized educational institutions students in the Republic of Bashkortostan (RB).Patients and methods. This case-control study included 32 patients aged 15 to 24 years studying in universities and secondary schools of the RB. The clinical and epidemiological indicators analysis was carried out based on data from the register of MS patients in the RB. 32 sex-, age-, place of birth and residence-matching patients with MS, who were not students, were included in the control group.Results and discussion. The median age of disease manifestation in students was 18 [16.5; 20] years, in the control group – 16 [14; 19] years (p=0.010). We found a lower «disease onset – diagnosis» in the students group of revealed a lower interval «disease onset – diagnosis» (0.5 [0; 1] years, p=0.006), and a shorter duration of MS compared to the control group ((2.8 [2; 4] years and 4 [2; 7] years, respectively, p=0.020). Students with MS predominantly had movement disorders: central paresis and cerebellar ataxia. Students also had a faster MS progression (0.4 [0.2; 0.6] EDSS scores per year, p=0.001), despite of the disease-modifying therapies.Conclusion. MS manifestation and course in students receiving disease-modifying therapies indicate the need for close follow-up, adherence control, and psychological support in the educational process.

Art therapy possibilities in the complex treatment of patients with multiple sclerosis

Objective: to study the effectiveness of art therapy methods in the complex treatment of neuropsychological disorders and quality of life improvement in patients with relapsing-remitting and secondary-progressive multiple sclerosis (MS).Patients and methods. A group of 42 patients (5 men and 37 women, mean age 32.9 years, mean EDSS severity 3.8 points) with MS underwent outpatient continuous active art therapy cycle. The mean group training cycle duration was six months. The comparison group included 15 age- and sex-adjusted individuals without neurological disorders. Tests on various drawing topics were carried out before and after a three-month therapy course. We used Hospital Anxiety and Depression Scale (HADS) to assess the severity of anxiety and depression and the SF-36 scale to evaluate the quality of life (QoL).Results and discussion. Before the art therapy start, light blue, yellow, pink, blue, and green colors prevailed in the drawings. There was no predominance of any color depending on MS severity or course. The green color predominated in this test in the control group, and the light blue color was significantly less represented. The art therapy course did not lead to a significant change in the severity of MS according to the Expanded Disability Status Scale (EDSS). After the art therapy course, the color scheme of the drawings was mainly represented by red, light blue, green, yellow, and blue colors. In addition, a red-orange color appeared in the drawings, which was completely absent before the course. Positive trends were noted according to HADS: a decrease in anxiety by 23% and depression by 19%. The physical component of QoL assessed by the SF-36 scale did not change substantially, but the psychological component significantly improved by 11%.Conclusion. The predominance of light blue color observed in MS is associated with damage to the nervous and musculoskeletal systems, and blue color – with psychological problems and depression. However, after a course of art therapy for MS, red, red-orange, yellow, and green colors representation increased significantly, which indicates an increase in positive attitude, a decrease in the level of depression, and an improvement in QoL.

Acting centrally or peripherally: A renewed interest in the central nervous system penetration of disease-modifying drugs in multiple sclerosis

With the recent approval of cladribine tablets, siponimod and ozanimod, there has been a renewed interest into the extent to which these current generation disease-modifying therapies (DMTs) are able to cross into the central nervous system (CNS), and how this penetration of the blood-brain barrier (BBB) may influence their ability to treat multiple sclerosis (MS).The integrity of the CNS is maintained by the BBB, blood-cerebrospinal fluid barrier, and the arachnoid barrier, which all play an important role in preserving the immunological environment and homeostasis within the CNS. The integrity of the BBB decreases during the course of MS, with a putative temporal relationship to disease worsening. Furthermore, it is currently considered that progression of the disease is mediated mainly by resident cells of the CNS.The existing literature provides evidence to show that some of the current generation DMTs for MS are able to penetrate the CNS and potentially exert direct effects on CNS-resident cells, in particular the CNS-penetrating prodrugs cladribine and fingolimod, and other sphingosine-1 phosphate receptor modulators; siponimod and ozanimod. Other current generation DMTs appear to be restricted to the periphery due to their high molecular weight or physicochemical properties.As more effective brain penetrant therapies are developed for the treatment of MS, there is a need to understand whether the potential for direct effects within the CNS are of significance, and whether this brings additional benefits over and above treatment effects mediated in the periphery. In turn, this will require an improved understanding of the structure and function of the BBB, the role it plays in MS and subsequent treatments.This narrative review summarizes the data supporting the biological plausibility of a potential benefit from therapeutic molecules entering the CNS, and discusses the potential significance in the current and future treatment of MS.

Synaptic Dysfunction in Multiple Sclerosis: A Red Thread from Inflammation to Network Disconnection.

Multiple sclerosis (MS) has been clinically considered a chronic inflammatory disease of the white matter; however, in the last decade growing evidence supported an important role of gray matter pathology as a major contributor of MS-related disability and the involvement of synaptic structures assumed a key role in the pathophysiology of the disease. Synaptic contacts are considered central units in the information flow, involved in synaptic transmission and plasticity, critical processes for the shaping and functioning of brain networks. During the course of MS, the immune system and its diffusible mediators interact with synaptic structures leading to changes in their structure and function, influencing brain network dynamics. The purpose of this review is to provide an overview of the existing literature on synaptic involvement during experimental and human MS, in order to understand the mechanisms by which synaptic failure eventually leads to brain networks alterations and contributes to disabling MS symptoms and disease progression.

Critical Role of Astrocyte NAD+ Glycohydrolase in Myelin Injury and Regeneration.

Western-style diets cause disruptions in myelinating cells and astrocytes within the mouse CNS. Increased CD38 expression is present in the cuprizone and experimental autoimmune encephalomyelitis models of demyelination and CD38 is the main nicotinamide adenine dinucleotide (NAD+)-depleting enzyme in the CNS. Altered NAD+ metabolism is linked to both high fat consumption and multiple sclerosis (MS). Here, we identify increased CD38 expression in the male mouse spinal cord following chronic high fat consumption, after focal toxin [lysolecithin (LL)]-mediated demyelinating injury, and in reactive astrocytes within active MS lesions. We demonstrate that CD38 catalytically inactive mice are substantially protected from high fat-induced NAD+ depletion, oligodendrocyte loss, oxidative damage, and astrogliosis. A CD38 inhibitor, 78c, increased NAD+ and attenuated neuroinflammatory changes induced by saturated fat applied to astrocyte cultures. Conditioned media from saturated fat-exposed astrocytes applied to oligodendrocyte cultures impaired myelin protein production, suggesting astrocyte-driven indirect mechanisms of oligodendrogliopathy. In cerebellar organotypic slice cultures subject to LL-demyelination, saturated fat impaired signs of remyelination effects that were mitigated by concomitant 78c treatment. Significantly, oral 78c increased counts of oligodendrocytes and remyelinated axons after focal LL-induced spinal cord demyelination. Using a RiboTag approach, we identified a unique in vivo brain astrocyte translatome profile induced by 78c-mediated CD38 inhibition in mice, including decreased expression of proinflammatory astrocyte markers and increased growth factors. Our findings suggest that a high-fat diet impairs oligodendrocyte survival and differentiation through astrocyte-linked mechanisms mediated by the NAD+ase CD38 and highlights CD38 inhibitors as potential therapeutic candidates to improve myelin regeneration.SIGNIFICANCE STATEMENT Myelin disturbances and oligodendrocyte loss can leave axons vulnerable, leading to permanent neurologic deficits. The results of this study suggest that metabolic disturbances, triggered by consumption of a diet high in fat, promote oligodendrogliopathy and impair myelin regeneration through astrocyte-linked indirect nicotinamide adenine dinucleotide (NAD+)-dependent mechanisms. We demonstrate that restoring NAD+ levels via genetic inactivation of CD38 can overcome these effects. Moreover, we show that therapeutic inactivation of CD38 can enhance myelin regeneration. Together, these findings point to a new metabolic targeting strategy positioned to improve disease course in multiple sclerosis and other conditions in which the integrity of myelin is a key concern.

The influence of intensity and neuropathic component of pain syndrome on the quality of life in patients with multiple sclerosis

The aim of the work. To analyze the influence of intensity and neuropathic component of pain syndrome on the quality of life structure characteristics in patients with multiple sclerosis (MS). Materials and methods. 104 MS patients with different types of MS course and complaints of pain during the last month were examined in the Lviv Regional Multiple Sclerosis Center. The patients were interviewed using standardized questionnaires (Pain Detect, VAS, SF-36) followed by an analysis of the pain characteristics influence on the quality of life. Results. When assessing the influence of the main characteristics of MS course, the relationship between the physical component of quality of life and levels of disability (EDSS) and the total number of relapses was found (r = -0.60, P < 0.01; r = -0.34, P < 0.01, respectively). However, the mental component of quality of life had no significant relationship with the level of disability and the number of relapses. The average pain intensity within a month on the VAS scale was 5.0 [4.0; 7.0]. 24.0 % of patients had low-intensity pain, 54.8 % – moderate, 21.2 % – high. In MS patients with low-intensity pain within a month, 5 of the 11 quality of life indicators were significantly higher, in particular, the overall physical component of quality of life – 38.1 [33.8; 48.5] % in low-intensity pain against 31.8 [28.1; 38.7] %, P = 0.02 – in moderate. In MS patients, the level of both physical (r = -0.25; P = 0.01) and mental (r = -0.21; P = 0.03) component of quality of life decreased with increasing pain intensity. The most notable correlation was observed between intensity of pain and such characteristics of quality of life as energy/fatigue (r = -0.37; P ˂ 0.01) and emotional well-being (r = -0.28; P ˂ 0.01). In 30.8 % of patients, pain was neuropathic, in 47.1 % – nociceptive, in 22.1 % – undetermined. MS patients with the neuropathic type of pain had significantly lower scores, 7 out of 11 indicators of quality of life, largely the mental component, than scores in MS patients with nociceptive type (Р < 0.05). Correlation analysis showed the association between an increase in the manifestation of neuropathic pain component and a decrease in all quality of life characteristics, except in health change. In MS patients with a neuropathic component, in increasing level of its manifestation, the mental component of health decreased clearly (r = -0.36; P ˂ 0.01), namely its social functioning characteristic (r = -0.35; P < 0.01). Conclusions. In MS patients, increasing intensity of pain decreases both physical and mental components of quality of life with the most significant decrease in energy/fatigue and emotional well-being as parts of the mental component of quality of life. The neuropathic component of pain and the level of its manifestation are largely associated with a decrease in the mental component of quality of life as the overall indicator and social functioning as its structural element.

1193Developing a Multifactorial Prognostic Index in Relapsing Onset Multiple Sclerosis and Clinically Isolated Syndrome

Abstract Background Disease course in multiple sclerosis (MS) is characterised by relapses and worsening of disability. This study aims to create, from available clinical, genetic, and environmental factors; a multifactorial prognostic index (MPI) to predict disease course in MS. Methods We analysed prospectively assessed MS cases (N = 253) with 2858 repeated measurements over 10-years. Of the 253 cases, N = 219 were diagnosed as relapsing-onset, while N = 34 remained as clinically isolated syndrome by the 10th-year review. Cox regression models with Least Absolute Shrinkage and Selection Operator were used to select potential genetic, clinical, and environmental factors that are predictive of relapses and/or worsening of disability. Multivariate Cox regression models with leave-one-out cross-validation were used to construct a MPI, from which robust dynamic predictions were obtained by landmarking. The predictive performance at diagnosis was evaluated using the Kullback-Leibler and Brier prediction error curves. Results The MPI predicted a quadratic time-dynamic disease course in terms of relapses (HR = 2.16, CI: 1.74-2.68; C-index=0.85) and worsening of disability (HR = 2.74, CI: 2.00-3.76; C-index=0.76). The Kullback-Leibler and Brier dynamic prediction error curves showed reasonable performance for both short- (≤5-years from diagnosis) and long-term (>5-years from diagnosis) prognostications, respectively. Conclusions The MPI provided reliable information that is relevant for long-term prognostication and may be used as a selection criterion or risk stratification tool for clinical trials. Key messages Using relevant clinical, environmental, and genotype data, we have created a MPI for people living with MS and clinically isolated syndrome.

A Narrative Review Study on the Effects of Obesity and Bariatric Surgery on Multiple Sclerosis.

Obesity is a major public health concern and should be considered in autoimmune inflammatory disorders, such as multiple sclerosis (MS). In these patients, obesity leads to increasing comorbidities as well as reduced quality of life. Obesity causes an inflammatory state in the body, especially in adolescents; obesity has a role in the pathogenesis of MS. Hence, it is identified as a lifestyle modifiable risk factor for MS disease. Among various treatments for obesity, bariatric surgery has been widely used. Although few studies have been performed on bariatric surgery in MS patients, in this review, we present the existing data regarding the effects of obesity on the MS course and evaluate the outcomes of bariatric surgery among this population.

The Level of Stress and Coping Strategies in Patients with Multiple Sclerosis and Their Relationships with the Disease Course.

Objectives: Stress is supposed to be linked with a background of multiple sclerosis (MS) and the disease course. Design: The study aimed to assess the level of stress and coping strategies in MS patients within a year of follow-up and to investigate the relationships between these aspects and factors related—or not—to MS. Methods: In 65 patients with MS, the Perceived Stress Scale (PSS-10), Type D Scale (DS14) and Coping Orientations to Problems Experienced (COPE) were performed at baseline and after a year. Baseline PSS-10, DS-14 and COPE scores were analyzed with regard to demographics, MS duration, treatment, indices of disability and self-reported stressful events (SEs). Final PSS-10 and COPE results were analyzed with reference to MS activity and SE within a year of follow-up. Results: Initially, 67% of patients reported a moderate or high level of stress and 31% met Type-D personality criteria. Diverse coping strategies were preferred, most of which were problem-focused. The negative affectivity DS-14 subscore (NEG) was correlated with disability level. Non-health-related SEs were associated with higher PSS-10 and NEG scores. After a year, the mean PSS-10 score decreased, while COPE results did not change significantly. Non-health-related SEs were associated with a higher PSS-10 score and less frequent use of acceptance and humor strategies. Those with an active vs. stable MS course during the follow-up did not differ in terms of PSS-10 and COPE results. Conclusions: MS patients experienced an increased level of stress. No significant relationships were found between stress or coping and MS course within a year. Non-health-related factors affected measures of stress more than MS-related factors.

Gender-Related Differences in Prodromal Multiple Sclerosis Characteristics: A 7-Year Observation Study.

Increasing evidence supports the observation that multiple sclerosis (MS) has a preclinical period, with various prodromal signs and symptoms more frequently represented in patients with confirmed MS many years later. Considering the apparent gender differences in the incidence and clinical course of MS, it remains unclear whether it could be reflected in prodromal symptom features. This study aimed to compare a broad spectrum of prodromal signs and symptoms between males and females in the 7-year period before the definite diagnosis of MS. Data came from the central register of the national payer of services, financed under the public healthcare system in Poland. They covered a 7-year period of patient health record claims, from 2009 to 2016. The following groups of symptoms were significant with women: musculoskeletal (p < 0.001), ophthalmic (p < 0.001), laryngological (p < 0.001), digestive system (p < 0.001), urinary tract (p < 0.001), mental (p < 0.001), cardiovascular (p < 0.001), complaints and headaches (p < 0.001). There was also a weak correlation with head injuries (p = 0.03) while dermatological and reproductive system complaints did not appear to be significant (p < 0.05). For males, the following groups of symptoms were significant: musculoskeletal (p < 0.001), ophthalmic (p < 0.001), laryngological (p = 0.007), cardiovascular system symptoms (p < 0.001), and headaches (p < 0.001). Interestingly, reproductive system problems were overrepresented in the male population (p = 0.008). There was no significant correlation with MS risk for dermatological, digestive, urinary, and mental complaints. Similarly, head injuries were not significant. Our results shed more light on well-known differences in the epidemiological and clinical characteristics between sexes in multiple sclerosis, and show differences in prodromal complaints before MS onset.

Association of Age With Contrast-Enhancing Lesions Across the Multiple Sclerosis Disease Spectrum.

To investigate the association of age and the presence of contrast-enhancing lesions (CELs) on cranial MRI scans in different disease courses of multiple sclerosis (MS), we describe the frequency of CELs as a function of age in 4 large randomized controlled trial (RCT) datasets. Using original trial data from CombiRx (Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis; clinicaltrials.gov identifier NCT00211887), a trial in relapsing-remitting MS; ASCEND (A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Participants With Secondary Progressive Multiple Sclerosis; clinicaltrials.gov identifier NCT01416181), a trial in secondary progressive MS; and the 2 primary progressive MS trials PROMISE and INFORMS; clinicaltrials.gov identifier NCT00731692), we describe the occurrence of CELs per age group at baseline for the entire trial cohort and at 1 year follow-up in the treatment arms. CombiRx included 1,008, ASCEND 889, PROMISE 943, and INFORMS 970 participants. At baseline, CEL frequency differed between datasets according to disease course: 39.6% of CombiRx, 23.9% of ASCEND, 14.0% of PROMISE, and 12.3% of INFORMS participants had CELs. This distribution by disease course was largely preserved within each age group. In all datasets, there was an almost linear decrease of the percentage of participants with CELs with advancing age. After 1 year of experimental treatment, CEL occurrence was reduced in all trial datasets, and almost absent in ASCEND. The decrease of CEL occurrence with advancing age was preserved in CombiRx, PROMISE, and INFORMS after 1 year of treatment. We investigated the association of the baseline factors age, disease duration, sex, and EDSS with having CELs at baseline with multivariable binary logistic regression models. Age was the only characteristic associated with the risk of CELs at baseline in all datasets, with higher age associated with a lower risk of CELs (odds ratios for having CELs at baseline per year increase in age: CombiRx: 0.96, 95% confidence interval [CI] 0.95-0.98; ASCEND: 0.94, 95% CI 0.92-0.97; PROMISE: 0.94, 95% CI 0.91-0.96; INFORMS: 0.97, 95% CI 0.94-0.99). Our analysis of 4 large, well-characterized RCT datasets shows that the association of age and CEL occurrence is a general phenomenon across the spectrum of MS disease courses. Our findings should be replicated in real-world MS datasets.

Astroglial and Microglial Purinergic P2X7 Receptor as a Major Contributor to Neuroinflammation during the Course of Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that leads to the progressive disability of patients. A characteristic feature of the disease is the presence of focal demyelinating lesions accompanied by an inflammatory reaction. Interactions between autoreactive immune cells and glia cells are considered as a central mechanism underlying the pathology of MS. A glia-mediated inflammatory reaction followed by overproduction of free radicals and generation of glutamate-induced excitotoxicity promotes oligodendrocyte injury, contributing to demyelination and subsequent neurodegeneration. Activation of purinergic signaling, in particular P2X7 receptor-mediated signaling, in astrocytes and microglia is an important causative factor in these pathological processes. This review discusses the role of astroglial and microglial cells, and in particular glial P2X7 receptors, in inducing MS-related neuroinflammatory events, highlighting the importance of P2X7R-mediated molecular pathways in MS pathology and identifying these receptors as a potential therapeutic target.

Home-based exercise training influences gut bacterial levels in multiple sclerosis

BackgroundMultiple sclerosis is associated with gut microbiome alterations. The current study aimed to investigate the effect of home-based exercise on gut bacteria in people with multiple sclerosis (MS). We also examined the association of exercise-induced gut bacterial modulation with circulating levels of inflammatory and anti-inflammatory cytokines. Materials and methodsForty-two people with MS (female/male: 31/11, expanded disability scale status <5) participated in this study and were divided into two groups: 6 months of home-based exercise (5 sessions per week) and controls. Before and after the intervention, the following parameters were assessed: gut microbiota, including faecalibacterium prausnitzii, akkermansia muciniphila, prevotella and bacteroides counts; cytokine levels including interleukin (IL)-10 and tumor necrosis factor-alpha (TNF-α); and psychosocial factors including anxiety, depression, and fatigue. ResultsHome-based exercise significantly increased prevotella counts, and decreased akkermansia muciniphila counts (p < 0.05); however, there were no significant effects on faecalibacterium prausnitzii and bacteroides counts (p > 0.05). There were no significant effects of home-based exercise on circulating cytokine levels (p > 0.05). Moreover, home-based exercise was associated with significant improvements in anxiety and depression (p < 0.05); however, fatigue revealed no significant change (p > 0.05). Akkermansia muciniphila, prevotella and bacteroides count changes in response to the intervention were correlated with changes in IL-10 (r = −0.052, r = 0.67, and r = −0.55, respectively). ConclusionIn general, our data revealed the effect of exercise on gut bacteria, especially prevotella, and akkermansia muciniphila counts, which can probably have a beneficial effect on MS disease pathology and course; however, the lack of changes in cytokines following exercise suggests the possible role of mechanisms other than modulation of circulating IL-10 and TNF- α levels.

Spinal Fluid Myeloid Microvesicles Predict Disease Course in Multiple Sclerosis.

In vivo measures of myeloid activity are promising biomarkers in multiple sclerosis. We previously demonstrated that cerebrospinal fluid (CSF) myeloid microvesicles are markers of microglial/macrophage activity and neuroinflammation in multiple sclerosis. Here, we aimed at investigating the diagnostic and prognostic value of myeloid microvesicles in a clinical setting. Six hundred one patients discharged with a diagnosis of neuroinflammatory, neurodegenerative, or no neurological disease were enrolled. Myeloid microvesicles were measured with flow cytometry as isolectin B4-positive events in fresh CSF. Clinical, demographical, and magnetic resonance imaging (MRI) data were collected at diagnosis (all patients) and during follow-up (n=176). CSF myeloid microvesicles were elevated in neuroinflammatory patients compared to the neurodegenerative and control groups. In multiple sclerosis, microvesicles were higher in patients with MRI disease activity and their concentration increased along with the number of enhancing lesions (p < 0.0001, Jonckheere-Terpstra test). CSF myeloid microvesicles were also higher in patients with higher disease activity in the month and year preceding diagnosis. Microvesicles excellently discriminated between the relapsing-remitting and control groups (receiver operator characteristic curve, area under the curve=0.939, p < 0.0001) and between radiologically isolated syndrome and unspecific brain lesions (0.942, p < 0.0001). Furthermore, microvesicles were independent predictors of prognosis for both the relapsing-remitting and progressive groups. Microvesicles independently predicted future disease activity in relapsing-remitting patients (hazard ratio [HR]=1.967, 95% confidence interval [CI] = 1.147-3.372), correcting for prognostic factors of standard clinical use. In the progressive group, microvesicles were independent predictors of disability accrual (HR=10.767, 95% CI=1.335-86.812). Our results confirm that CSF myeloid microvesicles are a clinically meaningful biomarker of neuroinflammation and microglial/macrophage activity in vivo. These findings may support a possible use in clinical practice during diagnostic workup and prognostic assessment. ANN NEUROL 2021;90:253-265.