Differential Cerebellar Functional Interactions during an Interference Task across Multiple Sclerosis Phenotypes

Multiple sclerosis risk has a well-established polygenic component, yet the genetic contribution to disease course and severity remains unclear and difficult to examine. Accurately measuring disease progression requires long-term study of clinical and radiological outcomes with sufficient follow-up duration to confidently confirm disability accrual and multiple sclerosis phenotypes. In this retrospective study, we explore genetic influences on long-term disease course and severity; in a unique cohort of clinically isolated syndrome patients with homogenous 30-year disease duration, deep clinical phenotyping and advanced MRI metrics. Sixty-one clinically isolated syndrome patients [41 female (67%): 20 male (33%)] underwent clinical and MRI assessment at baseline, 1-, 5-, 10-, 14-, 20- and 30-year follow-up (mean age ± standard deviation: 60.9 ± 6.5 years). After 30 years, 29 patients developed relapsing-remitting multiple sclerosis, 15 developed secondary progressive multiple sclerosis and 17 still had a clinically isolated syndrome. Twenty-seven genes were investigated for associations with clinical outcomes [including disease course and Expanded Disability Status Scale (EDSS)] and brain MRI (including white matter lesions, cortical lesions, and brain tissue volumes) at the 30-year follow-up. Genetic associations with changes in EDSS, relapses, white matter lesions and brain atrophy (third ventricular and medullary measurements) over 30 years were assessed using mixed-effects models. HLA-DRB1*1501-positive (n = 26) patients showed faster white matter lesion accrual [+1.96 lesions/year (0.64-3.29), P = 3.8 × 10-3], greater 30-year white matter lesion volumes [+11.60 ml, (5.49-18.29), P = 1.27 × 10-3] and higher annualized relapse rates [+0.06 relapses/year (0.005-0.11), P = 0.031] compared with HLA-DRB1*1501-negative patients (n = 35). PVRL2-positive patients (n = 41) had more cortical lesions (+0.83 [0.08-1.66], P = 0.042), faster EDSS worsening [+0.06 points/year (0.02-0.11), P = 0.010], greater 30-year EDSS [+1.72 (0.49-2.93), P = 0.013; multiple sclerosis cases: +2.60 (1.30-3.87), P = 2.02 × 10-3], and greater risk of secondary progressive multiple sclerosis [odds ratio (OR) = 12.25 (1.15-23.10), P = 0.031] than PVRL2-negative patients (n = 18). In contrast, IRX1-positive (n = 30) patients had preserved 30-year grey matter fraction [+0.76% (0.28-1.29), P = 8.4 × 10-3], lower risk of cortical lesions [OR = 0.22 (0.05-0.99), P = 0.049] and lower 30-year EDSS [-1.35 (-0.87,-3.44), P = 0.026; multiple sclerosis cases: -2.12 (-0.87, -3.44), P = 5.02 × 10-3] than IRX1-negative patients (n = 30). In multiple sclerosis cases, IRX1-positive patients also had slower EDSS worsening [-0.07 points/year (-0.01,-0.13), P = 0.015] and lower risk of secondary progressive multiple sclerosis [OR = 0.19 (0.04-0.92), P = 0.042]. These exploratory findings support diverse genetic influences on pathological mechanisms associated with multiple sclerosis disease course. HLA-DRB1*1501 influenced white matter inflammation and relapses, while IRX1 (protective) and PVRL2 (adverse) were associated with grey matter pathology (cortical lesions and atrophy), long-term disability worsening and the risk of developing secondary progressive multiple sclerosis.

Neurological deficits and progressing disability in patients with multiple sclerosis (MS) may hamper daily oral hygiene, but their relations with oral problems have not yet been clearly determined. The aim of this study was to identify the most significant dental problems and limitations of daily oral hygiene in Polish patients with MS. 199 patients with diagnosed MS (median age 37 years) treated in the neurological outpatient clinic were interviewed using a paper-based questionnaire. They provided answers on oral health, behaviours and the limitations of their daily oral hygiene. Clinical information regarding symptoms, MS phenotype, relapses, medication and degrees of disability was based on medical records. The most frequent symptoms were dry mouth (43.2%) and bleeding from gums (28.1%). Dry mouth was more frequent in patients with secondary-progressive MS (SPMS) than relapsing-remitting MS (65.4% vs 41.3%, p = 0.023). Patients with bleeding from gums had had MS for a longer duration (median 6 vs 4 years, p = 0.002). Difficulties in daily oral hygiene were more frequent in patients with SPMS (24.0% vs 8.1%; p = 0.016). Greater proportions of patients with muscle weakness of limbs, imbalance or pain brushed their teeth irregularly. Frequent (i.e. at least every six months) visits to the dentist's surgery were uncommon in patients with SPMS (12.0% vs 39.7%, p = 0.010). Dry mouth and bleeding from gums are more frequent in patients with longer lasting and more advanced types of MS. Daily oral hygiene and oral health self-control is limited in patients with MS, mainly due to motor deficits, balance problems and pain, and this becomes worse with disease duration. To minimise the burden of the disease, patients with MS require better education and improvement in their awareness regarding proper oral health control, such as the use of electric toothbrushes. In addition, patients with chronic and progressive disability from multiple sclerosis may benefit from better organised access to dental care.

Background: Multiple sclerosis (MS) is categorized into four subtypes, including clinically-isolated syndrome (CIS), primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), and relapsing-remitting multiple sclerosis (RRMS). On the other hand, radiologically-isolated syndrome (RIS) is characterized by the imaging manifestations of MS rather than its clinical symptoms. Objectives: This study aimed to compare the sociodemographic and neuroimaging findings of different MS phenotypes and RIS. Methods: The current cross-sectional study was conducted on 3716 patients at the Multiple Sclerosis Clinic of Kashani Hospital, Isfahan, Iran, from June 2018 to April 2019. Patients presenting with RIS, CIS, and MS were included in this study. Results: The age of disease onset was remarkably lower in patients with RRMS, while the body mass index was significantly higher in RIS (P-value < 0.05). Other factors, including gender, occupation, marital status, smoking, and family history of MS, showed no significant difference (P-value > 0.05). Neuroimaging assessments revealed significant differences in terms of the location of the plaques, the activity of the plaques, brain atrophy, lesion load, the number of cervical plaques, and the presence of longitudinally-extended transverse myelitis (P-value < 0.05), but not regarding the activity of cervical and thoracolumbar plaques and the number of thoracolumbar lesions (P-value > 0.05). Conclusions: Different MS phenotypes showed variations in terms of sociodemographic and neuroimaging characteristics. Follow-up studies are recommended to determine the risk factors predicting the conversion of RIS and CIS to other MS phenotypes.

Background and ObjectivesPatients with multiple sclerosis (MS) exhibit variability in disability progression and response to disease-modifying therapies (DMTs). Identifying those at greatest risk of disability worsening and most likely to benefit from high-efficacy DMTs remains challenging. We aimed to identify distinct disability worsening phenotypes, explore their mechanisms, and evaluate DMT impact across them.MethodsIn this multicenter cohort study, we analyzed clinical and MRI data from propensity-matched cohorts of treated and untreated patients with relapse-onset MS from the Italian MS Register. Inclusion criteria were as follows: ≥3 years of follow-up, ≤1 year between disease onset and first assessment, and complete clinical and baseline MRI data. Latent class mixture models were applied to Expanded Disability Status Scale (EDSS) scores from untreated patients to identify disability worsening phenotypes. We compared proportions of progression independent of relapse activity (PIRA) and relapse-associated worsening events across phenotypes. A random forest algorithm, trained (70%) and tested (30%) on baseline clinical and MRI features of untreated patients, was used to assign phenotypes to treated patients. Linear mixed-effects models estimated DMT impact on disability trajectories within each phenotype.ResultsWe analyzed data from 2,563 untreated (mean age 41.2 ± 10 years, 67% female) and 2,952 treated (mean age 40.8 ± 11.4 years, 66% female) patients with MS over a median follow-up of 10.1 (interquartile range: 7.0–13.0) years. Four phenotypes were identified in untreated patients: “minimal-worsening” (15%), “late-worsening” (70%), “early-worsening” (3%), and “rapid-worsening” (12%). In all phenotypes, PIRA represented the main disability accrual mechanism. “Early-worsening” and “rapid-worsening” phenotypes exhibited more brain and spinal cord T2-hyperintense and gadolinium-enhancing lesions at baseline. The classification algorithm assigned phenotypes to patients receiving DMTs with 71% accuracy: “minimal-worsening” (18%), “late-worsening” (61%), “early-worsening” (13%), and “rapid-worsening” (8%). DMT exposure significantly reduced disability accrual in all phenotypes, with high-efficacy DMTs (β = −0.16, standard error (SE) = 0.06, p < 0.001) and early escalation (β = −0.18, SE = 0.06, p < 0.001) proving especially beneficial for the “rapid-worsening” phenotype.DiscussionWe identified 4 clinically relevant disability worsening phenotypes in relapse-onset MS, primarily driven by PIRA, with greater CNS involvement linked to early and rapid progression. Despite reliance on EDSS alone, these phenotypes may inform personalized treatment and response assessment.

A significant correlation exists between disability and the volume of black holes (BHL VOL), defined as hypointense lesions on T1-weighted cranial magnetic resonance imaging. A consistent correlation has also been reported between urinary myelin basic protein-like material (MBPLM) and the transition toward secondary progression (SP) from relapsing-remitting (RR) multiple sclerosis (MS). To improve the management of MS through a noninvasive and cost-effective test for monitoring disease activity or disease status. From 662 patients with MS (86 with RR MS, 259 with SP MS without continued attacks, and 317 with SP MS with continued attacks), 24-hour urine samples were obtained at enrollment in the phase 3 Linomide (roquinimex) drug study. The urine specimens were analyzed for MBPLM and correlated with clinical features and findings on cranial magnetic resonance imaging. Significant but weak correlations existed between urinary MBPLM and BHL VOL in all patients with MS (r = 0.114, P =.003; n = 662), patients with SP MS without attacks (r = 0.185, P =.003; n = 259), and all patients with SP MS (r = 0.122, P =.003; n = 576). No significant correlations were detected in the RR MS group or any of the disease groups or subgroups whose Expanded Disability Status Scale score was 5.0 or lower. In subgroup analysis, the most significant correlation was detected between urinary MBPLM after adjustment for creatinine and BHL VOL in patients with SP MS with an Expanded Disability Status Scale score of 5.5 or higher but without continued relapses (r = 0.417, P<.001; n = 138). In patients with advanced SP MS, urinary MBPLM may possibly serve as an indicator of failed remission and axonal damage. Urinary MBPLM correlates with disease status in MS, especially the transition of RR MS to SP MS with advancing disability.

Early neurofilament light and glial fibrillary acidic protein levels improve predictive models of multiple sclerosis outcomes.

BackgroundHigh mobility group box protein 1 (HMGB1) is a transcriptional regulator that is receiving increasing attention in autoimmune disorders including multiple sclerosis (MS). Here, we investigated the role of HMGB1 in the peripheral blood compartment from MS patients.MethodsHMGB1 mRNA expression levels were determined by PCR in peripheral blood mononuclear cells (PBMC) of 29 healthy controls and 57 untreated MS patients (26 with relapsing-remitting MS - RRMS, 13 with secondary progressive MS - SPMS, and 18 with primary progressive MS - PPMS). HMGB1 protein levels were measured by ELISA in serum samples from 18 HC and 37 untreated MS patients (13 with RRMS, 14 with SPMS, and 10 with PPMS).ResultsHMGB1 expression levels were increased in PBMC from the whole MS group compared with controls (P = 0.03). Further stratification of the MS group revealed higher expression levels in PBMC from patients with relapse-onset MS, and differences were statistically significant for RRMS patients compared with PPMS patients and controls (P = 4 × 10−5 and P = 0.005, respectively) and also for SPMS patients compared with PPMS patients (P = 0.001). HMGB1 serum levels were increased in the whole MS group compared with controls (P = 2 × 10−4). In MS clinical forms, the highest HMGB1 serum levels were observed in RRMS patients, and differences were statistically significant compared to PPMS patients (P = 5 × 10−5), SPMS patients (P = 0.001), and controls (P = 0.001).ConclusionsThese results point to a role of HMGB1 mRNA and protein levels as disease activity biomarkers to discriminate the more inflammatory relapse-onset MS forms, particularly RRMS, from the less inflammatory PPMS form of the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0269-9) contains supplementary material, which is available to authorized users.

Vitamin B6 status is related to disease severity and modulated by endurance exercise in individuals with multiple sclerosis: a secondary analysis of a randomized controlled trial.

BackgroundThe onset of secondary progression is a pivotal event in the course of relapsing–remitting (RR) multiple sclerosis (MS). Patients with secondary progressive MS (SPMS) experience continuous worsening of symptoms independent...

Secondary progressive multiple sclerosis (SPMS) is a form of MS characterized by continuously worsening disability with or without superimposed relapses that occurs after a variable period of relapsing remitting disease and results in limited ambulation for almost all patients. The use of interferon beta (IFN beta) for immunomodulation in patients with SPMS has been evaluated in four recent clinical trials: The European multicentre trial on IFN beta-1b in SPMS (EUSPMS), the Secondary Progressive Efficacy Trial of Rebif (IFN beta-1a) in MS (SPECTRIMS), the North American Study of IFN beta-1b in SPMS (NASPMS), and the International MS Secondary Progressive Avonex Clinical Trial (IMPACT). EUSPMS was the only trial to demonstrate a significant positive effect of therapy on disease progression as measured by the expanded disability status scale (EDSS). However, results from all studies demonstrated significant positive effects of treatment on relapse, T2 lesion load, and gadolinium enhancement. Immunomodulation with IFN beta has the potential to significantly slow disease progression and improve quality of life for patients with SPMS. While results with monthly i.v. Ig were disappointing, positive effects on disease progression have been reported with the application of immunosuppressants, especially Mitoxantrone. The risk-benefit ratio of these cytostatic agents remains controversial. New strategies addressing the important neurodegenerative aspects of the disease are urgently needed.

The purpose of this work was to determine the extent of disease and disease severity in the conventional MR normal-appearing gray matter (NAGM) and white matter (NAWM) in patients with relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) utilizing quantitative magnetization transfer ratio (MTR) histogram analysis. Twenty-seven patients with MS (16 RR, 11 SP) and 16 healthy control subjects were studied. MTR was calculated in the totally segmented GM and WM without T2 lesions in each group. Each of the RR and SP MS patient groups had significantly smaller MTR histogram mean values in NAGM and NAWM than the healthy subjects (p </= 0.0015). SP MS patients had a significantly lower first quartile and MTR histogram peak height for NAGM only (p </= 0.004) when compared with both RR MS patients and healthy subjects. The T2 lesion load had a modest negative correlation with MTR values in both RR and SP MS, but only in NAGM. Separate analysis of GM and WM MTR histograms may allow better detection of subtle damage and better understanding of the natural history of MS disease and ultimately the response to therapeutics.

Introduction. Anti-B-cell therapy that prevents clonal expansion of B cells expressing CD20 is a significant achievement in the pharmacotherapy of multiple sclerosis (MS). Randomized studies have shown high efficacy of monoclonal antibodies (mAb), confirmed by a reduction in the annualized relapse rate (ARR), MRI activity, and the risk of disability progression. Divozilimab (DIV) is a humanized afucosylated anti-CD20 mAb with a modified Fc fragment that provides high effector activity. The aim is to evaluate the efficacy and safety of DIV in patients with various MS phenotypes in real-world clinical practice. Materials and methods. The prospective study included 43 patients: 24 with rapidly progressive MS, 9 with highly active MS, and 10 with secondary progressive MS with relapses. All received DIV therapy for 6–12 months. We assessed ARR, MRI activity (lesions with contrast enhancement (T1-Gd+), new/enlarged T2 lesions), changes in the Expanded Disability Status Scale (EDSS), CD19+ B-cell levels, and the safety profile. Data were analyzed before therapy, at 6 months, and at 12 months of treatment. Results. Over 12 months of therapy, ARR decreased from 1.3 to 0.03; the proportion of patients without T1-Gd+ lesions increased from 27.9% to 100%, and new T2 lesions were detected in 6.1%. The median EDSS decreased from 3.0 [2.0; 3.5] to 2.5 [2.0; 3.0]. Profound depletion of CD19+ B cells was noted (0% [0.0; 0.2]); NEDA-3 (No Evidence of Disease Activity-3) status was achieved in 84.9%. Adverse events were limited to mild/moderate infusion reactions (30.2% at the first infusion), and no serious adverse events were recorded. Conclusion. DIV provides rapid and sustained suppression of clinical and MRI activity in MS with pronounced B-cell depletion and a favorable safety profile, justifying its early use in patients with high disease activity.

To investigate the prevalence and characteristics of Restless Legs Syndrome (RLS) in patients with Behçet's Disease (BD) and Multiple Sclerosis (MS). Consecutive patients with BD and MS seen in the outpatient clinic were included in the study. As a control group, volunteer subjects without a known peripheral or central nervous system disorder were included. The BD group was divided into two sub-groups as BD with neurological involvement [Neuro-Behçet's Disease (NBD)] and BD without any neurological involvement (other BD) for further evaluation. Data on demographic characteristics, medical history and family history were collected, and all patients underwent neurological examination. The patients were evaluated for the presence of diagnostic criteria for RLS. The features and severity of RLS were evaluated in patients with RLS using Restless Legs Syndrome Identification Form, and the International Restless Legs Syndrome Study Group (IRLSSG) Rating Scale. The clinical and radiological findings of patients with BD and MS were retrieved from their medical files. The study included a total of 96 patients with BD (mean age 39.9±11.8; 51 males; 41 patients with NBD) and 97 patients with MS (mean age 34.97±4.1 years; 24 males). There were 100 healthy control subjects (mean age 36.18±11.10 years; 46 males). RLS was more prevalent in MS (22.8%) and NBD (22%) groups compared to the control group (10%; p=0.004 and 0.029, respectively) with a statistically significant difference. The prevalence of RLS was higher in MS patients with less disability. Most severe RLS symptoms were observed in the MS group. The rate of sleep disorders was also higher in MS group. Although stress appeared to be a factor worsening RLS in all groups, its prevalence was higher in the MS group (p=0.011). There was no correlation between the distribution of magnetic resonance imaging lesions and RLS in both MS and NBD groups. It is well established that RLS can accompany disorders involving the peripheral and central nervous systems such as all types of peripheral neuropathy, myelopathy, and Parkinson's disease. The present study showed that MS and NBD also seem to be a risk factor for RLS, being associated with more severe symptoms.

Background and Objectives: Multiple sclerosis (MS) is a demyelinating disease which usually manifests as clinically isolated syndrome (CIS). Approximately 70% of patients with CIS progress to MS. Therefore, there is a pressing need to identify the most accurate predictive factors of CIS developing into MS, some of which could be a clear clinical phenotype of early MS as well as lesions in magnetic resonance imaging (MRI), pathological findings in cerebrospinal fluid (CSF) and evoked potentials (EP) tests. The problem is of outstanding importance since early MS diagnosis and treatment prevents long-term disability. The aim of our study is to analyze the factors that could influence the progression of CIS to MS. Materials and Methods: This study is a retrospective data analysis which included patients with their primary CIS diagnosis between 1st January 2015 and 1st January 2020. The prevalence and predictive value of clinical symptoms, MRI lesions, pathological CSF and EP findings were evaluated in accordance with the final diagnosis and compared between the sexes and age groups. Results: Out of 138 CIS patients, 49 (35.5%) patients progressed to MS. MS patients were more likely to have a diminished sense of vibration and proprioception (χ2 = 9.033, p = 0.003) as well as spinal cord MRI lesions (χ2 = 7.209, p = 0.007) in comparison with the non-MS group. Positive oligoclonal bands (OCBs) in CSF (χ2 = 34.859, p ≤ 0.001) and pathological brainstem auditory evoked potential (BAEP) test findings (χ2 = 10.924, p ≤ 0.001) were more prevalent in the MS group. Diminished sense of vibration and proprioception increased the risk for developing MS by 13 times (p = 0.028), whereas positive OCBs in CSF increased the risk by 100 times (p < 0.001). MS patients that were older than 50 years were more likely to exhibit positive Babinski’s reflex (χ2 = 6.993, p = 0.03), decreased muscle strength (χ2 = 13.481, p = 0.001), ataxia (χ2 = 8.135, p = 0.017), and diminished sense of vibration and proprioception (χ2 = 7.918, p = 0.019) in comparison with both younger age groups. Conclusions: Diminished sense of vibration and proprioception, spinal cord MRI lesions, positive OCBs and pathological BAEP test findings were more common among patients that developed MS. Diminished sense of vibration and proprioception along with positive CSF OCBs are predictors of CIS progressing to MS. Older patients that develop MS have more symptoms in general, such as positive Babinski’s reflex, decreased muscle strength, ataxia, and diminished sense of vibration and proprioception.

Background: Use of quantitative magnetic resonance imaging (MRI) metrics as surrogates for clinical outcomes in multiple sclerosis (MS) trials is controversial. Objectives: We sought to validate, at the individual-patient level, the number of MRI active lesions, as a surrogate marker for relapses in MS. Methods: Individual-patient data from two large, placebo-controlled clinical trials of subcutaneous interferon β-1a in patients with relapsing–remitting or secondary progressive (SP) MS were analysed separately and as pooled data. The four Prentice criteria were applied to assess surrogacy for the number of new T2 MRI lesions. The predictive value of short-term treatment effects on this MRI marker for longer-term clinical relapses was also assessed. Results: All Prentice criteria were satisfied. The number of new T2 MRI lesions correlated with the number of relapses over the follow-up period. The proportion of treatment effect on relapses accounted for by the effect of treatment on new T2 MRI lesions over 2 years was 53% in patients with relapsing–remitting MS, 67% in patients with secondary progressive MS, and 62% in pooled data. In the pooled data, treatment effects on new lesions over 1 year mediated a good proportion (70%) of effects on relapses over the subsequent year. Conclusions: This study provides evidence that new T2 MRI lesion count is a surrogate for relapses in patients with MS treated with interferon or drugs with a similar mechanism of action. Short-term treatment effects on this MRI measure can predict longer-term effects on relapses.