MS Progression Research Articles

Novel contributors to B cell activation during inflammatory CNS demyelination; An oNGOing process

Over the past two decades, the development of targeted immunotherapeutics for relapsing-remitting multiple sclerosis has been successfully orchestrated through the efficacious modulation of neuroinflammatory outcomes demonstrated in the experimental autoimmune encephalomyelitis (EAE) model. In this model, the focus of developing immunomodulatory therapeutics has been demonstrated through their effectiveness in modifying the pro-inflammatory Th1 and Th17-dependent neuropathological outcomes of demyelination, oligodendrocytopathy and axonal dystrophy. However, recent successful preclinical and clinical trials have advocated for the significance of B cell-dependent immunopathogenic responses and has led to the development of novel biologicals that target specific B cell phenotypes. In this context, a new molecule, B-cell activating factor (BAFF), has emerged as a positive regulator of B cell survival and differentiation functioning through various signaling pathways and potentiating the activity of various receptor complexes through pleiotropic means. One possible cognate receptor for BAFF includes the Nogo receptor (NgR) and its homologs, previously established as potent inhibitors of axonal regeneration during central nervous system (CNS) injury and disease. In this review we provide current evidence for BAFF-dependent signaling through the NgR multimeric complex, elucidating their association within the CNS compartment and underlying the importance of these potential pathogenic molecular regulators as possible therapeutic targets to limit relapse rates and potentially MS progression.

Retinal nerve fiber layer thickness in multiple sclerosis with and without optic neuritis: a four-year follow-up study from Oman

BackgroundMultiple sclerosis (MS) is an autoimmune disease that attacks the central nervous system, with optic neuritis (ON) being a common early manifestation. Retinal nerve fiber layer (RNFL) thickness may be a biomarker of neuroaxonal damage in MS patients. We sought to evaluate changes in RNFL thickness over 4 years in Omani MS patients with or without ON in comparison to a healthy control group.MethodsThis retrospective case-control study involved 27 MS patients and 25 healthy controls. Optical coherence tomography was performed upon first diagnosis and at a four-year follow-up. Differences in mean RNFL thickness were calculated.ResultsA total of 51 eyes from the MS group and 50 eyes from the control group were evaluated. There was a significant reduction in mean RNFL thickness among MS patients with ON at follow-up (81.21 versus 72.14 μm; P = .003), whereas no significant RNFL thinning was observed among MS patients without ON. However, there was a significant reduction in RNFL thickness among MS patients compared to healthy controls (76.79 versus 93.72 μm; P = .009), regardless of ON presence/absence.ConclusionsAxonal damage was seen in the optic nerves of Omani MS patients. Moreover, there was a significant reduction in RNFL thickness among MS patients with ON as the disease progressed; however, while there was evidence of RNFL thinning in MS patients without ON, this difference lacked statistical significance. Evaluation of RNFL thickness may represent a useful biomarker for monitoring disease progression in MS and its association with ON.

Treatment of Multiple Sclerosis With Teriflunomide. Multicenter Study of Real Clinical Practice in the Valencian Community-Spain.

Introduction: We have different treatment alternatives for relapsing-remitting multiple sclerosis–RRMS–within the so-called platform drugs. It would be desirable to know the ideal drug for each patient. Real clinical practice studies provide us with data on drug efficacy in the medium and long term, safety beyond clinical trials, and can help us to know the patient profile appropriate for each therapy.Material and Methods: An observational multicenter study of real clinical practice in patients with RRMS who were treated with teriflunomide in the Valencian Community, since teriflunomide was authorized in Spain. The database created for this study collects retrospectively patients followed prospectively in the MS clinics.Objectives: To analyze the efficacy and safety of teriflunomide treatment in patients with RRMS under the conditions of real clinical practice, and to identify a patient profile responding to the treatment.Results: We obtained data from 340 patients who received at least one dose of 14 mg teriflunomide. The patients were 69.4% female to 30.6% male, had a mean age of 46.4 years, and a mean time of progression of MS of 11.5 years. The mean pre-teriflunomide relapse rate was 0.4 years, the mean EDSS scorewas 1.98, IgG Oligoclonal bands were present in the CSF of 66.2% of the patients, IgM Oligoclonal bands were present in 46.9%, and the mean number of gadolinium-enhancing lesions was 1.07 lesions per patient at the beginning of treatment. The average number of treatments previously received was 1.04, and 28.53% were naïve. After a follow-up of up to 4 years, a reduction in the annualized and cumulative annualized relapse rate was observed in the first year, in the second year, and in the third year, compared to the pre-treatment year. The EDSS scores were stabilized throughout the follow-up. Likewise, there was a reduction in gadolinium-enhancing lesions in the 1st and 2nd years compared to the pre-treatment period. Applying different generalized multiple linear regression models, we identified a profile of a responding patient to teriflunomide as a male without IgM oligoclonal bands in the CSF, a previous EDSS score of <3, and more than 5 years duration of MS.

CSF neurofilament light chain predicts 10-year clinical and radiologic worsening in multiple sclerosis.

BackgroundNeurofilament light chain (NfL) is an attractive biomarker of disease activity and progression in MS, but there is a lack in long-term prognostic data.ObjectiveTo test the long-term clinical and radiological prognostic value of cerebrospinal fluid (CSF)-NfL among newly diagnosed patients with MS.MethodsNewly diagnosed MS patients where followed prospectively with baseline CSF-NfL and repeated MRI and clinical assessments for up to 10 years. Associations between baseline CSF-NfL and longitudinal MRI and clinical assessments were found by Generalized Estimating Equations analysis.ResultsForty-two participants were included. CSF-NfL at baseline was significantly associated with the rate of atrophy in globus pallidus (p = 0.009) and hippocampus (p = 0.001) as evaluated by MRI. Baseline volumes of thalamus (β −0.33; 95% CI −0.57 to −0.10, p = 0.006), T1 (β 0.28; 95% CI 0.11 to 0.44, p = 0.001) and T2 (β 0.16; 95% CI 0.04 to 0.27, p = 0.008) lesions and baseline levels of CSF-NfL (β 0.9; 95% CI 0.3 to 1.5, p = 0.002) significantly predicted EDSS worsening over 10 years. Baseline CSF-NfL gave a comparable prediction to the best MRI volumetric predictors.ConclusionCSF-NfL predicted the clinical and radiological course of newly diagnosed patients with MS over a 10-year period, underlining its prognostic role.

CSF Levels of CXCL12 and Osteopontin as Early Markers of Primary Progressive Multiple Sclerosis

Background and ObjectivesTo evaluate the extent of intrathecal inflammation in patients with primary progressive MS (PPMS) at the time of diagnosis and to define markers and a specific inflammatory profile capable of distinguishing progressive from relapsing-remitting multiple sclerosis (RRMS).MethodsLevels of 34 pro- and anti-inflammatory cytokines and chemokines in the CSF were evaluated at the diagnosis in 16 patients with PPMS and 80 with RRMS. All patients underwent clinical evaluation, including Expanded Disability Status Scale assessment and a 3T brain MRI to detect white matter and cortical lesion number and volume and global and regional cortical thickness.ResultsHigher levels of CXCL12 (odds ratio [OR] = 3.97, 95% CI [1.34–11.7]) and the monocyte-related osteopontin (OR = 2.24, 95% CI [1.01–4.99]) were detected in patients with PPMS, whereas levels of interleukin-10 (IL10) (OR = 0.28, 95% CI [0.09–0.96]) were significantly increased in those with RRMS. High CXCL12 levels were detected in patients with increased gray matter lesion number and volume (p = 0.001, r = 0.832 and r = 0.821, respectively). Pathway analysis confirmed the chronic inflammatory processes occurring in PPMS.ConclusionsAt the time of diagnosis, a specific CSF protein profile can recognize the presence of early intrathecal inflammatory processes, possibly stratifying PPMS with respect to RRMS. Elevated CSF levels of CXCL12 and osteopontin suggested a key role of brain innate immunity and glia activity in MS. These molecules could represent useful candidate markers of MS progression, with implications for the pathogenesis and treatment of progressive MS.Classification of EvidenceThis study provides Class III evidence that CXCL12 and monocyte-related osteopontin may be correlated with PPMS, and IL-10 may be related to RRMS. It is may be correlated due to Bonferroni correction negating the statistical correlations found in the study.

125Clinical &amp; demographic determinants of self-reported diet program adherence in people living with multiple sclerosis

Abstract Background A range of diets have been recommended for people living with MS, ranging from low or no-meat Swank-inspired diets, to the modified Palaeolithic Wahls diet. While the clinical efficacy of these diets to modulate MS progression is uncertain, the popularity of these diets amongst people living with MS is manifest. Methods Data derived from the 5-year review of the HOLISM international cohort study. Self-reported adherence to diets were queried, ranging 1-5. Adherence was restricted to ≥ 12months adherence, and then dichotomised: those reporting 4-5/5 adherence defined 2nd-most adherent, 3-5/5 adherence defined 3rd-most adherent. Determinants of adherence were evaluated by log-binomial regression, adjusted for age, sex, socioeconomic status (SES), education, and fatigue. Due to low numbers, only the Overcoming MS (OMS), Swank and Wahls diets were quantitatively evaluated. Results 458/952 (48.1%) reported following MS-specific diets for ≥12months; 61.8% followed OMS, 12.7% Swank, 3.5% Wahls, 0.9% Ashton-Embry, 0.9% McDougal, 5.7% other. OMS adherence (2nd-most) was more common among males, higher SES, lower disability, less fatigue, and fewer comorbidities. Wahls adherence (2nd-most) was more common among participants with progressive MS or greater disability. Swank adherence (2nd-most) did not vary by any parameter. Analogous results were found using the 3rd-most adherent definition. Conclusions These results indicate that MS-specific diet adherence is common in this patient population, but uptake is highly heterogenous between demographic and clinical subgroups. Further study of diet uptake among MS patients is indicated, particularly as the efficacy of these diets in MS is yet uncertain. Key messages There is evidence for a marked tribalisation of diet adherence between the OMS, Swank, and Wahls diets, the former being more common among less clinically active RRMS participants and Wahls more common among more clinically active progressive participants.

V01-11 ROBOT-ASSISTED SURGICAL REPAIR OF URETERO-ILEAL ANASTOMOTIC STRICTURE AFTER CYSTECTOMY AND ILEAL CONDUIT IN NEUROLOGICAL PATIENT

You have accessJournal of UrologyIncontinence & Female Pelvic Medicine/Reconstructive Surgery (V01)1 Sep 2021V01-11 ROBOT-ASSISTED SURGICAL REPAIR OF URETERO-ILEAL ANASTOMOTIC STRICTURE AFTER CYSTECTOMY AND ILEAL CONDUIT IN NEUROLOGICAL PATIENT Gilles Dosin, Juliette Hascoet, Clement Mazouin, Zine-Eddine Khene, Gregory Verhoest, Romain Mathieu, Karim Bensalah, Lucas Freton, Emmanuel Voiry, Claire Richard, Camille Haudebert, Etienne Courboin, Andrea Manunta, and Benoit Peyronnet Gilles DosinGilles Dosin More articles by this author , Juliette HascoetJuliette Hascoet More articles by this author , Clement MazouinClement Mazouin More articles by this author , Zine-Eddine KheneZine-Eddine Khene More articles by this author , Gregory VerhoestGregory Verhoest More articles by this author , Romain MathieuRomain Mathieu More articles by this author , Karim BensalahKarim Bensalah More articles by this author , Lucas FretonLucas Freton More articles by this author , Emmanuel VoiryEmmanuel Voiry More articles by this author , Claire RichardClaire Richard More articles by this author , Camille HaudebertCamille Haudebert More articles by this author , Etienne CourboinEtienne Courboin More articles by this author , Andrea ManuntaAndrea Manunta More articles by this author , and Benoit PeyronnetBenoit Peyronnet More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001970.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Cystectomy and ileal conduit (IC) are sometimes indicated for patient with a neurogenic bladder. However stricture of the uretero-enteric anastomosis are a common complication after this procedure. Robot-assisted uretero-enteric stricture repair may decrease the post operative morbidity and possibly increase the chance of success thanks to tools such as indocyanine green (ICG) and near infrared fluorescence (Firefly). The objective of this video is to assess the feasibility of this procedure. METHODS: We present the case of a 47 year-old patient with multiple sclerosis since 1987. She had a IC in 2018 with a Wallace 1 anastomosis for neurogenic detrusor overactivity refractory to conservative treatment with upper urinary tract deterioration and inability to self catheterize due to MS progression (cognitive dysfunction and upper limb impairment). She experienced multiple urosepsis with long hospital stays and eventually she needed bilateral nephrostomy tubes. Antegrade opacification revealed a stricture of the left uretero-enteric anastomosis. RESULTS: The patient is placed in 23° Trendelenburg position. Six ports are placed (4 robotic and 2 for the assistant) and the Da Vinci Xi robot is docked. We begin with adhesiolysis which allows to identify the ileal conduit. We carefully preserve the peri ureteral fat to ensure the best possible ureteral vascularization. We cut the ureters distally. The blood supply to the ureters end is checked using IV indocyanine green (ICG) injection and near infrared fluorescence (Firefly) and the ureters are cut as high as necessary and the ureter spatulation. A new uretero-enteric anastomosis is created according the Wallace 1 technique between the “ureteral plate” and the proximal stump of the ileal conduit. Two ureteral stents are placed for 10 days. CONCLUSIONS: Uretero-enteric anastomotic stricture in neurological patients can be treated using a robotic approach refection by robotic assisted procedure in a fully intracorporeal way is feasible. The magnified 3D vision, the precise dissection using the endowrist and the use of ICG may help preserve adequate blood supply to the ureter and minimize the risk of stricture recurrence The absence of large incision could also favored enhanced post operative recovery and minimize the risk of incisional hernias in this frail patient population. Source of Funding: none © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e65-e65 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Gilles Dosin More articles by this author Juliette Hascoet More articles by this author Clement Mazouin More articles by this author Zine-Eddine Khene More articles by this author Gregory Verhoest More articles by this author Romain Mathieu More articles by this author Karim Bensalah More articles by this author Lucas Freton More articles by this author Emmanuel Voiry More articles by this author Claire Richard More articles by this author Camille Haudebert More articles by this author Etienne Courboin More articles by this author Andrea Manunta More articles by this author Benoit Peyronnet More articles by this author Expand All Advertisement Loading ...

N6-Methyladenosine RNA modification in cerebrospinal fluid as a novel potential diagnostic biomarker for progressive multiple sclerosis

BackgroundProgressive multiple sclerosis (PMS) is an uncommon and severe subtype of MS that worsens gradually and leads to irreversible disabilities in young adults. Currently, there are no applicable or reliable biomarkers to distinguish PMS from relapsing–remitting multiple sclerosis (RRMS). Previous studies have demonstrated that dysfunction of N6-methyladenosine (m6A) RNA modification is relevant to many neurological disorders. Thus, the aim of this study was to explore the diagnostic biomarkers for PMS based on m6A regulatory genes in the cerebrospinal fluid (CSF).MethodsGene expression matrices were downloaded from the ArrayExpress database. Then, we identified differentially expressed m6A regulatory genes between MS and non-MS patients. MS clusters were identified by consensus clustering analysis. Next, we analyzed the correlation between clusters and clinical characteristics. The random forest (RF) algorithm was applied to select key m6A-related genes. The support vector machine (SVM) was then used to construct a diagnostic gene signature. Receiver operating characteristic (ROC) curves were plotted to evaluate the accuracy of the diagnostic model. In addition, CSF samples from MS and non-MS patients were collected and used for external validation, as evaluated by an m6A RNA Methylation Quantification Kit and by real-time quantitative polymerase chain reaction.ResultsThe 13 central m6A RNA methylation regulators were all upregulated in MS patients when compared with non-MS patients. Consensus clustering analysis identified two clusters, both of which were significantly associated with MS subtypes. Next, we divided 61 MS patients into a training set (n = 41) and a test set (n = 20). The RF algorithm identified eight feature genes, and the SVM method was successfully applied to construct a diagnostic model. ROC curves revealed good performance. Finally, the analysis of 11 CSF samples demonstrated that RRMS samples exhibited significantly higher levels of m6A RNA methylation and higher gene expression levels of m6A-related genes than PMS samples.ConclusionsThe dynamic modification of m6A RNA methylation is involved in the progression of MS and could potentially represent a novel CSF biomarker for diagnosing MS and distinguishing PMS from RRMS in the early stages of the disease.

Fear of COVID-19, problems accessing medical appointments, and subjective experience of disease progression, predict anxiety and depression reactions in patients with Multiple Sclerosis

BackgroundDuring the current COVID-19 pandemic there are studies that have suggested a negative impact of the pandemic on the mental health of patients with multiple sclerosis (PwMS). In this sense, several factors may be related to the increase in experiences of anxiety and depression in PwMS during the current pandemic. ObjectiveIn this study we first explored the reactions of anxiety, depression and fear to COVID-19 in a group of PwMS that belong to the Ibero-American region. Besides, we explored whether having been positive to COVID-19, fear of COVID-19, the obstacles to attend medical appointments during the outbreak and subjective experience of MS progression, could predict the anxiety and depression reactions in our PwMS sample. Materials and methodsAn online cross-sectional survey was conducted on 202 MS patients from six countries (Argentina, Mexico, Spain, Dominican Republic, Venezuela and Cuba). For comparisons between variables an independent-samples t-test and one-way analysis of variance were used. Multiple linear regression was used to evaluate the effects of potential predictor variables over emotional reactions. ResultsOur results showed that PwMS who were positive for COVID-19 reported higher levels of fear of COVID-19 (p<.001) and also higher levels of anxiety (p<.001) compared to non-positive patients. Those patients who had difficulties attending their medical appointments during the outbreak showed higher levels of depression (p=.03) and anxiety (p=.019). Levels of anxiety (p<.001) and depression (p=.006) were also higher among patients with the subjective experience of MS disease progression. The reactions of fear of COVID-19, having been positive to COVID-19, problems attending medical appointments, and subjective experience of MS disease progression showed a high association with the negative impact of the pandemic on mental health of PwMS. ConclusionsOur results show that the situation generated by the COVID-19 pandemic has had a negative impact on the mental health of PwMS in our sample. Our results also alert to the importance of offering psychological care to patients with multiple sclerosis during the current outbreak, regardless of whether they have been positive for COVID-19.

Machine learning classifier to identify clinical and radiological features relevant to disability progression in multiple sclerosis

ObjectivesTo evaluate the accuracy of a data-driven approach, such as machine learning classification, in predicting disability progression in MS.MethodsWe analyzed structural brain images of 163 subjects diagnosed with MS acquired at two different sites. Participants were followed up for 2–6 years, with disability progression defined according to the expanded disability status scale (EDSS) increment at follow-up. T2-weighted lesion load (T2LL), thalamic and cerebellar gray matter (GM) volumes, fractional anisotropy of the normal appearing white matter were calculated at baseline and included in supervised machine learning classifiers. Age, sex, phenotype, EDSS at baseline, therapy and time to follow-up period were also included. Classes were labeled as stable or progressed disability. Participants were randomly chosen from both sites to build a sample including 50% patients showing disability progression and 50% patients being stable. One-thousand machine learning classifiers were applied to the resulting sample, and after testing for overfitting, classifier confusion matrix, relative metrics and feature importance were evaluated.ResultsAt follow-up, 36% of participants showed disability progression. The classifier with the highest resulting metrics had accuracy of 0.79, area under the true positive versus false positive rates curve of 0.81, sensitivity of 0.90 and specificity of 0.71. T2LL, thalamic volume, disability at baseline and administered therapy were identified as important features in predicting disability progression. Classifiers built on radiological features had higher accuracy than those built on clinical features.ConclusionsDisability progression in MS may be predicted via machine learning classifiers, mostly evaluating neuroradiological features.

Instrumentally assessed gait quality is more relevant than gait endurance and velocity to explain patient‐reported walking ability in early‐stage multiple sclerosis

People with multiple sclerosis (PwMS) often report walking limitations even when the gold standard Expanded Disability Status Scale (EDSS) indicates normal walking endurance/autonomy. The present multicenter study on early-stage PwMS aims at analyzing which aspects are associated with patient-reported walking limitations measured with the 12-item Multiple Sclerosis Walking Scale (MSWS-12). Eighty-two PwMS (EDSS≤2.5) were assessed using the Fullerton Advanced Balance Scale-short (FAB-s), the Fatigue Severity Scale (FSS) and the 6-min Walk Test (6MWT), the latter administered also to 21 healthy subjects. Participants performed the 6MWT wearing three inertial sensors on ankles and trunk. Instrumented metrics describing gait velocity (stride length and frequency) and quality (regularity, symmetry, instability) were computed from sensor data. Fatigue (FSS), balance (FAB-s), walking endurance (6MWT) and instrumented metrics were entered in a multiple regression model with MSWS-12 as dependent variable. Gait symmetry, gait instability, fatigue and balance were significantly associated with self-rated walking ability, whilst walking endurance and velocity were not. Fatigue, balance, gait symmetry and instability were more impaired in participants reporting mild-to-moderate (MSMM-PWL , 25≤MSWS-12<75) compared to those reporting none-to-minimal (MSnm-PWL , 0 ≤ MSWS-12 ≤ 25) perceived walking limitations. Compared to healthy subjects, gait symmetry and stability were reduced in MSnm-PWL and MSMM-PWL , even in those participants with EDSS≤1.5. Instrumentally assessed gait quality aspects (symmetry and instability) are associated with patient-reported walking ability in early-stage PwMS and seem sensitive biomarkers to detect subtle impairments even in the earliest stages of the disease (EDSS≤1.5). Future studies should assess their ability to follow walking change due to MS progression or pharmacological/rehabilitation interventions.

Disability Progression in MS is Independent of Lifestyle Behavior and Stress (2399)

Disability Progression in MS is Independent of Lifestyle Behavior and Stress (2399)

Exploring predictors of depressive symptoms in patients with multiple sclerosis: The effect of neuropathic pain, shame, and mindfulness

IntroductionMultiple Sclerosis (MS) is a chronic inflammatory, immune-mediated, demyelinating disease of the central nervous system, with a progressive course. It is potentially disabling and affects mainly young adults. Depression is the mental disorder with the greatest comorbidity with MS and tends to worsen its symptomatology and course. However, knowledge about the predictors of depression in patients with MS is scarce.ObjectivesThis preliminary study aimed to verify whether neuropathic pain (NP), internal (IS) and external (ES) shame and mindfulness predict depressive symptoms in patients with MS.MethodsThis cross-sectional study included a convenience sample of 95 patients diagnosed with MS and without other identified neurological diseases. Participants completed the Depression Subscale of the Depression, Anxiety and Stress Scales-21, the Analogue Pain Scale of the Pain Detect Questionnaire, the External and Internal Shame Scale, and the Mindfulness Subscale of the Self-Compassion Scale.ResultsAll potential predictors exhibited significant correlations with depressive symptoms and significantly predicted this symptomatology in simple linear regression models. Thus, they were included as covariates in the multiple linear regression model. This model explained a high percentage of the variance of depressive symptoms (40.5%) and identified NP, IS and mindfulness as significant predictors.ConclusionsInterventions aimed at preventing/reducing depression in patients with MS should minimize IS and develop mindfulness and NP coping skills, in order to promote mental health in this target population and possibly prevent the exacerbation and progression of MS symptomatology.DisclosureNo significant relationships.

Potential Role of CHI3L1+ Astrocytes in Progression in MS.

ObjectiveNeurofilament light protein (NfL) and chitinase 3–like 1 (CHI3L1) are biomarkers for acute neuroaxonal damage and local inflammation, respectively. Thus, we set out to evaluate how these biomarkers were associated with clinical features of demyelinating diseases in parallel with the expression in brain autopsies from patients with similar disease stages, assuming their comparability.MethodsNfL and CHI3L1 in CSF and serum CHI3L1 were assessed retrospectively in a cross-sectional cohort of controls (n = 17) and patients diagnosed with MS (n = 224), relapsing (n = 163) or progressive (n = 61); neuromyelitis optica (NMO, n = 7); and acute disseminated encephalomyelitis (ADEM, n = 15). Inflammatory activity was evaluated at the time of sampling, and CSF biomarker levels were related to the degree of inflammation in 22 brain autopsy tissues.ResultsDuring a clinical attack, the CSF NfL increased in MS, NMO, and ADEM, whereas CHI3L1 was only elevated in patients with NMO and ADEM and in outlier MS patients with extensive radiologic activity. Outside relapses, CHI3L1 levels only remained elevated in patients with progressive MS. CHI3L1 was detected in macrophages and astrocytes, predominantly in areas of active demyelination, and its expression by astrocytes in chronic lesions was independent of lymphocyte infiltrates and associated with active neurodegeneration.ConclusionsBoth CSF NfL and CHI3L1 augment during acute inflammation in demyelinating diseases. In MS, CHI3L1 may be associated with low-grade nonlymphocytic inflammation and active neurodegeneration and therefore linked to progressive disease.Classification of EvidenceThis study provides Class III evidence that CSF NfL and CHI3L1 levels increase in inflammatory brain diseases during acute inflammation.

Presenting Symptoms and Disease Severity in Multiple Sclerosis Patients.

Introduction: The study aims to determine an association between presenting symptoms in multiple sclerosis and measures of disease severity, including the expanded disability status score (EDSS) and MRI based lesion volumes. Methods: Data was collected as part of a larger 3 year MS study, from 2014 to 2017, to compare Vitamin A levels and MS progression. All data was collected from a single clinical site. Demographic data as well as date of diagnosis and use of disease modifying therapies. Patients not able to obtain MRIs or lab tests and histories of vitamin abnormalities were excluded from the study. 29 patients met inclusion criteria. We chose presenting symptoms of vision, balance, sensory function, and motor function as these represented the most common manifestations of the disease and mirror the domains of the EDSS, which is the most commonly used scale for MS disease severity. We also included neuroimaging based lesion volume as another objective measure for comparison. Results: Although duration of disease was different between comparator groups, no significant difference was found between them when EDSS and lesion volumes were compared. There was a difference in lesion volumes when comparing those patients that had presenting symptoms of visual changes or balance symptoms with those presenting with sensory changes. Conclusions: This study supports the notion that presenting symptoms are not associated with EDSS independent disease duration. It also verifies that severity of disease is not associated with lesion volumes. However, sensory symptoms as a presenting symptom was associated with less lesion volumes in our study.

Cerebellum and brain stem volume loss in relapsing remission multiple sclerosis by MRI volumetry: relation to neurological disability score and number of relapses

BackgroundMRI is the method of choice in the diagnosis of MS as well as in monitoring the disease activity. MRI volumetry is used to assess whole or regional brain volume loss which reflects neurodegenerative aspect of the disease and plays an important role in all stages of disease. The aim of this work is to study MRI volumetry in the evaluation of cerebellum and brain stem volume loss in RRMS patients and its correlation with neurological disability score and number of relapses.ResultsVolumes of whole brainstem, medulla, and pons showed a significant decrease in RRMS cases compared to controls (p < 0.05). Brainstem volume had a mean volume of 22.17 and 25.09 cm3 in cases and controls, respectively. However, midbrain volume showed no significant difference between cases and controls (p = 0.134). Volume of left cerebellar cortex showed a significant decrease in RRMS cases compared to controls (p < 0.001). It had mean volumes of 81.64 and 92.14 ml in cases and controls, respectively, at left cerebellar hemisphere, while right cerebellar hemisphere cortex volumes were 80.37 and 91.97 ml in cases and controls, respectively. Cerebellar white matter showed no significant volume decrease in cases and controls.ConclusionVolumetric MR imaging is an important tool for quantifying the MS disease, assesses MS activity, progression, and tissue loss. The degree and the pattern of atrophy on MRI images correlate significantly with the neurological disability score and number of relapses.

Polymorphisms in proinflammatory cytokines genes and susceptibility to Multiple Sclerosis

BackgroundMultiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder of the central nervous system (CNS). It is immunologically induced in genetically susceptible individuals. Proinflammatory cytokines play an important role as genetic polymorphisms in their genes might be involved in the susceptibility and pathogenesis of MS. ObjectiveIn this study, our goal was to analyze the association between the gene polymorphisms in interleukin-16 (IL-16) (rs4072111 C/T), tumor necrosis factor-α (TNF-α) -308 G/A (rs1800629 G/A) and IL-18 -607 C/A (rs1946518 C/A) and the susceptibility and clinical features of MS in an Egyptian cohort. MethodsWe genotyped these genetic polymorphisms in 150 subjects including 93 patients with MS and 57 unrelated healthy subjects. We employed polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) method for determining the IL-16 (rs4072111 C/T) and TNF-α -308 G/A (rs1800629 G/A) polymorphisms, and the allele- specific polymerase chain reaction (AS-PCR) method for IL-18-607 C/A (rs1946518 C/A) polymorphism. ResultsThe IL-16 (rs4072111 C/T) polymorphism was not polymorphic in both MS patients and the healthy volunteers. For the TNF-α-308 G/A (rs1800629 G/A) polymorphism, the mutant AA genotype and A allele are not associated with the susceptibility of MS, however, associated with the severity and disability progression of the disease. We observed a statistically significant increase in the mean values of Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) in patients with AA genotype and A allele compared with those of genotypes GG and GA, and the G allele, and regression analysis confirmed that this polymorphism is a predictor of disease disability using EDSS. For the IL-18 -607 C/A (rs1946518 C/A) polymorphism, the frequency of mutant AA genotype and A allele showed significant differences between the MS patients and healthy controls. ConclusionThe TNF-α-308 AA genotype and A allele could be related to disability progression and severity of MS and the IL-18-607 AA genotype A allele could be related to susceptibility of the disease in the Egyptian cohort.

Idebenone does not inhibit disability progression in primary progressive MS

BackgroundMultiple sclerosis (MS) is a chronic, immune-mediated neurodegenerative disorder of the central nervous system (CNS). While current MS therapies target the inflammatory processes, no treatment explicitly targets mitochondrial dysfunction and resulting axonal loss. Therefore, the aim of this study was to determine whether idebenone inhibits mitochondrial dysfunction and accumulation of disability in primary progressive MS (PPMS) and to enhance understanding of pathogenic mechanisms of PPMS progression using cerebrospinal fluid (CSF) biomarkers. MethodsThe double-blind, placebo-controlled Phase I/II clinical trial of Idebenone in patients with Primary Progressive MS (IPPoMS; NCT00950248) was an adaptively designed, baseline-versus-treatment, placebo-controlled, CSF-biomarker-supported trial. Based on interim analysis of the 1-year pre-treatment data, change in the area under the curve of Combinatorial Weight-Adjusted Disability Score (CombiWISE) became the primary outcome, with >80% power to detect ≥40% efficacy with 28 patients/arm treated for 2 years in baseline versus treatment paradigm. Changes in traditional disability scales and in brain ventricular volume were secondary outcomes. Exploratory outcomes included CSF biomarkers of mitochondrial dysfunction (Growth/differentiation factor 15 [GDF15] and lactate), axonal damage (neurofilament light chain [NFL]), innate immunity (sCD14), blood brain barrier leakage (albumin quotient) and retinal nerve fiber layer thinning. ResultsIdebenone was well tolerated but did not inhibit disability progression or CNS tissue destruction. Concentrations of GDF15, secreted predominantly by astrocytes and choroid plexus epithelium in vitro, increased after exposure to mitochondrial toxin rotenone, validating the ability of this biomarker to measure intrathecal mitochondrial damage. CSF GDF15 levels correlated strongly with age and MS patients had CSF levels of GDF15 significantly above age-adjusted healthy volunteers, with highest levels measured in PPMS. Idebenone did not change CSF GDF15 levels. ConclusionMitochondrial dysfunction exceeding normal aging reflected by age-adjusted CSF GDF15 is present in the majority of PPMS patients, but it is not inhibited by idebenone.

Vitamin D supplementation and serum neurofilament light chain in interferon-beta-1b-treated MS patients.

ObjectivesSerum neurofilament light chain (sNfL) is a promising biomarker of MS activity, progression, and treatment response. The aim of the present study was to address whether sNfL concentrations are affected by supplementation of vitamin D and correlate with disease activity in interferon‐beta‐1b (IFNb‐1b)‐treated Finnish MS.Materials and MethodsSerum samples were available of 32 participants of the Finnish vitamin D randomized controlled trial (17 vitamin D/15 placebo). Serum 25 hydroxyvitamin D was measured using radioimmunoassay and sNfL using single‐molecule array (Simoa). Correlation of sNfL with brain magnetic resonance imaging (MRI) activity, burden of disease (BOD, mm3), and disability was assessed at the study baseline and at 52 weeks.ResultsSerum NfL concentrations were similar in the patients randomized to high‐dose vitamin D and placebo at the study baseline and at month 12 follow‐up (p‐value). Concentrations of sNfL were higher in patients with Gadolinium‐enhancing lesions in brain MRI: median (95% CI) sNfL was 14.84 (9.9–42.5) pg/ml and 11.39 (8.9–13.2) pg/ml in patients without Gd+ lesions (p = .0144) and correlated with enhancing lesion volume (Pearson r = .36, p = .037) at the study baseline but not at week 52. Serum NfL did not correlate with the MRI BOD or disability measured by expanded disability status scale and 25‐foot walk test.ConclusionIn this small cohort of clinically stable IFN‐treated Finnish MS patients, sNfL levels were similarly low in patients supplemented with high‐dose vitamin D or placebo. Subclinical disease activity in MRI was associated with higher sNfL levels.

Comparing HCP and Patient Perceptions of Conversations about Disease Progression in MS (4304)

Comparing HCP and Patient Perceptions of Conversations about Disease Progression in MS (4304)