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The author discusses whether a useful yearly review of cognition in relapsing multiple sclerosis (MS) is or is not beyond most neurologists. He says that the significance of evaluating cognition at all stages of MS has been given weight by a series of papers from the Italian group led by Maria Pia Amato et al. He adds that these papers showed (among other findings) that patients with obviously benign MS after 18 years of illness could be subdivided into two groups.

Supervised exercise training has substantial benefits for persons with multiple sclerosis (MS), yet 80% of those with MS do not meet recommended levels of moderate-to-vigorous physical activity (MVPA). This same problem persisted for decades in the general population of adults and prompted a paradigm shift away from “exercise training for fitness” toward “physical activity for health.” The paradigm shift reflects a public health approach of promoting lifestyle physical activity through behavioral interventions that teach people the skills, techniques, and strategies based on established theories for modifying and self-regulating health behaviors. This paper describes: (a) the definitions of and difference between structured exercise training and lifestyle physical activity; (b) the importance and potential impact of the paradigm shift; (c) consequences of lifestyle physical activity in MS; and (d) behavioral interventions for changing lifestyle physical activity in MS. The paper introduces the “new kid on the MS block” with the hope that lifestyle physical activity might become an accepted partner alongside exercise training for inclusion in comprehensive MS care. [ABSTRACT FROM AUTHOR]

Background: To improve the consistency of standardized Expanded Disability Status Scale (EDSS) assessments, an electronic data capture tool and analysis tool was developed, Neurostatus e-Scoring (NESC). This tool allows real-time feedback by comparing entries with established scoring rules. Objective: To test whether using NESC reduces inconsistencies as compared to the paper-and-pencil version of the Expanded Disability Status Scale (pEDSS). Methods: In all, 100 multiple sclerosis (MS) patients were assessed in random order on the same day by pairs of neurologists, one using pEDSS and one NESC. We compared inter-rater reliability and frequency of inconsistencies in Neurostatus subscores, functional system (FS) scores, ambulation and EDSS steps. Results: Inconsistencies of any type were more likely to occur when using pEDSS (mean odds ratio (95% confidence interval (CI)) = 2.93 (1.62; 5.29)). This was also the case for FS score inconsistencies (2.54 (1.40; 4.61)) and more likely for patients in the lower EDSS range (≤3.5 vs >3.5) (5.32 (1.19; 23.77)). Overall, inter-rater agreement for the assessed Neurostatus subscores was high (median and inter-quartile range = 0.84 (0.73, 0.81)). Conclusion: Our data provide class II evidence that the use of NESC increases consistency of standardized EDSS assessments, and may thus have the potential to decrease noise and increase power of MS clinical trials. [ABSTRACT FROM AUTHOR]

Background: The impact of new asymptomatic spinal cord lesions (a-SL) in multiple sclerosis (MS) course is poorly characterized. Objective: The objective of this research paper is to assess the prognostic value of a-SL in predicting MS course. Methods: Relapsing--remitting MS patients who received serial MRI (brain and spinal) at baseline (t1) and within 12 to 36 months (t2) during clinical stability, and had a follow-up (t2--t3) ≥24 months were included. Relapses and disability progression were evaluated between t2 and t3. Results: Of 413 consecutive screened MS patients, 103 patients (65 females, median age 43 years) were included. After a median t1-t2 interval of 17 (IQR 13--26) months, 25.2% and 43.7% patients had ≥1 new a-SL (a-SL+) and asymptomatic brain lesions (a-BL+), respectively. Relapse risk between t2 and t3 (median interval: 42 (IQR 32--57.5) months) was significantly increased in a-SL+ and/or a-BL+ vs a-BL-- and a-SL-- (HR = 2.31, 95% CI = 1.13--4.72, p = 0.02). No differences in the risk of disability progression were found in a-SL+ and/or a-BL+ vs a-SL- and a-BL--. Conclusion: a-SL occur in one-quarter of clinically stable RRMS, and combined with a-BL contribute significantly in predicting future disease course. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is a chronic, progressive, and disabling disease of the central nervous system with dramatic variations in the combination and severity of symptoms it can produce. The lack of reliable disease-specific health-related quality of life (HRQL) measures for use in clinical trials prompted the development of the Neurology Quality of Life (Neuro-QOL) instrument, which includes 13 scales that assess physical, emotional, cognitive, and social domains, for use in a variety of neurological illnesses. Objective: The objective of this research paper is to conduct an initial assessment of the reliability and validation of the Neuro-QOL short forms (SFs) in MS. Methods: We assessed reliability, concurrent validity, known groups validity, and responsiveness between cross-sectional and longitudinal data in 161 recruited MS patients. Results: Internal consistency was high for all measures (α = 0.81--0.95) and ICCs were within the acceptable range (0.76-0.91); concurrent and known groups validity were highest with the Global HRQL question. Longitudinal assessment was limited by the lack of disease progression in the group. Conclusions: The Neuro-QOL SFs demonstrate good internal consistency, test-re-test reliability, and concurrent and known groups validity in this MS population, supporting the validity of Neuro-QOL in adults with MS. [ABSTRACT FROM AUTHOR]

Background: MRI studies have shown gray-matter abnormalities in fatigued multiple sclerosis (MS) patients. However, given that physical disability is highly correlated to MS fatigue, it is often difficult to disentangle its effect in these MRI findings. Objective: The objective of this research paper is to investigate gray-matter damage in mildly disabled MS patients, addressing which variables were better related to fatigue while controlling for physical disability and depression. Methods: Forty-nine relapsing--remitting MS (RRMS) patients and 30 controls underwent MRI (3T). Fatigue was assessed using the Fatigue Severity Scale (FSS). Multivariate logistic regression was performed to assess the contribution of clinical and MRI metrics to fatigue. Statistical analyses were performed controlling for disability and depression. Results: Fatigue was present in 22 (44.9%) patients. FSS score was highly correlated with EDSS (p = 0.00001). Patients with fatigue had lower brain cortical and subcortical gray-matter volumes. However, after controlling for EDSS, only the caudate and the accumbens volumes remained statistically significant. Conclusions: Fatigued MS patients have a global cortical and subcortical gray-matter atrophy that seems largely related to higher physical disability. However, striatal structures involved in effort-reward functions exhibited smaller volumes in fatigued patients, independently of physical disability and depressive symptoms, supporting the theory of cortico-striatal network impairment in MS fatigue. [ABSTRACT FROM AUTHOR]

Background: In search of the missing heritability in multiple sclerosis (MS), additional approaches adding to the genetic discoveries of large genome-wide association studies are warranted. Objective: The objective of this research paper is to search for rare genetic MS risk variants in the genetically homogenous population of the isolated Faroe Islands. Methods: Twenty-nine Faroese MS cases and 28 controls were genotyped with the HumanOmniExpressExome- chip. The individuals make up 1596 pair-combinations in which we searched for identicalby- descent shared segments using the PLINK-program. Results: A segment spanning 63 SNPs with excess case-case-pair sharing was identified (0.00173 < p > 0.00212). A haplotype consisting of 42 of the 63 identified SNPs which spanned the entire the Sortilinrelated vacuolar protein sorting 10 domain containing receptor 3 (SORCS3) gene had a carrier frequency of 0.34 in cases but was not present in any controls (p = 0.0008). Conclusion: This study revealed an oversharing in case-case-pairs of a segment spanning 63 SNPs and the entire SORCS3. While not previously associated with MS, SORCS3 appears to be important in neuronal plasticity through its binding of neurotrophin factors and involvement in glutamate homeostasis. Although additional work is needed to scrutinise the genetic effect of the SORCS3-covering haplotype, this study suggests that SORCS3 may also be important in MS pathogenesis. [ABSTRACT FROM AUTHOR]

Background: The role of genetic factors in influencing the clinical expression of multiple sclerosis (MS) is unclear. Objective: The objective of this paper is to identify genes, pathways and networks implicated in age at onset (AAO) and severity, measured using the Multiple Sclerosis Severity Score (MSSS), of primary-progressive MS (PPMS). Methods: We conducted a genome-wide association study (GWAS) of 470 PPMS patients of Italian origin:. Allelic association of 296,589 SNPs with AAO and MSSS was calculated. Pathway and network analyses were also conducted using different tools. Results: No single association signal exceeded genome-wide significance in AAO and MSSS analyses. Nominally associated genes to AAO and MSSS were enriched in both traits for 10 pathways, including: “oxidative phosphorylation” (FDRAAO=9*10−4; FDRMSSS=3.0*10−2), “citrate (TCA) cycle” (FDRAAO=1.6*10−2; FDRMSSS=3.2*10−3), and “B cell receptor signaling” (FDRAAO=3.1*10−2; FDRMSSS=2.2*10−3). In addition, an enrichment of “chemokine signaling pathway” (FDR=9*10−4) for AAO and of “leukocyte transendothelial migration” (FDR=2.4*10−3) for MSSS trait was observed, among others. Network analysis revealed that p53 and CREB1 were central hubs for AAO and MSSS traits, respectively. Conclusions: Despite the fact that no major effect signals emerged in the present GWAS, our data suggest that genetic variants acting in the context of oxidative stress and immune dysfunction could modulate the onset and severity of PPMS. [ABSTRACT FROM AUTHOR]

Background: Despite sensitivity of MRI to diagnose multiple sclerosis (MS), prognostic biomarkers are still needed for optimized treatment. Objective: The objective of this paper is to identify cerebrospinal fluid (CSF) diagnostic biomarkers of MS using quantitative proteomics and to analyze their expression at different disease stages. Methods: We conducted differential analysis of the CSF proteome from control and relapsing–remitting MS (RRMS) patients followed by verification by ELISA of candidate biomarkers in CSF and serum in control, clinically isolated syndrome (CIS), RRMS and progressive MS (PMS) patients. Results: Twenty-two of the 527 quantified proteins exhibited different abundances in control and RRMS CSF. These include chitinase 3-like protein 1 (CHI3L1) and 2 (CHI3L2), which showed a strong expression in brain of MS patients, especially in astrocytes and microglial cells from white matter plaques. CSF and serum CHI3L1 levels increased with the disease stage and CIS patients with high CSF (>189 ng/ml) and serum (>33 ng/ml) CHI3L1 converted more rapidly to RRMS (log rank test, p < 0.05 and p < 0.001, respectively). In contrast, CSF CHI3L2 levels were lower in PMS than in RRMS patients. Accordingly, CSF CHI3L1/CHI3L2 ratio accurately discriminated PMS from RRMS. Conclusions: CSF CHI3L1 and CHI3L2 and serum CHI3L1 might help to define MS disease stage and have a prognostic value in CIS. [ABSTRACT FROM AUTHOR]

Background and objective: Presentations of MS in fictional literature have not been previously researched. This paper surveys and analyses these portrayals of the disease for the first time. Material and methods: Relevant works in English and German were identified by means of keyword searches in online public access catalogues and search engines as well as old-fashioned research. The neurological and literary evaluation of these 7000 pages of text combines qualitative and quantitative methods. Results: Between 1954 and 2012 at least 55 literary works appeared with an MS motif (35 novels, 18 poems, one novella and one drama). The authors were predominantly female and a third of them suffered from the disease. Patients in the novels largely reflect real epidemiology as regards symptoms and disease progression, while diagnostic and therapeutic options play a secondary role. From a literary point of view, ‘entwicklungsromane’, ‘relationship novels’ and ‘young adult books’ can be discerned. MS is often portrayed in metaphoric language as the enemy: a demon, an animalistic being, prison or an abyss. Conclusion: The MS motif evidences a medicalization of the literature as well as a literary portrayal of anthropological experiences. Well-written novels can contribute to the de-stigmatization of MS and impart basic medical knowledge. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) and antiphospholipid syndrome (APS) share common clinical, laboratory and radiological features. We reviewed all the English papers on MS and APS published in the literature from 1965 to 2014 using PubMed and Google Scholar. We found that APS can mimic antiphospholipid antibodies (aPL)-positive MS in many ways in its clinical presentation. Nevertheless, APS diagnosis, clinical manifestations and management differ from those of MS. aPL were found in MS patients with titers ranging from 2% to 88%. The distribution and volume of lesions on magnetic resonance imaging (MRI) may help to differentiate MS from primary APS. In addition, atypical MS presentation can guide physicians toward an alternative diagnosis, especially when features of thrombosis and/or history of connective tissue disease are present. In that case, an anticoagulation trial could be worthwhile. [ABSTRACT FROM AUTHOR]

Background: Degeneration of central nervous system normal appearing white matter (NAWM) underlies disability andprogression in multiple sclerosis (MS). Axon loss typifies NAWM degeneration.Objective: The objective of this paper is to assess correlation between cortical lesion load and magnetisation transferratio (MTR) of the NAWM in MS. This was in order to test the hypothesis that cortical lesions cause NAWM degeneration.Methods: Nineteen patients with MS underwent 7 Tesla magnetisation-prepared-rapid-acquisition-gradient-echo(MPRAGE), and magnetisation transfer ratio (MTR) brain magnetic resonance imaging (MRI). Cortical lesions wereidentified using MPRAGE and MTR images of cortical ribbons. White matter lesions (WMLs) were segmented usingMPRAGE images. WML maps were subtracted from white matter volumes to produce NAWM masks. Pearsoncorrelation was calculated for NAWM MTR vs cortical lesion load, and WML volumes.Results: Cortical lesion volumes and counts all had significant correlation with NAWM mean MTR. The strongestcorrelation was with cortical lesion volumes obtained using MTR images (r = –0.6874, p = 0.0006). WML volume had nosignificant correlation with NAWM mean MTR (r = –0.08706, p = 0.3615).Conclusion: Our findings are consistent with the hypothesis that cortical lesions cause NAWM degeneration. This implicatescortical lesions in the pathogenesis of NAWM axon loss, which underpins long-term disability and progression in MS. [ABSTRACT FROM AUTHOR]

Background: Growing evidence suggests that vitamin D deficiency may be one of the most important environmentalfactors for the development of multiple sclerosis (MS).Objectives: The objectives of this paper are to evaluate serum 25-hydroxyvitamin D (25(OH)D) levels in patients withclinically isolated syndromes (CIS) and to examine whether they are related to MS risk.Methods: This is a retrospective study of 100 CIS patients hospitalized from 2000 to 2009 at San Raffaele Hospital,Milan, Italy. We evaluated baseline 25(OH)D level as well as clinical, brain magnetic resonance imaging (MRI) andcerebrospinal fluid (CSF) data.Results: A total of 52% of CIS patients had vitamin D deficiency (25(OH)D < 50 nmol/l). During follow-up (median: 7.17years), 55 patients developed clinically definite MS (CDMS). Patients with very low (< 10th percentile) and low (< 25thpercentile) 25(OH)D levels were particularly at risk of CDMS (HRs (95% CIs): 2.12 (0.91–4.96) and 1.61 (0.85–3.03),respectively), while no further reduction in the HRs of disease was observed at high levels of 25(OH)D. This associationwas even stronger after adjustment for additional risk factors for CDMS development (HRs (95% CIs) for 25(OH)Dlevels < 10th and 25th percentiles: 3.34 (1.32–8.45) and 2.04 (0.96–4.36), respectively).Conclusion: Low serum vitamin D is associated with increased MS risk in patients with CIS [ABSTRACT FROM AUTHOR]

Objective: The objective of this paper is to identify clinical or magnetic resonance imaging (MRI) predictors of longtermclinical progression in a large cohort of multiple sclerosis (MS) patients.Methods: A total of 241 relapsing–remitting (RR) MS patients were included in a nine-year follow-up (FU) study. Thereference MRIs were acquired at baseline (BL) as part of a multicenter, cross-sectional, clinical-MRI study. VolumetricMRI metrics were measured by a fully automated, operator-independent, multi-parametric segmentation method. Clinicalprogression was evaluated as defined by: conversion from RR to secondary progressive (SP) disease course; progressionof Expanded Disability Status Scale (EDSS); achievement and time to reach EDSS 4.Results: We concluded that conversion from RR to SP (OR 0.79; CI 0.7–0.9), progression of EDSS (OR 0.85; CI 0.77–0.93), achievement of EDSS 4 (OR 0.8; CI 0.7–0.9), and time to reach EDSS 4 (HR 0.88; CI 0.82–0.94) were all predictedby BL gray matter (GM) volume and, except for progression of EDSS, by BL EDSS (respectively: (OR 2.88; CI 1.9–4.36),(OR 2.7; CI 1.7–4.2), (HR 3.86; CI 1.94–7.70)).Conclusions: BL GM volume and EDSS are the best long-term predictors of disease progression in RRMS patients witha relatively long and mild disease. [ABSTRACT FROM AUTHOR]

Background:The accrual of brain focal pathology is considered a good substrate of disability in relapsing–remittingmultiple sclerosis (RRMS). However, knowledge on long-term lesion evolution and its relationship with disabilityprogression is poor.Objective:The objective of this paper is to evaluate in RRMS the long-term clinical relevance of brain lesion evolution.Methods:In 58 RRMS patients we acquired, using the same scanner and protocol, brain magnetic resonance imaging(MRI) at baseline and 10±0.5 years later. MRI data were correlated with disability changes as measured by the ExpandedDisability Status Scale (EDSS).Results:The annualized 10-year lesion volume (LV) growth was +0.25±0.5 cm3 (+6.7±8.7%) for T2-weighted (T2-W)lesions and +0.20±0.31 cm3 (+11.5±12.3%) for T1-weighted (T1-W) lesions. The univariate analysis showed moderatecorrelations between baseline MRI measures and EDSS at 10 years (p < 0.001). Also, 10-year EDSS worsening correlatedwith LV growth and the number of new/enlarging lesions measured over the same period (p < 0.005). In the stepwisemultiple regression analysis, EDSS worsening over 10 years was best correlated with the combination of baseline T1-Wlesion count and increasing T1-W LV (R = 0.61, p < 0.001).Conclusion:In RRMS patients, long-term brain lesion accrual is associated with worsening in clinical disability. This isparticularly true for hypointense, destructive lesions. [ABSTRACT FROM AUTHOR]

The article offers the authors' insights about the developments of the journal. The authors talk about the success of the journal of attracting papers of increasing quality which are making important and impactful contributions to the field of multiple sclerosis. They also tackle the creation of a new post of deputy editor in Europe to help manage the increasing volume of submissions.

Aim: We reviewed the clinical features of a sample of pediatric acquired demyelinating syndromes with the purpose of determining the appropriate protocol for follow-up after the first episode. Methods: A multicenter retrospective observational study was conducted on a cohort of 40 children diagnosed with a first episode of acquired demyelinating syndrome over the period 2012-2021. Patients were evaluated with clinical and neuroradiologic assessment after 3, 6, and 12 months, with a median follow-up of 4.0 years. Results: At the first acquired demyelinating syndrome episode, 18 patients (45%) were diagnosed with acute disseminated encephalomyelitis, 18 (45%) with clinical isolated syndrome, and 4 (10%) with multiple sclerosis. By month 12, 12 patients (30%) had progressed from an initial diagnosis of acute disseminated encephalomyelitis (2) or clinical isolated syndrome (10) to multiple sclerosis. Of these, 6 had clinical relapse and 6 radiologic relapse only. The first relapse occurred after a median of 3 months. Among the patients who had evolved toward multiple sclerosis, there was a prevalence of females (P =.014), higher oligoclonal bands positivity (P =.009), and older median age (P <.001) as compared with those who had remained stable. Interpretation: Both clinical and radiologic follow-up of children with acquired demyelinating syndromes is crucial, especially during the first year after acute onset, for early identification of multiple sclerosis and prompt initiation of disease-modifying treatment to delay axonal damage and to limit disability. [ABSTRACT FROM AUTHOR]

Background: A pro-inflammatory diet has been posited to induce chronic inflammation within the central nervous system (CNS), and multiple sclerosis (MS) is an inflammatory disease of the CNS. Objective: We examined whether Dietary Inflammatory Index (DII®)) scores are associated with measures of MS progression and inflammatory activity. Methods: A cohort with a first clinical diagnosis of CNS demyelination was followed annually (10 years, n = 223). At baseline, 5- and 10-year reviews, DII and energy-adjusted DII (E-DIITM) scores were calculated (food frequency questionnaire) and assessed as predictors of relapses, annualised change in disability (Expanded Disability Status Scale) and two magnetic resonance imaging measures; fluid-attenuated inversion recovery (FLAIR) lesion volume and black hole lesion volume. Results: A more pro-inflammatory diet was associated with a higher relapse risk (highest vs. lowest E-DII quartile: hazard ratio = 2.24, 95% confidence interval (CI) = −1.16, 4.33, p = 0.02). When we limited analyses to those assessed on the same manufacturer of scanner and those with a first demyelinating event at study entry (to reduce error and disease heterogeneity), an association between E-DII score and FLAIR lesion volume was evident (β = 0.38, 95% CI = 0.04, 0.72, p = 0.03). Conclusion: There is a longitudinal association between a higher DII and a worsening in relapse rate and periventricular FLAIR lesion volume in people with MS. [ABSTRACT FROM AUTHOR]

P095 Building Predictive Models of Non-Compliance in an Underserved MS Patient Population B L. Tardo b , B. Greenberg, M. Huichapa, M. McCreary, C. Chapman, L. Horton I Neurology, UT Southwestern Medical Center, Dallas, TX i B Background: b Minority patients with multiple sclerosis (MS) tend to have significant delays in diagnosis along with more disability. B Methods: b CLICK-MS (NCT03933215) and MASTER-2 (NCT03933202) are ongoing US-based, 54-month, single arm, observational studies examining real-world clinical and patient-reported outcomes of CladT3.5 in patients with relapsing MS following suboptimal response to prior injectable (CLICK-MS), oral, or infusion (MASTER-2) DMTs. M. Dykes SP 1 sp , B G. K. Zaid b SP 1 sp , S. Ngorsuraches SP 2 sp , W. K. Meador SP 1 sp SP 1 sp I Neurology, University of Alabama at Birmingham, Birmingham, AL i , SP 2 sp I Harrison Collage of Pharmacy, Auburn University, Auburn, AL i B Background: b African American (AA) patients with multiple sclerosis (MS) have higher inflammatory disease activity, disability accumulation and worse disease outcomes as compared to Caucasian American (CA) patients with MS. P062 Quantitative Spinal Cord MRI and Retinal Layers in Multiple Sclerosis as a Predictor of... B A. E. Mohamed b I Neurology, al-azhar university, cairo, EGYPT i B Background: b Quantitative spinal cord MRI and retinal layers in multiple sclerosis as a predictor of early progression(Al -azhar Egypt study) B Objectives: b Correlation between spinal cord MRI and retinal measures, and to evaluate whether these measures independently relate progression in multiple sclerosis (MS). [Extracted from the article]

The article examines the best threshold for the rule of five and demonstrates the predictive validity for subsequent multiple sclerosis trials risk relapses. The study shows that the best threshold definition is a threshold of five lesions. It considers the rule of five breakage as a significant imminent relapse predictor. The discovery of lesions as important relapse predictor is also noted.

Leptomeningeal enhancement (LME) is a novel imaging finding[1] that has been detected on delayed postcontrast fluid-attenuated inversion recovery (FLAIR) images on high-field and ultra-high-field magnetic resonance imaging (MRI).[1][2][3][4]-[5] LME has been postulated to be pathologically related to the disruption of the blood-meningeal barrier due to leptomeningeal inflammation[1] and potentially ectopic B-cell follicle-like aggregations. In this cohort, LME-positive cases had a fourfold increase in the cortical lesion number, a fivefold increase in thalamic lesions, and a fourfold increase in white matter lesions compared with LME-negative cases. [Extracted from the article]

Although over 20 disease modifying therapies are approved to treat Multiple Sclerosis (MS), these do not increase remyelination of demyelinated axons or mitigate axon damage. Previous studies showed that lanthionine ketenamine ethyl ester (LKE) reduces clinical signs in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS and increased maturation of oligodendrocyte (OL) progenitor cells (OPCs) in vitro. In the current study, we used the cuprizone (CPZ) demyelination model of MS to test if LKE could increase remyelination. The corpus callosum (CC) and somatosensory cortex was examined by immunohistochemistry (IHC), electron microscopy and for mRNA expression changes in mice provided 5 weeks of CPZ diet followed by 2 weeks of normal diet in the presence of LKE or vehicle. A significant increase in the number of myelinated axons, and increased myelin thickness was observed in the CC of LKE-treated groups compared to vehicle-treated groups. LKE also increased myelin basic protein and proteolipid protein expression in the CC and cortex, and increased the number of mature OLs in the cortex. In contrast, LKE did not increase the percentage of proliferating OPCs suggesting effects on OPC survival and differentiation but not proliferation. The effects of LKE on OL maturation and remyelination were supported by similar changes in their relative mRNA levels. Interestingly, LKE did not have significant effects on GFAP or Iba1 immunostaining or mRNA levels. These findings suggest that remyelinating actions of LKE can potentially be formulated to induce remyelination in neurological diseases associated with demyelination including MS. [ABSTRACT FROM AUTHOR]

Psychosine exerts most of its toxic effects by altering membrane dynamics with increased shedding of extracellular vesicles (EVs). In this study, we discovered that a fraction of psychosine produced in the brain of the Twitcher mouse, a model for Krabbe disease, is associated with secreted EVs. We evaluated the effects of attenuating EV secretion in the Twitcher brain by depleting ceramide production with an inhibitor of neutral sphingomyelinase 2, GW4869. Twitcher mice treated with GW4869 had decreased overall EV levels, reduced EV-associated psychosine and unexpectedly, correlated with increased disease severity. Notably, characterization of well-established, neuroanatomic hallmarks of disease pathology, such as demyelination and inflammatory gliosis, remained essentially unaltered in the brains of GW4869-treated Twitcher mice compared to vehicle-treated Twitcher controls. Further analysis of Twitcher brain pathophysiology is required to understand the mechanism behind early-onset disease severity in GW4869-treated mice. The results herein demonstrate that some pathogenic lipids like psychosine may be secreted using EV pathways. Our results highlight the relevance of this secretory mechanism as a possible contributor to spreading pathogenic lipids in neurological lipidoses. [ABSTRACT FROM AUTHOR]

The author discusses the use of McDonald Criteria 2010 in the diagnosis of multiple sclerosis, which understate the importance of cerebrospinal fluid (CSF) oligoclonal bands (OB). It mentions that multiple sclerosis diagnosis using McDonald Criteria considers principles such as dissemination in space, dissemination in time, and assurance of better explanation for the disease. It states that Xavier Montalban and his colleagues were able to produce a good paper showing the significance of CSFOBs.

Background: There is increasing evidence of prodromal multiple sclerosis (MS). Objective: The aim of this study was to determine whether fatigue, sleep disorders, anaemia or pain form part of the MS prodrome. Methods: This population-based matched cohort study used linked administrative and clinical databases in British Columbia, Canada. The odds of fatigue, sleep disorders, anaemia and pain in the 5 years preceding the MS cases' first demyelinating claim or MS symptom onset were compared with general population controls. The frequencies of physician visits for these conditions were also compared. Modifying effects of age and sex were evaluated. Results: MS cases/controls were assessed before the first demyelinating event (6863/31,865) or MS symptom onset (966/4534). Fatigue (adj.OR: 3.37; 95% CI: 2.76–4.10), sleep disorders (adj.OR: 2.61; 95% CI: 2.34–2.91), anaemia (adj.OR: 1.53; 95% CI: 1.32–1.78) and pain (adj.OR: 2.15; 95% CI: 2.03–2.27) during the 5 years preceding the first demyelinating event were more frequent among cases, and physician visits increased for cases relative to controls. The association between MS and anaemia was greater for men; that between MS and pain increased with age. Pre-MS symptom onset, sleep disorders (adj.OR: 1.72; 95% CI: 1.12–2.56) and pain (adj.OR: 1.53; 95% CI: 1.32–1.76) were more prevalent among cases. Conclusion: Fatigue, sleep disorders, anaemia and pain were elevated before the recognition of MS. The relative anaemia burden was higher in men and pain more evident among older adults. [ABSTRACT FROM AUTHOR]

B Thursday, February 27, 2020 b B Kenneth P. Johnson Memorial Lecture b Advances in Understanding Progressive Multiple Sclerosis U P. Calabresi u I Johns Hopkins University, Baltimore, MD i Multiple sclerosis (MS) is a heterogeneous disease with an unpredictable course and a wide range of severity; some individuals rapidly progress to a disabled state while others experience only mild symptoms. Applied Epigenomics for Understanding MS Pathogenesis U M. Jagodic u I Karolinska Institutet, Solna, Sweden i Although the cause of Multiple Sclerosis (MS) remains unknown, vast epidemiological data establish MS as a complex disease influenced by genetic and environmental factors. SESSION 3 - Immune Cell Networks in MS Lymphocyte-myeloid Cell Networks in MS U E. Bettelli u I University of Washington, Seattle, Washington i B Introduction: b Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system. Melanoma Cell Adhesion Molecule (MCAM) On Blood-Brain Barrier Endothelium Contributes To Neur... U M. Charabati u SP 1 sp , S. J. Zandee SP 1 sp , A. Fournier SP 1 sp , M. Lécuyer SP 2 sp , R. Zaminpeyma SP 1 sp , E. Peelen SP 1 sp , S. Larouche SP 1 sp , L. Bourbonnière SP 1 sp , N. Arbour SP 1 sp , C. Larochelle SP 1 sp , A. Prat SP 1 sp ; I SP 1 sp CRCHUM-University of Montreal, Montreal, QC, Canada, 2Institute for Multiple Sclerosis Research, University Medical Centre, Göttingen, Germany i B Background: b The trafficking of autoimmune leukocytes into the central nervous system (CNS) in multiple sclerosis (MS) is mediated via cell adhesion molecules. [Extracted from the article]

The number of reported cases of iatrogenic demyelination of the central nervous system (CNS) is on the rise. This is, in part, related to the recent expansion in the use of biologics. Review of literature from the past decade suggests that in addition to vaccines, tumor necrosis factor (TNF)-alpha inhibitors and checkpoint inhibitors are the most frequently cited inducers of central inflammation. About one-third of demyelinating cases in the setting of TNF-alpha inhibitors evolve into full-blown multiple sclerosis. In addition to demyelination, checkpoint inhibitors may also cause accelerated paraneoplastic encephalitis and other antibody-mediated conditions. Luckily, the overall prognosis of iatrogenic central inflammation is favorable, with most cases having partial or complete response to steroids and discontinuation of the offending agent. Long-term monitoring and initiation of maintenance immune-modulating therapy may be necessary in some patients. In this article, we provide an updated review of biologic-induced inflammation of the CNS. [ABSTRACT FROM AUTHOR]

Objective: Large demyelinating lesions with possible mass effect (tumefactive multiple sclerosis or tumefactive demyelination) can be mistaken for tumour-like space-occupying lesions suggesting a malignant outcome. Methods: We reviewed our own experience of multiple sclerosis subjects (n=28) with tumefactive demyelination to determine the relationship between clinical outcomes and lesion evolution, clinical outcomes and their relationship to different therapies. Patients with central nervous system demyelinating disease were identified from our database over the last 10 years. Results: No patient increased in extended disability status scale (EDSS). Overall, lesion regression was associated with improved EDSS. Lesion regression was also associated with therapy versus no therapy. No specific therapy or corticosteroid infusions improved EDSS over the long term. The absence of enhancement on follow up on magnetic resonance imaging portended lesion regression. Conclusion: Tumefactive demyelination may predict a more benign overall course and is susceptible to traditional immunomodulatory treatments. [ABSTRACT FROM AUTHOR]

Background: Demyelinating diseases of the central nervous system associated with autoantibodies against aquaporin-4 and myelin-oligodendrocyte-glycoprotein are mediated by different immunopathological mechanisms compared to multiple sclerosis. Objective: The purpose of this study was to evaluate serum and cerebrospinal fluid cytokine/chemokine profiles in patients with autoantibodies against aquaporin-4 or autoantibodies against myelinoligodendrocyte-glycoprotein-associated demyelination compared to multiple sclerosis and autoimmune encephalitis. Methods: Serum and cerebrospinal fluid cytokine/chemokine levels were analysed using Procartaplex Multiplex Immunoassays. First, we analysed a panel of 32 cytokines/chemokines in a discovery group (nine aquaporin-4-antibody seropositive, nine myelin oligodendrocyte glycoprotein-antibody seropositive, eight encephalitis, 10 multiple sclerosis). Significantly dysregulated cytokines/chemokines were validated in a second cohort (11 aquaporin-4-antibody seropositive, 18 myelin oligodendrocyte glycoprotein-antibody seropositive, 18 encephalitis, 33 multiple sclerosis). Results: We found 11 significantly altered cytokines/chemokines in cerebrospinal fluid and serum samples in the discovery group (a proliferation-inducing ligand, fractalkine=CX3CL1, growthregulated oncogene-α, interleukin-1 receptor antagonist, interleukin-6, interleukin-8=CXCL8, interleukin-10, interleukin-21, interferon-Ç-induced protein-10=CXCL10, monokine induced by interferon-Ç=CXCL9, macrophage inflammatory protein-1ß=CCL4). Most of these cytokines/chemokines were up-regulated in autoantibodies against aquaporin-4 or autoantibodies against myelinoligodendrocyte-glycoprotein positive patients compared to multiple sclerosis. We confirmed these results for cerebrospinal fluid interleukin-6 and serum interleukin-8, growth-regulated oncogene-α, a proliferation-inducing ligand and macrophage inflammatory protein-1b in the validation set. Receiveroperating characteristic analysis revealed increased levels of cerebrospinal fluid interleukin-6, serum interleukin-8 and growth-regulated oncogene-α in most patients with autoantibody-associated neurological diseases. Conclusion: This study suggests that distinctive cerebrospinal fluid and serum cytokine/chemokine profiles are associated with autoantibody-mediated demyelination, but not with multiple sclerosis. [ABSTRACT FROM AUTHOR]

Background: Reversible lymphocyte count reductions have occurred following daclizumab beta treatment for relapsing–remitting multiple sclerosis. Objective: To analyse total and differential lymphocyte levels and relationship with infection status. Methods: In DECIDE, blood samples were collected at 12-week intervals from daclizumab beta- (n = 919) or intramuscular interferon beta-1a–treated (n = 922) patients. Infections/serious infections were assessed proximate to grade 2/3 lymphopenia or low CD4+/CD8+ T-cell counts. Total safety population (TSP) data were additionally analysed from the entire clinical development programme (n = 2236). Results: Over 96 weeks in DECIDE, mean absolute lymphocyte count (ALC), CD4+ and CD8+ T-cell counts decreased <10% (7.1% vs 1.6%, 9.7% vs 2.0%, 9.3% vs 5.9%: daclizumab beta vs interferon beta-1a, respectively); shifts to ALC below lower limit of normal occurred in 13% versus 15%, respectively. Grade 3 lymphopenia was uncommon (TSP: <1%) and transient. Lymphocyte changes generally occurred within 24 weeks after treatment initiation and were reversible within 12 weeks of discontinuation. In DECIDE, mean CD4+/CD8+ T-cell counts were similar regardless of infection status. TSP data were consistent with DECIDE. Conclusion: When observed, ALC and CD4+/CD8+ T-cell count decreases in daclizumab beta–treated patients were generally mild-to-modest, reversible upon treatment discontinuation and not associated with increased risk of infections, including opportunistic infections. [ABSTRACT FROM AUTHOR]

The author claims that progressive resistance training (PRT) is not the best way to rehabilitate deficits due to multiple sclerosis (MS). She notes that the positive effect of PRT on the balance and fatique in MS patients is not clearly stated in several studies. She believes that the best intervention for MS is one that addresses the symptoms of the person, and assists in meeting their specific goals.

In a healthcare environment that is trying to achieve better clinical outcomes and patient satisfaction, shared decision-making is a well-established concept that is gaining more interest. Multiple sclerosis is a preference-sensitive condition and provides the opportunity to implement decision aids at various decision points in the disease process. Literature about patient education and outcomes of shared decision aids in multiple sclerosis has been growing over the last decade. In this topical review, we present an overview of the current literature on shared decision-making in multiple sclerosis. While limitations to the generalizability and applicability of decision aids exist, there is evidence that decision aids and shared decision-making can be valuable tools in the clinical care of multiple sclerosis patients. [ABSTRACT FROM AUTHOR]

The no evidence of disease activity (NEDA) composite measure has emerged as one attractive new target of therapies in relapsing–remitting multiple sclerosis (RRMS), consisting of the following features: (1) no relapses, (2) no disability progression, and (3) no magnetic resonance imaging (MRI) activity (new or enlarging T2 lesions or Gd-enhancing lesions). Achievement of NEDA status in patients receiving a disease-modifying therapy (DMT) seems to be an ambitious but ideal goal for therapies in RRMS. Recently, published post hoc analyses of clinical trials reported percentages of RRMS patients maintaining the NEDA status after 2 years of therapy ranging between 13% and 46%. Long-term assessment of NEDA patients in real-life settings showed very low probability to be NEDA in the long run. Against this scenario, immunoablative therapy followed by autologous hematopoietic stem cell transplantation (aHSCT) demonstrated the potential to maintain a much higher proportion of NEDA patients at 2 years (ranging from 78% to 83%) and also at 5 years (ranging from 60% to 68%). This is even more relevant when considering that MS patients who underwent aHSCT are much more active than patients usually enrolled in clinical trials. The emerging evidence of the efficacy of this therapeutic approach in early aggressive and treatment-resistant RRMS calls for the organization of a randomized comparative trial to fully evaluate the risk–benefit profile of aHSCT in patients with highly active MS not responding to DMTs. [ABSTRACT FROM AUTHOR]

The article presents abstracts on topics related to multiple sclerosis (MS) which include the challenges for MS care and research in the Middle East, the prevalence of neuromyelitis optica in New Zealand and Australia and the cognitive impairment and income among MS patients.

Background: Several reports indicate changes to prevalence, incidence, female-to-male ratio in multiple sclerosis. Diagnostic criteria, course definitions and clinical management of the disease have also undergone change during the recent decades. Objective: To investigate temporal trends in the diagnosis of primary progressive multiple sclerosis (PPMS) in Sweden. Methods: Through the Swedish MS registry we investigated the proportion of PPMS diagnosis in birth, diagnosis and age period cohorts using Poisson regression. Results: A total of 16,915 patients were categorised into six birth-cohorts from 1946 to 1975 and seven date-of-diagnosis-cohorts from 1980 to 2014. We observed a decrease in the uncorrected analysis of diagnosis of PPMS from 19.2% to 2.2% and an average decrease of 23% (p < 0.001) per 5-year birth-cohort in the adjusted analysis. An average 21% (p < 0.001) decrease per diagnosis-cohort was seen. In the age-specific diagnosis period cohorts the same decreasing trend of PPMS diagnosis was observed in almost all groups. Conclusion: The diagnosis of PPMS has significantly decreased in Sweden specifically after introduction of disease-modifying treatments. Such decrease can have severe impacts on the future research on PPMS. Our data also suggest that the current trend to emphasise presence or absence of inflammatory activity is already reflected in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Progranulin (GRN) is a multifunctional protein involved in inflammation and repair, and also a neurotrophic factor critical for neuronal survival. Progranulin is strongly expressed in multiple sclerosis (MS) brains by macrophages and microglia. Methods: In this study we evaluated GRN genetic variability in 400 MS patients, in correlation with clinical variables such as disease severity and relapse recovery. We also evaluated serum progranulin levels in the different groups of GRN variants carriers. Results: We found that incomplete recovery after a relapse is correlated with an increased frequency of the rs9897526 A allele (odds ratio (OR) 4.367, p = 0.005). A more severe disease course (Multiple Sclerosis Severity Score > 5) is correlated with an increased frequency of the rs9897526 A allele (OR 1.886, p = 0.002) and of the rs5848 T allele (OR 1.580, p = 0.019). Carriers of the variants associated with a more severe disease course (rs9897526 A, rs5848 T) have significantly lower levels of circulating progranulin (80.5 ± 9.1 ng/mL vs. 165.7 ng/mL, p = 0.01). Conclusion: GRN genetic polymorphisms likely influence disease course and relapse recovery in MS. [ABSTRACT FROM AUTHOR]

The life expectancy and average age of persons with multiple sclerosis (MS) have increased significantly during the last two decades. The introduction of disease-modifying therapies and a better delineation and understanding of the superimposed comorbidities often diagnosed in MS patients are probably the most important factors accountable for the increase in aging MS population worldwide. Healthcare teams must therefore address the problems arising due to advancing age superimposed on this chronic neurologic disease. In this review, we focus on the physiology of aging, its effects on MS disease course, and the pathological and immunological changes associated with aging and disease progression. Additionally, we discuss the common comorbidities that occur in aging persons with MS that may arise either as a result of the aging process or from relentless chronic MS disease progression as well as the challenges on differentiating the two processes for a more appropriate therapeutic approach. [ABSTRACT FROM AUTHOR]

Background: Several magnetic resonance imaging (MRI) studies investigated the evolution of multiple sclerosis (MS) lesions to understand the pathophysiological mechanisms leading to blood-brain barrier breakdown and lesion formation. Only a few assessed the early natural history of MS lesions using shortinterval longitudinal MRI. Objective: The purpose of this study was to characterize MS lesion occurrence and early evolution on high-resolution MRI acquired at weekly intervals. Methods: Active lesions were characterized on 3D fluid attenuation inversion recovery (FLAIR) and gadolinium-enhanced 3D T1-weighted MRI performed weekly (seven weeks) on five untreated patients with relapsing-remitting MS (RRMS). Results: Active lesions (n=212) were detected in all patients. All showed contrast-enhancement on at least one time-point. Most new lesions (83.5%) were visible on FLAIR and post-contrast T1-weighted images at first detection; 11.2% showed activity on FLAIR images, one or more weeks before the appearance of contrast-enhancement; 12.5% enhanced before being apparent on FLAIR. Conclusion: Blood brain barrier disruption is a constant step in the natural history of active MS lesions, but does not always constitute the initial event. These findings are consistent with the existence of a subpopulation of lesions with an 'inside-out' genesis, where neurodegenerative processes might precede microglial activation, and a subsequent adaptive immune response. [ABSTRACT FROM AUTHOR]

Background: Vitamin D insufficiency is a risk factor for multiple sclerosis (MS), and patients do not always show the expected response to vitamin D supplementation. Objective: We aimed to determine if vitamin D supplementation leads to a similar increase in serum 25-hydroxyvitamin-D (25(OH)D) levels in patients with MS and healthy controls (HCs). Methods: Participants in this open-label study were female, white, aged 18-60 years, had 25(OH)D levels ≤ 75 nmol/l at screening, and had relapsing-remitting MS (RRMS) or were HCs. Participants received 5000 IU/day of vitamin D3 for 90 days. Utilizing generalized estimating equations we examined the relationship between the primary outcome (serum 25(OH)D level) and the primary (MS versus HC status) and secondary predictors. Results: For this study 27 MS patients and 30 HCs were enrolled. There was no significant difference in baseline 25(OH)D level or demographics except for higher body mass index (BMI) in the MS group (25.3 vs. 23.6 kg/m2, p=0.035). In total, 24 MS subjects and 29 HCs completed the study. In a multivariate model accounting for BMI, medication adherence, and oral contraceptive use, MS patients had a 16.7 nmol/l (95%CI: 4.2, 29.2, p=0.008) lower increase in 25(OH)D levels compared with HCs. Conclusions: Patients with MS had a lower increase in 25(OH)D levels with supplementation, even after accounting for putative confounders. [ABSTRACT FROM AUTHOR]

Objective: To evaluate resting-state functional connectivity (FC) and relationship to brain volumes and cognition in a sample of cognitively preserved pediatric-onset multiple sclerosis (MS) patients. Methods: Sixteen cognitively intact pediatric-onset MS patients and 15 healthy age- and sex-matched controls underwent cognitive testing and 3T anatomical and functional MRI. Resting-state FC patterns were examined using region-of-interest-based timeseries correlations. Results: Compared to controls, pediatric-onset MS patients demonstrated higher FC of the precuneus, particularly with the anterior cingulate cortex (z=4.21, p<.001), frontal medial cortex (z=3.48, p<.001), and cerebellum (z=3.72, p<.001). Greater T2 lesion volume and lower normalized thalamic volume were associated with reduced FC of the thalamus, especially for FC with the right superior occipital region (t=-2.87, p=.0123 and t=2.27, p=.04 respectively). FC of the left frontal medial cortex was negatively correlated with composite cognitive z-score in the pediatric-onset MS group (p<.05). Conclusions: Greater resting-state FC between posterior and anterior brain regions is present in pediatriconset MS. With greater disease-related structural pathology, there is a disruption of thalamo-cortical FC. In the absence of actual cognitive impairment, heightened FC of the frontal medial cortex was associated with lower cognitive performance, suggesting that greater functional resources are recruited during resting-state in patients with reduced cognitive efficiency. [ABSTRACT FROM AUTHOR]

Background: MS-Line! was created to provide an effective treatment for cognitive impairment in multiple sclerosis (MS) patients. Objective: To assess the efficacy of MS-Line!. Methods: A randomized, controlled, single-blind, 6-month pilot study. Patients were randomly assigned to an experimental group (cognitive rehabilitation with the programme) or to a control group (no cognitive rehabilitation). Randomization was stratified by cognitive impairment level. Cognitive assessment included: selective reminding test, 10/36 spatial recall test (10/36 SPART), symbol digit modalities test, paced auditory serial addition test, word list generation (WLG), FAS test, subtests of WAIS-III, Boston naming test (BNT), and trail making test (TMT). Results: Forty-three patients (22 in the experimental group, 21 in the control group) were analyzed. Covariance analysis showed significant differences in 10/36 SPART (P=0.0002), 10/36 SPART delayed recall (P=0.0021), WLG (P=0.0123), LNS (P=0.0413), BNT (P=0.0007) and TMT-A (P=0.010) scores between groups. Conclusions: The study showed a significant improvement related to learning and visual memory, executive functions, attention and information processing speed, and naming ability in those patients who received cognitive rehabilitation. The results suggest that MS-Line! is effective in improving cognitive impairment in MS patients. [ABSTRACT FROM AUTHOR]

The article examines the anti-KIR4.1 antibodies in the serum of patients with neuromyelitis optica (NMO) and multiple sclerosis (MS). The study indicates the high anti-KIR4.1 antibodies serum levels in MS and NMO patients when compared to those in healthy controls. It points out that the antibodies do not discriminate between the demyelinating diseases.

The article examines the impact of focal optic nerve demyelination on the integrity of neighboring white matter in optic neuritis (ON). The study shows the development of chronic axonal loss in the optic tracts of ON patients. It notes the consideration of diffusion tensor imaging in ON as a means for fine in-vivo human model.

The article presents a study that examines the time course of decline of different cognitive domains in patients with multiple sclerosis (MS). The study developed a cox-proportional hazard models to examine the influence of MS onset type, age at onset, gender, depression and level of education on the time course, expressed as age or disease. It suggests that information processing speed (IPS) is the first cognitive deficit to emerge in MS.

The article presents a study that examines the long-term prognosis of multiple sclerosis (MS). The study investigates the changes in Center for Epidemiological Studies Depression Scale (CESD) scores in MS patients over four years of follow-up. It reveals that depression in MS is largely chronic, which suggests a different pathophysiology.

The article presents a study that determines the anti-Müllerian hormone (AMH) levels n females with relapsing-remitting MS (RRMS) in combination with other reproduction and lifestyle factors. The study included 76 reproductive-age females with RRMS and 58 healthy controls. It suggests that the majority of MS subjects with very low AMH levels were currently without medication requires further evaluation.

The article presents a study that compiles the fall rates across a broad range of ages and disease severity and assesss the extent to which MS-associated and demographic factors influence fall rates. The study analyzed individual data from studies in four countries that prospectively measured falls for three months. It suggests that people with multiple sclerosis (PwMS) are at high risk of falls.

The article presents a study that characterizes presentations to an open, rapid-access MS relapse clinic and the impact on disease management. The study conducted a retrospective review of outpatient episodes over a three-year period. It suggests that diagnosing MS relapses is crucial for disease management and yet remains challenging.

The article presents a study that evaluates the delayed-release dimethyl fumarate (DMF) demonstrated in newly diagnosed relapsing-remitting multiple sclerosis (RRMS) patients. The study included patients who were diagnosed with RRMS within 1 year prior to study entry. It suggests that delayed-release DMF improved clinical and neuroradiological outcomes relative to placebo in newly diagnosed RRMS patients.