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International audience; Background: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.Methods: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.Results: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P

Optic neuritis (ON) is an immune-mediated optic neuropathy associated with multiple immune-mediated neurological conditions. Our aim was to characterize the clinical and diagnostic features of first or initial episodes of ON associated with multiple sclerosis (MS)-associated (typical) and antibody-related (atypical) ON.Retrospective, single institution, medical record review. We analyzed demographic, clinical, laboratory, and radiographic findings of 139 patients who presented with first episodes of MS-associated ON (MS-ON), aquaporin 4 antibody-associated ON (AQP4-ON), and myelin oligodendrocyte glycoprotein antibody-associated ON (MOG-ON) between January 2015 and October 2019 without preceding diagnosis. Simple hypothesis testing assessed differences between groups were performed.Of 139 patients (109 [79 %] women; 29 [21 %] men; mean age 47 [SD, 14] years), 106 had MS-ON, 25 had AQP4-ON, and 8 had MOG-ON. Patients with MOG-ON had the highest recurrence rate (88 %) relative to MS-ON (28 %) and AQP4-ON (56 %) patients (P .001). Patients with AQP4-ON had the highest mean visual functional system scores (4.3 [SD, 1.8]) relative to MS-ON (2.0 [SD, 1.9]) and MOG-ON patients (2.8 [SD, 2.0]) (P .001).Patients presenting with initial episodes of ON exhibit a range radiographic and laboratory feature depending on the underlying associated disease. Understanding the variable characteristics of typical (MS-associated) and atypical (antibody-associated) ON may help physicians accurately diagnose and effectively treat ON.

SUMMARYMetabolic aberrations impact the pathogenesis of multiple sclerosis (MS) and possibly can provide clues for new treatment strategies. Using untargeted metabolomics, we measured serum metabolites from 35 relapsing-remitting patients and 14 healthy age-matched controls. Out of 632 known metabolites detected, 60 were significantly altered in relapsing-remitting MS (RRMS). Bioinformatics analysis identified an altered “metabotype” in RRMS patients, represented by 4 changed metabolic pathways of glycerophospholipid, citrate cycle, sphingolipid, and pyruvate metabolism. Interestingly, the common upstream metabolic pathway feeding these 4 pathways is the glycolysis pathway. Real-time bioenergetic analysis of the patient derived peripheral blood mononuclear cells, showed enhanced glycolysis, supporting the altered metabolic state of immune cells. Experimental autoimmune encephalomyelitis mice treated with the glycolytic inhibitor, 2-deoxy-D-glucose ameliorated the disease progression and inhibited the disease pathology significantly by promoting the anti-inflammatory phenotype of monocytes/macrophage in the central nervous system. Our study suggests that targeting glycolysis offers a potential target for MS.

The ongoing pandemic of the novel coronavirus of 2019 (COVID-19) has resulted in over 1 million deaths, primarily affecting older patients with chronic ailments. Multiple sclerosis (MS) patients have been deemed particularly vulnerable given their high rates of disability and increased susceptibility to infections. There have also been concerns regarding disease-modifying therapy (DMT) during the pandemic as many DMTs may increase the risk of infection due to some of their immunosuppressive properties. Furthermore, due to MS-related chronic inflammatory damage within the central nervous system, there have been concerns for worsening neurological injury by COVID-19. This has resulted in an alarmingly high level of anxiety and stress among the MS community leading to a lack of compliance with medications and routine check-ups, and even failure to obtain treatment for relapse. However, there is currently substantial evidence that MS and most DMT usage is not associated with increased COVID-19 severity. MS patients who suffer worse outcomes were more likely to be older and suffer from significant disabilities and comorbid conditions, which would also be expected from those in the general population. Likewise, there is little if any evidence demonstrating an increased susceptibility of MS patients to COVID-19-related neurological complications. Therefore, we aim to summarize the most recent findings related to COVID-19 and MS demonstrating that MS and most DMTs do not appear as risk factors for severe COVID-19.

This chapter addresses COVID-19 in the context of patients with demyelinating disorders of the central nervous system (CNS). Multiple sclerosis (MS) is the most common CNS demyelinating disease, and SARS-CoV-2 infection in patients with MS and other autoimmune demyelinating CNS disorders causes numerous concerns. As with other infectious diseases, COVID-19 may exacerbate pathology in patients with MS. Standard therapies for MS and immunosuppressive treatments for other CNS autoimmune disorders may pose unique risks during severe COVID-19. However, preliminary findings on SARS-CoV-2 infection suggest that some MS therapies may limit the aggressive immune response underlying severe COVID-19 complications. Furthermore, infection with SARS-CoV-2 may have the potential to trigger postinfection autoimmune disorders. Here we review the current understanding of COVID-19 in patients with MS and other CNS disorders and the impact of immunomodulatory therapies on these patients.

Multiple sclerosis (MS) patients have been considered a higher-risk population for COVID-19 due to the high prevalence of disability and disease-modifying therapy use; however, there is little data identifying clinical characteristics of MS associated with worse COVID-19 outcomes. Therefore, we conducted a multicenter prospective cohort study looking at the outcomes of 40 MS patients with confirmed COVID-19. Severity of COVID-19 infection was based on hospital course, where a mild course was defined as the patient not requiring hospital admission, moderate severity was defined as the patient requiring hospital admission to the general floor, and most severe was defined as requiring intensive care unit admission and/or death. 19/40(47.5%) had mild courses, 15/40(37.5%) had moderate courses, and 6/40(15%) had severe courses. Patients with moderate and severe courses were significantly older than those with a mild course (57[50–63] years old and 66[58.8–69.5] years old vs 48[40–51.5] years old, P = 0.0121, P = 0.0373). There was differing prevalence of progressive MS phenotype in those with more severe courses (severe:2/6[33.3%]primary-progressing and 0/6[0%]secondary-progressing, moderate:1/14[7.14%] and 5/14[35.7%] vs mild:0/19[0%] and 1/19[5.26%], P = 0.0075, 1 unknown). Significant disability was found in 1/19(5.26%) mild course-patients, but was in 9/15(60%, P = 0.00435) of moderate course-patients and 2/6(33.3%, P = 0.200) of severe course-patients. Disease-modifying therapy prevalence did not differ among courses (mild:17/19[89.5%], moderate:12/15[80%] and severe:3/6[50%], P = 0.123). MS patients with more severe COVID-19 courses tended to be older, were more likely to suffer from progressive phenotype, and had a higher degree of disability. However, disease-modifying therapy use was not different among courses., Highlights • In a multicenter study of 40 multiple sclerosis (MS) patients, different phenotypes and level of disability were associated with COVID-19 severity. • Poorer outcomes were associated with more severe MS disability. • The use of DMT for MS was not associated with worse outcome.

ImportanceMultiple sclerosis patients have been considered a higher-risk population for COVID-19 due to the high prevalence of disability and disease-modifying therapy use; however, no study has identified clinical characteristics of multiple sclerosis associated with worse COVID-19 outcomes.ObjectiveTo evaluate the clinical characteristics of multiple sclerosis, including staging, degree of disability, and disease-modifying therapy use that are associated with worse outcomes from COVID-19.DesignProspective cohort study looking at the outcomes of multiple sclerosis patients with COVID-19 between March 1stand May 18th2020.SettingThis is a multicenter study of three distinct hospital systems within the U.S.ParticipantsThe study included 40 consecutive patients with nasopharyngeal/oropharyngeal PCR-confirmed COVID-19 infection.ExposuresMultiple sclerosis staging, severe disability (based on baseline-extended disability status scale equal to or greater than 6.0) and disease-modifying therapy.Main Outcomes and MeasureSeverity of COVID-19 infection was based on hospital course, where a mild course was defined as the patient not requiring hospital admission, moderate severity was defined as the patient requiring hospital admission to the general floor only, and most severe was defined as requiring intensive care unit admission and/or death.ResultsFor the 40 patients, the median age was 52(45.5-61) years, 16/40(40%) were male, and 21/40(52.5%) were African American. 19/40(47.5%) had mild courses, 15/40(37.5%) had moderate courses, and 6/40(15%) had severe courses. Patients with moderate and severe courses were significantly older than those with a mild course (57[50-63] years old and 66[58.8-69.5] years old vs 48[40-51.5] years old, P=0.0121, P=0.0373). There was differing prevalence of progressive multiple sclerosis staging in those with more severe courses (severe:2/6[33.3%]primary-progressing and 0/6[0%]secondary-progressing, moderate:1/14[7.14%] and 5/14[35.7%] vs mild:0/19[0%] and 1/19[5.26%], P=0.0075, 1 unknown). Significant disability was found in 1/19(5.26%) mild course-patients, but was in 9/15(60%, P=0.00435) of moderate course-patients and 2/6(33.3%, P=0.200) of severe course-patients. Disease-modifying therapy prevalence did not differ among courses (mild:17/19[89.5%], moderate:12/15[80%] and severe:3/6[50%], P=0.123).Conclusions and RelevanceMultiple sclerosis patients with more severe COVID-19 courses tended to be older, were more likely to suffer from progressive staging, and had a higher degree of disability. However, disease-modifying therapy use was not different among courses.

Identification of non-invasive biomarkers of disease progression in multiple sclerosis (MS) is critically needed for monitoring the disease progression and for effective therapeutic interventions. Urine is an attractive source for non-invasive biomarkers because it is easily obtained in the clinic. In search of a urine metabolite signature of progression in chronic experimental autoimmune encephalomyelitis (EAE), we profiled urine at the chronic stage of the disease (day 45 post immunization) by global untargeted metabolomics. Using a combination of high-throughput liquid-and-gas chromatography with mass spectrometry, we found 105 metabolites (P 0.05) significantly altered at the chronic stage, indicating a robust alteration in the urine metabolite profile during disease. Assessment of altered metabolites against the Kyoto Encyclopedia of Genes and Genomes revealed distinct non-overlapping metabolic pathways and revealed phenylalanine-tyrosine and associated metabolism being the most impacted. Combined with previously performed plasma profiling, eight common metabolites were significantly altered in both of the biofluids. Metaboanalyst analysis of these common metabolites revealed that phenylalanine metabolism and Valine, leucine, and isoleucine biosynthetic pathways are central metabolic pathways in both bio-fluids and could be analyzed further, either for the discovery of therapeutics or biomarker development. Overall, our study suggests that urine and plasma metabolomics may contribute to the identification of a distinct metabolic fingerprint of EAE disease discriminating from the healthy control which may aid in the development of an objective non-invasive monitoring method for progressive autoimmune diseases like MS. Graphical Abstract Untargeted urinary metabolomics of a chronic mouse model of multiple sclerosis identified Phenylalanine, tyrosinetryptophan metabolism as the significantly altered metabolic pathway. Eight common metabolites were identified when we combined urinary and plasma metabolic signature, which revealed a perturbation of Phenylalanine metabolism and valine, leucineisoleucine metabolic pathways, involved in CNS dysfunction during diseases. The identified eight metabolic signature of urine and plasma may be of clinical relevance as potential biomarkers and guide towards the identification of specific metabolic pathways as novel drug targets.

Background: Magnetic resonance imaging (MRI) is widely used in clinical practice, and “abnormal brain MRI” findings often prompt assessment for multiple sclerosis (MS), even when there are no symptoms suggestive of the disease. Despite several studies involving individuals with “radiologically isolated syndrome” (RIS), little is known about what factors might predict future development of MS. The objective of this study was to longitudinally evaluate clinical and MRI characteristics of people who presented to an MS clinic because of incidental abnormal MRI findings but did not have typical symptoms of MS, in order to assess risk factors for developing MS. Methods: Thirty consecutive patients presenting to an MS clinic for evaluation of abnormal MRI findings were enrolled in the study. Clinical and paraclinical data, including MRI results, were reviewed. Magnetic resonance imaging findings of T2 hyperintensities measuring more than 3 mm in diameter and fulfilling at least three out of four Barkhof criteria, with or without gadolinium-enhancing lesions, were considered to be suggestive of MS. Results: The median follow-up time was 5.5 years. No participants without MRI findings suggestive of MS were diagnosed with MS (P = .005). Fifteen participants had MRI findings suggestive of MS. Seven of the 15 (47%) were diagnosed with MS on follow-up. Cerebrospinal fluid (CSF) testing results were available for 15 participants. Abnormal results were found in six participants, of whom five (83%) also had MRI findings suggestive of MS. Only two of the nine (22%) participants with normal CSF results (P = .04) had MRI findings suggestive of MS. Conclusions: In our cohort, none of the participants without MRI findings suggestive of MS developed MS. The participants with MRI findings suggestive of MS were more likely to develop symptoms and MRI changes typical of MS on follow-up.

This study was conducted to evaluate the association of adherence to disease-modifying agents (DMAs) and outcomes among multiple sclerosis (MS) patients in a practice setting. The study had a cross-sectional design. A survey was administered to 214 patients with relapsing-remitting multiple sclerosis (RRMS) to measure quality of life, health status, disability, and employment. Measures of health-care costs and adherence to DMAs were constructed using claims data. The relationship between DMA adherence and outcomes was evaluated using generalized estimating equation methods, adjusting for patient sociodemographic characteristics, comorbidities, medication on hand at the time of the survey, insurance status, prescription copay, and duration of disease. A total of 163 patients (76%) responded to the survey, of whom 111 had been dispensed a DMA. Mean adherence in the 12-month period preceding the survey was 78.1%. Patients with higher adherence had better mental health and pain interference scores. Increasing adherence was also associated with a greater likelihood of employment and lower Expanded Disability Status Scale score. These findings illustrate the potential for improved outcomes among RRMS patients who adhere to DMA regimens and highlight the importance of considering medication adherence when evaluating DMA use and outcomes in practice.

Sexual dimorphism of astrocytes and neurons is well documented in many brain and spinal cord structures. Sexual dimorphism of oligodendrocytes (Olgs) and myelin has received less attention. We recently showed that density of Olgs in corpus callosum, fornix, and spinal cord of wild-type male rodents is more densely packed than in females; myelin proteins and myelin gene expression are likewise greater in males than in female rodents. However, glial cell proliferation and cell death were two times greater in female corpus callosum. Endogenous sex hormones, specifically lack of androgens, produce an Olg female phenotype in castrated male mouse. In vitro studies using Olgs culture also showed differences between males and females Olg survival and signaling pathways in response to sexual hormones. Sexual dimorphism of white matter tracts and glia in rodents indicates the necessity for controlling gender in the experimental studies of neurodegenerative disorders. Most importantly, our studies suggest that hormones may contribute to sexual dimorphism observed in certain human diseases including multiple sclerosis.

We performed untargeted metabolomics in plasma of B6 mice with experimental autoimmune encephalitis (EAE) at the chronic phase of the disease in search of an altered metabolic pathway(s). Of 324 metabolites measured, 100 metabolites that mapped to various pathways (mainly lipids) linked to mitochondrial function, inflammation, and membrane stability were observed to be significantly altered between EAE and control (p < 0.05, false discovery rate

Objective Hemodynamic abnormality and disruption of white matter (WM) integrity are significant components in the pathophysiology of multiple sclerosis (MS) lesions. However, the roles of stratified lesions with distinct degrees of hemodynamic and structural injury in disease states remain to be explored. We tested the hypothesis that hemodynamic and structural impairment, as assessed by cerebral blood volume (CBV) and fractional anisotropy (FA), respectively, characterizes the extent of tissue injury, and the load of lesion with substantial tissue destruction would reflect the disease status and therefore, would be related to clinical disability. Methods Seven relapsing-remitting MS patients and seven healthy controls underwent perfusion, diffusion and conventional MRI scans. Based on T2-FLAIR and T1-weighted image, WM plaques were classified. After image coregistration, values of CBV and FA were estimated in three distinct lesion types (active, T1-hypointense and T1- isointense lesion) and compared with those obtained in WM from controls. A total of 1135 lesions were evaluated. Brain volumetric measurement and correlative analysis between brain atrophy, lesion volume and clinical disability were also performed. Results Compared with normal WM, significantly reduced CBV and FA were present in the T1-hypointense lesion, while insignificant changes in both parameters were exhibited in the T1-isointense lesion. However, increased CBV but significantly decreased FA was detected in the active lesion. A close spatial relationship between active and T1- hypointense lesion was observed. Lesion load represented by T1-hypointense plus active lesion volume significantly correlated with brain atrophy, which, in turn, significantly correlated with the severity of clinical disability. Conclusion A distinct combination of CBV and FA characterizes the status of a specific lesion type. A severe structural impairment does not solely occur in the T1-hypointense lesion, but is also associated with the active lesion. The burden of the lesion with extensive structural damage provides an image index, indicative of disease status.

Objectives To measure disease-modifying agent adherence and persistence among patients with multiple sclerosis (MS). Design Retrospective cohort study. Setting Multispecialty, salaried group practice in southeast Michigan, between June 1, 2004, and June 30, 2006. Patients 224 insured adult patients with relapsing remitting MS with an outpatient visit. Main outcome measures Medical record–documented receipt of medication recommendation and prescription. Pharmacy claims data–derived measures of dispensing and among patients with two or more dispensings, medication possession ratios (MPRs), and proportion of gap days were estimated. Among those initiating agent use, persistence was estimated. Results Mean cohort age was 47.6 years, while 77% of participants were women and 39% were black. Of patients, 81.8% had a recommendation for a disease-modifying agent, 75.0% had a prescription, and 66.5% had two or more dispensings. Among those with two or more dispensings, mean MPR between the first and last dispensing date was 83.8% (95% CI 80.8–86.8), while mean MPR for the entire 24-month period was 68.0% (64.4–71.7). MPR for the 24-month period decreased with increasing drug copayments and was lower among black patients, while MPR between the first and last dispensing date increased with increasing age. Among those initiating therapy, 43% were nonpersistent with medications within 14 months. Conclusion Medication adherence and persistence among patients with relapsing remitting MS is far from monolithic. Measuring medication adherence and persistence among defined populations is useful for understanding the relationship between medication use and outcomes in practice and for targeting patients and programs to improve medication adherence.

Sexual dimorphism of neurons and astrocytes has been demonstrated in different centers of the brain, but sexual dimorphism of oligodendrocytes and myelin has not been examined. We show, using immunocytochemistry andin situhybridization, that the density of oligodendrocytes in corpus callosum, fornix, and spinal cord is 20–40% greater in males compared with females. These differences are present in young and aged rodents and are independent of strain and species. Proteolipid protein and carbonic anhydrase-II transcripts, measured by real-time PCR, are approximately two to three times greater in males. Myelin basic protein and 2′, 3′-cyclic nucleotide 3′-phosphodiesterase, measured by Western blots, are 20–160% greater in males compared with females. Surprisingly, both generation of new glia and apoptosis of glia, including oligodendrocytes, are approximately two times greater in female corpus callosum. These results indicate that the lifespan of oligodendrocytes is shorter in females than in males. Castration of males produces a female phenotype characterized by fewer oligodendrocytes and increased generation of new glia. These findings indicate that exogenous androgens differentially affect the lifespan of male and female oligodendrocytes, and they can override the endogenous production of neurosteroids. The data imply that turnover of myelin is greater in females than in males. μ-Calpain, a protease upregulated in degeneration of myelin, is dramatically increased at both transcriptional and translational levels in females compared with males. These morphological, molecular, and biochemical data show surprisingly large differences in turnover of oligodendrocytes and myelin between sexes. We discuss the potential significance of these differences to multiple sclerosis, a sexually dimorphic disease, whose progression is altered by exogenous hormones.

Objective: To investigate changes in spontaneous brain activity in patients with relapsing-remitting multiple sclerosis (RRMS) and compare with resting-state network of healthy controls. Background Resting State connectivity using fMRI of the default-mode network (DMN) has been recently shown to be altered in patients with secondary and primary progressive MS. Dysfunction of DMN has been hypothesized to be the factor responsible for accumulation of cognitive deficits in patients with progressive MS. Design/Methods: Six patients with RRMS and 15 normal controls were scanned. fMRI images were acquired on a GE 3.0-T whole-body magnet using a gradient echo EPI sequence for whole-brain BOLD fMRI. For the resting state image set, 150 volumes were recorded while the subjects were lying quietly with eyes open. High resolution (IRSPGR) images were also acquired for brain segmentation. The brain was segmented into 104 regions using the high resolution 3D IRSPGR image and the HAMMER software and the temporal fMRI signals from all voxels in each segmented region were averaged to represent one signal for each region. Results: Resting state networks of different cognitive circuits (DMN, attention, language, memory, visual-spatial memory) were assessed in patients with MS and controls. Cross correlation of the resting state fMRI signals between every two nodes in each network was calculated for the patients and compared to the data from controls. All the pairs that had cross-correlation values outside the normal range were tagged and summed among all the patients. DMN analysis showed decreased correlation in cingulate region and lateral parietal cortices in patients with cognitive impairment, similar with a recent report in literature. Moreover, all or almost all assessed cognitive circuits showed decreased correlation in patients with MS with known cognitive deficit. Conclusions: Dysfunction of resting-state is seen in RRMS patients not only in DMN but also in other subsystems involved in cognitive process. Supported by: Henry Ford Hospital. Disclosure: Dr. Cerghet has nothing to disclose. Dr. Nejad-Davarani has nothing to disclose. Dr. Li has nothing to disclose. Dr. Jiang has nothing to disclose.