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Remyelination is crucial to recover from inflammatory demyelination in multiple sclerosis (MS). Investigating remyelination in vivo using magnetic resonance imaging (MRI) is difficult in MS, where collecting serial short-interval scans is challenging. Using experimental autoimmune encephalomyelitis (EAE) in common marmosets, a model of MS that recapitulates focal cerebral inflammatory demyelinating lesions, we investigated whether MRI is sensitive to, and can characterize, remyelination. In six animals followed with multisequence 7 T MRI, 31 focal lesions, predicted to be demyelinated or remyelinated based on signal intensity on proton density-weighted images, were subsequently assessed with histopathology. Remyelination occurred in four of six marmosets and 45% of lesions. Radiological-pathological comparison showed that MRI had high statistical sensitivity (100%) and specificity (90%) for detecting remyelination. This study demonstrates the prevalence of spontaneous remyelination in marmoset EAE and the ability of in vivo MRI to detect it, with implications for preclinical testing of pro-remyelinating agents.

Objective: Most contemporary data concerning the frequency and causes of multiple sclerosis (MS) misdiagnosis are from North America and Europe with different healthcare system structure and resources than countries in Latin America. We sought to determine the frequency, and potential contributors to MS misdiagnosis in patients evaluated at an MS referral center in Argentina. Methods: The study was a retrospective medical record review. We included patients evaluated at the MS Clinic at Fleni between April 2013 and March 2021. Diagnoses prior to consultation, final diagnoses after consultation, demographic, clinical and paraclinical data, and treatment were extracted and classified. Results: Seven hundred thirty-six patients were identified. Five hundred seventy-two presented with an established diagnosis of MS and after evaluation, misdiagnosis was identified in 89 (16%). Women were at 83% greater risk of misdiagnosis ( p = 0.034). The most frequent alternative diagnoses were cerebrovascular disease, radiological isolated syndrome (RIS), and headache. Seventy-four (83%) of misdiagnosed patients presented with a syndrome atypical for demyelination, 62 (70%) had an atypical brain magnetic resonance imaging (MRI), and 54 (61%) were prescribed disease-modifying therapy. Conclusion: Sixteen percent of patients with established MS were subsequently found to have been misdiagnosed. Women were at higher risk for misdiagnosis. Expert application of the McDonald criteria may prevent misdiagnosis and its associated morbidity and healthcare system cost.

The discontinuation of disease-modifying therapies (DMTs) in multiple sclerosis (MS) is commonly seen in real-world settings due to several factors.The aim of this study is to describe the frequency of disease activity after discontinuation of DMTs in MS patients included in the Argentinean MS and NMOSD registry.Patients with relapsing remitting MS (RRMS) and active secondary progressive MS (SPMS) were included based on the following criteria: they discontinued treatment for more than 6 months, they had been treated with a DMT for ≥2 years, and they had at least 6 months of follow-up in the registry after discontinuation. Demographic and clinical data were collected. Disease activity during follow-up was defined as the presence of a clinical relapse or a new magnetic resonance (MRI) lesion (either new lesions on T2-weighted sequence and/or contrast enhancement). Bivariate analysis was applied to identify clinical and demographic factors related to disease activity.We included 377 patients (75.5% RRMS, 22.5% SPMS) who had discontinued DMTs. The mean (SD) follow-up after discontinuation was 15.7 (7.9) months. After discontinuation, the presence of relapse was detected in 18.8% and 3.5% in RRMS and SPMS, respectively; and new MRI activity in 22% and 3.5%, respectively. We found that higher risk of relapse and MRI activity was associated with younger age (p 0.001), shorter disease duration (p 0.001), and RRMS phenotype (p = 0.006). Males showed higher MRI activity (p 0.011). This study provides real-world data that can guide physicians when considering discontinuation of DMTs.

The objectives of the present study were to describe the frequency of aggressive multiple sclerosis (aMS) as well as to compare clinical and radiological characteristics in aMS and non-aMS patients included in RelevarEM (NCT03375177).The eligible study population and cohort selection included adult-onset patients (≥18 years) with definite MS. AMS were defined as those reaching confirmed EDSS ≥ 6 within 5 years from symptom onset. Confirmation was achieved when a subsequent EDSS ≥ 6 was recorded at least six months later but within 5 years of the first clinical presentation. AMS and non-aMS were compared using the χ2 test for categorical and the Mann-Whitney for continuous variables at MS onset and multivariable analysis was performed using forward stepwise logistic regression with baseline characteristics at disease onset.A total of 2158 patients with MS were included: 74 aMS and 2084 non-aMS. The prevalence of aMS in our cohort was 3.4% (95%CI 2.7-4.2). AMS were more likely to be male (p = 0.003), older at MS onset (p 0.001), have primary progressive MS (PPMS) phenotype (p = 0.03), multifocal presentation (p 0.001), and spinal cord as well as infratentorial lesions at MRI during disease onset (p = 0.004 and p = 0.002, respectively).3.4% of our patient population could be considered aMS. Men, patients older at symptom onset, multifocal presentation, PPMS phenotype, and spinal cord as well as brainstem lesions on MRI at clinical presentation all had higher odds of having aMS.

Resumen Introduccion La esclerosis multiple es una enfermedad con componente autoinmune, y un numero significativo de pacientes se encuentra bajo tratamiento inmunomodulador e inmunosupresor. Frecuentemente los medicos tratantes se preguntan si la vacunacion podra tener un impacto en el desarrollo de la enfermedad, y si existen indicaciones o contraindicaciones para la vacunacion de acuerdo a las terapias indicadas. Objetivo Elaborar una guia de referencia sobre indicaciones y contraindicaciones de vacunacion para neurologos que participan en el manejo de pacientes con esclerosis multiple con o sin terapias modificadoras de la enfermedad. Desarrollo Se conformo un equipo de elaboracion de las guias entre los miembros del Grupo de Trabajo de Enfermedades Desmielinizantes de la Sociedad Neurologica Argentina (SNA). La metodologia implementada fue de acuerdo a recomendaciones establecidas por la SNA, basadas en evidencia, con clasificacion de la misma y elaboracion de las recomendaciones segun el formato GRADE. Conclusiones Se detallan las vacunas disponibles en Argentina, el impacto potencial que podrian tener en el curso de la enfermedad, las indicaciones de vacunacion previas al inicio de cada tratamiento y las contraindicaciones para cada vacuna de acuerdo a la terapia indicada.

The objective of this study was to describe and compare the baseline epidemiological data of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) patients included in RelevarEM (Clinical Trials registry number NCT03375177). RelevarEM is a longitudinal, strictly observational MS and NMOSD registry in Argentina. Epidemiological and comorbidity data from MS and NMOSD patients were described and compared. For comorbidities, the Charlson comorbidity index (CCI) was used to calculate the burden at entry. CCI was stratified in 0 and ≥ 1 and described for the entire cohort. A total of 1588 and 75 MS and NMOSD patients (respectively) were included. For MS patients, the mean age was 42 ± 7 years, female sex 65.3%, mean EDSS 2, and mean disease duration 8 ± 6 years. In NMOSD, the mean age was 40 ± 7 years, female sex 78.7%, mean disease duration 5 ± 3.5 years, and mean EDSS 2.5. The most frequent MS phenotype was RRMS in 82.4%. In MS, the CCI was 0 in 85.8.2% while ≥ 1 was in 14.2% of patients. Regarding phenotype stratification, CCI ≥ 1 was 3.9% in CIS, 13.5% in RRMS, 28.7% in SPMS, and 17.4% in PPMS (p

We aimed to analyze the accumulative risk of MRI and OB factors for evolution from RIS to MS in subjects included in the Argentinean MS registry (NCT03375177). RIS subjects were identified according to RIS diagnosis criteria. Subjects were longitudinally followed with clinical and MRI at intervals of 6 months. Time from RIS identification to the first clinical event was estimated using Kaplan–Meier. Multivariable Cox regression models were created to assess the independent predictive value of demographic characteristics, as well as clinical, OB and MRI data on time to the first clinical event. The single and increased risk factor of evolution of RIS was quantified. A total of 88 RIS subjects, mean follow-up time 42 ± 4 months were included. 39 (44.3%) and 23 (26.1%) had a new MRI lesion or a clinical event, respectively, during the follow-up. OB (HR 5.9, 95% CI 1.29–10.1, p = 0.004), infratentorial lesions (HR 3.7, 95% CI 1.09–7.5) and spinal cord lesions (HR 5.3, 95% CI 1.4–8.2, p = 0.01) at RIS identification were independent predictors associated with a subsequent clinical event. The accumulative risk showed that when two of the three factors (OB, infratentorial or spinal cord lesions) were present the HR was 10.4, 95% CI 4.4–22, p

Despite that different registries already exist in various countries in Europe and North America, no ongoing nationwide registry exists in Latin America (LATAM), a region where the disease behaves differently than in other regions. The objective of this document is to describe the methodology behind RelevarEM, the first nationwide MS registry in Argentina and LATAM. METHODS: In this article, we described the creation, implementation and data management of the nationwide MS registry in Argentina. The registry contains information on the structure, ethical aspects, implementation and variables of the registry (Clinical Trials registry number NCT NCT03375177). CONCLUSION: RelevarEM is the first MS nationwide registry in Argentina, as well as in LATAM, with the objective of providing reliable real-world data of MS in the country.

Background There has been an increase in the number of reports of multiple sclerosis (MS) rebound activity (RA), which is usually defined as a severe disease reactivation after natalizumab or fingolimod withdrawal that exceeds pre-treatment baseline inflammatory activity. The frequency and risk factors that could predict RA remain unknown. Fingolimod is currently the most frequently prescribed disease modifying therapy for MS in Argentina, so that there is a need to determine possible predictors of RA. Objectives To identify risk factors for developing RA after fingolimod cessation; to describe RA characteristics, management and evolution. Methods The study was a multicenter, retrospective, case-control study of patients with MS who had discontinued fingolimod and were followed up to nine months after discontinuation. Demographic, clinical and paraclinical data was extracted, including age, gender, MS phenotype, reason for discontinuation, number of relapses during the year prior to suspension, time treated with fingolimod, EDSS before, during and after rebound, MRI findings. Results 26 cases of RA were matched 1:1 with patients without RA. The median time elapsed to RA was 50 days. 68% showed worsening of the EDSS in the evaluation at 3 months of RA. When compared with the control group, no difference was found in terms of age, gender, phenotype, EDSS at the moment of suspension, reason for discontinuation, number of relapses in the previous year, and time on therapy. Conclusion In this case-controlled study, no risk factors could be identified to predict RA after fingolimod cessation. Further controlled, prospective, better powered studies are needed to confirm these findings.

Diagnostic accuracy is poor in demyelinating myelopathies, and therefore a challenge for neurologists in daily practice, mainly because of the multiple underlying pathophysiologic mechanisms involved in each subtype. A systematic diagnostic approach combining data from the clinical setting and presentation with magnetic resonance imaging (MRI) lesion patterns, cerebrospinal fluid (CSF) findings, and autoantibody markers can help to better distinguish between subtypes. In this review, we describe spinal cord involvement, and summarize clinical findings, MRI and diagnostic characteristics, as well as treatment options and prognostic implications in different demyelinating disorders including: multiple sclerosis (MS), neuromyelitis optica spectrum disorder, acute disseminated encephalomyelitis, anti-myelin oligodendrocyte glycoprotein antibody-associated disease, and glial fibrillary acidic protein IgG-associated disease. Thorough understanding of individual case etiology is crucial, not only to provide valuable prognostic information on whether the disorder is likely to relapse, but also to make therapeutic decision-making easier and reduce treatment failures which may lead to new relapses and long-term disability. Identifying patients with monophasic disease who may only require acute management, symptomatic treatment, and subsequent rehabilitation, rather than immunosuppression, is also important.

Introduction During the last 20 years, multiple sclerosis (MS) disease has seen major changes with new diagnostic criteria, a better identification of disease phenotypes, individualization of disease prognosis and the appearance of new therapeutic options in relapsing remitting as well as progressive MS. As a result, the management of MS patients has become more complex and challenging. The objective of these consensus recommendations was to review how the disease should be managed in Argentina to improve long-term outcomes in MS patients. Methods A panel of 36 experts in neurology from Argentina, dedicated to the diagnosis and care of MS patients, gathered both virtually and in person during 2018 and 2019 to carry out a consensus recommendation on the management of MS patients in Argentina. To achieve consensus, the methodology of “formal consensus-RAND/UCLA method” was used. Results Recommendations focused on diagnosis, disease prognosis, tailored treatment, treatment failure identification and pharmacovigilance process. Conclusions The recommendations of these consensus guidelines attempt to optimize the health care and management of patients with MS in Argentina.

The objective of this study was to describe and compare the baseline epidemiological data of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) patients included in RelevarEM (Clinical Trials registry number NCT03375177).RelevarEM is a longitudinal, strictly observational MS and NMOSD registry in Argentina. Epidemiological and comorbidity data from MS and NMOSD patients were described and compared. For comorbidities, the Charlson comorbidity index (CCI) was used to calculate the burden at entry. CCI was stratified in 0 and ≥ 1 and described for the entire cohort.A total of 1588 and 75 MS and NMOSD patients (respectively) were included. For MS patients, the mean age was 42 ± 7 years, female sex 65.3%, mean EDSS 2, and mean disease duration 8 ± 6 years. In NMOSD, the mean age was 40 ± 7 years, female sex 78.7%, mean disease duration 5 ± 3.5 years, and mean EDSS 2.5. The most frequent MS phenotype was RRMS in 82.4%. In MS, the CCI was 0 in 85.8.2% while ≥ 1 was in 14.2% of patients. Regarding phenotype stratification, CCI ≥ 1 was 3.9% in CIS, 13.5% in RRMS, 28.7% in SPMS, and 17.4% in PPMS (p 0.001 between groups). In NMOSD, the CCI was 0 in 64% while ≥ 1 was in 36%. The MS/NMOSD ratio found was 21/1.This is the first analysis of the longitudinal Argentinean registry of MS and NMOSD describing and comparing conditions that contributes to provide reliable real-world data in the country.

Background Myelin oligodendrocyte glycoprotein antibodies (MOG-ab) have been described in aquaporin-4-antibodies(AQP4-ab)-negative neuromyelitis optica spectrum disorder (NMOSD) patients. We aimed to evaluate the percentage of AQP4-ab-negative NMOSD patients who are positive for MOG-ab in a cohort of Argentinean patients included in RelevarEM (Clinical Trials registry number NCT03375177). Methods RelevarEM is a longitudinal, strictly observational multiple sclerosis (MS) and NMOSD registry in Argentina. Of 3031 consecutive patients (until March 2020), 165 patients with phenotype of suspected NMOSD, whose relevant data for the purpose of this study were available, were included. Data on demographic, clinical, paraclinical and treatment in AQP4-ab (positive, negative and unknown) and MOG-ab (positive and negative) patients were evaluated. Results A total of 165 patients (79 AQP4-Ab positive, 67 AQP4-Ab negative and 19 unknown) were included. Of these, 155 patients fulfilled the 2015 NMOSD diagnostic criteria. Of 67 AQP4-Ab-negative patients, 36 (53.7%) were tested for MOG-Ab and 10 of them (27.7%) tested positive. Serum AQP4-ab levels were tested by means of cell-based assay (CBA) in 48 (35.2%), based on tissue-based indirect immunofluorescence assays in 58 (42.6%) and enzyme-linked immunosorbent assay in 4 (2.9%). All MOG-ab were tested by CBA. Optic neuritis (90%) was the most frequent symptom at presentation and optic nerve lesions the most frequent finding (80%) in neuroimaging of MOG-ab-associated disease. Of these, six (60%) patients were under immunosuppressant treatments at latest follow-up. Conclusion We observed that 27.7% (10/36) of the AQP4-ab-negative patients tested for MOG-ab were positive for this antibody, in line with results from other world regions.

Background Multiple sclerosis (MS) is the most common chronic immune-mediated neurological disorder in young adults, more frequently found in women than in men. Therefore, pregnancy-related issues have become an object of concern for MS professionals and patients. The aim of this work was to review the existing data to develop the first Argentine consensus for family planning and pregnancy in MS patients. Methods A panel of expert neurologists from Argentina engaged in the diagnosis and care of MS patients met both virtually and in person during 2019 to carry out a consensus recommendation for family planning and pregnancy in MS. To achieve consensus, the procedure of the “formal consensus-RAND/UCLA method” was used. Results Recommendations were established based on published evidence and expert opinion focusing on pre-pregnancy counseling, pregnancy, and postpartum issues. Conclusion The recommendations of these consensus guidelines are intended to optimize the management and treatment of MS patients during their reproductive age in Argentina.

Background Although solid information on the natural history of primary progressive multiple sclerosis (PPMS) is available, evidence regarding impact of disease activity on PPMS progression remains controversial. Objective To describe the clinical characteristics, presence or absence of MRI activity, and natural history of a PPMS cohort from two referral centers in Argentina and assess whether clinical and/or radiological disease activity correlated with disability worsening. Methods Retrospective study conducted at two MS clinics in Buenos Aires, Argentina, through comparative analysis of patients with and without evidence of disease activity. Results Clinical and/or radiologic activity was presented in 56 (31%) of 178 patients. When stratified by age at onset, we found that for every 10 years of increase in age at onset, risk of reaching EDSS scores of 4 and 6 increased by 26% and 31%, respectively (EDSS 4: HR 1.26, CI 95%: 1.06–1.50; EDSS 6: HR 1.31, CI 95%: 1.06–1.62). Patients who presented clinical exacerbations reached EDSS scores of 6, 7 and 8 faster than those without associated exacerbations (p = 0.009, p = 0.016 and p = 0.001, respectively). Likewise, patients who presented gadolinium-enhancing lesions during the course of disease reached EDSS scores of 7 earlier (p = 0.002). Conclusion Older age at onset and presence of clinical and/or radiological disease activity correlated with accelerated disability progression in this cohort of PPMS patients.

Background In recent years, neurologists are noticing that evaluation of multiple sclerosis (MS) patients based on combining relapses, disability progression, and magnetic resonance imaging activity may be insufficient to adequately assess suboptimal responses to available therapy. Inclusion of quality of life (QoL) parameters may contribute to breach this gap. Objective To evaluate agreement levels between doctor and patient perception of QoL in MS. Methods A total of 700 MS patients and 300 neurologists were invited to participate in a cross-sectional study by answering an e-mail questionnaire. The survey collected information on demographical data and included the Short Form questionnaire (SF-36). After completing the questionnaire, patients were given a standard written description of each of the subdomains assessed by SF-36 and asked to identify which three were the most important determinants of their overall health-related QoL. Results A total of 135 neurologists and 380 MS patients responded the survey. Study population mean age was 42.1 ± 10.5 years, with 61% presenting relapsing-remitting MS. SF-36 results were physical function 68.4 ± 30, physical role limitation 56.8 ± 41.7, vitality 47.6 ± 21.4, pain 71.2 ± 26.1, social function 72.6 ± 28.6, emotional role limitation 63.2 ± 39.8, mental health 60 ± 14.1, and general health 55.8 ± 22. Doctors considered physical function (75%) and physical role limitation (70%) as the most important QoL determinants in MS, followed by emotional role limitation (52%). Patients however, assigned significantly different levels of importance to physical function (58%), and physical role limitation (46%) and considered vitality (52%) more important than their physicians (p

One of the biggest challenges in multiple sclerosis (MS) is the definition of treatment response/failure in order to optimize treatment decisions in affected patients. The objective of this consensus was to review how disease activity should be assessed and to propose recommendations on the identification of treatment failure in RRMS patients in Argentina. Methods A panel of experts in neurology from Argentina, dedicated to the diagnosis and care of MS patients, gathered both virtually and in person during 2016 and 2017 to carry out a consensus recommendation on the identification of treatment failure in RRMS patients. To achieve consensus, the methodology of “formal consensus-RAND/UCLA method” was used. Results Recommendations were established based on published evidence and the expert opinion. Recommendations focused on disease management, disease activity markers and treatment failure identification were determined. Main consensus were: ≥ 2 relapses during the first year of treatment and/or ≥ 3 new or enlarged T2 or T1 GAD + lesions and/or sustained increase of ≥ 2 points in EDSS or ≥ 100% in T25FW defines treatment failure in RRMS patients. Conclusions The recommendations of this consensus guidelines attempts to optimize the health care and management of patients with MS in Argentina.

It is generally accepted that autoimmune diseases like multiple sclerosis (MS) arise from complex interactions between genetic susceptibility and environmental factors. Genetic variants confer predis- position to develop MS, but cannot be therapeutically modified. On the other hand, several studies have shown that different lifestyle and environmental factors influence disease development, as well as activity levels and progression. Unlike genetic risk factors, these can be modified, with potential for prevention, particularly in high-risk populations. Most studies identifying particular lifestyle and environmental factors have been carried out in Caucasian patients with MS. Little or no data is available on the behavior of these factors in Latin American populations. Ethnic and geographic differences between Latin America and other world regions suggest potential regional variations in MS, at least with respect to some of these factors. Furthermore, particular environmental characteristics observed more frequently in Latin America could explain regional differences in MS prevalence. Site-specific studies exploring influences of local environmental factors are warranted. Fil: Correale, Jorge. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina Fil: Farez, Mauricio Franco. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina Fil: Gaitán, María Inés. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina

Objective Vascular permeability and inflammatory demyelination are intimately linked in the brain, but what is their temporal relationship? We aimed to determine the radiological correlates of the earliest tissue changes accompanying demyelination in a primate model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) in the common marmoset. Methods By 7T magnetic resonance imaging (MRI), T1 maps, proton density, and T2-weighted images were acquired before and after EAE induction in 5 marmosets (every other week before lesions appeared, weekly thereafter). From scans before and after intravenous injection of contrast material, we measured the evolution of lesional blood–brain barrier (BBB) permeability, comparing in vivo MRI to postmortem tissue examination. Results On average, BBB permeability increased 3.5-fold (p

T2⁎-weighted MRI at high field is a promising approach for studying noninvasively the tissue structure and composition of the brain. However, the biophysical origin of T2⁎ contrast, especially in white matter, remains poorly understood. Recent work has shown that R2⁎ (= 1/T2⁎) may depend on the tissue's orientation relative to the static magnetic field (B0) and suggested that this dependence could be attributed to local anisotropy in the magnetic properties of brain tissue. In the present work, we analyzed high-resolution, multi-gradient-echo images of in vivo marmoset brains at 7 T, and compared them with ex vivo diffusion tensor images, to show that R2⁎ relaxation in white matter is highly sensitive to the fiber orientation relative to the main field. We directly demonstrate this orientation dependence by performing in vivo multi-gradient-echo experiments in two orthogonal brain positions, uncovering a nearly 50% change in the R2⁎ relaxation rate constant of the optic radiations. We attribute this substantial R2⁎ anisotropy to local subvoxel susceptibility effects arising from the highly ordered and anisotropic structure of the myelin sheath.

Although Vitamin D is best known as a modulator of calcium homeostasis, it also has immune modulating potential. A protective effect of Vitamin D on Multiple Sclerosis (MS) is supported by the reduced risk associated with sun exposure and use of Vitamin D supplements. Moreover, high circulating levels of Vitamin D have been associated with lower risk of MS. To gain more insight into putative regulatory mechanisms of Vitamin D in MS pathogenesis, we studied 132 Hispanic patients with clinically definite MS, 58 with relapsing remitting MS (RR MS) during remission, 34 RR MS patients during relapse, and 40 primary progressive MS cases (PP MS). Sixty healthy individuals matched with respect to place of residence, race/ethnicity, age and gender served as controls. Levels of 25(OH) Vitamin D and 1,25(OH)(2) Vitamin D, measured by ELISA were significantly lower in RR MS patients than in controls. In addition, levels in patients suffering relapses were lower than during remissions. By contrast, PP MS patients showed similar values to controls. Proliferation of both freshly isolated CD4+ T cells and MBP-specific T cells was significantly inhibited by 1,25(OH)(2) Vitamin D. Moreover, activated Vitamin D enhanced the development of IL-10 producing cells, and reduced the number of IL-6 and IL-17 secreting cells. Notably, VDR expression was induced by 1,25(OH)(2) Vitamin D in both activated and resting cells. Interestingly, T cells were able to metabolize 25(OH) Vitamin D into biologically active 1,25(OH)(2) Vitamin D, since T cells express 1α-hydroxylase constitutively. Finally, 1,25(OH)(2) Vitamin D also increased the expression and biological activity of IDO, triggering significant increase in the number of CD4+CD25+ T regulatory cells. Collectively, these findings suggest that 1,25(OH)(2) VitaminD plays an important role in T cell homeostasis during the course of MS, suggesting correction of its deficiency may be useful during treatment of the disease.

The processes by which new white matter lesions in multiple sclerosis (MS) develop are only partially understood. Much of this understanding has come through magnetic resonance imaging (MRI) of the human brain. One of the hallmarks of new lesion development in MS is enhancement on T(1)-weighted MRI scans following the intravenous administration of a gadolinium-based contrast agent that shortens the longitudinal relaxation time of the tissue. Visible enhancement on the MRI results from the opening of the blood-brain barrier and reveals areas of active inflammation. The incidence and number of existing enhancing lesions are common outcome measures used in MS treatment clinical trials. Dynamic-contrast-enhanced MRI (DCE-MRI) can estimate the rate at which contrast agents pass from the plasma to MS lesions. In this paper, we develop a principal component-based framework for the analysis of these data that provides biologically meaningful quantification of blood-brain-barrier opening in new MS lesions. To accomplish this, we use functional principal components analysis to study directions of variation in the voxel-level time series of intensities both within and across subjects. The analysis reveals and allows quantification of typical spatiotemporal enhancement patterns in acute MS lesions, providing measures of magnitude, rate, shape (ring-like vs. nodular), and dynamics (centrifugal vs. centripetal). Across 10 subjects with relapsing-remitting and primary progressive MS, we found subjects to have between 0 and 12 gadolinium-enhancing lesions, the majority of which enhanced centripetally. We quantified the spatiotemporal behavior within each of these lesions using novel measures. Further application of these techniques will determine the extent to which these lesion measures can predict or track response to therapy or long-term prognosis in this disorder.

Objective: Multiple sclerosis (MS) lesions develop around small, inflamed veins. New lesions enhance with gadolinium on magnetic resonance imaging (MRI), reflecting disruption of the blood–brain barrier (BBB). Single time point results from pathology and standard MRI cannot capture the spatiotemporal expansion of lesions. We investigated the development and expansion of new MS lesions, focusing on the dynamics of BBB permeability. Methods: We performed dynamic contrast-enhanced (DCE) MRI in relapsing–remitting MS. We obtained data over 65 minutes, during and after gadolinium injection. We labeled spatiotemporal enhancement dynamics as centrifugal when initially central enhancement expanded outward and centripetal when initially peripheral enhancement gradually filled the center. Results: We detected 34 enhancing lesions in 200 DCE-MRI scans. In 65%, enhancement first appeared as a closed ring; in 18%, as a nodule; and in 18%, as an open ring. Lesions with initially nodular enhancement were smaller than those initially enhancing as rings (p < 0.0001). All initially nodular lesions enhanced centrifugally, whereas initially ringlike lesions enhanced centripetally, becoming nodular if small (82%) or nearly nodular if larger (18%). Open-ring lesions were periventricular or juxtacortical and enhanced centripetally. Centrifugally enhancing lesions evolved into centripetally enhancing lesions over several days. Interpretation: The rapid change of enhancement dynamics from centrifugal to centripetal reflects the outward growth of MS lesions around their central vein and suggests that factors mediating lesion growth and tissue repair derive from different locations at different times. We propose a model of new lesion growth that unites our imaging observations with existing pathology data. ANN NEUROL 2011

Objective: To investigate hypothalamic-pituitary-adrenal axis activity in well-defined multiple sclerosis (MS) patient subgroups. Methods: A total of 173 patients with clinically definite MS were studied: 40 with primary progressive, 41 with secondary progressive, 58 with relapsing-remitting in remission, and 34 with relapsing-remitting during acute relapse. Sixty healthy subjects served as controls. No patients were receiving steroid or other immunomodulatory therapy. Plasma cortisol, adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate (DHEAS), as well as urine cortisol levels, were measured using commercial radioimmunoassays. Glucocorticoid receptor (GR)–binding assay in peripheral blood mononuclear cells (PBMCs) was performed using [ 3 H]dexamethasone (Dex). PBMC production of the proinflammatory peptide corticotrophin-releasing hormone (CRH), interleukin (IL)-1β, IL-6, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α was evaluated using enzyme-linked immunosorbent spot assay. Results: All four groups of patients displayed significantly higher cortisol, ACTH, and DHEAS plasma concentrations and urine cortisol values than controls. Although 62% of MS patients did not suppress Dex, suppression test results did not correlate with IL-1β, IL-6, IFN-γ, or TNF-α production. GR-binding assays showed no differences in binding sites between patients and controls; however, all MS groups showed decreased GR affinity and sensitivity compared with controls. The numbers of IL-1β-, IL-6-, and TNF-α-secreting cells increased significantly in relapsing-remitting MS patients only during exacerbations; in contrast, IFN-γ-secreting cells increased during both exacerbations and remission. Finally, PBMC CRH-secreting cell numbers were considerably greater in all forms of MS. Conclusions: Patients with multiple sclerosis show hypothalamic-pituitary-adrenal axis hyperactivity, with lymphocytes expressing similar glucocorticoid receptor numbers to controls; however, binding affinity and glucocorticoid sensitivity of these lymphocytes seem to be reduced.

Background: The infratentorial compartment is cardinal for multiple sclerosis (MS) diagnosis. T2-weighted (T2) and proton density–weighted (PD) magnetic resonance imaging (MRI) can visualize infratentorial lesions, but only suboptimally. Objective: To combine PD and T2 for better lesion assessment. Methods: T2 and PD from 35 cases were averaged to form “PT2” images. Two raters counted infratentorial lesions and qualitatively assessed their conspicuity. Results: PT2 showed 244 infratentorial lesions, of which 94% and 74% were seen in PD and T2. PT2 received higher grades for image quality and lesion conspicuity ( p Conclusion: PT2 could improve our ability to diagnose and monitor MS.

Background Magnetic resonance imaging (MRI) can provide in vivo assessment of tissue damage, allowing evaluation of multiple sclerosis (MS) lesion evolution over time – a perspective not obtainable with postmortem histopathology. Relapsing–remitting experimental autoimmune encephalomyelitis (EAE) is an experimental model of MS that can be induced in the common marmoset, a small new world primate, and that causes perivenular white matter (WM) lesions similar to those observed in MS. Methods Brain lesion development and evolution were studied in vivo and postmortem in four marmosets with EAE through serial T2- and T2*-weighted scans at 7-tesla. Supratentorial WM lesions were identified and characterized. Results Of 97 lesions observed, 86 (88%) were clearly perivenular, and 62 (72%) developed around veins that were visible even prior to EAE induction. The perivenular configuration was confirmed by postmortem histopathology. Most affected veins, and their related perivascular Virchow-Robin spaces, passed into the subarachnoid space rather than the ventricles. Conclusion As in human MS, the intimate association between small veins and EAE lesions in the marmoset can be studied with serial in vivo MRI. This further strengthens the usefulness of this model for understanding the process of perivenular lesion development and accompanying tissue destruction in MS.

Objective In multiple sclerosis (MS), accurate, in vivo characterization of dynamic inflammatory pathological changes occurring in newly forming lesions could have major implications for understanding disease pathogenesis and mechanisms of tissue destruction. Here, we investigated the potential of ultrahigh-field magnetic resonance imaging (MRI; 7T), particularly phase imaging combined with dynamic contrast enhancement, to provide new insights in acute MS lesions. Methods Sixteen active MS patients were studied at 7T. Noncontrast, high-resolution T2* magnitude and phase scans, T1 scans before/after gadolinium contrast injection, and dynamic contrast-enhanced (DCE) T1 scans were acquired. T2*/phase features and DCE pattern were determined for acute and chronic lesions. When possible, 1-year follow-up 7T MRI was performed. Results Of 49 contrast-enhancing lesions, 44 could be analyzed. Centrifugal DCE lesions appeared isointense or hypointense on phase images, whereas centripetal DCE lesions showed thin, hypointense phase rims that clearly colocalized with the initial site of contrast enhancement. This pattern generally disappeared once enhancement resolved. Conversely, in 43 chronic lesions also selected for the presence of hypointense phase rims, the findings were stable over time, and the rims were typically thicker and darker. These considerations suggest different underlying pathological processes in the 2 lesion types. Interpretation Ultrahigh-field MRI and, especially, phase contrast, are highly sensitive to tissue changes in acute MS lesions, which differ from the patterns seen in chronic lesions. In acute lesions, the hypointense phase rim reflects the expanding inflammatory edge and may directly correspond to inflammatory byproducts and sequelae of blood–brain barrier opening. Ann Neurol 2013;74:669–678

Many multiple sclerosis (MS) lesions develop around small veins that are surrounded by perivenular inflammatory cells, but whether veins in the brains of people with MS are smaller or larger than similar veins in healthy volunteers or people with other neurologic diseases remains unknown. This question can be addressed by high-resolution, high-field-strength MRI.In a cross-sectional study performed on a standard 3 T clinical scanner, we acquired whole-brain T2*-weighted images with 0.55 mm isotropic voxels and reconstructed the courses of deep and superficial veins within the white matter. We compared the apparent diameters of intralesional and perilesional veins to those of extralesional MS veins, veins in healthy volunteers, and veins in individuals with other neurologic diseases.We studied veins in 19 MS cases, 9 healthy volunteers, and 8 individuals with other neurologic diseases, analyzing a total of 349 veins. The mean diameter of intralesional veins (0.76 ± 0.14 mm) was smaller than that of perilesional (1.18 ± 0.13 mm; p0.001) and extralesional (1.13 ± 0.14 mm; p0.001) veins, regardless of lesion size and location. Perilesional and extralesional MS veins were larger than non-MS veins (0.94 ± 0.14 mm; p0.001), and intralesional MS veins were smaller (p0.001).The small apparent size of intralesional MS veins may reflect compression by the perivascular inflammatory cuff within active lesions or hardening of the vascular wall in chronic lesions. The finding that extralesional veins are larger than similar veins in non-MS lesions may result from diffuse disease-related processes.

Background: We previously described two dynamics of contrast enhancement in scans of active multiple sclerosis lesions: Medium-sized, early lesions enhance centrifugally, whereas larger, slightly older lesions enhance centripetally. Due to technical limitations, our previous study did not characterize lesions < 5 mm in diameter, cortical enhancement, and anatomical structures within lesions. Objective: The objective of this paper is to obtain initial observations of these important aspects of lesion development on a 7 tesla scanner at high spatial resolution. Methods: We scanned eight patients, acquiring precontrast T2*-weighted scans, T1-weighted scans before and after contrast, and high-resolution dynamic contrast-enhanced scans during and up to 30 min after contrast. Results: We detected 15 enhancing lesions, obtaining dynamic data in 10: Five lesions < 4 mm enhanced centrifugally (initial central enhancement expanded outward), and five lesions > 4 mm enhanced centripetally (initial peripheral enhancement gradually filled the lesion). A leukocortical lesion initially showed enhancement in its white matter portion, which gradually spread into the cortex. Seventy-three percent of lesions were clearly perivenular. Conclusion: Most active lesions are perivenular, and the smallest lesions enhance centrifugally. This supports the idea that lesions grow outward from a central vein.

During the past decades, better understanding of relapsing-remitting multiple sclerosis disease mechanisms have led to the development of several disease-modifying therapies, reducing relapse rates and severity, through immune system modulation or suppression. In contrast, current therapeutic options for progressive multiple sclerosis remain comparatively disappointing and challenging. One possible explanation is a lack of understanding of pathogenic mechanisms driving progressive multiple sclerosis. Furthermore, diagnosis is usually retrospective, based on history of gradual neurological worsening with or without occasional relapses, minor remissions or plateaus. In addition, imaging methods as well as biomarkers are not well established. Magnetic resonance imaging studies in progressive multiple sclerosis show decreased blood-brain barrier permeability, probably reflecting compartmentalization of inflammation behind a relatively intact blood-brain barrier. Interestingly, a spectrum of inflammatory cell types infiltrates the leptomeninges during subpial cortical demyelination. Indeed, recent magnetic resonance imaging studies show leptomeningeal contrast enhancement in subjects with progressive multiple sclerosis, possibly representing an in vivo marker of inflammation associated to subpial demyelination. Treatments for progressive disease depend on underlying mechanisms causing central nervous system damage. Immunity sheltered behind an intact blood-brain barrier, energy failure, and membrane channel dysfunction may be key processes in progressive disease. Interfering with these mechanisms may provide neuroprotection and prevent disability progression, while potentially restoring activity and conduction along damaged axons by repairing myelin. Although most previous clinical trials in progressive multiple sclerosis have yielded disappointing results, important lessons have been learnt, improving the design of novel ones. This review discusses mechanisms involved in progressive multiple sclerosis, correlations between histopathology and magnetic resonance imaging studies, along with possible new therapeutic approaches.

To evaluate a magnetic resonance (MR) imaging contrast technique, called FLAIR*, that combines the advantages of T2-weighted fluid-attenuated inversion recovery (FLAIR) contrast and T2*-weighted contrast on a single image for assessment of white matter (WM) diseases such as multiple sclerosis (MS).This prospective pilot study was HIPAA compliant and institutional review board approved. Ten patients with clinically definite MS (eight men, two women; mean age, 41 years) provided informed consent and underwent 3.0-T MR imaging. Images from a T2-weighted FLAIR sequence were combined with images from a T2*-weighted segmented echo-planar imaging sequence performed during contrast material injection, yielding high-isotropic-resolution (0.55 × 0.55 × 0.55 mm(3)) FLAIR* images. Qualitative assessment was performed for image quality, lesion conspicuity, and vein conspicuity. Contrast-to-noise ratio (CNR) was calculated to compare normal-appearing WM (NAWM) with cerebrospinal fluid, lesions, and veins. To evaluate the differences in CNR among imaging modalities, a bootstrap procedure clustered on subjects was used, together with paired t tests.High-quality FLAIR* images of the brain were produced at 3.0 T, yielding conspicuous lesions and veins. Lesion-to-NAWM and NAWM-to-vein CNR values were significantly higher for FLAIR* images than for T2-weighted FLAIR images (P.0001). Findings on FLAIR* images included intralesional veins for lesions located throughout the brain and a hypointense rim around some WM lesions.High-isotropic-resolution FLAIR* images obtained at 3.0 T yield high contrast for WM lesions and parenchymal veins, making it well suited to investigate the relationship between WM abnormalities and veins in a clinical setting.

Vitamin D3 is best known as a calcium homeostasis modulator; however, it also has immune-modulating potential. In this study, we demonstrated that immunomodulatory effects of vitamin D3 are significantly stronger in females than in males in multiple sclerosis patients, as well as in healthy subjects. Inhibition of self-reactive T cell proliferation and reduction in IFN-γ– and IL-17–secreting cell numbers were considerably greater in females. Furthermore, the increase in IL-10–secreting and CD4+CD25+FoxP3+ regulatory T cell numbers were also greater in females. In parallel with these findings, female subjects had fewer CYP24A1 transcripts encoding the 1,25-dihydroxyvitamin D3-inactivating enzyme, as well as greater binding and internalization of vitamin D3-binding protein, a transporter for vitamin D3 and its metabolites. These gender-based disparities lead to the accumulation of vitamin D3 and its metabolites in target cells from female subjects and result in a more potent anti-inflammatory effect. Interestingly, 17-β estradiol reproduced these effects on self-reactive T cells and macrophages from male subjects, suggesting a functional synergy between 1,25-dihydroxyvitamin D3 and 17-β estradiol, mediated through estrogen receptor α. Collectively, these results demonstrate estrogen-promoted differences in vitamin D3 metabolism, suggesting a greater protective effect of vitamin D3-based therapeutic strategies in women.

Although Vitamin D is best known as a modulator of calcium homeostasis, it also has immune modulating potential. A protective effect of Vitamin D on multiple sclerosis is supported by the reduced risk associated with sun exposure and use of Vitamin D supplements. Moreover, high circulating levels of Vitamin D have been associated with lower risk of multiple sclerosis. In this study, we measured 1,25 (OH)(2) Vitamin D and 25 (OH) Vitamin D levels in multiple sclerosis patients separated into different clinical subgroups according to disease status. In addition, direct effects of 1,25 (OH)(2) Vitamin D on ex vivo CD4+ T cells and myelin-peptide specific T cell lines were investigated to gain more insight into putative regulatory mechanisms in the disease pathogenesis. One hundred and thirty-two Hispanic patients with clinically definite multiple sclerosis were studied, 58 with relapsing remitting multiple sclerosis during remission, 34 during relapse and 40 primary progressive multiple sclerosis cases. Sixty healthy individuals matched with respect to place of residence, race/ethnicity, age and gender served as controls. Levels of 25(OH)D(3) and 1,25(OH)(2)D(3), measured by ELISA were significantly lower in relapsing-remitting patients than in controls. In addition, levels in patients suffering relapse were lower than during remissions. In contrast, primary progressive patients showed similar values to controls. Proliferation of both freshly isolated CD4+ T cells and MBP-specific T cells was significantly inhibited by 1,25(OH)(2)D(3). Moreover, activated Vitamin D enhanced the development of IL-10 producing cells, and reduced the number of IL-6 and IL-17 secreting cells. Notably, Vitamin D receptor expression was induced by 1,25(OH)(2)D(3) in both activated and resting cells. Interestingly, T cells were able to metabolize 25(OH)D(3) into biologically active 1,25(OH)(2)D(3), since T cells express alpha1-hydroxylase constitutively. Finally, 1,25(OH)(2)D(3) also increased the expression and biological activity of indoleamine 2,3-dioxygenase, mediating significant increase in the number of CD4+CD25+ T regulatory cells. Collectively, these data suggest that 1,25(OH)(2)D(3) plays an important role in T cell homeostasis during the course of multiple sclerosis, thus making correction of its deficiency may be useful during treatment of the disease.

Human Herpesvirus 6 (HHV-6) is a ubiquitous virus with an estimated seroprevalence of 95% in the adult population. HHV-6 is associated with several neurologic disorders, including multiple sclerosis, an inflammatory demyelinating disease affecting the CNS. Animal models of HHV-6 infection would help clarify its role in human disease but have been slow to develop because rodents lack CD46, the receptor for cellular entry. Therefore, we investigated the effects of HHV-6 infections in a non-human primate, the common marmoset Callithrix jacchus. We inoculated a total of 12 marmosets with HHV-6A and HHV-6B intravenously and HHV-6A intranasally. Animals were monitored for 25 weeks post-inoculation clinically, immunologically and by MRI. Marmosets inoculated with HHV-6A intravenously exhibited neurologic symptoms and generated virus-specific antibody responses, while those inoculated intravenously with HHV-6B were asymptomatic and generated comparatively lower antibody responses. Viral DNA was detected at a low frequency in paraffin-embedded CNS tissue of a subset of marmosets inoculated with HHV-6A and HHV-6B intravenously. When different routes of HHV-6A inoculation were compared, intravenous inoculation resulted in virus-specific antibody responses and infrequent detection of viral DNA in the periphery, while intranasal inoculation resulted in negligible virus-specific antibody responses and frequent detection of viral DNA in the periphery. Moreover, marmosets inoculated with HHV-6A intravenously exhibited neurologic symptoms, while marmosets inoculated with HHV-6A intranasally were asymptomatic. We demonstrate that a marmoset model of HHV-6 infection can serve to further define the contribution of this ubiquitous virus to human neurologic disorders., info:eu-repo/semantics/published

We thank Dr. Handel and colleagues for their attention to our article on vitamin D as an environmental factor with a key role in the development of multiple sclerosis (MS) ([1][1], [2][2]). In agreement with findings from other published studies, we reported a significant decrease in 25

Like MS prevalence, oligoclonal bands (OCB) frequency seems to follow a latitudinal gradient. Argentina is extensive, latitude-wise, and previous studies have not found an MS prevalence latitudinal gradient. Our aim is to describe OCB prevalence in MS, clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS) patients included in the Argentinean MS and NMOSD registry (RelevarEM) and to investigate if it follows a latitudinal gradient.For each province, an average latitude was calculated, and OCB frequency was investigated. Multivariate logistical regression analysis and linear correlation were performed. Statistical analysis was repeated after excluding patients from centers using isoelectric focusing (IEF) in less than 95% of patients (CwIEF95).We included 2866 patients. OCB where positive in 73.9% of patients. No association or correlation were found between OCB and latitude of residence, even after excluding patients from (CwIEF95).OCB positivity does not follow a latitudinal gradient in Argentina. Also, OCB positivity is lower than described in other world regions.