Traditional first-line treatment failure rates in neuromyelitis optica spectrum disorder patients included in the Argentinean registry (RelevarEM).

BACKGROUND: Immunosuppressive therapies as azathioprine (AZA), mycophenolate mofetil (MMF) and rituximab (RTX) are widely prescribed as first-line treatment to prevent relapses in NMOSD. However, the rate of response to these traditional therapies is unknown in Argentina. We aimed to describe and compare treatment failure rates in NMOSD patients included in the Argentinean MS and NMOSD registry (RelevarEM, NCT03375177). METHODS: A retrospective cohort study was conducted in NMOSD patients included in RelevarEM (a nationwide, longitudinal, observational, non-mandatory registry of MS and NMOSD in Argentina). NMOSD patients were defined based on validate diagnostic criteria. Only NMOSD patients who received AZA or MMF for at least 6 months or RTX for at least 1 month were included. Patients who were receiving AZA, MMF, or RTX and then switched to another 1 of these 3 therapies were included if the above-mentioned criteria for each drug were fulfilled. Data on patient demographics, clinical, neuroradiological findings, and treatments administered were collected. Treatment failure was defined as any new attack/relapse that occurred despite immunosuppressive treatment. RESULTS: We included 139 NMOSD patients who were receiving AZA (n = 105), MMF (n = 5) or RTX (n = 29) with a mean follow-up time of 41.3 ± 11.4 months and median of EDSS at treatment initiation of 3. We observed a reduction in the annualized relapse rate from pre-treatment to post-treatment of 51.1 %, 48.4 %, and 79.1 % respectively with a Hazard Risk relative to RTX (95 % CI) of 1.67 (1.34-3.54, p = 0.01) for AZA and 2.01 (1.86-4.43, p = 0.008) for MMF. AZA, MMF and RTX failure was observed in 45/105 (42.8 %), 2/5 (40 %) and 3/29 (10.3 %) patients, respectively. CONCLUSIONS: Treatment failure rates were higher for AZA and MMF than RTX in Argentinean NMOSD patients in a real-world setting. High-efficacy treatment increases the opportunity to prevent attacks of NMOSD.

Real-World Effectiveness and Safety of Cladribine in Multiple Sclerosis: Longitudinal Data From the Nationwide Registry in Argentina.

OBJECTIVE: The aim was to evaluate patient profiles, effectiveness and safety of cladribine (CLAD) in patients with relapsing-remitting multiple sclerosis in Argentina. METHODS: This was a substudy included in RelevarEM (MS and neuromyelitis optica registry in Argentina, NCT03375177). Patients with MS who received CLAD tablets and were followed up for at least 24 months were included. Clinical evaluations every 3 months collect information about: a) clinical relapses; b) progression of physical disability, evaluated through Expanded Disability Status Scale, and c) new lesions found in the magnetic resonance imaging. Lymphopenia was evaluated during the follow-up and defined as grade 1: absolute lymphocyte count (ALC) 800-999/µL; grade 2: ALC 500-799/µL; grade 3: ALC 200-499/µL and grade 4: ALC <200/µL. RESULTS: A total of 240 patients were included from 19 centers from Argentina. The mean annualized relapse rate during the 12-month pre-CLAD initiation was 1.19 ± 0.56 versus 0.22 ± 0.18 at month 12 and 0.19 ± 0.15 at month 24 ( P < 0.001). A total of 142 (59.2%) fulfilled the criteria of disease activity during the 12 months before treatment initiation, whereas 27 (11.3%) fulfilled it at month 12 and 38 (15.8%) at month 24, P < 0.001. Regarding no evidence of disease activity (NEDA), 202 (84.2%) patients achieved NEDA status at month 12 and 185 (77%) at month 24. The most frequent incidence density of lymphopenia for course 2 observed was also for grade 1, 6.1 (95% confidence interval [CI] = 5.5-7.1). The overall incidence density of lymphopenia grade 4 was 0.1 (95% CI = 0.06-0.19). CONCLUSION: This information will help when choosing the best treatment option for Argentinean patients.

Diagnostic MRI Score to Differentiate Susac Syndrome from Primary Angiitis of the Central Nervous System and Multiple Sclerosis.

OBJECTIVE: Susac syndrome (SuS), multiple sclerosis (MS), and primary angiitis of the central nervous system (PACNS) present diagnostic challenges due to overlapping clinical features. We aimed to enhance diagnostic precision by developing the SPAMS (SuS, PACNS, MS) score, a practical radiological tool. METHODS: This multicenter study included 99 patients (43 SuS, 37 MS, 19 PACNS) from South American countries. Relevant MRI features were identified through an elastic-net model determined key variables. RESULTS: The SPAMS score assigned 2 points for snowball lesions, 1 point for spokes-like lesions, or if there are more than 4 lesions in the corpus callosum, corpus callosum involvement, or cerebellar involvement. It subtracted 1 point if gadolinium-enhancing lesions or 4 points if Dawson's fingers are present. Bootstrapping validated the optimal cutoff at 2 points, exhibiting a diagnostic performance of area under the curve = 0.931, sensitivity = 88%, specificity = 89%, positive predictive value = 88%, negative predictive value = 89%, and accuracy = 88%. INTERPRETATION: When specific MRI findings coexisted, the SPAMS score differentiated SuS from MS and PACNS. Access to MRI and standard protocol sequences makes it a valuable tool for timely diagnosis and treatment, potentially preventing disability progression and severe clinical outcomes. ANN NEUROL 2024.

Treatment strategies and responses for attacks of neuromyelitis optica spectrum disorder: A real-world retrospective cohort study.

We aimed to assess the treatment strategies utilized in patients with neuromyelitis optica spectrum disorder (NMOSD) experiencing relapses, including their frequency, types, and response after 6 months based on the Expanded Disability Status Scale (EDSS) score. METHODS: We conducted a retrospective study involving NMOSD patients from the Argentinean MS and NMOSD registry (RelevarEM, NCT03375177). Treatment response at 6 months was categorized as "good" if the EDSS score decreased by ≥1 point after a nadir EDSS score ≤ 3, or by ≥2 points after a nadir EDSS score > 3, "poor" if the EDSS score decrease was slighter, and as "absent" if the EDSS score remained unchanged or worsened. RESULTS: We included 120 NMOSD patients (seropositive N = 75), who experienced 250 NMOSD-related relapses and received 248 treatments. At 6 months, complete recovery was achieved in 70/98 (71.4%) and 15/19 (79%) patients, respectively. Predictors of a "good" response in our regression model were a younger age at disease onset (OR:3.54, CI95% 2.45-5.01, p < 0.0001) and a short delay from onset of relapse to treatment initiation (OR:1.56, CI95% 1.22-2.13, p = 0.004). CONCLUSIONS: Approximately two-thirds of patients experienced complete recovery, and younger age and a short delay to start treatment were independent predictors of a "good" response.

Human chorionic gonadotropin regulates cytokine production by lymphocytes from patients with multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) that primarily affects young adults, predominantly females. This was partially attributed to sex differences in immunity, which are influenced by changes in sex hormones occurring during women's life, among other factors. Furthermore, MS patients experience significant improvement in their symptoms during pregnancy when levels of female sex-hormones significantly increase. This phenomenon was attributed to immune adaptations occurring during gestation which are regulated by paternal antigens and sex hormones. The human chorionic gonadotropin (hCG) was shown to have strong immunosuppressive abilities. We aimed to analyze here the capacity of the hCG to regulate pro- and anti-inflammatory cytokine production by PBMC from MS patients. PBMC isolated from 17 MS patients receiving IFNß1a treatment were cultured with or without recombinant or urinary hCG. Cytokine production in the supernatants was assessed using a CBA array and cytokine production by lymphocytes and expression of co-stimulatory molecules in B-lymphocytes were evaluated by flow cytometry. hCG reduced the production of TNF by PBMC from MS patients while lowering the percentages of TNF producing T cells and diminishing the production of TNF by B cells. hCG significantly boosted the production of IL-10 by regulatory T cells and CD19high B cells from MS patients. Furthermore, hCG treatment lowered the percentages of CD80+CD86+ expressing B cells within PBMC from MS patients. Overall, our results described a novel and not yet explored mechanisms of action of hCG in the context of MS.

Selection of disease modifying therapies in multiple sclerosis based on patient's age and disease activity: Data from a nationwide registry.

BACKGROUND: Knowledge of the safety and efficacy of disease-modifying therapies (DMTs) in older patients with Multiple Sclerosis (pwMS) is limited due to their exclusion from clinical trials. Our purpose is to evaluate the choice of DMTs in pwMS older than 50 years old in a real-world setting. METHODS: Cross-sectional study of pwMS from the Argentine MS and NMOSD Registry. We included patients under 35 and above 50 years old prescribed DMTs. Disease activity was categorized as highly active (HA) or not highly active (NHA), and DMTs were classified as low efficacy therapies (LET) or high efficacy therapies (HET). RESULTS: 1460 patients (65% females) were enrolled. The HA group comprised 241 patients, 198 young (82.2%) and 43 older (17.8%). The NHA group included 1219 patients, 893 young (73%) and 326 older (27%). In the NHA group, older patients received LET more frequently than younger patients (66% versus 44%; p < 0.01). In the HA group, older patients received LET in 61% of cases, whereas younger patients received HET in 71% (p = 0.01). CONCLUSION: The study shows the preference of LET in older patients regardless of disease activity. However it does not demonstrate a difference in disability in older patients based on low vs high efficacy DMTs used, probably due to the design of the study. Further longitudinal studies are warranted to address this issue.

Iron deficiency in astrocytes alters cellular status and impacts on oligodendrocyte differentiation.

Iron deficiency (ID) has been shown to affect central nervous system (CNS) development and induce hypomyelination. Previous work from our laboratory in a gestational ID model showed that both oligodendrocyte (OLG) and astrocyte (AST) maturation was impaired. To explore the contribution of AST iron to the myelination process, we generated an in vitro ID model by silencing divalent metal transporter 1 (DMT1) in AST (siDMT1 AST) or treating AST with Fe3+ chelator deferoxamine (DFX; DFX AST). siDMT1 AST showed no changes in proliferation but remained immature. Co-cultures of oligodendrocyte precursors cells (OPC) with siDMT1 AST and OPC cultures incubated with siDMT1 AST-conditioned media (ACM) rendered a reduction in OPC maturation. These findings correlated with a decrease in the expression of AST-secreted factors IGF-1, NRG-1, and LIF, known to promote OPC differentiation. siDMT1 AST also displayed increased mitochondrial number and reduced mitochondrial size as compared to control cells. DFX AST also remained immature and DFX AST-conditioned media also hampered OPC maturation in culture, in keeping with a decrease in the expression of AST-secreted growth factors IGF-1, NRG-1, LIF, and CNTF. DFX AST mitochondrial morphology and number showed results similar to those observed in siDMT1 AST. In sum, our results show that ID, induced through two different methods, impacts AST maturation and mitochondrial functioning, which in turn hampers OPC differentiation.

Occurrence of area postrema syndrome during follow-up: phenotype and influence over NMOSD activity in LATAM in real-world settings.

INTRODUCTION: We aimed to assess the frequency, duration, and severity of area postrema syndrome (APS) during follow-up in neuromyelitis optica spectrum disorder (NMOSD) patients, as well as its association with inflammatory activity and prognostic factors of APS severity in a real-world setting. METHODS: We conducted a retrospective study on a cohort of Latin American (LATAM) NMOSD patients who had experienced APS during their follow-up. Patients from Mexico, Peru, Brazil, Colombia, Panama, Chile and Argentina patients who met 2015 NMOSD criteria were included. We evaluated data on symptom type (nausea, vomiting and/or hiccups), frequency, duration, severity (measured by APS severity scale), association with other NMOSD core relapses, and acute treatments (symptomatic and immunotherapy or plasmapheresis). Logistic regression was conducted to evaluate factors associated with APS severity (vs. mild-moderate). RESULTS: Out of 631 NMOSD patients, 116 (18.3%) developed APS during their follow-up. The most common APS phenotype was severe. Inflammatory activity (i.e., relapses) significantly decreased after the onset of APS. Half of the patients experienced isolated APS with a median duration of 10 days, and the most frequently used acute treatment was IV steroids. All three symptoms were present in 44.6% of the patients. APS symptoms resolved following immunotherapy. Logistic regression did not identify independent factors associated with the severity of APS. CONCLUSIONS: Our findings indicate that 18.3% of NMOSD patients developed APS during the follow-up period, with most patients fulfilling criteria for severe APS. The inflammatory activity decreased after the onset of APS compared to the previous year.

Clinical characteristics, course and prognosis of Multiple Sclerosis patients with epilepsy. A case control study: MS and epilepsy.

BACKGROUND AND PURPOSE: Although more common than in the general population, seizures are an atypical manifestation of multiple sclerosis (MS) and their pathophysiology is not well understood. This study aims to examine the prevalence, clinical characteristics, brain imaging findings and course of epilepsy, presenting in patients with MS. METHODS: Observational retrospective study of MS patients evaluated at a single MS reference center in Buenos Aires, Argentina, between 2011 and 2022, focusing on those who developed epilepsy (EMS). Clinical, demographic, and prognostic factors were evaluated and compared to a control group of non-epileptic MS patients (NEMS). To analyze specific epilepsy characteristics, a second control group of patients with non-lesional focal epilepsy (FNLE) was also included. RESULTS: Twenty-five patients (18 women), were diagnosed with epilepsy, corresponding to a prevalence of 1.95%. Comparison of brain imaging characteristics between EMS and NEMS patients showed brain atrophy (32% vs 6.1%, p<0.01), as well as cortical (26% vs 4%, p=0.03) and juxtacortical lesions (84% vs 55%, p=0.05), were more frequent in EMS patients. However, after multivariate analysis, cortical atrophy was the only variable linked to a significant increase in risk of epilepsy (OR 24, 95%CI=2.3-200, p<0.01). No significant differences in clinical characteristics, disease activity, disability levels, response to disease modified treatment (DMT) or lack of DMT efficacy were observed between MS patients with or without epilepsy. Most patients received anti-seizure medication (ASM), and seizure control was better in EMS than in FNLE patients (92% vs 58%, p=0.022) with no differences found in drug resistance. We did not find predictors of seizure recurrence in the population studied. CONCLUSION: We observed a lower prevalence of epilepsy in this group of MS patients, compared to other reported cohorts. Although epilepsy seems to have a benign course in MS patients, cortical atrophy appears to be an important contributor to the development of secondary epilepsy in MS patients. Further investigations will be necessary to identify risk factors or biomarkers predicting increased epilepsy risk in MS.

Clinical impact of gender and age at onset on disease trajectory in primary progressive multiple sclerosis patients.

BACKGROUND AND OBJECTIVES: Primary-progressive multiple sclerosis (PPMS) is characterized by gradual neurological deterioration without relapses. This study aimed to investigate the clinical impact of gender and age at disease onset on disease progression and disability accumulation in patients with this disease phenotype. METHODS: Secondary data from the RelevarEM registry, a longitudinal database in Argentina, were analyzed. The cohort comprised patients with PPMS who met inclusion criteria. Statistical analysis with multilevel Bayesian robust regression modeling was conducted to assess the associations between gender, age at onset, and Expanded Disability Status Scale (EDSS) score trajectories. RESULTS: We identified 125 patients with a confirmed diagnosis of PPMS encompassing a total of 464 observations. We found no significant differences in EDSS scores after 10 years of disease progression between genders (-0.08; credible interval (CI): -0.60, 0.42). A 20-year difference in age at onset did not show significant differences in EDSS score after 10 years of disease progression (0.281; CI: -0.251, 0.814). Finally, we also did not find any clinically relevant difference between gender EDSS score with a difference of 20 years in age at onset (-0.021; CI: -0.371, 0.319). CONCLUSION: Biological plausibility of gender and age effects does not correlate with clinical impact measured by EDSS score.

Incidence of SARS-CoV-2 infection in patients with multiple sclerosis who received SARS-CoV-2 vaccines and are under treatment with high-efficacy therapies in Argentina.

We aimed to evaluate the incidence of SARS-CoV-2 breakthrough infection of SARS-CoV-2 vaccines in people with MS (PwMS) on high-efficacy disease-modifying therapies (HET) included in the national MS registry in Argentina (RelevarEM). METHODS: Non-interventional, retrospective cohort study that collected information directly from RelevarEM. Adult PwMS who had been treated for at least 6 months with a HET (ocrelizumab, natalizumab, alemtuzumab, cladribine) who had received at least two doses of SARS-CoV-2 vaccines available in Argentina were included. Full course of vaccination was considered after the second dose of the corresponding vaccines. Cumulative incidence of SARS-CoV-2 infection was reported for the whole cohort by Kaplan-Meier survival curves (which is expressed in percentage) as well as incidence density (which is expressed per 10.000 patients/day with 95% CI). RESULTS: Two hundred twenty-eight PwMS were included. Most frequent first and second dose received was AstraZeneca vaccine, followed by Sputnik vaccine. Most frequent HETs used in included patients were cladribine in 79 (34.8%). We found an incidence density of breakthrough COVID-19 infection of 3.5 × 10.000 patients/day (95% CI 2.3-6.7) after vaccination in Argentina. We described the incidence rate after vaccination for every HET used, it being significantly higher for ocrelizumab compared with other HETs (p = 0.005). Only five patients presented a relapse during the follow-up period with no differences regarding the pre-vaccination period. CONCLUSIONS: We found an incidence density of breakthrough COVID-19 infection of 3.5 × 10.000 patients/day (95% CI 2.3-6.7) after vaccination in Argentina.

Remyelinating effect driven by transferrin-loaded extracellular vesicles.

Extracellular vesicles (EVs) are involved in diverse cellular functions, playing a significant role in cell-to-cell communication in both physiological conditions and pathological scenarios. Therefore, EVs represent a promising therapeutic strategy. Oligodendrocytes (OLs) are myelinating glial cells developed from oligodendrocyte progenitor cells (OPCs) and damaged in chronic demyelinating diseases such as multiple sclerosis (MS). Glycoprotein transferrin (Tf) plays a critical role in iron homeostasis and has pro-differentiating effects on OLs in vivo and in vitro. In the current work, we evaluated the use of EVs as transporters of Tf to the central nervous system (CNS) through the intranasal (IN) route. For the in vitro mechanistic studies, we used rat plasma EVs. Our results show that EVTf enter OPCs through clathrin-caveolae and cholesterol-rich lipid raft endocytic pathways, releasing the cargo and exerting a pro-maturation effect on OPCs. These effects were also observed in vivo using the animal model of demyelination induced by cuprizone (CPZ). In this model, IN administered Tf-loaded EVs isolated from mouse plasma reached the brain parenchyma, internalizing into OPCs, promoting their differentiation, and accelerating remyelination. Furthermore, in vivo experiments demonstrated that EVs protected the Tf cargo and significantly reduced the amount of Tf required to induce remyelination as compared to soluble Tf. Collectively, these findings unveil EVs as functional nanocarriers of Tf to induce remyelination.

There is much to be learnt about the costs of multiple sclerosis in Latin America / Hay mucho a ser aprendido sobre los costos de la esclerosis multiple en America Latina

METHOD: A systematic review of the literature from 1990 to 2011 was conducted. Outcome measures included: mean cost of disease modifying therapies (DMTs), mean cost of treatment of relapses and mean cost of disease by stage stratification measured by the expanded disability status scale (EDSS). RESULTS: Seven studies from three countries (Brazil, Argentina and Colombia) were included. In 2004, in Argentina, the mean cost of DMT treatment was reported to be USD 35,000 per patient treated. In Brazil, the total MS expenditure of DMTs rose from USD 14,011,700 in 2006 to USD 122,575,000 in 2009. Patient costs ranged between USD 10,543 (EDSS 8-9.5) and USD 25,713 (EDSS 3-5.5). Indirect costs markedly increased for the EDSS 8-9.5 patients. CONCLUSION: Further research assessing the economic burden of MS in LA is warranted. .

MÉTODOS: Revisión sistemática de la literatura desde 1990 hasta 2011. Los resultados evaluados fueron: coste medio de los tratamientos modificadores de la enfermedad (DMTs), coste medio del tratamiento de las recaídas y la media de coste de la enfermedad estratificado por la Expanded Disability Status Scale (EDSS). RESULTADOS: Siete estudios de tres países (Brasil, Argentina y Colombia) fueron incluidos. El costo promedio del tratamiento de DMTs fue de USD 35.000 por paciente para el año 2004 en Argentina y el total del costo de los DMTs aumentó de USD 14.011,700 en 2006 a USD 122.575,000 en Brasil en 2009. Los costos de pacientes oscilaron entre USD 10.543 (EDSS 8-9.5) y USD 25.713 (EDSS 3.5 a 5). Los costes indirectos aumentaron para la EDSS mayor discapacidad (EDSS 8-9.5). CONCLUSIÓN: Estudios adicionales del costo de la EM en AL son necesarios.. .

Compromiso neuronal en esclerosis multiple / Neuronal injury in multiple sclerosis

La esclerosis múltiple (EM) ha sido considerada clásicamente como una enfermedad desmielinzante. Si bien el compromiso neurodegenerativo fue previamente descripto, sólo recientemente ha sido enfatizado. Por estudiosos recientes se ha identificado la degeneración axonal como el mayor determinante de discapacidad neurológica irreversible en pacientes con EM. El daño axonal se inicia tempranamente y permanece silente durante años, la discapacidad neurológica se desarrolla cuando se alcanza cierto umbral de pérdida axonal y los mecanismos de compensación se agotan. Se han propuesto tres hipótesis para explicar el daño axonal: 1) El daño es causado por un proceso inflamatorio, 2) Existe una excesiva acumulación de Ca2+ intra-axonal, 3) Los axones desmienlinizados evolucionan a un proceso degenerativo producto de la falta de soporte trófico provisto por la mielina o células formadoras de mielina. Si bien la EM fue tradicionalmente considerada como una enfermedad de la sustancia blanca, el proceso de desmielinización tambiém ocurre en la corteza cerebral

The concept of multiple sclerosis (MS) as a demyelinating disease is deeply ingrained. Although the existence of a neurodegenerative component has always been apparent, it has only recently become emphasized. Thus, in recent years several studies have identified axonal degeneration as the major determinant of irreversible neurological disability in patients with MS. Axonal injury begins at disease onset and remains clinically silent for many years; irreversible neurological disability develops when a threshold of axonal loss is reached and CNS compensatory mechanisms are exhausted. The precise mechanisms of axonal loss are poorly understood, and three hypotheses have been proposed: 1) The damage is caused by an inflammatory process, 2) There is an excessive accumulation of intra-axonal Ca2+, 3) Demyelinated axons undergo degeneration due to lack of trophic support by myelin, or myelin forming cells. Although MS has traditionally been regarded as a disease of white matter, demyelination can also occur in the cerebral cortex. Cortical lesions exhibit neuronal injury represented by dendritic and axonal transection as well as neuronal apoptosis. Because conventional nuclear magnetic resonance (NMR) is limited in its ability to provide specific information about axonal pathology in MS, new techniques such as, diffusion-weighted MRI, proton magnetic resonance spectroscopy, functional MRI, as well as novel techniques designed to measure atrophy have been developed to monitor MS evolution. Recognition that MS is in part a neurodegenerative disease should trigger critical rethinking on the pathogenic mechanisms of this disease and provides new targets for a rational treatment