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We aimed to compare the ability of diffusion tensor imaging and multi-compartment spherical mean technique to detect focal tissue damage and in distinguishing between different connectivity patterns associated with varying clinical outcomes in multiple sclerosis (MS). Seventy-six people diagnosed with MS were scanned using a SIEMENS Prisma Fit 3T magnetic resonance imaging (MRI), employing both conventional (T1w and fluid-attenuated inversion recovery) and advanced diffusion MRI sequences from which fractional anisotropy (FA) and microscopic FA (µFA) maps were generated. Using automated fiber quantification (AFQ), we assessed diffusion profiles across multiple white matter (WM) pathways to measure the sensitivity of anisotropy diffusion metrics in detecting localized tissue damage. In parallel, we analyzed structural brain connectivity in a specific patient cohort to fully grasp its relationships with cognitive and physical clinical outcomes. This evaluation comprehensively considered different patient categories, including cognitively preserved (CP), mild cognitive deficits (MCD), and cognitively impaired (CI) for cognitive assessment, as well as groups distinguished by physical impact: those with mild disability (Expanded Disability Status Scale [EDSS] <=3) and those with moderate-severe disability (EDSS >3). In our initial objective, we employed Ridge regression to forecast the presence of focal MS lesions, comparing the performance of µFA and FA. µFA exhibited a stronger association with tissue damage and a higher predictive precision for focal MS lesions across the tracts, achieving an R-squared value of .57, significantly outperforming the R-squared value of .24 for FA (p-value <.001). In structural connectivity, µFA exhibited more pronounced differences than FA in response to alteration in both cognitive and physical clinical scores in terms of effect size and number of connections. Regarding cognitive groups, FA differences between CP and MCD groups were limited to 0.5% of connections, mainly around the thalamus, while µFA revealed changes in 2.5% of connections. In the CP and CI group comparison, which have noticeable cognitive differences, the disparity was 5.6% for FA values and 32.5% for µFA. Similarly, µFA outperformed FA in detecting WM changes between the MCD and CI groups, with 5% versus 0.3% of connections, respectively. When analyzing structural connectivity between physical disability groups, µFA still demonstrated superior performance over FA, disclosing a 2.1% difference in connectivity between regions closely associated with physical disability in MS. In contrast, FA spotted a few regions, comprising only 0.6% of total connections. In summary, µFA emerged as a more effective tool than FA in predicting MS lesions and identifying structural changes across patients with different degrees of cognitive and global disability, offering deeper insights into the complexities of MS-related impairments.
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Imagen de Difusión Tensora , Esclerosis Múltiple , Sustancia Blanca , Humanos , Femenino , Masculino , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Anisotropía , Adulto , Imagen de Difusión Tensora/métodos , Persona de Mediana Edad , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/patología , Disfunción Cognitiva/etiologíaRESUMEN
The relationship between brain diffusion microstructural changes and disability in multiple sclerosis (MS) remains poorly understood. We aimed to explore the predictive value of microstructural properties in white (WM) and grey matter (GM), and identify areas associated with mid-term disability in MS patients. We studied 185 patients (71% female; 86% RRMS) with the Expanded Disability Status Scale (EDSS), timed 25-foot walk (T25FW), nine-hole peg test (9HPT), and Symbol Digit Modalities Test (SDMT) at two time-points. We used Lasso regression to analyse the predictive value of baseline WM fractional anisotropy and GM mean diffusivity, and to identify areas related to each outcome at 4.1 years follow-up. Motor performance was associated with WM (T25FW: RMSE = 0.524, R2 = 0.304; 9HPT dominant hand: RMSE = 0.662, R2 = 0.062; 9HPT non-dominant hand: RMSE = 0.649, R2 = 0.139), and SDMT with GM diffusion metrics (RMSE = 0.772, R2 = 0.186). Cingulum, longitudinal fasciculus, optic radiation, forceps minor and frontal aslant were the WM tracts most closely linked to motor dysfunction, and temporal and frontal cortex were relevant for cognition. Regional specificity related to clinical outcomes provide valuable information that can be used to develop more accurate predictive models that could improve therapeutic strategies.
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Imagen de Difusión Tensora , Esclerosis Múltiple , Humanos , Femenino , Masculino , Esclerosis Múltiple/diagnóstico por imagen , Corteza Cerebral , Lóbulo Frontal , AnisotropíaRESUMEN
OBJECTIVE: To study the clinico-radiological paradox in multiple sclerosis (MS) relapse by analyzing the number and location of gadolinium-enhanced (Gd+) lesions on brain MRI before methylprednisolone (MP) treatment. METHODS: We analyzed brain MRI from 90 relapsed MS patients in two Phase IV multicenter double-blind randomized clinical trials that showed the noninferiority of different routes and doses of MP administration. A 1.5- or 3-T brain MRI was performed at baseline before MP treatment and within 15 days of symptom onset. The number and location of Gd+ lesions were analyzed. Associations were studied using univariate analysis. RESULTS: Sixty-two percent of patients had at least 1 Gd+ brain lesion; the median number was 1 (interquartile range 0-4), and 41% of patients had 2 or more lesions. The most frequent location of Gd+ lesions was subcortical (41.4%). Gd+ brain lesions were found in 71.4% of patients with brainstem-cerebellum symptoms, 57.1% with spinal cord symptoms and 55.5% with optic neuritis (ON). Thirty percent of patients with brain symptoms did not have Gd+ lesions, and only 43.6% of patients had symptomatic Gd+ lesions. The univariate analysis showed a negative correlation between age and the number of Gd+ lesions (p=0.002). CONCLUSION: Most patients with relapse showed several Gd+ lesions on brain MRI, even when the clinical manifestation was outside of the brain. Our findings illustrate the clinico-radiological paradox in MS relapse and support the value of brain MRI in this scenario.
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Gadolinio , Esclerosis Múltiple , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Gadolinio/uso terapéutico , Humanos , Imagen por Resonancia Magnética , Metilprednisolona/uso terapéutico , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/tratamiento farmacológico , RecurrenciaRESUMEN
OBJECTIVES: To gather, synthesize, and meta-analyze data regarding the risk factors associated with a severe course of COVID-19 among patients with multiple sclerosis (pwMS). METHODS: MEDLINE, Embase, Scopus, and WoS were searched in May 2021. Briefly, the eligibility criteria included: 1) studies assessing COVID-19 severity among adult pwMS; 2) definitive diagnoses or high clinical suspicion of COVID-19; 3) a categorization of COVID-19 severity into at least two categories; 4) quantitative effect size and precision measurements; and 5) English language; and 6) clear effect size/precision measures. internal validity of studies was assessed using the NIH Quality Assessment Tools. A list of possible risk factors was created based on the search results and was later used in extraction, synthesis, and meta-analysis of the data. RESULTS: Thirteen studies were included in the syntheses. Outcome measures were either extracted from the papers, obtained from the primary researchers or calculated manually. The meta-analyses showed a significantly (P<0.05) increased odds of a severe COVID-19 in pwMS with all of the assessed risk factors, except smoking and most DMTs. CONCLUSION: This study facilitates evidence-based risk/benefit assessments in practice. Older men with progressive MS on anti-CD20 therapies are more at risk of an unfortunate COVID-19 outcome.
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COVID-19 , Esclerosis Múltiple , Adulto , Anciano , Humanos , Masculino , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/epidemiología , Factores de Riesgo , SARS-CoV-2RESUMEN
BACKGROUND: The recent development of highly effective treatments for multiple sclerosis (MS) and the potential risk of infectious complications require the development of prevention and risk minimisation strategies. Vaccination is an essential element of the management of these patients. This consensus statement includes a series of recommendations and practical scenarios for the vaccination of adult patients with MS who are eligible for highly effective immunosuppressive treatments. METHODOLOGY: A formal consensus procedure was followed. Having defined the scope of the statement, we conducted a literature search on recommendations for the vaccination of patients with MS and specific vaccination guidelines for immunosuppressed patients receiving biological therapy for other conditions. The modified nominal group technique methodology was used to formulate the recommendations. DEVELOPMENT: Vaccination in patients who are candidates for immunosuppressive therapy should be considered before starting immunosuppressive treatment providing the patient's clinical situation allows. Vaccines included in the routine adult vaccination schedule, as well as some specific ones, are recommended depending on the pre-existing immunity status. If immunosuppressive treatment is already established, live attenuated vaccines are contraindicated. For vaccines with a correlate of protection, it is recommended to monitor the serological response in an optimal interval of 1-2 months from the last dose.
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Terapia de Inmunosupresión , Esclerosis Múltiple , Adulto , Consenso , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Vacunación , Vacunas AtenuadasRESUMEN
Within the last few decades, tropical coastal systems such as beaches, dunes, and mangrove forests have experienced high annual rates of loss worldwide due to natural and anthropogenic impacts. Historical remote sensing data have been used to map and monitor these fragile systems, as well as to track specific events through time. The purpose of this study was to examine coastal trends along Marismas Nacionales in Mexico, which is the largest wetland complex of the western coast of the Pacific Ocean. The opening of the Cuautla Canal in 1976 and the construction of several hydroelectric power dams have severely impacted this wetland system. Shoreline variability was estimated based on representative remote sensing images over half a century (1970 to 2019). Results indicate that, after 49 years, 805 ha of beach deposits have been lost in the Cuautla Canal and at the beach ridge region that should otherwise be an accretional coastal zone. Conversely, the southern section of the study site shows 406 ha of constant accretion during the same period due to the presence of the unobstructed San Pedro River. Our study highlights the adverse effects of engineering projects, such as inlets and hydroelectric dams throughout tropical coastal systems that have strongly depended on freshwater input from upstream rivers.
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Monitoreo del Ambiente/métodos , Sistemas de Información Geográfica , Ingeniería , México , Océano Pacífico , Tecnología de Sensores Remotos , Ríos , HumedalesRESUMEN
BACKGROUND AND PURPOSE: Oral or intravenous methylprednisolone (≥500 mg/day for 5 days) is recommended for multiple sclerosis (MS) relapses. Nonetheless, the optimal dose remains uncertain. We compared clinical and radiological effectiveness, safety and quality of life (QoL) of oral methylprednisolone [1250 mg/day (standard high dose)] versus 625 mg/day (lesser high dose), both for 3 days] in MS relapses. METHODS: A total of 49 patients with moderate to severe MS relapse within the previous 15 days were randomized in a pilot, double-blind, multicentre, non-inferiority trial (ClinicalTrial.gov, NCT01986998). The primary endpoint was non-inferiority of the lesser high dose by Expanded Disability Status Scale (EDSS) score improvement on day 30 (non-inferiority margin, 1 point). The secondary endpoints were EDSS score change on days 7 and 90, changes in T1 gadolinium-enhanced and new/enlarged T2 lesions on days 7 and 30, and safety and QoL results. RESULTS: The primary outcome was achieved [mean (95% confidence interval) EDSS score difference, -0.26 (-0.7 to 0.18) at 30 days (P = 0.246)]. The standard high dose yielded a superior EDSS score improvement on day 7 (P = 0.028). No differences were observed in EDSS score on day 90 (P = 0.352) or in the number of T1 gadolinium-enhanced or new/enlarged T2 lesions on day 7 (P = 0.401, 0.347) or day 30 (P = 0.349, 0.529). Safety and QoL were good at both doses. CONCLUSIONS: A lesser high-dose oral methylprednisolone regimen may not be inferior to the standard high dose in terms of clinical and radiological response.
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Glucocorticoides/administración & dosificación , Metilprednisolona/administración & dosificación , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Evaluación de Resultado en la Atención de Salud , Adulto , Método Doble Ciego , Estudios de Equivalencia como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Calidad de VidaRESUMEN
Electrical forces are the background of all the interactions occurring in biochemical systems. From here and by using a combination of ab-initio and ad-hoc models, we introduce the first description of electric field profiles with intrabond resolution to support a characterization of single bond forces attending to its electrical origin. This fundamental issue has eluded a physical description so far. Our method is applied to describe hydrogen bonds (HB) in DNA base pairs. Numerical results reveal that base pairs in DNA could be equivalent considering HB strength contributions, which challenges previous interpretations of thermodynamic properties of DNA based on the assumption that Adenine/Thymine pairs are weaker than Guanine/Cytosine pairs due to the sole difference in the number of HB. Thus, our methodology provides solid foundations to support the development of extended models intended to go deeper into the molecular mechanisms of DNA functioning.
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Emparejamiento Base , ADN/química , Enlace de Hidrógeno , Conformación de Ácido NucleicoRESUMEN
INTRODUCTION: Different criteria have been proposed for the response to treatment with interferon beta, and the Rio Score is one of the most widely used. The aim of this study was to validate the usefulness of the Rio Score in an independent cohort. PATIENTS AND METHODS: A multi-centre, prospective, longitudinal study was conducted on patients with relapsing-remitting multiple sclerosis treated with interferon beta. The patients were classified according to the presence of attacks, active lesions (new in T2 or gadolinium enhancing lesions) in magnetic resonance imaging, a confirmed increase in disability or combinations of these variables (attacks, increase on the Expanded Disability Status Scale and active lesions) after one year's treatment. Regression analysis was used in order to identify the response-predicting variables after a three-year follow-up. RESULTS: The sample consisted of 249 patients with relapsing-remitting multiple sclerosis. The logistic model confirmed that the presence of two (odds ratio = 6.6; CI 95% = 2.7-16.1; p < 0.0001) or three (odds ratio = 8.5; CI 95% = 1.6-46; p < 0.01) positive variables during the first year of treatment were indicative of a significant risk of activity (attacks or progression) in the next two years. CONCLUSIONS: The usefulness of the Rio Score is confirmed, in an independent cohort, as a means of identifying patients with a higher risk of developing clinical activity or progression of disability during treatment with interferon beta.
TITLE: Respuesta al tratamiento con interferon beta en pacientes con esclerosis multiple. Validacion del Rio Score.Introduccion. Se han propuesto diferentes criterios de respuesta al tratamiento con interferon beta, y el Rio Score es uno de los mas utilizados. El objetivo de este estudio fue validar la utilidad del Rio Score en una cohorte independiente. Pacientes y metodos. Estudio multicentrico, prospectivo y longitudinal de pacientes con esclerosis multiple remitente recurrente tratados con interferon beta. Los pacientes fueron clasificados basandose en la presencia de brotes, lesiones activas (nuevas en T2 o lesiones que captaban gadolinio) en la resonancia magnetica, incremento confirmado de la discapacidad o combinaciones de estas variables (brotes, incremento en la Expanded Disability Status Scale y lesiones activas) tras un año de tratamiento. Se utilizo un analisis de regresion con el fin de identificar las variables de prediccion de respuesta despues de un seguimiento de tres años. Resultados. Se incluyo a 249 pacientes con esclerosis multiple remitente recurrente. El modelo logistico confirmo que la presencia de dos (odds ratio = 6,6; IC 95% = 2,7-16,1; p < 0,0001) o tres (odds ratio = 8,5; IC 95% = 1,6-46; p < 0,01) variables positivas durante el primer año de tratamiento conferia un riesgo significativo de actividad (brotes o progresion) en los siguientes dos años. Conclusiones. Se confirma, en una cohorte independiente, la utilidad del Rio Score para identificar a pacientes con un mayor riesgo de desarrollar actividad clinica o progresion de la discapacidad durante el tratamiento con interferon beta.
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Interferón beta/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Evaluación de la Discapacidad , Progresión de la Enfermedad , Humanos , Factores Inmunológicos , Estudios Longitudinales , Imagen por Resonancia Magnética , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Multiple sclerosis (MS) shares some risk genes with other disorders hallmarked by an autoimmune pathogenesis, most notably IL2RA and CLEC16A. We analyzed 10 single-nucleotide polymorphisms (SNPs) in nine risk genes, which recently emerged from a series of non-MS genome-wide association studies (GWAS), in a Spanish cohort comprising 2895 MS patients and 2942 controls. We identified two SNPs associated with MS. The first SNP, rs6859219, located in ANKRD55 (Chr5), was recently discovered in a meta-analysis of GWAS on rheumatoid arthritis (RA), and emerged from this study with genome-wide significance (odds ratio (OR) = 1.35; P = 2.3 × 10(-9)). The second SNP, rs12785878, is located near DHCR7 (Chr11), a genetic determinant of vitamin D insufficiency, and showed a size effect in MS similar to that recently observed in Type 1 diabetes (T1D; OR = 1.10; P = 0.009). ANKRD55 is a gene of unknown function, and is flanked proximally by the IL6ST-IL31RA gene cluster. However, rs6859219 did not show correlation with a series of haplotype-tagging SNPs covering IL6ST-IL31RA, analyzed in a subset of our dataset (D'< 0.31; r(2)< 0.011). Our results expand the number of risk genes shared between MS, RA and T1D.
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Predisposición Genética a la Enfermedad , Esclerosis Múltiple/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Adulto , Alelos , Repetición de Anquirina/genética , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
OBJECTIVE: To describe the main characteristics of patients with primary Sjögren syndrome (SS) and white matter abnormalities (WMA) seen by a specialist SS unit. METHODS: The study cohort included 321 consecutive patients fulfilling the 2002 classification criteria for primary SS. We retrospectively analyzed the results of neuroimaging studies performed in patients who presented with neurological symptoms. Patients were further evaluated by three neurologists to determine fulfillment of the McDonald criteria for the diagnosis of multiple sclerosis (MS). RESULTS: Fifty-one (16%) patients had at least one neuroimaging study, and 25 of these had WMA. WMA were classified as vascular pathological changes in 21 patients: 10 had multiple small focal lesions, 7 had beginning confluence of lesions and 4 had diffuse involvement of the entire region. WMA were classified as inflammatory/demyelinating lesions (MS-like) in 4 patients who fulfilled the MRI Barkhof criteria. Patients with inflammatory/demyelinating lesions were younger (53.7 vs. 73.5 years, P = 0.001) and had a lower frequency of hypertension (25% vs. 86%, P = 0.031) and altered glomerular filtration rate (0% vs. 70%, P = 0.047) in comparison with patients with vascular lesions. The multivariate age-sex adjusted model including the seven variables which were statistically significant in the univariate analysis (antimalarial therapy, leukopenia, anti-La/SSB antibodies, diabetes, hypertension, metabolic syndrome and HDL-c levels) identified hypertension (P = 0.019) and HDL-c levels (P = 0.032) as independent predictors of WMA in primary SS patients. CONCLUSION: Neuroimaging studies disclosed WMA in 49% of patients with primary SS and suspected neurological involvement. WMA were identified as vascular pathological changes in 80% of the patients, and hypertension and HDL-c levels as predictive factors for this association.
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Encéfalo/patología , Síndrome de Sjögren/patología , Factores de Edad , Anciano , Estudios de Casos y Controles , HDL-Colesterol , Trastornos del Conocimiento/etiología , Femenino , Tasa de Filtración Glomerular , Humanos , Hipertensión/epidemiología , Imagen por Resonancia Magnética , Masculino , Trastornos de la Memoria/etiología , Debilidad Muscular/etiología , Estudios Retrospectivos , Convulsiones/etiología , Síndrome de Sjögren/complicaciones , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND The clinical outcome of glioblastoma (GBM) patients who receive radiotherapy alone or with chemotherapy is well established. However, little is known about how many patients do not receive this treatment. We consider it is important to investigate why a proportion of operated patients do not receive further treatment after surgery. METHODS We reviewed all consecutive GBM patients operated on in our hospital between January 2000 and December 2008. RESULTS A total of 216 patients with GBM were identified. Fifty-five (25%) did not receive any treatment after surgery. Univariate analysis showed that factors associated with no further treatment after surgery were older than 60 years (p=0.002), of female gender (p=0.03), had a KPS<70 (p<0.001) and had had a biopsy (p<0.001). Multivariate analysis indicated that age =60 years and KPS <70 were independent predictors of no further treatment after surgery. Gender was not an independent variable. However, women in the whole series were older than 60 years (p=0.01), and they had a worse KPS (p=0.02) and more biopsies (p=0.04) than men. In the whole group, median survival time was 10.4 months for men (n=125) vs. 7.2 months for women (n=91), log rank p<0.04. This difference was not observed in the group that was treated after surgery. CONCLUSIONS One out of four patients could not be treated after surgery. Independent predictors were older age and low KPS. These poor risk variables were more frequent in women and their survival was therefore lower than men in our series.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/terapia , Glioblastoma/mortalidad , Glioblastoma/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/cirugía , Quimioterapia Adyuvante , Terapia Combinada , Femenino , Glioblastoma/cirugía , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Radioterapia Adyuvante , Factores Sexuales , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
INTRODUCTION: The existence of antibodies to aquaporin-4 (AQP-4-ab) has identified neuromyelitis optica (NMO) and multiple sclerosis (MS) as different diseases. Although HLA-DRB1 alleles contribute to MS risk, recent studies suggest that HLA back-ground differs between patients with NMO or MS in non-Caucasians populations. Our study was aimed to analyze HLA-DRB1 distribution in Caucasians NMO patients. SUBJECTS AND METHODS: We recruited a cohort of 22 NMO patients (73% were AQP-4-ab positive), 228 MS patients and 225 healthy controls from Spain and we genotyped the HLA-DRB1 locus. Then, we performed a pool analysis using reported data from 45 NMO patients (53% were AQP-4-ab positive), 156 MS patients and 310 healthy controls from Caucasian French population. RESULTS: In the Spanish cohort, NMO was associated with increased frequency of DRB1*10 allele compared with MS (odds ratio, OR = 15.1; 95% confidence interval, 95% CI = 3.26-69.84; p = 0.012). In the pooled analysis, by comparison with healthy controls, NMO was associated with increased frequency of DRB1*03 allele (OR = 2.27; 95% CI = 1.44-3.58; p < 0.0008) which was related to AQP-4-ab seropositivity (OR = 2.74; 95% CI = 1.58-4.77; p < 0.0008). By contrast, MS was associated with increased frequency of DRB1*15 allele (OR = 2.09; 95% CI = 1.62-2.68; p < 0.0008) and decreased frequency of DRB1*07 allele (OR = 0.58; 95% CI = 0.44-0.78; p < 0.0008). CONCLUSIONS: Caucasian patients with NMO and MS have a different HLA-DRB1 allelic distribution. DRB1*03 allele seems to contribute to NMO seropositivity. Multicenter collaborative efforts are needed to adequately address the genetic contribution to NMO susceptibility.
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Alelos , Genotipo , Antígenos HLA-DR/genética , Neuromielitis Óptica/genética , Neuromielitis Óptica/inmunología , Población Blanca/genética , Acuaporina 4/genética , Acuaporina 4/inmunología , Estudios de Cohortes , Predisposición Genética a la Enfermedad , Antígenos HLA-DR/inmunología , Cadenas HLA-DRB1 , Humanos , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , EspañaRESUMEN
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with presumed autoimmune origin, triggered by genetic and environmental risk factors. A recent genome-wide association study conducted on MS identified new biallelic markers outside the HLA (human leucocyte antigen) region involved in disease susceptibility: rs1109670 (DDEF2); rs1458175 (PDZRN4); rs1529316 and rs2049306 (CSMD1); rs16914086 (TBC1D2); rs1755289 (SH3GL2); rs1841770 (ZIC1); rs651477 (EN1); rs7607490 (TRIB2); rs397020 (C20orf46); rs908821 (SLC25A36); rs7672826 (MGC45800) and rs9523762 (GPC5). We aimed at replicating these top association signals in a Spanish cohort of 2863 MS patients and 2930 sex- and age-matched controls. Only rs9523762 mapping in the GPC5 gene was significantly associated (G allele, P=1.6 × 10(-5); odds ratio (95% confidence interval)=1.23 (1.12-1.36)), supporting a role for this proteoglycan in MS predisposition. The independent replication of association signals to validate data generated by genome-wide association scans is a first step in the effort to improve patient care.
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Estudio de Asociación del Genoma Completo , Esclerosis Múltiple/genética , Adulto , Alelos , Estudios de Casos y Controles , Estudios de Cohortes , Replicación del ADN/genética , Femenino , Frecuencia de los Genes/genética , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad , Antígenos HLA/genética , Humanos , Masculino , Esclerosis Múltiple/inmunología , EspañaRESUMEN
Genome-wide association studies (GWAS) have revealed that different diseases share susceptibility variants. Twelve single-nucleotide polymorphisms (SNPs) previously associated with different immune-mediated diseases in GWAS were genotyped in a Caucasian Spanish population of 2864 multiple sclerosis (MS) patients and 2930 controls. Three SNPs were found to be associated with MS: rs1678542 in KIF5A (P=0.001, odds ratio (OR)=1.13, 95% confidence interval (CI)=1.05-1.23); rs3184504 in SH2B3 (P=0.00001, OR=1.19, 95% CI=1.10-1.27) and rs763361 in CD226 (P=0.00007, OR=1.16, 95%CI=1.08-1.25). These variants have previously been associated with rheumatoid arthritis and type 1 diabetes. The SH2B3 polymorphism has additionally been associated with systemic lupus erythematosus. Our results, in addition to validating some of these loci as risk factors for MS, are consistent with shared genetic mechanisms underlying different immune-mediated diseases. These data may help to shape the contribution of each pathway to different disorders.
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Antígenos de Diferenciación de Linfocitos T/genética , Predisposición Genética a la Enfermedad/genética , Cinesinas/genética , Esclerosis Múltiple/genética , Proteínas/genética , Proteínas Adaptadoras Transductoras de Señales , Enfermedades Autoinmunes/genética , Estudios de Casos y Controles , Estudio de Asociación del Genoma Completo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Polimorfismo de Nucleótido Simple/genética , España , Población Blanca/genéticaRESUMEN
INTRODUCTION: The description of a highly sensitive and specific biomarker for neuromyelitis optica (NMO-IgG/aquaporin-4 antibody) extended the clinical spectrum of NMO to limited forms such as optic neuritis (ON) and longitudinally extensive myelitis (LEM). OBJECTIVE: To asses the sensitivity and specificity of our assay, and to describe the clinical characteristics of the patients who were tested for NMO-IgG. METHODS: NMO-IgG was analysed by immunohistochemistry and confirmed by assay on HEK cells transfected with aquaporin-4. The clinical information was obtained from forms filled in by the referring neurologists. RESULTS: A total of 580 samples from 518 patients were analysed from November 2005 to September 2008. Clinical information was available from 358 (68%) patients. All 33 (100%) positive cases were followed up. Twenty-eight of the 43 (65%) patients diagnosed with NMO by the revised criteria of 2006 were positive; the sensitivity was 62.5% when applying the same criteria, but discounting the criterion of NMO-IgG status, or 57% when applying the criteria of 1999. NMO-IgG was detected in 3 (13%) of the recurrent LEM and 2 (4%) of the recurrent ON. NMO-IgG was not detected in the remaining patients (96 with a final diagnosis of multiple sclerosis; 80 with myelitis; 28 with non-recurrent ON; and 33 other diagnosis). CONCLUSIONS: No false positive cases were found in this large and non-selected study. NMO-IgG positive cases were mostly associated with NMO, and only in a low percentage with recurrent ON or LEM.
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Acuaporina 4/inmunología , Autoanticuerpos/inmunología , Inmunoglobulina G/inmunología , Neuromielitis Óptica , Adolescente , Adulto , Edad de Inicio , Anciano , Acuaporina 4/genética , Biomarcadores/metabolismo , Línea Celular , Niño , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/patología , Neuromielitis Óptica/fisiopatología , Estudios Retrospectivos , Sensibilidad y Especificidad , Adulto JovenRESUMEN
BACKGROUND: Plasma exchange (PE) is used to treat severe episodes of CNS demyelination unresponsive to corticosteroids. Predictors of long-term response are not well known. METHODS: We retrospectively reviewed the medical records of 41 patients consecutively treated by PE between January 1995 and July 2007. The primary outcome was improvement at 6 months after PE defined as decrease of >or=1 point in the Expanded Disability Status Scale (EDSS) score for patients with EDSS
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Encéfalo/patología , Enfermedades Desmielinizantes/terapia , Intercambio Plasmático/estadística & datos numéricos , Médula Espinal/patología , Enfermedad Aguda/terapia , Adolescente , Adulto , Animales , Encéfalo/fisiopatología , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/fisiopatología , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Enfermedad del Virus de Marburg/patología , Enfermedad del Virus de Marburg/fisiopatología , Enfermedad del Virus de Marburg/terapia , Persona de Mediana Edad , Esclerosis Múltiple/patología , Esclerosis Múltiple/fisiopatología , Esclerosis Múltiple/terapia , Mielitis Transversa/patología , Mielitis Transversa/fisiopatología , Mielitis Transversa/terapia , Neuromielitis Óptica/patología , Neuromielitis Óptica/fisiopatología , Neuromielitis Óptica/terapia , Intercambio Plasmático/métodos , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Médula Espinal/fisiopatología , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: To report the frequency and type of antibodies against neuronal surface antigens (NSA-ab) in limbic encephalitis (LE). METHODS: Analysis of clinical features, neuropathologic findings, and detection of NSA-ab using immunochemistry on rat tissue and neuronal cultures in a series of 45 patients with paraneoplastic (23) or idiopathic (22) LE. RESULTS: NSA-ab were identified in 29 patients (64%; 12 paraneoplastic, 17 idiopathic). Thirteen patients had voltage-gated potassium channels (VGKC)-ab, 11 novel NSA (nNSA)-ab, and 5 NMDA receptor (NMDAR)-ab. nNSA-ab did not identify a common antigen and were more frequent in paraneoplastic than idiopathic LE (39% vs 9%; p = 0.03). When compared with VGKC-ab or NMDAR-ab, the nNSA associated more frequently with intraneuronal antibodies (11% vs 73%; p = 0.001). Of 12 patients (9 nNSA-ab, 2 VGKC-ab, 1 NMDAR-ab) with paraneoplastic LE and NSA-ab, concomitant intraneuronal antibodies occurred in 9 (75%). None of these 12 patients improved with immunotherapy. The autopsy of three of them showed neuronal loss, microgliosis, and cytotoxic T cell infiltrates in the hippocampus and amygdala. These findings were compatible with a T-cell mediated neuronal damage. In contrast, 13 of 17 (76%) patients with idiopathic LE and NSA-ab (8 VGKC-ab, 4 NMDAR-ab, 1 nNSA-ab) and 1 of 5 (20%) without antibodies had clinical improvement (p = 0.04). CONCLUSIONS: In paraneoplastic limbic encephalitis (LE), novel antibodies against neuronal surface antigens (nNSA-ab) occur frequently, coexist with antibodies against intracellular antigens, and these cases are refractory to immunotherapy. In idiopathic LE, the likelihood of improvement is significantly higher in patients with NSA-ab than in those without antibodies.
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Anticuerpos/sangre , Antígenos de Superficie/inmunología , Encefalitis Límbica/inmunología , Encefalitis Límbica/patología , Neuronas/inmunología , Síndromes Paraneoplásicos/inmunología , Anciano , Anciano de 80 o más Años , Animales , Anticuerpos/análisis , Encéfalo/inmunología , Encéfalo/patología , Células Cultivadas , Femenino , Humanos , Inmunohistoquímica , Inmunoterapia , Encefalitis Límbica/mortalidad , Encefalitis Límbica/terapia , Masculino , Persona de Mediana Edad , Ratas , Resultado del TratamientoRESUMEN
INTRODUCTION: Autologous hematopoietic stem cell transplantation (AHSCT) remains as an experimental treatment for severe forms of multiple sclerosis (MS). We describe the clinical outcome of 14 patients included in a protocol of AHSCT after a median follow-up period of 6 years. METHODS: 14 patients (5 relapsing-remitting and 9 secondary progressive) with a median number of relapses in the year before of 3 (1-7), Expanded Disability Status Scale (EDSS) of 6 (4.5-6.5) and decile of the multiple Sclerosis Severity Store (MSSS) 9 (7-10) were included. The procedure included carmustine, cyclophosphamide, antithymocyte globulin and T-cell depletion by CD34+ selection. RESULTS: The 4.5-year progression-free survival was 71%. The 6 year actuarial probability of progression-free survival was 62.5% and the disease activity-free survival of 7.1%. The median EDSS was 6 (4-8.5) and the MSSS 8 (5-10). Only 2 patients presented enhanced T1 lesions. No long-term complications related to the procedure were observed. CONCLUSION: AHSCT cannot be deemed a curative treatment but may cause prolonged stabilisation or change the aggressive course of the disease.
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Trasplante de Células Madre Hematopoyéticas , Esclerosis Múltiple/terapia , Trasplante Autólogo , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Humanos , Esclerosis Múltiple/patología , Esclerosis Múltiple/fisiopatología , Resultado del TratamientoRESUMEN
We describe three patients with relapsing-remitting multiple sclerosis who presented with paroxysmal dysarthria. In one patient, the symptoms were the only manifestation of an acute relapse. In the other two patients, the attacks appeared during the recovery of a brainstem relapse. All three patients had an acute lower midbrain lesion. The location was central in two patients and left paramedian in the other, and probably involving cerebellothalamocortical pathways. Treatment with carbamazepine was effective.