心血管领域-心律失常方向

METHODS:BACKGROUND:Several disease-modifying therapies (DMT) are being used in paediatric patients with multiple sclerosis (MS) despite the limited number of randomised controlled clinical trials leading to approved indication in children. OBJECTIVES:The aim of this study was to describe clinical characteristics of the Danish population of paediatric onset MS, and the patterns of DMT utilisation in patients who started treatment before the age of 18 years. METHODS:We conducted a nationwide population-based cohort study, including 347 children with paediatric-onset MS (<18 years). Subjects were followed until their 25th birthday or end of follow-up. RESULTS:Median age at onset and diagnosis was 15.8 years and 17.2, respectively. The majority of the children had monosymptomatic presentation. In total, 140 children received DMT before the age of 18. Most started treatment with a moderate-efficacy drug (90%) of which interferon-beta was the most used (80%). However, since oral treatments became available, these have increasingly been used. During follow-up, 108 children switched or discontinued DMT. Fingolimod was prescribed more frequently than natalizumab as escalation therapy. CONCLUSION:We present that use of DMT in POMS varies over the observed period concurrently with the availability of disease modifying drugs with progressive use of oral and high-efficacy therapies.

METHODS:BACKGROUND:Autologous hematopoietic stem cell transplantation (aHSCT) receives increasing attention as a treatment option for MS. However, as there are no randomized controlled trials comparing aHSCT to best medical treatment as yet, aHSCT is not generally advised and implemented as a treatment option for MS. Neurologists are increasingly faced with patients asking questions regarding aHSCT and seeking commercially offered aHSCT abroad. The aim of this study is to evaluate MS patients' knowledge and expectations of aHSCT and their actual and desired sources of information. METHODS:137 MS patients visiting the Amsterdam University Medical Center MS clinic, completed a self-developed questionnaire with items on disease history, knowledge about aHSCT, expectations of aHSCT, information sources and the role they assign to their neurologists. RESULTS:Fifty-four percent is considering aHSCT either now or in the future, especially those who are dissatisfied with current treatment, have a shorter disease duration (≤ 10 years) or are more disabled (EDSS > 3.5). Only 25% report to have sufficient knowledge about aHSCT. Patients mainly use potentially unreliable information sources such as the internet and television, although they prefer information from their neurologist. Half of the patients think aHSCT to be superior to highly effective DMT. Expectations of efficacy in patients interested in aHSCT are significantly higher than in patients not wanting to undergo aHSCT. Only about one third of patients are able to mention at least one side effect. CONCLUSION:Many MS patients are considering aHSCT as a treatment option, although they think that they are not well-informed regarding aHSCT. They prefer their neurologist as a source of information. Therefore, neurologists should pro-actively inform their patients about the potential benefits and risks of aHSCT to enable them to choose the best treatment option.

METHODS:BACKGROUND AND RATIONALE:An increase of prevalence and incidence of multiple sclerosis (MS) has been reported in several countries, especially taking into account a long-term evaluation. This increasing trend often reflects improved case identification and ascertainment due to the refinement of diagnostic criteria. The aim of this study was to update the prevalence rate of MS in Tuscany (central Italy) as of 2017, and to assess if there has been an increasing trend of prevalence in this Region considering a short period of analysis, from 2014 to 2017. METHODS:To capture prevalent cases, a case-finding algorithm based on administrative data, previously created and validated, was used. As data sources, we considered hospital discharge records, drug-dispensing records, disease-specific exemptions from copayment to health care, home and residential long-term care, and inhabitant registry. RESULTS:As of January 1, 2017, 7809 cases were identified, of which 69.4% were females and 30.6% were males. Considering temporal variation, an increasing trend was observed, with standardized rates rising from 189.2 in 2014 to 208.7 per 100,000 in 2017. CONCLUSIONS:Results confirm that prevalence increases every year, probably mainly due to the difference between incidence and mortality, resulting in an increasing trend. Moreover, administrative data may accurately identify MS patients in a routinary way and monitor this cohort along disease care pathways.

METHODS:BACKGROUND:Neuromyelitis optica spectrum disorder (NMOSD) is a rare demyelinating disease in need of more studies to determine effective treatment regimens. The rarity of the disorder, however, makes large randomized-controlled trials challenging. Validation of the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code for NMO could facilitate the use of large healthcare claims data for future research. We aimed 1) to determine the positive predictive value (PPV) of the ICD-9-CM code for NMO as well as evaluate case-finding algorithms for the identification of patients with NMO/NMOSD and 2) to compare the evaluation of and treatment for pediatric versus adult patients. METHODS:This was a multicenter retrospective cohort study of patients with ≥ 1 ICD-9 code for NMO seen at 3 pediatric and 2 adult United States medical centers from 2001-2016. Using a standardized data entry form, pediatric and adult neurologists and rheumatologists reviewed patients' medical records to determine whether patients fulfilled the 2006 criteria for NMO and/or the 2015 criteria for NMOSD in order to determine the positive predictive value (PPV) for the ICD-9-CM code. Demographic and clinical information was abstracted from patient medical records to ascertain variables then evaluated in case-based finding algorithms for further identification of patients with true NMO/NMOSD. We also evaluated differences in clinical characteristics between pediatric and adult patients using chi-squared or Fisher's exact tests, as appropriate, to assess for treatment variation. RESULTS:A single code for NMO had a PPV of 47% across all sites, with significant site variation (0-77%). The best case-finding algorithm included at least 5 codes as well as a documented hospitalization (PPV = =90% for children and PPV = 92% for adults). Children were more likely to be evaluated by a rheumatologist or ophthalmologist, undergo magnetic resonance imaging of the orbits, and receive immunosuppressive and biologic agents than their adult counterparts. Rituximab was administered similarly among the two groups. CONCLUSION:The ICD-9 code for neuromyelitis optica (NMO) is inaccurate for identification of NMO/NMOSD. Using case-finding algorithms increases the PPV. The initial diagnostic evaluation and treatment of NMOSD differs significantly between children and adults.

METHODS::We and others have previously demonstrated the potential for circulating exosome microRNAs to aid in disease diagnosis. In this study, we sought the possible utility of serum exosome microRNAs as biomarkers for disease activity in multiple sclerosis patients in response to fingolimod therapy. We studied patients with relapsing-remitting multiple sclerosis prior to and 6 months after treatment with fingolimod. Disease activity was determined using gadolinium-enhanced magnetic resonance imaging. Serum exosome microRNAs were profiled using next-generation sequencing. Data were analysed using univariate/multivariate modelling and machine learning to determine microRNA signatures with predictive utility. Accordingly, we identified 15 individual miRNAs that were differentially expressed in serum exosomes from post-treatment patients with active versus quiescent disease. The targets of these microRNAs clustered in ontologies related to the immune and nervous systems and signal transduction. While the power of individual microRNAs to predict disease status post-fingolimod was modest (average 77%, range 65 to 91%), several combinations of 2 or 3 miRNAs were able to distinguish active from quiescent disease with greater than 90% accuracy. Further stratification of patients identified additional microRNAs associated with stable remission, and a positive response to fingolimod in patients with active disease prior to treatment. Overall, these data underscore the value of serum exosome microRNA signatures as non-invasive biomarkers of disease in multiple sclerosis and suggest they may be used to predict response to fingolimod in future clinical practice. Additionally, these data suggest that fingolimod may have mechanisms of action beyond its known functions.

METHODS::Introduction: Multiple sclerosis (MS) as a progressive chronic disease of the central nervous system (CNS) is characterized by demyelination and axonal loss. Results of genetic studies and clinical trials have proved a key role for the immune system in the pathogenesis of MS. Glucocorticoids (GR) are regarded as potent therapeutic compounds for autoimmune and inflammatory diseases which act through their receptors encoded by Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1) gene. Meanwhile, the long non-coding RNA (lncRNA) growth arrest specific 5 (GAS5) interacts with GR through binding to the DNA-binding domain (DBD) region and reduces GR transcriptional activity.Methods: The purpose of our study was to evaluate the association between MS and polymorphisms within NR3C1 (rs6189/6190, rs56149945, rs41423247) and GAS5 (rs55829688) genes in 300 relapsing-remitting MS patients and 300 healthy subjects.Results: We demonstrated significant differences in distribution of genotype, allele and haplotype frequencies of rs6189, rs41423247 and rs55829688 between the study groups.Conclusion: Our data may suggest that rs6189, rs41423247 and rs55829688 are associated with the increased risk of MS development. Future studies are needed to verify our results in larger sample sizes and elaborate the underlying mechanisms for contribution of these variants in MS disease.

METHODS:BACKGROUND AND PURPOSE:Single-fibre electromyography (SF-EMG) is considered as the most sensitive test for the diagnosis of MG. However, previous studies had limitations, such as a retrospective design, non-consecutive sampling, incorporation bias or were performed in small or mixed populations. Our aims were to determine the diagnostic sensitivity and specificity of SF-EMG of the orbicularis oculi in OMG and the utility of this test in relation to patients' clinical presentation. MATERIALS AND METHODS:We studied 232 consecutive patients referred to the SF-EMG laboratory for a suspected OMG. Stimulated SF-EMG was performed on the orbicularis oculi muscle. RESULTS:OMG was diagnosed in 165 cases and other disorders (OD) in 67. SF-EMG showed a sensitivity of 0.79 (95% CI 0.73-0.85) and a specificity of 0.80 (95% CI 0.71-0.90). False negative results were associated with mild symptoms and with isolated diplopia. Comparison of the diagnostic yield among patients with different clinical presentations showed a similar diagnostic accuracy of SF-EMG in patients with ptosis and in patients with ptosis and diplopia, significantly higher than in patients with isolated diplopia (P < 0.0001). Twenty-two patients with OMG presenting with isolated ptosis or diplopia, who initially tested negative, were re-tested in relation to a worsening of their symptoms showing a positivisation in 91% of cases. CONCLUSIONS:SF-EMG on the orbicularis oculi muscle is very sensitive in patients with ptosis. In contrast, in patients with isolated diplopia SF-EMG does not exclude OMG. Therefore, the interpretation of the results of the test should take into account the patients' clinical presentation.

METHODS::We evaluated the results of microvascular decompression (MVD) in patients with trigeminal neuralgia (TN) and multiple sclerosis (MS) and we studied the role of several clinical and surgical factors as possible prognosticators of good outcome. To do this we performed, to our knowledge, the first literature review with a pooled analysis of data. A PubMed search of literature was conducted using the following terms: "microvascular decompression", "trigeminal neuralgia" and "multiple sclerosis". We screened 64 articles. Of them, 7 studies were eligible for this review. As outcome indicators we used the acute pain relief (APR) and the recurrence of pain. An APR was obtained in 71.42% and a recurrence of pain was reported in 26.00% of cases, respectively. At univariate analysis, younger age at surgery (p = 0.0419) and performing MVD as the first treatment (p = 0.0384) were associated to a higher probability of APR. The evidence of an MRI brainstem lesion related to the TN (p = 0.0482) was associated to a lower probability to obtain an APR after MVD. None of the evaluated factors affect the probability of recurrence of pain. At multivariate analysis the evidence of a brainstem MRI lesion related to the TN emerged as a negative prognosticator of APR (p = 0.0169). Our literature pooled analysis showed that MVD is effective in treating patients with MS-related TN. The evidence on MRI of a demyelinating plaque related to the TN is associated with a worse response to MVD. These data could suggest that MVD would be indicated mainly in patients without brainstem MRI lesions.

METHODS:BACKGROUND:The multi-drug resistance transporter ABCG2, a member of the ATP-binding cassette (ABC) transporter family, mediates the efflux of different immunotherapeutics used in multiple sclerosis (MS), e.g., teriflunomide (teri), cladribine, and mitoxantrone, across cell membranes and organelles. Hence, the modulation of ABCG2 activity could have potential therapeutic implications in MS. In this study, we aimed at investigating the functional impact of abcg2 modulation on teri-induced effects in vitro and in vivo. METHODS:T cells from C57BL/6 J wild-type (wt) and abcg2-knockout (KO) mice were treated with teri at different concentrations with/without specific abcg2-inhibitors (Ko143; Fumitremorgin C) and analyzed for intracellular teri concentration (HPLC; LS-MS/MS), T cell apoptosis (annexin V/PI), and proliferation (CSFE). Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6J by active immunization with MOG35-55/CFA. Teri (10 mg/kg body weight) was given orally once daily after individual disease onset. abcg2-mRNA expression (spinal cord, splenic T cells) was analyzed using qRT-PCR. RESULTS:In vitro, intracellular teri concentration in T cells was 2.5-fold higher in abcg2-KO mice than in wt mice. Teri-induced inhibition of T cell proliferation was two fold increased in abcg2-KO cells compared to wt cells. T cell apoptosis demonstrated analogous results with 3.1-fold increased apoptosis after pharmacological abcg2-inhibition in wt cells. abcg2-mRNA was differentially regulated during different phases of EAE within the central nervous system and peripheral organs. In vivo, at a dosage not efficacious in wt animals, teri treatment ameliorated clinical EAE in abcg2-KO mice which was accompanied by higher spinal cord tissue concentrations of teri. CONCLUSION:Functional relevance of abcg2 modulation on teri effects in vitro and in vivo warrants further investigation as a potential determinant of interindividual treatment response in MS, with potential implications for other immunotherapies.

METHODS:INTRODUCTION:Magnetic resonance imaging is recognized as the most important diagnostic test in the diagnosis of multiple sclerosis, differential diagnosis and evaluation of progression/therapeutic response. However, to make optimal use of magnetic resonance imaging in multiple sclerosis, the use of a standard, reproducible and comparable imaging protocol is of uttermost importance. In this context, the Portuguese Society of Neuroradiology and the Group of Studies of Multiple Sclerosis, after a joint discussion, appointed a committee of experts to create recommendations adapted to the national reality on the use of magnetic resonance imaging in multiple sclerosis. This document represents the second part of the first Portuguese consensus recommendations on the use of magnetic resonance imaging in multiple sclerosis in clinical practice. MATERIAL AND METHODS:The Portuguese Society of Neuroradiology and the Group of Studies of Multiple Sclerosis, after discussing the topic in national meetings and after a working group meeting held in Figueira da Foz, May 2017, appointed a committee of experts that have developed several standard protocols on the use of magnetic resonance imaging on multiple sclerosis by consensus. The document obtained was based on the best scientific evidence and expert opinion. Portuguese multiple sclerosis consultants and departments of neuroradiology scrutinized and reviewed the consensus paper; comments and suggestions were considered. Standardized strategies of magnetic resonance imaging referral in clinical practice for diagnosis and follow-up of multiple sclerosis were published in the first part of this paper. RESULTS:We provide magnetic resonance imaging acquisition protocols regarding multiple sclerosis diagnostic and monitoring and the information to be included in the report for application across Portuguese healthcare institutions. CONCLUSION:We hope that these first Portuguese magnetic resonance imaging guidelines will contribute to optimize multiple sclerosis management and improve patient care in Portugal. :Introdução: A ressonância magnética é considerada o exame complementar mais importante para o diagnóstico de esclerose múltipla, seus diagnósticos diferenciais e avaliação da sua progressão/resposta terapêutica. No entanto, para um uso ótimo desta ferramenta na esclerose múltipla, é essencial a aplicação de um protocolo de imagem padronizado, reprodutível e comparável. Neste contexto, o Grupo de Estudos de Esclerose Múltipla e a Sociedade Portuguesa de Neurorradiologia, após discussão conjunta, designaram um comité de peritos para a criação de recomendações adaptadas à realidade nacional sobre a utilização da ressonância magnética na esclerose múltipla. Este documento corresponde à segunda parte das primeiras recomendações de consenso portuguesas sobre a utilização da ressonância magnética na esclerose múltipla na prática clínica. Material e Métodos: O Grupo de Estudos de Esclerose Múltipla e a Sociedade Portuguesa de Neurorradiologia após discussão do tema em reuniões de âmbito nacional e de uma reunião do grupo de trabalho que teve lugar na Figueira da Foz em maio de 2017, designaram um comité de peritos que elaboraram por método de consenso protocolos padronizados sobre o uso da ressonância magnética na esclerose múltipla. O documento teve como base a melhor evidência científica e a opinião dos peritos. Posteriormente, o documento foi enviado para escrutínio à maioria dos responsáveis de consulta de esclerose múltipla e dos departamentos de neurorradiologia; tendo sido considerados os seus comentários e sugestões. As estratégias padronizadas de referenciação imagiológica na prática clínica para o diagnóstico e seguimento da esclerose múltipla foram publicadas na primeira parte deste artigo. Resultados: Neste artigo são propostos os protocolos de aquisição de ressonância magnética adequados para o diagnóstico e monitorização da esclerose múltipla, bem como a informação a constar do relatório imagiológico, tendo em vista a sua aplicação nas várias instituições de saúde portuguesas. Conclusão: Os autores esperam que estas primeiras orientações portuguesas sobre a utilização da ressonância magnética na esclerose múltipla na prática clínica contribuam para otimizar a gestão desta patologia e melhorar o tratamento destes doentes em Portugal.