Longitudinal evaluation of brain damage with magnetic resonance imaging in multiple sclerosis patients and its relationship with clinical and immunological factors

Orientadores: Fernando Cendes, Leonilda Maria Barbosa dos SantosTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: A esclerose múltipla (EM) é uma doença inflamatória e desmielinizante do sistema nervoso central que afeta cerca de 2,5 milhões de pessoas em todo o mundo e implica em um importante impacto social e econômico para o estado, resultante de incapacidades funcionais sensitivo-motoras e cognitivas. Nas últimas décadas, o estudo e o entendimento da EM se beneficiaram dos avanços das técnicas de neuroimagem. A Ressonância Magnética (RM) tem sido usada para estudar tanto a história natural da doença quanto para monitorar a eficácia de tratamentos, mas a correlação dos achados da RM convencional com os dados clínicos ainda é insatisfatória. Com isso, tem surgido o interesse em outras técnicas de RM, entre elas a avaliação da substância cinzenta cerebral. Entretanto, apesar dos avanços em neuroimunologia e neuroimagem, ainda existem poucos dados que possam predizer a incapacidade em longo prazo. Com isso, nosso objetivo foi identificar fatores clínicos e de RM relacionados a uma pior evolução clínica em pacientes com EM. Inicialmente nós realizamos um levantamento dos dados de 197 pacientes acompanhados no ambulatório de EM do HC-UNICAMP, levando em conta informações clínicas e epidemiológicas e o tempo que cada paciente levou para atingir escores específicos de incapacidade. Nós observamos que o grupo levou 25,8 anos para atingir o EDSS de 6,0, mas que pacientes do sexo masculino, e principalmente aqueles com surtos frequentes nos primeiros anos e com envolvimento do tronco cerebral ou cerebelo apresentaram uma evolução pior. Posteriormente, estabelecemos um subgrupo menor de pacientes a fim de estudar o comportamento longitudinal da patologia cerebral e sua relação com a incapacidade clínica e cognitiva. Foram acompanhados, durante um período de 24 meses, 43 pacientes com EM forma remitente-recorrente e 29 indivíduos controles, submetidos a exame neurológico, neuropsicológico e RM cerebral. O desempenho nos testes clínicos e neuropsicológicos foi pior no grupo dos pacientes, e 44,2% deles foram classificados como tendo disfunção cognitiva. Um pior desempenho cognitivo estava associado à presença de atividade subclínica da doença na RM, com uma alta carga lesional cortical e com a atrofia do corpo caloso. Além disso, uma maior incapacidade clínica também estava relacionada com estas lesões corticais, tanto cerebrais quanto aquelas presentes no córtex cerebelar. Como a presença de atividade subclínica foi um indicador importante de disfunção cognitiva, foi avaliado em um subgrupo de 15 pacientes a produção de citocinas pró-inflamatórias comparando com os dados de RM. Aqueles pacientes com lesões ativas na RM apresentaram uma produção significativamente maior de citocinas pró-inflamatórias, 10 vezes maior de INF-? e 22 vezes maior de TNF-?. O grupo de 43 pacientes foi acompanhado longitudinalmente e no final de 24 meses a atrofia cortical foi de 2,57% e da substância cinzenta subcortical de 3,8%, ambos significativamente maiores que no grupo controle. A presença de atrofia do tálamo no início estava relacionada a um maior risco de disfunção cognitiva após dois anos. Além disso, a presença de uma alta carga de lesões corticais no início do estudo estava relacionada a um risco 5,14 vezes maior de incapacidade clínica após 24 meses. Pode-se concluir que a substância cinzenta, cortical e subcortical, está difusamente afetada nos pacientes com EM, e que este dano progride consideravelmente em um período de dois anos, com importante impacto clínico e cognitivoAbstract: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that affects about 2.5 million people worldwide. MS entails a significant economic impact due to both motor and cognitive functional impairments. In recent decades, the study and understanding of MS have benefited from advances in neuroimaging techniques. Magnetic resonance imaging (MRI) has been used to study both the natural history and to monitor the effectiveness of treatments, but the correlation of conventional MRI findings with clinical data is not yet fully satisfactory. Thus, there has been great interest in other MRI techniques, including the assessment of grey matter. Nevertheless, despite advances in neuroimmunology and neuroimaging, there are few data that can predict the long-term disability in MS patients. Therefore, our goal was to identify clinical and MRI factors related to a worse clinical outcome in patients with MS. Initially, we surveyed the data of 197 patients followed in the outpatient clinic of the MS center at UNICAMP University Hospital, gathering clinical and epidemiologic information and the time to achieve specific scores on EDSS disability scale. The median time from onset to the assignment of a disability score of 6 was 25.8 years, but male patients, especially those with frequent relapses in the first years of disease, and with involvement of the brainstem or cerebellum showed a worse outcome. Subsequently, we established a smaller subgroup of patients in order to study the longitudinal behavior of brain pathology as seen by MRI and its relationship to clinical and cognitive disability. We followed for a period of 24 months, 43 patients with relapsing-remitting MS and 29 healthy subjects, who underwent neurological examination, neuropsychological testing and brain MRI. At baseline, performance on clinical and neuropsychological tests was worse in the patients group, and 44.2% were classified as having cognitive dysfunction. Worse performance on neuropsychological battery was associated with the presence of subclinical MRI activity, with a high burden of cortical lesions and atrophy of the corpus callosum. In addition, worse clinical disability was also associated with these cortical lesions, both those in the brain as those present in the cerebellar cortex. As the presence of MRI subclinical disease activity was an important indicator of cognitive impairment, coupled with the fact that there are no strong biological markers so far, we assessed the production of proinflammatory cytokines in a subgroup of 15 patients and compared with MRI data. We found that patients with subclinical active MRI lesions had significantly higher production of proinflammatory cytokines, 10-fold greater in IFN-? and 22-fold in TNF-?. The group of 43 patients was followed longitudinally and after 24 months grey-matter atrophy was 2.57% in the cortex and 3.8% in subcortical structures, both rates significantly higher than in the control group. The presence of thalamus atrophy at the baseline was associated with an increased risk of cognitive dysfunction after 2 years. Furthermore, the presence of a high load of cortical lesions at baseline was related to a 5.14 fold increased risk of clinical disability after 24 months. It can be concluded that both cortical and subcortical grey matter are diffusely affected in MS patients, and that this damage progresses considerably over a period of two years, with important clinical and cognitive impactDoutoradoNeurologiaDoutor em Ciências Médica

[validation Of The Brazilian Version Of Mini-test Casi-s].

To determine CASI-S accuracy in the diagnosis of dementia. The Cognitive Abilities Screening Instrument - Short Form (CASI-S) was applied in 43 Alzheimer's disease (AD) patients and 74 normal controls. AD diagnosis was based on DSM-IV, NINCDS-ADRDA, and CAMDEX. CASI-S includes: registration, temporal orientation, verbal fluency (4-legged animals in 30s), and recall (3 words). Its maximum score is 33 points. A copy of 2 pentagons was added. ROC curve showed an accuracy of 0.87, with standard error of 0.032, and 95% confidence intervall between 0.795 and 0.925. The cut-off score for cognitive deficit was 23, with sensitivity of 76.7%, specificity 86.5%, positive likelihood ratio (LR) 5.68, and negative LR 0.27. The cut-off score for subjects 70 years or older was 20, with sensitivity of 71.4% and specificity 97.1%. CASI-S is a practical test, with high specificity, particularly in individuals above 70 years of age. The adding of the drawing test did not improve its accuracy.63416-2

Perspectiva da gestão do conhecimento e a educação de jovens e adultos: desafios e possibilidades

This article aims to identify the role of knowledge management in adult and youth education and school management practices that are correlated with knowledge management. The instruments used for data collection and analysis were the semi-structured interview and questionnaires. As a result, were identified practices compatible with the theoretical model of knowledge management, introducing using techniques and tools in order to effect improvements in educational devealopment.Key-words: adult and youth education, knowledge management, school management, innovative management of knowledge.Neste artigo objetiva-se identificar o papel que a gestão do conhecimento ocupa na educação de jovens e adultos e as práticas de gestão escolar que estão correlacionadas com as de gestão do conhecimento. Os instrumentos utilizados para coleta e análise dos dados foram à entrevista semiestruturada e a aplicação de questionário. Os resultados apontaram para a necessidade de consolidação de práticas compatíveis com o modelo teórico da gestão do conhecimento, apresentando a possibilidade de usar técnicas e ferramentas com o intuito de efetivar melhorias no desenvolvimento educativo.   Palavras-chave: educação de jovens e adultos, gestão do conhecimento, gestão escolar, gestão inovadora dos saberes

Aquaporin-4 Antibodies Are Not Related to HTLV-1\ud Associated Myelopathy

Introduction: The seroprevalence of human T-cell leukemia virus type 1 (HTLV-1) is very high among Brazilians (,1:200).\ud HTLV-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP) is the most common neurological complication of\ud HTLV-1 infection. HAM/TSP can present with an acute/subacute form of longitudinally extensive myelitis, which can be\ud confused with lesions seen in aquaporin-4 antibody (AQP4-Ab) positive neuromyelitis optica spectrum disorders (NMOSD)\ud on MRI. Moreover, clinical attacks in patients with NMOSD have been shown to be preceded by viral infections in around\ud 30% of cases.\ud Objective: To evaluate the frequency of AQP4-Ab in patients with HAM/TSP. To evaluate the frequency of HTLV-1 infection\ud in patients with NMOSD.\ud Patients and Methods: 23 Brazilian patients with HAM/TSP, 20 asymptomatic HTLV-1+ serostatus patients, and 34 with\ud NMOSD were tested for AQP4-Ab using a standardized recombinant cell based assay. In addition, all patients were tested for\ud HTLV-1 by ELISA and Western blotting.\ud Results: 20/34 NMOSD patients were positive for AQP4-Ab but none of the HAM/TSP patients and none of the\ud asymptomatic HTLV-1 infected individuals. Conversely, all AQP4-Ab-positive NMOSD patients were negative for HTLV-1\ud antibodies. One patient with HAM/TSP developed optic neuritis in addition to subacute LETM; this patient was AQP4-Ab\ud negative as well. Patients were found to be predominantly female and of African descent both in the NMOSD and in the\ud HAM/TSP group; Osame scale and expanded disability status scale scores did not differ significantly between the two\ud groups.\ud Conclusions: Our results argue both against a role of antibodies to AQP4 in the pathogenesis of HAM/TSP and against an\ud association between HTLV-1 infection and the development of AQP4-Ab. Moreover, the absence of HTLV-1 in all patients\ud with NMOSD suggests that HTLV-1 is not a common trigger of acute attacks in patients with AQP4-Ab positive NMOSD in\ud populations with high HTLV-1 seroprevalence.This study received financial support from the Brazilian government agencies FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo - www. fapesp.br/en) and CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - www.capes.gov.br). The work of S.J. and B.W. was supported by research grants from Bayer Schering Healthcare and from Merck Serono. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Plasmacytoid dendritic cells are increased in cerebrospinal fluid of untreated patients during multiple sclerosis relapse

The plasmacytoid dendritic cells (pDCs) express a high level of Toll-like receptor 9 (TLR-9), which recognizes viral DNA. Activated via TLR-9, pDCs also secrete large amounts of type I interferon which are involved either in stimulation or down regulation of immune response in multiple sclerosis (MS). In the present study, we determinate pDCs levels by flow cytometry in Cerebrospinal Fluid (CSF) and Peripheral Blood from MS patients in relapsing and in remitting phases of the disease, comparing with other non-inflammatory diseases (OND). We provide evidence that MS patients in relapse without any treatment have a significantly (p < 0.01) higher percentage of pDCs in CSF than do patients in remission or those with OND. No change in the percentage of pDCs was observed in the peripheral blood of any of these patients. The increase of pDCs in central nervous system during relapse may be explained either by a virus infection or a down regulatory process

Case report: Granzyme-B expression by T- and B- cells during severe AQP4-positive Neuromyelitis Optica spectrum disorder with fatal venous thromboembolism outcome

BackgroundThe expression of serine protease granzyme-B (GzmB) by circulating CD8+ T lymphocytes has been recently suggested as a biomarker for poor immunotherapy response and severe disability in patients with Neuromyelitis Optica spectrum disorders (NMOSD). In parallel, venous thromboembolism (VTE) has been reported mainly in NMOSD patients exhibiting transverse myelitis.Case presentationHere, we describe an Aquaporin-4 positive (AQP4-positive) NMOSD patient who showed short myelitis (SM) and experienced a fatal pulmonary thromboembolism/lower extremity deep vein thrombosis during anti-CD20 treatment. Flow cytometry analyses from the peripheral blood revealed an enhanced cytotoxic behavior through circulating CD8+GzmB+ T, CD4+GzmB+ T lymphocytes, and residual CD19+GzmB+ B cells.ConclusionsFatal VTE may be a rare outcome, particularly in patients exhibiting SM, and may share poorly understood immunological mechanisms with AQP4-positive NMOSD severity

Estructura de la semilla y desarrollo inicial de Byrsonima basiloba Juss. (Malpighiaceae)

Byrsonima basiloba Juss. is a fast growing shrub that produces edible and juicy fruits. This research studied the morphology and anatomy of seeds and seedlings. The hard endocarp was crested and triloculate, with one seed per locule. B. basiloba seed was composed of a testa and a tegmen with residual endosperm. The embryo was ivory, with long, foliaceous, circinate, anisophyllous cotyledons with disjointed apices. The embryonary axis was short, straight and occupied a small portion of the seed with short epicotyl, and radicle with a rudimentary root cap. In the seedlings, it was possible to differentiate the protoderm, procambium and ground meristem in the elongation zone. The differentiation process in this species occurred early in the embryo. Leaf primordia surrounded the shoot apical meristem, which contained a developing parenchyma, epidermis with trichomes, and the vascular system already partially differentiated, with xylem vessels with helical thickening. The stem/root transition region, which originated the xylopodium in the adult plant, was oblique to the stem axis. Cotyledons and eophylls were amphistomatic. The anatomical description can help with taxonomic identification of the species in the field, as well as to provide a guide to choosing explants for in vitro cultivation protocols.Byrsonima basiloba Juss. es un arbusto de rápido crecimiento que produce frutos comestibles y jugosos. Esta investigación estudió la morfología y anatomía de las semillas y plantas jóvenes de este arbusto. Su endocarpio duro contiene una semilla por lóculo. La semilla está compuesta por una testa y un tegumento con un endospermo residual. El embrión es de color marfil, con cotiledones largos circinados, anisófilos, foliáceas con ápices inconexos. El eje embrionario es corto, recto, con epicotilo corto y radícula, y con una tapa de raíz rudimentaria, y ocupa una pequeña porción de la semilla. En la plántula es posible diferenciar claramente la protoderma del procambium y del meristema primario. Inmediatamente por encima del promeristema se encuentran el parénquima cortical, la epidermis con pelo, y el cilindro vascular ya parcialmente diferenciado, así como los vasos del xilema con engrosamiento helicoidal, por lo que se puede concluir que la diferenciación de los tejidos de esta especie se produce muy temprano. La región de cuello, que se origina del xilopodium en la planta adulta, no muestra ningún cambio en el color, siendo oblicua al eje del vástago. Los cotiledones y eófilos son anfistomáticos. La descripción anatómica puede ayudar con la identificación taxonómica de las especies, como también proporcionar una guía para el futuro, en cuanto a protocolos de cultivo in vitro

A experiência da vida real com complicações cardiovasculares na primeira dose de fingolimode

Fingolimod is a new and efficient treatment for multiple sclerosis (MS). The drug administration requires special attention to the first dose, since cardiovascular adverse events can be observed during the initial six hours of fingolimod ingestion. The present study consisted of a review of cardiovascular data on 180 patients with MS receiving the first dose of fingolimod. The rate of bradycardia in these patients was higher than that observed in clinical trials with very strict inclusion criteria for patients. There were less than 10% of cases requiring special attention, but no fatal cases. All but one patient continued the treatment after this initial dose. This is the first report on real-life administration of fingolimod to Brazilian patients with MS, and one of the few studies with these characteristics in the world.Fingolimode é um tratamento novo e eficaz para esclerose múltipla (EM). A administração desta droga requer atenção especial para a primeira dose, uma vez que eventos adversos cardiovasculares podem ser observados nas seis horas iniciais da ingestão de fingolimode. O presente estudo consistiu de uma revisão de dados cardiovasculares de 180 pacientes com EM ao receberem a primeira dose de fingolimode. A taxa de bradicardia nestes pacientes foi maior do que aquele observada em estudos clínicos que tem critérios de inclusão muito rigorosos para seleção de pacientes. Menos de 10% dos casos necessitou de atenção especial, mas não houve casos fatais. Todos os pacientes exceto por um continuaram o tratamento após esta dose inicial. Este é o primeiro relato de dados de administração de fingolimode na vida real de pacientes brasileiros com EM, e um dos poucos trabalhos com estas características no mundo.Universidade Metropolitana de Santos Departamento de NeurologiaUniversidade Positivo Departamento de NeurologiaUniversidade Federal do Paraná Departamento de NeurologiaUniversidade Estadual de Campinas Departamento de NeurologiaUniversidade Federal de Juiz de Fora Departamento de NeurologiaHospital de Clínicas de Porto Alegre Departamento de NeurologiaPontifícia Universidade Católica Sorocaba Departamento de NeurologiaClínica Holus MedServiceHospital Beneficência Portuguesa de São Paulo Departamento de NeurologiaCentro Hospitalar Unimed Departamento de NeurologiaUniversidade Federal Fluminense Departamento de NeurologiaUniversidade Federal de São Paulo (UNIFESP) Departamento de NeurologiaHospital de Base do Distrito Federal Departamento de NeurologiaInstituto de Neurologia de Curitiba Departamento de NeurologiaUNIFESP, Depto. de NeurologiaSciEL

The Real-life Experience With Cardiovascular Complications In The First Dose Of Fingolimod For Multiple Sclerosis.

Fingolimod is a new and efficient treatment for multiple sclerosis (MS). The drug administration requires special attention to the first dose, since cardiovascular adverse events can be observed during the initial six hours of fingolimod ingestion. The present study consisted of a review of cardiovascular data on 180 patients with MS receiving the first dose of fingolimod. The rate of bradycardia in these patients was higher than that observed in clinical trials with very strict inclusion criteria for patients. There were less than 10% of cases requiring special attention, but no fatal cases. All but one patient continued the treatment after this initial dose. This is the first report on real-life administration of fingolimod to Brazilian patients with MS, and one of the few studies with these characteristics in the world.72712-

Segurança na mudança direta de natalizumabe para fingolimode em um grupo de pacientes com esclerose múltipla e positivos para JCV

To assess safety of the switch between natalizumab and fingolimod without a washout period. Methods Prospective data on 25 JCV positive patients who underwent this medication switch were collected and analyzed. Results After a median period of nine months from the medication switch, there were no safety issues to report. The patients had good disease control and no adverse events were reported. Conclusion Washout may not be necessary in daily practice when switching from natalizumab to fingolimod. Expertise on multiple sclerosis management, however, is essential for drug switching748650652Avaliar a segurança na mudança entre natalizumabe e fingolimode sem período de washout. Métodos Dados prospectivos de 25 pacientes positivos para vírus JC que tiveram sua medicação modificada foram coletados e analisados. Resultados Após uma mediana de nove meses da troca de medicação, não havia aspectos de segurança a relatar. Os pacientes estavam com bom controle da doença e não foram relatados eventos adversos. Conclusão Washout pode não ser necessário na prática diária para a mudança entre natalizumabe e fingolimode. No entanto, expertise no manejo de esclerose múltipla é essencial para esta troca entre medicaçõe