Das descrições de Charcot à compreensão atual dos sintomas neuropsiquiátricos na esclerose múltipla

Os distúrbios neuropsiquiátricos na esclerose múltipla são conhecidos desde a descrição clínico-patológica original de Charcot no final do século XIX. Charcot nas últimas décadas de sua vida se envolveu no campo da neuropsiquiatria. Isso produziu uma batalha de escolas rivais na época que ainda ecoa até hoje. A intuição de Charcot, incluindo a linha de pensamento de Babinski, um de seus discípulos mais famosos, foi a teoria correta da conexão entre os transtornos do humor e muitas das doenças do sistema nervoso. A preocupação da Medicina em estabelecer uma relação entre transtornos do humor e doenças vem das idades antiga e média, com referências encontradas na doutrina hipocrática. No entanto, foi apenas na segunda metade do século XIX e início do século XX que, com as descobertas de Charcot essa discussão foi realizada de maneira estruturada, estabelecendo os fundamentos da neuropsiquiatria.Neuropsychiatric disorders in multiple sclerosis have been known since the original clinicopathological description by Charcot in the late nineteenth century. Charcot, in the last decades of his life, became involved in the field of neuropsychiatry. This produced a battle between rival schools in the era that still echoes to this day. Charcot’s intuition, including the line of thought of Babinski, one of his most famous disciples, was that there was a connection between mood disorders and many of the diseases of the nervous system. Medicine’s concern with establishing a relationship between mood disorders and disease stems from the ancient and middle ages with references found in the Hippocratic doctrine. However, it was only in the second half of the nineteenth and early twentieth century, with Charcot’s discoveries, that this discussion was established in a structured way, laying the foundations of neuropsychiatry

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

Alterations of the human gut microbiome in multiple sclerosis

The gut microbiome plays an important role in immune function and has been implicated in several autoimmune disorders. Here we use 16S rRNA sequencing to investigate the gut microbiome in subjects with multiple sclerosis (MS, n=60) and healthy controls (n=43). Microbiome alterations in MS include increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, and correlate with variations in the expression of genes involved in dendritic cell maturation, interferon signalling and NF-kB signalling pathways in circulating T cells and monocytes. Patients on disease-modifying treatment show increased abundances of Prevotella and Sutterella, and decreased Sarcina, compared with untreated patients. MS patients of a second cohort show elevated breath methane compared with controls, consistent with our observation of increased gut Methanobrevibacter in MS in the first cohort. Further study is required to assess whether the observed alterations in the gut microbiome play a role in, or are a consequence of, MS pathogenesis

Neuromyelitis optica spectrum disorders : study of the clinical, immunological and neuroimaging aspects

Orientadores: Leonilda Maria Barbosa dos Santos, Benito Pereira DamascenoTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: A Neuromielite óptica (NMO) é uma doença inflamatória e desmielinizante do SNC, de natureza autoimune, caracterizada por surtos graves de neurite óptica e mielite transversa, de evolução mais freqüente na forma recidivante-remitente, com pouca remissão dos déficits entre as crises, altamente incapacitante. A presença do anticorpo anti-aquaporina 4 (anti-AQP4) foi descrito em 73% a 91% dos pacientes com diagnóstico de NMO. Doenças autoimunes podem frequentemente ser desencadeadas após infecções por micro-organismos, como agentes virais. A NMO e a infecção pelo HTLV-1 possuem prevalência coincidentemente elevada em certas áreas do globo, como o Brasil. Com o objetivo de avaliar a associação do HTLV-1 com a NMO, foi pesquisada a presença de anti-AQP4 e anti-HTLV-1 em 34 pacientes com DENMO, 43 pacientes infectados com HTLV-1, assintomáticos ou com a doença mielopatia associada ao HTLV-1 (HAM/TSP) e 23 controles sadios. Nenhum paciente com DENMO apresentou sorologia positiva para HTLV-1. Nenhum paciente infectado pelo HTLV-1 apresentou soropositividade para anti-AQP4. 60% dos casos de DENMO foram positivos para anti-AQP4. Esses resultados sugerem que a mielopatia associada à variante aguda da HAM/TSP e aquela associada ao anticorpo anti-AQP4 são entidades clínicas distintas, e provalvemente, não relacionadas de forma patogênica ao HTLV-1 em nosso meio. O cérebro humano expressa amplamente AQP4, mas estudos anatomopatológicos e de neuroimagem não detectaram lesões corticais desmielinizantes ou infiltrados inflamatórios no DENMO. A fim de avaliar melhor a presença de alterações estruturais nas substâncias cinzenta e branca encefálicas no DENMO, foram estudados 34 pacientes por RNM de 3T e tomografia de coerência óptica retiniana pareados com controles sadios, divididos nas apresentações NMO, mielite transversa longitudinal extensa (MTLE) e neurite óptica (NO), além de soropositivos versus soronegativo para anti-AQP4 e 5 anos ou menos de doença versus mais de 5 anos de doença. Houve maior grau de atrofia retiniana nos grupos NMO e NO, além dos grupos anti-AQP4+ e mais de 5 anos de doença. Foi constatado maior grau de atrofia cortical cerebral e estruturas da substância branca nos grupos NMO e MTLE, anti-AQP4+ e mais de 5 anos de doença. A atrofia retiniana se correlacionou positivamente com a atrofia do lobo occipital. Esses dados sugerem que o DENMO está associado à atrofia de estruturas das substâncias cinzenta e branca cerebrais; que a atrofia não se limita apenas às áreas das vias sensorial, motora e visual, mas é mais difusa; que quanto maior o tempo de doença e a presença do anticorpo anti-AQP4, maior é o grau de atrofia cortical, configurando estes fatores, tempo e anti-AQP4+, como de pior prognóstico; e a correlação positiva entre atrofia da camada de fibras nervosas retinianas e atrofia pericalcarina, além da escala de incapacidade funcional expandida (EDSS), sugere que a degeneração neuronal retrógrada e/ou anterógrada do tipo Walleriana é um importante causador da atrofia cortical no DENMOAbstract: Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system (CNS) of putative autoimmune aetiology, which is characterized by severe attacks of myelitis and optic neuritis (ON). A relapsing course with rapid accumulation of neurological deficits with little or no remission is common. The NMO is autoimmune in nature and antibodies to Aquaporin 4 (AQP4) are associated with the development of the disease. AQP4 is the most common water channel protein of CNS; present in astrocytes processes, endothelium and piamater meninges. It predominates at some sites of the CNS, as optic nerve, brain stem and gray matter of medulla, the same sites of the usual inflammatory lesions. Autoimmune diseases may be triggered by microorganism infections and NMO and HTLV-1 infection have coincidentally high prevalence in certain areas of the world including Brazil. To study a possible relationship between these two diseases, we determined the seroprevalence of antibodies to AQP4 in 43 patients with HTLV-1 infection, asymptomatic or with HTLV-1 associated myelopathy (HAM/TSP) and that of HTLV-1 antibodies in patients with neuromyelitis optica spectrum disorders (NMOSD). AQP4ab positivity was found in 60% of NMOSD patients, but in none of the HAM/TSP patients and none of the asymptomatic HTLV-1 infected individuals. Conversely, all AQP4-Ab-positive NMOSD patients were negative for HTLV-1 antibodies. The results argue both against a role of antibodies to AQP4 in the pathogenesis of HAM/TSP and against an association between HTLV-1 infection and the development of AQP4-Ab. Moreover, the absence of HTLV-1 in all patients with NMOSD suggests that HTLV-1 is not a common trigger of acute attacks in patients with AQP4-Ab positive NMOSD in populations with high HTLV-1 seroprevalence. Although AQP4 is also expressed widely in the human brain cortex, beyond the common sites of lesions in NMO, recent studies have found no MRI or histopathological evidence for cortical demyelination. To investigate magnetic resonance imaging (MRI) patterns of gray matter (GM) and white matter (WM) abnormalities in patients with NMO and its incomplete forms, isolated longitudinally extensive transverse myelitis and optic neuritis, and to assess the prognostic impact of GM and WM abnormalities in these conditions, we performed both 3T high-resolution T1-weighted and diffusion tensor MRI in thirty-four patients with NMO spectrum disorders (NMOSD) and 34 matched healthy controls. Voxel-based morphometry (SPM8/MATLAB2012b), cortical analyses (Freesurfer), and diffusion tensor imaging analyses (TBSS-FSL) were used to investigate brain abnormalities. In addition, retinal nerve fiber layer was measured by means of optic coherence tomography (OCT). These analyses resulted in following findings: (1) NMOSD is associated with GM and WM atrophy, which encompasses more brain structures than the motor, sensory, and visual pathways; (2) this atrophy is more widespread in patients with NMO and LETM than in patients with ON; (3) the extent of GM atrophy correlates with disease duration, and (4) GM/WM atrophy in NMOSD is more pronounced in AQP4 antibody-seropositive than in -seronegative patients. Furthermore, it was demonstrated for the first time in NMOSD a correlation between RNFL atrophy and GM atrophy in the occipital lobes as assessed by OCT, indicating a role for retrograde degeneration in GM atrophy and suggesting that the extent of brain GM/WM atrophy may be of prognostic relevance in NMOSDDoutoradoNeurologiaDoutor em Ciências Médica

Multiple sclerosis

Orientador: Leonilda Maria Barbosa dos Santos, Benito Pereira DamascenoDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: A Esclerose Múltipla (EM) é uma doença primária do sistema nervoso central. Geralmente, expressa-se numa fase clínica de surto e remissão, mediada por lesões focais inflamatórias agudas na substância branca cerebral e medula espinhal, podendo evoluir para uma fase progressiva, mediada por perda axonal e neuronal. Paralelamente ao aumento do conhecimento sobre a participação dos linfócitos na execução da resposta imune, cresce a importância das células dendríticas na subseqüente regulação da resposta imune adquirida. O presente estudo teve como objetivo avaliar o efeito do tratamento com o interferon beta na produção de citocinas pelos linfócitos Th17 / Th1 no sangue dos pacientes com EM forma remitente recorrente (EMRR), comparando-os com grupo controle e estudar a concentração de células dendríticas plasmocitóides (pDCs) no líquido cefalorraquiano (LCR) de pacientes com EMRR nas fases aguda e de remissão da doença. Trinta e quatro pacientes, divididos em grupos tratados com interferonß e não tratados, e um grupo controle de 20 voluntários sadios, foram avaliados quanto a resposta de linfoproliferação de células mononucleares extraídas do sangue periférico e colocadas em cultura com estímulo específico e inespecífico, além do grau de produção de citocinas pró- e anti- inflamatória. Posteriormente, a concentração de pDCs foi mensurada no LCR e sangue periférico de pacientes em fase de surto e em fase remissão da EMRR, comparadas com pacientes com doenças não inflamatórias do sistema nervoso central, analisados por citometria de fluxo. Os resultados demonstraram que o tratamento com o IFN-ß diminui a resposta proliferativa fisiológica dos linfócitos T de pacientes em tratamento, e modifica o padrão de citocinas pró- (IFN-? e IL-17) e anti- inflamatória (IL-10) nos pacientes com EMRR. As pDCs estão aumentadas no líquor de pacientes em surto, quando comparada a fase de remissão, sem correspondência no sangue periférico, indicando uma provável migração seletivaAbstract: Multiple sclerosis (MS) is a primary disease of the central nervous system, clinically characterized by relapses mediated by acute inflammatory lesions in white matter. With time, the disease could evolve to a neurodegenerative phase, characterized by axonal loss. In parallel to the importance of T helpers lymphocytes in the genesis of disease, enhance the knowledge about the participation of dendritic cells in orchestrating the immune response. The objective of this study is to evaluate the effect of interferon beta therapy on the cytokine production of Th1 and Th17 subsets from MS patients, comparing with controls, and to study the plasmacytoid dendritic cells concentration in cerebrospinal fluid of MS patients in different phases, relapse and remitting, of disease. The proliferative response of lymphocytes from PBMC from thirty four patients divided in two groups, interferon beta therapy and no treatment, and a control group with twenty individuals were evaluated in culture with specific and non specific stimulation. After that, the level of pro and anti-inflammatory cytokine production were measure. In a second step, the pDCs concentrations were measured in CSF and PBMC of patients in different phases, comparing with patients with others non inflammatory diseases. The results showed that interferon beta therapy diminished the proliferative response of T lymphocytes compared with the non treated group and modify cytokine production of IFN-y, IL-17 and IL-10 in MS patients. The pDCs were increased in CSF in phase of relapse compared with remittion, with no corresponding increasing in PBMC, indicating a selective migrationMestradoNeurologiaMestre em Ciências Médica

Prognostic Indicators For Long-term Disability In Multiple Sclerosis Patients.

Daily practice is still faced with uncertainty in predicting the long-term disability of multiple sclerosis (MS). Most information comes from northern hemisphere cohorts, but in South America this information is scarce, and race, genetic and environmental factors could play an important role in the heterogeneity observed in disease outcomes. We evaluated 197 patients attending our MS Center gathering clinical and demographic information. Outcome measures analyzed were time from first clinical symptom to EDSS of 6, 7 and 8. For survival analysis we employed Cox regression models and the Kaplan-Meier method. Time to EDSS 6 was 25.83 years (95% CI 15.36-36.31), and 36.25 years (95% CI 20.72-51.78) for EDSS 7. Male sex was associated with a 4.63 and 4.69 fold increased risk to EDSS 6 and 7, respectively (p<0.001 and p=0.006). Motor and brainstem symptoms at onset were also associated with an 8.1 and 13.1 fold increased risk to EDSS 6, respectively (p=0.04 and p=0.01). The number of relapses in five and ten years of disease onset was associated with a slightly increased risk to EDSS 8 (1.28 and 1.19, respectively; p=0.032 and p=0.015). Male patients presenting with frequent relapses, especially those with motor and brainstem involvement, deserve close observation and should be cautiously monitored to early signs of treatment failure.32429-3