Orientador: Denise Pontes Cavalcanti / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-22T09:53:23Z (GMT). No. of bitstreams: 1 Moreno_CarolinaAraujo_M.pdf: 4072523 bytes, checksum: 09921eee06d7c1098048c98a3f891b33 (MD5) Previous issue date: 2013 / Resumo: A hidropisia fetal não-imune (HFNI) é causada por um grupo heterogêneo de condições e atualmente corresponde à maior parte dos casos de hidropisia fetal. Em função da ampla diversidade etiopatogênica, a investigação dos casos de HFNI constitui um desafio diagnóstico. Esse estudo teve como objetivo a avaliação prospectiva e sistemática de uma série de casos de HFNI a partir de um protocolo de investigação ampliado, que incluiu a pesquisa de doenças metabólicas. O presente estudo também incluiu a revisão dos casos de HFNI registrados previamente pelo Programa de Genética Perinatal na maternidade da Unicamp. Durante aproximadamente dois anos (2010-2012), foram identificados 53 casos de HFNI. Nesse período, ocorreram 6.129 nascimentos na maternidade local, com registro de HFNI em 37 recém-nascidos, conferindo uma prevalência de 60 por 10.000 nascimentos, valor maior do que o observado no período anterior ao estudo (1987 a 2009). Para o restante da análise, quatro casos foram excluídos devido à impossibilidade de estudá-los adequadamente. A maioria dos hidrópicos nasceu pré-termo (43 - 73,5%). Houve registro de 23 nativivos (47%), 10 óbitos no período neonatal e 26 óbitos durante a gestação (53%), resultado em uma mortalidade geral (pré-natal e neonatal) de 73,4%. A hidropisia foi identificada no pré-natal na maioria dos casos (44 - 89,8%) e, apesar da condição ser comumente associada a mau prognóstico, em três pacientes (6,1%) houve resolução completa e espontânea da hidropisia durante a gestação. Os principais grupos diagnósticos encontrados foram: anomalias cromossômicas (17 casos - 34,7%), quadros sindrômicos (16,4% - oito casos), cardiopatias e infecções congênitas (8,2% - quatro casos cada). Os erros inatos do metabolismo (EIM) corresponderam a 6,1% da amostra (três casos de doenças de depósito lisossômico). Três casos (6,1%) foram classificados como idiopáticos. Comparando os diagnósticos da casuística prospectiva com aqueles observados no período 1987-2009, observou-se que os grupos diagnósticos mais frequentes, ou seja, anomalias cromossômicas, quadros sindrômicos e cardiopatias, foram os mesmos. No entanto, algumas diferenças foram observadas na casuística prospectiva, como a frequência maior de anomalias cromossômicas e de EIM, que podem ser explicadas respectivamente pela inclusão de abortos e pesquisa sistemática de doenças metabólicas. Por outro lado, a menor frequência do grupo de idiopáticos foi decorrente da ampliação do protocolo de investigação e da eliminação de casos inadequadamente estudados. Ressalta-se também que a frequência de EIM registrada no trabalho prospectivo (6%) foi superior à usualmente descrita na literatura e provavelmente aproxima-se da frequência real das doenças metabólicas em HFNI, justificando desse modo a pesquisa das mesmas na investigação de hidrópicos de causa não-imune após exclusão das condições mais comuns, como as anomalias cromossômicas, cardiopatias isoladas, infecções congênitas e síndromes conhecidas. Sendo assim, observou-se que o protocolo de investigação proposto permitiu o diagnóstico clínico-etiológico ou patogênico de mais de 90% dos casos, evidenciando que uma avaliação ampla e sistemática é capaz de identificar a maior parte dos fatores etiopatogênicos envolvidos na HFNI / Abstract: Non-immune hydrops fetalis (NIHF) is caused by a hetereogenous group of conditions, currently accounting for the most cases of hydrops fetalis. Because of the wide etiopathogenic diversity, the investigation of NIHF cases constitutes a real diagnostic challenge. This study aimed to evaluate prospectively and systematically a series of NIHF cases from an expanded research protocol including the investigation of metabolic diseases. The present study also aimed to revise the NIHF cases previously recorded by Perinatal Genetics Program (PGP) in the maternity hospital of Unicamp. During approximately two years (2010-2012), 53 cases were identified. In this period, among 6,129 births that occurred in our hospital, NIHF was identified in 37 newborns, given a birth prevalence of 60 per 10,000, higher than that was observed in the previous period - 23:10,000 (1987-2009). For purpose of all other analysis, four of the 53 cases evaluated had to be excluded due to inability to assess them correctly. Most hydropic individuals were born preterm (43 - 73.5%). Twenty-three patients (47%) were live births, 10 of them died before hospital discharge; and 26 (53%) died in the prenatal period, given an overall mortality of 73.4%. The hydrops were identified in prenatal period in most cases (44 - 89.8%), and despite being commonly associated with poor prognosis, three cases (6.1%) had complete and spontaneous resolution of hydrops during pregnancy. The main diagnostic groups were chromosomal abnormalities (17 - 34.7%), syndromic (8 - 16.4%), isolated heart defects (4 - 8.2%), and congenital infections (4 - 8.2%). Inborn errors of metabolism (IEM) occurred in three cases (6.1%), all represented by lysosomal storage diseases. Three cases (6.1%) were classified as idiopathic. The comparison of these diagnostic groups with those found during the retrospective period (1987-2009) showed that the most frequent groups, i.e. chromosomal abnormalities, syndromic and isolated cardiopathy, were the same. However, some differences were observed in the prospective series. For instance, the higher frequency of chromosomal abnormalities and IEM can be respectively explained because of the inclusion of abortions and due to systematic investigation of metabolic diseases. The lower frequency of idiopathic group, by the other hand, can be regarded as close related, first, to the expanded investigation and, second, to the exclusion of cases poorly studied. It is noteworthy that the recorded IEM frequency in the present prospective series (6%) was higher than the usually reported in the literature and seems to be more realistic, thus, justifying the inclusion of a systematic approach of these conditions in NIHF. This investigation, however, should be initiated after the exclusion of the more common causes, i.e., chromosomal abnormalities, isolated cardiopathy, congenital infections and known syndromes. In conclusion, the proposed investigation protocol allowed the clinical-etiological or pathogenic diagnosis in more than 90% of the cases, suggesting that the most etiopathogenic factors related to NIHF can be identified if a wide and systematic evaluation is performed / Mestrado / Genetica Medica / Mestra em Ciências Médicas

1er objectif : Mieux caractériser les surdités neuro-sensoriellesNous avons démontré dans ce travail de thèse que nous étions capablesd’individualiser le saccule et l’utricule pour faire le diagnostic d’hydropscompartiment par compartiment. L’intérêt repose sur les propriétés biomecaniquesdifferentes de ces deux structures notamment en terme decompliance. En isolant l’hydrops sacculaire, nous avons démontré qu’ilétait lié à la présence de surdité neurosensorielle pour les patients avecune Maladie de Ménière mais également qu’il pouvait être détecté pourdes patients présentant des surdités isolées sur les basses fréquences, quine sont habituellement pas classées comme porteurs cliniquement de laMaladie de Ménière. Nous avons mis au point une séquence 3D-FLAIRutilisable en pratique clinique pour la détection d’hydrops sacculaire,utilisable quelque soit le champ magnétique et le constructeur.Pour les patients porteurs de schwannomes cochléo-vestibulaires, nousavons démontré que le degré de perte auditive était cette fois liée à laprésence d’un hydrops utriculaire. Ce diagnostic peut être porté sansinjection de produit de contraste puisque la présence d’un schwannomeobstructif entraine mécaniquement une augmentation du taux protidiquedans la périlymphe et donc une discrimination périlymphe/endolymphesur les séquences T2 en echo de gradient.En revisitant l’anatomie histologique avec la remnographie, nous avonsproposé une théorie bi-compartimentale pour les échanges endolymphe/liquidecéphalorachidien ; supposant que l’utricule et le saccule joue un rôle detampon entre le cerveau et la cochlée. En cas d’obstruction mécanique,au niveau de l’aqueduc du vestibule pour la maladie de Ménière et dunerf cochléo-vestibulaire pour les tumeurs du conduit auditif interne ; letampon ne joue plus son rôle. Surviennent alors des lésions cellulaires desstéréocils de la cochlée et la surdité attenante.2ème objectif : Mieux caractériser les altérations structurelles neuronalesrétro-cochléaires des surdités neurosensoriellesDu point de vue biophysique de l’IRM, l’étude du nerf cochléaire possèdel’avantage de posséder une structure simple essentiellement composéed’une seule population de fibre à modéliser par voxel, au prix d’une régiond’étude compliquée intricant de l’os, du liquide et de l’air dans l’ostemporal. Nous avons donc commencer par développer un algorithmede pré-traitement des données de diffusion qui utilise toutes les toolboxrécentes pour corriger les artéfacts de susceptibilité magnétique, de mouvements, de champ B0 et B1, les courants de Foucaults, les arrtéfactsde Gibbs. Nous avons utilisée une séquence de Diffusion optimisée pourêtre utilisable en pratique clinique en cas de mouvements des patients,construite par bloc de 15 directions.Nous avons ensuite appris à utiliser des biomarqueurs quantitatifs, notammentle coefficient de diffusion apparent des fibres, directement issusdu signal de Diffusion dont nous avons préalablement testé la fiabilitésur des données de diffusion multi-compartimentale de haute qualité auniveau de l’encéphale. Nous avons ensuite proposée une méthode originaled’extraction de l’information des voxels du nerf cochléaire appelée spectralclustering pour obtenir ce coefficient de densité des fibres de façon robusteau niveau de notre population témoin. Enfin, nous avons implémenté unalgorithme de Manifold Learning pour l’analyse de ce signal de diffusion,qui surpasse les biomarqueurs scalaires en confrontation à des modèlespathologiques auditifs en tenant compte de l’hétérogénité du signal dediffusion dans un cluster. Nous avons ainsi démontré que les patientsporteurs de la maladie de Ménière présentaient une augmentation de ladensité de fibre, en faisant de particulier bosn candidats à l’implantationcochléaire, en accord avec les premières études cliniques fonctionnellessur le sujet. / Sensorineural hearing loss (SNHL) is a common functional disorder in humans. Besides clinical investigations, magnetic resonance imaging (MRI) is the modality of choice to explore the central auditory pathways. Indeed, new MRI sequences and postprocessing methods have revolutionized our understanding of inner ear and brain disorders.The inner ear is the organ of sound detection and balance. Within the inner ear, there are two distinct compartments filled with endolymph and perilymph.The accumulation of endolymph fluid is called “endolymphatic hydrops”. Endolymphatic hydrops may occur as a consequence of a variety of disorders, including Meniere’s Disease, immune-mediated diseases or internal auditory canal tumors.Previous classification for grading the amount of endolymph liquid using MRI has proposed a global semi-quantitative evaluation, without distinguishing the utricle from the saccule, whose biomechanical properties are different in terms of compliance.This work had two main objectives: 1°) to better characterize the role of endolymphatic hydrops in SNHL occurrence; 2°) to study secondary auditory pathways alterations.Part 1: Understanding the role and pathophysiology of endolymphatic hydrops in SNHL occurrence.Endolymphatic hydrops can be identified using MRI, acquired 4-6-hours after injection of contrast media. This work has demonstrated the feasibility and improved this technique in a clinical setting.Using optimized morphological sequences, we were able to illustrate inner ear microanatomy based on temporal bone dissection, and to distinguish the saccule and the utricle.In accordance with a multi-compartmental model, we observed that the saccular hydrops was a specific biomarker of low-tone SNHL in the context of typical or atypical forms of Meniere’s Disease. In addition, utricular hydrops was linked to the degree of hearing loss in patients with schwannomas. We raise the hypothesis that both saccule and utricle compartment play the role of a buffer in endolymph reabsorption. When their compliance is overstretched, inner ear endolymph regulation fails, subsequently leading to cochlear lesions such as loss of the shorter stereocilia of the hair cells, as suggested by experimental animal modelsThus, we were able to prove the high prevalence of endolymphatic hydrops in patients with SNHL.Part 2: Development of new imaging biomarkers to study the central auditory pathways.Diffusion-Weighted Imaging play a crucial role because it can help to assess the intracellular compartment by displaying the Brownian movements of water molecules. In the context of cochlear lesions, anterograde axonal degeneration has only been demonstrated in animal models. In the context of retrocochlear lesions, no MRI sequences have previously showed efficiency in distinguishing the cochlear from the facial nerve. This is crucial for safe surgery procedure.We have designed optimized postprocessing tools to explore SNHL patients with High-Angular Resolution DWI acquisition. We have included in the clinical setting software tools for B0 and B1 bias field artifacts’ correction, Denoising process, Gibbs artifacts’ correction, Susceptibility and Eddy Current artifacts management.The ultimate goal was to properly study the Fiber Orientation Distribution (FOD) along the auditory pathways in case-controlled studies, using top-of-the-art methods of fixels analysis and a newly developed toolbox with Machine Learning analysis of the Diffusion signal.We have studied reproducibility of these two methods on Multi-Shell Diffusion gradient scheme by test-retest procedure. We have then used the fixel method to seek for auditory pathways alterations in Meniere’s Disease and Machine Learning automatic analyses to extract Inner Auditory Canal cranial nerves.Thus, we have developed a new method for cranial nerves’ tractography using FOD spectral clustering, efficient in terms of computer requirement and in tumor condition.