Spectral-Domain Optical Coherence Tomography Findings in Neurofibromatosis Type 2

PURPOSE. Neurofibromatosis type 2 (NF2) is an autosomal-dominant disease, characterized by bilateral vestibular schwannomas, multiple central nervous system (CNS) tumors, skin tumors, and juvenile cataract. The present study assessed retinal abnormalities using spectraldomain optical coherence tomography (SD-OCT) in a case series of NF2 patients. METHODS. Nine NF2 patients from the neurofibromatosis outpatient reference center of the Federal University of Minas Gerais, in Brazil, were submitted to a complete anamnesis and a detailed ophthalmic evaluation, including SD-OCT, to detect retinal lesions. RESULTS. Of the nine NF2 patients evaluated, five had an early onset (<20 years) of NF2, and four patients had a late onset (>20 years) of symptoms. SD-OCT scans revealed retinal abnormalities in every patient with early onset (EOS) and in two patients with late onset (LOS) of the disease. In the EOS group, SD-OCT scans revealed flame-shaped epiretinal membranes (ERM) with peculiar characteristics in four eyes of three patients. Two patients had fine undulations of the inner retinal surface with a subtle ERM. Retinal hamartomas were present in four eyes of three patients with EOS; in two eyes, they were subclinical and were detected only by SD-OCT scans. In two patients with LOS and one patient with EOS, SD-OCT scans revealed retinal tufts of a nerve fiber layer. CONCLUSIONS. SD-OCT revealed ERM in most patients with NF2, therefore it may be a valuable exam for evaluating NF2 patients. Epiretinal membranes in NF2 has unique features, distinguishing it from idiopathic ERM or membranes associated with other diseases. We suggest that flame-shaped ERM seems to be specific for NF2 and that ERM can be considered as an important diagnostic sign of NF2

Tomografia de coerência óptica da retina contribui para o diagnóstico da neurofibromatose tipo 2

Exportado OPUSMade available in DSpace on 2019-08-13T17:20:30Z (GMT). No. of bitstreams: 1 disserat__o_vanessa_waisberg.pdf: 1868908 bytes, checksum: 5a6e6fbe1e2f4e52b47cbfbaa182bcb7 (MD5) Previous issue date: 6Tomografia de Coerência Óptica da Retina Contribui para o Diagnóstico da Neurofibromatose Tipo 2 Introdução: Neurofibromatose tipo 2 (NF2) é uma doença autossômica dominante caracterizada por schwannomas vestibulares bilaterais, múltiplos tumores do sistema nervoso central, tumores cutâneos e catarata juvenil. Um espectro bem definido de achados oculares tem sido especificamente associado à NF2. Os achados oftalmológicos descritos ainda precisam de estudos adicionais sobre sua prevalência, consequências e prognóstico para a doença. O presente estudo avaliou as anormalidades retinianas usando a tomografia de coerência óptica de domínio espectral (SD-OCT) em uma serie de pacientes com NF2. Esta é a maior série de olhos de pacientes com NF2 avaliada com SD-OCT da retina publicada até hoje e contribui com informações valiosas sobre a doença. Métodos: Nove pacientes com NF2 cadastrados no Centro de Referência de Neurofibromatoses da Universidade Federal de Minas Gerais passaram por uma avaliação clínica e oftalmológica detalhada, incluindo a SD-OCT para detectar lesões retinianas. Entre os nove pacientes com NF2, cinco tiveram início precoce dos sintomas (20 anos). Resultados: SD-OCT revelou anormalidades retinianas em todos os pacientes com NF2 de início precoce e em dois pacientes com NF2 de início tardio. No grupo de início precoce a SD-OCT revelou membrana epiretiniana (MER) em forma de chama de vela com características peculiares em quatro olhos de três pacientes. Dois pacientes tinham ondulações da superfície retiniana interna com MER discreta. Hamartomas de retina foram observados em quatro olhos de três pacientes com NF2 de início precoce; em dois olhos estes hamartomas eram subclínicos, detectados apenas com a SD-OCT. Em dois pacientes com NF2 de início tardio e um paciente com NF2 de início precoce a SD-OCT revelou tufos da camada de fibras nervosas da retina. Conclusão: SD-OCT revelou alterações retinianas na maioria dos pacientes com NF2 e é um exame valioso para avaliar estes pacientes. O exame foi bem tolerado por todos os pacientes com NF2, incluindo crianças e/ou pacientes com condições debilitantes. MER x associadas à NF2 possuem características que as diferenciam de MER idiopáticas ou associadas a outras doenças. Sugerimos que MER em forma de chama de vela parece ser específica da NF2 e que MER poderia ser incluída nos critérios diagnósticos da NF2.Retinal Optical Coherence Tomography Contributes To the Diagnosis of Neurofibromatosis Type 2 Background: Neurofibromatosis type 2 (NF2) is an autosomal-dominant disease, characterized by bilateral vestibular schwannomas, multiple central nervous system (CNS) tumors, skin tumors and juvenile cataract. A well-defined spectrum of ocular features has been specifically associated with NF2. More studies are needed on the prevalence, consequences and prognosis for the reported ophthalmologic findings. The present study evaluated retinal abnormalities using spectral domain optical coherence tomography (SD-OCT) in a case-series of NF2 patients. This is the largest series of NF2 eyes that were evaluated with retinal SD-OCT published to date, and it contributes valuable information about the disorder. Methods: Nine NF2 patients from the neurofibromatosis outpatient reference center of Federal University of Minas Gerais, Brazil underwent a detailed ophthalmic and medical history and a comprehensive ophthalmic evaluation, including SD-OCT, to detect retinal lesions. Of the nine NF2 patients evaluated, five had an early onset (20 years) of symptoms. Results: SD-OCT scans revealed retinal abnormalities in all patients with early onset (EOS) and in two patients with late onset (LOS) of the disease. In the EOS group, SD-OCT scans revealed flame-shaped epiretinal membranes (ERM) with peculiar characteristics in four eyes of three patients. Two patients had fine undulations of the inner retinal surface with a subtle ERM. Retinal hamartomas were present in four eyes of three patients with EOS; in two eyes, they were subclinical and were detected only by SD-OCT scans. In two patients with LOS and one patient with EOS, SD-OCT scans revealed retinal tufts of a nerve fiber layer. Conclusion: SD-OCT revealed retina and vitreous alterations in most patients with NF2, and it is a valuable exam for evaluating them. It was well tolerated for all patients with NF2, including children and/or patients with disabling conditions. ERM in NF2 has unique features, distinguishing it from idiopathic ERM or membranes associated xii with other diseases. We suggest that flame-shaped ERM seems to be specific for NF2 and that ERM could be included in the NF2 diagnostic criteria

Genetic and ocular alterations in neurofibromatosis type 2

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No. of bitstreams: 1 Tese Vanessa Waisberg .pdf: 12066791 bytes, checksum: 6ca89af6cb0e2710171017a502f5155f (MD5) Previous issue date: 2019-02-01RESUMO Alterações Genéticas e Oftalmológicas na Neurofibromatose Tipo 2 Introdução: Neurofibromatose tipo 2 (NF2) é uma doença autossômica dominante caracterizada por schwannomas vestibulares bilaterais, múltiplos tumores do sistema nervoso central, tumores cutâneos e catarata juvenil. A NF2 tem uma apresentação heterogênea e a gravidade da doença varia desde tumores isolados manifestados após a terceira década de vida a múltiplos tumores presentes na primeira infância. Um espectro bem definido de achados oculares tem sido especificamente associado à NF2. Existe grande variedade entre as mutações presentes no gene da NF2 causadoras da doença. Correlações fenótipo-genótipo foram observadas: as mutações tipo nonsense e frameshift estão associadas a quadros clínicos mais graves. Considerando a raridade e o potencial de associação entre os achados genéticos e oftalmológicos da NF2, o objetivo deste estudo foi descrever os achados moleculares e oftalmológicos em oito pacientes com diagnóstico clínico de NF2. Métodos: O exame oftalmológico foi realizado em 16 olhos de pacientes com NF2. O exame incluiu medida da acuidade visual, biomicroscopia, mapeamento de retina, retinografia colorida, retinografia com infravermelho e tomografia de coerência óptica de domínio espectral. A Análise molecular foi realizada por sequenciamento de exoma completo usando o DNA extraído das células mononucleares do sangue periférico de cada indivíduo. Resultados: Alterações oftalmológicas foram encontradas em todos os pacientes, e variaram desde alterações discretas, identificáveis somente através da OCT-SD, ao comprometimento ocular severo presente ao nascimento. Foram encontradas três categorias de mutações: mutações por interrupção prematura do códon (nonsense) em três pacientes, mutações tipo frameshift foram encontradas em dois pacientes e um paciente apresentou mutação tipo splice site. Três mutações novas foram identificadas. Conclusão: Um estudo descritivo sobre as características moleculares e oculares em pacientes com NF2 é de grande valor, uma vez que existem poucas publicações sobre este assunto. Os achados clínicos e genéticos incluem três novas mutações e acrescenta novas informações sobre as características oftalmológicas e moleculares da doença. Esses dados consistem em uma série de casos que podem ser usados em estudos adicionais sobre as correlações fenótipo-genótipo na NF2. Palavras-chave: Hamartoma, Mutação, Neurofibromatose tipo 2, membrana epirretiniana, retina, schwannoma vestibular, tomografia de coerência óptica.ABSTRACT Genetic and Ocular Alterations in Neurofibromatosis type 2 Background: Neurofibromatosis type 2 (NF2) is an autosomal-dominant disease, characterized by bilateral vestibular schwannomas, multiple central nervous system (CNS) tumors, skin tumors and juvenile cataract. A well-defined spectrum of ocular features has been specifically associated with NF2. NF2 has a heterogeneous presentation and the disease severity range widely; from a single tumor developed later in life to multiple tumors appearing in the first decade. NF2 disease-causing mutations includes nonsense, splice site and missense mutations. Genotype-phenotype correlations in NF2 have been proposed, with nonsense and frameshift mutations being associated with the most servere clinical presentation. Correlations between truncating mutations and ocular alterations have also been observed. The present study aims to describe ophthalmological and molecular findings in a series of eight patients with a clinical diagnosis of NF2. Methods: Eye examination was performed in 16 NF2 eyes and it included measurement of the visual acuity, biomicroscopy, dilated fundus examination, color fundus photography, infrared photography and spectral domain optical coherence tomography (SD-OCT). Molecular analysis was performed with whole-exome sequencing using DNA derived from peripheral blood mononuclear cells from each individual. Results: Ophthalmological features were observed in all patients, and range widely from subtle retinal alterations identified only by SD-OCT to severe ocular involvement present at birth. Three categories of mutations were found: three patients with premature termination codon (nonsense) mutations, two patients with frameshift mutations and one patient with splice site mutation. Three novel mutations were found. Conclusion: A descriptive study of ocular and molecular characteristics in NF2 patients is of significant value, since there are few previous reports on this subject. The clinical and genetic findings, including three novel mutations add new information on the understanding of genotype-phenotype correlations. Keywords: Epiretinal membrane, Hamartoma, Mutation, Neurofibromatosis type 2, optical coherence tomography, retina, vestibular schwannom

Neurofibromatosis: part 2 – clinical management

Part 1 of this guideline addressed the differential diagnosis of the neurofibromatoses (NF): neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH). NF shares some features such as the genetic origin of the neural tumors and cutaneous manifestations, and affects nearly 80 thousand Brazilians. Increasing scientific knowledge on NF has allowed better clinical management and reduced rate of complications and morbidity, resulting in higher quality of life for NF patients. Most medical doctors are able to perform NF diagnosis, but the wide range of clinical manifestations and the inability to predict the onset or severity of new features, consequences, or complications make NF management a real clinical challenge, requiring the support of different specialists for proper treatment and genetic counseling, especially in NF2 and SCH. The present text suggests guidelines for the clinical management of NF, with emphasis on NF1

Defibrotide Interferes With Several Steps of the Coagulation-Inflammation Cycle and Exhibits Therapeutic Potential to Treat Severe Malaria

Objective-The coagulation-inflammation cycle has been implicated as a critical component in malaria pathogenesis. Defibrotide (DF), a mixture of DNA aptamers, displays anticoagulant, anti-inflammatory, and endothelial cell (EC)-protective activities and has been successfully used to treat comatose children with veno-occlusive disease. DF was investigated here as a drug to treat cerebral malaria. Methods and Results-DF blocks tissue factor expression by ECs incubated with parasitized red blood cells and attenuates prothrombinase activity, platelet aggregation, and complement activation. In contrast, it does not affect nitric oxide bioavailability. We also demonstrated that Plasmodium falciparum glycosylphosphatidylinositol (Pf-GPI) induces tissue factor expression in ECs and cytokine production by dendritic cells. Notably, dendritic cells, known to modulate coagulation and inflammation systemically, were identified as a novel target for DF. Accordingly, DF inhibits Toll-like receptor ligand-dependent dendritic cells activation by a mechanism that is blocked by adenosine receptor antagonist (8-p-sulfophenyltheophylline) but not reproduced by synthetic poly-A, -C, -T, and -G. These results imply that aptameric sequences and adenosine receptor mediate dendritic cells responses to the drug. DF also prevents rosetting formation, red blood cells invasion by P. falciparum and abolishes oocysts development in Anopheles gambiae. In a murine model of cerebral malaria, DF affected parasitemia, decreased IFN-gamma levels, and ameliorated clinical score (day 5) with a trend for increased survival. Conclusion-Therapeutic use of DF in malaria is proposed. (Arterioscler Thromb Vasc Biol. 2012; 32:786-798.)Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of HealthDivision of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of HealthDFG, Bonn, Germany [SCHW 296/18-2]DFG, Bonn, GermanyBrazilian Malaria Network [MCT/CNPq/MS/SCTIE/DECIT/PRONEX 555648/2009-5]Brazilian Malaria NetworkNational Academy of Sciences of the Czech RepublicNational Academy of Sciences of the Czech Republic [Z60220518