ORA waveform in normal and keratoconic eyes Fine-needle aspiration ...

issn 0004-2749 versão impressa

Arquivos brasileiros

publicação oficial do conselho brasileiro de oftalmologia MARÇO/ABRIL 2013

d e

76 02

ORA waveform in normal and keratoconic eyes Fine-needle aspiration biopsy of melanocytic uveal tumors Light-induced retinal injury of mesenchymal stem cells Visual acuity and refraction of children in Paraguay Magnocellular pathway abnormalities in schizophrenia indexada nas bases de dados

medline | embase | isi | SciELO

© Johnson & Johnson do Brasil Indústria E Comércio de Produtos Para Saúde Ltda. ABRIL/2013

1ª

Senofilcon A - 1ACUVUE® OASYS® com HYDRACLEAR® PLUS: Reg.ANVISA 80148620045, 2ACUVUE® OASYS® para ASTIGMATISMO com HYDRACLEAR® PLUS: Reg.ANVISA 80148620054, 3ACUVUE® OASYS® com HYDRACLEAR® PLUS (Bandage): Reg.ANVISA 80148620058, Galyfilcon A - 4ACUVUE® ADVANCE® com HYDRACLEAR®: Reg.ANVISA 80148620026, Etafilcon A - 5ACUVUE® 2: Reg. ANVISA 80148620019, 61-DAY ACUVUE® MOIST®: Reg.ANVISA 80148620052 , 71-DAY ACUVUE® MOIST® para ASTIGMATISMO: Reg.ANVISA 80148620064 , 8ACUVUE® 2 COLOURS: Reg.ANVISA 80148620013, 9ACUVUE® CLEAR: Reg.ANVISA 80148620021 e 10ACUVUE® BIFOCAL: Reg.ANVISA 80148620016. Caixas com 306,7, 61,2,3,4,5,8,9,10 ou 28 lentes de contato (LC). Indicações: LC Esféricas1,4,5,6,9: Miopia, hipermetropia (presbiopia em regime de monovisão) afácica ou não afácica. LC Esféricas Coloridas8: Miopia, hipermetropia (presbiopia em regime de monovisão) afácica ou não afácica. LC Bifocais10: Presbiopia afácica ou não afácica associada ou não a miopia ou hipermetropia. LC Tóricas2,7: Astigmatismo afácico ou não afácico associado ou não a miopia ou hipermetropia. LC Terapêuticas3: As lentes de contato podem ser prescritas, em determinadas condições ou doenças oculares, como lentes de proteção para a córnea, a fim de aliviar o desconforto e servir como uma cobertura de proteção. O médico Oftalmologista informará se o usuário apresenta essa condição, podendo prescrever medicações adicionais ou programação de substituição para a condição específica. O usuário nunca deve tratar qualquer condição, usando lentes de contato ou medicação para os olhos, sem primeiro consultar o médico Oftalmologista. Contra-Indicações: Qualquer inflamação, infecção, doença ocular, lesão ou anormalidade que afete a córnea, conjuntiva ou pálpebras. Qualquer doença sistêmica que venha a afetar os olhos ou ser agravada pelo uso de LC; reações alérgicas das superfícies oculares ou anexas. Qualquer infecção ativa da córnea; olhos vermelhos ou irritados. Precauções e Advertências: Problemas oculares, incluindo úlceras de córnea, podem se desenvolver rapidamente e causar perda da visão. Em caso de desconforto visual, lacrimejamento excessivo, visão alterada, vermelhidão nos olhos ou outros problemas, retirar imediatamente as LC e contatar o Oftalmologista. Usuários de LC devem consultar seu Oftalmologista regularmente. Não usar o produto se a embalagem estéril de plástico estiver aberta ou danificada. Reações Adversas: Ardor, coceira ou sensação de pontada nos olhos. Desconforto quando a LC for colocada pela primeira vez. Sensação de que há algo no olho (corpo estranho, área raspada). Lacrimejamento excessivo, secreções oculares incomuns ou vermelhidão dos olhos. Acuidade visual deficiente, visão embaçada, arco-íris ou halos ao redor de objetos, fotofobia, ou olho seco, podem ocorrer caso as LC sejam usadas continuamente ou por tempo excessivamente longo. Se o usuário relatar algum problema, deve RETIRAR IMEDIATAMENTE AS LENTES e contatar o Oftalmologista. Posologia: Uso prolongado1,2,3,5,8,10– Um a 7 dias/6 noites de uso contínuo, inclusive durante o sono. Uso diário1,2,3,4,5,8,9,10 – Períodos inferiores a um dia de uso enquanto acordado. Descartáveis diárias6,7 – uso único. VENDA SOB PRESCRIÇÃO MÉDICA REFRACIONAL (LC com grau), VENDA SOB PRESCRIÇÃO MÉDICA (LC terapêutica plana), UTILIZAÇÃO SUJEITA À PRESCRIÇÃO MÉDICA (LC colorida plana). Johnson & Johnson Industrial Ltda. Rod. Pres. Dutra, Km 154 - S. J. dos Campos, SP. CNPJ: 59.748.988/0001-14. Resp. Téc.: Evelise S. Godoy – CRQ No. 04345341. Mais informações sobre uso e cuidados de manutenção e segurança, fale com seu Oftalmologista, ligue para Central de Relacionamento com o Consumidor: 0800-7274040, acesse www.acuvue.com.br ou consulte o Guia de Instruções ao Usuário. A PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO. 1. OS BORN, K.; VEYS, J. A new silicone hydrogel lens for contact lens-related dryeness. Part 1 - Material Properties. Optician, 2005; 6004(229): 39-41.

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Melhore a visão dos seus pacientes. As lentes Transitions se adaptam automaticamente aos ambientes, permitindo que só a quantidade certa de luminosidade chegue aos olhos. As lentes são transparentes em ambientes internos e escuras em ambientes com incidência de raios UV. Ofereça aos seus pacientes a oportunidade de ver a vida da maneira que ela deve ser vista. Ou, quem sabe, até melhor. Veja o melhor da vida em transitions.com.br.

Transitions e o “Swirl” são marcas registradas da Transitions Optical, Inc. ©2013 Transitions Optical, Inc. O desempenho fotossensível é influenciado pela temperatura, pela exposição aos raios UV e pelo material das lentes. Fotos meramente ilustrativas.

TRA-0008-13D-An-Simples_210x280-Medicos-CAVALOS.indd 1

4/1/13 6:11 PM

Ronda Propaganda

O cuidado com

Gel hipoalergênico: UÊCuida suavemente da limpeza da área dos olhos.1 UÊDemaquilante.1

Apresentação: Tubo com 40g e 100 compressas.1

Não deixa resíduos.1 Adequado para usuários de lentes de contato.1

BLEPHAGEL® Gel hipoalergênico. Higiene diária das pálpebras e dos cílios. Tubo de 40 g. Conteúdo: Gel para a higiene das pálpebras e dos cílios. Tubo de 40 g e 100 compressas. Composição: Aqua, poloxamer 188, PEG-90, sodium borate, carbomer, methylparaben. Indicações: BLEPHAGEL®, gel hipoalergênico, demaquilante, cuida suavemente da limpeza da área dos olhos. Pode ser recomendado aos utilizadores de lentes de contato. Propriedades: BLEPHAGEL®, hipoalergênico (formulado para MINIMIZAR OS RISCOS DE REAÎÍO ALÏRGICA
 SEM PERFUME NÍO Ï GORDUROSO LIMPA DE FORMA ADEQUADA AS PÈLPEBRAS ! SUA FØRMULA s &ACILITA A ADERÐNCIA DO PRODUTO s 0RODUZ UMA AGRADÈVEL SENSAÎÍO DE FRESCOR DESCONGESTIONANDO AS PÈLPEBRAS E RESPEITANDO O P( DA PELE s .ÍO DEIXA RESÓDUOS Precauções de utilização: s 0RODUTO DESTINADO A APLICAÎÍO SOBRE AS PÈLPEBRAS E CÓLIOS NÍO APLICAR NO OLHO s .ÍO UTILIZAR EM CRIANÎAS .°/ 53!2 %- 0%,% ,%3)/.!$! /5 )22)4!$! Modo de usar: Em média duas vezes por dia, de manhã e à noite, ou quantas vezes seja necessária a limpeza das pálpebras. 1) Aplicar uma pequena quantidade de BLEPHAGEL® sobre uma gaze limpa e macia. 2) &RENTE AO ESPELHO APLICAR COM DELICADEZA A gaze sobre as pálpebras e a base dos cílios com o olho fechado. 3) Passar suavemente, várias vezes a gaze com o BLEPHAGEL® sobre as pálpebras e a base dos cílios, friccionar com pequenos movimentos circulares a fim de retirar todos os resíduos. 4) Eliminar o BLEPHAGEL® restante com a ajuda de uma gaze limpa. 5) Repetir cada etapa para o outro olho utilizando sempre gazes limpas. Reg. M.S. nº 2.5203.0006. Importado por: 5.)°/ 15¶-)#! &!2-!#³54)#! .!#)/.!, 3! 2UA #EL ,UIZ 4ENØRIO DE "RITO  n %MBU 'UAÎU n 30 n #%0    n 3!# 

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Produzido em: Abril/2013

Referência Bibliográfica: 1) Bula do produto: Blephagel®. Registro MS nº2.5203.0006.001-4.

PUBLICAÇÃO OFICIAL DO CONSELHO BRASILEIRO DE OFTALMOLOGIA PUBLICAÇÃO OFICIAL DO CONSELHO BRASILEIRO DE OFTALMOLOGIA

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Arq Bras Oftalmol. São Paulo, v. 76, n. 2, p. 63-140, mar./abr. 2013

Conselho Administrativo

Editor-Chefe

Marco Antônio Rey de Faria Harley E. A. Bicas Roberto Lorens Marback Rubens Belfort Jr. Wallace Chamon

Wallace Chamon

Editores Anteriores Waldemar Belfort Mattos Rubens Belfort Mattos Rubens Belfort Jr. Harley E. A. Bicas

Editores Associados Augusto Paranhos Jr. Carlos Ramos de Souza Dias Eduardo Melani Rocha Eduardo Sone Soriano Galton Carvalho Vasconcelos Haroldo Vieira de Moraes Jr. José Álvaro Pereira Gomes

Luiz Alberto S. Melo Jr. Mário Luiz Ribeiro Monteiro Michel Eid Farah Norma Allemann Paulo Schor Rodrigo Pessoa Cavalcanti Lira Sérgio Felberg Suzana Matayoshi

Conselho Editorial Nacional Áisa Haidar Lani (Campo Grande-MS) Ana Luísa Höfling-Lima (São Paulo-SP) André Augusto Homsi Jorge (Ribeirão Preto-SP) André Messias (Ribeirão Preto-SP) Antonio Augusto Velasco e Cruz (Ribeirão Preto-SP) Arnaldo Furman Bordon (São Paulo-SP) Ayrton Roberto B. Ramos (Florianópolis-SC) Breno Barth (Natal-RN) Carlos Roberto Neufeld (São Paulo-SP) Carlos Teixeira Brandt (Recife-PE) Cristina Muccioli (São Paulo-SP) Denise de Freitas (São Paulo-SP) Eduardo Cunha de Souza (São Paulo-SP) Eduardo Ferrari Marback (Salvador-BA) Enyr Saran Arcieri (Uberlândia-MG) Érika Hoyama (Londrina-PR) Fábio Ejzenbaum (São Paulo-SP) Fábio Henrique C. Casanova (São Paulo-SP) Fausto Uno (São Paulo-SP) Flávio Jaime da Rocha (Uberlândia-MG) Ivan Maynart Tavares (São Paulo-SP) Jair Giampani Jr. (Cuiabá-MT) Jayter Silva de Paula (Ribeirão Preto-SP) João Borges Fortes Filho (Porto Alegre-RS) João Carlos de Miranda Gonçalves (São Paulo-SP) João J. Nassaralla Jr. (Goiânia-GO) João Luiz Lobo Ferreira (Florianópolis-SC) José Américo Bonatti (São Paulo-SP) José Augusto Alves Ottaiano (Marília-SP)

José Beniz Neto (Goiânia-GO) José Paulo Cabral Vasconcellos (Campinas-SP) Keila Miriam Monteiro de Carvalho (Campinas-SP) Luís Paves (São Paulo-SP) Luiz V. Rizzo (São Paulo-SP) Marcelo Francisco Gaal Vadas (São Paulo-SP) Marcelo Jordão Lopes da Silva (Ribeirão Preto-SP) Marcelo Vieira Netto (São Paulo-SP) Maria Cristina Nishiwaki Dantas (São Paulo-SP) Maria de Lourdes V. Rodrigues (Ribeirão Preto-SP) Maria Rosa Bet de Moraes e Silva (Botucatu-SP) Marinho Jorge Scarpi (São Paulo-SP) Marlon Moraes Ibrahim (Franca-SP) Martha Maria Motono Chojniak (São Paulo-SP) Maurício Maia (Assis-SP) Mauro Campos (São Paulo-SP) Mauro Goldchmit (São Paulo-SP) Mauro Waiswol (São Paulo-SP) Midori Hentona Osaki (São Paulo-SP) Milton Ruiz Alves (São Paulo-SP) Mônica Alves (Campinas-SP) Mônica Fialho Cronemberger (São Paulo-SP) Moysés Eduardo Zajdenweber (Rio de Janeiro-RJ) Newton Kara-José Júnior (São Paulo-SP) Norma Helen Medina (São Paulo-SP) Paulo E. Correa Dantas (São Paulo-SP) Paulo Ricardo de Oliveira (Goiânia-GO) Procópio Miguel dos Santos (Brasília-DF) Renato Curi (Rio de Janeiro-RJ) Roberto L. Marback (Salvador-BA) Roberto Pedrosa Galvão Fº (Recife-PE)

Roberto Pinto Coelho (Ribeirão Preto-SP) Rosane da Cruz Ferreira (Porto Alegre-RS) Rubens Belfort Jr. (São Paulo-SP) Sérgio Kwitko (Porto Alegre-RS) Sidney Júlio de Faria e Souza (Ribeirão Preto-SP) Silvana Artioli Schellini (Botucatu-SP) Suel Abujamra (São Paulo-SP) Tomás Fernando S. Mendonça (São Paulo-SP) Vera Lúcia D. Monte Mascaro (São Paulo-SP) Walter Yukihiko Takahashi (São Paulo-SP)

Internacional Alan B. Scott (E.U.A.) Andrew Lee (E.U.A.) Baruch D. Kuppermann (E.U.A.) Bradley Straatsma (E.U.A.) Careen Lowder (E.U.A.) Cristian Luco (Chile) Emílio Dodds (Argentina) Fernando M. M. Falcão-Reis (Portugal) Fernando Prieto Díaz (Argentina) James Augsburger (E.U.A.) José Carlos Cunha Vaz (Portugal) José C. Pastor Jimeno (Espanha) Marcelo Teixeira Nicolela (Canadá) Maria Amélia Ferreira (Portugal) Maria Estela Arroyo-Illanes (México) Miguel N. Burnier Jr. (Canadá) Pilar Gomez de Liaño (Espanha) Richard L. Abbott (E.U.A.) Zélia Maria da Silva Corrêa (E.U.A.)

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Maria de Lourdes Fleury F. Carvalho Tom Back

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Flávio Rezende Dias

Sociedade Brasileira de Catarata e Implantes Intra-Oculares

Armando Stefano Crema

Sociedade Brasileira de Cirurgia Plástica Ocular

Ricardo Mörschbacher

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Renato Ambrósio Júnior

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Rosa Maria Graziano

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Priscilla Luppi Ballalai Bordon

Sociedade Brasileira de Retina e Vítreo

Walter Yukihiko Takahashi

Sociedade Brasileira de Trauma Ocular

Nilva Simeren Bueno Moraes

Sociedade Brasileira de Uveítes

Wilton Feitosa de Araújo

Sociedade Brasileira de Visão Subnormal

Mayumi Sei

PUBLICAÇÃO OFICIAL DO CONSELHO BRASILEIRO DE OFTALMOLOGIA

PUBLICAÇÃO OFICIAL DO CONSELHO BRASILEIRO DE OFTALMOLOGIA

ISSN 0004-2749 (Versão impressa) ISSN 1678-2925 (Versão eletrônica)

Periodicidade: bimestral

Arq Bras Oftalmol. São Paulo, v. 76, n. 2, p. 63-140, mar./abr. 2013

Sumário | Contents Editorial | Editorial Médicos não se pagam V Doctors don’t break even

Paulo Schor

VII

Doctors don’t break even



Paulo Schor

Médicos não se pagam

Artigos Originais | Original Articles Contrast sensitivity after refractive lens exchange with a multifocal diffractive aspheric intraocular lens 63 Sensibilidad al contraste tras cirugía de cristalino transparente con lente intraocular multifocal asférica difractiva

Teresa Ferrer-Blasco, Santiago García-Lázaro, César Albarrán-Diego, Cari Pérez-Vives, Robert Montés-Micó

Efeito hipotensor de três formulações diferentes do tartarato de brimonidina em olhos normais 69 Hypotensive effect of three different formulations of brimonidine tartrate in normal eyes

Tulio Batista Abud, Marcio Scuoteguazza Filho, Edjane Souza Santos Oliveira, Jorge Felipe Abud, João Antonio Prata Junior

72

Prognostic implications of cytopathologic classification of melanocytic uveal tumors evaluated by fine-needle aspiration biopsy



Implicação prognóstica da classificação citopatológica dos tumores melanocíticos da úvea avaliados pela biópsia aspirativa com agulha fina



James Jay Augsburger, Zélia Maria Corrêa, Nikolaos Trichopoulos

Risk factors of age-related macular degeneration in Argentina 80 Fatores de risco para degeneração macular relacionada à idade na Argentina

María Eugenia Nano, Van Charles Lansingh, María Soledad Pighin, Natalia Zarate, Hugo Nano, Marissa Janine Carter, João Marcello Furtado, Clelia Crespo Nano, Luciana Fiocca Vernengo, José Domingo Luna, Kristen Allison Eckert

of magnocellular pathway abnormalities in schizophrenia: a frequency doubling technology study 85 Evaluation and clinical implications

Avaliação das alterações da via magnocelular na esquizofrenia usando FDT e suas implicações clínicas



Fabiana Benites Vaz de Lima, Carolina Pelegrini Barbosa Gracitelli, Augusto Paranhos Junior, Rodrigo Affonseca Bressan

Frequência de ocorrência de cavidade anoftálmica na região centro-oeste paulista e características dos portadores 90 Frequency of occurrence of anophthalmic socket in the Middle West region of the state of São Paulo and the carriers characteristics

Roberta Lilian Fernandes de Sousa, André Ricardo Carvalho Marçon, Carlos Roberto Padovani, Silvana Artioli Schellini

94

Visual acuity and refraction by age for children of three different ethnic groups in Paraguay



Marissa Janine Carter, Van Charles Lansingh, Gisela Schacht, Miguel Río del Amo, Miguel Scalamogna, Thomas Douglas France

Acuidade visual e refração por idade para crianças de três grupos étnicos diferentes no Paraguai

estruturais maculares de olhos de pré-escolares nascidos prematuros: 98 Características análise por tomografia de coerência óptica e oftalmoscopia binocular indireta

Structural features of macular eyes of preschoolers born preterm: analysis by optical coherence tomography, and indirect ophthalmoscopy



Lígia Beatriz Bonotto, Ana Tereza Ramos Moreira, Cristina Martins Faria Bortolotto

Light-induced retinal injury enhanced neurotrophins secretion and neurotrophic effect of mesenchymal stem cells in vitro 105 Lesão de retina induzida por luz aumentou a secreção de neurotrofinas e o efeito neurotrófico das células primordiais mesenquimais in vitro

Wei Xu Xiaoting Wang, Guoxing Xu, Jian Guo

ORA waveform-derived biomechanical parameters to distinguish normal from keratoconic eyes 111 Parâmetros biomecânicos derivados da forma da curva do ORA para discriminar olhos normais de ceratocones

Allan Luz, Bruno Machado Fontes, Bernardo Lopes, Isaac Ramos, Paulo Schor, Renato Ambrósio Jr.

Relatos de Casos | Case Reports



118

Retinopatia solar sem exposição anormal: relato de caso



Ricardo Alexandre Stock, Simone Louise Savaris, Erasmo Carlos Rodrigues de Lima Filho, Elcio Luiz Bonamigo

Solar retinopathy without abnormal exposure: case report

Bilateral lineal endotheliitis: case report 121 Endotelite linear bilateral: relato de caso

Liliana Moreno Garcia, Mauricio Vélez Fernandez

124

Traumatic avulsion of extraocular muscles: case reports



Nilza Minguini, Karin Suzete Ikeda, Keila Monteiro de Carvalho

Avulsão traumática de músculos extraoculares: relatos de casos

Unusual early recurrence of granular dystrophy after deep anterior lamellar keratoplasty: case report 126 Recorrência atípica e precoce de distrofia granular após transplante lamelar profundo: relato de caso

Paolo Rama, Karl Anders Knutsson, Carmen Rojo, Paola Carrera, Maurizio Ferrari



Artigos de Revisão | Review Articles

129

Dry eye disease caused by viral infection: review



Monica Alves, Rodrigo Nogueira Angerami, Eduardo Melani Rocha

Olho seco causado por infecções virais: revisão

Cartas ao Editor | Letters to the Editor



133

Positividade de cultura para o diagnóstico exato de endoftalmite por Pseudomonas aeruginosa



Yakup Aksoy, Yusuf Emrah Eyi, Kadir Colakoglu, Emre Zorlu, Fahri Gurkan Yesil

Culture positivity for exact diagnosis of Pseudomonas aeruginosa endophthalmitis

Authors’ reply 133 Resposta dos autores

Ricardo Luz Leitão Guerra, Bruno de Paula Freitas, Cintia Maria Felix Medrado Parcero; Otacílio de Oliveira Maia Júnior; Roberto Lorens Marback

Initial challenges in the career of ophthalmologists 134 Óbices iniciais na carreira do oftalmologista

Rodrigo Pessoa Cavalcanti Lira, Fernando Rodrigo Pereira Chaves, Carlos Eduardo Leite Arieta

137 Instruções para os Autores | Instructions to Authors

Editorial |

Editorial

Médicos não se pagam Doctors don’t break even Paulo Schor1

“Tenho 48 anos e ainda tenho vários anos até atingir o ponto mais alto da minha carreira”. Esta citação não pode ser ouvida a partir de praticamente qualquer profissional. Entre os analistas financeiros, por exemplo, 29 anos de idade já é tarde demais. Poucos empregados iria contratar um “brilhante matemático” com 35 anos de idade e um violinista virtuoso com 45 anos de idade é impensável. Os médicos são uma das poucas profissões em que idade se traduz em experiência e, de certa forma, mais sucesso. Infelizmente há um custo progressivo associado a esta maturação. Jovens estudantes sobrevivem com pizza e cerveja, os médicos residentes já exigem vinho e queijo Roquefort enquanto médicos mais experientes não sobrevivem sem Bourbon e cozinha francesa. No país que vivo (Brasil), as escolas privadas são mais desejadas até o ensino superior, e universidades públicas são a escolha depois disso. Nos EUA, o ensino médico público e gratuito é muito raro, se existente. Escolas de primeira linha podem custar até US$ 40K por ano(1). Depois da graduação, os médicos, geralmente, estão dispostos a sub-especializar e passar por programas de residência médica que mal os sustenta financeiramente. Mais dois ou três anos de especialização são necessários antes de um trabalho decente. Títulos de pós-graduação, como um Doutorado, são necessários para os cargos na Universidade. Participação em encontros científicos e autoria de manuscritos científicos são imperativos para a educação médica continuada, um congresso normal pode custar até US$ 600. Os custos e despesas pessoais (de educação e custo de vida) devem ser adicionados aos pagos pela sociedade (escola de medicina e hospitais), a fim de entregar um médico. Sabe-se que as escolas médicas são maus negócios. Não surpreendentemente, o MIT (Massachussets Institute of Technology) não tem uma... Hospitais de ensino são muito mais caros do que os normais, uma vez que os aprendizes usam mais recursos, incluindo uma longa curva de aprendizado. O custo do ensino de graduação em medicina aumentou mais de duas vezes do que a taxa de inflação nos últimos anos(2). É, portanto, um desafio equilibrar o sistema de saúde com base em mais e mais caros médicos. Várias tentativas foram feitas para a construção de uma organização de saúde de colaboração com os tecnólogos, técnicos e pessoal paramédico. O papel médico e do enfermeiro foi redirecionado para organizar a equipe e objetivar o diagnóstico e as medidas terapêuticas. Algumas economias surgem a partir desta estrutura, mas se perdem no modelo centrado no hospital, que valoriza equipamentos tecnológicos caros como ferramenta essencial para a prática. Seja por medo de ações judiciais ou pela pressão da indústria de alta tecnologia, exames caros são usados como meios para quase qualquer diagnóstico. Não é nenhuma surpresa que o dinheiro que vai para o sistema de saúde não é suficiente e, de fato, diminui a cada ano em comparação com o aumento dos custos. Este tipo de medicina nunca vai se pagar. Novas ideias e desenvolvimentos podem mudar esta realidade no curto prazo. A construção e a adoção generalizada de soluções móveis precisas, baratas e acuradas podem alterar o equilíbrio no sentido de um modelo médico centrado no paciente, capacitando a comunidade com autoexames e obrigando o sistema a diminuir o número de médicos e reduzir o custo do diagnóstico. Soluções prontas detectam saúde mais frequentemente do que a doença, evitando visitas e avaliações desnecessárias. A tecnologia dentro dos telefones celulares já provou ser capaz de detectar a miopia, hipermetropia e astigmatismo(3), e, logo oferecerá imagens dos vasos da retina e do nervo óptico(4), substituindo, pelo preço de US$ 300, um dispositivo de US$ 30K . Além disso, esses instrumentos ajudam a poupar dinheiro em termos de pessoal médico, uma vez que o autoexame é proposto, juntamente com a possibilidade de realizar esta tarefa fora de ambientes especiais e locais dispendiosos.

Submetido para publicação: 13 de junho de 2013 Aceito para publicação: 14 de junho de 2013 1

Professor Adjunto Livre Docente, Vice Chefe do Departamento de Oftalmologia, Escola Paulista de Medicina - UNIFESP.

Financiamento: Não houve financiamento para este trabalho. Divulgação de potenciais conflitos de interesse: P.Schor, Nenhum.

V

Médicos não se pagam

Não são esperadas apenas consequências econômicas a partir das tecnologias médicas móveis precisas, mas uma mudança no comportamento de médicos e consequentemente da formação médica. Médicos deixarão de ganhar a vida com a realização de exames ou por possuir aparelhos de diagnóstico, mas fazendo diagnósticos ao compreender os sinais e sintomas, bem como ao coletar e analisar dados a partir de várias fontes. A grande mudança de paradigma na educação médica, como descrita acima pode, pela primeira vez, trazer de volta a um nível de sustentabilidade o sistema de saúde e os custos de especialização médicas. Mais notavelmente, para o benefício de todos nós, pode iniciar um movimento em direção à medicina antiga (ou, se preferir, o Dr. Gregory House ou Sherlock Holmes), com base em evidências e pensamento racional.

Referências 1. TopUniversities. Worldwid university ranking, guides & events. How much does it cost to study in the US? [Internet]. London: QS Links; 2012. [cited 2013 Jun 13]. Available from: http://www.topuniversities.com/student-info/student-finance/how-muchdoes-it-cost-study-us 2. Adashi EY, Gruppuso PA. Commentary: the unsustainable cost of undergraduate medical education: an overlooked element of U.S. health care reform. Acad Med. 2010;85(5):763-5.

VI

3. Eyenetra. Eye care for 2.4 billion [Internet]. 2011. [cited 2013 Jun 6]. Available from: http://eyenetra.com 4. Boggess J, Khullar S, Lawson M. InSight: mobile retina imager for diabetic retinopathy [Internet]. Massachusetts: Massachusetts Institute of Technology; 2012. [cited 2013 Jun 6]. Available from: http://globalchallenge.mit.edu/teams/view/270

Editorial |

Editorial

Doctors don’t break even Médicos não se pagam Paulo Schor1

“I am 48 years old and still have several years until reach the highest point of my career”. This quote can’t be heard from almost any professional. Among financial analysts, for instance, 29 years old is already too late. Few employees would hire a 35-year old “brilliant mathematician” and a 45-year old virtuoso violinist is unthinkable. Doctors are one of the few professions where age translates into experience and, to some extent, more success. Unfortunately there is a progressive cost associated to this maturation. Young students survive on pizza and beer; residents already demand wine and blue cheese and senior doctors don’t survive without Bourbon and French cuisine. In the country I live (Brazil), private schools are preferable until College, and public Universities are the choice after that. In the US, public and free medical education is very rare if existent. Top-notch schools may cost up to 40K per year(1). After graduation doctors are usually willing to sub-specialize and go through residency programs that barely support them financially. An additional two or three years of specialization are required before a decent job. Post graduation degrees, such as a PhD, are necessary for University positions. Attending meetings and authoring-papers are a must for continuous medical education; a regular meeting might cost up to $600. The personal costs (living expenses and education) must be added to the ones paid by the society (medical school and training hospitals) in order to deliver a doctor. It is known that medical schools are bad businesses. Not surprisingly, MIT does not have one... Teaching hospitals are much more expensive than regular ones, since apprentices use more resources, including a long learning curve. The cost of undergraduate medical education has been rising at more than twice the inflation rate in recent years(2). It is, therefore, challenging to balance the health care system based on more and expensive doctors. Several attempts have been made to build a collaborative health organization with technologists, technicians and paramedical personnel. The doctor and nurse role has been redirected to organize the team and aim for the diagnosis and therapeutical measures. Some savings arise from this structure but are lost in the hospital-centered model, which values expensive technological equipment as essential tool for the practice. Either because of lawsuits fear, or the push of the high technology industry, expensive exams are used as means for almost any diagnosis. It is no surprise that the money that goes to the health care system is never enough and, in fact, decreases every year compared to the rising cost. This kind of medicine won’t ever break even. New ideas and developments might change this reality in the short term. The construction and widespread of accurate, inexpensive and precise mobile solutions may change the equilibrium towards a patient-centered medical model, empowering the community with self exams and compelling the system to decrease the number of doctors and lower the cost of diagnosis. Off-the-shelf solutions detect health more often than disease, avoiding unnecessary visits and evaluations. The technology inside mobile phones has already proved to be able to detect myopia, hyperopia and astigmatism(3), and shortly will offer retinal images of the vessels and optic nerve(4), substituting, for the price of $300, a $30K device. Additionally, these instruments help to save money in terms of medical personnel, since a self-exam is proposed, along with the possibility of performing this task outside special environments at expensive clinics. Not only economical consequences are to be expected from the accurate mobile medical technologies, but a shift in the medical behavior and consequent medical education. Doctors will no longer make a living on

Submitted for publication: June 13, 2013 Accepted for publication: June 14, 2013 1

Tenured Professor, Vice Chief of the Department of Opthalmology.

. Funding: No specific financial support was available for this study. Disclosure of potencial of interest: P.Schor, None.

VII

Doctors don’t break even

performing exams or owning diagnostic facilities, but in suspecting diagnoses from understanding signs and symptoms, as well as collecting and analyzing data from several sources. A major paradigm change in medical education as described above may, for the first time, bring back a level of sustainability to the health care system and doctors specialization costs. More notably, to the benefit of us all, it may initiate a movement towards the ancient medicine (or, if you will, Dr. Gregory House or Sherlock Holmes) based in evidences and rational thinking.

References 1. TopUniversities. Worldwid university ranking, guides & events. How much does it cost to study in the US? [Internet]. London: QS Links; 2012. [cited 2013 Jun 13]. Available from: http://www.topuniversities.com/student-info/student-finance/how-muchdoes-it-cost-study-us 2. Adashi EY, Gruppuso PA. Commentary: the unsustainable cost of undergraduate medical education: an overlooked element of U.S. health care reform. Acad Med. 2010;85(5):763-5.

VIII

3. Eyenetra. Eye care for 2.4 billion [Internet]. 2011. [cited 2013 Jun 6]. Available from: http://eyenetra.com 4. Boggess J, Khullar S, Lawson M. InSight: mobile retina imager for diabetic retinopathy [Internet]. Massachusetts: Massachusetts Institute of Technology; 2012. [cited 2013 Jun 6]. Available from: http://globalchallenge.mit.edu/teams/view/270

Artigo Original | Original Article

Contrast sensitivity after refractive lens exchange with a multifocal diffractive aspheric intraocular lens Sensibilidad al contraste tras cirugía de cristalino transparente con lente intraocular multifocal asférica difractiva Teresa Ferrer-Blasco1, Santiago García-Lázaro1, César Albarrán-Diego1, Cari Pérez-Vives1, Robert Montés-Micó1

ABSTRACT

RESUMEN

Purpose: To evaluate distance and near contrast sensitivity (CS) under photopic and mesopic conditions before and after refractive lens exchange (RLE) and implantation of the aspheric AcrySof ®ReSTOR ® (SN6AD3 model) intraocular lens (IOL). Methods: Seventy-four eyes of 37 patients after RLE underwent bilateral implantation with the aspheric AcrySof ReSTOR IOL. The patient sample was divided into myopic and hyperopic groups. Monocular uncorrected visual acuity at distance and near (UCVA and UCNVA, respectively) and monocular best corrected visual acuity at distance and near (BCVA and BCNVA, respectively) were measured before and 6 months postoperatively. Monocular CS function was measured at three different luminance levels (85, 5 and 2.5 cd/m2) before and after RLE. Post-implantation results at 6 months were compared with those found before surgery. Results: Our results revealed that patients in both groups obtained good UCVA and BCVA after RLE at distance and near vision in relation to pre-surgery values. No statistically significant differences were found between the values of CS pre and post-RLE at distance and near, at any lighting condition and spatial frequency (p>0.002). Conclusions: Refractive lens exchange with aspheric AcrySof ReSTOR IOL in myo­­­pic and hyperopic population provided good visual function and yield good distance and near CS under photopic and mesopic conditions.

Propósito: El propósito de este estudio fue evaluar la sensibilidad al contraste antes de la extracción de cristalino transparente y tras la implantación de la lente intraocular asférica AcrySof ®ReSTOR ® (SN6AD3) bajo condiciones fotópicas y mesópicas. Métodos: Se estudiaron 74 ojos de 37 pacientes tras ser sometidos a cirugía de cristalino transparente bilateral con la lente intraocular AcrySof ReSTOR (SN6AD3 model). Los pacientes fueron divididos en dos grupos: miopes e hipermétropes. A ambos grupos se les midió antes y a los 6 meses de la intervención quirúrgica la agudeza visual con la mejor corrección monocular en visión de lejos y de cerca, y la agudeza visual monocular no corregida para visión de lejos y de cerca. La función de sensibilidad al contraste fue medida a tres diferentes niveles de iluminación (85, 5 y 2.5 cd/m2) antes y después de la cirugía. Los resultados post-quirúrgicos a 6 meses fueron comparados con los pre-quirúrgicos. Resultados: Los pacientes de ambos grupos mostraron buenos niveles de agudeza visual no corregida y con la mejor corrección tras la implantación de la lente intraocular para visión de lejos y cerca en comparación a los valores pre-quirúrgicos. No se encontraron diferencias estadísticamente significativas entre los valores pre y postqui­rúrgicos de sensibilidad al contraste para cualquier distancia, frecuencia espacial o nivel de iluminación (p>0,002). Conclusiones: La cirugía de cristalino transparente con la lente intraocular asférica AcrySof ReSTOR en pacientes miopes e hipermétropes proporciona una buena función visual en visión de lejos y de cerca bajo condiciones fotópicas y mesópicas.

Keywords: Lens implantation, intraocular; Lens cristalline/surgery; Myopia/surgery; Hyperopia/physiopathology; Phacoemulsification; Visual acuity

Descriptores: Implantación de lentes intraoculares; Cristalino/cirugía; Miopía/cirugía; Hiperopia/fisiopatología; Hiperopia/cirugía; Facoemulsificación; Agudeza visual

INTRODUCTION Currently, refractive lens exchange (RLE) surgery in presbyopes patients with high myopia or hyperopia is focused not only on restoring visual acuity (VA) at distance and near but also on providing the best visual quality to patients. Bifocal refractive(1-3), diffractive(4-7), spherical hybrid(8-11) and aspheric hybrid(12-16) IOLs generate two focal points along the optical axis to provide good monocular uncorrected distance and near visual acuity (UCVA and UNVA, respectively) as well as functional intermediate vision. The bifocal IOLs have also been implanted in RLE with good results at distance and near vision(17-25). Recent studies with the hybrid spherical AcrySof ® ReSTOR® IOL (Alcon Laboratories, Inc.)(19-21,24,25) in RLE surgery report satisfactory visual re­­sults. These hybrids IOLs combine refractive and diffractive optics to

reduce the disadvantages of conventional refractive and diffractive IOLs in terms of contrast sensitivity. (CS)(26). Wavefront sensing technology recently has been applied in the design of news IOLs. The aspheric AcrySof ReSTOR (SN6AD3 model) was designed to produce negative spherical aberration (SA) to com­­ pensate the positive SA of the cornea(27). This design aims to decrease unwanted visual phenomena associated with multifocal IOL performance and to increase the depth of focus, thereby improving image quality(12-16). The contrast sensitivity function (CSF) gives information on visual performance for a range of object scales. The key question to be answered is whether this visual performance given by CSF in patients implanted with aspheric IOLs in RLE treatment is better or worse than

Submitted for publication: August 27, 2012 Accepted for publication: December 10, 2012

Funding: This study was supported in part by Ministerio de Ciencia e Innovación Research Grant to Robert Montés-Micó (#SAF2009-13342#)

Study carried out at Optics Department, University of Valencia, Spain

Disclosure of potential conflicts of interest: T.Ferrer-Blasco, None; S.García-Lázaro, None; C.Alabarrán-Diego, None; R.Montés-Micó, None.

1

Optics Department, University of Valencia, Spain.

Correspondence address: Santiago García-Lázaro PhD. Optics Department, Faculty of Physics. University of Valencia. C/ Dr. Moliner, 50. 46100. Burjassot (Valencia). SPAIN. E-mail: [email protected]

Arq Bras Oftalmol. 2013;76(2):63-8

63

Contrast sensitivity after refractive lens exchange with a multifocal diffractive aspheric intraocular lens

the natural lens. In addition, it could detect differences, in terms of visual performance, between myopic and hyperopic eyes. The purpose of this study was to show the visual quality by the CSF of patients implanted with the aspheric AcrySof ReSTOR SN6AD3 IOL, as a function of the illumination level under distance and near conditions, in 74 healthy, non-cataractous eyes divided into two groups (myopic and hyperopic) before and after RLE. METHODS

Study design The present prospective study was carried out on 74 consecutive eyes of 37 patients bilaterally implanted with the aspheric AcrySof ReSTOR IOL. Inclusion criteria were age between 45 and 70 years and the motivation to no longer wear any form of spectacle or contact lens correction for distance and near. Exclusion criteria included ≥1 Diopters (D) of corneal astigmatism, history of glaucoma or retinal detachment, corneal disease, previous corneal or intraocular surgery, abnormal iris, pupil deformation, macular degeneration or retinopathy, neuro-ophthalmic disease and history of prior ocular inflammation. The tenets of the Declaration of Helsinki were followed in this research. Informed consent was obtained from all patients after the nature and possible consequences of the study were explained. Approval from the Institutional Review Board was obtained. Before the RLE procedure, patients underwent a complete oph­­ thalmologic examination, including manifest and cycloplegic refraction, keratometry, slit-lamp biomicroscopy, Goldmann applanation tonometry, and binocular indirect ophthalmoscopy through dilated pupils. Axial length and anterior segment biometry were measured with the Zeiss Humphrey IOL Master biometer (Carl Zeiss Meditec, Inc., Dublin, CA). The SRK/T formula was used for the myopic patients (all myopic patients with axial length >24 mm). The Holladay II formula was used for IOL power calculation in hyperopic patients (all hyperopic patients with axial length <24 mm). The targeted refraction was emmetropia in all cases. All surgeries in this study were performed by phacoemulsification with the Infiniti Vision System (Alcon, Fort Worth, TX) using topical anaesthesia and a clear corneal 2.2-3.2 mm incision. Phacoemulsification was followed by irrigation and aspiration of the cortex, and IOL implantation in the capsular bag. There were no complications in any of the cases.

IOL specifications The aspheric AcrySof ReSTOR SN6AD3 IOL uses apodization, dif­­ fraction, and refraction. The apodized diffractive region is within the central 3.6 mm optic zone of the IOL. This area comprises 12 concentric steps of gradually decreasing (1.3 to 0.2 mm) height, creating multifocality from distance to near (2 foci). The refractive part of the optic surrounds the apodized diffractive region. This area directs light to a distant focal point for larger pupil diameters and is dedicated to vision at distance. The overall diameter of the IOL is 13.0 mm and the optic diameter, 6.0 mm. The IOL power used in this study varied from +10.00 to +30.00 D and incorporated a +4.00 D near addition (add). The IOL has an aspheric profile to correct positive SA of the cornea. The IOL material includes a blue light-filtering chromophore. It has been shown that the use of a blue-light filter is advisable because it prevents ultraviolet light alterations to the retina without disturbing CS and chromatic vision(28,29).

Visual performance measures Monocular uncorrected and best corrected visual acuity at dis­­­ tance and near (UCVA, UCNVA, BCVA and BCNVA, respectively) were measured before and after 6 months post-surgery. The measurements in distance vision were measured using 100% contrast Early 64

Arq Bras Oftalmol. 2013;76(2):63-8

Treatment Diabetic Retinopathy Study (ETDRS) charts (Optec 6500; Stereo Optical Co Inc, Chicago, Ill) under photopic conditions (85 candelas per square meter [cd/m2]) at 4 m. The measurements in near vision were measured using the Logarithmic Visual Acuity Chart 2000 New ETDRS (Precision Vision, LaSalle, Ill) at 40 cm under photopic conditions (85 cd/m2). The safety index of the procedure (ratio mean BCVA postoperative/mean BCVA preoperative) and the efficacy index (mean UCVA postoperative/mean BCVA preoperative) were calculated at 6 month after surgery. Monocular photopic and mesopic CS was measured with best distance correction using the Stereo Optical Functional Acuity Contrast Test (FACT Stereo Optical, Chicago, IL) in both groups before and 6 months after implantation. Absolute values of log10 CS were obtained for each combination of patient, spatial frequency, and luminance; means and standard deviations were calculated. The levels of chart luminance were 85, 5 and 2.5 cd/m2, the first being photopic (i.e. the luminance recommended in the manufacturer’s guidelines) and the others mesopic: room illumination was at similar levels. CS was measured first at the photopic level and then at the mesopic level. Patients were given 5 minutes to adapt to each level before testing. Pupil diameters were measured in each eye using a Colvard pupillometer (OASIS Medical Inc, Glendora, CA) under photopic and mesopic illumination conditions.

Data analysis All examinations were performed preoperatively and 6 months after IOL implantation by one clinician who was unaware of the objective of the study. Normality was checked by the Shapiro-Wilk test. Correlation analysis was performed to assess the differences between pre- and post-surgery outcomes at far and near and correlations in the CS measured at the 3 lighting conditions. Bonferroni correction was applied for multiple tests of correlation for the 5 frequencies (P<0.01/5). A probability less than 0.2% (P<0.002) was considered statistically significant. RESULTS Seventy-four eyes of 37 patients had RLE with ReSTOR SN6AD3 IOL. Eyes were divided into two groups, myopic (n=18, 11 female, 7 male) and hyperopic (n=19, 10 female, 9 male). Patients’ demographics are shown in table 1. There was no statistically significant differences in age or pupil diameter under mesopic conditions bet­ ween-groups (p>0.01). However, there were significant differences for pupil diameter under photopic conditions (p<0.01). After surgery and IOL implantation, the pupils of all patients were round, without iris trauma, and showed good responsiveness to light. All eyes were available for examination at 6 months. At 6 months after IOL implantation, the residual mean spherical equivalent (SE) refractive error was -0.12 ± 0.40 D and -0.04 ± 0.46 in myopic and hyperopic groups respectively. After surgery, none of the eyes required a secondary intervention. No potentially sight threatening complications such as persistent corneal edema, pupillary block, retinal detachment or endophthalmitis were observed during the postoperative period. In addition, no eye was in the need of Nd:YAG capsulotomy up to the postoperative last visit. Table 2 shows the VA values before and after the IOL implantation for distance and near. In myopic group the safety index (ratio mean BCVA postoperative/mean BCVA preoperative) was 1.05 and 1.22 in distance and near vision respectively. The efficacy index (mean UCVA postoperative/mean BCVA preoperative) was 0.85 and 1.14 in distance and near vision respectively. In hyperopic group the safety index was 1.02 and 1.14 in distance and near vision respectively. The efficacy index was 0.85 and 1.13 in distance and near vision respectively. The mean values of log10CS before and after RLE with the aspheric AcrySof ReSTOR IOL implantation are plotted as a series of CSFs in figure 1 for the myopic group and in figure 2 for the hyperopic group.

Ferrer-Blasco T, et al.

Left column shows distance CSFs at the 3 luminance levels (85, 5 and 2.5 cd/m2) and right column shows the results of the measurements at near conditions. For comparison, mean measurements for myopic eyes implanted with spherical AcrySof ReSTOR SA60D3 IOL found by Blaylock et al.(21) are included in figure 1. Similarly, mean measurements for hyperopic eyes implanted with the same IOL found by Ferrer-Blasco et al.(22) are included in figure 2. To explore the statistical significance of differences between pre- and post-RLE groups, t-tests were performed on the comparable data of the two groups (absolute log10CS values) at each spatial frequency and illumination level. The results showed no statistically significant differences between the values pre- and post-RLE at any distance, lighting condition and spatial frequency (P>0.002).

Table 1. Demographic characteristics of participants Myopic group Number of eyes Age (years) Range of age (years)

36

38

49.63 ± 4.15

51.29 ± 5.33

46 - 57

47 - 60

Gender (Male/Female) IOL power (D) Range IOL power (D)

Hyperopic group

7/11

9/10

12.66 ± 2.06

26.12 ± 1.55*

10 - 15.5

24 - 30

Axial length (mm)

25.61 ± 0.78

21.88 ± 0.62*

Range axial length (mm)

23.67 - 27.45

20.16 - 23.31

Preoperative sphere (D)

-6.55 ± 1.99

4.76 ± 1.42*

Range preoperative sphere (D)

4.25 - 11

3-7

0.48 ± 0.31

0.33 ± 0.35

0 - 1.00

0 - 0.75

K1 (D)

44.46 ± 1.21

42.98 ± 1.41*

K2 (D)

44.71 ± 1.23

43.63 ± 1.51

42 - 46

40.5 - 47

85 cd/m2

4.39 ± 0.78

3.48 ± 0.81*

5 cd/m

5.77 ± 0.59

5.02 ± 0.57

2.5 cd/m2

6.06 ± 0.52

5.86 ± 0.57

Preoperative cylinder (D) Range preoperative cylinder (D) Preoperative keratometry (K)

Range preoperative keratometry (K) Postoperative mean pupil diameter (mm)

2

IOL = intraocular lens; D = dioptres; means ± standard deviation. *= means statistically significant differences between both systems.

DISCUSSION The removal of the crystalline lens and replacement with a pseudophakic lens for the purposes of reducing or eliminating refractive errors has been labelled with many titles, including clear lensectomy, clear lens phacoemulsification, clear lens replacement, clear lens exchange, presbyopic lens exchange, and RLE. Several studies evaluating the clinical, functional, and quality-of-life outcomes after implantation of the multifocal spherical IOLs(17-22,24,25) show that these lenses improves high level of distance vision with additional benefit of increased range of near vision without additional correction in non-cataractous eyes. Blaylock et al.(21) and Ferrer-Blasco et al.(22) evaluated the CS under photopic and mesopic conditions before and after implantation of the spherical AcrySof ReSTOR IOL. These authors found postoperatively a reduction in mesopic CS in relation to photopic CS but with a performance comparable to the CS preoperative. This study is the first one assessing CS after RLE and implantation of a multifocal IOL with an aspheric design. Our results revealed that aspheric AcrySof ReSTOR IOL provided good and comparable safety and efficacy indexes in both groups. Our values agree with those found previously in 112 patients after RLE with bilateral spherical AcrySof ReSTOR IOL(19). There was no statistically significant difference between pre and postoperative BCVA in hyperopic group (p>0.01), however we found statistically significant difference in the myopic group (p<0.01; see table 2). Magnification and minimization of the retinal image in myopic and hyperopic patients, respectively, may play a significant role in this difference. If we focus now on CS we must first point out that the light distribution between distance and near foci depends on pupil diameter and varies from approximately 40% to 90% of the light to the distance focus for this IOL(26). Pupil diameter postoperative in myopic group under photopic conditions was 4.39 ± 0.78 mm, so the percentage of light for the distance/near focus was about 80/20. In the mesopic conditions pupil diameter was 5.77 ± 0.59 mm, and 6.06 ± 0.52 mm for 2.5 cd/mm2, about 90/10 of the light goes to distance/near focus. In hyperopic group the pupil diameter measured postoperative was 3.48 ± 0.81 mm and 5.02 ± 0.57 mm in photopic and mesopic conditions respectively, so the percentage of the light for the distance/ near focus was about 70/30 and 85/15. Analysing the results for distance, under photopic conditions, performance was very similar in both groups when compare the results of CSFs before and after surgery. There is some loss in photopic retinal image contrast with the aspheric AcrySof ReSTOR IOL al­­­­though this difference was not significant (p>0.002). Due to diffractive nature of the IOL, for small pupils a maximum of 40% of the total light passing through the pupil contributes to either the distance or near image, and the remainder of the light decreases retinal image contrast(26). The light energy focused on the distance focus was about 80% and 70% in myopic and hyperopic groups respectively

Table 2. Monocular visual acuity results for distance and near vision. Mean and standard deviation logMAR (logarithm of the minimum angle of resolution) values before and after 6 months post-AcrySof ReSTOR SN6AD3IOL implantation Myopic group

Hyperopic group

Before

After

p-value

Before

After

p-value

UCVA

0.90 ± 0.10

0.08 ± 0.15

<0.001

0.86 ± 0.12

0.11 ± 0.14

<0.001

BCVA

0.03 ± 0.05

0.01 ± 0.02

<0.01

0.05 ± 0.12

0.04 ± 0.10

<0.300

UCNVA

0.42 ± 0.11

0.03 ± 0.05

<0.001

0.91 ± 0.08

0.05 ± 0.08

<0.001

BCNVA

0.10 ± 0.01

0.01 ± 0.02

<0.01

0.10 ± 0.01

0.04 ± 0.06

<0.01

Distance (4 m)

Near (40 cm)

UCVA= uncorrected logMAR distance visual acuity, BCVA= best distance-corrected logMAR visual acuity, UCNVA= uncorrected near logMAR visual acuity, BCNVA= best distance-corrected near logMAR visual acuity.

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Contrast sensitivity after refractive lens exchange with a multifocal diffractive aspheric intraocular lens

CS= contrast sensitivity; cpd= cycles per degree.

CS= contrast sensitivity; cpd= cycles per degree.

Figure 1. Contrast sensitivity functions before (natural lens) and after refractive lens exchange with the aspheric AcrySof ReSTOR implantation in myopic group as a function of the distance and FACT chart luminance (85, 5 and 2.5 cd/m2). For comparison, results for spherical AcrySof ReSTOR IOL from Blaylock et al.(21) are included.

Figure 2. Contrast sensitivity functions before (natural lens) and after refractive lens exchange with the aspheric AcrySof ReSTOR implantation in hyperopic group as a func­­­tion of the distance and FACT chart luminance (85, 5 and 2.5 cd/m2). For comparison, results for spherical AcrySof ReSTOR IOL from Ferrer-Blasco et al.(22) are included.

and these values are enough to achieve a CS comparable with the natural lens, both with appropriate distance correction. Comparing between groups, at high spatial frequencies, CSF showed lower values in myopic than hyperopic patients under photopic conditions, although these differences were not statistically significant. A recent study with another diffractive IOL design has shown that a 65% of light energy for the distance focus is also acceptable for achieving good photopic distance CS(12). Under low lighting conditions, there is a little reduction in CSF results obtained with multifocal IOLs compared with the results with the natural lens at 5 cd/m2 and 2.5 cd/m2, particularly at higher spatial frequencies in both groups. This trend agrees with classic data for the effect of luminance level on CS(30). At these mesopic levels, pupil diameters are substantially larger, and it seems reasonable to attribute the observed reduction in mesopic CS at higher spatial frequencies to the additional blur introduced by the larger diameter, out-of-focus zones of the multifocal IOL. At near, the photopic and mesopic CSFs were similar pre- and post-RLE in both groups. These results agree with those found previously by Ferrer-Blasco et al.(22). In comparison with distance vision the reduction of CS under dim conditions correlated with the reduction of light energy concentrated at the near focus. In photopic the percentage of the light for the distance focus were between 80% and 70% but, in mesopic conditions, the percentage of the light contributes to near image is less than 30-20%. These percentages leading to noticeably worse the results of CS at near. Increasing pupil

diameter implies that more light is distributed for the distance foci and then better CS is expected for distance CSFs compared to near CSF at mesopic levels. These differences are slightly minimized due to the myosis during the accommodative process. One should consider that the loss in retinal image contrast has little effect on acuity as measured with high-contrast letters, since contrast can be reduced to quite low levels before acuity is affected(30). For comparison in myopic group we included in figure 1 the mean values obtained for the spherical AcrySof ReSTOR as found by Blaylock et at.(21) in 19 myopic patients (mean preoperative SE -3.89 ± 2.14 D). We should point out that these CS results were measured at 50 foot-candles in photopic level and 3 foot-candles in mesopic level with the SIFIMAV Vision Tester (Designs For Vision; Sydney, Australia). Caution should be exercised when comparing results, among different studies. The differences in conditions and measure systems between studies may play a role in the differences found but is obvious that the results of spherical AcrySof ReSTOR return to be lower. In hyperopic group we had included in figure 2 the results obtained by Ferrer-Blasco et al.(22) in 50 hyperopic patients (mean preoperative SE 2.18 ± 1.17) at the same conditions and with the same test in patients implanted with the spherical AcrySof ReSTOR. At higher spatial frequencies, the CS results of the spherical AcrySof ReSTOR IOL were lower compared with CS results of the aspheric IOL and natural lens. Differences between both IOLs become more evident when lighting conditions are reduced and pupil diameter is increased. This is an expected result considering the reduction of ocular SA for large

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Ferrer-Blasco T, et al.

IOL found a reduction compared to that obtained with a monofocal IOL(2). Our results were similar possibly because in these patients there was already a high degree of contrast-reducing scatter previous surgery (natural eye), giving a reduced CSF as compared with normal young eyes. Replacing the scattering crystalline with an IOL would remove this scatter, even if the diffractive IOL itself reduced the retinal image contrast by its simultaneous bifocal properties. In conclusion RLE with aspheric AcrySof ReSTOR in presbyopic population provided good visual function and yield good distance and near CS under photopic and mesopic conditions in myopic and hyperopic patients. Although mesopic CS is reduced at distance and near in relation to that found under photopic conditions, the performance is comparable to that obtained prior to surgery with the natural lens and better than the results obtained in patients implanted with spherical AcrySof ReSTOR. Further studies are needed to assess the stability, photic phenomena, such as starbursts and halos, patient satisfaction, the role of pupil size after this multifocal IOL implantation and intermediate visual acuity for comparison with others IOLs profiles. REFERENCES

CS= contrast sensitivity; cpd= cycles per degree. Figure 3. Contrast sensitivity functions after refractive lens exchange with the aspheric AcrySof ReSTOR implantation in myopic and hyperopic group as a function of the dis­­­­­­­ tance and FACT chart luminance (85, 5 and 2.5 cd/m2).

pupil diameters when an aspheric IOL is implanted, compared with that found in eyes with a spherical IOL(27). Maxwell et al.(23) compared the optical performance in RLE with 6 presbyopia-correcting IOLs of different designs (3 spherical models: Crystalens AT-50SE, AcrySof ReSTOR SA60D3 and ReZoom NXG1; 3 aspheric models: AcrySof ReSTOR SN6AD3, Acri.Lisa 366D, and Tecnis ZM900). They found that the aspheric AcrySof ReSTOR SN6AD3 IOL showed superior optical properties when the modulation transfer function and the United States Air Force 1951 Resolution Target in optical bench testing were analyzed. If we now compare the post-surgery CSF results found in both groups, similar outcomes were reported (see figure 3). Statistically significant differences were found related to pupil size between both groups (p<0.01), the pupil size in myopic group was slightly higher compared to that found in the hyperopic group (see table 1). According to the light distribution between distance and near foci, in this group a higher percentage of the light contributes to distance image but we need also to consider that there is an increasing effect of higher order optical aberrations especially in hybrid IOLs when the pupil increases. The balance between the advantage and disadvantage of the large pupils (light distribution versus optical aberrations) could be the reason of finding similar results in both groups. In general, the results found in both groups were similar in distance and near vision at the different lighting conditions (Figure 3) and pre and post-surgery (Figure 1 and 2) without statistically significant differences (p>0.002). Previous literature about CS with a multifocal

1. Leyland M, Pringle E. Multifocal versus monofocal intraocular lenses after cataract extraction. Cochrane Database Syst Rev. 2006;(4):CD003169. Update of Cochrane Database Syst Rev. 2003;(3):CD003169. Update in Cochrane Database Syst Rev. 2012; 9:CD003169. 2. Montés-Micó R, Alió JL. Distance and near contrast sensitivity function after multifocal intraocular lens implantation. J Cataract Refract Surg. 2003;29(4):703-11. 3. Montés-Micó R, España E, Bueno I, Charman WN, Menezo JL. Visual performance with multifocal intraocular lenses: mesopic contrast sensitivity under distance and near conditions. Ophthalmology. 2004;111(1):85-96. 4. Lindstrom RL. Food and Drug Administration study update. One year results from 671 patients with the 3M multifocal intraocular lens. Ophthalmology. 1993;100(1):91-7. 5. Walkow T, Liekfeld A, Anders N, Pham DT, Hartmann C, Wollensak J. A prospective evaluation of a diffractive versus a refractive designed multifocal intraocular lens. Oph­­­thalmology. 1997;104(9):1380-6. 6. Schmidinger G, Simader C, Dejaco-Ruhswurm I, Skorpik C, Pieh S. Contrast sensitivity function in eyes with diffractive bifocal intraocular lenses. J Cataract Refract Surg. 2005;31(11):2076-83. 7. Alfonso JF, Fernández-Vega L, Señaris A, Montés-Micó R. Quality of vision with the Acri. Twin asymmetric diffractive bifocal intraocular lens system. J Cataract Refract Surg. 2007;33(2):197-202. Comment in J Cataract Refract Surg. 2007;33(2):173-4. 8. Kohnen T, Allen D, Boureau C, Dublineau P, Hartmann C, Mehdorn E, et al. Euro­ pean multicenter study of the AcrySof ReSTOR apodized diffractive intraocular lens. Ophthalmology. 2006;113(4):584.e1. 9. Alfonso JF, Fernández-Vega L, Baamonde MB, Montés-Micó R. Prospective visual evaluation of apodized diffractive intraocular lenses. J Cataract Refract Surg. 2007; 33(7):1235-43. 10. Fernández-Vega L, Alfonso JF, Montés-Micó R, Amhaz H. Visual acuity tolerance to residual refractive errors in patients with an apodized diffractive intraocular lens. J Cataract Refract Surg. 2008;34(2):199-204. 11. de Vries NE, Webers CA, Montés-Micó R, Tahzib NG, Cheng YY, de Brabander J, et al. Long-term follow-up of a multifocal apodized diffractive intraocular lens after cataract surgery. J Cataract Refract Surg. 2008;34(9):1476-82. 12. Alfonso JF, Fernández-Vega L, Señaris A, Montés-Micó R. Prospective study of the Acri. LISA bifocal intraocular lens. J Cataract Refract Surg. 2007;33(11):1930-5. 13. Alfonso JF, Fernández-Vega L, Valcárcel B, Montés-Micó R. Visual performance after AcrySof ReSTOR aspheric intraocular lens implantation. J Optom. 2008;1:30-5. 14. Alió JL, Elkady B, Ortiz D, Bernabeu G. Clinical outcomes and intraocular optical quality of a diffractive multifocal intraocular lens with asymmetrical light distribution. J Cataract Refract Surg. 2008;34(6):942-8. 15. Alfonso JF, Puchades C, Fernández-Vega L, Montés-Micó R, Valcárcel B, Ferrer-Blasco T. Visual acuity comparison of 2 models of bifocal aspheric intraocular lenses. J Cataract Refract Surg. 2009;35(4):672-6. 16. Alfonso JF, Fernández-Vega L, Amhaz H, Montés-Micó R, Valcárcel B, Ferrer-Blasco T. Visual function after implantation of an aspheric bifocal intraocular lens. J Cataract Refract Surg. 2009;35(5):885-92. 17. Packer M, Fine IH, Hoffman RS. Refractive lens exchange with the array multifocal intraocular lens. J Cataract Refract Surg. 2002;28(3):421-4. 18. Dick HB, Gross S, Tehrani M, Eisenmann D, Pfeiffer N. Refractive lens exchange with an array multifocal intraocular lens. J Refract Surg. 2002;18(5):509-18. 19. Fernández-Vega L, Alfonso JF, Rodríguez PP, Montés-Micó R. Clear lens extraction with multifocal apodized diffractive intraocular lens implantation. Ophthalmology. 2007;114(8):1491-8.

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20. Goes FJ. Refractive lens exchange with the diffractive multifocal Tecnis ZM900 in­ traocular lens. J Refract Surg. 2008;24(3):243-50. 21. Blaylock JF, Si Z, Aitchison S, Prescott C. Visual function and change in quality of life after bilateral refractive lens exchange with the ReSTOR multifocal intraocular lens. J Refract Surg. 2008;24(3):265-73. 22. Ferrer-Blasco T, Montés-Micó R, Cerviño A, Alfonso JF, Fernández-Vega L. Contrast sensitivity after refractive lens exchange with diffractive multifocal intraocular lens implantation in hyperopic eyes. J Cataract Refract Surg. 2008;34(12):2043-8. Comment in J Cataract Refract Surg. 2008;34(12):2005. 23. Maxwell WA, Lane SS, MD, Zhou F. Performance of presbyopia-correcting intraocular lenses in distance optical bench tests. J Cataract Refract Surg. 2009;35(1):166-71. Comment in J Cataract Refract Surg. 2010;36(6):1060-2; author reply 1062-3. 24. Leysen I, Bartholomeeusen E, Coeckelbergh T, Tassignon MJ. Surgical outcomes of intraocular lens exchange: five-year study. J Cataract Refract Surg. 2009;35(6):1013-8. 25. Alfonso JF, Fernández-Vega L, Valcárcel B, Ferrer-Blasco T, Montés-Micó R. Outcomes

and patient satisfaction after presbyopic bilateral lens exchange with the ResTOR IOL in emmetropic patients. J Refract Surg. 2010;26(12):927-33. 26. Davison JA, Simpson MJ. History and development of the apodized diffractive in­ traocular lens. J Cataract Refract Surg. 2006;32(5):849-58. 27. Montés-Micó R, Ferrer-Blasco T, Cerviño A. Analysis of the possible benefits of aspheric intraocular lenses: review of the literature. J Cataract Refract Surg. 2009;35(1):172-81. Comment in J Cataract Refract Surg. 2009;35(6):962-3; author reply 963-4. 28. Rodríguez-Galietero A, Montés-Micó R, Muñoz G, Albarrán-Diego C. Comparison of contrast sensitivity and color discrimination after clear and yellow intraocular lenses implantation J Cataract Refract Surg. 2005;31(9):1736-40. 29. Rodríguez-Galietero A, Montés-Micó R, Muñoz G, Albarrán-Diego C. Blue-light filtering intraocular lens in patients with diabetes: contrast sensitivity and chromatic dis­­­crimination. J Catarac Refract Surg. 2005;31(11):2088-92. 30. Regan D, Neima D. Low-contrast letter charts as a test of visual function. Ophthalmology. 1983;90(10):1192-200.

Simpósio Internacional de Córnea do Hospital de Olhos de Sorocaba

24 a 26 de outubro de 2013 Sorocaba (SP)

Organização: Hospital de Olhos de Sorocaba

Informações: Tel.: (15) 3212-7077 E-mail: [email protected]

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Artigo Original | Original Article

Efeito hipotensor de três formulações diferentes do tartarato de brimonidina em olhos normais Hypotensive effect of three different formulations of brimonidine tartrate in normal eyes Tulio Batista Abud1, Marcio Scuoteguazza Filho2, Edjane Souza Santos Oliveira2, Jorge Felipe Abud2, João Antonio Prata Junior3

RESUMO

ABSTRACT

Objetivo: Comparar o efeito hipotensor a curto prazo das três formulações de colírio de tartarato de brimonidina, Alphagan®, Alphagan® P e Alphagan® Z em olhos normais. Método: Estudo prospectivo, randomizado, duplo-cego que contou com 60 vo­­­­­ luntários, os quais foram submetidos a exame oftalmológico inicial e aferição da pressão intraocular (PIO). Os participantes foram distribuídos em três grupos: 1 tartarato de brimonidina 0,15%, 2 tartarato de brimonidina 0,2% e 3 tartarato de brimonidina 0,1%, aleatoriamente, cada um recebeu uma gota de colírio em cada olho e a pressão intraocular foi aferida após 30 minutos, 1 hora e 2 horas. Resultados: Observou-se que todas as concentrações de tartarato de reduziram significativamente a pressão intraocular durante o tempo estudado, com p<0,05. Ao ser analisada a diferença percentual do efeito hipotensor de cada grupo, verificou-se que não há diferença significativa entre os colírios estudados: (1) -13,50%, (2) -11,50%, (3) -11,90% após 30 minutos (p=0,650); (1) -24,30%, (2) -18,60%, (3) -18,30% após 1 hora (p=0,324); (1) -29,14% (2) -21,20%, (3) -25,60% após 2 horas (p=0,068). Conclusão: Não há diferença estatisticamente significativa para redução da pres­­ são intraocular (no período de pico) entre as três formulações de brimonidina.

Purpose: To compare the hypotensive effect in normal eyes of three formulations with different concentrations of brimonidine tartrate: 0.2%; 0.15% and 0.1%. Methods: Prospective, randomized, double-blind study included 60 volunteers, who underwent initial ophthalmologic examination and measurement of intraocular pressure (IOP). Individuals were divided into three groups: (1) brimonidine tartrate 0.15%, (2) brimonidine tartrate 0.2% and (3) brimonidine tartrate 0.1% and randomly received one drop each of drops in each eye. The IOP was measured after 30 minutes, 1 hour and 2 hours. Results: We found that all concentrations of brimonidine tartrate significantly reduced intraocular pressure during the study period, with p<0.05. When analyzing the percentage difference of the hypotensive effect of each group, we found no significant difference between the studied groups: (1) -13.50%, (2) -11.50%, (3) -11.90% after 30 minutes (p=0.650); (1) -24.30%, (2) -18.60%, (3) -18.30% after 1 hour (p=0.324); (1) -29.14%, (2) -21.20%, (3) -25.60% after 2 hours (p=0.068). Conclusion: There is no statistically significant difference in intraocular pressure re­ duction (peak period) between the three formulations of brimonidine.

Descritores: Quinoxalinas; Anti-hipertensivos/administração & dosagem; Pressão intraocular; Tonometria ocular; Humor aquoso; Soluções oftálmicas; Estudos comparativos

Keywords: Quinoxalines; Antihypertensive agents/administration & dosage In­­­­t rao­­­ cular pressure; Tonometry, ocular; Aqueous humor; Ophtalmic solutions; Com­­­pa­­­ rative study

INTRODUÇÃO Desde o início do uso em 1996 da solução oftalmológica de tar­­­ tarato de brimonidina 0,2% (Alphagan®; Allergan, Irvine, CA), este agonista adrenérgico seletivo alfa-2 provou ser um efetivo e seguro agente para controle a longo prazo do glaucoma e da hipertensão ocular(1,2). O mecanismo pelo qual esta droga reduz a pressão intraocular (PIO) é principalmente pela diminuição da produção de humor aquoso e em menor importância pelo aumento da drenagem uveoescleral(2,3). Sua eficácia quando usada duas vezes ao dia é comparada à do maleato de timolol 0,5%, sendo considerada uma efetiva opção para monoterapia, terapia adjuvante e de substituição(4-6). É ainda considerada eficaz na prevenção da elevação da PIO após aplicação de laser na câmara anterior, como demonstrado por Chen e Seong(7,8). Alguns efeitos colaterais oculares são mais frequentes quando comparados com outras drogas, como secura ocular, edema

palpebral e sensação de ardor(9-11). Estudos mostraram menor risco de efeitos colaterais sistêmicos quando comparada com os beta-blo­ queadores(4,9,10,12,13). O colírio de tartarato de brimonidina 0,15% (Alphagan P®, Aller­­gan, Irvine, CA) teve em sua fórmula a substituição do conservante cloreto de benzalcônio pelo Purite® (Allergan). O primeiro é o con­­­servante antimicrobiano mais usado nas formulações tópicas oftalmológicas(14,15). Em altas concentrações é mais tóxico do que outros conservantes, podendo acumular por longos períodos nos tecidos oculares e induzir morte celular dose-dependente(16,17). Em contraste, Purite® (Allergan) é um microbicida com grande espectro antimicrobiano e muito baixo nível de toxicidade em células mamíferas(18). Quando exposto à luz, é con­­­vertido em componetes naturais da lágrima(19). Além da troca do conservante o Alphagan P® (Allergan, Irvine, CA) teve uma redução de 25% de droga ativa em sua fórmula. Estudos em

Submetido para publicação: 21 de junho de 2012 Aceito para publicação: 20 de janeiro de 2013

Financiamento: No specific financial support was available for this study.

Estudo realizado no Departamento de Oftalmologia Universidade Federal do Triângulo Mineiro Uberaba (MG). Physician, Setor de Córnea e Cirurgia Refrativa, Hospital Oftalmológico de Sorocaba/Banco de Olhos de Sorocaba, Sorocaba (SP), Brazil. 2 Physician, Departamento de Oftalmologia, Universidade Federal do Triângulo Mineiro, Uberaba (MG), Brazil. 3 Physician, Universidade Federal do Triângulo Mineiro, Uberaba (MG), Brazil. 1

Divulgação de potenciais conflitos de interesses: T.B.Abud, Nenhum; M.Scuoteguazza Filho, Nenhum; E.S.S.Oliveira, Nenhum; J.F.Abud, Nenhum; J.A.Prata Jr., Nenhum. Endereço para correspondência: Túlio Batista Abud. Rua Major Eustáquio, 662 - Apto. 101 Uberaba (MG) - 38010-270 - Brasil - E-mail: [email protected] Projeto CEP: 1495 - Universidade Federal do Triângulo Mineiro.

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Efeito hipotensor de três formulações diferentes do tartarato de brimonidina em olhos normais

animais sugerem que a biodisponibilidade do tartarato de brimonidina é maior quando formulado com Purite® (Allergan)(20). Por isso, Katz sugeriu que a formulação com 0,15% de tartarato de brimonidina possui mesma eficácia em reduzir a PIO quando comparada à de 0,2%(21). Alguns autores reportaram resultados semelhantes(22). Entretanto, estudo realizado por outros autores relata que em pacientes com íris marrom escura, tartarato de brimonidina 0,2% possui maior capacidade de reduzir a PIO(23). Seguindo o raciocínio de biodisponibilidade, foi lançado no mercado o Alphagan Z® (Allergan, Irvine, CA), o qual possui concentração da droga de 0,1%, mantendo o conservante Purite® na formulação. Quando usado duas vezes ao dia, teve mesma eficácia em reduzir a PIO comparado ao Alphagan P® (Allergan, Irvine, CA) em estudo randomizado de 12 meses(24). Entretanto, mostrou-se mais seguro quanto à reação sistêmica e toleralibilidade(25). Foi superior também à brinzolamida 1% na redução da PIO quando utilizado como terapia adjuvante ao latonoprost(26). O objetivo do presente estudo é avaliar o efeito hipotensor de três formulações de tartarato de brimonidina em pacientes normais a curto prazo. MÉTODOS Estudo prospectivo, duplo cego, randomizado, o qual foi realizado pelo departamento de glaucoma da Universidade Federal do Triângulo Mineiro, sob aprovação do comitê de ética pelo número de protocolo 1495. Os inclusos no estudo foram voluntários entre 18 e 60 anos sem patologia oftalmológica diagnosticada, sendo excluídos gestantes, menores de idade e idosos (>60 anos). Após exames de acuidade visual, biomicroscopia e fundo de olho, os 60 voluntários foram submetidos à aferição da PIO de ambos os olhos antes da instilação do colírio. Cada colírio recebeu uma numeração que era desconhecida tanto pelo médico examinador quanto pelo voluntário. Foi assim distribuído: colírio 1 tartarato de brimonidina 0,15% (Alphagan P®; Allergan, Irvine, CA) - 40 olhos, co­­­lírio 2 tartarato de brimonidina 0,2% (Alphagan®; Allergan, Irvine, CA) - 40 olhos, e colírio 3 tartarato de brimonidina 0,1% (Alphagan Z®; Allergan, Irvine, CA) - 40 olhos. Após a instilação de uma gota de colírio em cada olho, a PIO do voluntário era aferida após 30 minutos, 1 hora e 2 horas, utilizando o mesmo tonômetro de aplanação de Goldmann. Em cada voluntário foi utilizada a mesma formulação para ambos os olhos. Os dados estatísticos descritivos foram calculados, para realizar a comparação entre os períodos de estudo dentro de cada grupo utilizamos o teste de Friedman. Também foi analisada a variação da PIO pós instilação do colírio em valores porcentuais em relação à PIO inicial. As diferenças entre os grupos foram comparadas pelo teste de Kruskal-Wallis. Durante o tempo de avaliação da PIO os pacientes foram arguidos sobre efeitos colaterais sistêmicos e/ou locais.

RESULTADOS A amostra analisada foi composta por 120 olhos de 60 voluntá­­ rios com idade média (± desvio padrão) de 32,84 (± 10,81), sendo cada grupo composto por 40 olhos. Na tabela 1 consta as médias da pressão intraocular (PIO) com respectivos desvios padrões de cada colírio em relação ao tempo pré e pós instilação. Observou-se que todas as concentrações de tartarato de brimonidina (0,2%, 0,15%, 0,1%) reduziram a PIO durante o tempo estudado de forma estatisticamente significante (p<0,001 para colírios 1, 2 e 3). Ao ser analisada a diferença porcentual do efeito hipotensor de cada grupo, verificou-se que não há diferença significativa entre os colírios estudados: (1) -13,50%, (2) -11,50%, (3) -11.90% após 30 minutos (p=0,650); (1) -24,30%, (2) -18,60%, (3) -18,30% após 1 hora (p=0,324); (1) -29,14% (2) -21,20%, (3) -25,60% após 2 hora (p=0,068), como demonstrado no gráfico 1. Não foram relatados efeitos adversos sistêmico e locais após instilação dos colírios. DISCUSSÃO Neste estudo randomizado e duplo cego, as três formulações do colírio de tartarato de brimonidina mostraram-se eficazes na redução da PIO em pacientes sem patologia ocular, como relatado por diversos estudos na literatura. Durante o período de acompanhamento da PIO, não houve diferença porcentual significativa entre os três colírios, portanto sendo de mesma eficácia. Este resultado confirma achados de outros estudos que mostraram mesma capacidade de reduçao da PIO, entre estas formulações, porém sempre compararam somente duas das formulações. Katz e

TB= colírio de Tartarato de Brimonidina Gráfico 1. Comparação da redução porcentual média da pressão intraocular entre os grupos estudados nos diferentes intervalos de tempo após a instilação.

Tabela 1. Pressões intraoculares pré e pós-instilação do colírio estudado nos grupos 1,2 e 3 Tartarato de brimonidina 0,15% Colírio 1 Tempo

Tartarato de brimonidina 0,10% Colírio 3

PIO média

DP

PIO média

DP

PIO média

DP

p

Pré

12,350

2,1

13,475

2,4

13,300

2,7

0,100

30 min

10,750

2,7

11,875

2,4

11,650

2,4

0,120

1 hora

09,325

2,4

10,775

2,2

10,770

2,5

0,010

2 horas

8,700

2,1

10,500

2,5

09,800

2,7

0,002

p

<0,001

PIO= pressão intraocular; DP= desvio padrão.

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Tartarato de brimonidina 0,20% Colírio 2

Arq Bras Oftalmol. 2013;76(2):69-71

<0,001

<0,001

Abud TB, et al.

Mundorf chegaram a conclusão que Alphgan P® (Allergan, Irvine, CA) e Alphagan® (Allergan, Irvine, CA) têm a mesma eficácia, enquanto Cantor afirmou que Alphagan P® (Allergan, Irvine, CA) e Alphagan Z® (Allergan, Irvine, CA) também compartilham de mesma eficácia(21,22,24). O presente estudo e os outros mencionados concordam que apesar da menor concentração ativa de droga, a biodisponibilidade com o uso do conservante Purite® (Allergan) é maior, e assim proporciona mesma ação da droga. Entretanto, Chan et al., reportaram que Alphagan® (Allergan, Irvine, CA) possui eficácia maior quando utilizado duas vezes ao dia em indivíduos com íris marrom escura quando comparado ao Alpha­­­­­­gan P® (Allergan, Irvine, CA)(23). Já foi descrito que a pigmentação iriana pode influenciar no efeito de drogas antiglaucomatosas, pois tecidos pigmentados obtiveram maior concentração da droga, e redução mais lenta da mesma(27,28). Em seu estudo Kim et al., relata que a durabilidade da ação dos colírios nesta população é diferente, sendo maior com Alphagan® (Allergan, Irvine, CA) e que a ação de pico é semelhante entre os colírios(23). Neste estudo analisou-se a ação dos colírios por um curto período de tempo, avaliando-se somente a ação hipotensora de pico dos mesmos, e não a durabilidade e efeito a longo prazo como os demais estudos. A população do estudo é heterogênia e randomizada, portanto não foi usado como critério de inclusão ou exclusão a coloração iriana. Em relação a efeitos colaterais locais e sistêmicos, o tempo de estudo foi muito curto para qualquer análise. Até mesmo no período de duas horas, não se pode fazer análises por causa do uso de colírio anestésico durante as aferições da PIO. Katz e Kim concordaram quando compararam Alphagan® (Allergan, Irvine, CA) e Alphagan P® (Allergan, Irvine, CA), que com a redução da concentração ativa da droga, os efeitos colaterais oculares são menores e menos severos. Já Cantor et al., relatou que Alphagan Z® (Allergan, Irvine, CA) é mais seguro quanto à reação sistêmica e tolerabilidade quando comparado ao Alphagan P®(Allergan, Irvine, CA)(24). Sullivan-Mee et al., testaram a taxa de hipersensibilidade ao colírio genérico de tartarato de brimonidina 0,2% em pacientes usuários sem sintomas de tartarato de brimonidina Purite® 0,15% (Allergan, Irvine, CA), e obtiveram como resultado que esta taxa é similar aos de usuários originais de brimonidina 0,2%. Publicaram ainda, que quando estes pacientes retornaram ao uso de brimonidina Purite® 0,15% (Allergan, Irvine, CA) cerca de 80% obtiveram sucesso, concluindo que o conservante e que a menor concentração de droga estão implicados na hipersensibilidade aos colírios(29). CONCLUSÃO Este estudo foi pioneiro na comparação entre as três formulações no quesito eficácia hipotensora a curto prazo. Necessita-se de um estudo prospectivo randomizado de longa duração, que compare as três formulações quanto à eficácia hipotensora de pico e a longo prazo, bem como tolerabilidade e efeitos colaterais sistêmicos e locais. Em suma, o presente estudo concluiu que não houve diferença estatisticamente significativa na redução da PIO no período de pico entre as três formulações de colírio de tartarato de brimonidina testadas. REFERÊNCIAS 1. Melamed A, David R. Ongoing clinical assessment of the safety profile and efficacy of brimonidine compared with timolol: year-three results. Brimonidine Study Group II. Clin Ther. 2000;22(1):103-11. 2. Walters TR. Development and use of brimonidine in treating acute and chronic elevations of intraocular pressure: a review of safety, efficacy, dose response, and dosing studies. Surv Ophthalmol. 1996;41(Suppl. 1):S19-26.

3. Toris CB, Gleaseon ML, Camras, CB, Yablonski ME. Effects brimonidine on aqueous humor dynamics in human eyes. Arch Ophthalmol. 1995;113(12):1513-7. 4. Schuman JS, Horwitz B, Choplin NT, David R, Albracht D, Chen K. A 1-year study of brimonidine twice-daily in glaucoma and ocular hypertension: A controlled, randomized, multicenter clinical trial. The Chronic Brimonidine Study Group. Arch Ophthalmol. 1997;115(7):847-52. Comment in: Arch Ophthalmol. 1999;117(3):417-9. 5. Lee DA. Efficacy of brimonidine as replacement therapy in patients with open-angle glaucoma or ocular hypertension. Clin Ther. 2000;22(1):53-65. 6. Lee DA, Gornbein J, Abrams C. The effectiveness and safety of brimonidine as mono-, combination, or replacement therapy for patients with primary open-angle glaucoma or ocular hypertension: a post hoc analysis of an open-label community trial. The Glaucoma Trial Study Group J Ocul Pharmacol Ther. 2000;16(1):3-18. 7. Chen TC, Ang RT, Grosskreuz CL, Pasquale LR, Fan JT. Brimonidine 0.2% versus apraclonidine 0.5% for prevention of intraocular pressure elevations after anterior segment laser surgery. Ophthalmology. 2001;108(6):1033-8. Comment in: Ophthalmology. 2002; 109(5):828-9; author reply 829. 8. Seong GJ, Lee YG, Lee JH, Lim SJ, Lee SC, Hong YJ, et al. Effect of 0.2% brimonidine in preventing intraocular pressure elevation after Nd:YAG laser posterior capsulotomy. Ophthalmic Surg Lasers. 2000;31(4):308-14. 9. Schuman JS. Clinical experience with brimonidine 0.2% and timolol 0.5% in glaucoma and ocular hypertension. Surv Ophthalmol. 1996;41(Suppl. 1):S27-37. 10. Katz LJ. Brimonidine tartrate 0.2% twice-daily vs. timolol 0.5% twice-daily: 1-year results in glaucoma patients. Brimonidine Study Group. Am J Ophthalmol. 1999;127(1):20-6. 11. Serle JB. A comparison of the safety and efficacy of twice-daily brimonidine 0.2% versus betaxolol 0.25% in subjects with elevated intraocular pressure. The Brimonidine Study Group. Surv Ophthalmol. 1996;41(Suppl. 1):S39-47. 12. LeBlanc RP. Tweilve-month results of an ongoing randomized trial comparing brimonidine tartrate 0.2% and timolol 0.5% given twice daily in glaucoma or ocular hypertension. The Brimonidine Study Group. Ophthalmology. 1998;105(10):1960-7. 13. Javitt J, Goldberg I. Comparison of the clinical success rates and quality of life effects of brimonidine tartrate 0.2% and betaxolol 0.25% suspension in patients with open-angle glaucoma and ocular hypertension. Brominidine Outcomes Study Group II. J Glaucoma. 2000;9(5):398-408. 14. Berdy GJ, Abelson MB, Smith LM, George MA. Preservative-free artificial preparations. Assessment of corneal epithelial toxic effects. Arch Ophthalmol. 1992;110(4):528-32. 15. Pisella PJ, Fillacier K, Elena PP, Debbasch C, Baudouin C. Comparison of the effects of preserved and unpreserved formulations of timolol on the ocular surface of albino rabbits. Ophthalmic Res. 1992;32(1):3-8. 16. Gasset AR, Ishii Y, Kaufman HE, Miller T, Cytotoxicity of ophthalmic preservatives. Am J Ophthalmol. 1974;78(1):98-105. 17. De Saint Jean M, Debbasch C, Brignole F, Rat P, Warnet JM, Baoudouin C. Toxicity of preserved and unpreserved glaucoma topical drugs in an in vivo model of conjunctival cells. Curr Eye Res. 2000;20:85-94. 18. Grant R, Ajello M, Vlass E. Salt water or high tech? A look at two new rising solutions for contact lenses. Opician. 1996;212:38-41. 19. Masschelein WJ. Chlorine dioxide, chemistry and environmental impact of oxychlorine compounds. An Arbor, MI: Ann Arbor Science; 1979. 20. Data on file. Department of Pharmacokinetics and Drug Metabolism. Irvine: Allergan; 1999. 21. Katz LJ. Twelve-month evaluation of brimonidine-purite versus brimonidine in patients with glaucoma or ocular hypertension. J Glaucoma. 2002;11(2):119-26. 22. Mundorf T, Williams R, Whitcup S, Felix C, Batoosingh A. A 3-month comparison of efficacy ans safety of brimonidine-purite 0.15% and brimonidine 0.2% in patients with glaucoma or ocular hypertension. J Ocul Pharmacol Ther. 2003;19(1):37-44. Erratum in: J Ocul Pharmacol Ther. 2004;20(4):372. 23. Kim CY, Hong S, Seong GJ. Brimonidine 0.2% versus brimonidine Purite 0.15% in Asian ocular hypertension. J Ocul Pharmacol Ther. 2007;23(5):481-6. 24. Cantor LB, Safyan E, Liu CC, Batoosingh AL. Brimonidine-purite 0.1% versus brimonidine-purite 0.15% twice daily in glaucoma or ocular hypertension: a 12-month randomized trial. Curr Med Res Opin. 2008;24(7):2035-43. 25. Cantor LB, Liu CC, Batoosingh AL, Holland DA. Safety and tolerability of brimonidine purite 0.1% and brimonidine purite 0.15%: a meta-analysis of two phase 3 studies. Curr Med Res Opin. 2009;25(7):1615-20. 26. Day DG, Hollander DA. Brimonidine purite 0.1% versus brinzolamide 1% as adjunctive therapy to latanoprost in patients with glaucoma or ocular hypertension. Curr Med Res Opin. 2008;24(5):1435-42. 27. Acheampong AA, Shackleton M, Tang-Liu DD. Comparative ocular pharmacokinetics of brimonidine after a single dose application to the eyes of albino and pigmented rabbits. Drug Metab Dispos. 1995;23(7):708-12. 28. Acheampong AA, Shackleton M, Jonh B, Burke J, Wheeler L, Tang-Liu D. Distribution of brimonidine into anterior and posterior tissues of monkey, rabbit, and rat eyes. Drug Metab Dispos. 2002;30(4):421-9. 29. Sullivan-Mee M, Pensyl D, Alldredge B, Halverson K, Gerhardt G, Qualls C. Brimonidine hypersensitivity when switching between 0,2% and 0,15% formulations. J Ocul Phar­­­ macol Ther. 2010;26(4):355-60.

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71

Artigo Original | Original Article

Prognostic implications of cytopathologic classification of melanocytic uveal tumors evaluated by fine-needle aspiration biopsy Implicação prognóstica da classificação citopatológica dos tumores melanocíticos da úvea avaliados pela biópsia aspirativa com agulha fina James Jay Augsburger1, Zélia Maria Corrêa1, Nikolaos Trichopoulos2

ABSTRACT

RESUMO

Purpose: Determine whether cytopathologic classification of melanocytic uveal tumors evaluated by fine-needle aspiration biopsy (FNAB) is a significant prognostic factor for death from metastasis. Methods: Retrospective analysis of cases of clinically diagnosed uveal melanoma evaluated by fine-needle aspiration biopsy from 1980 to 2006. Main outcome evaluated was death from metastasis. Associations between baseline clinical variables and cytopathologic classification were evaluated using cross-tabulation. Prognostic significance of cytopathologic classification was evaluated by Ka­planMeier and Cox proportional hazards analysis. Results: Of 302 studied biopsies, 260 (86.1%) yielded sufficient cells for cytopathologic classification. Eighty of the 260 patients who had a sufficient specimen have already died (P=0.021), 69 from metastatic uveal melanoma. Cell type assigned by cytopathology was strongly associated with metastasis/metastatic death in this series (P=0.0048). Multivariate analysis showed cytopathologic classification to be an independently significant prognostic factor for metastatic death (P=0.0006). None of the 42 patients whose tumor yielded insufficient aspirates (sampled in at least two sites) have developed metastasis or died of metastasis thus far. Conclusion: In this series, cytopathology of fine-needle aspiration biopsy samples obtained from uveal melanomas was strongly prognostic of death from metastasis. Insufficiently aspirates (2 or more sites sampled) proved to be prognostic of a favorable outcome (i.e., not developing metastasis).

Objetivo: Determinar se a classificação citopatológica de tumores melanocíticos da úvea avaliados pela biópsia aspirativa com agulha fina (BAAF) é um fator prognóstico significativo para óbito por metástases. Métodos: Análise retrospectiva de casos diagnosticados clinicamente como melanoma uveal e avaliados pela biópsia aspirativa com agulha fina entre 1980 e 2006. O evento principal analisado foi óbito por metástase. Associações entre variáveis clínicas à apresentação e classificação citopatológica foram avaliadas usando tabulação cruzada. Significância prognóstica da classificação citopatológica foi avaliada por análise de riscos proporcionais de Cox e Kaplan-Meier. Resultados: Das 302 biópsias estudadas, 260 (86,1%) renderam um número suficiente de células para classificação citopatológica. Oitenta dos 260 pacientes que obtiveram um espécime suficiente (adequado) foram a óbito (P=0,021), 69 destes por melanoma uveal metastático. O tipo celular designado pela citopatologia apresentou forte associação com metástase/óbito por metástase nessa série (P=0,0048). Análise multivariada mostrou que a classificação citopatológica foi um fator prognóstico independente significativo para o óbito por metástase (P=0,0006). Nenhum dos 42 pacientes cujos tumores renderam um aspirado insuficiente (quando foram amostrados pelo menos 2 sítios) desenvolveu metástase e foi a óbito por metástase até o presente momento. Conclusão: Nessa série, a citopatologia dos espécimes obtidos pela biópsia aspirativa com agulha fina de melanomas uveais foi fortemente prognóstica para óbito por metástase. Os aspirados insuficientes (se duas ou mais áreas foram amostradas) provou ser um resultado prognóstico favorável (i.e., de não desenvolvimento de metástases).

Keywords: Choroid neoplasms; Melanoma/diagnosis; Cytodiagnosis; Melanoma/ surgery; Biopsy needle/methods; Biopsy, fine-needle; Uveal neoplasms/pathology

Descritores: Neoplasias da coróide; Melanoma/diagnóstico; Citodiagnóstico; Me­­ lanoma/cirurgia; Biopsia por agulha fina/métodos; Neoplasias uveais/patologia

INTRODUCTION Fine-needle aspiration biopsy (FNAB) has been used in a number of ophthalmic centers since the late 1970s and early 1980s as an ancillary diagnostic tool in selected cases of suspected primary uveal melanoma (1-12). In most of these early cases, the objective of the FNAB was to establish, confirm, or refute the clinical diagnosis of the evaluated intraocular tumor and direct baseline systemic evalua­ tion of the patient, treatment of the primary intraocular tumor, and post-treatment follow-up(1,4,5,9,13-15). Over the years, various authors have described and illustrated the cytomorphological and immuno­ cytochemical features of melanocytic uveal tumor cells obtained

by FNAB(1,13,15-21) and the relative frequencies of spindle, epithelioid, mixed and necrotic tumor cells in the obtained specimens(13,15,17). A few groups of investigators have described the correlation between cytopathological and histopathological classification of the uveal me­­­­lanoma cells in cases treated by enucleation or transcleral tumor resection,(4,10,15,17,22) and some investigators have also reported the frequency of insufficient aspirates for cytopathological diagnosis in their series and factors associated with this result (3,8,10,21-27).. To our knowledge, only one group of investigators has reported comparative cumulative actuarial survival curves of subgroups of patients with different cytopathologically assigned cell types in a peer reviewed

Submitted for publication: August 17, 2012 Accepted for publication: January 27, 2013

Funding: This work was supported in part by an Unrestricted Grant from Research to Prevent Blindness, Inc., New York, New York, to the Department of Ophthalmology, University of Cincinnati College of Medicine (James J. Augsburger, M.D., Chairman) and the Quest for Vision Fund of the Department of Ophthalmology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Study carried out at Department of Ophthalmology, University of Cincinnati College of Medicine. 1 2

Physician, Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio, USA. Physician, Clinic Eye Center, Wisconsin, USA.

Disclosure of potential conflicts of interest: J.J.Augsburger, None; Z.M.Corrêa, None; N.Trichopoulos, None. Correspondence address: Zélia M. Corrêa. 260 Stetson Street - Suite 5300 - Cincinnati - OH 45267 - USA - E-mail: [email protected] Protocolo de Comite de Ética e Pesquisa da Universidade de Cincinnati: 07-08-23-03 EE.

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Augsburger JJ, et al.

journal to date(15,28). These authors showed that the cumulative actua­ rial probabilities of metastasis and metastatic death increased as the percentage of epithelioid cells in the aspirate increased. Starting a little over a decade ago, investigators around the world began to report that chromosomal and transcriptional features of primary uveal melanoma cells were strongly associated with the pa­­­­tient’s likelihood of developing subsequent extraophthalmic metastasis and metastatic death(25,29-35) Several authors have shown that these chromosomal and transcriptional features can be determined on tumor specimens obtained by FNAB changing the indication for FNAB from purely diagnostic to investigational-prognostic(24,25,36-38). During the past few years, investigators from several of these centers have reported their experience with cytogenetic testing of the obtained FNAB aspirates(25,27,35,37,39-41). In some of these centers, the results of FNAB are already being used clinically to inform patients of their metastatic risk, direct surveillance testing for metastasis, and even identify high risk subgroups for possible future recruitment into clinical trials of adjuvant therapies intended to prevent or delay the onset of metastasis(25,35,40,42) However, in most reported studies of investigational-prognostic testing of uveal melanomas sampled by FNAB, cytopathologic diagnosis of the obtained tumor cells has not been reported. Meanwhile, many centers throughout the world do not have the resources to perform chromosomal and cytogenetic studies but cytopathology is readily available. The purpose of this study reported is to determine whether the cytopathological classification of the tumor cells obtained by FNAB in our diagnostic series accumulated prior to the start of our collaborative prognostic study was a significant prognostic indicator of the patients’ probability of metastatic death. METHODS The authors performed a retrospective descriptive study and out­­­comes analysis of all patients in our FNAB experience who had a melanocytic choroidal or ciliary body tumor suspected of being a primary uveal melanoma (i.e., having a pre-FNAB clinical diagnosis of unequivocal uveal melanoma, probable uveal melanoma but with atypical or dormant features, or melanocytic uveal nevus versus me­­­­­­­lanoma) during the years 1980 through 2006. This retrospective review has been approved by the Institutional Review Boards of all participating institutions (Wills Eye Hospital, Philadelphia, PA, USA (JJA); University of Cincinnati, Cincinnati, OH, USA (JJA, ZMC, and NT); and Santa Casa - Porto Alegre (ISCMPA), Porto Alegre, RS, Brazil (ZMC)). All biopsies were performed by the authors (JJA, ZMC) and evaluated by 4 different certified cytopathologists in the different institutions as part of patient care. Because the aim of this study was to evaluate our data retrospectively to see if cytologic classification of uveal melanocytic tumors is a meaningful result regardless of the surgical and laboratory setting, as well as the expertise of the pathologist evalua­ting the aspirated specimens, cytology and pathology slides were not reviewed. The technique used for FNAB has been published(3,4). For our analysis, cellularity of FNAB aspirates was classified dichotomously as sufficient or insufficient for cytopathologic classification. Insufficient aspirates were defined by the cytopathologist that analyzed the slides at the time of each FNAB as completely acellular or extremely paucicellular: less than 15 cells or red blood cells and de­­­bris only. To eliminate technical problems with the FNAB as a potential explanation for an insufficient aspirate, we excluded all cases of insufficient specimen that had been sampled only once by FNAB. The tumors that yielded a sufficient specimen for cytopathologic diagnosis were classified as spindle cell melanoma, epithelioid cell melanoma, mixed cell type (i.e., combined spindle and epithelioid cell types) melanoma, necrotic melanoma, unspecified melanoma (i.e., cells were ruptured or distorted precluding cell type classification), borderline melanocytic tumor (i.e., nevus versus melanoma), or

benign melanocytic nevus. This data was abstracted from the official pathology reports generated at the time of initial assessment of each set of specimens. No attempt was made to review or reclassify any specimens. The decision not to review the slides systematically was based on the fact that although specimen processing and cytopathological analysis followed similar standards, they were performed in multiple different laboratories in different hospitals in two different US states and two countries. Other features evaluated in this study were tumor size (largest linear basal diameter estimated from fundus mapping and thickness measured by A-scan ultrasonographic biometry), location of the anterior tumor margin relative to the ora serrata, patient age, patient gender, presence or absence of symptoms attributable to the intraocular tumor, best corrected distance visual acuity (Snellen notation) at the time of biopsy, pre-FNAB clinical diagnosis or differential diagnosis (nevus versus melanoma, probable melanoma but atypi­ cal, unequivocal melanoma), and indication for FNAB (diagnostic uncertainty, investigation [cytologic-histologic correlation], patient request for pathologic confirmation of the clinical diagnosis prior to consenting to recommended treatment). Data analysis included data summarization, analysis of the associations between sufficiency of the FNAB aspirates and other study variables and between cytopathologic classification and other study variables, and univariate and multivariate prognostic factor analysis of sufficiency of the FNAB aspirates for cytopathologic clas­­­­­sification and cytopathologic classification. Data summarization consisted of description of study variables, determination of minimum, maximum, mean and median values of all continuously distributed numerical variables, determination of counts and percentages of all intrinsically categorical study variables and of ordinal categorical subgroups of the continuously distributed numerical variables. Our analysis of as­­so­­­­ciation between relevant study variables consisted of cross tabulation analysis of the relationship bet­ ween sufficiency of the aspirates and selected independent study variables such as patient age [≤50 years, >50 to ≤65 years, or >65 years], patient gender, symptoms attributable to the tumor, largest linear basal diameter of tumor (≤10 mm, >10 to ≤15 mm, or >15 mm) estimated by fundus cartography, tumor thickness (≤3.5 mm, >3.5 to ≤7 mm, or >7 mm) measured by ultrasonographic A-scan biometry, tumor location (exclusively choroidal versus involving ci­­­liary body), pre-FNAB diagnosis or differential diag­­­nosis, and in­­­ dication for the FNAB and between cytopathologic classification of the cells obtained by FNAB and the same independent study variables. The strength of the associations between the evaluated pairs of variables was evaluated by chi-squared testing. Univariate assessment of the prognostic significance of sufficien­ cy of the FNAB aspirates and cytopathological classification of the tumor was performed by plotting and comparing Kaplan-Meier survival curves of the subgroups. The outcome evaluated in this analysis was patient death from metastatic uveal melanoma. Length of survival was computed as the interval between date of FNAB and date of death or most recent encounter in surviving patients. The significance of differences between the curves was determined using the log rank test. Multivariate analysis of the independent prognostic significance of sufficiency of the FNAB aspirates and cytopathologic classification of the tumor was performed using Cox proportional hazards modeling. A stepdown procedure was followed in this analysis, starting with all of the evaluated baseline study variables and eliminating the least significant variable (P≥0.1 to remove) in a stepwise fashion until only significant variables (P≤0.05) remained. All data analysis was performed using the commercially available statistical program SPSS 11.0 for Windows. A nominal alpha level of 0.05 was selected in advance of data analysis as our threshold for assigning statistical significance to differences revealed by the various statistical tests employed in this study.

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Prognostic implications of cytopathologic classification of melanocytic uveal tumors evaluated by fine-needle aspiration biopsy

RESULTS Review of our patient logbooks identified 448 cases of FNAB of solid intraocular tumors performed by the authors during the specified study period, 323 biopsies fulfilled our inclusion criteria. Twen­tyone of these cases were excluded prior to data analysis because they had been sampled at only one site and yielded an insufficient aspirate. The final study group after these exclusions consisted of 302 cases. The 302 patients ranged in age from 18 years to almost 90 years (mean 55.4 years, median 57.2 years). Other summary data on the evaluated study variables are presented in table 1. Of the 302 study biopsies, 260 (86.1%) yielded a sufficient number of cells for cytopathologic classification. In these 260 cases, the tumor cells were classified as malignant in 225 (86.6%), borderline [melanocytic nevus versus melanoma] in 24 (9.2%), and benign [me­­­ lanocytic nevus cells] in 11 (4.2%). Of the 225 tumors classified as malignant, the melanoma cell type was classified as epithelioid in 35 (15.6%), mixed in 31 (13.8%), spindle in 96 (42.7%), necrotic in 1 (0.4%), and unspecified in 62 (27.5%). The associations between sufficiency of the FNAB aspirates for cytopathologic classification and the independent study variables are presented in table 2. Inspection of this table shows that an insufficient specimen for cytopathologic classification was strongly

Table 1. Summary descriptive data on 302 cases of melanocytic choroidal and ciliary body tumors evaluated by FNAB Count

(%)

Young (age ≤50)

103

(34.1)

Intermediate (age >50 but ≤65)

102

(33.8)

Older (age >65)

097

(32.1)

Male

141

(46.7)

Female

161

(53.3)

Absent

067

(22.2)

Present

235

(77.8)

Good (va ≥20/40)

153

(50.7)

Intermediate (va <20/40 but >2/200

059

(19.5)

Poor (va ≤20/200)

090

(29.8)

Small (lbd ≤10)

122

(40.4)

Medium (lbd >10 but ≤15)

124

(41.1)

Large (lbd >15)

056

(18.5)

Thin (th ≤3.5)

118

(39.0)

Intermediate (th >3.5 but ≤7)

086

(28.5)

Thick (th >7)

098

(32.5)

Baseline variable Categories of variable Age (yr)

Sex

Symptoms

Best corrected distance visual acuity (va)

Largest basal diameter (lbd) of tumor (mm)

Thickness (th) of tumor (mm)

Intraocular location of tumor Exclusively choroidal

227

(75.2)

Involving ciliary body

075

(24.8)

74

Arq Bras Oftalmol. 2013;76(2):72-9

asso­­­ciated with smaller tumor size (especially thickness ≤3.5 mm), ex­­­clusively choroidal tumor location, lack of symptoms attributable to the tumor, clinical diagnosis of the tumor as a nevus versus melanoma, major diagnostic uncertainty as the indication for FNAB. The associations between cytopathologic classification of the tumor as­­ pirates and the independent study variables are presented in table 3. Inspection of this table shows that presence of symptoms, poor pre-FNAB visual acuity, large basal tumor diameter, thick tumor, ciliary body location, pre-FNAB clinical diagnosis of unequivocal melanoma, and patient request for pathologic confirmation of the clinical diagnosis were also significantly associated with death from metastasis. Eighty-two of the 302 study patients died through available fol­­­­low-up. The duration of follow-up after FNAB among surviving patients ranged from none at all (3 patients, 1.4%) to 7.3 years (median follow-up time=57.2 months). Two hundred sixty-six surviving patients (88.1%) had been followed for over 1 year after the FNAB, 215 (71.2%) had been followed for over 2 years after the FNAB, and 184 (60.9%) had been followed for over 3 years after the FNAB. The comparative survival curves of patients without and with a sufficient aspirate for cytopathologic diagnosis are shown in figure 1. Only 2 of the 42 patients whose tumor was sampled in at least two sites but nevertheless yielded insufficient aspirates from all sampled sites had died prior to the analysis date of this study. Neither of these patients died of metastatic uveal melanoma. In contrast, 80 of the 260 patients whose tumor yielded a sufficient specimen had died prior to the analysis date of this study. In 69 of these 80 patients, the cause of death was metastatic uveal melanoma. This difference was statistically significant (p=0.021, log rank test). In this series, patients whose tumor was classified as a mixed cell melanoma and those whose tumor was classified as a melanoma but not assigned a specific cell type by the pathologist had similar survival prognosis; consequently, we combined these patients for plotting of subgroup survival curves. Similarly, none of the patients whose tumor was classified as a benign nevus (n=11) or insufficient for cytopathologic classification (n=42) had died of metastatic uveal melanoma as of the analysis date of this study; consequently, we combined these patients for plotting of subgroup survival. Finally, we combined the one patient whose tumor was categorized as a necrotic melanoma with the subgroup of patients with epithelioid melanoma for plotting of subgroup survival. Figure 2 shows the survival curves of the patients in five subgroups defined by sufficiency versus insufficiency of the FNAB aspirates and melanocytic cell type simultaneously: (1) epithelioid cell or necrotic melanoma (n=36), mixed cell type or unspecified melanoma (n=93), spindle cell melanoma (n=96), borderline melanocytic choroidal tumor (n=24), and benign nevus or insufficient aspirate (n=53). Five-year melanoma specific mortality was 47.1% for the epithelioid cell and necrotic melanoma subgroup, 32.3% for the combined mixed cell type and unspecified melanoma subgroup, 19.0% for the spindle cell subgroup, 10.0% for the borderline melanocytic choroidal tumor subgroup, and 0% for the combined benign nevus and insufficient aspirate subgroup. The differences between these curves are all statistically significant (p=0.0048, log rank test of equality of survival curves). Cox proportional hazards modeling identified a three-term regression incorporating patient age (p=0.0003), largest linear basal dia­­­meter of the tumor (p=0.0018), and cytopathologic classification of the tumor cells obtained by FNAB (p=0.0006) as the best and only satisfactory 3-term model. Location of the tumor in the eye (exclusively choroidal versus involving ciliary body) did not prove to be a significant prognostic factor (p=0.18) when added to this model. DISCUSSION The results of our study indicate that cytopathologic classification of cells obtained by FNAB from melanocytic choroidal and ciliary body tumors diagnosed clinically as uveal melanomas is a significant

Augsburger JJ, et al.

Table 2. Association between baseline potential prognostic variables and sufficiency of FNAB aspirates for cytopathologic classification Sufficiency category of aspirates Insufficient (n=42)

Sufficient (n=260)

Count

(%)

Count

(%)

Younger (age ≤50)

10

(23.8)

093

(35.8)

Intermediate (age >50 but ≤65)

22

(52.4)

080

(30.8)

Older (age >65)

10

(23.8)

087

(33.5)

Male

18

(42.9)

123

(47.3)

Female

24

(57.1)

137

(52.7)

Absent

22

(52.4)

045

(17.3)

Present

20

(47.6)

215

(82.7)

Small (lbd ≤10)

28

(66.7)

094

(36.2)

Medium (lbd >10 but ≤15)

14

(33.3)

110

(42.3)

Large (lbd >15)

0

(0.0)

056

(21.5)

Thin (th ≤3.5)

39

(92.9)

079

(30.4)

Intermediate (th > 3.5 but ≤7)

03

(7.1)

083

(31.9)

Thick (th >7)

0

(0.0)

098

(37.7)

Exclusively choroidal

40

(95.2)

187

(71.9)

Involving ciliary body

02

(4.8)

073

(28.1)

Nevus versus melanoma

29

(69.0)

040

(15.4)

Probable melanoma but atypical

11

(26.2)

073

(28.1)

Unequivocal melanoma

02

(4.8)

147

(56.5)

Major diagnostic uncertainty

40

(95.2)

113

(43.5)

Investigation (cytologic-histologic correlation)

01

(2.4)

111

(42.7)

Request for pathologic confirmation of diagnosis by informed patient

01

(2.4)

036

(13.8)

Chi-squared

df

P

7.57

2

<0.0230

0.29

1

<0.5900

25.8

1

<0.0010

18.1

2

<0.0010

59.7

2

<0.0010

10.3

1

<0.0010

65.3

2

<0.0001

38.9

2

<0.0010

Potential prognostic variables Categories of variable Age of patient (yr)

Gender of patient

Symptoms attributable to tumor

Largest basal diameter (lbd) of tumor (mm)

Thickness (th) of tumor (mm)

Intraocular location of tumor

Pre-fnab clinical diagnosis or differential diagnosis

Indication for fnab

prognostic factor for metastatic death. Although melanoma cell type assigned by histopathologic analysis of the entire tumor in an enucleated eye and cell type assigned by cytopathologic study of FNAB aspirates of that tumor are unlikely to be identical, at least in a proportion of cases in any large series(4), the fact that the cytopathologically assigned cell type provided an ordinal categorical discrimination in survival prognosis similar to that obtained with histopathologically assigned cell type reassures us that FNAB based tumor cell type assignment is a valid pathologic exercise. Several groups have reported the cytopathological classification of the tumor cells they obtained during FNAB(13,15,16,18), and occasional groups have also reported cytopathological versus histopathological classification of tumors evaluated by FNAB and managed by enucleation and transcleral resection(10,15,17,22,35). Although reported studies of cytopathological classification of tumor cells obtained by FNAB and histopathological classification of the entire tumor evaluated follo-

wing enucleation show reasonably good agreement between these assignments(10,17,19,22,35), many clinicians and ophthalmic pathologists remain skeptical about the reliability and prognostic value of melanoma pathological classification based on FNAB. This skepticism seems to stem from concern about the potential for FNAB to yield non-re­ presentative tumor specimens, recognition that cytology provides only cellular features and not tissue features of the tumors (which are important for histopathological classification), and realization that there is considerable variability in histopathological classification of uveal melanomas by ophthalmic pathologists who analyze the same microslides of selected tumors(43,44). The results of our study suggest that this skepticism is largely undeserved. As mentioned in our Introduction, there is limited published information documenting the expected differential survival of patients with tumors classified as spindle, mixed, and epithelioid melanomas on the basis of FNAB cytology. To our knowledge, only

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Prognostic implications of cytopathologic classification of melanocytic uveal tumors evaluated by fine-needle aspiration biopsy

Table 3. Association between baseline potential prognostic variables and cytopathologic classification Cytopathologic classification Insufficient and nevus

Borderline

Spindle cell melanoma

Mixed cell melanoma

Epithelioid and necrotic melanoma

(n=53) Count (%)

(n=23) Count (%)

(n=86) Count (%)

(n=104) Count (%)

(n=36) Count (%)

Younger (age ≤50)

35 (66.0)

18 (78.3)

48 (55.8)

54 (51.9)

20 (55.6)

Intermediate (age >50 but ≤65)

14 (26.4)

5 (21.7)

31 (36.0)

36 (34.6)

11 (30.6)

4 (07.5)

0 (00.0)

7 (08.1)

14 (13.5)

5 (13.9)

Male

20 (37.7)

13 (56.5)

38 (44.2)

50 (48.1)

20 (55.6)

Female

33 (62.3)

10 (43.5)

48 (55.8)

54 (51.9)

16 (44.4)

Absent

25 (47.2)

10 (43.5)

18 (20.9)

13 (12.5)

1 (02.8)

Present

28 (52.8)

13 (56.5)

68 (79.1)

91 (87.5)

35 (97.2)

Good (va ≥20/40)

39 (73.6)

15 (65.2)

48 (55.8)

41 (39.4)

10 (27.8)

Intermediate (va <20/40 but >20/200)

10 (18.9)

7 (30.4)

15 (17.4)

19 (18.3)

8 (22.2)

4 (07.5)

1 (04.3)

23 (26.7)

44 (42.3)

18 (50.0)

Small (lbd ≤10)

33 (62.3)

11 (47.8)

34 (39.5)

32 (30.8)

12 (33.3)

Medium (lbd >10 but ≤15)

19 (35.8)

10 (43.5)

43 (50.0)

41 (39.4)

11 (30.6)

1 (01.9)

2 (08.7)

9 (10.5)

31 (29.8)

13 (36.1)

Chisquared

df

P

09.7

8

<0.290

04.0

4

<0.400

38.8

4

<0.001

39.5

8

<0.001

37.8

8

<0.001

78.0

8

<0.001

09.9

4

<0.042

92.8

8

<0.001

79.4

8

<0.001

Potential prognostic variable Category of variable Age of patient (yr)

Older (age > 65) Gender of patient

Symptoms attributable to tumor

Pre-fnab visual acuity (va)

Poor (va ≤20/200) Largest basal diameter (lbd) of tumor (mm)

Large (lbd >15) Thickness (th) of tumor (mm) Thin (th ≤3.5 mm)

50 (94.3)

17 (73.9)

51 (59.3)

38 (36.5)

13 (36.1)

Intermediate (th >3.5 but ≤7)

2 (03.8)

5 (21.7)

21 (24.4)

20 (19.2)

3 (08.3)

Thick (th >7)

1 (01.9)

1 (04.3)

14 (16.3)

46 (44.2)

20 (55.6)

Exclusively choroidal

47 (88.7)

15 (65.2)

68 (79.1)

71 (68.3)

26 (72.2)

Involving ciliary body

6 (11.3)

8 (34.8)

18 (20.9)

33 (31.7)

10 (27.8)

Nevus versus melanoma

33 (62.3)

8 (34.8)

18 (20.9)

8 (07.7)

2 (05.6)

Probable melanoma but atypical

18 (34.0)

9 (39.1)

25 (29.1)

24 (23.1)

8 (22.2)

2 (03.8)

6 (26.1)

43 (50.0)

72 (69.2)

26 (72.2)

51 (96.2)

17 (73.9)

43 (50.0)

32 (30.8)

10 (27.8)

Investigation (cyto-histo correlation*)

1 (01.9)

2 (08.7)

30 (34.9)

57 (54.8)

22 (61.1)

Patient request for pathologic confirmation of diagnosis

1 (01.9)

4 (17.4)

13 (15.1)

15 (14.4)

4 (11.1)

Intraocular location of tumor

Pre-fnab clinical diagnosis or differential diagnosis

Unequivocal melanoma Indication for fnab Major diagnostic uncertainty

*= these aspirates were performed immediately after the enucleation but in the same manner diagnostic FNABs were performed.

one group of investigators has reported actuarial survival curves of subgroups of patients with different cytopathologically assigned cell types in a peer-reviewed journal to date (15,28). These authors showed that the cumulative actuarial probabilites of metastasis and death increase as the percentage of epithelioid cells in the aspirate (which they graded as none, 1 to 50%, greater than 50%) increase. In contrast to our series, these authors excluded cases in which FNAB did not 76

Arq Bras Oftalmol. 2013;76(2):72-9

yield sufficient cells for cytopathologic classification or yielded cells interpreted as nevus cells. They also pulled the slides from each of the biopsies and reached a consensus about the categorical percentage of epithelioid cells in each specimen. In our current study, different pathologists from various backgrounds reviewed and interpreted the cases in our series. Although this fact may be criticized in the light of a retrospective analysis, we are reassured about the validity of mela-

Augsburger JJ, et al.

Figure 1. Comparative actuarial survival curves (Kaplan-Meier) of subgroups of 302 patients with clinically diagnosed primary posterior uveal melanoma evaluated by FNAB. The subgroups are based on sufficiency of the aspirates for cytopathologic classification of the tumor cells. Solid line is for cases with a sufficient aspirate (n=260), and dashed line is for cases with an insufficient aspirate (n=42).

Figure 2. Comparative actuarial survival curves (Kaplan-Meier) (in years) based on cytopathologic classification of tumor cells obtained by FNAB. From top to bottom, the lines are for melanocytic uveal nevus or insufficient aspirate (n=53), borderline melanocytic uveal tumor (n=23), spindle cell melanoma (n=86), unspecified or mixed cell type of melanoma (n=104), and epithelioid or necrotic melanoma (n = 36).

nocytic tumor cell classification as a prognostic indicator for death for metastasis because this diversity of evaluations still manages to yield significant results. The results of our study also show that insufficient cellularity of FNAB aspirates from presumed uveal melanomas that have been sampled in more than one site is a favorable prognostic indicator for patient survival. We speculate that insufficient cellularity of the aspirates is an indicator of cohesiveness of tumor cells and that this feature is in turn responsible for the observed more favorable survival prog-

nosis. Unfortunately, none of the cases that yielded an insufficient aspirate came to enucleation so we cannot confirm this theory. As mentioned in our Introduction, failure of FNAB to yield a sufficiently cellular specimen of a presumed choroidal or ciliary body melanoma for cytopathologic classification is a problem encountered in many reported series(8,10,21-26). In the various reported series, the principal factors associated with such insufficiency have been limited tumor thickness(22), the differential diagnostic subcategory of the tumor (i.e., “unequivocal melanoma” versus “atypical but probable melanoma” versus “nevus versus melanoma”)(45), and the intention category of the biopsy (i.e., diagnostic, investigational, prognostic). As specified in our Methods section, we excluded cases in which FNAB yielded an insufficient aspirate for cytopathologic classification when the ophthalmic surgeon had sampled only one tumor site. There are two practical reasons why we did this. During the early years of the senior author’s experience with post-enucleation FNABs (performed for cytopathologic-histopathologic correlation), we noted that occasional tumors sampled in only one site yielded an insufficient aspirate for cytopathologic diagnosis and yet proved on histopathological study of the whole tumor to be unequivocal uveal melanomas. However, we also noted that when 2 or more tumor sites were sampled, at least one sufficient aspirate for cytopathologic classification was almost always obtained in these cases. We speculated at that time that technical problems with the procedure (e.g., inadequate suction, obstruction of the needle lumen) may have been responsible for the insufficiently cellular specimen in at least some of these cases. We also recognized that, in some patients whose posterior uveal tumor was sampled in 2 or more sites, cells of different cytopathologic characteristics were recovered from the dif­ ferent sites(46,47). By sampling 2 or more tumor sites, at least one site was likely to show higher grade tumor cells if they were present in the tumor. We decided at that time (1987) to sample all subsequent tumors coming to FNAB in at least two sites using separate biopsy needles in an attempt to minimize these potential sources of error. In spite of extensive use of FNAB in several referral centers, this in­­­vasive procedure has not been adopted as a routine diagnostic test in most eyes being treated by a method that does not yield a tumor tissue specimen. Reasons for lack of general application of FNAB in patients with a clinically diagnosed primary posterior uveal melanoma include (1) belief that clinical diagnosis is extremely accurate in patients with choroidal and ciliary body melanomas(48), (2) concern that biopsy may disseminate tumor cells leading to a lowered survival prognosis(49,50), (3) concern that biopsy will worsen the visual prognosis of many eyes that can be managed by eye-preserving methods(49), (4) belief that FNAB will lead frequently to erroneous diagnosis due to sampling errors, and (5) lack of conviction that cytopathologic ana­­­lysis of FNAB aspirates can effectively distinguish between tumors of lower and higher risk of metastasis. The latter two concerns have already been addressed above. While it is true that the diagnostic accuracy rate in eyes enucleated after entry into the Collaborative Ocular Melanoma Study (COMS) was extremely high (over 99%)(48), readers should realize that pa­­­tients with possible choroidal melanomas that were atypical or about which there was major diagnostic uncertainty were not enrolled in COMS. As Char and Miller have shown, the diagnostic error rate when both typical and atypical choroidal and ciliary body tumors are considered is substantially higher than that suggested by COMS(51). The diagnostic error rate in patients with small clinically diagnosed choroidal melanomas (i.e., melanocytic choroidal tumors ≤3.5 mm thick) without invasive clinical features has never been determined by any large scale clinical-pathologic correlation study (in large part because most eyes with small presumed choroidal melanomas are not managed by enucleation). To date, there is only one published case of tract seeding of uveal melanoma cells to the exterior of the eye reported following clinical FNAB of a choroidal or ciliary body melanoma(52). In over 600 FNABs

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Prognostic implications of cytopathologic classification of melanocytic uveal tumors evaluated by fine-needle aspiration biopsy

to date in our total experience, we have not encountered this problem. To date, there is no published evidence showing lower survival among patients who underwent FNAB than among similar patients who did not. While many ophthalmologists have expressed concern that biopsy will worsen the visual prognosis of many eyes that are managed by eye-preserving methods, there is no evidence from any comparative study of patients with choroidal and/or ciliochoroidal melanomas who did versus did not undergo FNAB prior to or at the time of treatment of the intraocular tumor showing any significant differential in terms of post-treatment visual outcome. At this point, a potential question ophthalmologists have is how did the cytopathologic results influence patient management in our series? Patients whose tumors were classified pathologically as melanomas were usually treated promptly by either I-125 plaque ra­­­diotherapy or enucleation, while patients whose tumors were classified pathologically as benign nevi were usually left untreated unless the choroidal or ciliary body tumor exhibited progressive post-biopsy enlargement or developed invasive clinical features (e.g., eruption through Bruch’s membrane, retinal invasion). Patients whose tumor yielded an insufficient number of cells for cytopathologic diagnosis or were classified cytopathologically as borderline melanocytic uveal tumors were managed early on somewhat arbitrarily on a case-byca­se basis with regard to factors other than the pathologic diagnosis of the tumor (e.g., tumor size, symptoms attributable to tumor). Ho­­­wever, since our preliminary analysis of this series revealed the prognostic value of cytopathologic classification of melanocytic tu­­ mor cells and insufficient aspirates, we have tended to manage all cases that yielded insufficient aspirates for cytopathologic diagnosis in spite of multiple tumor site sampling during FNAB and all cases classified as benign melanocytic uveal nevus by periodic monitoring initially and all cases classified as borderline melanocytic uveal tumor or any category of melanoma by prompt treatment (usually I-125 pla­­ que radiotherapy or enucleation). Many readers might wonder why we are presenting evidence about cytopathologic classification of the cells obtained by FNAB from melanocytic choroidal and ciliary body tumors at this time. In most centers, chromosomal and/or transcriptional prognostic testing of FNAB aspirates obtained from clinically diagnosed posterior uveal melanomas has largely supplanted diagnostic uncertainty as an indication for FNAB. In some ocular oncology centers, FNAB is being employed almost routinely at this time to classify a patient’s risk category for subsequent development of uveal melanoma metastasis(5,40). In most of the reported series, the authors have not reported the cytopathologic nature of the obtained tumor cells. Both monosomy 3 identified by chromosomal testing and class 2 ge­ne expression profile determined by transcriptional testing have been shown to be much stronger prognostic factors for metastasis and metastatic death than cell type classification of the entire tumor evaluated post-enucleation, and there is no reason to believe that cytopathology alone will be better than histopathologic assessment in terms of prognosis. However, while we are treating patients with smaller tumors in a conservative manner, what monosomy 3 and class 2 gene expression profile of a cellular aspirate from a uveal tumor does is indicate that the evaluated cells were not melanoma cells having high risk of metastasis. Furthermore, this series precedes the validation and commercially available genetic tests and addresses the fact that there are still several centers around the world with limited resources and sophisticated laboratory testing not available but understanding how the cytology of an FNAB aspirate may provide another option in the evaluation and diagnosis of patients with melanocytic choroidal tumors. CONCLUSION Our study showed cytopathologic classification of tumor cells obtained from melanocytic choroidal and ciliary body tumors by 78

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FNAB to be a statistically significant and clinically meaningful prognostic factor for subsequent death from metastatic uveal melanoma. Based on our experience, we believe that melanocytic posterior uveal tumors coming to FNAB should be sampled in at least 2 sites to minimize the chance of obtaining insufficient aspirates due to technical problems and maximize the chance of obtaining a representative sample of the entire tumor. REFERENCES 1. Jakobiec FA, Coleman DJ, Chattock A, Smith M. Ultrasonically guided needle biopsy and cytologic diagnosis of solid intraocular tumors. Ophthalmology. 1979;86(9): 1662-81. 2. Krzystolik Z, Cerniak B, Woyke S. [Diagnosis of intraocular melanoma by thin-needle aspiration biopsy]. Klin Oczna. 1982;84(9):279-82. Polish. 3. Augsburger JJ, Shields JA. Fine needle aspiration biopsy of solid intraocular tumors: indications, instrumentation and techniques. Ophthalmic Surg. 1984;15(1):34-40. 4. Augsburger JJ, Shields JA, Folberg R, Lang W, O’Hara BJ, Claricci JD. Fine needle aspiration biopsy in the diagnosis of intraocular cancer. Cytologic-histologic correlations. Ophthalmology. 1985;92(1):39-49. 5. Davey CC, Deery AR. Through the eye, a needle: intraocular fine needle aspiration biopsy. Trans Ophthalmol Soc U K. 1986;105(Pt 1):78-83. 6. Char DH, Kroll SM, Stoloff A, Kaleta-Michaels S, Crawford JB, Miller TR, et al. Cytomorphometry of uveal melanoma. Comparison of fine needle aspiration biopsy samples with histologic sections. Anal Quant Cytl Histol. 1991;13(4):293-9. 7. Foulds WS. The uses and limitations of intraocular biopsy. Eye (Lond). 1992;6(Pt 1):11-27. 8. Shields JA, Shields CL, Ehya H, Eagle RC, De Potter P. Fine-needle aspiration biopsy of suspected intraocular tumors. The 1992 Urwick Lecture. Ophthalmology. 1993; 100(11):1677-84. 9. Shanmugam MP, Biswas J. Fine needle aspiration biopsy in the diagnosis of intraocular mass lesions. Indian J Ophthalmol. 1997;45(2):105-8. 10. Eide N, Syrdalen P, Walaas L, Hagmar B. Fine needle aspiration biopsy in selecting treatment for inconclusive intraocular disease. Acta Ophthalmol Scand. 1999; 77(4):448-52. 11. Beckrakis NE, Foerster MH, Bornfeld N. Biopsy in indeterminate intraocular tumors. Ophthalmology. 2002;109(2):235-42. 12. Kvanta A, Seregard S, Kopp ED, All-Ericsson C, Landau I, Berglin L. Choroidal biopsies for intraocular tumors of indeterminate origin. Am J Ophthalmol. 2005;140(6):1002-6. Comment in: Am J Ophthalmol. 2005;140(6):1094-5. 13. Czerniak B, Woyke S, Domagala W, Krzystolik Z. Fine needle aspiration biopsy of intraocular malignant melanoma. Acta Cytol. 1983;27(2):157-65. 14. Midena E, Segato T, Piermarocchi S, Boccato P. Fine needle aspiration biopsy in oph­­ thalmology. Surv Ophthalmol. 1985;29(6):410-22. 15. Char DH, Miller TR, Ljung BM, Howes EL Jr, Stoloff A. Fine needle aspiration biopsy in uveal melanoma. Acta Cytol. 1989;33(5):589-605. 16. Dávila RM, Miranda MC, Smith ME. Role of cytopathology in the diagnosis of ocular malignancies. Acta Cytol. 1998;42(2):362-6. 17. Folberg R, Augsburger JJ, Gamel JW, Shields JA, Lang WR. Fine-needle aspirates of uveal melanomas and prognosis. Am J Ophthalmol. 1985;100(5):654-7. 18. Scrogg MW, Johnston WW, Klintworth GK. Intraocular tumors. A cytopatholgic study. Acta Cytol. 1990;34(3):401-8. 19. Char DH, Miller TR, Crawford JB. Cytopathologic diagnosis of benign lesions simulating choroidal melanomas. Am J Ophthalmol. 1991;112(1):70-5. 20. Faulkner-Jones BE, Foster WJ, Harbour JW, Smith ME, Dávila RM. Fine needle aspiration biopsy with adjunct immunohistochemistry in intraocular tumor management. Acta Cytol. 2005;49(3):297-8. 21. Augsburger JJ, Corrêa ZM, Schneider S, Yassin RS, Robinson-Smith T, Ehya H, et al. Diagnostic transvitreal fine needle aspiration biopsy of small melanoytic choroidal tumors in nevus versus melanoma category. Trans Am Ophthalmol Soc. 2002;100: 225-32; discussion 232-4. 22. Cohen VM, Dinakaran S, Parsons MA, Rennie IG. Transvitreal fine needle aspiration biopsy: the influence of intraocular lesion size on diagnostic biopsy result. Eye (Lond). 2001;15(Pt 2):143-7. 23. Jensen OA, Prause JU, Scherfig E. Transvitreal retino-choroidal biopsy of suspected malignant lesions of the choroid. Follow-up of cases over 7 years. Acta Ophthalmol Scand. 1997;75(4):409-11. 24. Naus NC, Verhoeven AC, van Drunen E, Slater R, Mooy CM, Paridaens DA, et al. Detection of genetic prognostic markers in uveal melanoma biopsies using fluorescence in situ hybridization. Clin Cancer Res. 2002;8(2):534-9. 25. Midena E, Bonaldi L, Parrozzani R, Tebaldi E, Boccassini B, Vujosevic S. In vivo detection of monosomy 3 in eyes with medium-sized uveal melaoma using transscleral fine needle aspiration biopsy. Eur J Ophthalmol. 2006;16(3):422-5. 26. Midena E, Bonaldi L, Parrozzani R, Radin PP, Boccassini B, Vujosevic S. In vivo monosomy 3 detection of posterior uveal melanoma: 3-year follow-up. Graefes Arch Clin Exp Ophthalmol. 2008;246(4):609-14. 27. Young TA, Burgess BL, Rao NP, Glasgow BJ, Straatsma BR. Transscleral fine-needle

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aspiration biopsy of macular choroidal melanoma. Am J Ophthalmol. 2008;145(2): 297-302. 28. Char DH, Kroll SM, Miller T, Castro J, Quivey J. Irradiated uveal melanomas: cytopathologic correlation with prognosis. Am J Ophthalmol. 1996;122(4):509-13. 29. Prescher G, Bornfeld N, Hirche H, Horsthemke B, Jockel KH, Becher R. Prognostic implications of monosomy 3 in uveal melanoma. Lancet. 1996;347(9010):1222-5. 30. Patel KA, Edmondson ND, Talbot F, Parsons MA, Rennie IG, Sisley K. Prediction of prognosis in patients with uveal melanoma using fluorescence in situ hybridisation. Br J Ophthalmol. 2001;85(12):1440-4. 31. Scholes AG, Damato BE, Nunn J, Hiscott P, Grierson I, Field JK. Monosomy 3 in uveal melanoma: correlation with cliical and histologic predicors of survival. Invest Ophthalmol Vis Sci [Internet]. 2003[cited 2012 Oct 15];44:1008-11. Available from: http://www.iovs.org/content/44/3/1008.long 32. Onken MD, Worley LA, Ehlers JP, Harbour JW. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res. 2004;64(20):7205-9. 33. Sandinha MT, Farquharson MA, McKay IC, Roberts F. Monosomy 3 predicts death but not time until death in choroidal melanoma. Invest Ophthalmol Vis Sci [Internet]. 2005[cited 2012 Set 12];46(10):3497-501. Available from: http://www.iovs.org/ content/46/10/3497.long 34. Worley LA, Onken MD, Person E, Robirds D, Branson J, Char DH, et al. Transcriptomic versus chromosomal prognostic markers and clinical outcome in uveal melanoma. Clin Cancer Res. 2007;13(5):1466-71. 35. Damato B, Duke C, Coupland SE, Hiscott P, Smith PA, Campbell I, et al. Cytogenetics of uveal melanoma: a 7-year clinical experience. Ophthalmology. 2007;114(10):1925-31. 36. Sisley K, Nichols C, Parsons MA, Farr R, Rees RC, Rennie IG. Clinical applications of chromosome analysis, from fine needle aspiration biopsies, of posterior uveal melanomas. Eye (Lond). 1998;12(Pt 2):203-7. 37. Onken MD, Worley LA, Dávila RM, Char DH, Harbour JW. Prognostic testing in uveal melanoma by transcriptomic profiling of fine needle biopsy specimens. J Mol Diagn. 2006;8(5):567-73. 38. Young TA, Rao NP, Glasgow BJ, Moral JN, Straatsma BR. Fluorescent in situ hybridization for monosomy 3 via 30-guage fine-needle aspiration biopsy of choroidal melanoma in vivo. Ophthalmology. 2007;114(1):142-6. 39. Shields CL, Materin MA, Teixeira L, Mashayekhi A, Ganguly A, Shields JA. Small choroidal melanoma with chromosome 3 monosomy on fine-needle aspiration biopsy. Oph­­­thalmology. 2007;114(10):1919-24.

40. Shields CL, Ganguly A, Materin MA, Teixeira L, Mashayekhi A, Swanson LA, et al. Chro­­­mosome 3 analysis of uveal melanoma using fine-needle aspiration biopsy at the time of plaque radiotherapy in 140 consecutive cases: the Deborah Iverson, MD, Lectureship. Arch Ophthalmol. 2007;125(8):1017-24. Comment in: Arch Ophthalmol. 2007;125(8):1122-3. 41. Young TA, Burgess BL, Rao NP, Gorin MB, Straatsma BR. High-density genome array is superior to fluorescence in-situ hybridization analysis of monosomy 3 in choroidal melanoma fine needle aspiration biopsy. Mol Vis. 2007;13:2328-33. 42. Triozzi PL, Eng C, Singh AD. Targeted therapy for uveal melanoma. Cancer Treat Rev. 2008;34(3):247-58. 43. Gass JD. Problems in the differential diagnosis of choroidal nevi and malignant melanomas. The Edward Jackson Memorial Lecture. Am J Ophthalmol. 1977;83(3):299-323. 44. McLean IW, Foster WD, Zimmerman LE, Gamel JW. Modifications of Callender’s classification of uveal melanoma at the Armed Forces Institute of Pathology. Am J Ophthalmol. 1983;96(4):502-9. 45. Augsburger JJ. Diagnostic biopsy of selected intraocular tumors. Am J Ophthalmol. 2005;140(6):1094-5. 46. Maat W, Jordanova ES, van Zelderen-Bhola SL, Barthen ER, Wessels HW, Schalij-Delfos NE, et al. The heterogeneous distribution of monosomy 3 in uveal melanomas: implications for prognostication based on fine-needle aspiration biopsies. Arch Pathol Lab Med. 2007;131(1):91-6. 47. Mensink HW, Vaarwater J, Kiliç E, Naus NC, Mooy N, Luyten G, et al. Chromosome 3 intratumor heterogeneity in uveal melanoma. Invest Ophthalmol Vis Sci [Internet]. 2009[cited 2012 Jul 27];50(2):500-4.Available from: http://www.iovs.org/ content/50/2/500.long 48. Accuracy of diagnosis of choroidal melanomas in the Collaborative Ocular Melanoma Study. COMS report no. 1. Arch Ophthalmol. 1990;108(9):1268-73. Erratum in: Arch Ophthalmol. 1990;108(12):1708. 49. Murray TG. Ocular Oncology [Internet]. Miami: Bascom Palmer Eye Institute; 20022012. [cited 2013 Jan 3]. Available from: www.eyecancermd.org/diagnosis.html 50. American Cancer Society. How is eye cancer diagnosed? New York: ACS; 2009. [cited 2012 Jun 21]. Available from: http://www.cancer.org/cancer/eyecancer/detailedguide/ eye-cancer-diagnosis 51. Char DH, Miller T. Accuracy of presumed uveal melanoma diagnosis before alternative therapy. Br J Ophthalmol. 1995;79(7):692-6. 52. Caminal JM, Sanz S, Carreras M, Catala I, Arruga J, Roca G. Epibulbar seeding at the site of a transvitreal fine needle aspiration biopsy. Arch Ophthalmol. 2006;124(4):587-9.

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Artigo Original | Original Article

Risk factors of age-related macular degeneration in Argentina Fatores de risco para degeneração macular relacionada à idade na Argentina María Eugenia Nano1, Van Charles Lansingh2, María Soledad Pighin3, Natalia Zarate1, Hugo Nano2, Marissa Janine Carter4, João Marcello Furtado5, Clelia Crespo Nano1, Luciana Fiocca Vernengo6, José Domingo Luna6, Kristen Allison Eckert4

ABSTRACT

RESUMO

Purposes: To assess the risk factors of age-related macular degeneration in Ar­­­ gentina using a case-control study. Methods: Surveys were used for subjects’ antioxidant intake, age/gender, race, body mass index, hypertension, diabetes (and type of treatment), smoking, sun­ light exposure, red meat consumption, fish consumption, presence of age-related macular degeneration and family history of age-related macular degeneration. Main effects models for logistic regression and ordinal logistic regression were used to analyze the results. Results: There were 175 cases and 175 controls with a mean age of 75.4 years and 75.5 years, respectively, of whom 236 (67.4%) were female. Of the cases with age-related macular degeneration, 159 (45.4%) had age-related macular degeneration in their left eyes, 154 (44.0%) in their right eyes, and 138 (39.4%) in both eyes. Of the cases with age-related macular degeneration in their left eyes, 47.8% had the dry type, 40.3% had the wet type, and the type was unknown for 11.9%. The comparable figures for right eyes were: 51.9%, 34.4%, and 13.7%, respectively. The main effects model was dominated by higher sunlight exposure (OR [odds ratio]: 3.3) and a family history of age-related macular degeneration (OR: 4.3). Other factors included hypertension (OR: 2.1), smoking (OR: 2.2), and being of the Mestizo race, which lowered the risk of age-related macular degeneration (OR: 0.40). Red meat/fish consumption, body mass index, and iris color did not have an effect. Higher age was associated with progression to more severe age-related macular degeneration. Conclusion: Sunlight exposure, family history of age-related macular degenera­­­tion, and an older age were the significant risk factors. There may be other variables, as the risk was not explained very well by the existing factors. A larger sample may produce different and better results.

Objetivo: Determinar os fatores de risco para degeneração macular relacionada à idade na Argentina utilizando um estudo caso-controle. Métodos: Questionários foram usados para a obtenção de informações dos partici­ pantes em relação à ingesta de antioxidantes, idade/sexo, raça, índice de massa corporal, hipertensão, diabetes (e tipo de tratamento), tabagismo, exposição à luz solar, consumo de carne vermelha/peixe, presença de degeneração macular relacionada à idade e história familiar de degeneração macular relacionada à idade. Modelos de efeito principal para regressão logística e regressão logística ordinal foram usados para analisar os resultados. Resultados: Foram recrutados 175 casos e 175 controles com uma média de idade de 75,4 anos e 75,5, respectivamente, dos quais 236 (67,4%) eram mulheres. Cento e cinquenta e nove (45,4%) tinham degeneração macular relacionada à idade em seus olhos esquerdos, 154 (44,0%) em seus olhos direitos, e 138 (39,4%) em ambos os olhos. Entre os casos de degeneração macular relacionada à idade no olho esquerdo, 47,8% apresentavam o tipo seca, 40,3% o tipo úmida, e o tipo era desconhecido em 11,9%. Os achados para os olhos direitos foram: 51,9%, 34,4% e 13,7%, respectivamente. O modelo de efeito principal foi dominado por maior exposição à luz solar (OR [odds ratio]: 3,3) e história familiar de degeneração macular relacionada à idade (OR: 4,3). Outros fatores incluindo hipertensão (OR: 2,1), tabagismo (OR: 2,2), e pertencente à raça mestiça, que diminuiram o risco de degeneração macular relacionada à idade (OR: 0,40). Consumo de carne vermelha e de peixe, índice de massa corporal e coloração da íris não foram fatores de risco. Idade avançada foi associada com progressão para degeneração macular relacionada à idade mais grave. Conclusão: Exposição à luz solar, história familiar de degeneração macular relaciona­­­ da à idade, e idade avançada foram os fatores de risco significativos. Podem existir outras variáveis, já que os riscos não foram bem explicados pelos fatores existentes. Um maior tamanho amostral poderia produzir resultados diferentes e melhores.

Keywords: Age-related macular degeneration; Risk factors; Sunlight exposure; Fa­­­mily history; Argentina; Case-control study

Descritores: Degeneração macular relacionada à idade; Fatores de risco; Exposição solar; História familiar; Argentina; Estudo caso-controle

INTRODUCTION Age-related macular degeneration (AMD) causes 5% of global blindness and 1% of visual impairment(1,2). In the early stages of AMD, deposits of drusen are observed in the retina between the retinal pigment epithelium and choroid in the macular region(3). The disease progresses to more advanced stages, leading to 2 types of late AMD: geographic atrophy of the retinal pigment epithelium and photoreceptor cells (dry AMD) and aberrant choroidal neovascularization (wet AMD), which leads to central vision loss(3).

AMD is the leading cause of blindness among the elderly in developed countries with prevalence of late AMD at 1.2-1.7%(4-9). While AMD has generally been a greater issue in developed countries, studies from India suggest similar prevalence (1.4-1.8%) for late AMD as the population continues to age in developing countries(10,11). China, on the other hand, has a considerably lower prevalence as confirmed by the Beijing Eye Study(12). AMD was considered untreatable until argon laser treatment and, later, photodynamic therapy were applied(13). Today, intravitreal an­

Submitted for publication: January 17, 2013 Accepted for publication: January 31, 2013

Financial support: Preparation of the manuscript was funded by ORBIS, which had no role in any aspect of the study.

Study carried out at Fundación Hugo Nano, Buenos Aires.

Disclosure of potential conflicts of interest: M.E.Nano, employed by Fundación Hugo Nano; V.C.Lansingh, employed by the IAPB; M.S.Pighin, None; N.Zarate, employed by Fundación Hugo Nano; H.Nano, None; M.J.Carter, employed by Strategic Solutions and is a paid consultant to ORBIS and the IAPB; J.M.Furtado, None; C.C.Nano, None; L.F.Vernengo, None; J.D.Luna, employed by Centro Privado de Ojos Romagosa-Fundación VER Córdoba; K.A.Eckert, employed by Strategic Solutions.

Fundación Hugo Nano, Buenos Aires, Argentina. 2 International Agency for the Prevention of Blindness/VISION 2020 Latin America. 3 Hospital Distrital Lago Argentino “Dr José Formenti”, El Calafate, Santa Cruz, Argentina. 4 Strategic Solutions, Inc., Cody, WY - USA. 5 Universidade Federal de São Paulo, São Paulo, Brazil. 6 Centro Privado de Ojos Romagosa-Fundación VER Córdoba, Argentina. 1

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Correspondence address: Van C. Lansingh. International Agency for the Prevention of Blindness/ VISION 2020 Latin America. 3720 San Simeon Cr. Weston, FL 33331, USA Email: [email protected]

Nano ME, et al.

ti-vascular endothelial growth factor (VEGF) therapy is the preferred treatment, which has decreased the annual incidence of visual impairment due to AMD by 32-50% in some developed countries(13-16). Anti-VEGF therapy is effective, although it does not restore vision to previous levels in the majority of subjects treated, and it requires multiple injections that are very costly(17). Over the past 2 decades, efforts have been made to identify as­­ sociations between AMD and risk factors with varied results, but it is generally agreed that older age, female gender, Caucasian race, and family history of AMD are significant unmodifiable risk factors to developing the disease and/or progressing to late AMD and smoking might be a modifiable risk factor. An algorithm was developed to predict which subjects with early/intermediate AMD are most likely to progress to late dry/wet AMD, by assessing the following variables: 6 genetic variants, age, sex, education, baseline AMD grade, smoking, Body Mass Index (BMI), and nutritional supplement use(18). Multivariate risk models were next modified to additionally include time varying rates of progression of up to 12 years and macular drusen size in both eyes at baseline to follow the disease progression in the Age-Related Eye Disease Study(19). Of the 2,937 subjects who participated in study, 819 progressed to late AMD during the 12-year follow-up period. Age, smoking, BMI, genetic variants, advanced AMD in one eye and drusen size in both were independently associated with progression(19). In Latin America, AMD treatment is very costly, and little research has been done on the disease(20). Approximately 8.3% of the population of Latin America and the Caribbean is 65 years or older(21). Argentina has one of the highest elderly populations in the region with up to 13.1% being 65 years or older, and 97% of the population of Argentina is White (mainly of Spanish and Italian descent) and 3% is Mestizo (of mixed White and Indigenous race), Indigenous, or of another race(21,22). Despite its significantly aging population, there have been no studies to date on AMD in Argentina, where epidemiological studies on blindness suggest that AMD may be the cause of 3-4% of blindness(20). The objective of this case-control study is to assess the risk factors for the development and progression of AMD in Argentina. METHODS The study adhered to the tenets of the Declaration of Helsinki, and the IRB of the Fundación Hugo D. Nano in Buenos Aires, Argentina determined that it was exempt from formal IRB review. Fundación Nano in Buenos Aires, Argentina contacted ophthalmologists throughout the country to participate in the study, and 28 participated, including 12 retina specialists and 2 general ophthalmologists. The ophthalmologists considered all new patients seen over a 2-month period in 2011 at their respective outpatient clinics for the survey on the possible risk factors of AMD provided that they did not have maculopathy. After patients voluntarily consented, surveys were conducted by their respective ophthalmologists during their consultations. The participating ophthalmologists and their subjects were from Buenos Aires City (the Federal Capital) and 5 interior provinces: Gran Buenos Aires, Santa Cruz, Santa Fe, Entre Rios, and Cordoba. In the survey, subjects answered questions, when applicable, on their age, gender, race, iris color, systemic hypertension (defined as systolic blood pressure ≥130), diabetes (Type I or Type II and type of treatment), cholesterol, status of AMD in each eye, family history of AMD, smoking and exposure to smoking, red meat consumption, fish consumption, and antioxidants intake. Weight, height, and abdominal diameter were measured at the time of the survey to calculate BMI, and the status of AMD in each eye was also measured during the same consultation. The treating ophthalmologists submitted the subjects to oph­­ thal­­­mological examination, classified AMD in each eye based on the

standard classification of the disease, and also performed an Amsler grid test on each eye. Early AMD was classified as a presence of a few medium-sized drusen and/or pigment abnormalities(23). Intermediate AMD was classified as a presence of at least one large drusen, numerous medium-sized drusen, and/or geographic atrophy that did not extend to the center of the macula. Advanced non-neovascular AMD was classified as presence of drusen and geographic atrophy extending to the center of the macula. Advanced neo-vascular AMD was classified as presence of choroidal neovascularization and any of its potential sequelae, including subretinal fluid, lipid deposition, hemorrhage, retinal pigment epithelium detachment, and a fibrotic scar(23). Subjects with no history or signs of AMD were selected as controls. Risk analysis was performed with a main effects model for logis­­­ tic regression and ordinal logistic regression. Antioxidant status (taking antioxidants or not) was omitted from the potential list of variables because about 15% of data were missing for the cases and controls. Age and gender were checked but not included in any simple logistic regression models as they are controlled for in the case matching. Race was categorized as White, Mestizo, and other (Indigenous, Black, or Asian), with White as reference. BMI was cal­­­ culated by dividing weight in kilograms by the square of height in meters and categorized as being normal/slightly underweight (>18.5 kg/m2 and <25 kg/m2), overweight (25-29.9 kg/m2), and obese or morbidly obese (≥30 kg/m2)(24). Systemic hypertension was categorized as present or not, with no hypertension as reference. Diabetes was categorized as present (Type I or Type II) or not, with no diabetes as reference. Diabetes treatment was categorized as none, diet, oral drugs, and insulin, but treatment was only used if diabetes was a significant factor. Smoking was categorized as current smoker or not; packs per day (0, <1, 1-2, or >2); smoking years (0 years; <10 years; 10-20 years, and >20 years); and years of giving up smoking (0 years, <10 years, 10-20 years, >20 years, and never smoked). Lives with smoker and lived with smoker were employed as dichotomous variables (present or not). Sunlight exposure was classified as an ordinal 2-level factor (light to moderate: 0-2 hours per day of sun­ light exposure and moderate to heavy: +6 hours per day). Red meat consumption was classified as an ordinal 4-level factor (never, once a week, twice a week, and 3 or more times a week). Fish consumption was also classified as an ordinal 4-level factor (never, once a month, once a week, and 3 or more times a week). Iris color was categorized as brown, light to blue, and intermediate, with brown as reference. AMD was categorized as present or not for each eye. For the logistic regression, AMD was classified as present for the cases only and not for the controls. AMD type was categorized as none, dry, wet, or unknown, but was only used in the ordinal logistic regression. Fundus status for either eye was not used in the logistic regression. In the logistic regression main effects model, all variables were initially entered into a single block, and those with a p value >0.15 were removed. Non-significant variables (p>0.05) were then removed singly with each remaining significant variable in a single block. Variables with a p value less than 0.05 were significant. Retention of variables in the model was determined by Wald significance and block significance (chi square). Non-linearity of retained variables was not examined; for a small dataset these would need to be modeled in a mixed model although some idea of non-linearity could be obtained from the adjusted odds ratios (ORs). In the ordinal logistic regression main effects model, the most severe AMD indication in either eye was taken as the score (1-4) for the dependent variable. All variables were entered into a single block and those with a p value >0.05 removed. The variables age and BMI categories were retained. RESULTS There were 175 cases and 175 controls, of whom 236 (67.4%) were female. The mean ages of the cases and controls were 75.4 years (SD:

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7.75) and 75.5 years (SD: 7.87), respectively, showing that the cases were well matched to controls age-wise. Of the cases, 154 (88.0%) had AMD in their right eyes, 159 (90.9%) had AMD in their left eyes, and 138 (78.9%) had AMD in both eyes. Of the cases with AMD in their right eyes, 80 (51.9%) had the dry type, 53 (34.4%) had the wet type, and in 21 (13.7%), the type was unknown. The comparable figures for left eyes were: 76 (47.8%), 64 (40.3%), and 19 (11.9%), respectively. The severity of AMD in each eye is shown in tables 1A and 1B based on the complete data for each eye available at the time of analysis. With regard to demographics of all subjects, 284 were White (81.1%), 52 Mestizo (14.9%), and 14 of other races (4.0%). Fifty-eight percent reported on the surveys that they had systemic hypertension (n=203), and 49 reported to have diabetes (14.0%), of whom 7 controlled their diabetes through diet (2.0%), 38 through oral drugs (10.9%), and 4 with insulin (1.1%). Almost one-third of subjects had a BMI that indicated they were slightly underweight or of normal weight (n=116, 33.1%), 142 (40.6%) were overweight, and 92 (26.3%) were obese or morbidly obese. Fifty-four subjects (15.4%) said they currently smoked, 40 subjects (11.4%) said they currently lived with a smoker, and 105 subjects (30.0%) said they previously lived with a smoker. Two-hundred-and-nine subjects (59.7%) said they had never smoked, while 141 subjects had smoked at some point in their life, of which 53 (15.1%) had given up for more than 20 years. Other data on smoking were too inconsistent to provide reliable results. The majority had brown irises (222, 63.4%), while 80 (22.9%) had light-to-blue color, and 48 (13.7%) had intermediate color irises. Fifty-two subjects (14.9%) said they had a family history of AMD. The numbers were the same for those that had no family history or did not know (n=149 each; 42.6% each). The majority of subjects received moderate-to-heavy sunlight exposure (n=247, 70.6%), while only 103 (29.4%) of subjects had li­ ght-to-moderate sunlight exposure. Fish and red meat consumption are shown in table 2. The final main effects model in the logistic regression (Table 3) had a Nagelkerke R2 of 0.267, a Hosmer and Lemeshow test value of 0.578, and an overall percentage of correct classifications of 68.9% (cut point 0.5).

Table 1. A) Severity of age-related macular degeneration in each eye for logistic regression analysis* Right eye n (%)

Left eye n (%)

Early

43 (26.9)

40 (24.5)

Severe

31 (19.4)

25 (15.3)

Advanced non-neovascular

32 (20.0)

43 (26.4)

Advanced neovascular

54 (33.7)

55 (33.8)

AMD severity

*= the table above shows severity for the eyes with complete data at the time of the logistic regression analysis. Three eyes did not have complete data and were not included. AMD= age-related macular degeneration.

Table 1. B) Severity of age-related macular degeneration in each eye for ordinal logistic regression analysis* Right eye n (%)

Left eye n (%)

Early

43 (26.9)

38 (23.8)

Severe

31 (19.4)

25 (15.6)

Advanced non-neovascular

32 (20.0)

41 (25.6)

Advanced neovascular

54 (33.7)

47 (29.4)

AMD severity

*= the table above shows severity for the eyes with complete data at the time of the ordinal logistic regression analysis. AMD= age-related macular degeneration.

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Interpretation of the main effects model shows that it is dominated by higher sunlight exposure (OR: 3.3) and a family history of AMD (OR: 4.3) (Table 3). The unknown category for AMD family history was also very significant because it most likely contains many subjects who have a family history of AMD. Other factors include systemic hypertension (OR: 2.1) and smoking (OR: 2.2). Finally, being of the Mestizo race lowers the risk of getting AMD (OR: 0.40). For the ordinal logistic regression, the final main effects model had a Nagelkerke R2 of 0.263, a model fitting p value of 1.9 x 10-7, with significant parameters listed in table 4. In this ordinal logistic

Table 2. Fish and meat consumption Meat n (%)

Fish n (%)

026 (7.4)

094 (26.9)

—

060 (17.1)

Once a week

080 (22.9)

134 (38.3)

Twice a week

137 (39.1)

—

Three or more times a week

107 (30.6)

062 (17.7)

Consumption rate Never Once a month

Table 3. Main effects model, logistic regression Parameter

B*

SE†

Race

P‡

OR§

95% CI||

0.016

Mestizo

-0.924

0.363

0.011

0.397

0.20-0.81

Other

-0.931

0.618

0.132

0.394

0.12-1.32

-0.752

0.247

0.002

2.122

1.31-3.44

Hypertension Smoker

-0.782

0.357

0.028

2.187

1.09-4.40

Moderate-to-heavy sunlight exposure

-1.188

0.275

1.5 x 10-5

3.281

1.91-5.62

AMD familial history

7.8 x 10-6

Yes

-1.465

0.371

7.9 x 10-5

4.329

2.09-8.96

Unknown

-1.067

0.263

5.1 x 10

2.907

1.74-4.87

-5

*B= logistic coefficients; †SE= standard error; ‡P (value)= significance; §OR= odds ratio; ||CI= confidence intervals. The reference for race is White, for hypertension no hypertension, for smoking status no smoking, for sunlight exposure light-to-moderate exposure (0-6 hours of sunlight exposure per day), and for age-related macular degeneration (AMD) familial history no history of AMD.

Table 4. Main effects model, ordinal logistic regression Parameter

B coefficient*

P†

OR‡

95% CI§

Obese

-1.041

0.007

2.830

1.330-6.060

Overweight

-0.280

0.478

1.320

0.610-2.860

>84

-3.859

5.6 x 10-6

0.021

0.004-0.110

80-84

-2.697

0.000045

0.067

0.018-0.250

75-79

-2.020

0.001

0.133

0.039-0.450

70-74

-1.593

0.012

0.203

0.059-0.700

65-69

-1.042

0.117

0.353

0.096-1.300

BMI category||

Age category (years)

¶

*= coefficients for the predictor variables; †P (value)= significance; ‡OR= odds ratio; §CI= confidence intervals; ||BMI= body mass index reference is normal or slightly underweight (18.5 kg/m2 and <25 kg/m2); ¶= reference is <65 years.

Nano ME, et al.

regression, an OR >1 means an association with a lower score or less AMD severity, while an OR <1 indicates an association with higher scores or higher AMD severity. As expected, age shows a steady dose-response relationship with higher age associated with progression to more severe AMD. Higher BMI, however, appears somewhat protective in AMD progression (only obese BMI is significant), which might indicate selection bias, but the explanation for this is unknown. DISCUSSION Increased sunlight exposure and a family history of AMD were the most significant risk factors in developing AMD that were observed in this study in addition to hypertension, smoking, and being white. An older age was a significant risk for disease progression. Sunlight exposure has produced inconsistent results as a risk factor in other research. A study carried out in the South of France, which used ambient solar radiation to test for an association of more sunlight exposure with AMD, did not conclude that there was an effect; however, a Canadian study considered sunlight exposure to be a possible risk factor(5,25). For family history, the results of the unknown variable (OR: 2.9) are also significant and suggest that many of these subjects may indeed have a family history of AMD. It is, therefore, very important that greater attention in Argentina be given to raising awareness of AMD and its risks not only with subjects, but with their families, who should be informed of the association between family history and AMD. These results and recommendations were also confirmed by another case-control study in the UK, which found that family history was associated with a 12-fold increase in the odds for disease(3). Being of the Mestizo race reduces the risk of developing AMD (OR: 0.40). Other Hispanic populations have also been found to have a reduced risk of developing late AMD(9). The US National Health and Nutrition Examination Survey III was a national representative population-based, cross-sectional study that looked at the prevalence and risk factors for AMD in non-Hispanic whites, non-Hispanic blacks, and Mexican Americans. The rates were overall not very different, but late AMD was higher among whites. White and black women were more likely to develop it then their male counterparts. However, Mexican-American women did not have an increased risk(9). That said, the proportion of the Mexican population that is Mestizo is 60%, and only 9% is white, whereas 97% of the population of Argentina is White and only 3% is Mestizo, Indigenous, or of another race(22). (It should be further noted that the majority of subjects in this study were white (81%), which is a close representative proportion of the demographics of the country). Therefore, from a national, demographic perspective, almost the entire population of Argentina has an increased risk of developing AMD. It is interesting to note that red meat consumption, fish consumption, BMI, and iris color did not result in an association with AMD. The previously mentioned Canadian study determined that family history, obesity, and smoking were significant risk factors, and a lighter colored iris (and sun exposure) was a possible factor(5). Fish consumption as a risk factor has also produced mixed results in other studies. Studies in the United States (US) and Australia found that fish consumption reduces the risk of developing AMD, whereas another cohort in Australia did not find any significant association(26-29). An older age was the significant risk factor for progression to more severe AMD. It was not clear, however, why a higher BMI, with the exception of the obese category, seemed to reduce the risk. Another study found that a greater BMI, waste circumference, and waist to hip ratio increased the risk for progression to late AMD(30). This case-control study was the first investigation of AMD in Argentina, and the results of the study mirror to an extent the risks factors concluded in other work. There were, however, some limitations that may have impacted the results. Subjects were not randomly

selected for participation. The methodology for obtaining the data relied heavily on follow-up personal communications between the researchers and the participating ophthalmologists. Unfortunately, incomplete data were not uncommon. Undiagnosed diabetes and systemic hypertension might bias their respective association with AMD. It should also be noted that the classification response (not shown) was not that good, so there may be other variables that are needed in the risk analysis model. The sample size was also small; a larger sample size with more participating regional eye care programs would perhaps provide a broader perspective to the risk factors of AMD in Argentina, more data, and different significant variables. In the ordinal logistic regression, a test for parallel lines could not be run because convergence could not be attained or ascertained in estimating the general model. The levels of the variables were still plotted (not shown), and in both instances were distinctly non-parallel, which is a limitation of this model. The existing factors seemingly do not explain very well the risk of developing AMD, but these factors also produced inconsistencies among previous studies. Sunlight exposure, family history of AMD, and being older were the significant risk factors for the development and progression of AMD revealed in this case-control study in Argentina. There may be other variables, as the risk was not explained very well by the existing factors. However, apart from age and family history, the literature search generally demonstrated conflicting results from one study to the next, which may suggest that risk factors are specific to each population in each of their environments, based on the variable exposures. A future study in Argentina that uses a larger sample may produce different, stronger, and/or better results. ACKNOWLEDGEMENTS The authors would like to thank ORBIS for their financial support of the study. The authors would also like to thank all the ophthalmologists who helped collect the data. Andrea Aguilar - Buenos Aires Province, Inés Balogh-Kovacs - Bue­­ nos Aires Province, Agustina Borrone - Buenos Aires Province, Santiago Castro Feijoó - Buenos Aires Province, Estanislao Cima - Buenos Aires Province, Claudia Colodro Guillén - Buenos Aires Province, Edgardo De Mauri - Buenos Aires Province, Ricardo Goñi - Buenos Aires Province, Natalia Menarini - Buenos Aires Province, David Moreno Figueredo - Buenos Aires Province, Federico Morriello - Buenos Aires Province, María Eugenia Pais - Buenos Aires Province, Enrique Paz - Buenos Aires Province, Marcelo Rivamonti - Buenos Aires Province, José Tintel Pantich - Buenos Aires Province, Claudio Juarez - Santa Cruz Province, Joaquín Bafalluy - Santa Fe Province, Guillermo Navar­­ ro - Entre Rios Province, José Luna Pinto - Cordoba Province, Eduardo Zábalo - Cordoba Province, Rafael Iribarren - Buenos Aires City - Federal Capital, David Pelayes - Buenos Aires City - Federal Capital, Pablo Rivera - Buenos Aires City - Federal Capital, Marcelo Zas - Buenos Aires City - Federal Capital, Andrés Bastién - Buenos Aires City - Federal Capital, Carmen Demetrio - Buenos Aires City - Federal Capital, Guillermo Iribarren - Buenos Aires City - Federal Capital. REFERENCES 1. Pascolini D, Mariotti SP. Global estimates of visual impairment: 2010. Br J Ophthalmol. 2012;96(5):614-8. 2. World Health Organization. Global data on visual impairments 2010. Geneva: World Health Organization; 2012. [cited 2012 Dec 20]. Available from: http://www.who.int/ blindness/GLOBALDATAFINALforweb.pdf. 3. Shahid H, Khan JC, Cipriani V, Sepp T, Matharu BK, Bunce C, Harding SP, Clayton DG, Moore AT, Yates JR; Genetic Factors in AMD Study Group. Age-related macular degeneration: the importance of family history as a risk factor. Br J Ophthalmol. 2012; 96(3):427-31. 4. Bressler NM. Age-related macular degeneration is the leading cause of blindness. JAMA. 2004;291(15):1900-1. Comment on Arch Ophthalmol. 2004;122(4):564-72. 5. Cruess AF, Berger A, Colleaux K, Greve M, Harvey P, Kertes PJ, et al. Canadian expert

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consensus: optimal treatment of neovascular age-related macular degeneration. Can J Ophthalmol. 2012;47(3):227-35. Erratum in Can J Ophthalmol. 2012;47(5):460. 6. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology. 1992;99(6):933-43. 7. Mitchell P, Smith W, Altebo K, Wang JJ. Prevalence of age-related maculopathy in Australia. The Blue Mountain Eye Study. Ophthalmology. 1995;102(10):1450-60. 8. Vingerling JR, Diclemans I, Hofman A, Grobbee DE, Hijmering M, Kramer CF, et al. The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology. 1995;102(2):205-10. Comment in Ophthalmology. 1996;103(2):196-7. 9. Klein R, Klein BE, Jensen SC, Mares-Perlman JA, Cruickshanks KJ, Palta M. Age-related maculopathy in a multiracial United States population: the National Health and Nutrition Examination Survey III. Ophthalmology. 1999;106(6):1056-65. 10. Gupta SK, Murthy GV, Morrison N, Price GM, Dherani M, John N, et al. Prevalence of early and late age-related macular degeneration in a rural population in northern India: the INDEYE feasibility study. Invest Ophthalmol Vis Sci. 2007;48(3):1007-11. 11. Krishnaiah S, Das T, Nirmalan PK, Nutheti R, Shamanna BR, Rao GN, et al. Risk factors for age-related macular degeneration: findings from the Andhra Pradesh eye disease study in South India. Invest Ophthalmol Vis Sci. 2005;46(12):4442-9. 12. Xu L, Li Y, Zheng Y, Jonas JB. Associated factors for age related maculopathy in the adult population in China: the Beijing eye study. Br J Ophthalmol. 2006;90(9):1087-90. Comment in Br J Ophthalmol. 2006;90(9):1073-4. 13. Cheung N, Wong TY. Changing trends of blindness: the initial harvest from translational public health and clinical research in ophthalmology. Am J Ophthalmol. 2012; 153(2):193-5. 14. Roston E, McKibbin M. Visual impairment certification secondary to ARMD in Leeds, 2005-2010: is the incidence falling? Eye (Lond). 2012;26(7):933-6. 15. Skaat A, Chetrit A, Belkin M, Kinori M, Kalter-Leibovici O. Time trends in the incidence and causes of blindness in Israel. Am J Ophthalmol. 2012;153(2):214-21.e1. 16. Bloch SB, Larsen M, Munch IC. Incidence of legal blindness from age-related macular degeneration in Denmark: year 2000 to 2010. Am J Ophthalmol. 2012;153(2): 209-13.e2. 17. Klein BE, Klein R. Forecasting age-related macular degeneration through 2050. JAMA. 2009;301(20):2152-3. 18. Seddon JM, Reynolds R, Maller J, Fagerness JA, Daly MJ, Rosner B. Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci. 2009;50(5):2044-53.

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19. Seddon JM, Reynolds R, Yu Y, Daly MJ, Rosner B. Risk models for progression to advanced age-related macular degeneration using demographic, environmental, genetic, and ocular factors. Ophthalmology. 2011;118(11):2203-11. 20. Furtado JM, Lansingh VC, Carter MJ, Milanese MF, Peña BN, Ghersi HA, et al. Causes of blindness and visual impairment in Latin America. Surv Ophthalmol. 2012;57(2): 149-77. 21. United Nations, Department of Economic and Social Affairs. Population Division, Po­­­pulation Estimates and Projections Section. World Population Prospects, the 2010 Revision. Stamdar variants (Updated: 28 June 2011). [cited 2012 Oct 29]. Available from: http://esa.un.org/wpp/Excel-Data/population.htm. 22. Central Intelligence Agency. The World Factbook 2012. Washington, DC: Central Intelligence Agency; 2012. [cited 2012 Nov 1]. Available from https://www.cia.gov/ library/publications/the-world-factbook/index.html. 23. Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med. 2008; 358(24):2606-17. Review. Erratum in: N Engl J Med. 2008;359(16):1736. 24. World Health Organization. Global strategy on diet, physical activity, and health. [cited 2012 Dec 19]. Available from: http://www.who.int/dietphysicalactivity/child hood_what/en. 25. Delcourt C, Carrière I, Ponton-Sanchez A, Fourrey S, Lacroux A, Papoz L; POLA Study Group. Light exposure and the risk of age-related macular degeneration: the Pathologies Oculaires Liées à l’Age (POLA) study. Arch Ophthalmol. 2001;119(10): 1163-8. 26. Chong EW, Robman LD, Simpson JA, Hodge AM, Aung KZ, Dolphin TK, et al. Fat consumption and its association with age-related macular degeneration. Arch Ophthalmol. 2009;127(5):674-80. 27. Christen WG, Schaumberg DA, Glynn RJ, Buring JE. Dietary ω-3 fatty acid and fish intake and incident age-related macular degeneration in women. Arch Ophthalmol. 2011;129(7):921-9. 28. Tan JS, Wang JJ, Flood V, Mitchell P. Dietary fatty acids and the 10-year incidence of age-related macular degeneration: the Blue Mountains Eye Study. Arch Ophthalmol. 2009;127(5):656-65. 29. Seddon JM, George S, Rosner B. Cigarette smoking, fish consumption, omega-3 fatty acid intake, and associations with age-related macular degeneration: the US Twin Study of Age-Related Macular Degeneration. Arch Ophthalmol. 2006;124(7):995-1001. 30. Seddon JM, Cote J, Davis N, Rosner B. Progression of age-related macular degeneration: association with body mass index, waist circumference, and waist-hip ratio. Arch Ophthalmol. 2003;121(6):785-92.

Artigo Original | Original Article

Evaluation of magnocellular pathway abnormalities in schizophrenia: a frequency doubling technology study and clinical implications Avaliação das alterações da via magnocelular na esquizofrenia usando FDT e suas implicações clínicas Fabiana Benites Vaz de Lima1,2, Carolina Pelegrini Barbosa Gracitelli3, Augusto Paranhos Junior3, Rodrigo Affonseca Bressan1,2

ABSTRACT

RESUMO

Background: Visual processing deficits have been reported for patients with schi­­­ zophrenia. Previous studies demonstrated differences in early-stage processing of schizophrenics, although the nature, extent, and localization of the disturbance are unknown. The magnocellular and parvocellular visual pathways are associated with transient and sustained channels, but their respective contributions to schizophrenia-related visual deficits remains controversial. Purpose: The aim of this study was to evaluate magnocellular dysfunction in schi­­­zophrenia using frequency doubling technology. Methods: Thirty-one patients with schizophrenia and 34 healthy volunteers were examined. Frequency doubling technology testing was performed in one session, consisting of a 15-minute screening strategy followed by the C-20 program for frequency doubling technology. Results: Schizophrenic patients showed lower global mean sensitivity (30,97 ± 2,25 dB) compared with controls (32,17 ± 3,08 dB), p<0.009. Although there was no difference in the delta sensitivity of hemispheres, there was a difference in sensitivity analysis of the fibers crossing the optic chiasm, with lower mean sensitivity in the patient group (28,80 dB) versus controls (30,66 dB). The difference was higher in fibers that do not cross the optic chiasm, with lower mean sensitivity in patients (27,61 dB) versus controls (30,26 dB), p<0.005. Conclusions: Our results suggest that there are differences between global sen­­­­ sitivity and fiber sensitivity measured by frequency doubling technology. The different sensitivity of fibers that do not cross the optic chiasm is consistent with most current etiological hypotheses for schizophrenia. The decreased sensitivity responses in the optic radiations may significantly contribute to research assessing early-stage visual processing deficits for patients with schizophrenia.

Histórico: Déficits de processamento visual foram relatados em pacientes com esquizofrenia. Estudos anteriores demonstraram diferenças no estágio inicial de processamento de esquizofrênicos, embora a natureza, extensão e localização do distúrbio são desconhecidas. As vias magnocelulares e parvocelular visuais são associados com canais transitórios e sustentado, mas suas respectivas contribuições para a esquizofrenia relacionados com déficits visuais permanece controverso. Objetivo: Avaliar a disfunção magnocelular na esquizofrenia usando a tecnologia de frequência dupla. Métodos: Trinta e um pacientes com esquizofrenia e 34 voluntários saudáveis ​​foram examinados. Tecnologia de frequência dupla foi realizada em uma sessão, consistindo de uma estratégia de rastreio de 15 minutos, seguido do programa de C-20 para tecnologia de frequência dupla. Resultados: Os pacientes esquizofrênicos apresentaram sensibilidade média inferior global (30,97 ± 2,25 dB), em comparação com os controles (32,17 ± 3,08 dB), p<0,009. Embora não tenha ocorrido diferença na sensibilidade do delta de hemisférios, houve uma diferença na análise de sensibilidade das fibras que atravessam a quiasma, com menor sensibilidade média no grupo de pacientes (28,80 dB) versus controlos (30,66 dB). A diferença foi maior em fibras que não cruzam o quiasma óptico, com menor sensibilidade média em pacientes (27,61 dB) versus controles (30,26 dB), p<0,005. Conclusões: Nossos resultados sugerem que há diferenças entre a sensibilidade global e sensibilidade da fibra medida pela tecnologia de frequência dupla. A sensibilidade diferente de fibras que não cruzam o quiasma óptico é compatível com a maioria das atuais hipóteses etiológicas para a esquizofrenia. As respostas diminuição da sensibilidade nas radiações ópticas podem contribuir significativamente para pesquisar a avaliação em estágio inicial déficits de processamento visual em pacientes com esquizofrenia.

Keywords: Schizophrenia; Visual perception; Visual pathways; Basal nucleus of Meynert

Descritores: Esquizofrenia; Percepção visual; Vias visuais; Núcleo basal de Meynert

INTRODUCTION Schizophrenia is a severe mental disorder and considered a pu­­­ blic health issue. The cost of schizophrenia includes lost income, public aid, and drug and psychosocial treatments(1). Despite all the treatments currently available, patients with schizophrenia still suffer from a combination of symptoms, such as delusions, hallucinations, and social withdrawal(1,2). Among many hypotheses for schizophrenia’s etiology, the neurodevelopmental model is one of the most important(3). The visual pathway may be a good marker for central nervous system develop­ ment. The recent advances in understanding the neural networks

involved in visual perception allow a better comprehension of the pathophysiology of neurodevelopmental and psychiatric disorders(4,5). Schizophrenia patients’ exhibit deficits in several neurophysiologic measures of information processing that have been proposed as candidate endophenotypes(6). A number of studies that provide evidence to support the hypothesis that the deficit in the magnocellular pathway is a trait of vulnerability to schizophrenia(7,8). Deficits in visual performance of patients with schizophrenia have been described for many years, but this may be due to several factors, from peripheral sensory abnormalities (slow neuronal transmission) to losses in higher cortical functioning(6,9-11). Furthermore, fai-

Submitted for publication: January 24, 2013 Accepted for publication: January 31, 2013

Funding: No specific financial support was available for this study.

Study was carried out at Universidade Federal de São Paulo - UNIFESP - São Paulo (SP), Brazil. Laboratório Interdisciplinar de Neuroimagem e Cognição (LiNC), Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo (SP), Brazil. Physician, Programa de Esquizofrenia - PROESQ - Universidade Federal de São Paulo - UNIFESP - São Paulo (SP), Brazil. 3 Physician, Departament of Ophthalmology, Universidade Federal de São Paulo - UNIFESP - São Paulo (SP), Brazil. 1

2

Disclosure of potential conflicts of interest: F.B.V.de Lima, is employee of AstraZeneca; C.P.B.Gracitelli, None; A.Paranhos Jr, None; R.A. Bressan has received grant/ research support from Janssen-Cilag, AstraZeneca, Eli Lilly, and Novartis. Correspondence address: Carolina Pelegrini Barbosa. Rua Botucatu, 821 - São Paulo (SP) 04023-062 - Brazil - E-mail: [email protected]

Arq Bras Oftalmol. 2013;76(2):85-9

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Evaluation of magnocellular pathway abnormalities in schizophrenia: a frequency doubling technology study and clinical implications

lures in this system cause a lack of information to the visual cortex, and these result in clinical symptoms for patients(12). The most frequent clinical symptoms include selective attention in sustained attention and disturbance of short-term visual memory(13-15). The subcortical projections of the retina to the cerebral cortex are formed mainly by two pathways (magnocellular and parvocellular) related to subdivisions of the lateral geniculate body with the same name. These pathways are of great importance because they contain approximately 90% of axons leaving the retina and maintain their anatomical segregation of projections through the lateral geniculate body in the V1 layer 4C of the striate cortex(14). Psychophysical studies of specific visual functions have been used to measure visual performance and understand retinal ganglion cell functioning. Some studies suggested that the visual deficit is in the magnocellular pathway, or the transient channels. Other studies claim that the visual deficit is in the parvocellular pathway or the sustained channels, or the interaction of the abnormal magnocellular and parvocellular channels(16-18). Although many studies have established that there are differences in early visual processing in schizophrenia patients, the nature, extent, and location of this abnormality remain uncertain(19,20). The magnocellular pathway is formed by large neurons that pro­­­ject the visual stimuli to the dorsal visual stream, and is primarily involved with the motion and location of the stimulus (the “where” system)(20). The parvocellular pathway is composed of smaller neurons, with slower neuronal driving, which project to the ventral visual stream and is primarily responsible for recognition of the object (the “what” system). Despite the preference of the dorsal and ventral magnocellular and parvocellular neurons, visual information also crosses between hemispheres(20). The physiological responses of ganglion cells in the magnocel­ lular and parvocellular pathways are similar in some domains and completely different in others. The major difference is the response to color sensitivity. Parvocellular neurons respond to the stimulus of alternation green/red or blue/yellow, and show some response despite the change of color luminescence. In the case of magnocellular neurons, there is no response to alternation of colors when the luminescence is balanced(21). Another difference in physiological responses between parvocellular and magnocellular neurons is present in contrast sensitivity. The response to contrast sensitivity is much greater in magnocellular cells, which respond to stimuli with contrast less than 2%, while the parvocellular cells rarely respond to a contrast less than 10%(20,21).In other dimensions of visual stimuli, including spatial response, temporal, and luminescence contrast, neurons via the parvocellular and magnocellular pathways have different responses; however, there is overlap in the rates of sensitivity(20). The aim of this study was to evaluate the initial visual processing (perception of the stimulus by ganglion cells) using frequency doubling technology (FDT) in patients with schizophrenia compared with healthy controls, and evaluate the relationship between the deficit in visual processing with socio-demographic factors and clinical factors associated with chronicity, such as negative symptoms, duration of the disease, and antipsychotic drug use. METHODS

Participants We recruited patients with diagnoses of schizophrenia from the Schizophrenia Program at the Federal University of São Paulo. The control group was recruited from the hospital staff community and students at the same university. The participation of individuals in the study was voluntary and all signed the Term of Free and Informed Consent, previously approved by the Ethics Committee of the Federal University of São Paulo. 86

Arq Bras Oftalmol. 2013;76(2):85-9

Inclusion criteria for patients included: 1) fulfill the diagnosis of schi­­­­zophrenia made through the application of the Structured Clinical Interview for DSM-IV (SCID) by a trained psychiatrist; 2) good vision (visual acuity greater 20/60) tested by Snellen chart; 3) intraocular pressure lower than 20 mmHg measured by Perkins tonometry; and 4) normal biomicroscopic examination and normal optic nerve (excavation/disc equal to or less than 0.6 SD) assessed by a ophthalmologist(22). The exclusion criteria for patients included: 1) presence of a his­­­ tory of abuse on alcohol or drugs; 2) presence of any neurological disease that could affect performance on the test; and 3) diseases af­­­fecting the visual field. The inclusion criteria for controls: 1) mental status assessment by Self-Report Questionnaire (SRQ-20) with cut-off less than or equal to 7 positive answers; and 2) the same ophthalmologic inclusion criteria applied for the schizophrenic patients. A family history of glaucoma was allowed(23). The exclusion criteria for controls: 1) presence of psychiatric illness; 2) substance abuse; 3) diseases affecting the visual field; and 4) presence of a systemic disease that can potentially affect the visual system.

Psychiatric assessment The presence of positive and negative symptoms was assessed by the Positive and Negative Syndromes Scale (PANSS)(24). Schizoph­ renic patients were classified into negative, positive, or mixed according to the parameters of Andreasen and Olsen(24). Patients were evaluated and classified according to antipsychotic medication in use. The type of antipsychotics included first and second generation antipsychotics or a combination of both. The dose of chlorpromazine equivalents for each antipsychotic used at the time of examinations was calculated. Control participants were evaluated with the SRQ-20 and were excluded from the study if their scores were higher than 7.

Ophthalmologic evaluation Participants were submitted to an ophthalmological examination, which included: measurement of visual acuity, refraction, slit-lamp biomicroscopy of the anterior chamber, measurement of intraocular pressure, and fundus examination. Patients and volunteers were tested: light stimuli were presented and participants responded according to their ability to detect the stimuli. Participants first received the necessary instructions for performing the examination. Next, participants began a 15-minute strategy of screening, where participants learned to recognize the stimuli and adapt to the test. The stimuli were presented on the computer screen and the participants were required to press a button when they saw the gray square. Testing was conducted in a darkened room. FDT measures the contrast needed for detection of the stimulus. Each grating target is a square extending approximately 10º in diameter. Targets are presented in one of 18 areas located 20° radius of the visual field temporally and 30º nasally(25). FDT was performed with the C-20 program, which is the proper evaluation of the magnocellular cells, using a sinusoidal pattern of light stimuli and temporal frequency of 50 Hz(25,26). FDT was measured with the frequency doubling visual field instrument (Carl Zeiss Meditec, Dublin, CA).

Statistical analysis The analyses of FDT global retinal sensitivity were performed com­­­paring the mean-deviation (MD) of patients versus controls using unpaired t test. The right hemisphere analysis included the mean sensitivity of the right nasal and left temporal hemifields. The left hemisphere analysis included the mean sensitivity of the right temporal and left nasal hemifields. We also performed a retinal sensitivity analysis between the fibers crossing the optic chiasm and those that do not cross.

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Statistical analyses were performed using the SPSS statistical package, version 17.0, (SPSS Inc., Chicago, USA). Generalized estimated equation (GEE) was performed to evaluate differences among the groups and to correct the dependency between the eyes, according to hemispheres, and fibers that cross or do not cross the optic chiasm(27). As a secondary analysis, MD values were used as the dependent variable in the logistic regression model with the following independent variables: age, gender, disease duration, antipsychotic treatment, positive and negative symptoms, and education level. RESULTS We evaluated 31 outpatients (24 male/7 female) diagnosed with schizophrenia using the SCID criteria of the DSM-IVR, and 34 health controls (8 male/26 female). The participants’ socio-demographic characteristics are described in table 1. The ophthalmologic evaluation revealed that both groups had visual acuity, as tested by Snellen chart, that was higher than 20/60 (Table1). Intraocular pressure was normal (less than 20 mmHg) for both groups, although there was a significant difference between groups of less than 2 mmHg. This difference is not clinically relevant and cannot affect the FDT results. In the sample studied, only two patients were employed at the time of evaluation; the remaining 32 (94%) were retired or receiving sickness benefit. All patients were using antipsychotic drugs or other psychotropic agents for at least 6 months. The patients were also assessed by the PANSS scale and classified according to symptomatic group: ten were classified as negative type, ten were positive type, 11 were any kind, and three were mixed type. The participants’ clinical characteristics are described in table 2. Table 3 shows the global MD FDT test in control and schizophrenia groups. Three patients were excluded from the FDT analysis due to poor performance on the test. The patients with schizophrenia showed lower global mean sensitivity values (30.97 dB ± 2.25) in comparison with the control group mean (32.17 dB ± 3.08), p<0.009. There was no difference in the delta sensitivity of hemispheres between patients and controls (p<0.88) (Figure1). There was a difference in sensitivity analysis of the fibers crossing the optic chiasm between patients and controls, with lower mean sensitivity in the schizophrenia group (28.80 dB) than in the control group (30.66 dB), p=0.005 (Figure 2). The difference in sensitivity analysis of the fibers that did not cross the optic chiasm between patients and controls was higher, with lower mean sensitivity (27.61 dB) in the patient group versus (3026 dB) the control group (p=0.02). There was no significant correlation between the global mean sensitivity values and the following independent variables: age, gender, length of time with diagnoses, antipsychotics used, presence or absence of positive and negative symptoms, and education level. DISCUSSION This study evaluated the visual processing deficits in schizophrenia by use of FDT. The advantages of FDT for early detection of magnocellular dysfunction are well documented. FDT shows good specificity (86-100%) at high sensitivity (93%), and has global indices that correlate highly with those of standard perimetry(26). The finding in this study of a deficit in the magnocellular pathway in schizophrenia is consistent with results from some previous psychophysical studies, although they have also produced conflicting results(28). A number of psychophysical tests have been used to measure visual performance and to understand retinal ganglion cell deficits in schizophrenia(8,28). Some studies using a visual backward masking paradigm, during which participants are asked to detect a stimulus

Table 1. Socio-demographic characteristics of patients with schizophrenia and healthy control participants Control (n=34)

Schizophrenic (n=31)

p-value

(8/26)

(24/7)

0.005

VA (logMAR) - Mean (SD)

00.01 (0.04)

00.04 (00.06)

0.100

Age (years) - Mean (SD)

32.10 (13.7)

37.80 (12.30)

0.081

IOP (mmHg) - Mean (SD)

12.16 (2.44)

14.13 (02.99)

0.005

Refraction - Mean (SD)

-0.33 (1.41)

-0.21 (02.81)

0.835

Gender (M/F)

M= male; F= female; SD= standard deviation; IOP= intraocular pressure; VA= visual acuity; Refraction= espheric equivalent.

Table 2. Clinical characteristics of the schizophrenic patients Patients (n = 34)

Mean

SD

Range

Disease duration (years)

014.32

010.71

1 - 53

Age of onset (years)

022.76

008.79

12 - 40

PANSS-N

019.76

005.85

7 - 34

PANSS-P

018.38

007.25

9 - 34

GAF

043.94

011.05

20 - 65

CPZ (mg/d)

367.50

242.56

50 - 1175

SD= standard deviation; PANSS-N= negative PANSS score; PANSS-P= positive PANSS score; GAF= Global Assessment of Functioning scale score; CPZ= chlorpromazine equivalent (mg/day).

Table 3. FDT results of global mean retinal sensitivity (FDT-MD) of schizophrenic patients and healthy control Schizophrenic n=31

Control n=34

p-value

FDT-MD (dB) Mean (SD)

30.97 (2.25)

32.17 (3.08)

p<0.009

FDT-MD (dB) Crossing fibers

28.80 (5.02)

30.66 (2.48)

P=0.005

FDT-MD (dB) N-crossing fibers

27.61 (5.49)

30.26 (2.83)

P=0.002

Delta MD

28.58 (6.38)

30.43 (2.66)

P<0.88

FDT-MD = global mean sensitivity values; crossing fibers= fibers that cross the optic chiasm; n-crossing fibers= fibers that do not cross the optic chiasm; Delta MD= delta sensitivity of hemispheres.

immediately followed by a mask, increased the possibility that the mask, which is processed by an overactive magnocellular pathway, may influence the lower performances on target detections(18,29). Studies using luminance contrast sensitivity measurements showed more pronounced differences. Schwartz et al.(15) found selective contrast sensitivity impairments for temporally modulated low frequency gratings, which stimulate magnocellular neurons. Kéri et al.(30) observed intact contrast sensitivity for magnocellular pathway stimuli. A limitation of this study is that there has not been extensive tes­­ting of its psychophysical properties. Furthermore, the impact of training requires better investigation and test-retest reliability should be measured, especially in patients with cognitive impairments(31). New evidence from functional magnetic resonance imaging sup­ ports the hypothesis that schizophrenia is associated with impaired functioning of the magnocellular pathway and that these deficits

Arq Bras Oftalmol. 2013;76(2):85-9

87

Evaluation of magnocellular pathway abnormalities in schizophrenia: a frequency doubling technology study and clinical implications

Figure 1. FDT-MD: global mean sensitivity values (in dB); right and left hemispheres; presented as box-plots.

is evidence that a hypo-dopaminergic state could affect contrast sensitivity and color perception(34). However, previous studies have shown no significant correlations between the antipsychotic dose and deficits in the magnocellular pathway(32,33). In contrast, Braff and Saccuzzo(35) found that medications reduced the backward masking deficit. In our sample, there was no correlation between FDT response and chlorpromazine-equivalent doses. There is some evidence in literature that supports a right hemisphere advantage for processing global information, and left hemisphere preference for local information(36). In our study, there was no difference in the delta sensitivity of hemispheres between patients and controls. However, Braus et al.(37) used functional magnetic resonance imaging and found a hypoactivation in the magnocellular pathway, particularly in the right hemisphere of schizophrenic patients, but found no evidence of abnormal functioning in the area of the parvocellular pathway. It was possible to verify the difference in sensitivity analysis of the fibers that do not cross the optic chiasm between patients and controls because of the particularities of ganglion cell anatomy(38). The ganglion cells of the right and left eye visual receptive fields reflect half of the visual field in the opposite hemisphere. The crossing of fibers occurs in the retinal optic chiasm, where medial fibers cross the chiasm to join sides with the temporal fibers. In other words, the temporal retina ipsilateral hemispheric projection displays in the same side, while the nasal retina contralateral hemispheric projection displays in the opposite side. Because of this distribution of fibers, each outer half of the visual field is represented in the opposite cerebral hemisphere(38). To the best of our knowledge, this is the first time in the literature that analyses of sensitivity between fibers that cross and do not cross the chiasm have been performed. The evidence presented here, for a lower sensitivity in fibers that do not cross the optic chiasm, is consistent with most current etiological hypotheses for schizophrenia involving genetic factors and anatomical processes (e.g., dysmyelination)(3,39). Our study showed significant decreased sensitivity responses in the optic radiations, which was consistent with the results from Butler et al. using diffusion tensor imaging to examine white matter integrity in schizophrenia(40). The present findings suggest that there are differences between global sensitivity and fiber sensitivity measured by FDT, and may contribute to a significant body of research to assess early-stage visual processing deficits for patients with schizophrenia. REFERENCES

Figure 2. FDT-MD: global mean sensitivity values (in dB); crossing fibers (Decussation Yes) and n-crossing fibers (Decussation No); presented as box-plots.

may contribute to high-order cognitive deficits(32). Based on previous available data, it was hypothesized that a negative correlation would be found such that patients with the highest level of negative symptoms would show the greatest deficit in the magnocellular pathway(33). In general, the results of the contrast sensitivity and masking studies suggest that visual processing is more intact in groups with predominantly positive symptoms and good premorbid history. In our sample, there was no correlation between length of time with the disease and age of onset. In this study all patients were using antipsychotic drugs or other psychotropic agents for at least 6 months, and the medication effect cannot be excluded. Dopamine is present in the retina and there 88

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1. Blomqvist AG, Léger PT, Hoch JS. The cost of schizophrenia: lessons from an international comparison. J Ment Health Policy Econ. 2006;9(4):177-83. 2. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. DSM-IV. 4th edition. Washington (DC): American Psychiatry Association; 1994. 3. Pantelis C, Yücel M, Wood SJ, Velakoulis D, Sun D, Berger G, et al. Structural brain imaging evidence for multiple pathological processes at different stages of brain development in schizophrenia. Schizophr Bull. 2005;31(3):672-96. 4. Murray RM, Lewis SW. Is schizophrenia a neurodevelopmental disorder? Brit Med J (Clin Res Ed). 1987;295(6600):681-2. 5. Brenner CA, Krishnan GP, Vohs JL, Ahn WY, Hetrick WP, Morzorati SL, et al. Steady state responses: electrophysiological assessment of sensory function in schizophrenia. Schizophr Bull. 2009;35(6):1065-77. 6. Green MF, Nuechterlein KH. Backward masking performance as an indicator of vulnerability to schizophrenia. Acta Psychiatr Scand Suppl. 1999;395:34-40. 7. Kéri S, Benedek G. Visual contrast sensitivity alterations in inferred magnocellular pathways and anomalous perceptual experiences in people at high-risk for psychosis. Vis Neurosci. 2007;24(2):183-9. 8. Bedwell JS, Brown JM, Miller LS. The magnocellular visual system and schizophrenia: what can the color red tell us? Schizophr Res. 2003;63(3):273-84. 9. Butler PD, Abeles IY, Weiskopf NG, Tambini A, Jalbrzikowski M, Legatt ME, et al. Sensory contributions to impaired emotion processing in schizophrenia. Schizophr Bull. 2009; 35(6):1095-107. 10. Butler PD, Silverstein SM, Dakin SC. Visual perception and its impairment in schizophrenia. Biol Psychiatry. 2008;64(1):40-7.

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illusion-based pattern electroretinogram for glaucoma. Invest Ophthalmol Vis Sci. 2000;41(12):3818-26. 27. Liang KY, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika. 1986;73(1):13-22. 28. Skottun BC, Skoyles JR. On identifying magnocellular and parvocellular responses on the basis of contrast-response functions. Schizophr Bull. 2011;37(1):23-6. 29. Skottun BC, Skoyles JR. A few remarks on attention and magnocellular deficits in schi­­­zophrenia. Neurosci Biobehav Rev. 2008;32(1):118-22. 30. Kéri S, Antal A, Szekeres G, Benedek G, Janka Z. Visual information processing in patients with schizophrenia: evidence for the impairment of central mechanisms. Neu­­­rosci Lett. 2000;293(1):69-71. 31. Green MF, Butler PD, Chen Y, Geyer MA, Silverstein S, Wynn JK, et al. Perception measurement in clinical trials of schizophrenia: promising paradigms from CNTRICS. Schizophr Bull. 2009;35(1):163-81. Review. 32. Martínez A, Hillyard SA, Dias EC, Hagler DJ Jr, Butler PD, Guilfoyle DN, et al. Magnocellular pathway impairment in schizophrenia: evidence from functional magnetic resonance imaging. J Neurosci. 2008;28(30):7492-500. Erratum in J Neurosci. 2008; 28(37):9319. 33. Butler PD, Harkavy-Friedman JM, Amador XF, Gorman JM. Backward masking in schizophrenia: relationship to medication status, neuropsychological functioning, and dopamine metabolism. Biol Psychiatry. 1996;40(4):295-8. 34. Djamgoz MB, Hankins MW, Hirano J, Archer SN. Neurobiology of retinal dopamine in relation to degenerative states of the tissue. Vision Res. 1997;37(24):3509-29. 35. Braff DL, Saccuzzo DP. Effect of antipsychotic medication on speed of information processing in schizophrenic patients. Am J Psychiatry. 1982;139(9):1127-30. 36. Evans MA, Shedden JM, Hevenor SJ, Hahn MC. The effect of variability of unattended information on global and local processing: evidence for lateralization at early stages of processing. Neuropsychologia. 2000;38(3):225-39. 37. Braus DF, Weber-Fahr W, Tost H, Ruf M, Henn FA. Sensory information processing in neuroleptic-naive first-episode schizophrenic patients: a functional magnetic resonance imaging study. Arch Gen Psychiatry. 2002;59(8):696-701. 38. Tootell RB, Switkes E, Silverman MS, Hamilton SL. Functional anatomy of macaque striate cortex. II. Retinotopic organization. J Neurosci. 1988;8(5):1531-68. 39. Davis KL, Stewart DG, Friedman JI, Buchsbaum M, Harvey PD, Hof PR, et al. White matter changes in schizophrenia: evidence for myelin-related dysfunction. Arch Gen Psychiatry. 2003;60(5):443-56. Review. 40. Butler PD, Hoptman MJ, Nierenberg J, Foxe JJ, Javitt DC, Lim KO. Visual white matter integrity in schizophrenia. Am J Psychiatry. 2006;163(11):2011-3.

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89

Artigo Original | Original Article

Frequência de ocorrência de cavidade anoftálmica na região centro-oeste paulista e características dos portadores Frequency of occurrence of anophthalmic socket in the Middle West region of the state of São Paulo and the carriers characteristics Roberta Lilian Fernandes de Sousa1, André Ricardo Carvalho Marçon2, Carlos Roberto Padovani3, Silvana Artioli Schellini4

RESUMO

Abstract

Objetivo: Observar a frequência de ocorrência de casos de cavidade anoftálmica na região centro-oeste paulista e descrever o perfil demográfico dos portadores em estudo populacional. Métodos: Estudo transversal, de caráter observacional e de amostragem aleatória, realizado em 12 cidades da região centro-oeste do estado de São Paulo, para as quais o centro de referência é a cidade de Botucatu. Os participantes foram determinados por sorteio que levou em conta o local de moradia, tendo sido estabelecida uma amostra de 11.453 indivíduos. Todos os exames foram feitos utilizando uma Unidade Oftalmológica Móvel. O protocolo da pesquisa consistiu de dados demográficos e exame oftalmológico completo (anamnese, antecedentes oculares e sistêmicos, antecedentes familiares, avaliação da acuidade visual com e sem correção, tonometria, biomicroscopia, fundoscopia e exame refracional). Todos os dados obtidos foram transferidos para tabela Excel e submetidos à análise descritiva e apresentados como frequência de ocorrência. Resultados: A frequência de ocorrência de cavidade anoftálmica na região cen­ tro-oeste paulista foi de 0,96‰. Dentre os sujeitos examinados, foram encontrados 11 casos de cavidade anoftálmica, com acometimento de 0,7‰, no sexo feminino e 1,3‰, do sexo masculino. Dentre as causas de cavidade anoftálmica foram encontradas glaucoma (olho cego doloroso), microftalmia, trauma e endoftalmite. Os indivíduos eram, em sua maioria, de idade superior ou igual a 40 anos, tendo sido encontrado apenas um caso com idade abaixo de 19 anos. Conclusão: A cavidade anoftálmica ocorreu em 0,96‰ dos habitantes da região centro-oeste paulista, acometendo mais frequentemente os homens e com grande variação de idade de acometimento.

Purpose: To observe the frequency of the occurrence of the anophthalmic socket in the Middle West region of the state of São Paulo and to describe the demographic profile of the carriers in a population-based data. Methods: A cross-sectional study involve a random sampling carried out in twelve cities of the Middle West region of the state of São Paulo, for which the reference center is the city of Botucatu was done. The participators were chosen by assortment which considered the houses of these people. It was established a sampling with 11,453 people. All the exams were realized using a Mobile Ophthalmologic Unit. The research protocol included the demographic data and the complete ophthalmologic exam (anamnesis, ocular and systemic antecedents, familiar antecedents, visual acuity with and without correction, tonometry, biomicroscopy, fundoscopy, and refraction exam). All the data were transferred to an Excel spreadsheet and submitted to a descriptive analysis and were presented by the frequency of the occurrence. Results: Ophthalmic socket frequency in the Middle West region of the state of São Paulo was 0.96‰. We found 11 cases of anophthalmic socket, with involvement of 0.7 ‰ in females and 1.3 ‰, male. The most common causes of anophthalmic socket were glaucoma (blind painful eye), microphthalmia, trauma, and endophthalmitis. The majority of the people were 40 years old or more, and we found just one person younger than 19 years old. Conclusion: The anophthalmic socket occurred in 0.96‰ of the habitants of the Middle West region of São Paulo State, occurring mainly in male and with large variety of the affected ages.

Descritores: Procedimentos cirúrgicos oftalmológicos; Cavidade anoftálmica; Epi­­­demiologia; Estudos transversais; Técnicas de diagnóstico oftalmológico; Vi­­­ gilância da população

Keywords: Ophthalmologic surgical procedures; Anophthalmic socket; Epidemiology; Cross-sectional studies; Population surveillance

INTRODUÇÃO Órbita anoftálmica ou cavidade anoftálmica é o nome dado à órbita que se apresenta sem o olho, ausente devido a causa congênita ou após remoção por meio de evisceração ou enucleação. A remoção do olho é a indicação cirúrgica do estágio final de várias doenças oculares, tais como glaucoma absoluto, phthisis bulbi,

panuveítes; trauma com perda substancial de conteúdo e nos quais a reconstrução do olho é impossível; tumores oculares; ou após pro­­­ cedimentos cirúrgicos que cursam com infecção intraocular disseminada (endoftalmite)(1). Embora sejam conhecidas as causas de remoção do olho ou de seu conteúdo em alguns serviços de referência, principalmente

Submetido para publicação: 5 de Maio de 2012 Aceito para publicação: 21 de Janeiro de 2013

Financiamento: Não houve financiamento para este trabalho.

Trabalho realizado no Departamento de Oftalmologia, Otorrinolaringologia e Cirurgia de Cabeça e Pescoço da Faculdade de Medicina de Botucatu, Universidade Estadual Paulista - UNESP - Botucatu (SP), Brasil. Médica, Departamento de Oftalmologia, Otorrinolaringologia, Cirurgia de Cabeça e Pescoço, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista - UNESP - Botucatu (SP), Brasil. Acadêmico de Medicina, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista UNESP - Botucatu (SP), Brasil. 3 Professor Titular, Departamento de Bioestatística, Instituto de Biociências, Universidade Estadual Paulista - UNESP - Botucatu (SP), Brasil. 4 Professora Titular, Departamento de Oftalmologia, Otorrinolaringologia, Cirurgia de Cabeça e Pescoço da Faculdade de Medicina de Botucatu, Universidade Estadual Paulista - UNESP - Botucatu (SP), Brasil. 1

2

90

Arq Bras Oftalmol. 2013;76(2):90-3

Divulgação de potenciais conflitos de interesse: R.L.F.de Sousa, Nenhum; A.R.C.Marçon, Nenhum; C.R.Padovani, Nenhum; S.A.Schellini, Nenhum. Endereço para correspondência: Roberta Lilian Fernandes de Sousa. Rua Marília, 427 - Apto. 3 Botucatu (SP) - 18608-560 - Brasil - E-mail: [email protected] Aprovado pelo Comitê de Ética em Pesquisa da Faculdade de Medicina de Botucatu sob o número 4001/2011.

Sousa RLF, et al.

serviços de Hospitais-Escola(2), a prevalência de casos de cavidade anoftálmica na população geral não é conhecida. A maioria dos trabalhos relata as técnicas utilizadas para a remoção do olho e avalia sua eficiência(3), não especificando o perfil dos pacientes e nem as causas pelas quais houve a necessidade da cirurgia. Com o objetivo de mostrar a frequência de ocorrência destes casos na população geral, assim como traçar um perfil dos portadores de cavidade anoftálmica em nosso meio, é que foi realizado este trabalho. MÉTODOS Este estudo é parte de uma pesquisa realizada na região centrooes­te do Estado de São Paulo, realizada em 12 cidades para as quais o centro de referência em Saúde é a cidade de Botucatu e que teve como intuito conhecer as causas de cegueira na população geral. Trata-se de um estudo de base populacional, transversal, observacional, realizado nos anos de 2006 a 2008. O tamanho amostral foi estimado em 12.000 indivíduos, tendo por base dados históricos de prevalência de cegueira no nosso meio(4). Os sujeitos foram escolhidos por sorteio, baseando-se, para estabelecimento da amostra, em dados demográficos do Censo de 2005 e nos setores censitários utilizados naquele censo. Foi sorteada a primeira residência do setor censitário e, a partir dela, foi escolhida a quinta residência do lado ímpar da rua e assim sucessivamente. Utilizou-se uma Unidade Móvel equipada para atendimento oftalmológico para acessar a população, além das dependências de Postos de Saúde localizados nas cidades visitadas. A equipe era composta por membros da Faculdade de Medicina de Botucatu, além de integrantes das Secretarias de Saúde dos Municípios. O protocolo da pesquisa foi aprovado pelo Comitê de Ética em Pesquisa da Faculdade de Medicina de Botucatu e consistiu de da­­ dos demográficos e exame oftalmológico completo (anamnese, antecedentes oculares e sistêmicos, antecedentes familiares, acuidade visual com e sem correção óptica, tonometria, biomicroscopia, fundoscopia e exame refracional). Os dados obtidos nas consultas foram transferidos para tabela Excel. Foram examinados 11.453 indivíduos, sendo analisados, no presente estudo, os dados dos portadores de cavidade anoftálmica, observando-se variáveis descritivas tais como sexo, idade, causa da perda ocular e cidade de procedência daqueles indivíduos. A análise

estatística foi apresentada segundo a frequência de ocorrência da variável em estudo(5). Resultados Foram examinados 11.453 indivíduos das 12 cidades da região centro-oeste paulista. Destes, 4.586 eram do sexo masculino e 6.867, do sexo feminino (Tabela 1). A tabela 1 mostra ainda, os porcentuais de participantes atendidos em cada Município, em comparação à população total dos mesmos. Dentre todos os examinados, foram encontrados 11 portadores de cavidade anoftálmica, ou seja, a frequência de ocorrência de cavidade anoftálmica na região estudada foi de 0,96‰ (IC 95% [0,39‰ ≤ n ≤ 1,53‰]). Considerando-se o total de participantes da amostra de acordo com o sexo, em valores absolutos, foram examinadas 6.867 mulheres, das quais cinco apresentavam anoftalmia, com frequência de ocorrência de 0,7‰, enquanto os homens, para um total de 4.586 homens examinados, foram encontrados seis portadores de cavidade anoftálmica, com frequência de ocorrência de 1,3‰. Ou seja, a anoftalmia foi mais frequente em homens. Houve uma grande variação quanto à idade dos portadores de cavidade anoftálmica: três indivíduos apresentavam idade entre 10 e 19 anos, três entre 40 e 49 anos, um entre 50 e 59 anos, três entre 60 e 69 anos e três com idade maior que 70 anos (Tabela 2). Quanto à cor da pele, três portadores de cavidade anoftálmica eram brancos, um era negro e não havia informação da cor da pele em sete destes pacientes. Dos 11 indivíduos, seis apresentavam cavidade anoftálmica à direita e cinco, à esquerda (Tabela 2). Em relação às causas da perda ocular, dois casos haviam sido sub­­­metidos à remoção do olho após trauma ocular, dois por glaucoma, dois por endoftalmite, dois por uveíte e um por malformação congênita (microftalmia). Não foram obtidos dados sobre a causa da perda ocular em dois participantes (Tabela 2). Sete indivíduos (63,6%) residiam na cidade de Botucatu, um era da cidade de Areiópolis, um de Taguaí e dois, da cidade de Piraju. Dois indivíduos eram aposentados e dois trabalhavam no domicílio. Não foi possível obter dados de profissão de sete portadores de cavidade anoftálmica. Quanto à acuidade visual do olho contralateral, avaliada pela tabela de Snellen e com o uso da melhor correção óptica, sete apre-

Tabela 1. Distribuição dos casos de cavidade anoftálmica detectados segundo sexo dos participantes do estudo e município de moradia Sexo Município

Masculino

Feminino

Total de participantes de cada município

Porcentual da população atendida (%)

Casos de cavidade anoftálmica

Arandu

0.278

0. 468

00. 746

12,40

00

Areiópolis

0. 301

0. 457

00. 758

07,13

01

Bofete

0. 269

0. 423

0.0 692

08,07

00

Botucatu

1.096

1.458

02.554

02,11

07

Conchas

0. 373

0. 640

01.013

06,54

00

Itaí

0. 347

0. 673

01.020

04,50

00

Manduri

0. 386

0. 634

01.020

11,79

00

Pereiras

0. 352

0. 543

00. 895

12,18

00

Pratânia

0. 256

0. 441

00. 697

16,17

00

Piraju

0. 359

0. 441

00. 800

02,83

02

São Manuel

0. 278

0. 167

00. 445

01,17

00

Taguaí

0. 291

0. 522

00. 813

08,45

01

Total

4.586

6.867

11.453

-

11

Arq Bras Oftalmol. 2013;76(2):90-3

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Frequência de ocorrência de cavidade anoftálmica na região centro-oeste paulista e características dos portadores

Tabela 2. Dados descritivos referentes aos portadores de cavidade anoftálmica detectados na região centro-oeste do Estado de São Paulo Indivíduo 01

Município de origem

Faixa etária

Cor da pele

Sexo

Olho afetado

Causa da perda do olho

Areiópolis

60 - 69

Negra

Masc

OD

Trauma

02

Botucatu

≥70

-

Fem

OD

Trauma

03

Botucatu

60 - 69

-

Masc

OD

Endoftalmite

04

Botucatu

50 - 59

-

Masc

OE

Sem dados

05

Botucatu

40 - 49

-

Fem

OE

Sem dados

06

Botucatu

10 - 19

-

Masc

OE

Sem dados

07

Botucatu

≥70

-

Fem

OD

Sem dados

08

Botucatu

60 - 69

-

Masc

OD

Endoftalmite

09

Piraju

40 - 49

Branca

Fem

OE

Uveíte

10

Piraju

40 - 49

Branca

Fem

OE

Glaucoma

11

Taguaí

≥70

Branca

Masc

OD

Glaucoma

Fem= feminino; Masc= masculino; OD= olho direito; OE= olho esquerdo

sentavam visão maior ou igual a 0,7, um apresentava visão entre 0,3 e 0,7 e um tinha visão menor que 0,05. Um dos indivíduos em que a perda ocular ocorreu por glaucoma, apresentava buraco macular no olho contralateral. Dois dos portadores de cavidade anoftálmica eram diabéticos e os demais não apresentavam alterações sistêmicas relacionadas com a causa da perda ocular. Dez pacientes receberam prescrição de novas lentes para o olho contralateral e apenas uma correção óptica foi mantida. DISCUSSÃO Estudos sobre cavidade anoftálmica e causas de perda do bulbo ocular são escassos, podendo-se dizer que este é o primeiro estudo de base populacional e aleatorizado envolvendo portadores de cavidade anoftálmica. O presente estudo foi desenvolvido utilizando dados de estudo mãe sobre as causas de cegueira na população de determinada região do Estado de São Paulo onde a atenção à Saúde é feita pela Faculdade de Medicina de Botucatu(4). Para aquele estudo, o n amostral foi baseado em estudos prévios que apontavam para uma taxa de cegueira na população de cerca de 1‰. Assim, foi determinado que cerca de 12 mil pessoas deveriam ser examinadas, em uma população escolhida ao acaso. A oportunidade de se encontrar portadores de cavidade anoftálmica, ou seja, a frequência de ocorrência de cavidade anoftálmica, em habitantes desta região foi de 0,96‰. O total de pacientes atendidos equivale a uma média de 7,77% do total de habitantes destas cidades, porcentual significativo e que pode realmente expressar as características da comunidade estudada(6). Embora a frequência de portadores de anoftalmia seja baixa, a perda do olho ou de seu conteúdo deixa sequela e incapacidade importante e é sempre o intuito do oftalmologista evitá-la. Considerando-se o total de participantes da amostra de acordo com o sexo, a frequência de ocorrência de cavidade anoftálmica em mulheres foi de 0,7‰, enquanto nos homens foi de 1,3‰, quase o dobro do que apresentaram as mulheres. É clássico considerar os homens mais sujeitos a traumas, tanto recreacionais, como decorrentes de atividades laborais(2), com maiores chances de perder o olho que as mulheres. Com relação à idade no momento da coleta dos dados, não hou­­­­ve predominância de ocorrência da cavidade anoftálmica em uma determinada faixa etária. No entanto, a idade da perda não foi apurada. Com esta ressalva, nota-se que a maioria dos indivíduos apresentava idade acima de 60 anos na época do levantamento. 92

Arq Bras Oftalmol. 2013;76(2):90-3

Quanto à cor da pele, a informação estava ausente em porcentual expressivo dos portadores, o que dificulta a avaliação do parâmetro. Entretanto, não há motivo para considerar que a cor da pele possa influenciar na perda do bulbo ocular. Não houve influência da lateralidade na perda do bulbo. Nossos dados confirmam que, em que pese o desenvolvimento de novos tratamentos ou técnicas operatórias, o trauma, as infecções (endógenas ou exógenas) e o glaucoma, continuam sendo importantes causadores de perdas irreversíveis para os olhos(7). Há estudos que apontam os problemas acontecidos na zona rural como potencialmente piores para o olho, devido à dificuldade de se ter atendimento especializado em curto espaço de tempo. O presente estudo levantou apenas a condição presente na área urbana, não sendo possível comparar com a zona rural. A avaliação do olho contralateral permitiu reconhecer condição de cegueira segundo a definição da OMS(7) que seria acuidade visual pior que 0,05 em ambos os olhos em apenas uma pessoa. Nas demais, o olho contralateral encontrava-se com visão que poderia ser considerada normal. Ressalte-se que houve necessidade de nova correção óptica em 10 dos 11 indivíduos, ou seja, apenas o que se encontrava em condição de cegueira não se beneficiou com mudança de lentes corretivas. Outro benefício das lentes corretivas seria a proteção do olho contralateral de possíveis traumas, o que diminuiria a chance de cegueira bilateral(8). Importante também observar que um dos pacientes que havia perdido um olho por glaucoma, apresentava outra alteração no olho contralateral que impedia a boa visão, o que mostra a importância de exame completo na determinação das reais causas de perda de visão. Levando-se em conta as causas de cegueira na população, na região do estudo, a prevalência de cegueira é de 0,4%(4) e de portadores de cavidade anoftálmica é de 0,96‰. Perder a visão é considerado desastroso. No entanto, a remoção do olho ou de seu conteúdo, mesmo que a visão esteja ausente, é buscada somente em casos extremos, em condições de dor insuportável, quando há tumores extensos ou prejuízo estético muito importante. Nos demais casos, muitas vezes até por se ter esperança ainda de se obter qualquer melhora ou até mesmo por tratar-se de procedimento mutilante, o indivíduo protela a realização destes procedimentos. Talvez esta seja a razão da diferença tão marcante entre o número de pessoas cegas e o número de portadores de cavidade anoftálmica. O oftalmologista precisa conhecer o portador de cavidade anoftálmica, observando seu perfil e suas ansiedades. Conhecer o perfil e as causas desta condição permite instalar serviços de prevenção. Conhecer a prevalência destes casos, por sua vez, é uma excelente

Sousa RLF, et al.

forma de melhorar o atendimento aos pacientes, permitindo a im­­­­plantação de serviços que possam ajudá-los a enfrentar a nova realidade de portadores de cavidade anoftálmica. CONCLUSÃO A frequência de ocorrência de cavidade anoftálmica em habitantes da região centro-oeste paulista foi de 0,96‰, acometendo principalmente homens e com grande variação de idade de acometimento. REFERÊNCIAS 1. Burgett RA, Nunery WR. Órbita anoftálmica. In: Chen WP. Cirurgia plástica oftalmológica: princípios e prática. Rio de Janeiro: Revinter; 2005. Cap 26, p.369-85.

2. Mattos BS, Carvalho JC. Prevalência das perdas do globo ocular. I. Estudo das variáveis lado, etiologia, sexo. Rev Odontol Univ São Paulo. 1988;2(3):175-81. 3. Su GW, Yen MT. Current trends in managing the anophthalmic socket after primary enucleation and evisceration. Ophthal Plast Reconstr Surg. 2004;20(4):274-80. 4. Schellini SA, Durkin SR, Hoyama E, Hirai F, Cordeiro R, Casson RJ, et al. Prevalence of refractive errors in a Brazilian population: the Botucatu eye study. Ophthalmic Epidemiol. 2009;16(2):90-7. 5. Norman GR, Streiner DL. Biostatistics: the bare essentials. 3rd ed. USA: People’s Medical Publishing House; 2008. p. 393. 6. Instituto Brasileiro de Geografia e Estatística - IBGE. Disponível em: HTTP://www.ibge. gov.br 7. Resnikoff S, Pascolini D, Etya’ale D, Kocur I, Pararajasegaram R, Pokharel GP, et al. Global data on visual impairment in the year 2002. Bull World Health Organ. 2004;82(11): 844-51. 8. Bilyk JR. Enucleation, evisceration, and sympathetic ophthalmia. Curr Opin Ophthalmol. 2000;11(5):372-86.

Encontro Anual da Academia Americana de Oftalmologia

16 a 19 de novembro de 2013 Nova Orleans, Louisiana (EUA)

Informações: Site: www.aao.org

Arq Bras Oftalmol. 2013;76(2):90-3

93

Artigo Original | Original Article

Visual acuity and refraction by age for children of three different ethnic groups in Paraguay Acuidade visual e refração por idade para crianças de três grupos étnicos diferentes no Paraguai Marissa Janine Carter1, Van Charles Lansingh2, Gisela Schacht3, Miguel Río del Amo5, Miguel Scalamogna3, Thomas Douglas France4

ABSTRACT

RESUMO

Purpose: To characterize refractive errors in Paraguayan children aged 5-16 years and investigate effect of age, gender, and ethnicity. Methods: The study was conducted at 3 schools that catered to Mennonite, in­­­digenous, and mixed race children. Children were examined for presenting visual acuity, autorefraction with and without cycloplegia, and retinoscopy. Data were analyzed for myopia and hyperopia (SE ≤-1 D or -0.5 D and ≥2 D or ≥3 D) and astigmatism (cylinder ≥1 D). Spherical equivalent (SE) values were calculated from right eye cycloplegic autorefraction data and analyzed using general linear modelling. Results: There were 190, 118, and 168 children of Mennonite, indigenous and mixed race ethnicity, respectively. SE values between right/left eyes were nonsignificant. Mean visual acuity (VA) without correction was better for Mennonites compared to indigenous or mixed race children (right eyes: 0.031, 0.090, and 0.102 logMAR units, respectively; P<0.000001). There were 2 cases of myopia in the Mennonite group (1.2%) and 2 cases in the mixed race group (1.4%) (SE ≤-0.5 D). The prevalence of hyperopia (SE ≥2 D) was 40.6%, 34.2%, and 46.3% for Mennonite, indigenous and mixed race children. Corresponding astigmatism rates were 3.2%, 9.5%, and 12.7%. Females were slightly more hyperopic than males, and the 9-11 years age group was the most hyperopic. Mennonite and mixed race children were more hyperopic than indigenous children. Conclusions: Paraguayan children were remarkably hyperopic and relatively free of myopia. Differences with regard to gender, age, and ethnicity were small.

Objetivo: Caracterizar os erros de refração em crianças paraguaias com idades entre 5 e 16 anos e investigar efeito da idade, gênero e etnia.  Métodos: O estudo foi realizado em três escolas que atendiam crianças de etnia Menonita, indígena e mista. As crianças foram examinadas em relação à acuidade visual, autorrefração com e sem cicloplegia, e retinoscopia. Os dados foram analisados ​​para correção de miopia e hipermetropia (EE ≤-1 D ou -0,5D e ≥ 2D ou ≥3 D) e astigmatismo (cilindro ≥1 D). Valores equivalentes esféricos (EE) foram calculados a partir dos dados de autorrefração cicloplegiada do olho direito e analisados ​​por meio de modelagem linear geral.  Resultados: Foram avaliadas 190, 118 e 168 crianças de etnias Menonita, indígena e mista, respectivamente. Diferenças entre os valores de EE de olhos direitos e esquerdos não foram significantes. A acuidade visual (AV) sem correção foi melhor para Menonitas em relação às crianças da etnia indígena ou mista (olho direito: 0,031, 0,090 e 0,102 logMAR, respectivamente; P<0,000001). Houve 2 casos de miopia no grupo Menonita (1,2%) e 2 casos no grupo de etnia mista (1,4%) (SE ≤-0,5 D). A prevalência de hipermetropia (SE ≥2 D) foi de 40,6%, 34,2% e 46,3% para as etnias Menonita, indígena e mista. As taxas correspondentes de astigmatismo foram de 3,2%, 9,5% e 12,7%. As mulheres foram ligeiramente mais hipermétropes do que os homens, e o grupo de 9 a 11 anos de idade foi a mais hipermétrope. Crianças da etnia Menonita e mista se mostraram mais hipermétropes do que as crianças indígenas.  Conclusões: As crianças paraguaias são notavelmente hipermétropes e relativamente livres de miopia. Diferenças com relação ao sexo, idade e etnia são pequenas.

Keywords: Refractive error/ethnology; Myopia; Hyperopia; Astigmatism; Ethnicity and health; Visual acuity; Humans; Child; Adolescent; Paraguay

Descritores: Erros de refração/etnologia; Miopia; Hiperopia; Astigmatismo; Origem étnica e saúde; Acuidade visual; Humanos; Criança; Adolescente; Paraguai

INTRODUCTION The prevalence of refractive errors in school children worldwide varies considerably. For example, the prevalence of myopia is relatively low in the United States (U.S.)(1-4) with a range of 4-19% (depending on age and ethnicity), but much higher in Greece(5) at 37%, and highest of all in Taiwan(6,7) with a range of 12-85%, depending on age. In Latin America, a great variance has also been observed with a lower prevalence of myopia in Brazil (4-6%), a higher prevalence in Chile (3-19%), and a very high prevalence in Mexico (75%)(8-10). There are multifactorial reasons for these ranges. First, younger children are generally more hyperopic, while myopia prevalence increases as children age. Emmetropia at an early age seems to carry a higher risk of developing myopia, and parental history may influence

its development in offspring(11,12). Second, there is no universal agree­ ment on the definition of myopia. The prevalence of myopia was calculated in Singapore as 30.7% or 45.8%, depending on whether a spherical equivalent cut-off point of -1.00 D or -0.25 D was used(13). Third, environmental conditions, such as being in a closed environment or increased work can have a profound impact. For example, the “epidemic” of myopia observed in Asia in recent decades could be due to children spending more time in high rise apartments, more intensive school work, and other stress factors(14-17). Finally, ethnicity may also be associated with the genetic predisposition of myopia or refractive error(2-4,14,18). In Latin America, the role of ethnicity in refractive errors has been less explored. The goal of this study was to examine refractive errors

Submitted for publication: January 16, 2013 Accepted for publication: January 31, 2013

Funding: Preparation of this manuscript was funded by Fundacion Vision, ORBIS, and the International Agency for the Prevention of Blindness (IAPB).

Study was carried out in Fundación Vision, Asuncion, Paraguay.

Disclosure: M.J.Carter, employed by Strategic Solutions and is a paid consultant to ORBIS and the IAPB; V.C.Lansingh, employed by the IAPB; G.SchCHT, employed by Fundacion Vision; M.R. del Amo, None; M.Scalamogna, employed by Fundacion Vision; T.D.France, employed by the University of Wisconsin.

Strategic Solutions, Inc., Cody, WY. International Agency for the Prevention of Blindness/VISION 2020, Buenos Aires, Argentina. 3 Fundación Vision, Asuncion, Paraguay. 4 Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI. 5 Affiliation should be Fundacion Vision, Asuncion, Paraguay. 1 2

94

Arq Bras Oftalmol. 2013;76(2):94-7

Correspondence address: Marissa Carter. Strategic Solutions, Inc. - 1143 Salsbury Ave - Cody - WY 82414 - USA - E-mail: [email protected]

Carter MJ, et al.

in Paraguayan school children of 3 ethnicities: Mennonite (White, of German extraction), indigenous (Macca Indians), and mixed race (of European and indigenous). This is first study looking at ethnicity and refractive error in Paraguay. METHODS The study was conducted during April and May 2005 in a boarding school for indigenous children in Asuncion, a rural Mennonite community school (the only such school in the geographic area with children ultimately of White, Germanic extraction), and a mixed race school in Asuncion. In each school, the study was conducted until all the children present had been examined over approximately a 2-day period by 2 third-year ophthalmology residents trained by an experienced ophthalmologist for a week (90% agreement between the residents and ophthalmologist). Consent for the study was given by the parents of each child and the study was approved by the Fundacion Vision IRB. Patient anonymity was preserved. The study also adhered to the tenets of the Declaration of Helsinki in 1995 (as revised in Tokyo 2004). Each child was examined for presenting visual acuity (VA; with available correction), autorefraction with and without cycloplegia, and retinoscopy (with cycloplegia) by the 2 residents. The autore­ fractor (Seiko GR-2100, Hiroshima, Japan) was calibrated to the manufacturer’s specifications prior to each use. The VA examination employed a Snellen chart for 6 meters, followed by noncycloplegic refraction using the autorefractor. Cycloplegia was induced by 2 drops of cyclopentolate and after a 45-60-minute waiting period, each child was re-examined using the autorefractor and then retinoscopy. The following data were collected for right and left eyes, and recorded in Excel sheets (Microsoft Inc, Redmond, WA): presenting visual acuity (Snellen values), sphere, cylinder, and axis values (autorefraction with and without cycloplegia; retinoscopy with cycloplegia). After a pilot study that analyzed the different methods, autorefraction with cycloplegia was chosen as the method to study differences. Spherical equivalent (SE) in D was calculated as sphere measurement + (0.5 x cylinder measurement).

Statistical analysis The results were analyzed using PASW 19 (SPSS Inc., Chicago, IL). SE values were compared between right and left eyes using general linear modelling (essentially MANOVA) with ethnicity as the factor to determine if they were equivalent for analytical purposes. VAs were converted into the following Snellen categories: 20/20 (or better) to 20/40; 20/40 to 20/60; 20/60 to 20/200; and worse than 20/200. The VAs for each ethnic group were compared using gamma and Kendall’s tau b for right eyes. The number of cases of myopia, hyperopia, and astigmatism in any eye was first determined using the following definitions: myopia, SE ≤-1 D; hyperopia, SE ≥3 D; and astigmatism, cylinder ≥1 D(19). Myopia and hyperopia cases were also determined using the following additional definitions: myopia, SE ≤-0.5 D; hyperopia, ≥2D. The number of cases for each category of refractive error for the 3 groups was analyzed by chi square. Because right SE data were non-normal, a logistic regression was conducted in which SE data were divided into hyperopic (relaxed definition of ≥2D) using ethnicity, gender, and age (≤8 years, 9-11 years, and ≥12 years) as factors using all data. RESULTS

Demographics There were 190, 118, and 168 children of Mennonite (≤8 years: 74; 9-11 years: 53; ≥12 years: 63), indigenous (≤8 years: 36; 9-11 years: 32; ≥12 years: 51), and mixed race ethnicity (≤8 years: 34; 9-11 years: 97; ≥12 years: 37).

Spherical equivalent: right versus left eyes Although Box’s M test showed significant violation of homogeneity of variance (p<0.001), Levene’s test was non-significant for both independent variables (SE for right and left eyes). Because Box’s M is very sensitive to small violations of homoscedasticity, we determined that selection of right eye data for further analysis was reasonable based on the nonsignificant differences between right and left eyes regarding SE between ethnic groups. For the different ethnic groups, SE means were slightly higher for left eyes in 2 groups: Mennonite: mean right eye SE=1.84, mean left eye SE=1.89; indigenous: mean right eye SE=1.69, mean left eye SE=1.68; mixed race: mean right eye SE=1.76, mean left eye SE=1.80).

Visual acuity Visual acuity without correction was similar between ethnic groups although the Mennonites had a significantly higher proportion of right eyes in the 20/20 to 20/40 Snellen VA category (98.4% vs. 94.0% for indigenous and mixed race ethnicities), p=0.029 (Table 1). There were no clear differences within age groups according to ethnicity.

Myopia, hyperopia, and astigmatism There was 1 case of myopia in the Mennonite group (0.6%) and 2 cases in the mixed race group (1.4%). Relaxing the definition of myopia to SE ≤-0.5 D only added 1 case to the Mennonite group (1.2%). Ten cases of hyperopia were observed in each of the Mennonite and mixed race groups (5.3% and 5.9%, respectively), but only 6 cases in the indigenous group (5.1%) for the definition SE ≥3D (P=0.944). Using a definition of hyperopia of SE ≥2 D, increased the number of cases: Mennonite: 69 (40.6%); indigenous: 38 (34.2%); and mixed race: 68 (46.3%); P=0.150. However, while there only 6 cases of astigmatism identified in the Mennonite group (3.2%), there were 16 and 15 cases, respectively, in the mixed race and indigenous groups (9.5% and 12.7%, respectively) (P=0.006). The distribution of astigmatism cases showed that two-thirds of Mennonite children had unilateral astigmatism, while in indigenous and mixed race children, the proportion was lower (56% and 33%, respectively) (Table 2). The proportion of eyes with more severe astigmatism (≥2.00 D) was slightly higher for Mennonite children compared to the other groups. Females had a higher prevalence of astigmatism than males (10.1% versus 6.7%), but this result was not significant.

Logistic regression In the final model, the -2 log likelihood was 143.2 and the Nagelkerke R2 was 0.102. Only age and gender were significant in the model (Table 3). Being younger, specifically ≤8 years, increased the odds of being hyperopic (OR: 4.31). Being female also increased the odds (OR: 2.91). Ethnicity was not a significant variable in the model. DISCUSSION In this study of Paraguayan children of 3 different ethnicities, we noted some significant differences in refractive errors. Overall, presenting VA was slightly better for Mennonite children compared to the indigenous and mixed race children, although the difference was small. For all the groups, the prevalence of myopia was very low using a definition of ≤-1.00 D. Even when the cut point was lowered to -0.5 D, the overall prevalence of myopia was still only 0.9%. Hyperopia was more common - low at 4% using the SE ≥3 D definition - but much higher when using the less stringent moderate hyperopia definition of SE ≥2 D (40.9%). Most studies, including those done in Brazil, Chile, and Mexico have found a much lower prevalence than our figure for moderate hyperopia(2,8-11). Past studies of refractive errors in children in the U.S. have also looked at ethnicity(2,3), but the most recent study, the Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error

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Visual acuity and refraction by age for children of three different ethnic groups in Paraguay

Table 1. Distribution of visual acuity by ethnicity using right eye data. Data in parenthesis represent percentages Ethnicity

20/20 to 20/40

20/40 to 20/60

20/60 to 20/100

<20/100

Mennonite

185 (98.4)

0 (0)

1 (0.5)

2 (1.1)

Indigenous

110 (94.0)

4 (3.4)

1 (0.9)

2 (1.7)

Mixed race

159 (94.0)

2 (1.2)

3 (1.8)

5 (3.0)

Table 2. Distribution of astigmatism by child (unilateral or bilateral) and spherical equivalent values (D) by eye Ethnicity

Unilateral

Bilateral

1.00

Mennonite

4

2

0

1.25-1.75 2.00-2.75 ≥3.00 3

3

1

Indigenous

9

7

7

12

2

4

Mixed race

5

10

7

8

6

2

Table 3. Logistic regression showing odds ratios (OR) of significant variables for hyperopia (dependent variable) Variable

OR

95% CI*

≤8

4.31

1.18-15.72

9-11

1.04

0.227-4.73

0.963

Gender§

2.91

1.02-8.32

0.046

Age (years)

P† 0.013

‡

0.270

CI= confidence interval; †P= significance; ‡= ≥12 years; §= male.

*

Study, is considered the largest and most diverse study(4). New cases of myopia that developed in 4,556 school-aged children were observed from 1989 through 2009 and occurred in 16.4% of the children. By ethnicity, 27.3% of Asians developed new cases of myopia, 21.4% of Hispanics, 14.5% of Native Americans, 13.9% of African-Americans, and 11% of Caucasians(4). This suggests that in our Paraguayan population, children are more hyperopic compared with other child populations, which ex­­­ plains why myopia is relatively uncommon. Authors of an investigation of indigenous people aged 12 to 59 years in the northwestern Amazon region of Brazil determined that only 2.7% of eyes had myopia of -1.0 D or more(18). By comparison, Brazilians from the small city in which the study was performed had higher rates of myopia (6.4% of eyes), and younger, slightly educated Brazilians had a myopia prevalence of 11.3% in their eyes. Although the authors of this study ascribed the myopic differences to illiteracy, which might be true in this instance, the children in our study were literate, which indicates that other factors are at work, such as genetics, low stress, non-intensive near work, and perhaps more exposure to the outside environment. While hyperopia appeared to be significantly different between the ethnic groups, logistic regression showed that this difference was primarily due to age. However, astigmatism was also significant lower in the Mennonite children. The prevalence of astigmatism in indigenous children was 12.7%, similar to the level of astigmatism in the indigenous Amazon study (15.5%)(18). There were some refractive error differences by gender with females being more hyperopic than males. Females also had a higher prevalence of astigmatism, although it was nonsignificant. Older children (≥12 years) were also significantly less hyperopic compared to younger children, and although the trend was similar to that reported by Maul et al in Chilean children(9), whereas the shift we observed was about 0.15 D, in the Chilean study it was approximately 0.55 D. 96

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Within the Latin American region, it is possible that child populations differ when it comes to refractive errors, and some of this difference may be due to ethnicity. Other potential factors that may influence can be the actual time spent at school, usually more in city settings when compared to their rural counterparts, and amount of time spent in outdoor activities. There are some limitations to this study. First, we observed a large but consistent difference in spherical equivalent between au­­­­torefraction conducted under cycloplegia and autorefraction conducted under non-cycloplegic conditions. Although some researchers use non-cycloplegic autorefraction data, we preferred the use of cycloplegic data to avoid the effects of accommodation. In their study of 1443 Australian school children, Fotedar et al., noted that autorefraction without cycloplegia tended to substantially overestimate myopia and missed some cases of moderate hyperopia(20). The mean SE difference between cycloplegia and non-cycloplegia in their study was 0.84 D, whereas it was larger in our study - about 1.10 D. In addition, we noted a small significant difference between SE data obtained from cycloplegic autorefraction versus retinoscopy. While retinoscopy has in the past been the gold standard of refractive error measurement, based on our knowledge of administering both techniques to children, it was felt that autorefraction would provide more consistent data compared to retinoscopy. However, this choice may have led to some systemic error that might have influenced the analysis. Second, there may have been some confounding effect in regard to location of the school (i.e., rural versus urban setting), although if this had been a large effect, we should have seen it in the mixed race group. Third, our samples were relatively small, which influenced the accuracy of our analysis. Finally, although the residents were well trained, we did not assess the intraclass correlation coefficient to determine if the data obtained by one resident were different to the other. As a final note, it is worthy to mention that Paraguay has a rather unclear concept of ethnicity regarding the demographics of its population. In the 20th century, it was widely accepted that up to 95% of the country was mixed race(21). The most recent census in 2002 only counted for the indigenous population, and found that up to 1.7% is indigenous(22). A more recent study analyzed the Paraguayan white population in the 21st century based on the trends of European immigration in the last century and languages spoken at home, concluding that up to 20% of the country is of European (White) descent(21). This is relevant to the study discussion since it was understood, while conducting the study, that the Mennonite population was the only White representation in Paraguay. It would be also interesting to include non-Mennonite White children, as well as Asian children in a more comprehensive study, considering that Asians make up 3.5%(21) of the population (twice as much as the indigenous population). For now, this study is the first investigation of refractive error in Paraguayan children that looks at ethnicity and further suggests that ethnicity might influence one’s risk of developing refractive error. ACKNOWLEDGMENTS The authors would like to thank the Fundacion Vision, ORBIS, and the International Agency for the Prevention of Blindness for their financial support of this study and Kristen Eckert of Strategic Solutions for her assistance in editing the manuscript. REFERENCES 1. Chen PC, Chang RJ, Lee DA, Wheeler NC. Prevalence of ocular disorders among 6- and 7-year-olds in Santa Monica, California. J Am Optom Assoc. 1996;67(6):358-65. 2. Kleinstein RN, Jones LA, Hullett S, Kwon S, Lee RJ, Friedman NE, Manny RE, Mutti DO, Yu JA, Zadnik K; Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error Study Group. Refractive error and ethnicity in children. Arch Ophthalmol. 2003;121(8):1141-7. 3. Giordano L, Friedman DS, Repka MX, Katz J, Ibironke J, Hawes P, et al. Prevalence of refractive error among preschool children in an urban population: the Baltimore

Carter MJ, et al.

Pediatric Eye Disease Study. Ophthalmology. 2009;116(4):739-46. Comment in: Oph­­­ thalmology. 2010;117(6):1278-9. 4. Kleinstein RN, Sinnott LT, Jones-Jordan LA, Sims J, Zadnik K; for the Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error Study Group. New cases of myopia in children. Arch Ophthalmol. 2012;130(10):1274-9. 5. Mavracanas TA, Mandalos A, Peios D, Golias V, Megalou K, Gregoriadou A, et al. Prevalence of myopia in a sample of Greek students. Acta Ophthalmol Scand. 2000; 78(6):656-9. 6. Lin LL, Shih YF, Tsai CB, Chen CJ, Lee LA, Hung PT, et al. Epidemiologic study of ocular refraction among schoolchildren in Taiwan in 1995. Optom Vis Sci. 1999;76(5):275-81. 7. Shih YF, Chiang TH, Lin LL. Lens thickness changes among schoolchildren in Taiwan. Invest Ophthalmol Vis Sci. 2009;50(6):2637-44. 8. Salomão SR, Cinoto RW, Berezovsky A, Mendieta L, Nakanami CR, Lipener C, et al. Prevalence and causes of visual impairment in low-middle income school children in Sao Paulo, Brazil. Invest Ophthalmol Vis Sci [Internet]. 2008[cited 2010 Jun 21]; 49(10):4308-13. Available from: http://www.iovs.org/content/49/10/4308.long 9. Maul E, Barroso S, Munoz SR, Sperduto RD, Ellwein LB. Refractive error study in children: results from La Florida, Chile. Am J Ophthalmol. 2000;129(4):445-54. 10. Castanon Holguin AM, Congdon N, Patel N, Ratcliffe A, Esteso P, Toledo Flores S, et al. Factors associated with spectacle-wear compliance in school-aged Mexican children. Invest Ophthalmol Vis Sci [Internet]. 2006[cited 2010 Jul 21];47:925-8. Available from: http://www.iovs.org/content/47/3/925.long 11. Morgan IG, Rose KA, Ellwein LB; Refractive Error Study in Children Survey Group. Is emmetropia the natural endpoint for human refractive development? An analysis of population-based data from the refractive error study in children (RESC). Arch Ophthalmol. 2010;88(8):877-84. 12. Jones-Jordan LA, Sinnott LT, Manny RE, Cotter SA, Kleinstein RN, Mutti DO, Twelker JD, Zadnik K; Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error (CLEERE) Study Group. Early childhood refractive error and parental history of myopia

as predictors of myopia. Invest Ophthalmol Vis Sci [Internet]. 2010[cited 2012 Jun 23]; 51(1):115-21. Available from: http://www.iovs.org/content/51/1/115.long 13. Luo HD, Gazzard G, Liang Y, Shankar A, Tan DT, Saw SM. Defining myopia using refractive error and uncorrected logMAR visual acuity >0.3 from 1334 Singapore school children ages 7-9 years. Br J Ophthalmol. 2006;90(3):362-6. 14. Wu HM, Seet B, Yap EP, Saw SM, Lim TH, Chia KS. Does education explain ethnic differences in myopia prevalence? A population-based study of young adult males in Singapore. Optom Vis Sci. 2001;78(4):234-9. 15. Goldschmidt E, Lam CS, Opper S. The development of myopia in Hong Kong children. Acta Ophthalmol Scand. 2001;79(3):228-32. 16. Rose KA, Morgan IG, Smith W, Mitchell P. High heritability of myopia does not preclude rapid changes in prevalence. Clin Experiment Ophthalmol. 2002;30(3):168-72. 17. Saw SM. A synopsis of the prevalence rates and environmental risk factors for myopia. Clin Exp Optom. 2003;86(5):289-94. 18. Thorn F, Cruz AA, Machado AJ, Carvalho RA. Refractive status of indigenous people in the northwestern Amazon region of Brazil. Optom Vis Sci. 2005;82(2):267-72. 19. Vitale S, Ellwein L, Cotch MF, Ferris FL 3rd, Sperduto R. Prevalence of refractive error in the United States, 1999-2004. Arch Ophthalmol. 2008;126(8):1111-9. 20. Fotedar R, Rochtchina E, Morgan I, Wang JJ, Mitchell P. Rose KA. Necessity of cycloplegia for assessing refractive error in 12-year-old children: a population-based study. Am J Ophthalmol. 2007;144(2):307-9. 21. Fernández FL. Composición étnica de las tres areas culturales del continente Americano al comienzo del siglo XXI. Convergencia [Internet]. 2005[cited 2010 Jun 21]; 38:185-232. Available from: http://convergencia.uaemex.mx/rev38/38pdf/LIZCANO. pdf 22. Paraguay. Dirección general de estadísticas, encuestas, y censos (DGEC). II Censo Nacional a de Población y Viviendas 2002 [Internet]. Paraguay: DGEC; 2002. [cied 2012 Dec 13]. Available from: http://www.dgeec.gov.py/publicaciones/Biblioteca/ censo_indigena/capitulo%201.pdf

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Artigo Original | Original Article

Características estruturais maculares de olhos de pré-escolares nascidos prematuros: análise por tomografia de coerência óptica e oftalmoscopia binocular indireta Structural features of macular eyes of preschoolers born preterm: analysis by optical coherence tomography, and indirect ophthalmoscopy Lígia Beatriz Bonotto1, Ana Tereza Ramos Moreira2, Cristina Martins Faria Bortolotto3

RESUMO

ABSTRACT

Objetivo: Comparar a estrutura retiniana da mácula e fóvea entre prematuros com retinopatia da prematuridade (ROP) estágios II e III pós-tratamento, com ROP estágios II e III regredida espontaneamente e sem ROP, através de exames de tomografia de coerência óptica (OCT) e da oftalmoscopia binocular indireta (OBI). Métodos: Estudo do tipo transversal, observacional e não cego. Foram incluídas crianças prematuras nascidas entre 06/1992 e 06/2006 e examinadas entre 06/2009 e 12/2010; idade gestacional menor ou igual a 32 semanas e peso ao nascer menor ou igual a 1.599 g; com mínimo de três consultas durante o período de seleção; sem retinopatia da prematuridade ou com diagnóstico de ROP estágios II ou III em pelo menos um dos olhos com regressão espontânea ou após tratamento; máximo de seis meses de idade cronológica para o primeiro exame no serviço; idade cronológica mínima de quatro anos no período da reavaliação. Foram excluídas crianças prematuras que não compareceram ou que não tinham condições clínicas para a realização dos exames de reavaliação. Os prematuros foram divididos em três grupos: G1- com ROP pós-tratamento; G2- com ROP pós-regressão espontânea; e G3- sem ROP. Os exames realizados foram OBI e OCT. Resultados: Vinte e quatro prematuros (48 olhos) apresentaram os critérios exi­­­­ gidos para a pesquisa, com idade média cronológica entre 5 e 6 anos. À OBI, houve diferença estatística significativa para a presença de alterações na retina dos prematuros do grupo G1. No entanto estas alterações corresponderam às lesões cicatriciais deixadas pelo tratamento da ROP, sem comprometimento visível da região macular. À OCT houve diferença estatística significativa para a maior espessura foveal para os prematuros do grupo G1. Considerando-se o olho esquerdo, não houve diferença estatística significativa relacionada à espessura da fóvea entre G1 e G3. Não houve diferença entre os três grupos estudados quanto às alterações encontradas nas camadas da retina ao OCT. Conclusão: Os prematuros com ROP pós-tratamento apresentaram espessura foveal maior que os prematuros com ROP pós-regressão espontânea e espessura foveal semelhante aos prematuros sem ROP em relação à avaliação do olho esquerdo. Em relação às alterações das camadas da retina detectadas ao OCT, os três grupos foram semelhantes, sem expressão de diferença para o grupo tratado neste estudo.

Purpose: Compare the retinal structure of the macula and fovea among premature infants with retinopathy of prematurity (ROP) stages II and III post treatment, premature infants with ROP stages II and III with spontaneous regression and premature infants without ROP, through optical coherence tomography (OCT) and binocular indirect ophthalmoscopy (BIO) examinations. Methods: Cross-sectional observational and not-blinded study. There were included premature infants born between 06/1992 and 06/2006 and examined between 06/2009 and 12/2010; gestational age less than or equal to 32 weeks and birth weight less than or equal to 1,599 g; with a minimum of three visits during the selection period; without retinopathy of prematurity, or with the diagnosis of ROP stages II or III in at least one eye with spontaneous regression or after ROP treatment; maximum of six months of chronological age for the first examination at the service; minimal chronological age of four years old in the reassessment period. There were excluded premature infants who did not attend or did not have clinical conditions for the reassessment examination. The premature infants were divided into three groups: G1 - with ROP post-treatment; G2 - with ROP post-spontaneous regression; and G3 - without ROP. The exams performed were BIO and OCT. Results: Twenty-four premature infants (48 eyes) presented the criteria required for the research, chronological age ranging from 5 to 6 years. At BIO, there was a statistically significant difference for the presence of alterations in the retina of premature infants from group G1. However these changes corresponded to the cicatricial lesions left by the ROP treatment, without visible impairment to the macular region. At OCT there were statistically significant differences for the greatest foveal thickness between premature infants from groups G1 and G2. Considering the left eye, there was no statistically significant difference related to the thickness of the fovea between G1 and G3. There was no difference among the three groups studied in relation to the changes of the retinal layers at OCT. Conclusion: Premature infants with ROP post-treatment showed foveal thickness greater than premature infants with ROP post-spontaneous regression; and foveal thickness similar to premature infants without ROP in relation to assessment of the left eye. Regarding the changes of the retinal layers detected at OCT, the three groups were similar, without expression of difference for the treated group in this study.

Descritores: Retinopatia da prematuridade; Mácula lutea/anatomia & histologia; Tomografia de coerência óptica; Oftalmoscopia; Pré-escolar

Keywords: Retinopathy of prematurity; Macula lutea/anatomy & histology; Tomogra­ phy, optical coherence; Ophthalmoscopy; Child, preschool

Introdução O estudo da interferometria óptica iniciou-se em 1969 e deu origem aos equipamentos atuais de tomografia de coerência óptica (OCT)(1). A partir dos anos 90 com contínua progressão, houve grande impulso no conhecimento e na aplicabilidade médica deste método

que utiliza uma imagem refletida da luz do laser após atravessar as camadas do tecido, in vivo(2). Atualmente os aparelhos de tomografia de coerência óptica (OCT) apresentam dados comparativos de normalidade padronizados para comparação entre adultos acima de 18 anos. Abaixo desta

Submetido para publicação: 11de julho de 2012 Aceito para publicação: 3 de dezembro de 2012

Financiamento: Não houve financiamento para este trabalho.

Trabalho realizado no Hospital Sadalla Amin Ghanem em Joinville, SC. Médica, Hospital Sadalla Amin Ghanem e UTI Neonatal da UNIMED, Joinville (SC), Brasil. Professora de Oftalmologia, Universidade Federal do Paraná - UFPR - Curitiba (PR), Brasil; Médica, Hospital de Olhos do Paraná, Curitiba (PR), Brasil. 3 Médica, Setor de Tomografia de Coerência Óptica do Hospital Sadalla Amin Ghanem, Joinville (SC), Brasil. 1 2

98

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Divulgação de potenciais conflitos de interesse: L.B.Bonotto, None; A.T.R.Moreira, None; C.M.F.Bortolotto, None. Endereço para correspondência: Lígia Beatriz Bonotto. Rua Abdon Batista, 146 - Joinville (SC) 89201-010 - Brasil E-mail: [email protected] / [email protected]

Bonotto LB, et al.

idade, não existe ainda uma escala normativa de valores. Vários fatores podem interferir nas medidas do nervo óptico e da espessura foveal e macular como: idade, peso ao nascimento, raça, refração e ambliopia. A busca de uma padronização para as medidas retinianas ao OCT entre a população infantil deu origem a vários trabalhos. Nes­­­tes estudos, a espessura foveal variou de 157 a 221 micra entre crianças consideradas saudáveis do ponto de vista oftalmológico e clínico geral, na idade variável entre 1 e 18 anos. Estas medidas podem servir de base comparativa para o presente estudo(3-5). Entre as crianças nascidas prematuramente observam-se, ao exa­­­me de OCT, alterações típicas na região macular e foveal quando comparadas às crianças nascidas a termo(6-8). A ciência ainda não tem uma resposta precisa para explicar o que realmente acontece com a maturação destas camadas retinianas, entre nascidos prematuros(6). Em 2010, nos EUA, pesquisadores compararam a avaliação das imagens por OCT de pacientes adultos nascidos prematuros, e adultos nascidos a termo. Os autores observaram uma alteração na arquitetura foveal dos pacientes com história de prematuridade, mas a maioria deles apresentava boa acuidade visual(7). No Brasil, o único estudo publicado sobre a estruturação retiniana ao OCT foi conduzido entre 12 prematuros, todos portadores de retinopatia da prematuridade (ROP), e idade variável entre 45 e 90 dias de vida. Nestes, a OCT demonstrou camadas retinianas pouco diferenciadas com aumento da refletividade do epitélio da retina pigmentar-coriocapilar na área macular(8). Em vários estudos, observa-se que a aparência oftalmoscópica da retina, especialmente mácula e fóvea, não está diretamente ligada à resposta visual. Olhos em que retina apresenta repuxamento do feixe papilo-macular (“draping”) e ausência de depressão foveal podem desenvolver visão normal ou próxima ao normal. Os estudos do aspecto retinográfico e ao OCT não esclarecem como olhos com retina aparentemente normal podem apresentar um contorno anormal ao OCT(9-11). Atualmente a OCT é considerada como uma ferramenta para melhor compreender as particularidades do desenvolvimento macular e retiniano dos prematuros, tanto na fase ativa da ROP como após esta fase. No entanto, a OBI ainda é considerada como a melhor maneira de se avaliar as retinas dos prematuros. A OCT realizada na fase ativa da ROP, apresentou vantagem em comparação à OBI ao mostrar alterações pré-retinianas e retinianas (cistos maculares e membranas pré-retinianas) que classificariam a ROP em estágios mais avançados que o exame padrão ouro (OBI). No entanto, para as alterações vasculares, a OBI foi superior a OCT de controle portátil(12). Com a intenção de se avaliar se os pré-escolares de nascimento prematuro e com retinopatia regredida após tratamento apresentavam maior incidência de alteração macular e foveal do que os pre­­­maturos com retinopatia de regressão espontânea, este estudo teve como objetivo comparar a estrutura retiniana da mácula e da fóvea entre prematuros com ROP estágios II e III pós-tratamento, prematuros com ROP estágios II e III regredida espontaneamente e prematuros sem ROP, através de exames de OCT e da oftalmoscopia binocular indireta (OBI). MÉTODOS Estudo transversal observacional não cego. Critérios de inclusão: crianças pré-escolares que tiveram nascimento prematuro durante o período de junho de 1992 e junho de 2006; idade gestacional (IG) ≤32 semanas e peso ao nascimento (PN) ≤1.599 g; que tiveram realizado o mínimo de três consultas durante o período de seleção; com diagnóstico de ROP estágios II ou III em pelo menos um dos olhos com regressão espontânea ou terem sido submetido a tratamento da ROP; terem realizado o primeiro exame no serviço até seis meses de idade cronológica; e possuírem idade cronológica mínima de quatro anos no período da reavaliação (junho/2009 a dezembro/2010).

Critérios de exclusão: dentre os incluídos no estudo, os que não pu­­­deram comparecer ou cujas condições clínicas não permitiam com­­­parecimento para os exames de reavaliação, como em caso de comprometimento severo do sistema nervoso central ou de síndromes impeditivas. Os prematuros, que cumpriram com os critérios de inclusão e que obtiveram dos seus responsáveis legais o consentimento esclarecido assinado em relação aos exames requeridos pelo estudo foram divididos nos seguintes grupos: • Grupo G1 - recém-nascidos prematuros que apresentaram ROP, estágios II e III e que foram submetidos ao tratamento por laser ou por crioterapia; • Grupo G2 - recém-nascidos prematuros que apresentaram ROP, estágios II e III, com regressão espontânea da doença; • Grupo G3 - recém-nascidos prematuros que não desenvolveram a ROP. As crianças pré-escolares agrupadas nos três grupos descritos acima foram submetidas à OBI sob midríase (ciclopentolato a 1% e tropicamida a 1%), com imagens arquivadas em DVD. A OBI foi realizada pela mesma profissional durante o período de seleção e durante a reavaliação. Na avaliação através da OBI, foram utilizadas as mesmas referências quanto à localização das alterações retinianas utilizadas na Classificação Internacional da ROP(13,14): a. normal (NL), OBI normal; b. alterado (ALTNT), alteração não causada pelo tratamento da ROP, como tração dos vasos da região macular, prega fibrosa no feixe pa­­­­pilo-macular ou ectopia da região macular; c. alteração (PCZ2 e 3), com pontos cicatrizados do tratamento entre as zonas II e III da retina; d. alteração (PCZ1 e 2), com pontos cicatrizados do tratamento entre as zonas I e II; e. alteração (PCZ2), com pontos de cicatrização a partir da zona II; f. DTTR, descolamento total tardio de retina. Para o cálculo da diferença estatística em relação à presença de alterações retinianas à fundoscopia (OBI) entre os grupos estudados, todos os tipos de alteração encontrados foram agrupados em único grupo (grupo com alteração). A OCT foi realizada em todas as crianças em ambos os olhos, sob midríase máxima (tropicamida a 0,5% e fenilefrina a 5%, em cada olho por três vezes antes do exame), utilizando-se o equipamento Cirrus HD-OCT (Carl Zeiss Meditec Inc.). As análises foram realizadas mediante a aplicação de programas específicos para cortes tomográficos: “macular cube 512X128” e “5 radial raster”, cortes aquisição de 5 a 10 imagens para cada olho com comprimento de 6 mm, e duração variável entre 5 e 20 minutos. Todos os exames foram realizados pelo mesmo profissional. Neste estudo, as alterações observadas nas camadas retinianas foram classificadas conforme a quantidade de alterações e camadas envolvidas: a. Normal (NL), sem alteração; b. 1 ALT, presença de uma alteração (ex.: retificação do contorno foveal); c. 2 ALT, presença de duas alterações (ex.: retificação do contorno foveal e espessamento da região macular); d. 3 ALT, presença de três alterações (ex.: contorno foveal atenuado, espessamento da região macular e aumento da refletividade da camada interna da retina). Para os exames de OBI e OCT não foram utilizados formulários padronizados e os profissionais executantes dos exames tiveram acesso aos resultados. Para o cálculo de diferença estatística entre os grupos estudados, todas as alterações foram agrupadas em único grupo, indiferentemente ao número de alterações ou às camadas envolvidas. Os resultados da OCT foram avaliados comparando-se o grupo de pacientes tratados com os que apresentaram regressão espontânea da retinopatia. E posteriormente este grupo foi comparado com os prematuros sem ROP, para avaliar o significado da agressividade da ROP nas possíveis alterações encontradas.

Análise estatística Para avaliação da associação entre variáveis dicotômicas, foi considerado o teste Exato de Fisher (exemplo: OBI alterado versus OBI

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normal; OCT de retina alterada versus OCT normal). Para a comparação entre grupos em relação às variáveis quantitativas, foi considerado o teste não paramétrico de Mann-Whitney. Os valores de p<0,05 indicaram significância estatística para ambos os testes utilizados no estudo, considerando-se o intervalo de confiança de 95%. O estudo foi realizado para cada olho direito e para cada olho esquerdo, de cada prematuro, dos três grupos estudados. E a comparação entre os grupos foi realizada, separadamente, para os olhos direitos e para os olhos esquerdos de cada grupo. Os dados foram analisados com o programa computacional Statistica v.8.0. O estudo foi avaliado e aprovado pelo Comitê de Ética em Pesquisa do Hospital São José, Joinville, SC, onde o HOSAG está vinculado. RESULTADOS Foram avaliados para o estudo 432 recém-nascidos prematuros cadastrados e examinados para ROP no período de seleção (junho de 1992 a junho de 2006), no referido Hospital de Olhos. Destes, 266 não foram selecionados para reavaliação, por apresentarem idade gestacional e peso ao nascimento maior que o recomendado nos cri­­­térios de inclusão. Para a reavaliação proposta na idade pré-escolar, permaneceram 166 prematuros deste grupo avaliado. Destes, 103 foram excluídos por não cumprirem com os outros critérios de inclusão; 39 foram excluídos por dificuldade de contato, óbito, acompanhamento em outro serviço, entre outros motivos, como a recusa em participar ou o não comparecimento aos exames. Para a atual pesquisa de reavaliação durante a idade pré-escolar foram incluídos 24 recém-nascidos prematuros, distribuídos nos três grupos: G1 - ROP e tratamento, 7 pacientes; G2 - ROP e regressão espontânea, 8 pacientes; e G3 - prematuros sem ROP, 9 pacientes (Quadro 1).

Os resultados da comparação dos exames da oftalmoscopia bi­­ nocular indireta estão representados na tabela 3. A comparação entre o grupo de prematuros com ROP tratada e o grupo de prematuros sem ROP não se justifica clinicamente. DISCUSSÃO Esta pesquisa reforça a ideia de que as alterações encontradas ao exame de OCT são uma manifestação da organização estrutural da retina do prematuro e parece não sofrer influência da gravidade da ROP ou do processo de tratamento exigido pela ROP em seu estágio mais severo(6-8). Existe uma diferença estatisticamente significativa entre a espessura foveal do grupo G1 e do grupo G2, observada neste estudo. No entanto, quando se comparou o grupo de prematuros com ROP tratada com o grupo de prematuros sem ROP, não houve diferença significativa quando analisados os olhos esquerdos dos dois grupos. Esta diferença foi encontrada somente em relação aos olhos direitos destes grupos. Esta constatação não sustentou a hipótese de que a retina dos nascidos prematuros com ROP tratada teriam maior espessura foveal e mais alterações na estrutura macular. A assimetria da doença em relação aos olhos direito e esquerdo, no

Quadro 2. Características descritivas do exame de oftalmoscopia binocular indireta de pré-escolares nascidos prematuros componentes dos grupos G1 e G2 com retinopatia da prematuridade Grupos

Paciente

Tipo de tratamento

01

Laser

PCZ 2 e 3

PCZ 2 e 3

02

Laser

PCZ 2 e 3

PCZ 2 e 3

Oftalmoscopia binocular indireta

03

Laser

PCZ 1 e 2**

PCZ 1 e 2

A distribuição dos pacientes dos grupos G1 e G2, conforme a oftalmoscopia indireta da retina encontra-se resumida no quadro 2. Todos os prematuros do grupo G3, sem ROP, apresentaram retina aplicada sem alteração no aspecto anatômico à oftalmoscopia binocular indireta.

04

Laser

PCZ 2***

PCZ 2

05

Laser

PCZ 2

PCZ 2

06

Crioterapia

PCZ 2

DTTR****

07

Laser

PCZ 2 e 3

PCZ 2 e 3

08

ROP regredida

Normal

Normal

09

ROP regredida

Normal

Normal

10

ROP regredida

Normal

Normal

11

ROP regredida

Normal

Normal

12

ROP regredida

Normal

Normal

13

ROP regredida

Normal

Normal

14

ROP regredida

Alterado

Alterado

15

ROP regredida

Alterado

Alterado

G1

G2

Tomografia de coerência óptica Os aspectos da ultraestrutura retiniana observados no exame de OCT dos prematuros dos grupos G1, G2 e G3 estão representados no quadro 3. O aspecto tomográfico descritivo da retina dos prematuros dos três grupos do estudo está representado no quadro 4. Os resultados comparativos, relacionados à espessura foveal, en­­­ tre o grupo G1 e grupo G2 e entre o grupo G1 e G3 estão represen­ tados na tabela 1. Em relação à comparação entre os grupos G1 e G2 e entre G1 e G3, referentes às alterações nas camadas da retina, os resultados estão representados na tabela 2.

Olho direito

Olho esquerdo

G1= ROP estágio II e III pós-tratamento; G2= ROP estágio II e III regredida; PCZ 2 e 3 e 1 e 2= pontos cicatriciais entre zonas 2 e 3; e entre zonas 1 e 2; PCZ 2= pontos cicatriciais a partir da zona 2; DTTR= descolamento total de retina; ROP= retinopatia da prematuridade.

Quadro 1. Dados demográficos dos três grupos de pré-escolares de nascimento prematuro classificados em três grupos de retinopatia da prematuridade (G1, G2, G3) considerando-se as variáveis sexo, idade cronológica na reavaliação, idade gestacional, peso ao nascimento e número de consultas entre o período de seleção e a reavaliação Grupos

Sexo

ICR (anos)

IG (semanas)

PN (gramas)

Número de consultas

N

M (%)

F (%)

Média

DP

Média

DP

Média

DP

Média

DP

G1

7

71

29

6,1

1,6

28,1

1,9

1.015,0

123,5

24,4

20,5

G2

8

25

75

6,5

1,9

27,2

1,6

0963,7

123,0

19,8

13,9

G3

9

78

22

5,1

0,9

28,4

2,5

0991,1

258,4

09,7

04,2

G1= ROP estágio II e III pós-tratamento; G2= ROP estágio II e III regredida; G3= sem ROP; M= masculino; F= feminino; ICR= idade cronológica na reavaliação; IG= idade gestacional; PN= peso de nascimento; DP= desvio padrão; N= número total

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Quadro 3. Características descritivas do exame de tomografia de coerência óptica (OCT) de pré-escolares nascidos prematuros componentes dos grupos G1, G2 e G3 em relação à espessura foveal e a características do vítreo e da interface vitreorretiniana Grupos

OCT

N

Olho direito

N

Olho esquerdo

G1

Espessura foveal (micra)

7

271 (226-313)

5*

257,8 (217-280)

Vítreo

7

S/ALT

5*

S/ALT

Interface vitreorretiniana

7

S/ALT

5*

S/ALT

Espessura foveal (micra)

8

214,2 (196-231)

8

213,8 (191-237)

G2

G3

Vítreo

8

S/ALT

8

S/ALT

Interface vitreorretiniana

8

S/ALT

8

S/ALT 223,4 (180-265)

Espessura foveal (micra)

9

219,3 (176-258)

9

Vítreo

9

S/ALT

9

S/ALT

Interface vitreorretiniana

9

S/ALT

9

S/ALT

G1= ROP estágio II e III pós-tratamento; G2= ROP estágio II e III regredida; G3= sem ROP; S/ALT= sem alteração. NOTA: (*) dois prematuros não realizaram o exame no olho esquerdo, um por apresentar descolamento tardio de retina e outro por não permitir o exame neste olho.

Quadro 4. Características descritivas do exame de tomografia de coerência óptica (OCT) de pré-escolares nascidos prematuros componentes dos grupos G1, G2 e G3 em relação às alterações retinianas

Grupos G1

G2

Alterações retinianas ao OCT

Pré-escolar nascido prematuro

Olho direito

Olho esquerdo

01

CFA e ERM

CFA

Grupos

02

RCF

RCF

N

03

RCF e AERF

RCF e AERF

Média

271,0

214,3

257,8

213,9

04

CFA, AERF e ARSN

CFA e ARSN

Mediana

276,0

211,0

262,0

213,0

05

CFA, ERM e ARCIR

CFA, ERM e ARCIR

Mínimo

226,0

196,0

217,0

191,0

06

RCF, ERM e ARCIR

NR

Máximo

313,0

231,0

280,0

237,0

029,5

011,9

024,7

015,4

G1

G3

G1

G3

7

9

5

9

Espessura foveal ao OCT Olho direito

07

RCF e ERM

NR

DP

08

CFP

CFP

Valor de p

09

G3

Tabela 1. Média comparativa da espessura foveal obtida pelo exame de tomografia de coerência optica (OCT) em pré-escolares nascidos prematuros componentes dos grupos G1 e G2 e entre os componentes dos grupos G1 e G3

CFP e AECPEX

CFP

10

CFA

CFP

11

CFP

CFA e ERM

12

CFP

CFP

13

CFA

CFA

14

CFP e ARCIR

CFP e ARCIR

15

CFP

CFP

16

CFP

CFP

17

CFP

CFP

18

CFA, ERM

CFA, ERM

19

CFA

CFA

20

RCF, ERM

RCF, ERM

21

CFA

CFA

22

CFA

CFA

23

CFP, ARCIR

CFP, ARCIR

24

CFA

CFA

AERF= aumento da espessura da região foveal; AECPEX= aumento da espessura da camada plexiforme externa da retina; ARCIR= aumento da refletividade da camada interna da retina; ARSN= aumento da refletividade do setor nasal da retina; CFA= contorno foveal atenuado (ainda mantem algum vestígio de depressão foveal); CFP= contorno foveal preservado; ERM= espessamento da região macular; NR= não realizado; RCF= retificação do contorno foveal (sem nenhum vestígio de depressão foveal)

Grupos N

Olho esquerdo

G1

G2

G1

G2

7

8

5

8

0,001

0,011

Média

271,0

219,3

257,8

223,4

Mediana

276,0

224,0

262,0

225,0

Mínimo

226,0

176,0

217,0

180,0

Máximo

313,0

258,0

280,0

265,0

DP

029,5

024,9

024,7

026,9

Valor de p

0,003

0,060

p* Teste não paramétrico de Mann-Whitney, p<0,05, para intervalo de confiança de 95%. G1= prematuros com ROP pós tratamento; G2= prematuros com ROP e regressão espontânea; G3= prematuros sem ROP.

grupo G1 principalmente, também prejudicou esta comparação. A comparação estatística entre os grupos G2 e G3 não foi realizada, desconsiderou-se esta necessidade diante do resultado obtido com a análise dos resultados da OCT entre G1 e G3. Outros pesquisadores que realizaram uma pesquisa semelhante não encontraram diferença em relação à espessura foveal entre prées­colares nascidos prematuros com ROP pós-tratamento e com ROP regredida e entre os nascidos prematuros com ROP e aqueles sem ROP(6). Apesar de a frequência de alterações nas camadas da retina entre os prematuros tratados para a regressão da retinopatia ter sido alta (100%), não houve diferença estatisticamente significativa en­­­tre os grupos estudados. Em relação às alterações das camadas re­­­­tinianas, os

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Tabela 2. Comparação entre as alterações retinianas observadas ao exame de tomografia de coerência optica (OCT) em pré-escolares nascidos prematuros componentes dos grupos G1 e G2 e entre os componentes dos grupos G1 e G3 Olho direito Grupo G1 e Grupo G2 Sem alteração retiniana

Com alteração retiniana

Total

G1

Olho esquerdo

G2

G1

G2

0

4

0

5

0,00%

50,00%

0,00%

62,50%

7

4

5

3

100,00%

50,00%

100,00%

37,50%

7

8

5

237,0

0,077

Valor de p

0,075

Grupo G1 e Grupo G3

G1

G3

G1

G3

Sem alteração retiniana

0

2

0

2

0,00%

22,22%

0,00%

22,22%

7

7

5

7

100,00%

77,78%

100,00%

77,78%

7

9

5

9

Com alteração retiniana

Total

0,475

Valor de p

0,475

p* Teste não paramétrico de Mann-Whitney, p<0,05, para intervalo de confiança de 95%.

Tabela 3. Comparação entre as alterações retinianas observadas ao exame de oftalmoscopia binocular indireta (OBI) em pré-escolares nascidos prematuros componentes dos grupos G1 e G2 e entre os componentes dos grupos G1 e G3

Variável Sem alteração retiniana à OBI

Com alteração retiniana à OBI

Total Valor de p*

Olho direito

Olho esquerdo

Grupos

Grupos

G1

G2

G1

G2

0

6

0

6

0,00%

75,00%

0,00%

75,00%

7

2

7

2

100,00%

25,00%

100,00%

25,00%

7

8

7

8

p: 0,007

p: 0,007

Valor de p<0,05 para intervalo de confiança de 95%. Com alteração retiniana no grupo G1= marcas de ablação deixadas pelo tratamento da ROP; Com alteração retiniana no grupo G2= alterações não provocadas pelo tratamento para a ROP.

prematuros sem ROP foram mais comparáveis com o grupo tratado do que os prematuros com ROP regredida espontaneamente (Tabela 2). Uma explicação plausível é suportada por outros investigadores, de que estas alterações retinianas poderiam ser um processo inerente à prematuridade(6,7). Na análise comparativa dos achados da oftalmoscopia binocular indireta entre os grupos G1 e G2, encontrou-se diferença estatisti­ camente significativa para o grupo G1 (p=0,007 AO, intervalo de con­­­fiança 95%). No grupo G1 este resultado expressa as alterações secundárias às sequelas deixadas pelo tratamento na fase aguda da ROP, a laser ou por crioterapia. Todos os prematuros sem ROP apresentaram à OBI, retina aplicada com aspecto anatômico normal. Todos os pacientes componentes dos três grupos realizaram o exame de OBI na idade pré-escolar (reavaliação), exceto o prematuro que apresentou descolamento tardio de retina (OE), no grupo G1. Todos apresentaram a região macular e foveal com brilho, depressão 102

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e pigmentação normais, resultado inesperado para os Grupos G1 e G2. Acreditava-se que naqueles pacientes do grupo G1 em que as cicatrizes do tratamento que tivessem se aproximado mais da região macular pudessem apresentar, em associação, um deslocamento da região foveal ou mesmo um desarranjo da arquitetura vascular. Em relação às particularidades do grupo G2, também seria esperado que após a regressão espontânea da ROP, alguns casos apresentassem mudança da relação papilo-foveal ou alterações periféricas típicas da ROP cicatricial, principalmente em crianças prematuras que chegaram a ter uma classificação de ROP próxima ao critério exigido para indicação do tratamento(14,15). No grupo G2, um prematuro apresentou ROP estágio III plus, na extensão de quatro horas contínuas no OD e estágio III plus, oito horas descontínuas no OE, sem informação sobre a zona acometida; critérios que indicam o tratamento para a ROP. Por dificuldades técnicas, o tratamento a laser não foi realizado e o exame de revisão relevou, à OBI, a regressão espontânea da ROP, com preservação do polo posterior e sem sequela. A grande maioria destes prematuros com doença plus foi selecionada para tratamento, segundo os critérios dos Comitês de 1984 e 1987(13,14). Entre 2003 e 2005, foram realizadas revisões da Classificação Internacional da ROP, e, em 2007 no Brasil, com o objetivo de regular a importância da presença da doença plus como base para a indicação de tratamento da ROP na zona I e zona II, em qualquer estágio da retinopatia(16-18). Atualmente, a presença da doença plus é indicação indiscutível para tratamento, no entanto, na época em que os pré-escolares nascidos prematuros tiveram suas primeiras avaliações, a doença plus esteve presente em seis dos oito pacientes do grupo G2. Portanto, alguns pacientes classificados como G2 tinham ficado próximo à classificação para o grupo de G1 tratamento. No grupo G2 apenas dois prematuros apresentaram alteração à oftalmoscopia binocular indireta nos dois olhos: um com aumento da tortuosidade vascular e outro com aumento da escavação do nervo óptico, ambos com a região macular e foveal preservada. A preservação anatômica das regiões maculares e foveais à oftalmoscopia indireta após o tratamento da ROP observada na presente pesquisa, também é reportada por outros grupos(15,19,20). Quanto à avaliação comparativa do aspecto fundoscópico com as imagens do OCT, relatou-se um fator em comum indiferentemente da metodologia empregada, a dificuldade de se relacionar os achados do exame de oftalmoscopia indireta com o aspecto observado nos exames de OCT em relação à anatomia do polo posterior(6,7,11). Isto difere do que é encontrado em trabalhos de seguimento de pacientes adultos com diabetes onde os autores conseguem estabelecer boa correlação entre a biomicroscopia de fundo e as alterações en­­­contradas na OCT, chegando a sugerir o exame como fator preditivo para tratamento(21). Neste estudo, os pacientes diabéticos sem edema macular prévio à panfotocagulação, apresentaram aumento da espessura foveal ao longo do seguimento, embora sem repercussões funcionais(21). Devido à fisiopatologia semelhante entre as duas doenças retinianas (diabetes e ROP, ambas vasoproliferativas), esperar-se-ia respostas semelhantes nos exames. Na avaliação das crianças prematuras não haviam sido realizadas as OCT prévias ao tratamento, na fase aguda ou imediatamente após a fase aguda da ROP, dados que poderiam auxiliar na comparação destes dois tipos de retinopatia. A realização dos exames de OCT em crianças apresenta grau de complexidade técnica relacionada à colaboração, principalmente em prematuros em qualquer idade, pois este exame exige imobilidade e adequada fixação do olhar para obtenção de imagens de boa qua­­­lidade. As crianças prematuras apresentam alta incidência de problemas neuropsicomotores (controle inadequado do movimento corporal, de cabeça, ou postura inadequada) e maior dificuldade de permanecerem imóveis durante realização do exame. Estas carac­ terísticas limitam a empregabilidade do exame de OCT em crianças. Atualmente existe a comercialização de equipamentos portáteis de

Bonotto LB, et al.

OCT, mais indicados para o exame de crianças prematuras internadas e com fase ativa de ROP, mas ainda são de comercialização restrita. De acordo com as mais recentes publicações relacionadas ao de­­­senvolvimento foveal no ser humano nascido a termo e prematuro, procurou-se entender o fato de 100% dos prematuros tratados apresentarem alteração na estrutura da fóvea às imagens do OCT (Figura 1). Isto sugere uma modificação na estrutura retiniana foveal destes pacientes. Há dificuldade em se diferenciar se estes achados do grupo G1 seriam decorrentes da gravidade da ROP, da própria condição da prematuridade em si, ou ainda, se seriam causadas pelos tratamentos a laser ou por crioterapia realizados nas áreas tratadas. Estudos que relacionam a formação normal da região foveal humana são escassos. Data de 1986 uma pesquisa sobre a análise histológica do desenvolvimento foveal humano, que demonstrou que a região foveal é identificável após 22 semanas de idade gestacional e que permanece imatura até o nascimento. A formação da depressão foveal se dá próximo à época do nascimento e continua até 15 meses de idade(22). A imaturidade da região foveal pode ter seu ritmo normal de desenvolvimento alterado no nascimento prematuro por várias razões. Nos prematuros com ROP tratados, em especial, a intervenção a laser ou por crioterapia, é um fator de influência a ser considerado. O tratamento da ROP geralmente é realizado entre as 36a a 48a semanas de idade gestacional, época em que a região foveal estaria no auge do seu ajuste e especificação(15,22). Estudos atuais realizados em prematuros com a utilização da tomografia de coerência óptica, aparelhos de domínio espectral e

OD

OE

Figura 1. Tomografia de coerência óptica de olhos direito (OD) e esquerdo (OE) de pré-escolar do sexo masculino, aos 8 anos de idade, nascido prematuro, e componente do Grupo G1, com retinopatia da prematuridade regredida após tratamento a laser. Acuidade visual OD: 20/30; e OE: 20/25.

portáteis, vem trazendo informações sobre a região macular e da retina destes prematuros ainda durante o período de seleção. Em 2007 foi publicado um estudo sobre tomografia de coerência óptica utilizada em 12 bebês prematuros com ROP (estágios 1, 2 e 3) e idade gestacional entre a 28a e 36a semanas, na época do exame. A depressão foveal esteve presente em 23% destes prematuros(8). Em 2011, um grupo publicou os resultado das imagens do OCT na fase aguda da ROP e, no mesmo grupo de pacientes, analisou as imagens do OCT após a resolução desta fase. Os autores descreveram dois tipos de alteração ao OCT durante a fase aguda da retinopatia da prematuridade: edema cistoide da mácula; e aumento moderado da espessura foveal e a depressão mantida, com associação a múltiplos vacúolos agrupados ou confluentes e opticamente hiporreflexivos lo­­­calizados entre as camadas da retina. Os pesquisadores constataram que 100% destes olhos apresentavam o contorno foveal normalizado na segunda fase do estudo, independente do tipo de alteração encontrada durante a fase aguda da ROP(23). Este dado obtido questiona a concepção de que as mudanças ocorridas na fase inicial da formação da fóvea do prematuro seriam mantidas até a vida adulta. Em 2012, o OCT de domínio espectral foi avaliado em outro gru­­­ po de prematuros, que apresentavam entre 31 a 36 semanas de idade gestacional (para o calculo da IG, considerou-se o último perío­do menstrual materno). Os autores se propuseram a observar se a severidade do edema cistoide de mácula, encontrado em 50% dos 42 prematuros estudados, tinha algum valor preditivo para a necessidade de tratamento. Eles concluíram que o edema cistoide de mácula não estava diretamente relacionado com a gravidade preditiva para tratamento da retinopatia da prematuridade, mas a espessura foveal e parafoveal aumentada sim(24). A relação encontrada neste estudo pode oferecer uma explicação para o que foi encontrado no grupo G1 do presente estudo, pois a espessura foveal foi significativamente maior nos prematuros deste grupo G1 em relação ao grupo G2. Infelizmente, a metodologia entre os estudos é variável, o que dificulta as comparações. Por outro lado, é importante compreender o que acontece com as alterações observadas ao OCT na fase aguda, no momento da re­­ gressão após tratamento ou após sua regressão espontânea e, mais tarde, na infância e na vida adulta destes nascidos prematuros. Em 2010, autores encontraram alterações na arquitetura macular e foveal nas imagens do OCT em nascidos prematuros com ROP com idade média de 39 anos. As alterações encontradas foram: diminuição da depressão foveal, aumento da espessura macular e continuidade da camada interna da retina sobre a região foveal. Estes investigadores demonstraram com este estudo, que as alterações destes prematuros se mantêm até a vida adulta(7). No entanto, estes são trabalhos isolados realizados em populações diferentes, com metodologia diversa. Não existe até o momento um trabalho linear, realizado com um mesmo grupo de prematuros, da fase aguda até fase a adulta, que unisse estes aspectos nos diferentes períodos de maturação foveal e retiniana do prematuro. A pesquisa ideal implicaria em complexidade metodológica e longo período de observação e de acompanhamento. Neste trabalho, a amostra foi considerada homogênea nos três grupos em relação aos dados demográficos (idade no momento do re-exame, peso ao nascimento, idade gestacional). A dificuldade encontrada para reunir crianças de nascimento prematuro dentro dos critérios de inclusão prejudicou o tamanho da amostra, mas a alta incidência de alterações nas camadas da retina, observadas ao exame de OCT, sugere que este seja relacionado à condição de prematuridade. O estudo não permitiu relacionar as alterações com a gravidade da ROP. CONCLUSÃO Os pré-escolares nascidos prematuros com ROP pós-tratamento apresentaram maior espessura foveal que os prematuros pós-re­

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gressão espontânea e apresentaram semelhança ao grupo de prematuros sem ROP, quando considerada a avaliação do olho esquerdo. As alterações nas camadas da retina da série de pacientes e observadas ao OCT não demonstraram diferença comparativa entre os três grupos do estudo. O estudo sugere que o emprego da tecnologia de OCT em crian­­­ ças nascidas prematuras pode contribuir para a compreensão das alterações estruturais relacionadas à condição de prematuridade. REFERÊNCIAS 1. Simonsohn G, Kleeberger L, Plohn HJ. Die Verteilung des Brechungsindex in der Augenlinse. Optik. 1969;29:81-6. 2. Fercher AF. Optical coherence tomography - development, principles, applications. Z Med Phys. 2010;20(4):251-76. Review. 3. El-Dairi MA, Asrani SG, Enyedi LB, Freedmann SF. Optical coherence tomography in the eyes of normal children. Arch Ophthalmol. 2009;127(1):50-8. 4. Kee SY, Lee SY, Lee YC. Thicknesses of fovea and retinal nerve fiber layer in amblyopic and normal eyes in children. Korean J Ophthalmol. 2006;20(3):177-81. 5. Gupta G, Donahue JP, You T. Profile of the retina by optical coherence tomography in the pediatric age group. Am J Ophthalmol. 2007;144(2):309-10. 6. Ecsedy M, Szamosi A, Karkó C, Zubovics L, Varsányi B, Németh J, Récsán Z. A comparison of macular structure imaged by optical coherence tomography in preterm and full-term children. Invest Ophthalmol Vis Sci. 2007;48(11):5207-11. 7. Baker PS, Tasman W. Optical coherence tomography imaging of the fovea in retinopa­ thy of prematurity. Ophthalmic Surg Lasers Imaging. 2010;41(2):201-6. 8. Lago Ad, Matieli L, Gomes M, Baba NT, Farah ME, Belfort Junior R, et al. Stratus optical coherence tomography findings in patients with retinopathy of prematurity. Arq Bras Oftalmol. 2007;70(1):19-21. 9. Soong GP, Shapiro M, Seiple W, Szlyk JP. Macular structure and vision of patients with macular heteropia secondary to retinopathy of prematurity. Retina. 2008;28(8): 1111-6. 10. Joshi MM, Trese MT, Capone A Jr. Optical coherence tomography findings in stage 4A retinopathy of prematurity: a theory for visual variability. Ophthalmology. 2006; 113(4):657-60. 11. Recchia FM, Recchia CC. Foveal dysplasia evident by optical coherence tomography in patients with a history of retinopathy of prematurity. Retina. 2007;27(9):1221-6. 12. Lee AC, Maldonado RS, Sarin N, O’Connell RV, Wallace DK, Freedman SF, et al. Macu-

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lar features from spectral-domain optical coherence tomography as an adjunct to indirect ophthalmoscopy in retinopathy of prematurity. Retina. 2011;31(8):1470-82. 13. An international classification of retinopathy of prematurity. The Committee for the Classification of Retinopathy of Prematurity. Arch Ophthalmol. 1984;102(8):1130-4. 14. An international classification of retinopathy of prematurity. II. The classification of retinal detachment. The International Committee for the Classification of the Late Stages of Retinopathy of Prematurity. Arch Ophthalmol. 1987;105(7):906-12. Erratum in Arch Ophthalmol. 1987;105(11):1498. 15. Katoch D, Sanghi G, Dogra MR, Beke N, Gupta A. Structural sequelae and refractive outcome 1 year after laser treatment for type 1 prethreshold retinopathy of prematurity in Asian Indian eyes. Indian J Ophthalmol. 2011;59(6):423-6. 16. International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity Revisited. Arch Ophthalmol. 2005;123(7):991-9. 17. Zin A, Florêncio T, Fortes Filho JB, Nakanami CR, Gianini N, Graziano RM, et al. Proposta de diretrizes brasileiras do exame e tratamento de retinopatia da prematuridade (ROP). Arq Bras Oftalmol. 2007;70(5):875-83. 18. Early Treatment for Retinopathy of Prematurity Cooperative Group. Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol. 2003;121(12):1684-94. Comment in Arch Ophthalmol. 2005;123(3):406-7; discussion 409-10. Arch Ophthalmol. 2003;121(12):1769-71. 19. Talu S, Cormos D, Zaharia G, Stefanut C, Popa M, Lucaci DI. [Prognostic factors for laser treatment in retinopathy of prematurity]. Oftalmologia. 2011;55(1):84-9. Romanian. 20. Galván Ledesma A, Morales Guillén C, Pastor Ramos MT, Vázquez Marouschek Mdel C. [Diode laser photocoagulation of retinopathy of prematurity]. Arch Soc Esp Oftalmol. 2011;86(11):368-73. Spanish. 21. de Oliveira Maia Jr O, Takahasshi WY, Nakashima Y. Espessura macular e acuidade visual na retinopatia diabética tratada por panfotocoagulação. Arq Bras Oftalmol. 2008;71(3):394-9. 22. Yuodelis C, Hendrickson A. A qualitative and quantitative analysis of the human fovea during development. Vision Res. 1986;26(6):847-55. 23. Vinekar A, Avadhani K, Sivakumar M, Mahendradas P, Kurian M, Braganza S, et al. Understanding clinically undetectal macular changes in early retinopathy of prematurity on spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2011;52(8):5183-8. 24. Maldonado RS, O’Connell R, Ascher SB, Sarin N, Freedman SF, Wallace DK, et al. Spectral-domain optical coherence tomographic assessment of severity of cystoid macular edema in retinopathy of prematurity. Arch Ophthalmol. 2012;130(5): 569-78.

Artigo Original | Original Article

Light-induced retinal injury enhanced neurotrophins secretion and neurotrophic effect of mesenchymal stem cells in vitro Lesão de retina induzida por luz aumentou a secreção de neurotrofinas e o efeito neurotrófico das células primordiais mesenquimais in vitro Wei Xu1, Xiaoting Wang1, Guoxing Xu1,2, Jian Guo1,2

ABSTRACT

RESUMO

Purpose: To investigate neurotrophins expression and neurotrophic effect change in mesenchymal stem cells (MSCs) under different types of stimulation. Methods: Rats were exposed in 10,000 lux white light to develop light-induced retinal injury. Supernatants of homogenized retina (SHR), either from normal or light-injured retina, were used to stimulate MSCs. Quantitative real time for polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) were conducted for analysis the expression change in basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) in MSCs after stimulation. Conditioned medium from SHR-stimulated MSCs and control MSCs were collected for evaluation their effect on retinal explants. Results: Supernatants of homogenized retina from light-injured rats significantly promoted neurotrophins secretion from MSCs (p<0.01). Conditioned medium from mesenchymal stem cells stimulated by light-injured SHR significantly reduced DNA fragmentation (p<0.01), up-regulated bcl-2 (p<0.01) and down-regulated bax (p<0.01) in retinal explants, displaying enhanced protective effect. Conclusions: Light-induced retinal injury is able to enhance neurotrophins se­­­ cretion from mesenchymal stem cells and promote the neurotrophic effect of mesenchymal stem cells.

Objetivo: Investigar a expressão de neurotrofinas e mudança no efeito neurotrófico de células-tronco mesenquimais (MSCs) sob diferentes tipos de estimulação. Métodos: Os ratos foram expostos em 10.000 lux de luz branca para desenvolver a lesão da retina induzida por luz. Os sobrenadantes de homogeneizado de retina (SHR) quer a partir de retina normal ou da lesada por luz, foram usados para estimular as células-tronco mesenquimais. O RT-PCR quantitativa e ELISA foram realizados para análise da alteração de expressão do fator básico de crescimento de fibroblastos (bFGF), do fator neurotrófico derivado do cérebro (BDNF) e do fator neurotrófico ciliar (CNTF) em MSCs após a estimulação. O meio condicionado de células-tronco mesenquimais estimuladas por SHR e controles foram coletadas para avaliação de seu efeito sobre os explantes de retina. Resultados: SHR de retinas de rato lesadas por luz promoveram aumento significa­­­tivo de secreção de neurotrofinas em MSCs (p<0,01). O meio condicionado de SHR lesado por luz reduziu significativamente a fragmentação do DNA de MSCs (p<0,01), elevação de Bcl-2 (p<0,01) e redução de bax (p<0,01) em explantes de retina, mostrando um aumento do efeito protetor. Conclusões: A lesão da retina induzidos pela luz é capaz de aumentar a secreção de neurotrofinas e promover o efeito neurotrófico de células-tronco mesenquimais.

Keywords: Fibroblast growth factor 2; Ciliary neurotrophic factor; Retina/inju­­­ ries; Mesenchymal stromal cells; Stem cells; Brain-derived neurotrophic factor

Descritores: Fator 2 de crescimento de fibroblastos; Fator neurotrófico ciliar; Retina/ lesões; Células mesenquimais estromais; Células-tronco; Fator neurotrófico derivado do encéfalo

INTRODUCTION Mesenchymal stem cells (MSCs) are self-renewal and multipo­ tent cell source widely existed in mesenchymal tissues, which play a significant role in tissue regeneration and injury repair. It has been reported that MSCs are able to differentiate into multilineage tissue cells(1), including retinal cells(2,3), making MSCs an alternative therapeutic source for some irreversible retinal disorders such as age-related macular degeneration (AMD), retinitis pigmentosa (RP), glaucoma. However, clinical cell replacement is still far away unless technical barriers like directional differentiation, large scale output of target cells and reconstruction of the complicated network among the existed retinal cells and the regenerated cells were overcome. In addition, heterogeneous populations like multipotent adult progenitor cells (MAPCs), marrow-isolated adult multilineage inducible (MIAMI) cells, multipotent adult stem cells (MASCs) and very small embryonic-like

stem cells (VSELs) may overlap in MSCs(4). The emerging evidence that MSCs are pericytes for the common features they shared(5). These make MSCs a controversial cell source. Nonetheless, MSCs are promising for its potential applications in neuroprotection and immunomodulation apart from tissue regeneration. Accumulating findings have indicated a neuroprotective role of MSCs in central nervous system (CNS) disorder as well as in retinal disorder. Neurotrophins secreted from MSCs promote the survival of host cells and the repair process during injury enabling MSCs an attractive therapeutic source for a variety of neurological disease, e.g. multiple sclerosis and stroke(6). Neurotrophic effect of MSCs was also reported in retinal disorders. MSCs attenuated cell death in retinal ganglion cells (RGCs) suffering from in vitro insult(7) and promoted RGCs survival in glaucoma animal model(8). Systemic administration of MSCs delayed progress of retinal degeneration in RCS rats(9). These

Submitted for publication: September 24, 2012 Accepted for publication: January 31, 2013

Funding: This work was supported by National Natural Science Foundation of China (No.81271026) and Innovative Platform Foundation of Fujian Province, China (No.2010Y2003).

Study carried out at Department of Ophthalmology, First Affiliated Hospital of Fujian Medical Uni­ versity.

Disclosure of potential conflicts of interest: W.Xu, None; X.Wang, None; G.Xu, None; J.Guo, None.

Department of Ophthalmology, First Affiliated Hospital of Fujian Medical University, Fuzhou City, China. 2 Fujian Institute of Ophthalmology, Fuzhou City, China. 1

Correspondence address: Guoxing Xu. Department of Ophthalmology. First Affiliated Hospital of Fujian Medical University. 20 Chazhong Road, Fuzhou City 350005 (China) E-mail: [email protected]

Arq Bras Oftalmol. 2013;76(2):105-10

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Light-induced retinal injury enhanced neurotrophins secretion and neurotrophic effect of mesenchymal stem cells

suggested potential application of MSCs for neuroprotection in retinal diseases. Cytokines secreted from MSCs might involve in the neurotrophic effect. Therefore, we quantitatively analyzed neurotrophins expression change in MSCs stimulated by light-induced retinal injury in an in vitro model to evaluate their potential roles in retinal neuroprotection. METHODS

Animals All animal procedures in this study were in accordance with the Association for Research in Vision and Opthalmology (ARVO) Statement for the Use of Animals in Ophthalmic and Vision Research. Sprague-Dawley (SD) rats (6 to 8 weeks of age) were maintained in cyclic light condition (80 lux, 12 hours on-off ) and had access to food and water ad libitum before use.

Light-induced retinal injury Rats were exposed to 10,000 lux white light for 24 hours in separate cages and the pupils were dilated with atropine ointment. After light exposure, rats underwent dark adaptation for 24 hours. For evaluation of light-induced injury, rats were randomly selected after light exposure and dark adaptation and euthanized. The eyes were enucleated, fixed and embedded. The eye sections were stained for terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) using a kit (Roche) in accordance with the manufacturer’s protocol.

Supernatants of homogenized retina (SHR) preparation Normal and light damaged rats were sacrificed respectively. The retinas were harvested for supernatants of homogenized retina (SHR) preparation under a sterile condition as previously described(10). Brie­­­ fly, retinas were homogenized in Dulbecco’s modified Eagle’s medium (DMEM) (Gibco). The suspensions were centrifuged at 12,000 g, 4°C for 20 min. The supernatants were obtained and diluted to a final protein concentration at 200 μg/ml, and supplemented with 2% vol/vol fetal bovine serum (FBS) (Gbico), penicillin (100 U/ml) and streptomycin (100 μg/ml) and stored at -20°C before use.

Cell culture SD rat mesenchymal stem cells (Cyagen) were cultured in mesenchymal stem cell growth medium (Cyagen). Cells from passage 3-5 were used for this study. When the cells reached 70% confluence, the media was changed to either normal or light-damaged SHR and renewed every 2 days. MSCs cultured in 2% FBS+DMEM were set as control. After 2 days and 5 days culture, MSCs were rinsed in phosphate-buffered saline (PBS) twice and maintained in DMEM for 24 hours in humidified incubator with 5% CO2 at 37°C. The supernatants were collected and centrifuged at 12000 g, 4°C for 20 min.

Retinal explants culture Normal rats were sacrificed. Retinas were harvested and radically dissected into four equal-sized pieces. The pieces were randomly transferred into 24-well plate pre-added 500 μl supernatant collected from different groups of MSCs and supplemented with 1% B27+N2 (Invitrogen) in each well. Retinal explants were cultured for 24 hours in humidified incubator with 5% CO2 at 37°C and harvested for cell death detection and histology analysis. Three conditioned media were used for retinal explants culture, which were conditioned me­­ dium (CM) from control MSCs (CM-MSCs), conditioned medium from normal SHR stimulated MSCs (CM-NSHR) and conditioned medium from light-injured SHR stimulated MSCs (CM-ISHR). Retinal explants cultured in DMEM supplemented with 1% B27+N2 were set as control. 106

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in vitro

Quantitative real time-polymerase chain reaction (RT-PCR) analysis Total RNA from both MSCs and retinal explants was isolated using RNeasy Mini Kit (Qiagen) according to the manufacturer’s protocol and treated with RNase free DNase to eliminate genomic DNA contamination. Two microgram total RNA was reverse transcribed into cDNA with PrimeScript® 1st strand cDNA Synthesis Kit (Takara). Realti­me polymerase chain reaction (PCR) was performed on an Agilent Stratagene Mx3000P QPCR Systems using SYBR® Premix Ex TaqTM Kit (Takara). Primer sets were listed in table 1. glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an endogenous control. Real-time PCR data was analyzed using comparative CT method(11, 12).

Enzyme-linked immunosorbent assay Supernatants from MSCs were tested for the protein levels of bFGF, brain-derived neurotrophic factor (BDNF), CNTF using ELISA kit (Cusabio) according to the manufacturer’s instructions. For retinal cell death detection, an ELISA kit (Roche) was used to assay DNA fragmentation in retinal explants. The explants were gently rinsed in PBS twice and homogenized in 200 μl lysis buffer. The following procedures were in accordance with manufacturer’s protocol.

Histological analysis Retinal explants were fixed for 24 hours at 4ºC by replacing the media with 4% paraformaldehyde. With minimal damage, the explants were in situ infiltrate with 30% sucrose for 24 hours at 4ºC, em­ bedded in OCT and frozen. The frozen tissue was adjusted to enable a cross section. The sections were transferred to slides pretreated with polylysine. The slices were stained with hematoxylin and eosin for histological analysis.

Statistical analysis Data and statistical analysis were performed using SPSS software (version 19.0). Data are given as mean ± SEM. Analysis of variance (ANOVA) was conducted for comparison of neurotrophins expression and neurotrophic effect among groups at two time points. Statistical significance was set at P<0.05. RESULTS

Light-induced retinal injury Retinal injury was induced after intensive light exposure for 24h, as indicated by TUNEL staining (Figure 1). Apoptotic cells sparsely dispersed among the layers of retina with the majority in outer nuclear layer (ONL). The ONL thickness was slightly reduced. Part of nuclei in the ONL disappeared, forming a serrated shape.

Morphology of MSCs after stimulation MSCs growth was slow down in media containing 2% vol/vol FBS. Most cells maintained their fibroblast-like morphology, while a

Table 1. Primer sets for RT-qPCR Sense

Antisense

bFGF

5’-TTCCCACCCGGCCACTTCAAG-3’

5’-GTTCGCACACACTCCCTTGA-3’

CNTF

5’-AAACACCTCTGACCCTTCAC-3’

5’-AGTCATCTCACTCCAACGAT-3’

BDNF

5’-GGAGCCTCCTCTGCTCTTT-3’

5’-TTTTGATACCGGGACTTTCT-3’

Bax

5’-GTGGTTGCCCTCTTCTACTTTG-3’

5’-CACAAAGATGGTCACTGTCTGC-3’

Bcl-2

5’-ACGAGTGGGATACTGGAGATG-3’

5’-TAGCGACGAGAGAAGTCATCC-3’

5’-GGAAACCCATCACCATCTTC-3’

5’-TGGTTCACACCCATCACAAA-3’

GAPDH

Xu W, et al.

small amount of cells grew out long processes and connected with each other, especially after 5 days stimulation by either normal SHR or light-injured SHR. These cells displayed typical neuronal appearance (Figure 2). In contrast, cells cultured in 2% vol/vol FBS+DMEM did not display neuronal morphology.

Change in neurotrophins expression Quantitative RT-PCR showed mRNA levels of bFGF, BDNF and ciliary neurotrophic factor (CNTF) were up-regulated both in normal SHR (NSHR) stimulation group (p<0.01) and light-injured SHR (ISHR) stimulation group (p<0.01) in contrast to control group. However, no significant difference was detected in protein levels between NSHR stimulation group and control group (p>0.05). Light-injured SHR (ISHR) stimulation promoted neurotrophins secretion from MSCs. The concentration of bFGF was 255 ± 11 ng/ml after ISHR stimulation for 5 days versus 102 ± 7 ng/ml in control group. BDNF increased from 17.8 ± 1.4 pg/ml in control group to 24.6 ± 2.4 pg/ml (2 days) and 45.2 ± 3.0 pg/ml (5 days) in ISHR stimulation group. The concentration of ciliary neurotrophic factor (CNTF) was also identified up-regulation

A

B

Figure 1. TUNEL staining for evaluation of light-induced retinal injury. Apoptotic cells distributed mainly in the outer nuclear layer (ONL) after light exposure, ONL thickness was slightly reduce, part of the outer nuclei disappeared forming a serrated edge (A). No positive staining was identified in control retina (B). ONL,. Scale bar indicates 50 μm.

from 118 ± 14 pg/ml to 216 ± 14 pg/ml after 5 days of ISHR stimulation (Figure 3).

Neuroprotective effect of conditioned media Bcl-2 and bax expression in retinal explants were identified for evaluation the neuroprotective effect of conditioned medium from control MSCs (CM-MSCs), conditioned medium from normal SHR stimulated MSCs (CM-NSHR) and conditioned medium from lightin­jured SHR stimulated MSCs (CM-ISHR). CM-ISHR, CM-NSHR and CM-MSCs induced up-regulation of bcl-2 in contrast to control group. CM-ISHR and CM-MSCs also induced down-regulation of bax (Figure 4a, b, p<0.05). In addition, CM-ISHR induced bcl-2 up-regulation and bax down-regulation more significantly in comparison with the rest two groups, suggesting a better neurotrophic effect. Calculation of bcl-2/bax ratio among groups showed all conditioned media signi­ ficantly increased bcl-2/bax ratio with the max in CM-ISHR group (Figure 4c, p<0.01). DNA fragmentation was analyzed in retinal explants for evaluation cell death inhibition effect of conditioned media. All three conditioned media significantly reduced DNA fragmentation (Figure 4d, p<0.01). Among the conditioned media, CM-ISHR displayed the best preservative effect on retinal explants. Histological analysis showed retinal explants underwent severe destruction after 24 hours culture. The tissue lysed and ripped, especially in the explants cultured in control medium. The major damage appeared in the inner nuclear layer (INL) and the ganglion cell layer (GCL). However, the explants cultured in CM-ISHR group were best preserved. All layers of retina were tightly attached, except from disrupture of the outer segment (Figure 5). DISCUSSION Potential applications of MSCs include the plasticity, neuro­pro­ tection and immunomodulation(13). Due to various cytokines se­­­­creted from MSCs might involve in the process of tissue repair(14), previous attention that merely focused on the differentiation of MSCs into

A

C

E

B

D

F

Figure 2. Morphology of MSCs cultured in different media for 2 days (a, c, e) and 5 days (b, d, f). Cells cultured in 2% FBS+DMEM remained fibroblast-like shape (a, b). However, a small amount of cells grew out multiple processes and connected with each other, displaying neuronal appearance in normal SHR (c, d) and light-injured SHR (e, f) stimulated MSCs. Scale bars indicate 100 μm.

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Light-induced retinal injury enhanced neurotrophins secretion and neurotrophic effect of mesenchymal stem cells

A

B

C

D

E

F

in vitro

Ctrl= control MSCs; NSHR= MSCs stimulated by normal SHR; ISHR= MSCs stimulated by light-injured SHR. ** P <0.01. Figure 3. Neurotrophins expression in MSCs after stimulation. Both mRNA levels (a, c, e) and protein levels (b, d, f) were induced up-regulation by ISHR. Although bFGF and BDNF expression in MSCs stimulated by NSHR were identified significant difference in mRNA level, no difference was identified in protein level (d).

target cells has changed. Therefore, this cell source was considered as a drugstore during injury(15). The three therapeutic potentials of MSCs should be placed at an equally important position, especially when directional differentiation of MSCs into target cells and effective integration of target cells into the complex retinal neuro-network are still unavailable. Our results revealed that light-induced retinal injury was able to promote neurotrophins secretion in MSCs and consequently enhanced the retinal protective effect. This offers the possibility to take advantage of MSCs as modulators during retinal injury. Moreover, the therapeutic potential of MSCs can be enhanced by pre-stimulation. Cytokines involved in retinal injury varied depending on the ty­ pes of injury that retina suffered. Light-induced retinal injury was a well-established model, as confirmed by TUNEL staining. CNTF and bFGF are two major trophic factors which play significant roles in 108

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li­ght-induced retinal degeneration(16). Both fibroblast growth factor receptor (FGFR) and CNTFRα are localized on photoreceptors sug­ gesting direct effects of these two neurotrophins on photoreceptors(17). Although BDNF do not impact directly on photoreceptors, it has photoreceptor rescue effect though the activation of glial cell (18). Thus these neurotrophic factors were selected in our study. Reports have shown that both systemic administration and local administration of MSCs were found to be beneficial to retinal disorders. The protective effect of MSCs does not necessarily need a full integration of the graft to the host tissue(6), which indicated that the neurotrophic effect of MSCs did not depend on the differentiation of the transplanted cells. MSCs are able to enhance myelin formation without differentiation(19). In addition, a variety of neurotrophins we­­­re identified expression in MSCs that contribute to the protective effect in tissue repair. The cell source acts as mediators during repair

Xu W, et al.

A

B

C

D

Ctrl= control medium; CM-MSCs= conditioned medium from control MSCs; CM-NSHR= conditioned medium from MSCs stimulated by normal SHR; CM-ISHR= conditioned medium from MSCs stimulated by light-injured SHR. * P<0.05, ** P<0.01. Figure 4. Neurotrophic effect of conditioned media from different groups. Conditioned media increased bcl-2 expression and ratio of bcl-2/bax in retinal ex­­­ plants (a, c). Bax expression decreased in CM-ISHR group (b). DNA fragmentation also reduced in conditioned media, with minimal in CM-ISHR group (d).

A

C

E

G

B

D

F

H

Figure 5. Hematoxylin and eosin staining for retinal explants. The cultured explants severely lysed and ripped in contrast to fresh explant (a). Only the ONL remained in control medium group (b). CM-MSCs for 2 days (c) and 5 days (d) displayed protective effect on retinal explants. CM-NSHR for 2 days (e) was neurotrophic, however, the trophic effect decreased in CM-NSHR for 5 days (f). The tissue structure was better preserved in CM-ISHR for 2 days (g) and 5 days (h). ONL, outer nuclear layer; CM-MSCs, conditioned medium from control MSCs; CM-NSHR, conditioned medium from normal SHR; CM-ISHR, conditioned medium from light-injured SHR. Scale bar indicates 50 μm.

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Light-induced retinal injury enhanced neurotrophins secretion and neurotrophic effect of mesenchymal stem cells

process in tissue injury. Possible mechanism might be that MSCs enhance survival of host cells through cytokines secretion and promote endogenous regeneration through interaction with host cells. It should be mentioned that the interaction between MSCs and the host cells also requires intercellular signal transmission, probably the cytokines. It is not clear to what extend neurotrophins secretion from MSCs play a role in retinal injury. However, our results by quantitative analysis of the diverse neurotrophins change in response to light-induced retinal injury suggested that a wide spectrum of neurotrophins might be up-regulated in MSCs where injury existed. Use of an in vitro model for retinal neuroprotection screening provides a convenient way for evaluation neurotrophic effect of MSCs(20). Retinal explants underwent progressive degeneration during in vitro culture. Therefore, we set 24-hour culture as a point for assessment of the protective effect. The results suggested that neurotrophic effect of MSCs was significantly enhanced by injury stimulation. Nevertheless, the condition ex vivo was different from the pathological process in vivo, further investigations are necessary. Our results showed that conditioned medium (CM) from control MSCs also displayed a protective effect on retinal explants. This was in accordance with the previous report by Inoue et al. that conditioned medium from MSCs promoted retinal cell survival in vitro(21). CM from normal SHR stimulated MSCs was also identified to be neurotrophic. However, the protective effect was weaker in contrast to CM from control MSCs, as detected that bcl-2 expression level was lower. One possible explanation is that MSCs stimulated by normal SHR might undergo neuronal differentiation, thus altered the biological function and consequently led to decreased neuroprotective effect. Though MSCs stimulated by light-injured SHR might also display neuronal differentiation, the situation was more complicated due to the coexis­­­­ted injury response. The results were also distinct. Insight into the interactions between retinal injury and MSCs response could be achieved via a co-culture system, but long term survival and better functional preservation of retinal cells in vitro are yet to be settled. Two factors that might impact on the protective effect of MSCs are cell passages and growth density. Therefore, we selected MSCs from passage 3 to passage 5 which maintained the biological function more similar to in vivo condition and stimulated the cells when reaching a confluence of 70% which kept the cells at relatively equal growth situation. The cells stimulated by both SHRs seemed to undergo differentiation, as the morphological change was identified. However, Choi et al.(22), reported no significant variation of the MSCs surface markers after pretreatment. Some authors(23) identified return of differentiated MSCs to undifferentiated state. Although previous work by Zhang et al.(10), demonstrated neuronal markers expression on MSCs after light-injured SHR stimulation using a similar model, we did not test the neuronal or retinal markers on MSCs, since stimulation of MSCs for 2 days and 5 days was not long enough for a stable differentiation. In addition, only a small amount of cells were identified undergoing morphological change. Even though, these durations were able to induce up-regulation of neurotrophins. The up-regulation of neurotrophins secretion in MSCs, especially bFGF, probably contributed to retinal differentiation and act as a positive feed-back during differentiation, as was reported that bFGF was superior in inducing MSCs to express retinal neuron-specific markers(24). The dramatic expression change of these neurotrophins after injury stimulation implicated significant roles they play in MSCs response to retinal injury, but further investigations into the correlation between neurotrophins secretion from MSCs and their neurotrophic effect is necessary. CONCLUSION We found that light-injured SHR stimulation significantly increased neurotrophins secretion and neurotrophic effect of MSCs. Since using MSCs for neuroprotection is currently a more practicable way 110

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in vitro

over cell replacement, our study provided an alternative therapeutic potential for enhancing the trophic effect of MSCs. REFERENCES 1. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002;418(6893):41-9. Comment in: Nature. 2002;418(6893):1. Nature. 2002;418(6893): 25-7. Nature. 2007;447(7146):763. 2. Kicic A, Shen WY, Wilson AS, Constable IJ, Robertson T, Rakoczy PE. Differentiation of marrow stromal cells into photoreceptors in the rat eye. J Neurosci. 2003;23(21): 7742-9. 3. Castanheira P, Torquetti L, Nehemy MB, Goes AM. Retinal incorporation and differentiation of mesenchymal stem cells intravitreally injected in the injured retina of rats. Arq Bras Oftalmol. 2008;71(5):644-50. 4. Ratajczak MZ, Zuba-Surma EK, Machalinski B, Ratajczak J, Kucia M. Very small embryonic-like (VSEL) stem cells: purification from adult organs, characterization, and biological significance. Stem Cell Rev. 2008;4(2):89-99. 5. Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 2008;3(3):301-13. Comment in: Cell Stem Cell. 2008;3(3):229-30. 6. Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases. Lancet Neurol. 2011;10(7):649-56. 7. Harper MM, Adamson L, Blits B, Bunge MB, Grozdanic SD, Sakaguchi DS. Brain-derived neurotrophic factor released from engineered mesenchymal stem cells attenuates glutamate- and hydrogen peroxide-mediated death of staurosporine-differentiated RGC-5 cells. Exp Eye Res. 2009;89(4):538-48. 8. Johnson TV, Bull ND, Hunt DP, Marina N, Tomarev SI, Martin KR. Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma. Invest Ophthalmol Vis Sci [Internet]. 2010[cited 2012 Jan 3];51(4):2051-9.Available from: http://www.iovs.org/cgi/pmidlookup?view=long&pmid=19933193 9. Wang S, Lu B, Girman S, Duan J, McFarland T, Zhang QS, et al. Non-invasive stem cell therapy in a rat model for retinal degeneration and vascular pathology. PLoS One. 2010;5(2):e9200. 10. Zhang Y, Wang W. Effects of bone marrow mesenchymal stem cell transplantation on light-damaged retina. Invest Ophthalmol Vis Sci [Internet]. 2010[cited 2011 Jun 21];51(7):3742-8.Available from: http://www.iovs.org/cgi/pmidlookup?view=long&p mid=20207980 11. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402-8. 12. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101-8. 13. Xu W, Xu GX. Mesenchymal stem cells for retinal diseases. Int J Ophthalmol. 2011; 4(4):413-21. 14. Stappenbeck TS, Miyoshi H. The role of stromal stem cells in tissue regeneration and wound repair. Science. 2009;324(5935):1666-9. 15. Caplan AI, Correa D. The MSC: an injury drugstore. Cell Stem Cell. 2011;9(1):11-5. 16. Joly S, Pernet V, Chemtob S, Di Polo A, Lachapelle P. Neuroprotection in the juvenile rat model of light-induced retinopathy: evidence suggesting a role for FGF-2 and CNTF. Invest Ophthalmol Vis Sci [Internet]. 2007[cited 2012 Jul 21];48(5):2311-20. Available from: http://www.iovs.org/content/48/5/2311.long 17. Valter K, Bisti S, Gargini C, Di Loreto S, Maccarone R, Cervetto L, et al. Time course of neurotrophic factor upregulation and retinal protection against light-induced damage after optic nerve section. Invest Ophthalmol Vis Sci [Internet]. 2005[cited 2010 Jul 21];46(5):1748-54.Available from: http://www.iovs.org/content/46/5/1748.long 18. Saito T, Abe T, Wakusawa R, Sato H, Asai H, Tokita-Ishikawa Y, et al. TrkB-T1 receptors on Muller cells play critical role in brain-derived neurotrophic factor-mediated photoreceptor protection against phototoxicity. Curr Eye Res. 2009;34(7):580-8. 19. Arriola A, Kiel ME, Shi Y, McKinnon RD. Adjunctive MSCs enhance myelin formation by xenogenic oligodendrocyte precursors transplanted in the retina. Cell Res. 2010; 20(6):728-31. 20. Bull ND, Johnson TV, Welsapar G, DeKorver NW, Tomarev SI, Martin KR. Use of an adult rat retinal explant model for screening of potential retinal ganglion cell neuroprotective therapies. Invest Ophthalmol Vis Sci [Internet]. 2011[cited 2012 Oct 21]; 52(6):3309-20.Available from: http://www.iovs.org/content/52/6/3309.long 21. Inoue Y, Iriyama A, Ueno S, Takahashi H, Kondo M, Tamaki Y, et al. Subretinal transplantation of bone marrow mesenchymal stem cells delays retinal degeneration in the RCS rat model of retinal degeneration. Exp Eye Res. 2007;85(2):234-41. 22. Choi YJ, Li WY, Moon GJ, Lee PH, Ahn YH, Lee G, et al. Enhancing trophic support of mesenchymal stem cells by ex vivo treatment with trophic factors. J Neurol Sci. 2010; 298(1-2):28-34. 23. Sun X, Ge J, Jiang R, Duan S, Song G, Duan Y, et al. Induced differentiation of bone marrow mesenchymal stem cells towards retinal ganglion precursor cells. Cell Res. 2008;18(s76). 24. Liu DN, Yin ZQ, Wu N, Wang YH, Chen LF. Rat bone marrow stromal cells express retinal phenotypic markers following different induction protocols. Ophthalmic Res. 2009;41(4):186-93.

Artigo Original | Original Article

ORA waveform-derived biomechanical parameters to distinguish normal from keratoconic eyes Parâmetros biomecânicos derivados da forma da curva do ORA para discriminar olhos normais de ceratocones Allan Luz1,2,3, Bruno Machado Fontes1,3, Bernardo Lopes3, Isaac Ramos3, Paulo Schor1, Renato Ambrósio Jr.1,3,4

ABSTRACT

RESUMO

Purpose: To evaluate the ability of the Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments, Buffalo, NY) to distinguish between normal and keratoconic eyes, by comparing pressure and waveform signal-derived parameters. Methods: This retrospective comparative case series study included 112 patients with normal corneas and 41 patients with bilateral keratoconic eyes. One eye from each subject was randomly selected for analysis. Keratoconus diagnosis was based on clinical examinations, including Placido disk-based corneal topography and rotating Scheimpflug corneal tomography. Data from the ORA best waveform score (WS) measurements were extracted using ORA software. Corneal hysteresis (CH), corneal resistance factor (CRF), Goldman-correlated intraocular pressure (IOPg), cornea-compensated intraocular pressure (IOPcc), and 37 parameters derived from the waveform signal were analyzed. Differences in the distributions among the groups were assessed using the Mann-Whitney test. Receiver operating characteristic (ROC) curves were calculated. Results: Statistically significant differences between keratoconic and normal eyes were found in all parameters (p<0.05) except IOPcc and W1. The area under the ROC curve (AUROC) was greater than 0.85 for 11 parameters, including CH (0.852) and CRF (0.895). The parameters related to the area under the waveform peak during the second and first applanations (p2area and p1area) had the best performances, with AUROCs of 0.939 and 0.929, respectively. The AUROCs for CRF, p2area, and p1area were significantly greater than that for CH. Conclusion: There are significant differences in biomechanical metrics between normal and keratoconic eyes. Compared with the pressure-derived parameters, corneal hysteresis and corneal resistance factor, novel waveform-derived ORA pa­­­rameters provide better identification of keratoconus.

Objetivo: Avaliar a capacidade do Ocular Response Analyzer (ORA; Reichert Oph­ thalmic Instruments, Buffalo, NY) em discriminar olhos com ceratocone de olhos normais e comparar parâmetros derivados da pressão dos parâmetros derivados da forma da curva. Métodos: Estudo comparativo retrospectivo série de casos que incluiu 112 pacientes com olhos normais e 41 pacientes com ceratocone bilateral. Um olho de cada indivíduo foi randomicamente selecionado para análise. O diagnóstico de ceratocone foi baseado em exame clínico, incluindo topografia de Plácido e tomografia Scheimpflug. Informação do melhor waveform score foi extraída do software do ORA. Histerese corneana (CH), fator de resistência corneana (CRF), pressão intraocular correlacionada com Goldman (IOPg), pressão intraocular compensada pela córnea (IOPcc) e 37 novos parâmetros derivados da forma da curva do sinal do ORA foram analisados. Diferenças nas distribuições dos grupos foram avaliadas pelo teste Mann-Whitney. Curvas ROC foram calculadas. Resultados: Diferenças estatisticamente significantes foram encontradas entre os olhos normais e ceratocones em todos os parâmetros (p<0,05) salvo IOPcc e W1. A área sob a curva ROC (AUROC) foi maior que 0.85 em 11 parâmetros, incluindo CH (0,852) a CRF (0,895). Os parâmetros relacionados com a área sob o pico da forma de onda durante a segunda e primeira aplanação (p2area e p1area) obtiveram as melhores performances, com AUROCs de 0,939 e 0,929, respectivamente. Os valores de AUROCs do fator de resistência corneana, p2area e p1area foram significativamente maiores que os valores de histerese corneana. Conclusão: Existem diferenças significantes nas medidas biomecânicas entre olhos normais e com ceratocone. Comparados com os parâmetros derivados da pressão, histerese corneana e fator de resistência corneana, os parâmetros derivados da forma da curva proporcionaram melhor identificação dos ceratocones.

Keywords: Cornea; Keratoconus; Corneal diseases; Refractive surgical procedures; Software; Biomechanics

Descritores: Córnea; Ceratocone; Doenças da córnea; Procedimentos cirúrgicos re­­ frativos; Software; Biomecânica

INTRODUCTION In 2005, the Ocular Response Analyzer (ORA; Reichert Technologies, Depew, New York) was launched as the first commercial device claiming to provide in vivo measurements of corneal biomechanics(1). It utilizes a dynamic bi-directional applanation process in which two applanation pressure measurements are recorded: the first, while the cornea is moving inward (P1); and the second, while the cornea returns(2). The primary output measurements, derived from the air puff re­­­­corded pressure during the first and second applanations, are

Goldmann-correlated intraocular pressure (IOPg), defined as the ave­­­­­rage between P1 and P2; corneal hysteresis (CH), defined as the difference between P1 and P2; corneal resistance factor (CRF), which includes a constant factor designed to optimize the correlation with central corneal thickness (CCT); and corneal compensated intraocular pressure (IOPcc), which includes a constant based on CRF for cor­­­­­relation with CCT(2). Further information about the corneal response is provided by infrared waveform signal analysis, which corresponds to the deformation movement of the cornea caused by the air puff(3). These novel

Submitted for publication: April 9, 2012 Accepted for publication: January 31, 2013

Funding: No specific financial support was available for this study.

Study carried out at Instituto de Olhos Renato Ambrosio - Rio de Janeiro, Brazil. Department for Ophthalmology of the Universidade Federal de São Paulo, São Paulo, Brazil. Hospital de Olhos de Sergipe, Aracaju, Brazil. Rio de Janeiro Corneal Tomography and Biomechanics Study Group. 4 Instituto de Olhos Renato Ambrósio, Visare Personal Laser and Refracta-RIO, Rio de Janeiro, Brazil. 1 2

3

Disclosure of potential conflicts of interest: A.Luz, None; B.M.Fontes, None; B.Lopes, None; I.Ramos, None; P.Schor, None, R.Ambrósio Jr, is a consult of OCULUS Optikgeräte GmbH. Correspondence address: Allan Luz. Rua Campo do Brito, 995 - Aracaju (SE) - 49020-380 Brazil - E-mail: [email protected] The ethics committee of the Universidade Federal de São Paulo, Brazil (protocol 1210/10).

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ORA waveform-derived biomechanical parameters to distinguish normal from keratoconic eyes

parameters based on a complex analysis of the waveform signal were thought to improve sensitivity and specificity for distinguishing normal and keratoconic corneas(2-5). Kerautret et al., reported a case that demonstrated the importance of ORA waveform signal analysis in the evaluation of LASIKin­­duced ectasia compared with a stable post-LASIK cornea with a similar CH value(6). Parameters from the waveform signal have been studied for sta­­­­ging the severity of keratoconus(7). In addition, changes after myo­­­­­­pic LASIK and the estimated elasticity coefficient of the cornea were evaluated using waveform signal parameters(8,9). Although CH and CRF were found to be unchanged after corneal crosslinking (CXL)(10,11), waveform-derived parameters were significantly changed after CXL(3,12). In a previous study(13), our group reported lower values for keratoconic eyes with normal central corneal thickness. Many other studies by different investigators have also found lower values for keratoconus(14-16), by testing only the traditional ocular biomechanical metrics pressure-derived parameters CH and CRF. This study was conducted to evaluate pressure-derived parameters (CH, CRF, IOPg, and IOPcc) and 37 novel parameters derived from the waveform signal of the ORA with regard to their ability to distinguish normal from keratoconic eyes. METHODS The study constituted a comparative case series. The retrospective study involved 112 patients with normal corneas and 41 patients with bilateral keratoconus; one eye from each subject was randomly selected. The research followed the tenets of the Declaration of Helsinki and was approved by the ethics committee of the Federal University of São Paulo, Brazil (protocol 1210/10). Patients examined at the Instituto de Olhos Renato Ambrósio (Rio de Janeiro, Brazil) were retrospectively enrolled. Patients were selected from a database of patients with normal corneas who were candidates for refractive surgery and from a database of cases diagnosed as having keratoconus in both eyes. All eyes were examined by a fellowship-trained cornea and re­­ fractive surgeon (R.A.). Along with a comprehensive ocular examination, all eyes were examined by Placido disk-based corneal topography (Atlas Corneal Topography System; Humphrey, San Leandro, CA) and rotating Scheimpflug corneal tomography (Pentacam HR; Oculus, Wetzlar, Germany). The diagnosis of keratoconus was made based on clinical data, including Placido disk-based axial topography corneal curvature maps(17); criteria used in the Collaborative Longitudinal Evaluation of Keratoconus study(18); and Pentacam corneal tomography(5). Keratoconus cases with a history of corneal surgery or with extensive corneal scarring were excluded from the study. The patients underwent clinical evaluation and testing with the ORA during the same visit. All measurements were obtained between 8 AM and 6 PM. At least two consecutive measurements were performed, and the best waveform score (WS) from each patient was included in the analysis. The ORA determines corneal biomechanical properties by using an applied force displacement relationship, as described previously(1,14-16). Briefly, a precisely metered air pulse is delivered to the eye, causing the cornea to move inward, past applanation, and into slight concavity. Milliseconds after the initial applanation, the air pump generating the air pulse is shut off, and the pressure applied to the eye decreases in an inverse-time, symmetrical fashion. As the pressure decreases, the cornea passes through a second applanated state while returning from concavity to its normal convex curvature. Energy absorption during rapid corneal deformation delays the occurrence of the inward and outward applanation signal peaks, resulting in a difference between the applanation pressures. The difference bet­ ween these inward and outward motion applanation pressures is 112

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the CH, which indicates viscous damping in the cornea and reflects the capacity of corneal tissue to absorb and dissipate energy. CRF is a measure of the cumulative effects of both the viscous and elastic resistance encountered by the air jet while deforming the corneal surface; it is an indicator of the overall resistance of the cornea. The CRF was derived empirically to maximize its correlation with the central corneal thickness(19). It can be considered as weighted by the elastic resistance, because of its stronger correlation with the central corneal thickness than with CH. Although CH and CRF are related, they can differ significantly in some cases, and each provides distinct information about the cornea. Using the new ORA software (version 2.04), the 37 new parameters described in table 1 were calculated based on the waveform of the ORA signal. Statistical analyses were performed using BioEstat 5.0 (Instituto Mamirauá, Amazonas, Brazil) and Med-Calc 11.1 (MedCalc Software, Mariakerke, Belgium). The nonparametric Mann-Whitney U test (Wilcoxon rank sum test) was used to assess variable distributions between the keratoconic and normal cornea groups. Receiver operating characteristic (ROC) curves and the areas under the ROC curves (AUROCs) were calculated for all parameters to determine the test’s overall predictive accuracy. The standard error of the AUROC was assessed with the DeLong method(20). The binomial exact method was used to calculate the confidence interval (CI) for the AUROC. Nonparametric pairwise comparisons were performed to determine the significance of differences between AUROCs, using the Hanley-McNeil method for calculating the standard error(21). Values of P<0.05 indicated statistical significance. RESULTS Single eyes randomly selected from the 112 patients with normal unoperated eyes and 41 patients with bilateral keratoconus were enrolled. In the normal and keratoconic groups, the average patient ages were 39.0 ± 17.9 years (range: 12.0 to 78.1 years) and 30.2 ± 10.8 years (range: 16.1 to 63 years), respectively, and the male/female percentages were 40.1/59.9 and 63.3/36.4, respectively. The SimK1 and SimK2 simulated keratometry values and the maximal keratometry value in the keratoconic group were 47.52 ± 5.53 diopters (D) (range: 39.90 to 69.40 D), 49.75 ± 7.12 D (range: 41.80 to 72.80), and 55.59 ± 7.63 D (range: 45.38 to 83.19 D), respectively. Significant differences were found between normal and keratoconic eyes for all parameters (Mann-Whitney U test, P<0.05) with the

Table 1. Designation of the parameters

Parameter Area Height Width

Upper 75% of peak height (23 parameters)

Upper 50% of peak height (14 parameters)

p1area, p2area

p1area1, p2area1

h1, h2

h11, h21

w1, w2

w11, w21

Aspect ratio

aspect1, aspect2

aspect11, aspect21

Slope

uslope1, dslope1, uslope2, dslope2

uslope11, dslope11, uslope21, dslope21

Slew rate

slew1, slew2, mslew1, mslew2

—

path1, path2

path11, path21

aindex, bindex

—

dive1, dive2

—

aplhf

—

Path Irregularity Dive High frequency

1 = first peak of upper 75% of peak height, 2 = second peak of upper 75% of peak height, 11 = first peak of upper 50% of peak height, 21 = second peak of upper 50% of peak height3.

Luz A, et al.

Table 2. ORA parameters measured in normal and keratoconus eyes Normal Mean

SD

Max

Kerato Min

P value U

CH

10,34

1,67

14,30

5,50

<0.0001

CRF

10,08

1,83

15,50

5,70

IOPg

14,55

3,34

25,60

6,90

IOPcc

15,23

3,21

26,30

aindex

9,09

1,22

10,00

Mean

SD

Max

Min

7,85

1,79

13,40

4,40

<0.0001

6,89

2,07

15,00

3,10

<0.0001

10,97

3,54

22,20

4,30

7,60

0.1375

14,82

3,15

26,40

9,50

3,82

<0.0001

7,21

2,63

10,00

1,25

bindex

9,40

1,05

10,00

4,65

0.0032

7,70

3,02

10,00

0,21

p1area

4371,53

1233,63

9037,44

1402,00

<0.0001

2123,88

1060,98

4849,13

278,19

p2area

2837,73

851,47

4610,50

993,63

<0.0001

1263,50

614,66

3138,88

272,75

aspect1

22,60

6,28

39,31

7,82

<0.0001

13,55

7,71

44,19

2,37

aspect2

23,07

9,62

55,02

4,63

<0.0001

16,89

13,27

66,71

2,80

uslope1

81,36

32,91

187,17

25,81

<0.0001

43,99

29,40

140,75

5,69

uslope2

104,10

44,29

239,13

14,68

<0.0001

57,41

41,39

176,38

6,25

dslope1

32,59

9,29

60,83

11,55

<0.0001

20,84

11,02

60,79

3,83

dslope2

30,52

14,05

83,21

5,59

0.0010

26,56

26,56

146,13

3,08

w1

21,64

2,99

30,00

15,00

0.0514

20,68

5,09

31,00

10,00

w2

18,21

3,86

34,00

10,00

0.0108

16,39

6,74

37,00

5,00

h1

477,40

109,20

644,44

225,00

<0.0001

257,92

110,68

458,06

68,63

h2

392,15

111,84

621,75

156,19

<0.0001

215,36

106,57

545,81

69,95

dive1

398,96

148,23

636,50

17,50

<0.0001

205,84

117,07

439,00

17,50

dive2

319,04

110,55

601,50

120,50

<0.0001

157,20

88,56

382,50

16,25

path1

22,02

3,80

35,64

14,17

<0.0001

28,47

10,22

54,86

14,67

path2

26,08

6,34

51,14

11,57

<0.0001

33,79

9,45

59,00

18,43

mslew1

133,45

42,71

239,50

41,75

<0.0001

77,36

39,51

184,00

20,25

mslew2

154,00

57,95

332,75

34,75

<0.0001

98,24

56,81

255,00

16,25

slew1

81,29

34,63

187,17

17,50

<0.0001

46,41

29,23

140,75

11,29

slew2

104,26

43,99

239,13

23,31

<0.0001

62,38

39,23

176,38

9,50

aplhf

1,34

0,31

2,50

0,90

<0.0001

1,74

0,44

3,10

1,00

p1area1

1891,81

628,60

4362,63

564,25

<0.0001

900,96

510,77

2468,63

117,75

p2area1

1225,07

398,54

2142,25

380,75

<0.0001

536,47

293,80

1556,25

123,50

aspect11

29,81

9,88

66,25

10,71

<0.0001

19,63

12,29

63,84

4,19

aspect21

32,29

14,25

69,91

4,56

<0.0001

22,93

15,84

66,88

3,90

uslope11

78,68

35,25

181,38

18,63

<0.0001

44,12

27,31

128,25

9,75

uslope21

85,60

38,35

198,00

15,13

<0.0001

52,95

41,90

176,38

9,50

dslope11

50,13

22,36

154,13

15,30

<0.0001

36,27

25,69

128,38

5,83

dslope21

50,73

27,27

137,38

5,79

0.0027

40,56

32,01

131,75

5,71

w11

11,18

2,12

17,00

5,00

0.0108

9,88

3,51

17,00

4,00

w21

9,02

2,76

23,00

4,00

0.0003

7,37

2,77

17,00

4,00

h11

318,27

72,80

429,63

150,00

<0.0001

171,94

73,79

305,38

45,75

h21

261,43

74,56

414,50

104,13

<0.0001

143,57

71,05

363,88

46,63

path11

31,70

7,64

57,88

15,19

0.0006

38,59

11,98

69,00

16,70

path21

36,28

9,97

66,57

14,59

0.0002

45,01

13,60

74,37

22,08

Significant differences were found between normal and keratoconic eyes for all parameters (Mann-Whitney U test, P<0.05) with the exception of IOPcc (P=0.1375) and W1 (P=0.0514).

Arq Bras Oftalmol. 2013;76(2):111-7

113

ORA waveform-derived biomechanical parameters to distinguish normal from keratoconic eyes

Demonstration of the overlapped values P2area Figure 1. Distribution of normal and keratoconus eyes for P2area.

Demonstration of the overlapped values CRF Figure 3. Distribution of normal and keratoconus eyes for CRF.

respectively (Table 3). The AUROCs for p2area, p1area, and CRF were significantly greater than the AUROC for CH. Table 4 summarizes the pairwise comparisons of ROC curves for the 11 parameters with AUROCs >0.85.

Demonstration of the overlapped values CH Figure 2. Distribution of normal and keratoconus eyes for CH.

exception of IOPcc (P=0.1375) and W1 (P=0.0514) (Table 2). Corneal hysteresis was 7.85 ± 1.79 mmHg (range: 13.40 to 4.40 mmHg) in the keratoconus group and 10.34 ± 1.67 mmHg (range: 14.30 to 5.50) in the control group (P<0.0001). The corneal resistance factor was 6.89 ± 2.07 mmHg (range: 15.0 to 3.10) in the keratoconus group and 10.08 ± 1.83 mmHg (range: 15.50 to 5.70) in the control group (P<0.0001). The p2area was 1263.50 ± 614.66 (range to 3138.88 to 272.75) in the keratoconus group and 2837.73 ± 851.47 (range: 4610.50 to 993.63) in the control group (P<0.0001). The p1area was 2123.88 ± 1060.98 (range: 4849.13 to 278.19) in the keratoconus group and 4371.53 ± 1233.63 (range: 9037.44 to 1402.00 (P<0.0001). The data are summarized in table 2. Box-plot distributions of p2area, CH and CRF are shown in figures 1, 2 and 3, respectively. The AUROC was greater than 0.85 for 11 parameters, including CH (0.852) and CRF (0.895). The parameters related to the area of the waveform during the second and first applanations had the best performances, with AUROCs of 0.939 and 0.929 for p2area and p1area, 114

Arq Bras Oftalmol. 2013;76(2):111-7

DISCUSSION The identification of keratoconus and related conditions when screening refractive candidates is of particularly high clinical importance because failure to identify these cases is considered to be the main cause of ectasia after LASIK(5,22,23). This study analyzed 37 novel waveform signal parameters using the ORA 2.04 software and demonstrated that the classic CH and CRF pressure parameters might not be used to distinguish normal eyes from those with keratoconus, as significant overlap is present. The keratoconic cornea has a conical curvature with three characteristic features: thinning of the corneal stroma with folding artifacts, breaks in the Bowman’s layer due to a weak collagen fiber network and deposition of iron in the basal layers of the corneal epithelium. Additional structural changes may also be observed depending on the severity of the disease(24). A decrease in the number of collagen lamellae concomitant with an increase in the ground substance (proteoglycans) is frequently observed in the stroma(25). Loss of collagen fibrils in the stroma has been linked to proteolytic enzymes or decreased levels of proteinase inhibitors such as corneal α1 inhibitor and α2 macroglobulin(26). Keratoconic eyes have low tensile strength, thinning, and protrusion(27). Lower resistance to deformation is attributable not only to thinning but also to the presence of more fragile corneal stromal collagen fibrils in keratoconic eyes than in normal eyes(13). Thus, reduced central corneal thickness is only part of the screening process for keratoconus identification. Previous studies(22,28) have demonstrated that biomechanical pressure metrics are significantly lower in keratoconus corneas than in normal corneas. Data presented by Fry and David Luce(7) suggested that wave­ form parameters provided from the ORA signal may be more sen­­­­sitive than the pressure parameters CH and CRF in identifying abnormal corneas. CH and CRF had different distributions between normal and keratoconic corneas in the present study. Nevertheless, significant overlap was noted and even for the new parameters in the present study, no cutoff value with high sensitivity and specificity could be established for the differentiation of keratoconus and

Luz A, et al.

Table 3. Data summary from receiver operating characteristic curve of new ora parameters in normal and keratoconic eyes Sensibility

Especificity

AUROC

IC 95%

p2area

Parameter

<1554,438

80.5

96.4

0.939

0,888 to 0,971

p1area

<2865,500

82.9

89.3

0.929

0,877 to 0,965

p2area1

<765,625

85.4

90.2

0.926

0,873 to 0,962

h1

<353,438

80.5

87.5

0.917

0,861 to 0,955

h11 p1area1

Cutoff

<235,625

80.5

87.5

0.917

0,861 to 0,955

<1329,750

85.4

85.7

0.908

0,851 to 0,949

<8,600

87.8

80.4

0.895

0,835 to 0,939

dive2

<182,500

68.3

89.3

0.873

0,810 to 0,921

h2

<266,250

73.2

87.5

0.869

0,805 to 0,918

h21

<177,500

73.2

87.5

0.869

0,805 to 0,918

<8,700

75.6

86.6

0.852

0,786 to 0,904

aspect1

<18,839

87.8

75.0

0.849

0,782 to 0,901

mslew1

<99,250

82.9

80.4

0.848

0,781 to 0,901

<326,500

85.4

75.0

0.845

0,777 to 0,898

CRF

CH

dive1 uslope1

<55,700

75.6

81.2

0.840

0,772 to 0,894

IOPg

<12,100

85.4

77.7

0.830

0,760 to 0,885

dslope1

<25,841

73.2

79.5

0.814

0,743 to 0,872

slew1

<62,714

80.5

72.3

0.810

0,739 to 0,869

aspect11

<23,275

78.0

76.8

0.804

0,732 to 0,864

uslope11

<48,875

73.2

78.6

0.796

0,723 to 0,857

uslope2

<46,357

56.1

92.9

0.787

0,713 to 0,849

aplhf

>1,300

87.8

55.4

0.771

0,696 to 0,835

slew2

<83,833

78.0

66.1

0.768

0,693 to 0,832

<119,000

70.7

73.2

0.761

0,685 to 0,826

aindex

<8,942

68.3

70.5

0.758

0,682 to 0,824

path2

>27,241

78.0

64.3

0.754

0,678 to 0,820

uslope21

<46,500

63.4

88.4

0.751

0,675 to 0,817

dslope11

<31,000

56.1

83.0

0.728

0,650 to 0,796

mslew2

path1

>25,699

46.3

87.5

0.716

0,638 to 0,786

aspect2

<17,510

65.9

74.1

0.708

0,629 to 0,779

aspect21

<21,225

63.4

76.8

0.703

0,624 to 0,774

path21

>43,367

51.2

81.2

0.688

0,609 to 0,761

<7,000

56.1

72.3

0.682

0,602 to 0,755

path11

>37,353

51.2

83.0

0.672

0,592 to 0,746

dslope2

<19,286

53.7

82.1

0.663

0,582 to 0,737

dslope21

<39,000

68.3

59.8

0.647

0,565 to 0,722

w21

bindex

<6,290

31.7

96.4

0.644

0,563 to 0,720

w11

<9,000

43.9

82.1

0.622

0,540 to 0,699

w2

<13,000

41.5

89.3

0.621

0,540 to 0,698

w1

<21,000

65.9

53.6

0.586

0,504 to 0,665

IOPcc

<17,100

90.2

22.3

0.558

0,475 to 0,638

The AUROC was greater than 0.85 for 11 parameters. The parameters related to the area of the waveform during the second and first applanations had the best performances.

healthy corneas. The AUROCs for p2area and p1area were significantly higher than those for CH and CRF (Table 4). Both p1area and p2area are proportional to the time required to change from the

convex to the concave cornea configuration and vice versa. Small values of p1area and p2area represent rapid change and indicate that the cornea shows less damping(4).

Arq Bras Oftalmol. 2013;76(2):111-7

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ORA waveform-derived biomechanical parameters to distinguish normal from keratoconic eyes

Table 4. Pairwise comparison of ROC curves P2area P1area

P1area

P2area1

H1

H11

P1area1

CRF

Dive2

H2

H21

CH

0,6914

0,0519

0,4371

0,4371

0,2582

0,1872

0,0340

0,0054

0,0054

0,0181

0,9011

0,4848

0,4848

0,0228

0,3552

0,0337

0,0142

0,0142

0,0641

0,7379

0,7379

0,5084

0,3308

0,0941

0,0250

0,0250

0,0407

1,0000

0,7181

0,5500

0,1158

0,0898

0,0898

0,1388

P2area1 H1 H11

0,7181

P1area1

0,5500

0,1158

0,0898

0,0898

0,1388

0,7423

0,2463

0,1434

0,1434

0,1984

CRF

0,6450

Dive2 H2 H21

0,5357

0,5357

0,0161

0,8382

0,8382

0,6797

1,0000

0,7185 0,7185

The AUROCs for p2area, p1area, and CRF were significantly greater than the AUROC for CH.

REFERENCES

The p2area and p1area were superior to CRF and CH, with AUROCs greater than those for CRF and CH Figure 4. Combined receiver operating curves for CH, CRF, P2area, P1area and P2area1.

The pressure parameters CRF and CH were significant different, as groups, between keratoconus and normal eyes in the present study, with CRF being superior to CH. The importance of CRF compared with CH is consistent with previous findings suggesting that CRF best correlates with optical aberrations in keratoconic eyes(29). However, in the present study, p2area and p1area were superior to CRF and CH, with AUROCs greater than those for CRF and CH (Table 3 and Figure 4). Yet, biomechanical data should not be used as the solo criteria in the diagnosis or screening of keratoconus since corneal curvature (given by Placido disk or corneal tomography elevation technologies) study remains the gold standard. Further studies are necessary to integrate the parameters derived from the waveform signal with artificial intelligence techniques for detecting corneal curvature characteristics of keratoconus. These sen­­­­­ sitive techniques will be useful for detecting milder forms of ectasia when assessing the risk for ectasia after LASIK. The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck.com/certificate/0eVwb2 116

Arq Bras Oftalmol. 2013;76(2):111-7

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25. Sawaguchi S, Yue B, Chang I, Sugar J, Robin J. Proteoglycan molecules in keratoconus corneas. Invest Ophthalmol Vis Sci [Internet]. 1991[cited 2011 Jun 21];32(6):1846-53. Available from: http://www.iovs.org/content/32/6/1846.long 26. Mackiewicz Z, Maatta M, Stenman M, Konttinen L, Tervo T, Konttinen YT. Collagenolytic proteinases in keratoconus. Cornea. 2006;25(5):603-10. Erratum In: Cornea. 2006; 25(6):760. 27. Reeves SW, Ellwein LB, Kim T, Constantine R, Lee PP. Keratoconus in the Medicare population. Cornea. 2009;28(1):40-2. 28. Saad A, Lteif Y, Azan E, Gatinel D. Biomechanical properties of keratoconus suspect eyes. Invest Ophthalmol Vis Sci [Internet]. 2010[cited 2012 Mar 21];51(6):2912-6. Available from: http://www.iovs.org/content/51/6/2912.long 29. Piñero DP, Alio JL, Barraquer RI, Michael R, Jiménez R. Corneal biomechanics, refraction, and corneal aberrometry in keratoconus: an integrated study. Invest Oph­­­­thalmol Vis Sci [Internet]. 2010[cited 2012 Nov 21];51(4):1948-55. Available from: http://www.iovs.org/content/51/4/1948.long

XXXVII Congresso Brasileiro de Oftalmologia XXX Congresso Pan-Americano de Oftalmologia 7 a 10 de agosto de 2013 RioCentro Rio de Janeiro (RJ)

Informações: Site: www.cbo2013.com.br

Arq Bras Oftalmol. 2013;76(2):111-7

117

Relato de Caso |

Case Report

Solar retinopathy without abnormal exposure: case report Retinopatia solar sem exposição anormal: relato de caso Ricardo Alexandre Stock1, Simone Louise Savaris2, Erasmo Carlos Rodrigues de Lima Filho2, Elcio Luiz Bonamigo1

ABSTRACT

RESUMO

Solar retinopathy is photochemical damage to the retina, usually caused, by direct or indirect solar observation resulting from the use of hallucinogenic drugs, mental disorders or during eclipses. There may be a loss of visual acuity. We report the case of a 38-year-old patient who presented with a clinical diagnosis of solar retinopathy in the left eye, no prior history of sun exposure, normal visual acuity and complaints of metamorphopsia. Optical coherence tomography showed a rupture of the retinal pigment epithelium, confirming class II solar retinopathy. Visual acuity tends to normalize after 3 to 9 months, but not always. Thus, there is a real need to educate people about using eye protection during sun exposure especially given that some people may be highly susceptible to retinal damage, which was presumably the case for this patient. Finally, we note the importance of optical coherence tomography in diagnosing solar retinopathy.

Retinopatia solar é o dano fotoquímico à retina causado, geralmente, pela observação solar, direta ou indireta, devido ao uso de drogas alucinógenas, distúrbios psíquicos ou durante eclipses. Pode haver, ou não, perda de acuidade visual. Relata-se o caso de uma paciente, 38 anos, com quadro de retinopatia solar em olho esquerdo, sem história prévia de exposição solar, apresentando acuidade visual normal e queixa de metamorfopsia. A tomografia de coerência óptica mostrou ruptura do epitélio pigmentar da retina, confirmando retinopatia solar padrão II. A acuidade visual tende a normalizar-se entre 3 a 9 meses, mas nem sempre. Assim, enfatiza-se a necessidade de orientação à população sobre proteção ocular durante exposição solar pela possibilidade de existirem pessoas com susceptibilidade elevada ao dano retiniano, como se presume possa ter ocorrido com esta paciente. Finalmente, destaca-se a importância da tomografia de coerência óptica para o diagnóstico da retinopatia solar.

Keywords: Retina/pathology; Sunlight/adverse Effects; Visual Acuity/radiation ef­­­­­­­ fects; Retinitis/etiology; Tomography, optical coherence/classification; Case report

Descritores: Retina/patologia; Luz solar/efeitos adversos; Acuidade visual/efeitos da ra­­­­­­ dia­­­­ção; Retinite/etiologia; Tomografia de coerência óptica/classificação; Relato de caso

INTRODUCTION Solar retinopathy, also known as photomaculopathy, eclipse re­­­­­­ tinopathy and foveomacular retinitis, is retinal damage resulting from direct or indirect solar observations during a solar eclipse or on a normal day(1). Light can damage the retina via mechanical, thermal or photochemical means, either alone or in combination. Photoche­ mical damage (actinic) occurs during prolonged low irradiance ex­ posure that lasts more than 10 seconds(2). Retinal impairment can be mild or severe(3). Young people are most vulnerable to damage(3). The earliest definitive report was in the eighteenth century and involved five cases of maculopathy due to exposure to the sun, fire or snow(4). The objective of the present study is to report the case of a patient suffering from solar retinopathy and to discuss its disease etiology and prevention. 

in either eye and no fundoscopic changes in the RE, but there were changes in the retinal pigment epithelium (RPE) in the macular area of the LE. Optical coherence tomography (OCT) was performed that same day and indicated that there was an interruption of the inner hyperreflective layer (I-HRL) and an absence of reflectivity of the underlying layer, which is consistent with solar retinopathy (Figure 1). The patient returned after 45 days to undergo fluorescein an­­ gio­­­­­­­graphy, which was normal (Figure 2). The patient had stable vi­­­ sual acuity and was asked to return in six months to repeat exams. The OCT showed the same alteration in the left eye (Figure 3). The retinography and the retinal fluorescein remained normal (Figure 4).

CASE REPORT A.M.R.B., 38, female, white, married, complained of metamorphopsia in the left eye for five months. The patient denied using medication regularly, having any systemic diseases or having a history of abnormal solar exposure. Upon physical examination, the patient had 20/20 visual acuity in both eyes, including -4.75 sph. -0.50 cyl. at 20° in the right eye (RE) and -5.25 sph. in the left eye (LE). Biomicroscopy showed no changes

Submitted for publication: March 21, 2013 Accepted for publication: May 23, 2013 Study carried out at Universidade do Oeste do Estado de Santa Catarina. - UNOESC, Campus Joaçaba, (SC), Brazil. Physician, Universidade do Oeste do Estado de Santa Catarina - UNOESC - Campus Joaçaba (SC), Brazil. 2 Medical Student, Universidade do Oeste do Estado de Santa Catarina - UNOESC - Campus Joaçaba (SC), Brazil. 1

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DISCUSSION Solar retinopathy is multifactorial and is dependent on photo­ biology, personal susceptibility, exposure time and geophysical con­­­ditions(5). The incidence of solar retinopathy is low and is not always related to a history of sun exposure(1). The observation of solar eclipses, hallucinogenic drug use and psychiatric disorders can explain most exposures(6). The thermal effect of microscope light or indirect ophthalmoscope light can cause retinal damage similar to that of solar exposure(7). In 1978, three cases of solar retinopathy with minimal exposure were reported as being due to the patients’ high

Funding: No specific financial support was available for this study. Disclosure of potential conflicts of interest: R.A.Stock, None; S.L.Savaris, None. E.C.R.Lima Filho, None; E.L.Bonamigo, None. Corresponding author: Elcio Luiz Bonamigo. Rua Francisco Lindner, 310 - Joaçaba (SC) - 89600-000 - Brazil - E-mail: [email protected] Ethics Committee: Ruling No 102.613/2012 of the Committee on Ethics in Research at the Uni­­ versity of the West of Santa Catarina State (Comitê de Ética em Pesquisa da Universidade do Oeste de Santa Catarina - UNOESC).

Stock RA, et al.

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B Figure 1. A) Normal optical coherence tomography (OCT) of the right eye. B) Optical coherence tomography (OCT) of the left eye showing an interruption in the inner hyperreflective layer (I-HRL) and an absence of reflectivity of the underlying layer.

Figure 3. Follow up after six months: A) Normal optical coherence tomography (OCT) of the right eye. B) Optical coherence tomography (OCT) of the left eye showing an interruption in the inner hyperreflective layer (I-HRL) and an absence of reflectivity of the underlying layer.

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Figure 2. Retinography and normal retinal fluorescein angiogram of the right eye (A and B). Retinography and normal retinal fluorescein angiogram of the left eye (C and D).

Figure 4. Follow up after six months showing retinography and normal retinal fluorescein angiogram of the right eye (A and B). Retinography and normal retinal fluorescein angiogram of the left eye (C and D).

susceptibility(8). In the present case report, the patient denied having abnormal light exposure. The ocular optical system functions as a magnifying glass, converging light rays onto the macula and explaining the generation of photic injury(7). Susceptibility to damage varies between individuals(9). Young people are more vulnerable because of the greater transparency of their lens although their capacity for regeneration is greater(9). Patients exposed to abnormal luminosity may have visual loss or be asymptomatic(1). In case reports of solar retinopathy, symptoms begin a few hours after direct observation of the sun(5). In most cases,

patients present with asymmetric bilateral impairment and reduced visual acuity from 20/40 to 20/80, which may decline to 20/200 or worse in severe injuries(5). Symptoms including glare, central or paracentral scotoma, migraine and metamorphopsia typically follow exposure(5,7). In the present case report, the patient’s only symptom was metamorphopsia. The macula may appear normal on ophthalmoscopic images im­­­mediately following exposure(5). After 24 hours, there may be a loss of the foveal reflex or grayish thickening of the retinal pigment epithelium(5). These symptoms tend to disappear within a week and a yellowish injury appears in the fovea(1,5,10). After 14 days, the lesion is

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replaced by a lamellar or juxtafoveolar defect with well-demarcated reddish irregular edges, which may resolve in mild cases(1,5,9). Some authors consider this lamellar defect of solar retinopathy to be pathognomonic(8). Fluorescein angiography may indicate early infiltration in the fovea centralis in the acute phase of the disease, and a retinal pigment epithelial window defect may appear at later stages(10). However, in most cases, as in the present case, there is no change(9). The diagnosis can be confirmed using clinical history and a fundoscopy. However, the advent of OCT has helped to both confirm a diagnosis, assess the extent of the lesion and monitor its progression(2,6). In the present case, the OCT examination detected a rupture of the pigment epithelium. Foveal alterations in solar retinopathy that are diagnosed using third-generation optical coherence tomography (Stratus OCT) are divided into three classes: (I) fragmentation of the inner hyperreflective layer (I-HRL) and fusion of the inner and outer hyperreflective (O-HRL) layers without spaces, which is manifest in the absence of reflectivity; (II) an interruption of the I-HRL and a lack of reflectivity of the underlying layer, which is usually hypo-reflective and corresponds to the photoreceptor outer segment, and the reflectivity of the layer of photoreceptor nuclei, which are located internally or overlying the I-HRL, is preserved; (III) changes in group II combined with a lack of reflectivity in the inner layer of I-HRL, which is normally hypo-reflective and corresponds to the photoreceptor nuclei(2). The present case report was consistent with the pattern of class II solar retinopathy. Solar retinopathy usually has a favorable prognosis, and visual acuity returns to 20/20 or 20/40 levels within 3 to 9 months(9). Currently, there is no effective treatment, and patients are monitored until they achieve visual stabilization(6,10). Exposure to sunlight because of observing an eclipse, drug use for religious reasons or microscope and ophthalmoscope light are

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the main causes of solar retinopathy and are all easily preventable. However, the present case, which was not the result of eye injury based on the angiographic examination or a history of abnormal light exposure, emphasizes the value of OCT in diagnosing solar re­­­­­­­­tinopathy and alerting individuals to the possibility that they are highly susceptible to damage. These results highlight the need to educate individuals about preventive measures and recommend that they reduce the duration of their exposure to light and use protective eyewear with effective filters. REFERENCES 1. Comander J, Gardiner M, Loewenstein J. High-resolution optical coherence tomography findings in solar maculopathy and the differential diagnosis of outer retinal holes. Am J Ophthalmol. 2011;152(3):413-9. 2. Farah ME. Tomografia de coerência óptica: OCT. 2nd ed. Rio de Janeiro: Cultura Médica: Guanabara Koogan; 2010. 3. Mainster MA. Solar eclipse safety. Ophthalmology. 1998;105(1):9-10. 4. Saint-Yves C. Nouveau traité des maladies des yeux, les remedes qui y conviennent, & les operations de chirurgie que leurs guerisons exigent avec de nouvelles decouvertes sur la structure de l’oeil, qui prouvent l’organe immnédiat de la vue. Paris: Chez Pierre-Augustin le Mercier; 1722. 5. Sampaio ER, Casella AM, Farah ME. Retinopatia solar após ritual religioso na cidade de Londrina. Arq Bras Oftalmol. 2004;67(2):271-5. 6. Pinheiro A, Souza EC, Moura FC, Vessani RM, Takahashi W. Estudo com tomografia de coerência óptica em pacientes com retinopatia solar. Rev Bras Oftalmol. 2004; 63(5/6):310-4. 7. Riordan-Eva P, Whitcher JP. Oftalmologia geral de Vaughan & Asbury. 17th ed. Porto Alegre: AMGH; 2011. 8. Gladstone GJ, Tasman W. Solar retinitis after minimal exposure. Arch Ophthalmol. 1978;96:1368-9. 9. Zisman M, Nehemy MB. Retinopatia solar: relato de 5 casos. Rev Bras Oftalmol. 1995; 54(9):43-8. 10. Kung YH, Wu TT, Sheu SJ. Subtle solar retinopathy detected by fourier-domain optical coherence tomography. J Chin Med Assoc. 2010;73(7):396-8.

Relato de Caso |

Case Report

Bilateral lineal endotheliitis: case report Endotelite linear bilateral: relato de caso Liliana Moreno Garcia1, Mauricio Vélez Fernandez2

ABSTRACT

RESUMO

To report the case of a patient with bilateral herpetic lineal endotheliitis successfully treated with topic steroids and systemic antiviral. 17 year old female with blurred vision, at evaluation localized edema was observed on both corneas associated to Descemet folds and a line of pigmented precipitates. Topic prednisolone and oral acyclovir are initiated with complete resolution of signs and symptoms. Lineal endotheliitis is produced as an answer of endotelial cells to viral infection; maybe due to an immune reaction against some antigens from herpes virus family. It has the potential of relapses even in the absence of viral replication, with secondary untreatable stromal edema. It responds well to antiviral and steroids treatment, although, on those patients who don’t improve, is necesary to make additional tests.

Relatar o caso de uma paciente com endotelite linear herpética bilateral tratado com sucesso por meio de corticoides tópicos e antivirais sistêmicos. Paciente do sexo feminino, 17 anos de idade, com a visão turva, na avaliação foi observado edema localizado em ambas as córneas associadas a dobras de Descemet e uma linha de precipitados ceráticos pigmentados. Prednisolona tópica e aciclovir oral foram utilizados com resolução completa dos sinais e sintomas. A endotelite linear é uma resposta das células endoteliais à infecção viral, talvez devido a uma reação imunológica contra alguns antígenos do vírus da família do herpes. Tem o potencial de recidiva, mesmo na ausência de replicação viral, com edema estromal secundário intratável. Ela responde bem ao tratamento antiviral e esteroides, embora, em pacientes que não melhoram, é necessária a realização de testes adicionais.

Keywords: Endothelium, corneal; Simplexvirus; Corneal edema/drug therapy; Prednisolone/therapeutic use; Acyclovir/therapeutic use; Humans; Male; Ado­­­ lescent

Descritores: Epitélio posterior; Simplexvirus; Edema da córnea/quimioterapia; Prednisolona/uso terapéutico; Aciclovir/uso terapéutico; Humanos; Feminino; Ado­­­­­­­­ lescen­­­t e

INTRODUCTION Corneal endothelium inflammation is known as endotheliitis, and the lineal type is believed as caused by virus from the family Herpesviridae such as Herpes simplex, Citomegalovirus and Varicella zoster virus. It was first described in 1985 by Robin in a patient with intraocular inflammation associated with Herpes simplex infection and progressive endotheliitis with a line of keratic precipitates(1). There are reports of some idiopathic or autoimmune forms of endotheliitis in which they failed in detecting the virus as responsible cause, that’s why some authors believed this was immunologically mediated or presumed autoimmune(2-4). The involvement of corneal endothelium secondary to Herpes simplex infection is classified in lineal, diffuse and disciform based on the distribution of keratic precipitates and the configuration of the overlying stromal and epithelial edema. The lineal form is clinically seen as localized progressive corneal edema from the periphery to the center along with a line of keratic precipitates and associated with mild inflammatory anterior chamber reac­­tion(3). The successful treatment with topic or systemic antiviral and steroids has been reported(2,4-6). Recurrences are associated with lost of endothelial cells that can generate permanent and irreversible corneal edema.

She consulted at cornea service after presenting ten days of blurred vision in both eyes; this was the first episode, associated to redness, photophobia and mild ocular pain. No history of systemic disease was recorded, only previous mild contusive trauma on right eye two months ago without consequences. Currently is not under systemic or topic treatment. Clinical exam reveals visual acuity by right eye counting fingers and left eye 20/100 with Snellen chart. We could observe in both eyes corneal edema localized at superior two thirds (Figure 1), Descemet´s membrane folds along with a line of pigmented keratic precipitates at the border of the edema, and details of anterior chamber reaction could not be noted because of the opacity (Figure 2); there was not epithelial defect identified or marks of an old dendritic keratitis. Intraocular pressure (IOP) was measured at 12 mmHg on both eyes. The rest of the exam was normal. With the clinical suspect of lineal endotheliitis, we decided to initiate treatment with oral acyclovir 400 mg, five times per day, and pred­­­­nisolona 1%, every 4 hours in both eyes. Serologic analysis for immunoglobulins G and M of Herpes simplex virus (HSV), cytomegalovirus (CMV), Human Immunodeficiency virus (HIV) and endothelial count were requested. After first week of treatment, the patient manifested improvement in symptoms and in vision; we could document visual acuity (VA) of 20/20 in right eye and 20/25 in left eye and the corneal edema was absent, in endothelium remained few pigmented precipitates and mild anterior chamber reaction (Figure 3). Unfortunately the patient could not make her blood tests, but because of the good clinical response, we decided

CASE REPORT Here we report the case of a 17 year old female patient, immunocompetent, from Apartadó (located at Northeast of Colombia).

Submitted for publication: April 27, 2013 Accepted for publication: May 24, 2013

Funding: No specific financial support was available for this study.

Study carried out at Universidad Pontificia Bolivariana, Medellín, Colombia.

Correspondence address: Liliana Moreno García. Transversal 38 # 72-148, Apto. 201 - Edificio Torre Lujo. Medellín (Antioquia), Colombia - E-mail: [email protected]

1 2

Ophthalmology Resident, Universidad Pontificia Bolivariana, Medellín. Ophthalmologist - Cornea, profesor, Universidad Pontificia Bolivariana, Medellín.

Disclosure of potential conflicts of interest: L.M.Garcia, None; M.V.Fernandez None.

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to continue oral acyclovir until two weeks were completed and taper of steroids.

DISCUSSION We perform a search on data bases of lineal endotheliitis. There are various mechanisms of ocular disease associated to HSV infection including direct cell damage of live viruses, immune and inflammatory mechanisms or structural damage. On the spectrum of herpetic corneal infection, endothelial involvement is classified according to the configuration of stromal and epithelial secondary edema and the distribution of the keratic precipitates in disciform, difuse or

Figure 1. Right eye with stromal edema and Descemet folds over keratic precipitates.

Figure 2. Right eye in retroillumination, keratic precipitates can be observed.

Figure 3. Right eye after one week of treatment.

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lineal. Clinical manifestation of endotheliitis includes ocular pain, pho­­­­­­­tophobia, conjunctival injection, visual compromise and often there is not history of previous infectious epithelial keratitis(3). Most common form of presentation is disciform that usually is central; the difuse is harder to treat for poor response to standard management and finally the lineal is characterized for localized stromal edema that initiates in the corneal periphery and advances towards the center, associated to a line of keratic precipitates delimitating the edema, it might be circumferential or sectorial reminding the reject line after corneal transplant described by Khodadoust(2). In some cases can be observed satellite lesions of keratic precipitates organized in nummular forms (coin) outside the line of precipitates and have been related to CMV infection(4-6); also some times the IOP could rise in an intermittent way. It has been described bilateral compromise in the third part of patients and mostly found the HSV as causal agent in these cases(1). Statements in favor of endothelium being the site of inflammation and no the stroma, are the fact that the only stromal finding is edema located over the damaged endothelium delineated with pigmented precipitates, and stromal infiltration and neovascularization signs of stromal inflammation are notably absent; a consequence of this chronic inflammation are the lost of endothelial cells and un­ treatable corneal edema(3). Pathophysiology that explains the direct effect on the endothe­ lium and therefore clinical symptoms has been studied. In 1985 Ro­­­­ bin et al., isolated for the first time HSV from a sample of aqueous humor of a patient with progressive endotheliitis(1). Latter there were reports of various cases where HSV, CMV, varicella zoster virus (VZV) were found by polymerase chain reaction from aqueous humor from immunocompetent and immunosupressed patients with characteristics similar to lineal endotheliitis(5-8). In cases in which etiology agent could not be found have been attributed to a immune mediated reaction, some have associated it to connective tissue diseases as lupus, scleroderma, and Sjogren syndrome(2,7). Some observations that support this hypothesis are the similitude of the precipitates line found on this entity and the endothelial rejection line seen on penetrating keratoplasty, also the fact that steroids are essential for the success of the treatment. Experimental models have shown the presence of an “anterior-chamber associated immune deviation (ACAID)” that refers to a relative diminished or suppression of cell mediated immune response, but the humoral response intact. The anterior chamber of rabbits was sensitized with inactivated virus, thereafter live virus were inocula­ ted and local edema associated to endothelial precipitates and mild anterior chamber reaction were observed. It is presumed that once exists a latent infection and this is intermittently activated, a variable charge of live virus reach the anterior chamber and develop a reaction against viral antigens, endothelium infection happens when previous formed antibodies are unable to neutralize live virus. This phenomenon shares characteristics with Posner Scholssman syndrome associated with HSV infection in which the primary site of infection is the trabeculum or as Fuch´s heterochromic iridociclitis(4). Corneal edema progression from limbary periphery to the center, as in lineal endotheliitis, might be related with viral activation of the virus located on the trabeculum or ciliary body(5). Diagnosis usually is made by the presence of specific clinical signs but sometimes is necessary to make analysis from samples. Corneal biopsy taken previous to keratoplasty would be needed to make sure about the presence of the virus in endothelium, but this is not possible in most of cases and would not be practical. Polymerase chain reaction (PCR) of aqueous samples is a very important tool, however, it takes some difficulties related to de little volume extracted from anterior chamber, and this affects the manipulation of the sample. In vivo confocal microscopy findings have revealed the presence of cells that resemble the characteristic owl´s eye (acidophilic intranuclear inclusion bodies) related to HSV infection(4).

Garcia LM, Fernandez MV

Oral acyclovir has been reported as treatment given 200-800 mg five times a day and in cases of CMV infection, gancyclovir has been used. Steroids as oral prednisolona, associated to the antiviral, have been given 60 mg daily with gradual tapering according to clinical answer. Topical steroids have been used as well. Variable visual out­­­comes have been reported even with aggressive treatment, it could be associated to endothelial lost secondary to inflammatory recurrences(4-8). On this case, the patient did not count with personal history of connective tissue diseases, nor previous history of presumed infective keratitis. Clinical presentation and dramatic response to treatment suggest clearly viral etiology, very probable by HSV, because of the bilateral involvement on an immunocompetent patient. The primary cause of this kerato-uveitis in absence of epithelial defect or history of this is unknown, however we can not dismiss the possible presence of live virus in ocular tissues after an asymptomatic primo infection, that has been reported in literature(3). We consider that in our case, additional studies as PCR of aqueous humor, would not be justified because the procedure to take that samples require ocular puncture with all the risks it takes, and the clinical response was adequate after only one week after initiation. Here we report the first episode on this patient, and maybe that is why the visual outcomes where the best with the standard treatment. Is reasonable to observe the patient in time for the possibility of recurrences and progressive endothelial lost with not so good response to subsequent treatment.

Lineal endotheliitis is a corneal endothelial cell response to vi­­ral infection and can be associated to immune reaction. It has the potential of recurrences even without viral replication, loss of endothelial cells and secondary vision decrease. It has clinical response to oral acyclovir and topic steroids treatment; in those patients, who could not get adequate response is indicated to take additional exams like aqueous humor PCR to make a precise diagnosis and start oriented therapy. Serologic tests for CMV, HIV, and HSV should be made as part of the complete study of the patient and don’t discard the immune role. REFERENCES 1. Robin JB, Steigner JB, Kaufman HE. Progressive herpetic corneal endotheliitis. Am J Ophthalmol. 1985;100(2):336-7. 2. Hori Y, Maeda N, Kosaki R, Inoue T, Tano Y. Three cases of idiopathic ‘multiple-parallelli­ne’ endotheliitis. Cornea. 2008; 27(1):103-6. 3. Holland EJ, Schwartz GS. Classification of herpes simplex virus keratitis. Cornea. 1999; 18(2):144-54. 4. Suzuki T, Ohashi Y. Corneal endotheliitis. Semin Ophthalmol. 2008;23(4):235-40. 5. Koizumi N, Suzuki T, Uno T, Chihara H, Shiraishi A, Hara Y, et al. Cytomegalovirus as an etiologic factor in corneal endotheliitis. Ophthalmology. 2008;115(2):292-7. 6. Koizumi N, Yamasaki K, Kawasaki S, Sotozono C, Inatomi T, Mochida C, et al. Cytomegalovirus in aqueous humor from an eye with corneal endotheliitis. Am J Oph­­­thalmol. 2006; 141(3):564-5. 7. Shen YC, Wang CY, Chen YC, Lee YF. Progressive herpetic linear endotheliitis. Cornea. 2007;26(3):365-7. 8. Hwang YS, Hsiao CH, Tan HY, Chen KJ, Chen TL, Lai CC. Corneal endotheliitis. Ophthalmology. 2009;116(1):164.

16o Congresso de Oftalmologia USP e 15o Congresso de Auxiliar de Oftalmologia 29 e 30 de novembro de 2013 Centro de Convenções Rebouças São Paulo (SP)

Informações: Secretaria Executiva Organização de Eventos JDE Tels.: (11) 5082-3030 / 5084-9174 Site: www.jdeeventos.com.br / www.oftalmologiausp.com.br

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Case Reports

Traumatic avulsion of extraocular muscles: case reports Avulsão traumática de músculos extraoculares: relatos de casos Nilza Minguini¹, Karin Suzete Ikeda², Keila Monteiro de Carvalho³

ABSTRACT

RESUMO

We described the clinical, surgical details and results (motor and sensory) of the retrieving procedure of traumatically avulsed muscles in three patients with no pre­­­vious history of strabismus or diplopia seen in the Department of Ophthalmolo­­­ gy, State University of Campinas, Brazil. The slipped muscle portion was reinserted at the original insertion and under the remaining stump, which was sutured over the reinserted muscle. For all three cases there was recovery of single binocular vision and stereopsis.

Foram descritos os quadros clínicos, detalhes cirúrgicos e resultados (motores e sensoriais) da reinserção de músculos traumaticamente avulsionados, em três pacientes sem estória prévia de estrabismo ou diplopia, atendidos no Departamento de Oftalmologia da Universidade Estadual de Campinas. A porção muscular deslizada foi reinserida na linha da inserção original e sob o coto remanescente, o qual foi acomodado e suturado sobre o músculo reinserido. Para os três casos houve recuperação da visão binocular única e da estereopsia.

Keywords: Eye injuries; Oculomotor muscles/injuries; Strabismus/surgery; Diplopia; Depth perception; Case reports

Descritores: Traumatismos oculares; Músculos oculomotores/lesões; Estrabismo/ cirurgia; Diplopia; Percepção de profundidade; Relatos de casos

INTRODUCTION Extraocular muscle avulsion of traumatic etiology is not frequent(1,2). The medial and inferior recti are the most frequently inju­­ red muscles. This has been explained by reflex reaction of up and out movement of the eye (Bells’ phenomenon) when eye injury is threa­­tening. Chances of retrieving a transected muscle are higher in cases of trauma comparing to inadverted transaction during muscle surgery, as their attachments to other extraocular muscles and nearby tissues are often preserved(2). Excluding the medial rectus that lacks attachment to another muscle, an intact muscle disinserted by trauma will typically be located in a sufficiently anterior position for a standard transconjunctival approach with no need of orbitotomy(3). Preoperative high resolution CT scans with proper techniques and magnetic resonance imaging can identify the damaged muscle in detail. The oculocardiac reflex is also an effective aid in identifying the tissue as muscle, during repairing surgery(4). In this series, we describe the clinical and surgical findings, repairing technique and the surgical results from three patients that were admitted to University of Campinas Clinical Hospital, Brasil, victims of ocular trauma and consequent muscle disinsertion.

emergency room complaining of double vision and limitation of mo­­­vement of her left eye. She had no previous history of strabismus or ambliopia. Examination on presentation revealed visual acuities of 20/20 in her right eye and 20/50 in her left eye. The patient had a large angle left exotropia and loss of left adduction. A tendon stump of approximately 2.5 mm could be observed through a medial bulbar conjunctival laceration. A retinal hemorrhage and a laceration of inferior lacrimal canaliculus were also noted. On surgical exploration rupture of the globe was not found. The lost medial rectus muscle could be located when oculocardiac reflex was observed with traction of the suspected tissue located at the equator. The tissue was then sutured at its original insertion point under the preserved tendon stump which was then blended and sutured over the reinserted muscle. The conjunctiva and lacrimal lacerations were also repaired. One week later alignment was straight in all positions of gaze with no limitation on ductions or versions. No double vision was present and a stereoacuity of 40 seconds of arc was measured. Retinal treatment was not necessary and visual acuity had normalized. (Figure 1).

CASE REPORT

Case 1 A 17-year-old female was victim of a dog bite in her left me­­ dial orbital region. Approximately two hours later, she came to the

Case 2 A 50-year-old, presented with exodeviation of the left eye, which suddenly developed after her face was struck with a suspended hook three hours previously. Visual acuity of this eye was reduced to 20/50 and adduction was severely limited. A 10 mm long, crescent-shaped, wound was seen in the medial conjunctiva and it was apparent that the medial rectus had been avulsed. At surgery it was possible to lo­­ calize and relocate the snapped muscle with the aid of oculocardiac reflex and using the same technique as in case 2. Motility and senso-

Submitted for publication: March 18, 2013 Accepted for publication: May 23, 2013

Funding: No specific financial support was available for this study

Study carried out at Universidade Estadual de Campinas - Unicamp - Campinas (SP), Brazil.

Correspondence address: Nilza Minguini. Departamento de Oftalmo/ORL - Hospital de Clínicas Unicamp. Rua Vital Brasil, 251 - Campinas (SP) - 13083-888 - Brazil E-mail: [email protected]

Assistant Physician, Department of Ophthalmology and Otorhinolaryngology, Faculty of Medical Sciences, Universidade Estadual de Campinas - Unicamp - Campinas (SP), Brazil. 2 Ophthalmologist and postgraduate student, Department of Ophthalmology and Otorhinolaryngo­­­­ logy, Faculty of Medical Sciences, Universidade Estadual de Campinas - Unicamp - Campinas (SP), Brazil. 3 Professor, Department of Ophthalmology and Otorhinolaryngology, Faculty of Medical Sciences, Universidade Estadual de Campinas - Unicamp - Campinas (SP), Brazil. 1

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Disclosure of potential conflicts of interest: N.Minguini, None; K.S.Ikeda, None; K.M.Carvalho; None

Research Ethical Commmittee, Universidade Estadual de Campinas - Unicamp, Campinas (SP), Brazil. Pratocol: no 013/2012

Minguini N, et al.

A

B Figure 1. Case 1 - Preoperative exotropia in primary position and limitation of adduction of the left eye (A). The same patient seven days after surgery (advancing the left medial rectus) showing no limitation of left eye adduction (B). Figure 3. Case 3 - Patient at two weeks of follow-up. Motility examination showing nor­­­­malized depression and a slight limitation of elevation. The reduced right palpebral fissure can be observed.

A

B Figure 2. Case 2 - Preoperative exotropia in primary position and limitation of adduction of the left eye (A). The same patient at sixty days after surgery (advancing the left medial rectus) showing a residual limitation of left eye adduction (B).

rial results were satisfactory. Although a moderate limitation of left eye adduction had persisted, primary position alignment and normal stereoacuity were recovered (Figure 2).

Case 3 A 58-year-old woman presented to the State University of Campinas Clinical Hospital complaining of double vision with a history of trauma in her right eye caused by a hook of a wire coat-hanger. On examination, best-corrected visual acuity was 20/40 in the right eye and 20/25 in the left. She had no history of strabismus or double vision before this accident. In primary position, the right eye was hypertropic and the infraduction of this eye was almost absent. A inferior bulbar conjunctival laceration was diagnosed and it became apparent that the inferior rectus muscle had been avulsed near its insertion, because there were 3mm of tendon hanging loose from the scleral insertion. No retinal lesions or hemorrhages were noted. The intraocular pressure was normal and rupture of the globe was considered unlikely. At surgery, performed 24 hours after the accident, the proximal portion of the muscles could not be easily found. No ocular-cardiac reflex was presented when traction was done on any suspected tissue, except when the inferior oblique was hooked. Then, amounts of lacerated and swollen tissues above the inferior oblique were brought to the inferior rectus insertion and sutured bellow the remaining portion of tendon with 6-0 VicrylTM. The tendon stump was blended and sutured over the supposed newly sutured muscle belly. At two weeks of follow up, motility examination showed that depression was normalized, but a slight limitation of elevation was found. No double vision was present in primary and down gaze positions. Visual acuity was bilaterally normal. Stereoacuity of 40 seconds of arc was measured. Further surgery for repairing reduced palpebral fissure has been rejected by the patient (Figure 3).

DISCUSSION A severed nerve to an extraocular muscle, or a crushed muscle must always be considered as differential diagnosis of a transected muscle in cases of strabismus due to ocular trauma. In this series, tendon stumps at the insertion sites were incontestable evidences of the right diagnosis rationale. Certainly, the surgical technique employed in this series, as it had resembled a resection procedure, had induced a change in both load and length/tension muscle properties. However, there must have been a muscle adaptation which can explain the efficacy of the procedures for the three reported cases, all of them ending up with maximal grade of stereopsy. The time limit during which a muscle may be recovered with good function is unknown(5,6). Wright had suggested that the procedure should be done as soon as 7 to 10 days after the traumatic event(5). In this series, the surgeries were performed at 1 to and 3 days after trauma, fact that should have corroborated the good sensorial and motor results. There were not requested imaging studies for the patients of this series. Some authors feel diagnostic imaging do not need to be done routinely for cases of slipped or lost muscles(7). In agreement with them, we also consider that these tests did not prove to be essential for the cases reported, since clinical signs were considered sufficient for surgical planning. REFERENCES 1. Plagger DA, Parks MM. Recognition and repair of the “lost” rectus muscle. A report of 25 cases. Ophthalmology. 1990;97(1):131-6. 2. MacEwen CJ, Lee JP, Fells P. Aetiology and management of the ‘detached’ rectus muscle. Br J Ophthalmol. 1992;76(3):131-6. 3. Knapp P. Lost muscle. In: Symposium on strabismus: transactions of the New Orleans Academy Ophthalmology. St Louis: CV Mosby; 1978. p.301-6. 4. Apt L, Isenberg SJ. The oculocardiac reflex as a surgical aid in identifying a slipped or ‘lost’ extraocular muscle. Br J Ophthlamol. 1980;64(5):362-5. 5. Wright KW. Discussion. Ophthalmology. 1990; 97(1):136-7. [discussion on: Plagger DA, Parks MM. Recognition and repair of the “lost” rectus muscle. A report of 25 cases. Ophthalmology. 1990;97(1):131-6]. 6. Underdahl JP, Demer JL, Goldberg RL, Rosembaum AL. Orbital wall Approach with preoperative orbital imaging for identification and retrieval of lost or transected extraocular muscles. J AAPOS. 2001;5(4):230-7. 7. Greenwald MJ, Ticho BH, Engle JM. Extraocular muscle surgery. In Krupin T: Atlas of Complications of Ophthalmic Surgery. London: Wolfe; 1993. p.11-5.

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Relato de Caso |

Case Report

Unusual early recurrence of granular dystrophy after deep anterior lamellar keratoplasty: case report Recorrência atípica e precoce de distrofia granular após transplante lamelar profundo: relato de caso Paolo Rama1, Karl Anders Knutsson1,2, Carmen Rojo2, Paola Carrera3,4, Maurizio Ferrari3,4,5

ABSTRACT

RESUMO

We report an atypical case of granular corneal dystrophy recurrence after deep anterior lamellar keratoplasty. We describe clinical features, histopathological analysis of the lamellar graft specimen and DNA analysis results. The slit-lamp examination and histopathological findings from the graft specimen indicated the confinement of the typical deposits of granular corneal dystrophy deep in the graft interface area. This localization is atypical, since in most cases recurrences in grafts tend to be initially superficial and situated in the epithelial or subepithelial corneal layers. Molecular genetic analysis revealed an already described mutation and a new intronic variant. The unusual localization and timing of this recurrence of granular corneal dystrophy after deep anterior lamellar keratoplasty suggests that corneal stromal keratocytes may play a role in the formation of granular deposits.

É relatado um caso atípico de recorrência de distrofia corneana granular após transplante lamelar anterior profundo. São descritas as características clínicas, a análise histopatológica do espécime do enxerto lamelar e os resultados de análises de DNA. O exame com lâmpada de fenda e a análise histopatológica do espécime do enxerto demonstram o confinamento dos depósitos típicos da distrofia corneana granular profundamente, na área de interface do enxerto. Esta localização é atípica, uma vez que, na maioria dos casos de recidivas em enxertos, estes tendem a ser no início localizados superficialmente, nas camadas epiteliais ou subepitelial da córnea. A análise genética molecular revelou uma mutação já descrita e uma nova variante intrónica. A localização incomum e o tempo de aparecimento da presente recorrência da distrofia corneana granular após transplante lamelar anterior profundo sugere que ceratócitos do estroma corneano possam desempenhar algum papel na formação dos depósitos granulares.

Keywords: Corneal transplantation; Corneal dystrophies, hereditary; Cornea/ pa­­­­­­thology; Corneal stroma; Corneal keratocytes; Epithelium, corneal/cytology; Re­­­­­­­­­­­­­currence

Descritores: Transplante de córnea/efeitos adversos; Distrofias hereditárias da córnea; Córnea/patologia; Substância própria; Ceratócitos da córnea; Epitélio anterior/ citologia; Recidiva

INTRODUCTION Granular corneal dystrophy (GCD) is a bilateral autosomal domi­ nant corneal dystrophy characterized by small, breadcrumb-like, grayish-white, stromal opacities(1). In early stages, lesions occupy the anterior central stroma, but later can coalesce and occupy deeper stromal layers(2).Visual function usually remains good until the fifth decade and most patients require no treatment as visual acuity remains adequate for their needs. However, if opacities become denser and occupy the visual axis, corneal transplantation may be necessary. Most authors agree that typical recurrences are superficial and early involvement is noted to be central and epithelial(2). Later on, the recurrent material adopts the classic breadcrumb-like appearance of GCD, gradually involving subepithelial and stromal layers. Lyons et al.(2), reported that the time of recurrence can range from 13 to 73 months and shows no significant difference between penetrating keratoplasty (PK) and lamellar keratoplasty (LK). This case report des-

cribes the clinical, histopathological and molecular genetic findings of an atypical case of GCD recurrence.

Submitted for publication: February 1, 2013 Accepted for publication: May 8, 2013

Funding: No specific financial support was available for this study.

Study carried out at San Raffaele University, Milano, Italy. Ophthalmology - Cornea and Ocular Surface Unit, San Raffaele Scientific institute, Milano. Department of Ophthalmology, San Raffaele Scientific Institute, Milano. Genomic Unit for the Diagnosis of Human Pathologies, Center for Genomics, Bioinformatics and Biostatistics, San Raffaele Scientific Institute, Milano. 4 Diagnostica e Ricerca San Raffaele SpA, Milano. 5 Vita-Salute San Raffaele University, Milano. 1 2 3

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METHODS The corneal specimen was stained with hematoxylin and eosin, Congo red, Masson trichrome and periodic acid-Schiff (PAS). After pre-test genetic counseling, the patient gave her consent to the molecular analysis. Genomic DNA was extracted from a peripheral blood leukocyte sample using standard protocols. Transforming growth factor beta-induced gene (TGFBI also known as BIGH3) whole coding region and exon junctions were analyzed by directly sequencing specific polymerase chain reaction (PCR) products on both strands. Dye terminator reaction sequences were loaded on a 3730AB (Applied Biosystems, Foster City, CA) automatic sequencer. Sequences were assembled and compared to the reference

Disclosure of potential conflicts of interest: P.Rama, None; K.A.Knutsson, None; C.Rojo, None; P.Carrera, None; M.Ferrari, None. Corresponding address: Rama Paolo. Via Olgettina 60. San Raffaele Hospital - Cornea and Ocular Surface Unit - Milano, Italy - E-mail: [email protected] The study was performed with informed consent and following all the guidelines for experimental investigations required by the Institutional Review Board or Ethics Committee of which all authors are affiliated.

Rama P, et al.

ENSG00000120708 with the Sequencer V.4 (GeneCodes Co., Ann Arbor, MI). RESULTS

Clinical findings A 43-year-old Caucasian female was diagnosed with advanced GCD. Best spectacle-corrected visual acuity (BSCVA) was 0.2 (20/100) for the right eye and 0.5 (20/40) for the left eye. In January 2000, she underwent deep anterior lamellar keratoplasty (DALK) on the right eye, with no complications. During the six month follow-up, BSCVA was 0.63 (20/30) and on slit-lamp examination she presented an early recurrence of corneal opacities in the host-donor interface (Figure 1). Progressive worsening of the disease required PK in March 2001 on the same eye. After two years, minor recurrence developed, initially involving the subepithelial corneal layers and later the superficial stroma. In October 2005, PK was performed on the left eye and minor epithelial recurrence was observed after a period of two years.

Histology report Deep stromal deposits were observed at the host-donor interface. They were eosinophilic in tissue samples stained with hematoxylin and eosin and had a bright red color in samples stained with Masson trichrome (Figure 2). Sections stained with PAS and Congo red were negative and the granules lacked birefringence on polarization.

Figure 1. Recurrence of multiple corneal opacities at the host-donor interface of the lamellar graft.

Figure 2. Histopathological section of the lamellar graft with deep stromal deposits at the host-donor interface. (Masson trichrome original magnification x 150).

Molecular genetic analysis Sequence analysis revealed the presence of TGFBI heterozy­­­­gous variants: i) the c.1663C>T transition resulting in the p.Arg555Trp mis­­­sense substitution in the putative protein, already described in association with corneal dystrophy, particularly the GCD type 1 (Groenouw’s type 1 granular corneal dystrophy) (1); ii) a novel intronic variant IVS16-5T>C; iii) a number of known variants reported in dbSNP as polymorphisms (IVS6+119A>G, IVS7+47T>C, c.981A>G, IVS10-43A>G, c.1417C>T, IVS11-252T>C, c.1620T>C, IVS12+23G>A, IVS13-71A>G, IVS13-54T>A, IVS14+44T>C, IVS15-73G>A). The patient reported paternal-side family history; however, we could not analyze her aged parents. DISCUSSION Mutations in the TGFBI gene on chromosome 5q31 are associated with phenotypically distinct corneal dystrophies, including GCD(1). The transforming growth factor-beta induced protein, also known as keratoepithelin (KE), is an adhesion protein which is strongly expressed by the corneal epithelium, by other corneal cells in minor quantities and is a component of the extracellular matrix in many tissues. It is secreted by corneal epithelial cells and can be found in normal stroma, covalently bound to type VI collagen. KE is a small molecule, about the size of albumin, which allows diffusion from its epithelial source to the stroma. Cases of deep stromal involvement in suture canals and the host-do­nor interface have been reported(3,4), but are less common than superficial recurrences(2). In our case, the opacities were atypical as they recurred after a short period of time (6 months) and occurred only in the deep layers of the host-donor interface. Numerous mechanisms could explain this particular case. Mutated KE secreted by epithelial cells can diffuse across the graft-host junction and localize in the deeper stromal layers at the interface. Alteration of the host keratocytes might be responsible for the localization of the deposits in the stroma. Alternatively, host keratocytes could be directly responsible for the deposition of the material. Production of abnormal material has been reported after LASIK in patients with Avellino corneal dystrophy(5) and radial keratectomy in a patient with GCD(6). In these cases, collagen damage may determine keratocyte activation, favoring the production of deposits, and an identical mechanism could be hypothesized for eyes that undergo DALK surgery. In our patient, molecular analysis revealed the presence of se­­veral variants, mostly common polymorphisms; in addition the p.Arg555Trp mutation and a new intronic unclassified variant (IVS16-5T>C) were detected. The p.Arg555Trp has been reported several times and noticeably, if compared to other TGFBI mutations, it has been correlated with a lower severity(7) as assessed by age at first graft and time to recurrence. On the contrary, a higher degree of severity has been described in patients homozygous for the p.Arg555Trp. In our patient, we observed a rather severe phenotype, characterized by early onset and multiple recurrences; we would argue that the IVS16-5T>C, located near the splice acceptor site of intron 16 might possibly have a negative influence on the splicing process. Great advances have been made in the characterization of stromal corneal dystrophies, especially after the discovery of various mu­­­tations in the TGFBI gene and the different phenotypic alterations that can arise. Almost all studies point to an epithelial origin of the deposits, as KE is indeed produced by these cells. However, no studies have been able to explain how KE deposits accumulate in the stromal layers. Our case is unique because the deposits localize at the host-donor interface over a short period of time, suggesting that the host keratocytes might play a role in the formation of the characteristic deposits.

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ACKNOWLEDGEMENTS Special thanks to Dr. Pietro Maria Donisi of the Department of Pathology, General Hospital of Venice, Italy. REFERENCES 1. Klintworth GK. Corneal dystrophies. Orphanet J Rare Dis. 2009;4:7. 2. Lyons CJ, McCartney AC, Kirkness CM, Ficker LA, Steele AD, Rice AS. Granular corneal dystrophy. Visual results and pattern of recurrence after lamellar or penetrating keratoplasty. Ophthalmology. 1994;101(11):1812-7.

3. Salouti R, Hosseini H, Eghtedari M, Khalili MR. Deep anterior lamellar keratoplasty with Melles technique for granular corneal dystrophy. Cornea. 2009; 28(2):140-3. 4. Frising M, Wildhardt G, Frisch L, Pitz S. Recurrent granular dystrophy of the cornea: an unusual case. Cornea 2006; 25: 614-7. 5. Roh MI, Grossniklaus HE, Chung SH, Kang SJ, Kim WC, Kim EK. Avellino corneal dys­­ trophy exacerbated after LASIK: scanning electron microscopic findings. Cornea. 2006;25(3):306-11. 6. Feizi S, Pakravan M, Baradaran-Rafiee AR, Yazdani S. Granular corneal dystrophy manifesting after radial keratotomy. Cornea. 2007;26(10):1267-9. 7. Ellies P, Renard G, Valleix S, Boelle PY, Dighiero P. Clinical outcome of eight BIGH3-lin­ ked corneal dystrophies. Ophthalmology. 2002;109(4):793-7.

XXXIII Congresso do Hospital São Geraldo 30 de outubro a 2 de novembro 2013 Dayrell Hotel & Centro de Convenções Belo Horizonte (MG)

Informações: Tel.: (31) 3342-3888 E-mail: [email protected] Site: www.hospitalsaogeraldo.com.br

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Artigo de Revisão |

Review Article

Dry eye disease caused by viral infection: review Olho seco causado por infecções virais: revisão Monica Alves1,2, Rodrigo Nogueira Angerami3, Eduardo Melani Rocha1

ABSTRACT

RESUMO

Dry eye disease and ocular surface disorders may be caused or worsened by viral agents. There are several known and suspected virus associated to ocular surface diseases. The possible pathogenic mechanisms for virus-related dry eye disease are presented herein. This review serves to reinforce the importance of ophthalmologists as one of the healthcare professional able to diagnose a potentially large number of infected patients with high prevalent viral agents.

A síndrome do olho seco e as doenças de superfície ocular podem ser causadas ou agravadas por agentes virais. Diversos vírus são causadores ou tem associação suspeitada com as doenças de superfície ocular. Esta revisão apresenta os possíveis mecanismos patogênicos envolvidos no olho seco causado por infecões virais e reinforça a importância do oftalmologista como um dos profissionais de saúde capazes de diagnosticar um grande número de pacientes infectados por agentes virais altamente prevalentes.

Keywords: Dry eye syndromes/diagnosis; Eye infections, viral; Eye infections

Descritores: Síndromes do olho seco; Infecções oculares virais; Infecções oculares

INTRODUCTION Dry eye disease (DED) and ocular surface disorders may be cau­­­­sed or worsened by viral agents. There are several known and suspected virus associated to DED(1-3). The pathogenic mechanisms and therapeutic approach for virus-related DED are reviewed herein. The ocular surface comprises a unique and vital component of vision. The interface composed by cornea transparency and the tear film is a major refractive surface of the visual system(4-6). All components of the ocular surface are intrinsic linked by the continuity of the epithelia to the tear film and by the reflex innervation and the endocrine, vascular and immune systems. The synergic function of the ocular surface components and the harmonic influence of the sensory and motor nerves, hormones and fluids are responsible for the maintenance of a regular, comfortable and perfect refractive surface(7-9). In this context, viral infections might cause direct damage to the ocular surface, such as herpes virus or indirectly through interference in lacrimal gland function. DED is a widely prevalent and multifactorial disorder involving multiple interacting mechanisms and a great range of signs and symptoms. Dysfunction of any component of the ocular surface and/ or tear film can lead to dry eye causing lower tear secretion, alterations in its composition and distribution and eventually leading to epithelial damage and inflammation(4). Sjögren syndrome is one of the most complicated forms of DED. It is a chronic disease affecting exocrine glands, mainly lacrimal and salivary ones, but also organs and systems can be involved. It is characterized by an aggressive lymphocytic infiltration and circulating autoantibodies that lead to damage and dysfunction of glands and target organs(1). Although the pathogenesis of Sjögren Syndrome

is considered a multifactorial process, it has been postulated that some viral infection could play a significant role on initiating and/or perpetrating the autoimmune response(10). Viruses can trigger autoimmune reactions through several me­­­ chanisms affecting different tissues in both animal models and humans. Virus infection can induce neoantigen expression due to molecular mimicry between viral and host antigens resulting in the production of autoantibodies, cytotoxic T-cell or both directed to different host tissues(11). Once the innate immune response is initiated in glandular and dendritic cells there is an up-regulation of adhesion proteins and an increased production of chemokines that become activated and start acting as antigen-presenting cells. Those events could eventually lead to overproduction of immunoglobulins, autoantibodies and memory lymphocytes and subsequently tissue damage and dysfunction due to apoptosis and inflammation(12). The occurrence of Sjögren syndrome-like illness, reported as dry eye symptoms or signs, in patients having confirmed viral infections, such as human T-cell lymphotropic virus (HTLV), human immunodeficien­cy virus (HIV), Epstein-Barr virus (EBV), and hepatitis C virus (HCV), as well as the beneficial effect of anti-viral treatment, brings circumstantial evi­­­dence that their mechanism maybe pathogenically associated(3,13). The aim of this review is to summarize the knowledge on the role of virus infection in the pathogenesis of DED, plausible mechanisms and implications for diagnosis and therapeutic strategies.

Viral infections related do dry eye The best-studied viral agents related to systemic infection and DED manifestation are HTLV, HIV, HCV and EBV. Table 1 shows major characteristics of those viruses.

Submitted for publication: January 16, 2013 Accepted for publication: January 31, 2013

Funding: No specific financial support was available for this study.

Study carried out at Universidade de São Paulo, Ribeirão Preto (SP), Brazil.

Correspondence address: Monica Alves. Departamento de Oftalmologia, Otorrinolaringologia e Cirur­­­ gia de Cabeça e Pescoço. Faculdade de Medicina de Ribeirão Preto. Universidade de São Paulo. Av. Bandeirantes, 3900 - Ribeirão Preto (SP) - 14049-900 - Brazil E-mail: [email protected]

Universidade de São Paulo, USP - Ribeirão Preto (SP), Brazil. Pontifícia Universidade Católica de Campinas, PUC Campinas - Campinas (SP), Brazil. Universidade Estadual de Campinas, Unicamp - Campinas (SP), Brazil.

1 2 3

Disclosure of potential conflicts of interest: M.Alves, None; R.N.Angerami, None; E.M.Rocha, None.

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The potential pathogenic mechanisms to DED associated to the viral infection in the lacrimal gland are the following:

HTLV The human T-cell lymphotropic virus (HTLV) infection is endemic in Japan, the Caribbean basin, Central and South America and Africa. It is transmitted through sexual intercourse, breast-feeding, blood transfusion and sharing of contaminated syringes and needles. HTLV is characterized by asymptomatic infection in most of seropositive cases. Although 90% of the approximately 20 million infected people worldwide remain asymptomatic carriers during their lives, HTLV infection is also associated with systemic and ocular complications(14). HTLV infection is etiologically linked to two potential fatal diseases: 1) the malignant proliferation of T cell causing the adult leukemia/lymphoma (ATL) and 2) a neuromyelopathy known as tro­­­­pical spastic paraparesis (TSP). ATL is considered an aggressive lym­­­­ phoproliferative malignancy with short survival in its acute form, occurring in less than 5% in HTLV infected people. TSP is a chronic meningomyelitis in the spinal cord, with demyelination and axonal degeneration leading to the development of a slowly progressive spastic paraparesis, high impairment of gait, autonomic dysfunction and profound repercussions on abilities and quality of life of the patients(15,16). HTLV also causes dermatitis, pneumonia, polymyositis, thyroiditis and Sjögren’s like syndrome(16). HTLV ocular lesions may present as uveitis, dry eye, keratitis and retinal vasculitis(17). The prevalence of uveitis is controversial in different parts of the world. In Japan, for instance, a 35.4% prevalence of uveitis in patients infected with HTLV was observed, while in Martinique, the prevalence was 14.5%(18). The incidence of dry eye in seropositive patients was 36.4% in study conducted in the region of highest prevalence of HTLV infection in Brazil. Moreover, 54.4% of DED in TSP patients and 20.3% in asymptomatic seropositives. In those patients immunophenotyping analysis shown high levels of both CD4+ and CD8+(19). Another study, evaluating 200 infected patient found 37% of DES accompanied by lymphoplasmocytoid infiltration of secondary salivar gland(20,21). Serological studies demonstrated the prevalence of antibodies to HTLV in Sjögren patients ranging from 23-36%, significantly higher

than that among blood donors. Salivary IgA antibodies to HTLV were found in seropositive HTLV patients with SS(22,23). Indeed, two independent studies confirmed the presence of HTLV genome in salivary glands samples from patients with Sjögren(24,25).

HIV HIV (human immunodeficiency virus) infection may present with a large variety of primary and secondary (caused by opportunistic infections) ocular manifestations, some of those have threatening potential to vision and life quality. The incidence and presentation of the AIDS epidemic and its correlated complications have dramatically changed since the introduction of the potent antiretroviral therapies (also know as highly active antiretroviral therapy, or HAART), but remains as a dramatic public health in very low income countries. DED appears to be much more prevalent among individuals with AIDS (21.4-38.8% of HIV-infected men, 16.9% of HIV-infected women) than in the general population(13,26,27). Burtin et al. evaluated the ocular surface and DED complains in a group of HIV positive patients. According to this study, 70% of them had complained of DED symptoms, 85% present at least one clinical sign of ocular surface dysfunction tested through Schirmer test, tear break-up time and lissamine stain and the impression cytology revealed a decrease in the number of dendritic cells(28). Geier et al. showed that decreased tear production occurs in ap­­­proximately 20% to 25% of patients with HIV infection without correlation with the CD4+v lymphocites blood count, or to the severity of HIV disease, in a group of 144 HIV patients(29). Although the entire pathogenesis of the aqueous tear deficiency in HIV-infected remain unclear, it may be associated with lymphocytic infiltration and destruction of the lacrimal gland acini and ducts. In fact, a Sjögren’s syndrome-like picture may be present in HIV -infected patients who develop the diffuse infiltrative lymphocytosis syndrome (DILS). Thus, it is an exclusion criteria for individuals under investigation for Sjögren syndrome(30). DILS is a disorder in patients with HIV infection that is characterized by the enlargement of salivary and lacrimal glands and a varying intensity of DED symptoms. In addition, DILS is accompanied by persistent circulating and infiltration of CD8-positive lymphocytes. DILS may mimic Sjögren’s syndrome in

Table 1. Major characteristics of virus associated to dry eye disease Major clinical manifestation

Major ocular manifestation

Virus

Type

HTLV

Retrovirus (Oncornavirus)

Adult T-cell leukemia/lymphoma Neuromyelopathy

Uveitis Dry eye

Blood and blood products transfusion, breastfeeding; sexual intercourse

Transmission

HIV

Retrovirus (Lentivirus)

Acquired immunodeficiency syndrome

Dry eye

Sexual intercourse; blood and blood products transfusion; maternal fetal; injection drug users;

HCV

RNA virus (Flavivirus)

Hepatitis Cirrhosis Liver failure Hepatocellular carcinoma Extrahepatic manifestations (e.g. glandular, renal, dermatological, hematological, joints)

Retinopathy Scleritis Keratitis Dry eye

Injection drug users; blood and blood products transfusion; needlestick injuries in health care settings; sexual intercourse (rare); maternal fetal (rare); contaminated needles and instruments (tattoo, piercings)

EBV

DNA virus (Herpesvirus)

Infectious mononucleosis Burkitt’s lymphoma Nasopharingeal carcinoma

Dry eye

Exchanging of saliva Direct contact

HSV-1

DNA virus (Herpesvirus)

Mucocutaneous lesions (typical oral and skin watery blisters) Meningitis, encephalitis, Bell’s palsy

Keratitis Blepharitis Conjunctivitis Uveitis Retinitis

Direct contact

HTLV= human T-cell lymphotropic virus; HIV= human immunodeficiency virus; HCV= hepatitis C virus; EBV= Epstein-Barr virus; HSV-1= herpes simplex virus-1.

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terms of symptoms and parotid and lacrimal glands involvement. On the other hand, it differs by the high frequency of extra glandular sites of lymphocytic infiltration, such as lungs, muscles and liver, scarcity or absence of serum autoantibodies and the nature of infiltrating lymphocytes. While in Sjögren syndrome presents lymphocytic infiltration of CD4+ and in DILS it is a CD8+ lymphocytes and anti-Ro and anti-La are seen less frequently(2,31). The prevalence of DILS had drop­ ped significantly after the introduction of HAART, indirectly inferring that the HIV infection contributes to DILS pathogenesis.

Hepatitis C Hepatitis C virus (HCV) is frequently associated with autoimmune features and extra hepatic manifestations, especially with chronic infection(32). The prevalence of HCV infection in patients with primary SS have been analyzed in different studies and its is comparatively higher than in the general population although varying geographically(3,33,34). Ocular manifestations such as retinopathy, scleritis and keratitis have been well documented(35). Cacoub et al. evaluating a group of 312 HCV patients found xerostomia and/or xeroftalmia symptoms in 10%(36) which makes the ocular surface one of the most important sites of manifestations in HCV infected patients(37). Both entities, Sjögren syndrome and HCV, are characterized by B-cell hyperactivity although related to different etiologies, autoimmune and infectious respectively. HCV have demonstrated capability to infect and replicate in the salivary and lacrimal gland tissues leading to lymphocytic infiltration, signs and symptoms of SS. Patients with Sjögren syndrome associated to HCV infection have demographic, immunological and clinical different profiles. Comparatively, Sjögren syndrome-HCV patients are older aged, higher incidence of extra glandular manifestations, especially cryoglobulinemia, and have negative Ro/La antibodies and hypocomplementemia. Again the American European criteria for Sjögren syndrome, exclude Sjögren diagnosis in patients who are HCV positive(30).

EBV EBV (Epstein Barr virus) is herpes virus that infects epithelial cell located in oropharyngeal tissues, salivary glands and B-lymphocytes. The virus occurs worldwide and most people become infected with EBV during the first two decades of life. In the United States, as many as 95% of adults between 35 and 40 years of age have been infected. Primary EBV infection is usually asymptomatic and resolves spontaneously. Occasionally, EBV infection may cause infectious mononucleosis characterized by fever, pharyngitis and general lymphadenopathy(38). After the primary infections it remains latent and occasionally reactivates in salivary glands(39). EBV infection of B cell activates intrinsic pathway that results on continuous cellular division and consequently lymphoproliferation. There is increasing evidence suggesting that EBV infection may be related to lacrimal gland lymphocytic proliferation of Sjögren syndrome, which leads to decreased aqueous tear production and severe DED(40,41). Many studies have reported primary Sjögren syndrome development immediately after serological confirmation of infectious mononucleosis(42-44). EBV genome has been amplified from the majority of lacrimal gland biopsies of Sjögren patients postulating that EBV may be considered a risk factor for the lacrimal gland pathologic mechanisms of Sjögren syndrome(43). Salivary and lacrimal glands differ in the type of EBC infection observed in biopsies from Sjögren patients. Minor salivary gland shows CD4 T cells infiltration and less severe inflammation. On the other hand, in lacrimal gland biopsies the infiltrating cell type is predominately B-lymphocytes and EBV antigen and EBV DNA are detected in ductal epithelia associated high levels of lymphoproliferation surrounding infected ducts or focci replacing secretory acini(45).

HSV and ocular surface HSV-1 (herpes simplex virus-1) ocular infection is a common cau­­­se of ocular surface disorder. It can present in a broad range of manifestations from primary blepharoconjuntivitis to recurrent forms of keratitis and even intraocular involvement as that seen in retinitis and uveitis(46,47). Although there is no evidence of HVS direct infection in the lacrimal gland it has been demonstrated that corneal sensation and tear production are significant lower in patients with ocular herpetic disease(48,49). CONCLUSIONS Circumstantial evidence suggests that systemic and ocular viral infections, along with many environmental and other risks factors, may play an important role in the pathogenesis of dry eye disease. Patients with moderate to severe dry eye disease and other clinical manifestations should be investigated by serology of mentioned viral systemic infections. Many studies confirmed the association of viruses and lacrimal gland dysfunction and many others have been addressed efforts to the understanding its mechanisms. Future re­ search should characterize this subpopulation, the application of diag­­­­nostic tools and the possible benefits of specific antiviral treatment as a therapeutic approach for dry eye disease. Finally, the present review reinforces the importance of ophthalmologists as one of the healthcare professional able to diagnose a potentially large number of infected patients with high prevalent viral agents. Moreover, it may contribute to make more widely known the possible association between viral infections and dry eye disease and the importance of including an ophthalmologic evaluation as part of the medical approach to patients infected with specific chronic viral infections. REFERENCES 1. Sipsas NV, Gamaletsou MN, Moutsopoulos HM. Is Sjögren’s syndrome a retroviral disease? Arthritis Res Ther. 2011;13(2):212. Review. 2. Vitali C. Immunopathologic differences of Sjögren’s syndrome versus sicca syndrome in HCV and HIV infection. Arthritis Res Ther. 2011;13(4):233. 3. Ramos-Casals M, García-Carrasco M, Brito Zerón MP, Cervera R, Font J. Viral etiopathogenesis of Sjögren’s syndrome: role of the hepatitis C virus. Autoimmun Rev. 2002; 1(4):238-43. 4. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2):75-92. 5. Gipson IK. The ocular surface: the challenge to enable and protect vision: the Friedenwald lecture. Invest Ophthalmol Vis Sci. 2007;48(10):4390; 4391-8. 6. Pflugfelder SC. Tear dysfunction and the cornea: LXVIII Edward Jackson Memorial Lecture. Am J Ophthalmol. 2011;152(6):900-9.e1. 7. Williams K, Watsky M. Gap junctional communication in the human corneal endothelium and epithelium. Curr Eye Res. 2002;25(1):29-36. 8. Pflugfelder SC. Tear fluid influence on the ocular surface. Adv Exp Med Biol. 1998; 438:611-7. 9. Tseng SC, Tsubota K. Important concepts for treating ocular surface and tear disorders. Am J Ophthalmol. 1997;124(6):825-35. Review. 10. Mitsias DI, Kapsogeorgou EK, Moutsopoulos HM. The role of epithelial cells in the initiation and perpetuation of autoimmune lesions: lessons from Sjögren’s syndrome (autoimmune epithelitis). Lupus. 2006;15(5):255-61. 11. Moutsopoulos HM, Papadopoulos GK. Possible viral implication in the pathogenesis of Sjögren’s syndrome. Eur J Med. 1992;1(4):219-23. Review. 12. Katsifis GE, Moutsopoulos NM, Wahl SM. T lymphocytes in Sjögren’s syndrome: contributors to and regulators of pathophysiology. Clin Rev Allergy Immunol. 2007; 32(3):252-64. 13. DeCarlo DK, Penner SL, Schamerloh RJ, Fullard RJ. Dry eye among males infected with the human immunodeficiency virus. J Am Optom Assoc. 1995;66(9):533-8. 14. de Thé G, Bomford R. An HTLV-I vaccine: why, how, for whom? AIDS Res Hum Retroviruses. 1993;9(5):381-6. 15. Proietti FA, Carneiro-Proietti AB, Catalan-Soares BC, Murphy EL. Global epidemiology of HTLV-I infection and associated diseases. Oncogene. 2005;24(39):6058-68. 16. Goncalves DU, Proietti FA, Ribas JG, Araújo MG, Pinheiro SR, Guedes AC, et al. Epidemiology, treatment, and prevention of human T-cell leukemia virus type 1-associated diseases. Clin Microbiol Rev. 2010;23(3):577-89. Review.

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17. Kamoi K, Mochizuki M. HTLV infection and the eye. Curr Opin Ophthalmol. 2012; 23(6):557-61. 18. Mochizuki M, Watanabe T, Yamaguchi K, Yoshimura K, Nakashima S, Shirao M, et al. Uveitis associated with human T-cell lymphotropic virus type I. Am J Ophthalmol. 1992;114(2):123-9. 19. Pinheiro SR, Martins-Filho OA, Ribas JG, Catalan-Soares BC, Proietti FA, Namen-Lopes S, et al. Immunologic markers, uveitis, and keratoconjunctivitis sicca associated with human T-cell lymphotropic virus type 1. Am J Ophthalmol. 2006;142(5):811-5. 20. Merle H, Cabre P, Olindo S, Merle S, Smadja D. Ocular lesions in 200 patients infected by the human T-cell lymphotropic virus type 1 in martinique (French West Indies). Am J Ophthalmol. 2002;134(2):190-5. 21. Yamamoto JH, Segurado AA, Hirata CE, Sampaio MW, Souza EC, Nukui Y, et al. Human T-cell lymphotropic virus type 1 infection and ocular manifestations in Sao Paulo, Brazil. Arch Ophthalmol. 1999;117(4):513-7. 22. Eguchi K, Matsuoka N, Ida H, Nakashima M, Sakai M, Sakito S, et al. Primary Sjögren’s syndrome with antibodies to HTLV-I: clinical and laboratory features. Ann Rheum Dis. 1992;51(6):769-76. 23. Terada K, Katamine S, Eguchi K, Moriuchi R, Kita M, Shimada H, et al. Prevalence of serum and salivary antibodies to HTLV-1 in Sjögren’s syndrome. Lancet. 1994; 344(8930):1116-9. Comment in Lancet. 1995;345(8941):71-2. 24. Sumida T, Yonaha F, Maeda T, Kita Y, Iwamoto I, Koike T, et al. Expression of sequences homologous to HTLV-I tax gene in the labial salivary glands of Japanese patients with Sjögren’s syndrome. Arthritis Rheum. 1994;37(4):545-50. 25. Mariette X, Agbalika F, Daniel MT, Bisson M, Lagrange P, Brouet JC, et al. Detection of human T lymphotropic virus type I tax gene in salivary gland epithelium from two patients with Sjögren’s syndrome. Arthritis Rheum. 1993;36(10):1423-8. Comment in Arthritis Rheum. 1996;39(9):1609-11. 26. Lucca JA, Farris RL, Bielory L, Caputo AR. Keratoconjunctivitis sicca in male patients infected with human immunodeficiency virus type 1. Ophthalmology. 1990;97(8): 1008-10. 27. Lucca JA, Kung JS, Farris RL. Keratoconjunctivitis sicca in female patients infected with human immunodeficiency virus. Clao J. 1994;20(1):49-51. 28. Burtin T, Guepratte N, Bourges JL, Garcher C, Le Hoang P, Baudouin C. [Abnormalities of the ocular surface in patients with AIDS]. J Fr Ophtalmol. 1998;21(9):637-42. French. 29. Geier SA, Libera S, Klauss V, Goebel FD. Sicca syndrome in patients infected with the human immunodeficiency virus. Ophthalmology. 1995;102(9):1319-24. Erratum in Ophthalmology 1996;103(2):204. 30. Vitali C. Classification criteria for Sjögren’s syndrome. Ann Rheum Dis. 2003;62(1):94-5; author reply 95. 31. Kordossis T, Paikos S, Aroni K, Kitsanta P, Dimitrakopoulos A, Kavouklis E, et al. Prevalence of Sjögren’s-like syndrome in a cohort of HIV-1-positive patients: descriptive pathology and immunopathology. Br J Rheumatol. 1998;37(6):691-5. 32. Ramos-Casals M, Jara LJ, Medina F, Rosas J, Calvo-Alen J, Mañá J, Anaya JM, Font J; HISPAMEC Study Group. Systemic autoimmune diseases co-existing with chronic

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hepatitis C virus infection (the HISPAMEC Registry): patterns of clinical and immunological expression in 180 cases. J Intern Med. 2005;257(6):549-57. 33. Verbaan H, Carlson J, Eriksson S, Larsson A, Liedholm R, Manthorpe R, et al. Extrahepatic manifestations of chronic hepatitis C infection and the interrelationship between primary Sjögren’s syndrome and hepatitis C in Swedish patients. J Intern Med. 1999;245(2):127-32. 34. King PD, McMurray RW, Becherer PR. Sjögren’s syndrome without mixed cryoglobulinemia is not associated with hepatitis C virus infection. Am J Gastroenterol. 1994; 89(7):1047-50. 35. Baratz KH, Fulcher SF, Bourne WM. Hepatitis C-associated keratitis. Arch Ophthalmol. 1998;116(4):529-30. 36. Cacoub P, Renou C, Rosenthal E, Cohen P, Loury I, Loustaud-Ratti V, et al. Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients. The GERMIVIC. Groupe d’Etude et de Recherche en Medecine Interne et Maladies Infectieuses sur le Virus de l’Hepatite C. Medicine (Baltimore). 2000;79(1):47-56. 37. Gomes RL, Marques JC, Albers MB, Endo RM, Dantas PE, Felberg S. Superfície ocular e hepatite C. Arq Bras Oftalmol. 2011;74(2):97-101. 38. Cohen JI. Epstein-Barr virus infection. N Engl J Med. 2000;343(7):481-92. 39. Pflugfelder SC, Crouse CA, Atherton SS. Ophthalmic manifestations of Epstein-Barr virus infection. Int Ophthalmol Clin. 1993;33(1):95-101. 40. Whittingham S, McNeilage J, Mackay IR. Primary Sjögren’s syndrome after infectious mononucleosis. Ann Intern Med. 1985;102(4):490-3. 41. Pflugfelder SC, Wilhelmus KR, Osato MS, Matoba AY, Font RL. The autoimmune nature of aqueous tear deficiency. Ophthalmology. 1986;93(12):1513-7. 42. Pflugfelder SC, Roussel TJ, Culbertson WW. Primary Sjögren’s syndrome after infectious mononucleosis. JAMA. 1987;257(8):1049-50. 43. Pflugfelder SC, Crouse C, Pereira I, Atherton S. Amplification of Epstein-Barr virus genomic sequences in blood cells, lacrimal glands, and tears from primary Sjögren’s syndrome patients. Ophthalmology. 1990;97(8):976-84. 44. Gaston JS, Rowe M, Bacon P. Sjögren’s syndrome after infection by Epstein-Barr virus. J Rheumatol. 1990;17(4):558-61. 45. Pflugfelder SC, Crouse CA, Monroy D, Yen M, Rowe M, Atherton SS. Epstein-Barr virus and the lacrimal gland pathology of Sjögren’s syndrome. Am J Pathol. 1993;143(1):49-64. 46. Liesegang TJ, Melton LJ 3rd, Daly PJ, Ilstrup DM. Epidemiology of ocular herpes simplex. Incidence in Rochester, Minn, 1950 through 1982. Arch Ophthalmol. 1989; 107(8):1155-9. 47. Liesegang TJ. Herpes simplex virus epidemiology and ocular importance. Cornea. 2001; 20(1):1-13. 48. Keijser S, van Best JA, Van der Lelij A, Jager MJ. Reflex and steady state tears in patients with latent stromal herpetic keratitis. Invest Ophthalmol Vis Sci. 2002;43(1):87-91. 49. Simard-Lebrun A, Boisjoly H, Al-Saadi A, Choremis J, Mabon M, Chagnon M. Association between unilateral quiescent stromal herpetic keratitis and bilateral dry eyes. Cornea. 2010;29(11):1291-5.

Cartas ao Editor | Letters to the Editor

Culture positivity for exact diagnosis of Pseudomonas aeruginosa endophthalmitis Positividade de cultura para o diagnóstico exato de endoftalmite por Pseudomonas aeruginosa Yakup Aksoy1, Yusuf Emrah Eyi2, Kadir Colakoglu3, Emre Zorlu4, Fahri Gurkan Yesil5

Dear Editor, We read the article ‘‘An outbreak of forty five cases of Pseudomonas aeruginosa acute endophthalmitis after phacoemulsification” written by Guerra et al., with interest(1). They described an outbreak of Pseudomonas aeruginosa endophthalmitis post cataract surgery and discussed clinical findings, treatment and outcomes. We thank to the authors for their lightening analysis and we would like to make some contributions. Postoperative endophthalmitis is one of the most destroying com­­­plication of intraocular surgery. Pseudomonas aeruginosa is a Gram negative, non-fermentative bacteria which causes severe endophthalmitis, ulcerative keratitis which are more rapidly progressive and visual acuity outcomes is generally poor(2,3). Pseudomonas aerugi­ nosa also causes severe life-threatening diseases such as menin­goen­ cephalitis, endocarditis, pneumonia and sepsis. The treatment of endophtalmitis usually emprical at the begening. But the laboratorial diagnosis of the causative agent should always be pursued, in order to ensure a more specific treatment, to guide final therapeutic modifications and to prevent any visual impairment due to a wrong or delayed diagnosis(4). İn this article authors reported that forty-five patients were diag­­­nosed as Pseudomonas aeruginosa but also they informed that cultures for pseudomonas were positive in only twenty-six patients. İn nineteen patients cultures for Pseudomonas were negative. We believe that the culture positivity is a necessity for diagnosis of ‘’Pseudomonas aeruginosa endophthalmitis’’ and in these nineteen

culture negative patients the causative agent is not definite. Chen et al., reported a retrospective, noncomparative, consecutive case series of 71 patients and they had analysed medical records of patients only who had culture-proven P. aeruginosa endophthalmitis(2). Goldschmidt et al., suggested as an alternative method ‘’the real timepolymerase chain reaction’’ in rapid pathogens diagnosis of bacterial endophthalmitis(5). Culture positivity is not possible everytime in all samples for endophthalmitis, but using such kind of new methods may facilitate to find causative agent and reduce the number of patients with culture-negative. We celebrate Guerra and friends for the presentation and offer our respects.

Submitted for publication: May 27, 2013 Accepted for publication: May 29, 2013

Funding: No specific financial support was available for this study.

Ophthalmology Department, Hakkari Military Hospital, Hakkari, Turkey. Emergency Department Medicine, Hakkari Military Hospital, Hakkari, Turkey. 3 Ophthalmology Department, Kasımpasa Military Hospital, Istanbul, Turkey. 4 Neurosurgery Department, GATA Haydarpasa Education Hospital, Istanbul, Turkey. 5 Cardiovascular Surgery Department, Gülhane Military Medical Academy, Ankara, Turkey. 1 2

References 1. Guerra RL, Freitas B de P, Parcero CM, Maia Júnior O de O, Marback RL. An outbreak of forty five cases of Pseudomonas aeruginosa acute endophthalmitis after phacoemulsification. Arq Bras Oftalmol. 2012;75(5):344-7. 2. Chen KJ, Sun MH, Lai CC, Wu WC, Chen TL, Kuo YH, et al. Endophthalmitis caused by Pseudomonas aeruginosa in Taiwan. Retina. 2011;31(6):1193-8. 3. Lipener C, Ribeiro AL. Úlcera de córnea bilateral por pseudomonas em usuário de lente de contato descartável. Arq Bras Oftalmol. 1999;62(6):747-9. 4. Uesuguı E, Cypel-Gomes MC, Atique D, Goulart DG, Gallucci FR, Nishiwaki-Dantas MC, et al. Identificação laboratorial dos patógenos oculares mais frequentes e sua suscetibilidade in vitro aos agentes antimicrobianos. Arq Bras Oftalmol. 2002;65(3): 339-42. 5. Goldschmidt P, Degorge S, Benallaoua D, Basli E, Batellier L, Boutboul S, et al. New test for the diagnosis of bacterial endophthalmitis. Br J Ophthalmol. 2009;93(8):1089-95.

Disclosure of potential conflicts of interest: Y.Aksoy, None; Y.E.Eyi, None; K.Colakoglu, None; E.Zorlu, None; F.G.Yesil, None. Correspondence address: Yakup Aksoy. E-mail: [email protected]

Authors’ reply Resposta dos autores Ricardo Luz Leitão Guerra1, Bruno de Paula Freitas2, Cintia Maria Felix Medrado Parcero2; Otacílio de Oliveira Maia Júnior1; Roberto Lorens Marback3

Dear Editor, We are pleased with the interest in our paper and appreciate the valuable comments that complements the presented article and pro­­­vide usefull information. I would like to highlight one peculiarity of our presentation.

It is known that real-time polymerase chain reaction (PCR) has improved the diagnosis of bacterial endophthalmitis(1,2), but conventional microbiology methods, such as culture, are routinely used for microorganisms laboratory characterization and the positivity range from 24% to 85% according to different studies(3).

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Indeed cultures were not positive in all the presented cases. However, due to diagnostic method limitations and analyzing the clinical findings and uniform response to the treatment, as well as all patients had been operated in two consecutive days in a single center by the same surgeon, lead the authors to believe that is acceptable the presumptive diagnosis in cases that culture was not positive. We thank to the authors for their commendation of our paper.

References 1. Goldschmidt P, Degorge S, Benallaoua D, Basli E, Batellier L, Boutboul S, et al. New test for the diagnosis of bacterial endophthalmitis. Br J Ophthalmol. 2009;93(8):1089-95. 2. Bispo PJ, de Melo GB, Hofling-Lima AL, Pignatari AC. Detection and gram discrimination of bacterial pathogens from aqueous and vitreous humor using real-time PCR assays. Invest Ophthalmol Vis Sci [Internet]. 2011[cited 2012 Jan 3];52(2):873-81. Available from: http://www.iovs.org/content/52/2/873.long 3. Bispo PJ, Melo GB, d’Azevedo PA, Höfling-Lima AL, Yu MC, Pignatari AC. [Culture proven bacterial endophthalmitis: a 6-year review]. Arq Bras Oftalmol. 2008;71(5):617-22. Portuguese.

Physician, Department of Ophthalmology, Hospital São Rafael, Fundação Monte Tabor, Salvador (BA), Brazil. Physician 3 Professor, Department of Ophthalmology, Hospital São Rafael, Fundação Monte Tabor, Salvador (BA), Brazil. 1

2

Initial challenges in the career of ophthalmologists Óbices iniciais na carreira do oftalmologista Rodrigo Pessoa Cavalcanti Lira1, Fernando Rodrigo Pereira Chaves1, Carlos Eduardo Leite Arieta1

Dear Editor, The curriculum of most ophthalmology courses does not include or has not emphasized the fundaments of management, marketing, economics, and accounting in private practice. Consequently, the young ophthalmologists enter the labor market without a proper understanding of these important aspects of a career. The inexperience in dealing with routine tasks of a business, such as taxes, cash flow, and bank loans, are factors that can lead to the closure of the medical office in its first years of life(1). The aim of this study is to describe the main challenges faced by young ophthalmologists in the first decade of their career. We conducted a descriptive study with physicians from Brazil, who attended an ophthalmology congress. Inclusion criteria were as follows: being medical ophthalmologist under 40 years of age, and having completed more than 5 and less than 10 years of specialization in ophthalmology. The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration From the database of the congress, participants who met the inclusion criteria were randomly invited to answer two questionnaires. In the first questionnaire, by e-mail, we collected data on gender, age, time of completion of specialization, and the answer to the fol­­­­lowing question: What were the three major challenges in your personal experience during the exercise of ophthalmology? Challenges were defined as the personal choices made at the beginning of the career that contributed negatively to professional success. After accounting for the initial results, the 10 most frequently mentioned answers were listed. In the second questionnaire, the same volunteers were once again interviewed by e-mail and asked to choose, among this 10-item list, the three major challenges in their personal experience. The order of presentation of the options was randomly different for each volunteer to provide equal exposure of each item. Forty-eight ophthalmologists were interviewed, with a mean age of 37 years (SD: 2 years, range: 33-40 years) and mean time of com134

Arq Bras Oftalmol. 2013;76(2):133-5

pletion of the specialization course in ophthalmology of 8 years (SD: 1 year, range: 5-10 years). Twenty-four (50%) were male. All agreed to participate. Table 1 details the frequency of answers (144 citations=3 per respondent). The lack of administrative and financial knowledge was the most common difficulty faced by young ophthalmologists in the first decade of their careers. This fact is unfortunate, considering the various sources of supplementary education that can meet much of this

Table 1. Initial challenges in the career in ophthalmology Frequency N (%)

Male N (%)

Female N (%)

P

Lack of administrative and financial knowledge

42 (29.2)

18 (25.0)

24 (33.3)

0.27*

Delay in opening own business

028 (19.4)

11 (15.2)

17 (23.6)

0.21*

Working in many places simultaneously

024 (16.7)

11 (15.2)

13 (18.0)

0.65*

Association with persons of dubious reputation

009 (06.3)

06 (08.3)

03 (04.1)

0.49†

Having to submit to unethical working conditions

009 (06.3)

04 (05.5)

05 (06.9)

0.99†

Corporate group expansion without set standards

009 (06.3)

07 (09.7)

02 (02.7)

0.17†

Exclusive dedication to a job

007 (04.9)

01 (01.3)

06 (08.3)

0.12†

Lack of alternative career plan

006 (04.2)

04 (05.5)

02 (02.7)

0.68†

Hastiness

006 (04.2)

06 (08.3)

0 (0)

0.03†

Lack of humility

004 (02.8)

04 (05.5)

0 (0)

0.12†

Total

144 (100)

72 (100)

72 (100)

Item

*= Chi-square test; †= Fisher’s exact test.

Cartas ao Editor | L etters

demand for knowledge(2-4). For example, in 2006, the International Council of Ophthalmology published the “Principles and Guidelines of a Curriculum for Education of the Ophthalmic Specialist”(5). It includes specific management issues such as cooperativism, civil society, marketing, contract negotiation, professional defense, career planning, retirement, consumer protection codes, employee recruitment, clinic management, auditing, quality strategies, taxation, applied financial mathematics, billing, health surveillance, legislation, among others(5) Although the sample of this study was not designed to test gender differences (there was no statistically significant difference), some interesting findings were observed. For example, the delay in opening own business and the exclusive dedication to a job, were most cited by women. Conversely, the lack of humility, the hastiness, and the corporate group expansion without set standards, were most cited by men. Studies to evaluate professional practice of young ophthalmologists are scarce. The authors are unaware of previous manuscript describing the major challenges of ophthalmologists in the first decade of their career and we could find no reference to it in a computerized

Submitted for publication: May 23, 2013 Accepted for publication: May 29, 2013 1

Universidade Estadual de Campinas.

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search at PubMed. Although these results should not be generalized, they may help not only those at the beginning of their career but also every ophthalmologist who wants to reflect on what to prioritize in their professional practice. References 1. Serviço Brasileiro de Apoio a Micro e Pequena Empresa. 10 anos de monitoramento da sobrevivência e mortalidade de Empresas [Internet]. São Paulo: SEBRAE-SP; 2008. [citado 2012 Dec 21]. Disponível em: http://www.sebraesp.com.br/arquivos_site/ biblioteca/EstudosPesquisas/mortalidade/livro_10_anos_mortalidade.pdf%20%20 2. Chiarantano S, Regonha E, Scarpi MJ. O controle financeiro e seus benefícios na estruturação de clínica oftalmológica. Rev Adm Saúde [Internet] 2006[citado 2010 Apr 23];8(3):33-9. Disponível em: http://www.cqh.org.br/files/RAS30_o%20controle.pdf 3. Olson RJ. Ten-year experience in managing a capitates ophthalmology carve-out by an academic eye center. J Ambul Care Manage. 1997;20(1):1-7. 4. Solomon MD, Lee PP, Mangione CM, Kapur K, Adam JL, Wickstrom SL, et al. Characteristics of eye care practices with managed care contracts. Am J Manag Care. 2002; 8(12):1057-67. 5. International Council of Ophthalmology. Principles and guidelines of a curriculum for edu­­­cation of the ophthalmic specialist. Klin Monbl Augenheilkd. 2006;223(Suppl 4):S3-48.

Funding: No specific financial support was available for this study. Disclosure of potential conflicts of interest: R.P.C.Lira, None; F.R.P.Chaves, None; C.E.L.Arieta, None. Correspondence address: Rodrigo Pessoa Cavalcanti Lira. Rua Irma Maria David, 200 - Apto. 1302 - 52061-070 - Recife (PE) - E-mail: [email protected]

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6/21/13 12:36 PM

Instruções para Autores |

O ARQUIVOS BRASILEIROS DE OFTALMOLOGIA (ABO, ISSN 00042749 - versão impressa e ISSN 1678-2925 - versão eletrônica), publi­ cação bimestral oficial do Conselho Brasileiro de Oftalmologia, obje­­­­­­­­­­­­­­­tiva divulgar estudos científicos em Oftalmologia, Ciências Visuais e Saúde Pública, fomentando a pesquisa, o aperfeiçoamento e a atua­ lização dos profissionais relacionados à área. Metodologia São aceitos manuscritos originais, em português, inglês ou espanhol que, de acordo com a metodologia empregada, deverão ser caracterizados em uma das seguintes modalidades:

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Estudos Teóricos Estudos descritivos que se refiram à descrição e análise teórica de novas hipóteses propostas com base no conhecimento existente na literatura. Tipos de Manuscritos A forma do manuscrito enviado deve enquadrar-se em uma das categorias a seguir. Os limites para cada tipo de manuscrito estão entre parênteses ao final das descrições das categorias. A contagem de palavras do manuscrito refere-se do início da introdução ao final da discussão, portanto, não participam da contagem a página de rosto, abstract, resumo, referências, agradecimentos, tabelas e figu­­­ras incluindo legendas.

Editoriais Os editoriais são feitos a convite e devem ser referentes a assuntos de interesse atual, preferencialmente relacionados a arti­­­­­­ gos publicados no mesmo fascículo do ABO (limites máximos: 1.000 palavras, título, 2 figuras ou tabelas no total e 10 referências).

Artigos Originais Artigos originais apresentam experimentos completos com resultados nunca publicados (limites máximos: 3.000 palavras, tí­­­­tulo, resumo estruturado, 7 figuras ou tabelas no total e 30 referên­ cias). A avaliação dos manuscritos enviados seguirá as prioridades abaixo: 1. Informação nova e relevante comprovada em estudo com metodologia adequada. 2. Repetição de informação existente na literatura ainda não comprovada regionalmente baseada em estudo com metodologia adequada. 3. Repetição de informação existente na literatura e já compro­vada regionalmente, desde que baseada em estudo com me­­todologia adequada. * Não serão aceitos manuscritos com conclusões especulativas, não comprovadas pelos resultados ou baseadas em estudo com metodologia inadequada.

Instructions to Authors

Relatos de Casos ou Série de Casos Relatos de casos ou série de casos serão considerados para publicação se descreverem achados com raridade e originalidade ainda não comprovadas internacionalmente, ou quando o relato apresentar respostas clínicas ou cirúrgicas que auxiliem na elu­­ cidação fisiopatológica de alguma doença (limites máximos: 1.000 pa­­­lavras, título, resumo não estruturado, 4 figuras ou tabelas no total e 10 referências).

Cartas ao Editor As cartas ao editor serão consideradas para publicação se incluí­ rem comentários pertinentes a manuscritos publicados anterior­ mente no ABO ou, excepcionalmente, resultados de estudos origi­­­nais com conteúdo insuficiente para serem enviados como Artigo Original. Elas devem introduzir nova informação ou nova interpre­­ tação de informação já existente. Quando seu conteúdo fizer referência a algum artigo publicado no ABO, este deve estar citado no primeiro parágrafo e constar das referências. Nestes casos, as cartas estarão associadas ao artigo em questão, e o direito de réplica dos autores será garantido na mesma edição. Não serão publicadas cartas de congratulações (limites máximos: 700 palavras, título, 2 figuras ou tabelas no total e 5 referências).

Manuscritos de Revisão Manuscritos de revisão seguem a linha editorial da revista e são aceitos apenas por convite do editor. Sugestões de assuntos para artigos de revisão podem ser feitas diretamente ao editor, mas os manuscritos não podem ser enviados sem um convite prévio (limi­­­ tes máximos: 4.000 palavras, título, resumo não estruturado, 8 figuras ou tabelas no total e 100 referências). Processo Editorial Para que o manuscrito ingresse no processo editorial, é fundamental que todas as regras tenham sido cumpridas. A secretaria editorial comunicará inadequações no envio do manuscrito. Após a notificação, o autor correspondente terá o prazo de 30 dias para adequação do seu manuscrito. Se o prazo não for cumprido, o ma­­­ nuscrito será excluído. Os manuscritos enviados ao ABO são avaliados inicialmente pelos editores quanto à adequação do seu conteúdo à linha edito­­ rial do periódico. Após essa avaliação, todos os manuscritos são encaminhados para análise e avaliação por pares, sendo o anonima­­ to dos avaliadores garantido em todo o processo de julgamento. O anonimato dos autores não é implementado. Após a avaliação editorial inicial, os comentários dos avaliado­­ res podem ser encaminhados aos autores como orientação para as mo­d ificações que devam ser realizadas no texto. Após a imple­ men­­ta­ção das modificações sugeridas pelos avaliadores, o manuscrito re­visado deverá ser encaminhado, acompanhado de carta (enviada como documento suplementar) indicando pon­t ual­m en­ te todas as modificações realizadas no manuscrito ou os motivos pelos quais as modificações sugeridas não foram efetuadas. Ma­­­­­­­­­­­­nuscritos que não vierem acompanhados da carta indicando as modificações ficarão retidos aguardando o recebimento da mes­ ma. O prazo para envio da nova versão do manuscrito é de 90 dias após a comunicação da necessidade de modificações, sendo ex­­­­cluído após esse prazo. A publicação dependerá da aprovação final dos editores. Os trabalhos devem destinar-se exclusivamente ao Arquivos Brasileiros de Oftalmologia, não sendo permitido envio simultâneo a outro periódico, nem sua reprodução total ou parcial, ou tradução para publicação em outro idioma, sem autorização dos editores. Arq Bras Oftalmol. 2013;76(2):137-40

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Autoria Os critérios para autoria de manuscritos em periódicos médi­­ cos está bem estabelecido. O crédito de autoria deve ser baseado em indivíduos que tenham contribuído de maneira concreta nas seguintes três fases do manuscrito: I. Concepção e delineamento do estudo, coleta dos dados ou análise e interpretação dos dados. II. Redação do manuscrito ou revisão crítica do manuscrito com relação ao seu conteúdo intelectual. III. Aprovação final da versão do manuscrito a ser publicada. O ABO requer que os autores garantam que todos os autores preenchem os critérios acima e que nenhuma pessoa que preencha esses critérios seja preterida da autoria. Apenas a posição de chefia de qualquer indivíduo não atribui a este o papel de autor, o ABO não aceita a participação de autores honorários. É necessário que o autor correspondente preencha e envie o formulário de Declaração de Contribuição dos Autores como docu­­­ mento suplementar. Preparação do Artigo Os artigos devem ser enviados exclusivamente de forma eletrô­ nica, pela Internet, na interface apropriada do ABO. As normas que se seguem foram baseadas no formato proposto pelo Inter­na­tional Com­mittee of Medical Journal Editors (ICMJE) e publicadas no artigo: Uniform Requirements for Manuscripts Submitted to Bio­medical Journals. O respeito às instruções é condição obrigatória para que o tra­­­ balho seja considerado para análise. O texto deve ser enviado em formato digital, sendo aceitos apenas os formatos .doc. ou .rtf. O corpo do texto deve ser digitado em espaço duplo, fonte tamanho 12, com páginas numeradas em al­­garismos arábicos, iniciando-se cada seção em uma nova pági­na. As seções devem se apresentar na sequência: Página de Rosto, Abstract e Keywords, Resumo e Descritores, Introdução, Métodos, Resultados, Discussão Agradecimentos (eventuais), Referências, Tabelas (opcionais) e Figuras (opcionais) com legenda. 1. Página de Rosto. Deve conter: a) título em inglês (máximo de 135 caracteres, incluindo espaços); b) título em português ou es­panhol (máximo de 135 caracteres, incluindo espaços); c) tí­tulo resumido para cabeçalho (máximo 60 caracteres, incluindo os es­p aços); d) nome científico de cada autor; e) titulação de cada autor (área de atuação profissional*, cidade, estado, país e, quando houver, depar­tamento, escola, Universidade); f ) nome, endereço, telefone e e-mail do autor correspondente; g) fontes de auxilio à pesquisa (se hou­ver); h) número do projeto e instituição responsável pelo parecer do Co­mitê de Ética em Pesquisa; i) declaração dos conflitos de in­teresses de todos os autores; j) número do registro dos ensaios clí­nicos em uma base de acesso público. *Médico, estatístico, enfermeiro, ortoptista, fisioterapeuta, estudante etc.

Aprovação do Comitê de Ética em Pesquisa. Todos os estudos que envolvam coleta de dados primários ou relatos clínico-ci­ rúrgicos, sejam retrospectivos, transversais ou prospectivos, de­­­­­vem indicar, na página de rosto, o número do projeto e nome da Ins­ tituição que forneceu o parecer do Comitê de Ética em Pes­­­quisa. As pesquisas em seres humanos devem seguir a Declaração de Helsinque, enquanto as pesquisas envolvendo animais devem seguir os princí­pios propostos pela Association for Research in Vision and Oph­thal­mo­logy (ARVO). É necessário que o autor correspondente envie, como documento suplementar, a aprovação do Comitê de Ética em Pesquisa ou seu parecer dispensando da avaliação do projeto pelo Comitê. Não cabe ao autor a decisão sobre a necessidade de avaliação pelo Comitê de Ética em Pesquisa. 138

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Declaração de Conflito de Interesses. A página de rosto deve conter a declaração de conflitos de interesse de todos os autores (mesmo que esta seja inexistente). Para maiores informações sobre os potenciais conflitos de interesse acesse: Chamon W, Melo LA Jr, Paranhos A Jr. Declaração de conflito de interesse em apresenta­ ções e publicações científicas. Arq Bras Oftalmol. 2010;73(2):107-9. É necessário que todos os autores enviem os Formulários para De­­­cla­­­ ra­­­­­­­­ção de Conflitos de Interesse como documentos suplementares. Ensaios Clínicos. Todos os Ensaios Clínicos devem indicar, na pá­gina de rosto, número de registro em uma base internacional de re­­gis­­­­ tro que permita o acesso livre a consulta (exemplos: U.S. Na­­tional Ins­­­t i­t utes of Health, Australian and New Zealand Clinical Trials Registry, Inter­national Standard Randomised Controlled Trial Num­­­­ber - ISRCTN, University Hos­pital Medical Information Net­work Clinical Trials Registry - UMIN CTR, Ne­derlands Trial Register). 2. Abstract e Keywords. Resumo estruturado (Purpose, Methods, Re­­­­sults, Conclusions) com, no máximo, 300 palavras. Resumo não estruturado com, no máximo, 150 palavras. Citar cinco descritores em inglês, listados pela National Library of Medicine (MeSH - Me­dical Subject Headings). 3. Resumo e Descritores. Resumo estruturado (Objetivos, Méto­­­dos, Resultados, Conclusões) com, no máximo 300 palavras. Resumo não estruturado com, no máximo, 150 palavras. Citar cinco des­ critores, em português listados pela BIREME (DeCS - Descritores em Ciências da Saúde). 4. Introdução, Métodos, Resultados e Discussão. As citações no texto devem ser numeradas sequencialmente, em números arábi­­­cos sobrescritos e entre parênteses. É desaconselhada a citação no­minal dos autores. 5. Agradecimentos. Colaborações de pessoas que mereçam re­conhecimento, mas que não justificam suas inclusões como auto­­res, devem ser citadas nessa seção. Estatísticos e editores médi­­cos po­dem preencher os critérios de autoria e, neste caso, de­v em ser reconhecidos como tal. Quando não preencherem os crité­rios de autoria, eles deverão, obrigatoriamente, ser citados nesta seção. Não são aceitos escritores não identificados no manus­­­crito, portanto, escritores profissionais devem ser reconhecidos nes­ta seção. 6. Referências. A citação (referência) dos autores no texto deve ser numérica e sequencial, na mesma ordem que foram citadas e identificadas por algarismos arábicos sobrescritos. A apresen­ta­ ção deve estar baseada no formato proposto pelo International Com­­mittee of Medical Journal Editors (ICMJE), conforme os exem­­plos que se seguem. Os títulos de periódicos devem ser abreviados de acordo com o estilo apresentado pela List of Journal Indexed in Index Medicus, da National Library of Medicine. Para todas as referências, cite todos os autores, até seis. Nos traba­­ lhos com sete ou mais autores, cite apenas os seis primeiros, seguidos da expressão et al. Exemplos de referências: Artigos de Periódicos Costa VP, Vasconcellos JP, Comegno PEC, José NK. O uso da mitomicina C em cirurgia combinada. Arq Bras Oftalmol. 1999; 62(5):577-80. Livros Bicas HEA. Oftalmologia: fundamentos. São Paulo: Contexto; 1991.

Capítulos de livros Gómez de Liaño F, Gómez de Liaño P, Gómez de Liaño R. Exploración del niño estrábico. In: Horta-Barbosa P, editor. Estrabismo. Rio de Ja­neiro: Cultura Médica; 1997. p. 47-72. Anais Höfling-Lima AL, Belfort R Jr. Infecção herpética do recém-nascido. In: IV Congresso Brasileiro de Prevenção da Cegueira; 1980 Jul 28-30, Belo Horizonte, Brasil. Anais. Belo Horizonte; 1980. v.2. p. 205-12. Teses Schor P. Idealização, desenho, construção e teste de um cera­tô­­­­metro cirúrgico quantitativo [tese]. São Paulo: Universidade Federal de São Paulo; 1997. Documentos Eletrônicos Monteiro MLR, Scapolan HB. Constrição campimétrica causada por vigabatrin. Arq Bras Oftalmol. [periódico na Internet]. 2000 [citado 2005 Jan 31]; 63(5): [cerca de 4 p.]. Disponível em:http://www.scielo. br/scielo.php?script=sci_arttext&pid=S0004-274920000005000 12&lng=pt&nrm=iso 7. Tabelas. A numeração das tabelas deve ser sequencial, em alga­ rismos arábicos, na ordem em que foram citadas no texto. Todas as tabelas devem ter título e cabeçalho para todas as colunas e se­rem apresentadas em formatação simples, sem linhas verticais ou preen­chimentos de fundo. No rodapé da tabela deve constar legenda para todas as abreviaturas (mesmo que definidas previa­ mente no texto) e testes estatísticos utilizados, além da fonte bi­bliográfica quando extraída de outro trabalho. Todas as tabelas devem estar contidas no documento principal do manuscrito após as referências bibliográficas, além de serem enviadas como documento suplementar. 8. Figuras (gráficos, fotografias, ilustrações, quadros). A nu­­­­ meração das figuras deve ser sequencial, em algarismos arábi­­ cos, na ordem em que foram citadas no texto. O ABO publicará as figuras em preto e branco sem custos para os autores. Os manus­­­ critos com figuras coloridas apenas serão publicados após o pagamento da respectiva taxa de publicação de R$ 500,00 por manuscrito. Os gráficos devem ser, preferencialmente, em tons de cinza, com fundo branco e sem recursos que simulem 3 dimensões ou profundidade. Gráficos do tipo torta são dispensáveis e devem ser substi­ tuídos por tabelas ou as informações serem descritas no texto. Fotografias e ilustrações devem ter resolução mínima de 300 DPI para o tamanho final da publicação (cerca de 2.500 x 3.300 pixels, para página inteira). A qualidade das imagens é considerada na avaliação do manuscrito. Todas as figuras devem estar contidas no documento principal do manuscrito após as tabelas (se houver) ou após as referências bibliográficas, além de serem enviadas como documento suplementar. No documento principal, cada figura deve vir acompanhada de sua respectiva legenda em espaço duplo e numerada em algarismo arábico. Os arquivos suplementares enviados podem ter as seguintes extensões: JPG, BMP, TIF, GIF, EPS, PSD, WMF, EMF ou PDF, e devem ser nomeados conforme a identificação das figuras, por exemplo: “grafico_1.jpg” ou “figura_1A.bmp”. 9. Abreviaturas e Siglas. Quando presentes, devem ser precedidas do nome correspondente completo ao qual se referem, quando ci­tadas pela primeira vez, e nas legendas das tabelas e figuras (mesmo que tenham citadas abreviadas anteriormente no texto). Não devem ser usadas no título e no resumo.

10. Unidades: Valores de grandezas físicas devem ser referidos de acordo com os padrões do Sistema Internacional de Unidades. 11. Linguagem. A clareza do texto deve ser adequada a uma pu­­blicação científica. Opte por sentenças curtas na forma direta e ati­va. Quando o uso de uma palavra estrangeira for absolutamente ne­cessário, ela deve aparecer com formatação itálica. Agentes te­ra­pêuticos devem ser indicados pelos seus nomes genéricos seguidos, entre parênteses, pelo nome comercial, fabricante, ci­ dade, es­tado e país de origem. Todos os instrumentos ou apare­­ lhos de fabricação utilizados devem ser citados com o seu nome comercial, fabricante, cidade, estado e país de origem. É necessária a colocação do símbolo (sobrescrito) de marca registrada ® ou ™ em todos os nomes de instrumentos ou apresentações comerciais de drogas. Em situações de dúvidas em relação a estilo, terminologia, medidas e assuntos correlatos, o AMA Manual of Style 10th edition deverá ser consultado. 12. Documentos Originais. Os autores correspondentes devem ter sob sua guarda os documentos originais como a carta de aprovação do comitê de ética institucional para estudos com humanos ou animais; o termo de consentimento informado assinado por todos os pacientes envolvidos, a declaração de concordância com o con­ teúdo completo do trabalho assinada por todos os autores e declaração de conflito de interesse de todos os autores, além dos re­gistros dos dados colhidos para os resultados do trabalho. 13. Correções e Retratações. Erros podem ser percebidos após a publicação de um manuscrito que requeiram a publicação de uma correção. No entanto, alguns erros, apontados por qualquer leitor, podem invalidar os resultados ou a autoria do manuscrito. Se al­­guma dúvida concreta a respeito da honestidade ou fidedignidade de um manuscrito enviado para publicação for levantada, é obri­gação do editor excluir a possibilidade de fraude. Nestas si­tuações o editor comunicará as instituições envolvidas e as agências financiadoras a respeito da suspeita e aguardará a decisão final desses órgãos. Se houver a confirmação de uma publicação frau­­dulenta no ABO, o editor seguirá os protocolos sugeridos pela In­ter­na­tional Committee of Medical Journal Editors (ICMJE) e pelo Com­mittee on Publication Ethics (COPE). Lista de Pendências Antes de iniciar o envio do seu manuscrito o autor deve confir­­­ mar que todos os itens abaixo estão disponíveis:

□ Manuscrito formatado de acordo com as instruções aos autores. □ Limites de palavras, tabelas, figuras e referências adequados



□ Todas as figuras e tabelas inseridas no documento principal



□ Todas as figuras e tabelas na sua forma digital para serem



□ Formulário





para o tipo de manuscrito.

do manuscrito.

enviadas separadamente como documentos suplementares. de Declaração da Participação dos Autores preen­chido e salvo digitalmente, para ser enviado como do­­cumento suplementar. □ Formulários de Declarações de Conflitos de Interesses de todos os autores preenchidos e salvos digitalmente, para serem enviados como documentos suplementares. □ Número do registro na base de dados que contem o proto­­colo do ensaio clínico constando na folha de rosto. □ Versão digital do parecer do Comitê de Ética em Pesquisa com a aprovação do projeto, para ser enviado como documento suplementar. Arq Bras Oftalmol. 2013;76(2):137-40

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Lista de Sítios da Internet Interface de envio de artigos do ABO http://www.scielo.br/ABO Formulário de Declaração de Contribuição dos Autores http://www.cbo.com.br/site/files/Formulario Contribuicao dos Autores.pdf International Committee of Medical Journal Editors (ICMJE) http://www.icmje.org/ Uniform requirements for manuscripts submitted to biomedical journals http://www.icmje.org/urm_full.pdf Declaração de Helsinque http://www.wma.net/en/30publications/10policies/b3/index.html Princípios da Association for Research in Vision and Ophthal­mo­logy (ARVO) http://www.ar vo.org/eweb/dynamicpage.aspx?site=ar vo2& webcode=AnimalsResearch Chamon W, Melo LA Jr, Paranhos A Jr. Declaração de conflito de interesse em apresentações e publicações científicas. Arq Bras Oftalmol. 2010;73(2):107-9. http://www.scielo.br/pdf/abo/v73n2/v73n2a01.pdf Princípios de Autoria segundo ICMJE http://www.icmje.org/ethical_1author.html

Australian and New Zealand Clinical Trials Registry http://www.anzctr.org.au International Standard Randomised Controlled Trial Number - ISRCTN http://isrctn.org/ University Hospital Medical Information Network Clinical Trials Registry - UMIN CTR http://www.umin.ac.jp/ctr/index/htm Nederlands Trial Register http://www.trialregister.nl/trialreg/index.asp MeSH - Medical Subject Headings http://www.ncbi.nlm.nih.gov/sites/entrez?db=mesh&term= DeCS - Descritores em Ciências da Saúde http://decs.bvs.br/ Formatação proposta pela International Committee of Medical Journal Editors (ICMJE) http://www.nlm.nih.gov/bsd/uniform_requirements.html List of Journal Indexed in Index Medicus http://www.ncbi.nlm.nih.gov/journals AMA Manual of Style 10th edition http://www.amamanualofstyle.com/

Formulários para Declaração de Conflitos de Interesse http://www.icmje.org/coi_disclosure.pdf

Protocolos da International Committee of Medical Journal Editors (ICMJE) http://www.icmje.org/publishing_2corrections.html

U.S. National Institutes of Health http://www.clinicaltrials.gov

Protocolos da Committee on Publication Ethics (COPE) http://publicationethics.org/flowcharts

Editada por Ipsis Gráfica e Editora S.A.

Rua Vereador José Nanci, 151 - Parque Jaçatuba CEP 09290-415 - Santo André  - SP Fone: (0xx11) 2172-0511 - Fax (0xx11) 2273-1557 Diretor-Presidente: Fernando Steven Ullmann; Diretora Comercial: Helen Suzana Perlmann; Diretora de Arte: Elza Rudolf; Editoração Eletrônica, CTP e Impressão: Ipsis Gráfica e Editora S.A. Periodicidade: Bimestral; Tiragem: 7.200 exemplares

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Publicidade conselho brasileiro de oftalmologia R. Casa do Ator, 1.117 - 2º andar - Vila Olímpia São Paulo - SP - CEP 04546-004 Contato: Fabrício Lacerda Fone: (5511) 3266-4000 - Fax: (5511) 3171-0953 E-mail: [email protected]

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Olho Seco

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Muco-adesivo 2,4

Pós-Cirurgia Refrativa1

Alta capacidade de retenção de água 2,3

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da cicatrização pós-cirurgias Tratamento sintomático do olho seco.

Lubrificação e hidratação de lentes de contato.

Referências Bibliográficas: 1) Bula do produto: Hyabak. Registro MS nº 80424140002. 2) Snibson GR, Greaves JL, Soper ND, Tiffany JM, Wilson CG, Bron AJ. Ocular surface residence times of artificial tear solutions. Cornea. 1992 Jul;11(4):288-93. 3) Nakamura M, Hikida M. Nakano T, Ito S, Hamano T, Kinoshita S. Characterization of water retentive properties of hyaluronan. Cornea. 1993 Sep;12(5):433-6. 4) Gomes JA, Amankwah R, Powell-Richards A, Dua HS. Sodium hyaluronate (hyaluronic acid) promotes migration of human corneal epithelial cells in vitro. Br J Ophthalmol. 2004 Jun;88(6);821-5. SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO. Informações adicionais disponíveis à classe farmacêutica mediante solicitação. Bula do produto: HYABAK®. Solução sem conservantes para hidratação e lubrificação dos olhos e lentes de contacto. Frasco ABAK®. COMPOSIÇÃO: Hialuronato de sódio 0,15g. Cloreto de sódio, trometamol, ácido clorídrico, água para preparações injetáveis q.b.p. 100 mL. NOME E MORADA DO FABRICANTE: Laboratoires Théa, 12 rue Louis Blériot, 63017 CLERMONT-FERRAND CEDEX 2 - França. QUANDO SE DEVE UTILIZAR ESTE DISPOSITIVO: HYABAK® contém uma solução destinada a ser administrada nos olhos ou nas lentes de contato. Foi concebido: • Para humedecimento e lubrificação dos olhos, em caso de sensações de secura ou de fadiga ocular induzidas por fatores exteriores, tais como, o vento, o fumo, a poluição, as poeiras, o calor seco, o ar condicionado, uma viagem de avião ou o trabalho prolongado à frente de uma tela de computador. • Nos utilizadores de lentes de contato, permite a lubrificação e a hidratação da lente, com vista a facilitar a colocação e a retirada, e proporcionando um conforto imediato na utilização ao longo de todo o dia. Graças ao dispositivo ABAK®, HYABAK® permite fornecer gotas de solução sem conservantes. Pode, assim, ser utilizado com qualquer tipo de lente de contato. A ausência de conservantes permite igualmente respeitar os tecidos oculares. ADVERTÊNCIAS E PRECAUÇÕES ESPECIAIS DE UTILIZAÇÃO: • Evitar tocar nos olhos com a ponta do frasco. • Não injetar, não engolir. Não utilize o produto caso o invólucro de inviolabilidade esteja danificado. MANTER FORA DO ALCANCE DAS CRIANÇAS. INTERAÇÕES: É conveniente aguardar 10 minutos entre a administração de dois produtos oculares. COMO UTILIZAR ESTE DISPOSITIVO: POSOLOGIA: 1 gota em cada olho durante o dia, sempre que necessário. Nos utilizadores de lentes: uma gota em cada lente ao colocar e retirar as lentes e também sempre que necessário ao longo do dia. MODO E VIA DE ADMINISTRAÇÃO: INSTILAÇÃO OCULAR. STERILE A - Para uma utilização correta do produto é necessário ter em conta determinadas precauções: • Lavar cuidadosamente as mãos antes de proceder à aplicação. • Evitar o contato da extremidade do frasco com os olhos ou as pálpebras. Instilar 1 gota de produto no canto do saco lacrimal inferior, puxando ligeiramente a pálpebra inferior para baixo e dirigindo o olhar para cima. O tempo de aparição de uma gota é mais longo do que com um frasco clássico. Tapar o frasco após a utilização. Ao colocar as lentes de contato: instilar uma gota de HYABAK® na concavidade da lente. FREQUÊNCIA E MOMENTO EM QUE O PRODUTO DEVE SER ADMINISTRADO: Distribuir as instilações ao longo do dia, conforme necessário. CONSERVAÇÃO DE DISPOSITIVO: NÃO EXCEDER O PRAZO LIMITE DE UTILIZAÇÃO, INDICADO NA EMBALAGEM EXTERIOR. PRECAUÇÕES ESPECIAIS DE CONSERVAÇÃO: Conservar a uma temperatura inferior a 25ºC. Depois de aberto, o frasco não deve ser conservado mais de 8 semanas.

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NOVA GAMA DE LENTES VARILUX. EQUILÍBRIO EM MOVIMENTO COM AMPLO CAMPO DE VISÃO.

Até hoje nenhuma lente multifocal havia sido capaz de eliminar o efeito de flutuação sem prejudicar a amplitude dos campos de visão. Varilux S series rompe esta barreira com uma nova concepção em lentes multifocais. As novas tecnologias Nanoptix e SynchronEyes, presentes em toda a linha Varilux S series, proporcionam equilíbrio em movimento com amplos campos de visão. A versão Varilux S 4D explora um parâmetro inédito de personalização medido pelo Visioffice: o olho dominante, que aprimora o tempo de resposta visual, proporcionando ao usuário foco imediato. É a visão absoluta que os usuários de lentes multifocais sempre buscaram.

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