Download ORA waveform in normal and keratoconic eyes Fine-needle

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!# n #.0* n &ARM 2ESP $ANIELA "ATISTA 0AIVA n
#2&-' N Fabricado por: ,!"/2!4/)2%3 4(²! n RUE ,OUIS "LÏRIOT n #,%2-/.4&%22!.$ #EDEX n &2!.#% &2!.±!
Material dirigido exclusivamente a profissionais habilitados a prescrever e/ou dispensar medicamentos.
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
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PUBLICAÇÃO OFICIAL DO
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PUBLICAÇÃO OFICIAL DO CONSELHO BRASILEIRO DE OFTALMOLOGIA
ISSN 0004-2749
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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
85Evaluation
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:
98Características
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.
Arq Bras Oftalmol. 2013;76(2):63-8
65
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
66
Arq Bras Oftalmol. 2013;76(2):63-8
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
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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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Contrast sensitivity after refractive lens exchange with a multifocal diffractive aspheric intraocular lens
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]
68
Arq Bras Oftalmol. 2013;76(2):63-8
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.
Arq Bras Oftalmol. 2013;76(2):69-71
69
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.
70
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.
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Arq Bras Oftalmol. 2013;76(2):69-71
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.
72
Arq Bras Oftalmol. 2013;76(2):72-9
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.
Arq Bras Oftalmol. 2013;76(2):72-9
73
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
Arq Bras Oftalmol. 2013;76(2):72-9
75
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
Arq Bras Oftalmol. 2013;76(2):72-9
77
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
Arq Bras Oftalmol. 2013;76(2):72-9
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.
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Arq Bras Oftalmol. 2013;76(2):72-9
79
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
80
Arq Bras Oftalmol. 2013;76(2):80-4
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:
Arq Bras Oftalmol. 2013;76(2):80-4
81
Risk factors of age-related macular degeneration in Argentina
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.
82
Arq Bras Oftalmol. 2013;76(2):80-4
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.
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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
85
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.
Lima FBV, et al.
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.
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Figure 2. FDT-MD: global mean sensitivity values (in dB); crossing fibers (Decussation
Yes) and n-crossing fibers (Decussation No); presented as box-plots.
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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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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
91
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
Arq Bras Oftalmol. 2013;76(2):94-7
95
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.
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Arq Bras Oftalmol. 2013;76(2):94-7
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.
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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
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Arq Bras Oftalmol. 2013;76(2):98-104
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
Arq Bras Oftalmol. 2013;76(2):98-104
99
Características estruturais maculares de olhos de pré-escolares nascidos prematuros:
análise por tomografia de coerência óptica e oftalmoscopia binocular indireta
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
100
Arq Bras Oftalmol. 2013;76(2):98-104
Bonotto LB, et al.
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
Arq Bras Oftalmol. 2013;76(2):98-104
101
Características estruturais maculares de olhos de pré-escolares nascidos prematuros:
análise por tomografia de coerência óptica e oftalmoscopia binocular indireta
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
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Arq Bras Oftalmol. 2013;76(2):98-104
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
Arq Bras Oftalmol. 2013;76(2):98-104
103
Características estruturais maculares de olhos de pré-escolares nascidos prematuros:
análise por tomografia de coerência óptica e oftalmoscopia binocular indireta
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.
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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
105
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
Arq Bras Oftalmol. 2013;76(2):105-10
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.
Arq Bras Oftalmol. 2013;76(2):105-10
107
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
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Arq Bras Oftalmol. 2013;76(2):105-10
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.
Arq Bras Oftalmol. 2013;76(2):105-10
109
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
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Arq Bras Oftalmol. 2013;76(2):105-10
in vitro
over cell replacement, our study provided an alternative therapeutic
potential for enhancing the trophic effect of MSCs.
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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).
Arq Bras Oftalmol. 2013;76(2):111-7
111
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
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Arq Bras Oftalmol. 2013;76(2):111-7
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
115
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,
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Figure 4. Combined receiver operating curves for CH, CRF, P2area, P1area and
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The pressure parameters CRF and CH were significant different, as
groups, between keratoconus and normal eyes in the present study,
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with CH is consistent with previous findings suggesting that CRF best
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4). Yet, biomechanical data should not be used as the solo criteria in
the diagnosis or screening of keratoconus since corneal curvature
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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
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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
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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
118
Arq Bras Oftalmol. 2013;76(2):118-20
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.
A
A
B
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.
A
B
A
B
C
D
C
D
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
Arq Bras Oftalmol. 2013;76(2):118-20
119
Solar retinopathy without abnormal exposure: case report
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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Arq Bras Oftalmol. 2013;76(2):118-20
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.
Arq Bras Oftalmol. 2013;76(2):121-3
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Bilateral lineal endotheliitis: case report
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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Arq Bras Oftalmol. 2013;76(2):121-3
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
Arq Bras Oftalmol. 2013;76(2):121-3
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Relatos de Casos |
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
124
Arq Bras Oftalmol. 2013;76(2):124-5
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.
Arq Bras Oftalmol. 2013;76(2):124-5
125
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
126
Arq Bras Oftalmol. 2013;76(2):126-8
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.
Arq Bras Oftalmol. 2013;76(2):126-8
127
Unusual early recurrence of granular dystrophy after deep anterior lamellar keratoplasty: case report
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
128
Arq Bras Oftalmol. 2013;76(2):126-8
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.
Arq Bras Oftalmol. 2013;76(2):129-32
129
Dry eye disease caused by viral infection: review
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.
130
Arq Bras Oftalmol. 2013;76(2):129-32
Alves M, et al.
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.
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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).
Arq Bras Oftalmol. 2013;76(2):133-5
133
Cartas ao Editor | L etters
to the
E ditor
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.
to the
E ditor
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]
Arq Bras Oftalmol. 2013;76(2):133-5
135
CBO anúncio programa cbo paciente P/B.indd 1
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 descritivos ou analíticos que envolvam análises em
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Estudos analíticos que envolvam resultados populacionais.
Estudos de Experimentação Laboratorial
Estudos descritivos ou analíticos que envolvam modelos ani­­­
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Estudos descritivos que se refiram à descrição e análise teórica
de novas hipóteses propostas com base no conhecimento existente
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A forma do manuscrito enviado deve enquadrar-se em uma das
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cias). A avaliação dos manuscritos enviados seguirá as prioridades
abaixo:
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metodologia adequada.
2.Repetição de informação existente na literatura ainda não
comprovada regionalmente baseada em estudo com metodologia adequada.
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regionalmente, desde que baseada em estudo com me­­todologia
adequada.
* Não serão aceitos manuscritos com conclusões especulativas, não
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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
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Para que o manuscrito ingresse no processo editorial, é fundamental que todas as regras tenham sido cumpridas. A secretaria
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a notificação, o autor correspondente terá o prazo de 30 dias para
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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
137
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.
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O ABO requer que os autores garantam que todos os autores
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É necessário que o autor correspondente preencha e envie o
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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
Arq Bras Oftalmol. 2013;76(2):137-40
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
139
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
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Arq Bras Oftalmol. 2013;76(2):137-40
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]
3448-Hyabak Anun Med BULA NOVA_Layout 1 9/20/11 1:32 PM Page 1
Olho Seco
&
Muco-adesivo 2,4
Pós-Cirurgia
Refrativa1
Alta capacidade de retenção de água 2,3
Hidratação prolongada
Conforto prolongado
Ph e osmolaridade semelhantes às do filme lacrimal normal 2
Visco-elástico 4
Mais conforto ao paciente
Melhora as propriedades de adesão intercelular 3,4
Indicado para usuários de lentes de contato 1
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.
UNIÃO QUÍMICA FARMACÊUTICA NACIONAL S/A
Divisão GENOM
Unidade Brasília: Trecho 01 Conjunto 11 Lote 6 a 12
Pólo de Desenvolvimento JK
Santa Maria- Brasília - DF - CEP: 72549-555
Ronda Propaganda
Lançamento no Brasil!
Varilux S series®, Varilux S 4D®, Varilux S fi ®, Varilux S design® e Varilux S design short® são marcas registradas da Essilor International.
NOVA GAMA DE LENTES VARILUX.
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A versão Varilux S 4D explora um parâmetro inédito de personalização medido pelo Visioffice: o olho dominante, que aprimora o
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