Sociedade Brasileira de Retina e Vítreo by Futuro Comunicação

fevereiro 2013 • nº 30

universovisual.com.br

Progressos baseados em evidências ARTIGO Modifield technique for active removal of silicone oil in a single step 23-gauge sutureless system. Outcomes and complications

ARTIGO Hemorrhagic events after intraocular injection of bevacizumab

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R$ 5,90

18/02/13 22:33

Padrão de eficácia na DMRI neovascular2,9

C A D A L I N H A DE V I S Ã O G A N H A É UMA PARTE DA VIDA RECUPERADA 1 O MUNDO É LINDO > PARA O MUNDO É LINDO > PARA SER SER VISTOVISTO

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LUCENTIS®: padrão de eficácia na DMRI neovascular2,5 • • •

LUCENTIS é o tratamento que pode recuperar as atividades diárias prejudicadas pela DMRI neovascular.1-11 TM

•

LUCENTIS® é o padrão-ouro para tratamento de DMRI neovascular, pois permite que os pacientes possam recuperar ou manter a visão3,7,10 LUCENTIS® permite aos pacientes reconquistar a independência e capacidade de realizar atividades da vida diária, como a leitura1,3,4,9 LUCENTIS® foi desenvolvido exclusivamente para uso ocular e sua segurança e eficácia foram demonstradas em estudos clínicos3, 8,9,10,11 LUCENTIS® permite um regime de tratamento individualizado, para obtenção dos melhores resultados em AV6

O tratamento que auxilia os pacientes no exercício das atividades diárias.9 Contraindicação: Pacientes com infecções oculares ou perioculares ativas ou suspeitas. Interação medicamentosa: Não foram realizados estudos de interação formal. LUCENTIS® - ranibizumabe - Forma farmacêutica e apresentações: Solução para injeção a 10 mg/mL. Embalagem com 1 frasco-ampola contendo 2,3 mg de ranibizumabe em 0,23 mL de solução, uma agulha com filtro para retirada do conteúdo do frasco, uma agulha para injeção intravítrea e uma seringa para retirada do conteúdo do frasco e para injeção intravítrea. Indicações: Tratamento da degeneração macular neovascular (exsudativa ou úmida) relacionada à idade (DMRI). Tratamento de deficiência visual devido ao edema macular diabético (EMD). Posologia: A dose recomendada é de 0,5 mg (0,05 mL) administrada como injeção intravítrea única. O intervalo entre as duas doses não deve ser menor que 1 mês. Os pacientes devem ser monitorados mensalmente para verificar a acuidade visual. O tratamento é administrado mensalmente e continuado até que a acuidade visual máxima seja alcançada, confirmada pela acuidade visual estável por três avaliações mensais consecutivas durante o tratamento com Lucentis®. O tratamento é retomado com injeções mensais quando o monitoramento indicar uma perda da acuidade visual devido a DMRI úmida ou EMD e deve continuar até que a acuidade visual estável seja alcançada por três avaliações mensais consecutivas. Lucentis® e fotocoagulação a laser em EMD: Lucentis® tem sido utilizado concomitantemente com fotocoagulação a laser nos estudos clínicos. Quando administrado no mesmo dia, Lucentis® deve ser administrado pelo menos 30 minutos após a fotocoagulação a laser. Lucentis® pode ser administrado em pacientes que receberam fotocoagulação a laser previamente. Lucentis® deve ser administrado por um oftalmologista qualificado usando técnicas assépticas. Deve ser administrada adequada anestesia e um microbicida tópico de amplo espectro antes da injeção. O paciente deve ser instruído para se auto-administrar colírio contendo antimicrobianos 4 vezes ao dia por 3 dias antes e após cada injeção. Não é recomendado para crianças e adolescentes. Contraindicações: Hipersensibilidade ao ranibizumabe ou a qualquer um dos excipientes, pacientes com infecções oculares ou perioculares ativas ou suspeitas, pacientes com inflamação intraocular ativa. Precauções e Advertências: Injeções intravítreas foram associadas com endoftalmite, inflamação intraocular, descolamento de retina regmatogênico, ruptura da retina e catarata traumática iatrogênica. Portanto, técnicas de injeção asséptica apropriadas devem ser utilizadas. Os pacientes devem ser monitorados durante a semana seguinte à injeção para permitir um tratamento precoce caso ocorra uma infecção. Aumentos transitórios na pressão intraocular (PIO) têm sido observados nos primeiros 60 minutos após a injeção de Lucentis®. Aumentos sustentados da PIO também tem sido relatados. A pressão intraocular e a perfusão da cabeça do nervo óptico devem ser apropriadamente monitoradas e controladas. Existe um risco potencial de eventos tromboembólicos arteriais após uso intravítreo de inibidores do fator de crescimento endotelial vascular (VEGF). Uma taxa de acidente vascular cerebral numericamente maior foi observada em pacientes tratados com ranibizumabe 0,5 mg comparado com ranibizumabe 0,3 mg ou controle, entretanto, as diferenças não foram estatisticamente significantes. Pacientes com fator de risco de acidente vascular cerebral conhecido, incluindo histórico de acidente vascular cerebral anterior ou ataque isquêmico transiente, devem ser cuidadosamente avaliado por seu médico se o tratamento de Lucentis® é apropriado e se o benefício sobrepõe o potencial risco. Assim como todas as proteínas terapêuticas existe um potencial de imunogenicidade com Lucentis®. Lucentis® não foi estudado em pacientes com infecções sistêmica ativas ou em pacientes com condições oculares simultâneas como descolamento de retina ou buraco macular. Não deve ser usado durante a gravidez a menos que o benefício esperado supere o risco potencial para o feto. Para as mulheres que desejam engravidar e têm sido tratadas com ranibizumabe, é recomendável esperar pelo menos 3 meses após a última dose de ranibizumabe antes de engravidar, recomenda-se o uso de contraceptivos eficazes em mulheres com potencial para engravidar, amamentação não é recomendada. Após o tratamento, os pacientes podem desenvolver distúrbios visuais transitórios, que podem interferir na habilidade de dirigir veículos ou operar máquinas. Pacientes não devem dirigir veículos ou operar máquinas enquanto esses sintomas persistirem. Interações medicamentosas: Não foram realizados estudos de interação formal. Reações

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adversas: muito comuns: inflamação intraocular, vitreíte, descolamento do vítreo, hemorragia retiniana, distúrbio visual, dor no olho, moscas volantes, hemorragia conjuntival, irritação dos olhos, sensação de corpo estranho nos olhos, lacrimejamento aumentado, blefarite, olho seco, hiperemia ocular, prurido nos olhos, pressão intra-ocular aumentada, nasofaringite, dor de cabeça e artralgia. Comuns: degeneração retiniana, distúrbio retiniano, descolamento retiniano, ruptura retiniana, descolamento do epitélio pigmentar retiniano, ruptura do epitélio pigmentar retiniano, redução da acuidade visual, hemorragia vítrea, distúrbio vítreo, uveíte, irite, iridociclite, catarata, catarata sub-capsular, opacificação da cápsula posterior, ceratite ponteada, abrasão da córnea, turvação da câmara anterior (flare), visão borrada, hemorragia no local da injeção, hemorragia no olho, conjuntivite, conjuntivite alérgica, secreção do olho, fotopsia, fotofobia, desconforto ocular, edema palpebral, dor palpebral, hiperemia conjuntival, acidente vascular cerebral, gripe, infecção do trato urinário*, anemia, ansiedade, tosse, náusea, reações alérgicas (rash, prurido, urticária, eritema). Incomuns: cegueira, endoftalmite, hipópio, hifema, ceratopatia, adesão da íris, depósito corneal, estria corneal, dor no local da injeção, irritação no local de injeção, sensação estranha no olho, irritação na pálpebra. Graves: relacionadas com injeções intravítreas incluem endoftalmite, descolamento de retina regmatogênico, ruptura da retina e catarata traumática iatrogênica * Observado apenas na população com EMD. USO ADULTO VENDA SOB PRESCRIÇÃO MÉDICA. MS - 1.0068.1056. Informações completas para prescrição disponíveis à classe médica mediante solicitação. BSS 10.06.11. MS 31.08.07 + DOU 08.06.09 + BSS 10.06.11+ DOU 24.12.12 + Farm Resp. Referências bibliográficas: 1. Brown MM, Brown GC, Stein JD, Roth Z, Campanella J, Beauchamp GR. Age-related macular degeneration: economic burden and value-based medicine analysis. Can J Ophthalmol. 2005;40:277-287. 2. LUCENTIS® summary of product characteristics. Basel, Switzerland: Novartis Pharma AG; 2006. 3. Rosenfeld PJ, Brown DM, Heier JS, et al, for the MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431. 4. Williams RA, Brody BL, Thomas RG, Kaplan RM, Brown SI. The psychosocial impact of macular degeneration. Arch Ophthalmol. 1998;116:514-520. 5. Ferrara N, Damico L, Shams N, Lowman H, Kim R. Development of ranibizumab, an anti–vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina. 2006;26:859-870. 6. Die Redaktionellen Mitarbeiter sind an Ende der Beitrags Gelistet; Klin Monatsbl Augenheilkd;2007;224:559-566. 7. Mordenti J et cols. Toxicol Pathol;1999;27(5):536-44. 8. Regillo CD et cols; Am J Ophthalmol; 2008; 145:235-248. 9. Neil M. Bressler, MD; Tom S. Chang, MD; Jennifer T. Fine, ScD; Chantal M. Dolan, PhD; James Ward, PhD; (ANCHOR) Research Group ARCH OPHTHALMOL/VOL 127 (NO. 1), JAN 2009 10. Frank G. Holz, MD,1 Winfried Amoaku, MD, PhD,2 Juan Donate, MD,3 Robyn H. Guymer, MD,4 Ulrich Kellner, MD,5 Reinier O. Schlingemann, MD,6 Andreas Weichselberger, PhD,7 Giovanni Staurenghi, MD,8 SUSTAIN Study Group_ Ophthalmology Volume 118, Number 4, April 2011. 11. David S. Boyer, MD,1 Jeffrey S. Heier, MD,2 David M. Brown, MD,3 Steven F. Francom, PhD,4 Tsontcho Ianchulev, MD,4 Roman G. Rubio, MD4 Ophthalmology Volume 116, Number 9, September 2009 ANÚNCIO DESTINADO EXCLUSIVAMENTE À CLASSE MÉDICA. 2013 - © - DIREITOS Produzido em 02/13 RESERVADOS - NOVARTIS BIOCIÊNCIAS S/A - PROIBIDA A REPRODUÇÃO TOTAL OU PARCIAL SEM A AUTORIZAÇÃO DO TITULAR.

2/6/13 10:47 AM

Padrão de eficácia na DMRI neovascular2,9

C A D A L I N H A DE V I S Ã O G A N H A É UMA PARTE DA VIDA RECUPERADA 1 O MUNDO É LINDO > PARA O MUNDO É LINDO > PARA SER SER VISTOVISTO

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LUCENTIS®: padrão de eficácia na DMRI neovascular2,5 • • •

LUCENTIS é o tratamento que pode recuperar as atividades diárias prejudicadas pela DMRI neovascular.1-11 TM

•

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2/6/13 10:47 AM

Sociedade Brasileira de Retina e Vítreo (SBRV) 2012-2014 Presidente

Walter Yukihiko Takahashi (wytakahashi@uol.com.br)

Vice-presidente

André Marcelo Vieira Gomes (andremv@uol.com.br) Vice-presidentes regionais Norte: Edmundo Frota de Almeida Sobrinho (ealmeida@amazon.com.br) Nordeste: Otacílio de Oliveira Maia Junior (otacilio.maia@hsr.com.br) Centro-Oeste: Arnaldo Pacheco Cialdini (cialdini@cbco.com.br) Sudeste: Aderbal de Albuquerque Alves Jr. (aderbaloftalmo@uol.com.br) Sul: Mario Junqueira Nobrega (mjn@terra.com.br) Secretário Geral Antônio Marcelo Barbante Casella (mbcasella@gmail.com) Tesoureiro Fausto Uno (funo@uol.com.br) Diretor de Comunicação Jorge Rocha (jorgerocha1970@yahoo.com.br) Diretor de publicação Magno Antônio Ferreira (drmagno@hobc.com.br) Diretor de Curso Arnaldo Furman Bordon (afbordon@terra.com.br) Diretor de Assuntos Internacionais Mauricio Maia (maiamauricio@terra.com.br) Diretor de Assuntos Profissionais Alvaro Haverroth Hilgert (ahhilgert@terra.com.br) Editor chefe Magno Antônio Ferreira Editores associados Ácacio Muralha, André Gomes, Antônio Marcelo Barbante Casella, Eduardo Buchele Rodrigues, Mauricio Maia Conselho editorial Arnaldo Pacheco Cialdini, Álvaro Haverroth Hilgert, Carlos Alexandre Garcia, Eduardo Cunha de Souza, Danilo Soriano, Fabio Ribas, Francisco Cordeiro, Francisco Max Damico, J. Fernando Arevalo (Venezuela), Hisashi Suzuki, Jacó Lavisky, Joao Jorge Nassarala Júnior, Jorge Mitre, João Lobo, José Augusto Cardillo, John Helal Jr., Lawrence Chong (USA), Lihteh Wu, Márcio Bittar Nehemy, Marcos Pereira Ávila, Mario Nóbrega, Magno Ferreira, Michel Eid Farah, Osias Francisco de Souza, Oswaldo Moura Brasil, Paulo Henrique Morales, Pedro Paulo Bonomo, Rodrigo Jorge, Raul Vianna, Suel Abujamra, Silvana Vianello, Teodomiro Garrido e Walter Takahashi.

Edição 30 – fevereiro 2013

Publisher Flavio Mendes Bitelman Editora Marina Almeida – Mtb 45725/SP Diretora de arte Ana Luiza Vilela Gerentes Comerciais e de Marketing Fernanda Ferret e Nara Monteiro Gerente Administrativa Juliana Vasconcelos Capa: Ana Luiza Vilela Importante: A formatação e adequação dos anúncios às regras da ANVISA são de responsabilidade exclusiva dos anunciantes. Redação, administração, publicidade e correspondência: Rua Cônego Eugênio Leite, 920 Pinheiros, São Paulo, SP, Brasil, CEP 05414-001 Tel.: (11) 3061-9025 / FAX (11) 3081-4506 E-mail: marina.almeida@universovisual.com.br Tiragem: 3.500 exemplares Impressão: Ipsis Gráfica e Editora S.A. A Revista da Sociedade Brasileira de Retina e Vítreo (SBRV) é uma publicação trimestral da Jobson Brasil. As opiniões expressas nos artigos são de responsabilidade dos autores. Nenhuma parte desta edição pode ser reproduzida sem a autorização da Jobson Brasil e da Sociedade Brasileira de Retina e Vítreo.

Retina 29_expediente.indd 4

18/02/13 22:32

Mudando o jogo Em 1968, Dick Fosbury revolucionou o salto em altura desenvolvendo uma técnica que o levou ao ouro olímpico, elevando o nível para os atletas de todo o mundo.

É hora de reescrever as regras da cirurgia vitreorretiniana. •

Conheça a sonda ULTRAVIT® 5000 cpm com ciclo de trabalho controlado pelo cirurgião para reduzir roturas iatrogênicas e complicações pós-operatórias1

•

Confiança na compensação de PIO estável e integrada2

•

Melhora os resultados do paciente e leva a uma recuperação visual mais rápida com as plataformas MIVS ALCON® 3

•

Aumenta a eficácia durante a remoção de catarata com o Ultrassom Torcional OZil®4

•

Melhora a renovação de OR em 39% com os Componentes de Eficácia V-LOCITY®5

1. Rizzo S, et al. Comparative Study of the Standard 25-gauge Vitrectomy System vs the New Ultra-high-speed Vitrectomy System. Retina Today, encarte de setembro, 2010. 2. Dados em arquivo, Alcon Research 954-2020-003. 3. Nagpal M, Wartikar S, Nagpal K. Comparison of clinical outcomes and wound dynamics of sclerotomy ports of 20, 25, and 23 gauge vitrectomy. Retina. 2009;29(2):225-231. 4. Dr J Zacharias, ASCRS 2010 Film Festival, Best Video of Category, JCRS (a ser enviado)4 5. Dados da Alcon em arquivo 954-0000-004.

AlconRetina.com

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01/02/2012 18:32:44

EDITORIAL

ANDRÉ GOMES

MAGNO FERREIRA

EDUARDO RODRIGUES

E que venha 2013!

ais um ano rapidamente se foi. Calorosas celebrações reunindo amigos e familiares em pensamentos positivos e resoluções para um novo ano eclodiram. Ano aquele que nos brindou com inúmero avanços e novos dados que nos foram apresentados em abundância em eventos de qualidade, nacionais e mundo afora. Novos resultados de estudos de grande relevância como CATT e IVAN, novos agentes “anti-VEGFs” para tratamento da DMRI, oclusões venosas e edema macular diabético, a aprovação de um tratamento não cirúrgico para a adesão vítreo-macular, novas técnicas e instrumental cirúrgicos... E nada melhor que o recomeço para remoermos as estatísticas, as significâncias, aprofundarmos nosso domínio baseado em evidências e nos lançarmos para o enfrentamento dos desafios diários da prática da retinologia. O ano de 2013 promete. Nosso encontro anual que acontece em abril, sempre carregado de sucesso e repercussão mundial, está mais recheado que nunca. Capitaneado pelo nosso ilustre e determinado Prof. Dr. Marcio Nehemy, o evento em Belo Horizonte, com um programa pautado pela excelência científica, reúne todos os elementos para tornar-se digno de nossas memorias. Nossa sociedade não para de crescer. Imbuída de objetivos constantes de aprimoramento, a diretoria da SBRV continua a busca para se tornar uma entidade

Retina 30_editorial.indd 6

em sintonia com o elevado nível de sofisticação dos especialistas em retina do nosso país. Parcerias éticas tem sido buscadas e estabelecidas. Nossos diretores têm trabalhado com afinco em busca da futura indexação de nossa revista. A comissão de reforma estatutária instalada não mede esforços para alcançar, em breve, um estatuto atualizado e em concordância com o perfeito funcionamento da nossa entidade. Programa de diretrizes envolvendo procedimentos recentes utilizados em nossa especialidade estão no forno, sendo aperfeiçoados em conjunto com o CBO. Nosso site está em constante aperfeiçoamento. Enfim, visualiza-se uma entidade que seja orgulho e ao mesmo tempo mereça o respeito tanto do especialista nacional associado como da retinologia mundial. O recente interesse em estreitar laços e aumentar a colaboração mútua, partido das sociedades de especialistas em retina dos Estados Unidos, Europa e Panamericana, revela que o rumo adotado parece estar correto. Apreciem sem moderação a entrevista com o renomado cirurgião americano Pravin Dugel, e os artigos incluídos neste número. Ajustem-se nas cadeiras para um ano cientificamente próspero e promissor. Um forte abraço a todos!

André V. Gomes Vice-presidente da SBRV

18/02/13 16:48

Transformações

30º edição da revista da Sociedade Brasileira de Retina e Vítreo apresenta vários progressos, na área de retina, na entrevista concedida pelo colega Pravin Dugel. Nesta matéria ele discursa sobre assuntos como a chegada da Ocriplasmina no mercado americano, estudos avançados de anti-platelet-derived growth factor (anti-PDGF) e sistemas de vitrectomia alto corte. Ocriplasmina (Jetrhea) começa, no mês de janeiro de 2013, a ser comercializada no EUA por US$ 3.950,00 por ampola de 2 ml (2.5 mg/ml). Aflibercept (Eylia) deve estar até março de 2013 também disponível no Brasil para tratamento ocular quimioterápico com antiangiogênico. Ficamos, portanto, animados com as perspectivas para 2013, após dois ou três anos sem grandes mudanças na propedêutica e terapia de retina. Esta edição da revista também conta com artigos científicos originais de diferentes regiões do Brasil. Ferreira et al. publicam aqui o artigo intitulado “Modified technique for active removal of silicone oil in a single step 23-gauge sutureless system: outcomes and complications”. Este artigo conclui que a técnica apresentada é acessível a todos os cirurgiões de retina, rápida, e com bons resultados anatômicos e visuais. Hosoume et al. reportam complicações sistêmicas e locais com o uso de bevacizumabe intravítreo, e alertam os colegas que injeções intravítreas devem ser monitoradas. A partir desta edição, a revista conta com Eduardo Büchele Rodrigues, Professor de Oftalmologia da Universidade Federal de São Paulo, como co-editor associado da revista juntamente com Magno Ferreira. Terminamos desejando a todos os membros da nossa querida sociedade um ótimo 2013, e convidando-os a submeter artigos para a publicação.

SUMÁRIO Edição 30 – Fevereiro 2013

ENTREVISTA Interview with Pravin Dugel

ARTIGO Modifield technique for active removal of silicone oil in a single step 23-gauge sutureless system. Outcomes and complications

ARTIGO Hemorrhagic events after intraocular injection of bevacizumab

Boa leitura!

Magno Ferreira Editor chefe Eduardo Buchele Rodrigues Editor associado

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18/02/13 16:48

ENTREVISTA

Interview with Pravin Dugel

ARQUIVO UNIVERSO VISUAL

Pravin Dugel

“I think the main thing that will change with the vitrectomy machines that we have now is our ability to control the fluidics”

raduated Summa Cum Laude from Columbia University and attended UCLA School of Medicine, Pravin Dugel, then completed his residency in ophthalmology at the Doheny Eye Institute, USC School of Medicine. Thereafter, he completed his medical retina fellowship at the Bascom Palmer Eye Institute and his surgical retina fellowship at the Doheny Eye Institute, where then was elected to serve on the faculty as the Resident Director. Dr Dugel joined Retinal Consultants of Arizona in July, 1994. Dugel has authored more than 200 papers, 35 book chapters and has been invited to lecture at prestigious meetings, Visiting Professorships and Universities worldwide. He is on the Editorial Board of several major journals. Dugel is internationally recognized as a major clinical researcher, having been a primary investigator in over 50 multicenter clinical trials. His research and educational contributions earned him the prestigious Senior Honor Award from the American Academy of Ophthalmology (AAO). Dugel is involved in numerous prestigious organizations. Locally, he has been President of the Phoenix Ophthalmology Society and is on the Board of Directors of the Arizona Ophthalmology Society. Nationally, he is on the Board of Directors of the American Society of Retina Specialists (ASRS), Chairman of the ASRS Research and Therapeutics Committee and Chairman of the AAO Media Relations Committee. Internationally, he is on the Board of Directors of the Asia Pacific Vitreoretinal Society and in the Organizing Committee of and has been honored by the Pan Pacific Academy of Ophthalmology, European Vitreoretinal Society, Chinese Vitreoretinal Society, Indian Vitreoretinal Society, Korean Vitreoretinal Society and the World Ophthalmology Congress. Dugel has received numerous awards including amongst others, the Heed Foundation Fellowship Award, The Ronald G. Michels Surgical Fellowship Award, AAO Senior Honor Award, ASRS Honor Award, AAO Secretariat Award. Dr Dugel has been named “one of the best 35 ophthalmologists in the USA” by the Becker Institute. Currently, Dr Dugel serves as Managing Partner of Retinal Consultants of Arizona and Founding Member of the Spectra Eye Institute. He is also Clinical Associate Professor, Doheny Eye Institute, Keck School of Medicine, University of Southern California (USC). SBRV: Pravin, what do you think that will change in the future with vitrectomy? How are the next steps in vitrectomy surgery?

8 F E V E R E I R O 2 0 1 3 | RET IN A & V ITR EO

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18/02/13 16:45

Pravin Dugel: I think the main thing

that will change with the vitrectomy machines that we have now is our ability to control the fluidics. I think there is a turn that we’ve taken with our newer machines, where the parameters that we can set, that we’ve never had before; things such as duty cycles, things such as flow control and things such as ultra-high speed cutting, and I think what we’ll learn to do is to operate with as little flow as possible, as safely as possible, and with as high cut rate as possible. That will make our surgery a lot safer. The second thing that I think will also happen is that we’ll learn how to use our cutter as a multifunctional tool, so learn to use the parameters to use duty cycle control, for instance, to make our cutter into a vertical scissor, a horizontal scissor or maybe even simulate a phaco fragmatome, so that we’ll be going in and out of the eye less, it’ll be safer, it’ll be more efficient, and I think it’ll be able to do a lot more with the cutter and with our vitrectomy instrumentation. I think we’re just beginning to understand the importance of these fluidic parameters so, inside the eye, as far as the vitrectomy instrumentation is concerned, I think that’s gonna be the biggest change. Outside the eye, the thing that I’m quite fascinated with is Ocriplasmin, as you know, the trial, maybe three trials have been done and it has been shown to be very successful in macular holes, in causing post vitreous detachments… What we don’t know, and this hasn’t been looked at, but is fascinating to think about, is whether it can be used as an adjunct to surgery, as one of the most difficult surgeries we do are traction detachments, for instance, in diabetics, and it would be possible to inject Ocriplasmin maybe a day before, so that, when we do our surgery, the

traction would be much easier to remove, so is fascinating to think along those trends in the future, to see Ocriplasmin as a role, as an adjunct to surgery, we don’t know the answer yet, but I think that answer will come pretty soon. SBRV: Thank you, Pravin, and the next question I want to ask you, what about the treatment for age-related macular degeneration? What do you think is coming in the near future to treat this disease? Dugel: I think the main thing with age-

related macular degeneration is the treatment burden. We know now, especially from the CATT II study, that even if we treat a patient every single month for a year, it doesn’t confer any permanent structural advantage whatsoever, in other words, in the CAT II data, when patients were switched over from monthly treatment to PRN treatment, it was as though they were never treated monthly anyway. So the bottom line is that the anti-VEGF monotherapy gives you no permanent structural benefit whatsoever, and that’s not just true in macular degeneration, that’s true in DME, that’s true in vein occlusion, and that’s why we have to keep on treating forever. When you think about it from a physiologic sense, the people in oncology already know why we have this resistance. They´ve been able to figure out that, when a new vascular complex grows, there’s a group of cells called the “tip cells”. These cells lead the growth, and these are the only naked endothelial cells, they produce a factor called PDGF or platelet-derived growth factor, which stimulates pericytes, it recruits and matures pericytes, these pericytes come and cover the neovascular complex and make them resistant to anti-VEGF monotherapy, and that’s why we have to keep on treating forever, because of this pericyte

resistance, so our treatment burden at this point is unacceptable and absolutely not sustainable, so none of our patients are getting the kind of results that we think they’re getting from the ANCHOR and MARINA studies, because we simply can’t treat monthly forever. So the answer to this is to find out how we can make this treatment more sustainable, and the only thing that I can see to make this more sustainable is to do what the oncologist do, no oncologist ever treats a complicated process such as antigenesis with only one factor, with only one drug in the one factor, even if it is the most important factor, all of these processes are treated with a combination treatment, so I think combination treatment is the only way to have a sustainable treatment model and I think the combination that I’m most excited about is the combination of anti-PDGF, which will inhibit and strip pericytes, with antiVEGF, because that to me seems to make sense, and because the phase I data is so promising. The phase II data will be presented at a sub-academy day, at a Sub day, in a retina meeting in Chicago, so I’m very much looking forward to that, but at the end of the day, combination therapy is the only way that we’re gonna have a sustainable treatment model. The next step after that is to put that combination treatment in some kind of a drug delivery device, and ultimately, that’s gonna be the most sustainable, so the first step to answer the question is gonna be combination treatment, the second step is going to be to put that combination treatment in a drug delivery device. SBRV: Thank you very much Pravin, for this update, a very important opinion about the new treatments in vitrectomy and also in age-related macular degeneration and the issues in ophthalmology and retina. ■

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Modifield technique for active removal of silicone oil in a single step 23-gauge sutureless system. Outcomes and complications Magno Antônio Ferreira, MD, PhD 1; Rafael Lacerda Furlanetto, MD 1; Roberta Franceschini Traldi, MD 1; Raquel Eustáquio Alves Ferreira, MD 1; Marcos Antônio Ferreira, MD 2; Flavio Jaime da Rocha, MD, PhD 1; Lúcio Borges Araújo, PhD 3 1. Department of Ophthalmology, Federal University of Uberlandia, Brazil 2. Pan-American Institute Of Ophthamology, Brasilia, Brazil 3. Department of Mathematic, Federal University of Uberlandia, Brazil

This article has never been submitted to any other journal before Financial Support and Competing Interests: none Keywords: Silicone oil removal, 23-gauge vitrectomy, transconjunctival sutureless vitrectomy ABSTRACT Purpose: To describe a modified technique for active removal of silicone oil (SO) in a single-step 23-gauge transconjunctival sutureless vitrectomy (TSV) without opening a 20-gauge sclerotomy or cannula insertion into the eye. The outcomes and complications before and after the procedure were analyzed. Materials and Methods: Forty-six eyes of 41 patients with vitrectomy indications for different pathologies were operated on with single step 23-gauge TSV with 1300-centistokes SO and submitted to active SO removal, using a modified technique. The technique consisted of using the Viscous Fluid Controller- VFC (Accurus® Alcon

Laboratories, Inc., Fort Worth, TX) pre set with the vacuum of 500 mmHg and the Vented Gas Fluid InjectorVGFI (Accurus® Alcon Laboratories, Inc., Fort Worth, TX) pre set with infusion pressure of 30 mmHg. The 20-gauge cannula that comes with the VFC pack was fitted in the interior edge of the trocar and aspirated the SO without entering into the eye. Preoperative and postoperative complications, time to perform the procedure, intraocular pressure (IOP) and anatomical and visual results were evaluated. Results: Tractional retinal detachment (RD) accompanied by vitreous hemorrhage (VH) were present in 21 eyes (45.65%); RD in 10 patients (21.75 %), RD and proliferative vitreoretinopathy (PVR)

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in 4 eyes (8.7%), combined tractional and rhegmatogenous RD in 3 eyes (6.5%), giant retinal tear (GRT) with RD in 3 eyes (6.5%), RD with vitreous opacities secondary to toxoplasmosis in 2 patients (4.3%), tractional RD only was present in one eye (2.2%), trauma with RD, GRT and VH in 1 eye (2.2) and RD with macular hole (MH) in one eye (2,2%) . All patients underwent single step 23-gauge TSV. The mean removal time for 1300-centistokes SO were 3.05±0.27 (range 2.40- 3.55) minutes. No suture was placed in any sclerotomy. Mean follow-up was 19.91 ± 7.14 (range 8-32) months. Mean preoperative bestcorrected visual acuity (BCVA) was counting fingers (CF) less than 50 cm or 2.6 logarithm of the minimum angle of resolution (logMAR) and the mean postoperative BCVA 20/125 or 0.8 logMAR on the last visit (p< 0.0001). Four patients needed reoperation, and time since the first

surgery until the final SO removal was counted. Membrane peeling was performed during SO removal in three patients. One patient that had RD and vitreous opacity secondary to toxoplasmosis presented IOP of zero one month later and phthisis even though the retina was attached. The mean IOP on the first postoperative day was 10.8 ± 3.18 (range 5-20) mmHg and three eyes (6.5%) had IOP ≤ 6mmHg. The IOP difference was statistically significant only in the first postoperative day (p<0.0001). Conclusions: This feasible and accessible technique to remove SO in a 23-gauge TSV was extremely effective, non time-consuming, with good anatomic and visual outcomes, and seems to be reproducible in most patients. Further studies should be performed to evaluate safety and effectiveness of this technique when removing SO with different viscosities.

INTRODUCTION

scarred conjunctiva, mainly in eyes, which have been operated more than once. Transconjunctival sutureless vitrectomy (TSV) provides potential advantages over traditional 20 gauge vitrectomy, including faster wound healing, less conjunctival scarring, improved patient comfort, decreased inflammation, reduced postoperative astigmatic change, and shortening of surgical opening and closing time.10 The 25-gauge TSV system was first developed by Fujii et al in 2002. 11 Initially, 25-gauge vitrectomy was used in limited cases such as core vitrectomy, epiretinal membrane peeling and macular hole surgery.12,13 The development of secondgeneration 25-gauge instruments and brighter xenon light sources enabled bimanual surgery and more peripheral vitreous dissection.14,15 However, inferior fluidics, and flexible instruments are inherent to the 25-gauge system. Besides, infusion of SO in the 25-gauge vitrectomy setting is more time-consuming due to its reduced microcannula lumen (0.5 mm) when compared to the 20-gauge system (0.9 mm). Slightly larger instruments are more feasible to solve some of these problems. 16 Eckardt described a 23-gauge TSV in 2005, targeting some of the shortcomings

ilicone oil (SO) was first used in vitreoretinal surgery in 1962 and since then has been widely used as an intraocular tamponade in complex retinal detachments.1 Quick visual rehabilitation is achieved by SO, which has the advantage of long-acting tamponading effect with relatively stable physico-chemical property. However, the incidence and severity of its complications such as glaucoma, cataract, and keratopathy especially in aphakic eyes increase with duration of its intraocular stay.2-4 Therefore, as a general principle, it is recommended that SO should be removed once the objectives of the tamponade have been achieved and the retinal status is stable to minimize the long-term complications associated with its use.5 Many authors have reported their techniques and preferences for removal of SO.4,6-9 There are anterior and posterior segment approaches. The disadvantages of SO removal from posterior segment are the need for conjunctival dissection and making three sclerotomies that must be sutured later. This procedure is often difficult and time-consuming due to

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“Silicone oil (SO) was first used in vitreoretinal surgery in 1962 and since then has been widely used as an intraocular tamponade in complex retinal detachments”

of the 25-gauge system.17 The 23-gauge instruments are more rigid than those of the 25-gauge system and behave more like traditional 20-gauge instruments, allowing more peripheral vitrectomy and higher complexity maneuvers. Wider lumens of 23-gauge instruments also improve illumination and fluid flow, reducing the vitrectomy time and facilitating injection and removing SO. The 23-gauge system also utilizes oblique self-sealing scleral tunnels, which reduce the potential complication of postoperative leakage.17 Kapran have described his technique for active removal of SO in 25-gauge sutureless system for 1000 and 5000-centistokes with good anatomic and functional results without need of suture, no choroidal detachment, folds or endophthalmitis and the hypotony was transient lasting 3-7 days in nine cases out of 28 (32.1%).18 Passive removal of SO with 25-gauge system has been published showing also good results with hypotony only in 2 hours after SO removal and no need of sutures.19 Unfortunately some commercially available systems used for active aspiration of SO up to now comes with a cannula of 20-gauge caliber, what leads the surgeon to open a 20-gauge sclerotomy. Acquisition of 23 or 25-gauge cannulas is not always possible and may rise surgery costs. In this study we describe a modified technique for active removal of SO in a single-step 23-gauge sutureless system without opening a 20-gauge sclerotomy or cannula insertion into the eye. The outcomes and complication before and after the procedure were analyzed.

MATERIAL AND METHODS This retrospective interventional cases series enrolled patients that presented different pathologies and were submitted to 1300-centistokes SO removal with a single step 23-gauge TSV in a private eye hospital in Uberlandia, Brazil, between June 2007 and March 2010. The possible risks and benefits of the treatment were explained to the patients and written informed consent in accordance with the Declaration of Helsinki was obtained before surgical procedures. Approval to review patient’s charts was obtained from the Institutional Review Board. The inclusion criteria were eyes submitted prior to 23-gauge TSV with 1300-centistokes SO implantation in the same hospital. Criteria to remove SO was retina attached for at least three months with one or more surgeries and each surgery was performed by the same surgeon (M.A.F). In this paper, preoperative data were obtained from the last patient visit before the first surgery (vitrectomy with SO implantation). Postoperative data refers to information after SO removal surgery and were collected on day 1, week 1 and Month 1 after surgical procedure, except for the visual acuity. Best corrected visual acuity (BCVA) was measured with the Snellen chart before the first surgery and at least one month after SO removal, and was converted into logMAR score for statistical analysis. Pre- and postoperative intraocular pressure (IOP), followup time, and complications were also registered. IOP was measured with a calibrated Goldmann applanation tonometer and IOP measurements of 6 mmHg or less were considered the definition of hypotony. Any important information between surgeries that could interfere in final results was also noted. Since all surgeries were recorded, SO removal time was able to be analyzed before movie edition. Slit lamp findings of the cornea, conjunctiva, and anterior chamber were saved as well. SURGICAL PROCEDURE Surgical steps described below refers only to SO removal surgery. All surgical procedures were performed under monitored anesthesia care with a peribulbar block. The Accurus® surgical system (Alcon Laboratories, Inc., Fort Worth, TX) with xenon light illuminator and singlestep transconjunctival 23-gauge trocars were used for all cases. The first sclerotomy was made in the inferotemporal region and 23-gauge infusion cannula was attached to the microcannula after withdrawing the trocar. Once the

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SURGICAL TECHNIQUE 1307

FIGURE 1: Active removal of silicone oil with 23-gauge system, using a 20-gauge cannula without entering into the eye. Top left, late stage of SO removal showing a bleb of silicone oil been removing using a 20-gauge cannula into the trocar. Top right, showing the decreasing size of the SO bleb. Bottom left, small bleb of SO getting inside the cannula. Bottom right, end stage with a very small bleb disappearing of the pupillary area

GRAPHIC 1: VISUAL ACUITY (VA) CHANGE BEFORE AND AFTER SURGERY

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TABLE 1. CHARACTERISTICS OF PREOPERATIVE RETINAL PATHOLOGIES AND PARTICIPATION

PREOPERATIVE RETINAL PATHOLOGY

CASES, NO

PARTICIPATION, %

Combined DTRD and IVH

45.65

Rhegmatogenous RD

21.75

Combined RD and PVR

8.7

Combined DTRD and RD

6.5

Combined GRT and RD

6.5

Combined RD, Toxoplasmosis and Vitreous Opacity

4.3

DTRD

2.2

Combined Trauma, RD, GRT and IVH

2.2

Combined Macular Hole and RD

2.2

100

TOTAL

VDTRD = Diabetic Tractional Retinal Detachment; IVH = Intra-Vitreous Hemorrhage; RD = Retinal Detachment; PVR = Proliferative Vitreoretinopathy; GRT = Giant Retinal Tear

infusion cannula line was opened, two more microcannula were placed in the superonasal and superotemporal regions. Incisions with trocars were created in an angled approach of 20° to 30° parallel to the limbus. The orbital retractor (Schepens orbital retractor, Asico, Westmont, IL) was placed in the opposite side of the tunnel construction to avoid eye movement. The sclera was penetrated 3.5 mm or 4 mm posterior to the limbus depending on the lens status with the bevel up. Once the trocar was advanced into the sclera to the point of reaching the trocar sleeve, the cannula was rotated 90° perpendicular to the globe aiming toward the midvitreous cavity and fully inserted into the eye. The technique used to remove SO consisted of using de Viscous Fluid Controller - VFC (Accurus® Alcon Laboratories, Inc., Fort Worth, TX) pre set with the vacuum of 500 mmHg and the Vented Gas Fluid Injector - VGFI (Accurus® Alcon Laboratories, Inc., Fort Worth, TX) pre set with infusion pressure of 30 mmHg. The cannula used in each procedure was the 20-gauge cannula that comes within the VFC pack. It was inserted just in the interior edge of the

trocar, fitting it, and aspirating the oil without entering into the eye. At the end of the procedure, when the amount of oil decreased and the SO bubble was very mobile, scleral depression was used to move the bubble into the trocar used for aspiration (Figure 1). RESULTS Forty-six eyes of 41 patients (27 males; 14 females) that underwent 23-gauge vitrectomy with 1300-centistokes SO implantation were enrolled. The mean age was 55.56±14.62 (range, 25-88) years. The mean followup ± SD was 19.91±7.14 (range, 8-32) month. Table 1 summarizes participants according to their preoperative retinal pathologies. The mean preoperative BCVA was counting fingers (CF) less than 50 cm according to Snellen scale (range, Light Perception to CF at 3 meters) or 2.60±0.62 logMAR. The mean postoperative Snellen BCVA was approximately 20/125 (range, No Light Perception to 20/25; mean ± SD, 0.83±0.55 logMAR). Detailed information about each participant is showed in Graphic 1. Comparing with

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TABLE 2. CHARACTERISTICS OF THE EYES HAVING SILICONE OIL REMOVAL WITH MODIFIED TECHNIQUE ACTIVE SUTURELESS 23-GAUGE SYSTEM PATIENT LFL MJOS DGD MM MM LRD EPS LCR LRD FRVM RCM MHCM APO APO CEM CEM LPR MMS MA MA MBS OM RJS MFS OVM EJV RTC ACB IFA ABM DP ROA AS HGA RFG ORA IA FCA JJP BLAF JAT JAC BAF JEMS CAM MJAS

AGE, GENDER

F/U, MO

SO R, MO

DIAGNOSIS

PREOP BCVA, LOGMAR

POSTOP BCVA, LOGMAR

TIME SO R, SEC

52, M 59, F 61, M 54, M 54, M 25, F 68, F 69, M 25, F 28, F 69, M 60, F 30, M 30, M 61, M 61, M 57, M 47, M 59, M 59, M 57, F 53, M 41, M 45, F 65, M 73, M 42, M 27, M 68, F 52, M 57, M 48, M 49, F 62, M 41, F 54, M 73, M 31, M 86, M 63, F 58, M 54, M 88, F 59, M 71, F 62, F

32 27 27 25 24 24 19 17 16 32 26 28 29 21 16 10 11 21 17 10 10 16 25 10 10 31 28 26 25 25 25 23 19 17 23 17 13 11 10 8 27 24 24 11 9 17

6 3 6 4 3 4 3 3 5 7 3 6 6 5 4 3 3 3 1 4 4 4 8 3 3 12 4 3 4 4 4 5 13 6 6 6 5 6 6 3 4 6 6 3 17 6

DTRRD DTRD + IVH DTRD + IVH DTRD + IVH DTRD DTRD + IVH DTRD + IVH DTRD + IVH DTRD + IVH DTRD + IVH DTRD + IVH DTRD + IVH DTRD + IVH DTRD + IVH DTRD + IVH DTRD + IVH DTRD + IVH DTRD + IVH DTRRD DTRRD DTRD + IVH DTRD + IVH DTRD + IVH DTRD + IVH DTRD + IVH RD + PVR RD RD RD GRT + RD RD RD RD RD RD + TOXO + VO RD GRT + RD RD + TOXO + VO RD + PVR RD GRT + RD T + RD + GRT + IVH RD + PVR RD + PVR RD + MH RD

1.70 1.50 3.00 3.00 1.70 3.00 3.00 3.00 3.00 3.00 2.00 3.00 3.00 1.70 3.00 3.00 3.00 3.00 1.70 1.70 3.00 3.00 3.00 1.50 1.40 3.00 3.00 1.40 3.00 3.00 1.40 3.00 3.00 3.00 3.00 3.00 3.00 3.00 2.00 3.00 3.00 3.00 2.00 3.00 2.00 3.00

0.20 0.60 3.00 1.00 1.00 1.00 0.70 0.10 0.60 1.00 1.30 0.30 0.60 0.60 0.60 0.40 0.30 0.10 1.00 0.70 1.00 1.00 0.70 0.60 0.50 1.40 0.30 0.10 0.50 0.60 1.00 0.70 0.80 0.70 Phthisis 0.60 0.40 0.80 1.40 2.00 0.60 0.70 1.30 2.00 1.70 1.00

195 200 220 185 200 195 180 160 160 180 165 190 170 190 190 180 165 170 180 185 190 195 180 195 180 160 165 160 175 200 185 175 170 175 180 165 160 195 185 190 195 200 160 165 165 185

F/U, mo = follow-up in months; SO R, mo = silicone oil removal in months; Preop BCVA = preoperative best-corrected visual acuity; Postop BCVA= postoperative best corrected visual acuity; Time SO R, sec = time for silicone oil removal in seconds; DTRD = diabetic tractional retinal detachment; IVH = intravitreous hemorrhage; DTRRD = diabetic tractional rhegmatogenous retinal detachment; RD = retinal detachment; PVR = proliferative vitreoretinopathy; GRT = giant retinal tear; TOXO = inactive toxoplasmosis; VO = vitreous opacity; T = trauma; MH = macular hole

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preoperative BCVA, the visual improvement was statistically significant (p< 0.0001). Forty-one eyes (89.13%) improved two or more lines of vision according to Snellen scale. Visual acuity remained the same in 4 out of 46 eyes (8.67%). One eye (2.2%) developed phthisis, which presented before surgery RD associated with toxoplasmosis and vitreous opacity. Following the procedure, he developed an anterior fibrosis and severe hypotony with secondary phthisis. The mean SO removal time was 3.05±0.27 (range 2.40 – 3.55) minutes. The mean time from the SO implantation to its removal was 5.06±2.83 months (range, 1-17 month). Removal of SO only 1 month later occurred in one eye that previously presented combined Diabetic Tractional Retinal Detachment (DTRD) and rhegmatogenous retinal detachment (RD), and macular change was observed on the first postoperative day. One-week later optical coherence tomography (OCT) was performed and sub-foveal perfluoroctane bleb was detected. The SO was removed one month later and the sub-foveal perfluoroctane bleb was removed with sub-retinal cannula 20-G/32-G curved (BD, Visitec, NJ, USA). During such procedure one sclerotomy was transformed in 20 gauge and had to be sutured with 7-0 vycril. This was the only sclerotomy that had to be sutured and was not related to the SO removal procedure itself. These results are summarized in Table 2. The mean preoperative IOP±SD was 14.28±2.57 (range 10-20 mmHg). Statistically significant difference between IOP before and after SO removal was seen only in the first postoperative day, since the mean first day postoperative IOP±SD was 10.8±3.18 (range 5-20 mmHg) (p<0.0001). Three eyes (6.5%) presented hypotony at this occasion. The mean first week IOP ± SD was 14.96±5.06 (range 6-28 mmHg) and the difference was not statistically significant (p=0.33). Also, the difference between IOP was not statistically significant one month after surgery (14.39±3.77mmHg, 0-24 mmHg, and 0.83; mean, range and significance, respectively). Four patients (8.7%) were re-operated on, one three times and three needed two surgeries, excluding the surgery to remove SO. In exception, one eye presented re-bleeding after SO removal and re-operation had to be performed leaving it with balanced saline solution (BSS). All other eyes were re-operated and left with SO until the retina was completely attached for at least three months and time from the first surgery to the SO removal was counted. Membrane

“Transconjunctival sutureless vitrectomy (TSV) provides potential advantages over traditional 20 gauge vitrectomy, including faster wound healing, less conjunctival scarring”

peeling during final SO removal was done in three eyes (6.5%). Re-bleeding occurred in two eyes (4.3%) and was treated with non-steroidal anti-inflammatory (NSAIDs) with resolution of the bleeding in one eye. The other eye the bleeding did not solve with NSAIDs and was re-operated on with membrane dissection in the posterior pole with good anatomic result. One patient (2.2%) had macular edema and was treated with Bevacizumab associated with Triamcinolone with resolution of the edema. None of the eyes had endophthalmitis, choroidal detachment or persistent hypotony except the eye that developed phthisis. These results are summarized in table 3. DISCUSSION A few techniques have been described to remove intraocular SO.4,6-9,20 Infusion of BSS is made into the vitreous cavity for SO removal and it is either allowed to flow out passively through a sclerotomy port,4 or is removed by active suction.20 In aphakic eyes, SO can be removed through a superior limbal or clear cornea incision and the infusion can be provided through pars plana or from an anterior chamber maintainer. Passive SO removal through pupillary area combined with cataract surgery has also been published.9 However, it is only feasible for aphakic eyes and it necessitates the disruption of the posterior capsule integrity, which may be disadvantageous. Besides, using an anterior segment approach has severe limitations if an additional vitreoretinal procedure is necessary. Silicone oil removal using sutureless system

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TABLE 3. INTRAOCULAR PRESSURE BEHAVIOR AND POSTOPERATIVE COMPLICATIONS OF EYES HAVING SILICONE OIL REMOVAL WITH MODIFIED TECHNIQUE ACTIVE SUTURELESS 23-GAUGE SYSTEM PATIENT NAME LFL MJOS DGD MM MM LRD EPS LCR LRD FRVM RCM MHCM APO APO CEM CEM LPR MMS MA MA MBS OM RJS MFS OVM EJV RTC ACB IFA ABM DP ROA AS HGA RFG ORA IA FCA JJP BLAF JAT JAC BAF JEMS CAM MJAS

PREOP IOP (MMHG)

IOP DAY 1 (MMHG)

IOP WEEK 1 (MMHG)

IOP MONTH 1 (MMHG)

COMPLICATIONS AFTER SO R

16 13 18 13 14 15 15 14 17 12 11 16 19 15 15 14 11 16 13 12 20 16 15 14 12 11 18 14 20 13 11 17 13 15 10 16 18 15 13 15 14 10 14 12 12 10

12 12 12 15 13 16 13 11 14 8 9 8 9 13 15 13 9 12 7 12 9 16 20 11 10 7 8 15 8 5 8 10 9 9 8 12 9 10 16 6 5 10 12 9 10 12

11 13 16 18 16 20 11 12 19 10 11 11 16 15 12 11 14 13 19 16 19 21 18 14 12 10 14 14 18 24 17 28 14 15 6 14 25 25 26 8 11 8 10 12 10 11

15 11 15 18 18 15 14 14 18 12 10 12 16 16 15 16 14 12 17 15 20 18 16 16 11 11 16 16 21 18 24 12 10 17 0 12 16 16 16 12 14 10 12 12 10 13

VH VH / RE-OP / MP RE-OP / MP CME / B+T G 3 RE-OP AF / PHY ERM / MP GA 2 RE-OP OMH -

Preop IOP = preoperative intraocular pressure; IOP Day 1 = intraocular pressure in the first postoperative day; IOP Week 1 = intraocular pressure in the first postoperative week; IOP Month 1 = intraocular pressure in the first postoperative month; SO R= silicone oil removal; VH = vitreous hemorrhage; RE-OP = re-operation; MP = membrane peeling; CME = cystoid macular edema; B+T = Bevacizumab and triancinolone; G= glaucoma; AF/PHY = anterior fibrosis and phthisis; ERM = epiretinal membrane; GA= geographic atrophy; OMH: open macular hole

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has advantages of extracting the oil from pars plana and avoiding conjunctival peritomies and suturing of sclera and conjunctiva. Also this technique can be performed in pseudophakic, aphakic, and phakic eyes successively.18,19 Sutureless surgery avoids the local inflammatory reaction due to suture materials and eliminates the irritation from exposed sutures. Time to remove SO depends of viscosity of the oil and using of passive or active aspiration. There have been reported SO removal using active aspiration taking 4 to 5 minutes.20 In the study by Yildirim et al, mean surgical time was approximately 9 minutes for the passive washout of 1300-centistokes SO group, and 7.6 minutes for the active aspiration of 5700-centistokes.9 Using sutureless 25-gauge system with passive aspiration of 1000-centistokes SO was achieved in a mean period of 7.3 minutes, which is considerably short. Other researches also tried to remove passively 5000-centistokes SO through 25-G transconjunctival sutureless sclerotomies, but it took a very long time and they did not recommend this technique for 5000-centistokes SO.19 Kapran using also 25-gauge system with active aspiration reported mean time of 3.31 for 1000-centistokes and 10.27 for 5000-centistokes.18 Song and colleagues 24 took a shorter mean time (about 6.8 minutes) for active removal of 5000-centistokes SO using a different approach. In their report, they compared two commercially available trocarcannula systems and found out no statistical difference in removal time between the two systems. On the other hand, they describe a different approach to remove heavy SO without entering into the eye using a hand-made device from other equipment attached to trocar-cannula systems, what probably leads to more costs and time-consuming. In the current paper, we describe a safe technique to remove SO actively using standardized and commercially available instruments which come inside the same package necessary for retinal surgery and do not need assembly, saving time and cost. Our mean time for 1300-centistokes SO removal was 3.05 minutes, what means that it took shorter time than previous publications cited here previously, even though no attempt has been made to removal SO with high viscosity. Regarding IOP change after SO removal using 23-gauge system and active aspiration of 5000-centistokes, Song and colleagues 24 found hypotony in 4 eyes (23.53%) on postoperative day, but all resolved within 1 week. In our study, we detected a statistically significant decrease in IOP just

â&#x20AC;&#x153;In conclusion, using this feasible and accessible technique to remove 1300-centistokes SO in a 23-gauge TSV was extremely safe and effective, with good anatomic and visual outcomesâ&#x20AC;?

at the first postoperative day, when hypotony occurred in 3 (6.5%) eyes. This finding is similar to other previous reports, which also found transient hypotony in the first postoperative day. 24.25 They suggested that subclinical BSS leakage could be considered one possible explanation for this transient hypotony, but, in our study, we did not observe localized bleb formation at the sclerotomy site, reenforcing the safety of the procedure. The IOP increased to within normal limits after one week without any additional procedure, taking into account that no suture was placed in any sclerotomy. Despite our efforts, one patient developed chronic hypotony and phthisis. For sutureless surgery, a theoretical risk is endophthalmitis. In our study we did not experience this complication, but we cannot affirm that the risk does not exist, because of the limited number of cases. Re-detachment rate after SO removal has been reported to vary between 6% and 33%.4,21-23 In our cases series we did not have any re-detachment after definitively removal of SO. Four patients were re-operated on, one three times as re-proliferation occurred secondary to PVR and three eyes needed two surgeries, excluding the intervention to remove the SO. Among patients that performed two surgeries, one had re-proliferation, one re-detachment without proliferation and one presented re-bleeding after SO removal without improvement with topical medication. in this last case SO was not injected after the surgery, leaving the eye with BSS. Since the nature of our analysis is a retrospective, noncontrolled, non-randomized case series, it is limitation of

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our study. However, the size of our sample, follow-up time, accessibility and feasibility of this new technique highlight the importance of our study. In conclusion, using this feasible and accessible technique to remove 1300-centistokes SO in a 23-gauge TSV was extremely safe and effective, with good anatomic and visual outcomes. In general, it seems to be reproducible in most patients, non time-consuming, no need of further costs, such as acquisition of cannula from another company. Further studies should be performed, attempting to evaluate removal of SO with different viscosities and to verify reproducibility of our results. â&#x2013;

REFERENCES 1. Cibis PA, Becker B, Okun E, Canaan S. The use of liquid silicone in retinal detachment surgery. Arch Ophthalmol 1962.68:590-9. 2. Abrams GW, Azen SP, Barr CC, Lai MY, Hutton WL, Trese MT, Irvine A, Ryan SJ. The incidence of corneal abnormalities in the Silicone Study. Silicone Study Report 7. Arch Ophthalmol, 1995. 113(6): p. 764-9. 3. Barr CC, Lai MY, Lean JS, Linton KL, Trese M, Abrams G, Ryan SJ, Azen SP. Postoperative intraocular pressure abnormalities in the Silicone Study. Silicone Study Report 4. Ophthalmology, 1993. 100(11): p. 1629-35. 4. Casswell AG, Gregor ZJ. Silicone oil removal. II. Operative and postoperative complications. Br J Ophthalmol, 1987. 71(12): p. 898-902. 5. Gallemore RP, McCuen MB. Silicone oil in vitreoretinal surgery. In: Ryan SJ, Wilkinson CP, eds. Retina. 4th edition. Philadelphia, PA: Elsevier Mosby; 2006: p.2231. 6. Gonvers M. Temporary silicone oil tamponade in the management of retinal detachment with proliferative vitreoretinopathy. Am J Ophthalmol, 1985. 100(2): p. 239-45. 7. McCuen BW 3rd, de Juan E Jr, Machemer R. Silicone oil in vitreoretinal surgery. Part 1: Surgical techniques. Retina, 1985. 5(4): p. 189-97. 8. Jonas JB, Budde WM, Panda-Jonas S. Cataract surgery combined with transpupillary silicone oil removal through planned posterior capsulotomy. Ophthalmology, 1998. 105(7): p. 1234-7; discussion 1237-8. 9. Yildirim R, Aras C, Ozdamar A, Bahcecioglu H. Silicone oil removal using a self-sealing corneal incision under topical anesthesia. Ophthalmic Surg Lasers, 1999. 30(1): p. 24-6. 10. Fine HF, Iranmanesh R, Iturralde D, Spaide RF. Outcomes of 77 consecutive cases of 23-gauge transconjunctival vitrectomy surgery for posterior segment disease. Ophthalmology, 2007. 114(6): p. 1197-200.

11. Fujii GY, De Juan E Jr, Humayun MS, Pieramici DJ, Chang TS, Awh C, Ng E, Barnes A, Wu SL, Sommerville DN. A new 25-gauge instrument system for transconjunctival sutureless vitrectomy surgery. Ophthalmology, 2002. 109(10): p. 1807-12; discussion 1813. 12. Lakhanpal RR, Humayun MS, de Juan E Jr, Lim JI, Chong LP, Chang TS, Javaheri M, Fujii GY, Barnes AC, Alexandrou TJ. Outcomes of 140 consecutive cases of 25-gauge transconjunctival surgery for posterior segment disease. Ophthalmology, 2005. 112(5): p. 817-24. 13. Ibarra MS, Hermel M, Prenner JL, Hassan TS. Longer-term outcomes of transconjunctival sutureless 25-gauge vitrectomy. Am J Ophthalmol, 2005. 139(5): p. 831-6. 14. Lesnoni G, Rossi T, Gelso A. 25 Gauge vitrectomy instrumentation: a different approach. Semin Ophthalmol, 2004. 19(1-2): p. 49-54. 15. Riemann CD, Miller DM, Foster RE, Petersen MR. Outcomes of transconjunctival sutureless 25-gauge vitrectomy with silicone oil infusion. Retina, 2007. 27(3): p. 296-303. 16. Erakgun T, Egrilmez S. Surgical outcomes of transconjunctival sutureless 23-gauge vitrectomy with silicone oil injection. Indian J Ophthalmol, 2009. 57(2): p. 105-9. 17. Eckardt C. Transconjunctival sutureless 23-gauge vitrectomy. Retina, 2005. 25(2): p. 208-11. 18. Kapran Z, Acar N. Active removal of silicone oil with 25-gauge sutureless system. Retina, 2007. 27(8): p. 1133-5. 19. Kapran Z, Acar N. Removal of silicone oil with 25-gauge transconjunctival sutureless vitrectomy system. Retina, 2007. 27(8): p. 1059-64. 20. Garodia VK, Kulkarni A. Silicone oil removal using vitrectomy machine: A simple and safe technique. Retina, 2001. 21: p. 685-687. 21. Lesnoni G, Rossi T, Nistri A, Boccassini B. Long-term prognosis after removal of silicone oil. Eur J Ophthalmol, 2000. 10(1): p. 60-5. 22. Franks WA, Leaver PK. Removal of silicone oil - - rewards and penalties. Eye (Lond), 1991. 5 ( Pt 3): p. 333-7. 23. Scholda C, Egger S, Lakits A, Haddad R. Silicone oil removal: results, risks and complications. Acta Ophthalmol Scand, 1997. 75(6): p. 695-9. 24. Song ZM, Chen D, Ke ZS, Wang RH, Wang QM, Lu F, Qu J. A new approach for active removal of 5,000 centistokes silicone oil through 23-gauge cannula. Retina. 2010 Sep;30(8):1302-7. 25. Gupta OP, Ho AC, Kaiser PK, et al. Short-term outcomes of 23-gauge pars plana vitrectomy. Am J Ophthalmol 2008;146: 193â&#x20AC;&#x201C;197.

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Hemorrahagic events after intraocular injection of bevacizumab Marcelo Hosoume; Eduardo Buchele Rodrigues; Otaviano Magalhães Jr; Hélio Shiroma; Maurício Maia; Fernando Marcondes Penha; João Paulo Duprat; Luis Felipe Hagemann; Carsten H Meyer; Michel Eid Farah Department of Ophthalmology, Federal University of São Paulo (UNIFESP), São Paulo-SP, Brazil.

Financial disclosure: none Statement about Conformity with Author Information: retrospective case series Other Acknowledgments: none INTRODUCTION

evacizumab (Avastin®, Genentech Inc., San Francisco, USA) is a full length humanized monoclonal antibody that binds to all subtypes of vascular endothelial growth factor A (VEGF-A) and therefore inhibits new blood vessel formation. The drug is approved by the US Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer in combination with other chemotherapeutic agents.1 Recent reports have suggested that intravitreal bevacizumab may be useful in the treatment of several ocular diseases such as choroidal neovascularization (CNV), diabetic macular edema, proliferative diabetic retinopathy (PDR), and macular edema associated with retinal venous occlusive (RVO) disease.2 – 8 Systemic bevacizumab treatment is not without adverse effects. Patients receiving systemic bevacizumab in combination with 5-fluorouracil (5-FU) for treatment of colorectal cancer have twice the risk of serious thromboembolic events compared with those treated with 5-fluorouracil alone.9 In addition, higher incidence of high blood pressure (HBP), proteinuria, thromboembolism and wound healing complications after the administration of anti-VEGF agents have been reported.10,11 Systemic administration of bevacizumab combined with 5-FU was shown to result in various degrees of hemorrhage in 20 to 40% of patients.12

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There is so far little data on the risk of systemic and ocular hemorrhage after intraocular bevacizumab administration. Recently, a few episodes of ocular and systemic hemorrhage after intravitreal bevacizumab injection were described in case reports and small case series.13 -16 In regard to the anti-VEGF fragment ranibizumab, pooled data of the MARINA and ANCHOR trials disclosed a statistically significant increase in non-ocular hemorrhagic rates.17 The purpose of this retrospective case series is to report patients who developed hemorrhage following intraocular bevacizumab injection. PATIENTS AND METHODS We reviewed medical records and obtained follow-up information on all patients who developed hemorrhage after intraocular injection of bevacizumab from February 2006 through December 2007 at 8 centers in Brazil and Germany. All of the bevacizumab injections were compiled to estimate an incident rate. The off-label status of this medication and possible systemic and ocular complications were discussed in detail, and informed consent was obtained from all patients prior to any treatment. Pre-injection examination included Snellen or ETDRS visual acuity evaluation, slit-lamp biomicroscopy, intraocular pressure measurement, and dilated fundus examination. The type of lesion, time to hemorrhage, dose, number and administration route of injections were documented. Other features analyzed included age, sex, race, right eye versus left eye, previous therapy and surgery performed prior to the bevacizumab treatment. We screened all patients regarding systemic disorders including coagulation defects, and any use of anticoagulants was noted. Patients were not offered bevacizumab therapy if they had untreated systemic HBP, myocardial infarction, or a cerebrovascular accident during the prior 6 months. All patients who developed sudden and significant hemorrhagic episodes after intraocular bevacizumab injection were included in the study. The presence of intraocular hemorrhage was attested by fundus photography (FP), fluorescein angiography (FA) and optical coherence tomography (OCT). Periocular hemorrhages were documented by digital photography. The interval from bevacizumab injection to hemorrhage (days) was determined. The onset of intraocular hemorrhage was defined as the time point of decreased visual acuity consequent to the hemorrhagic event. For systemic hemorrhages, the patient’s information

was used to define the bleeding event. Patients were examined sooner than their scheduled follow-up appointments upon any complaint of visual loss or new symptoms. Cases were submitted to the primary author for review and confirmation. In the technique of intravitreal injection, a 0.10-ml aliquot of commercially available bevacizumab was prepared for each patient and placed in a 30-gauge syringe using aseptic techniques. Afterward, in a standard fashion using 5% povidone/iodine and an eyelid speculum, 1.25 mg (0.05 ml) or 2.50 mg (0.10 ml) of bevacizumab were injected intravitreally, 3.5 - 4 mm posterior to the limbus, through the pars plana under topical anesthesia. Following the injection, intraocular pressure and retinal artery perfusion were determined, and patients were instructed to administer topical antibiotics for 3 to 7 days. The injections were executed using a cotton bud in the limbus in attempt to minimize damage to the conjunctiva. The anterior chamber administrations were performed after the patient underwent topical anesthesia, disinfection with 5% povidone/ iodine and placement of a lid speculum. The injections of 2.50 mg (0.10 ml) were carried out at the corneal periphery and a cotton tip was used to exert opposite pressure at the time of the anterior chamber injection. All cases that developed small subconjunctival hemorrhage shortly after the application (0-24 hours)– typical of a result of iatrogenic or surgical trauma – were excluded. Repeated injections were offered if CNV activity persisted, or subretinal fluid or fresh hemorrhage was noted, in addition to loss of vision. RESULTS Two injections of 2.50 mg of bevacizumab were given in the anterior chamber, while fourteen were intravitreal administrations, eight injections of 1.25 mg and six of 2.50 mg. Sixteen patients out of 2,260 (0.7%) had hemorrhagic episodes after administration of intraocular bevacizumab. Eleven (69%) patients were Caucasian and five (31%) patients were Hispanic. The mean age of the study group was 63.7 years (range of 21 to 82 years), 75% were female (12 women and 4 men). Nine (56%) of the injections were performed in the right eye and 7 (44%) in the left eye. Seven (44%) patients had systemic HBP, one (6%) patient had diabetes mellitus type 2, and one (6%) had hypercholesterolemia. Three (19%) patients were taking aspirin and one coumarin. The detailed findings of all 16 patients are presented in Table 1.

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The underlying ocular diseases were age-related macular degeneration (AMD) in 12 patients (9 occult CNV, 3 classic CNV), one RVO with optic disc neovascularization, one high myopia(myopic CNV), one PDR accompanied by iris neovascularization, and one iris melanoma where the patient underwent lesion resection and bevacizumab administration during surgery. Of the 9 occult CNV, five presented with a clear pigment epithelial detachment (PED) of varying sizes on FA, two late leakage on FA of undetermined source, and two had a large hemorrhage without PED on FA which subsequently increased bleeding area. Past ocular history regarding the treated eye pointed out 3 (19%) pseudophakic eyes, one (6%) laser photocoagulated, and two (12%) showing low myopia. In the fellow eye there was disciform scar in two patients. The mean intraocular pressure at the time of administration was 17.0 mmHg (range of 10 - 43 mmHg). The number of injections before hemorrhagic episode varied from 1 to 5, whereas the mean was 1.87 injections. The mean time from injection to the hemorrhagic episode was 11.9 days (range of1 to 30 days). Two patients had systemic hemorrhages: metrorrhagia1 and severe epistaxis.1 Intraocular hemorrhages were observed in twelve patients: vitreous hemorrhage1, vitreous hemorrhage associated with subretinal hemorrhage3, subretinal hemorrhage7 and diffuse intraretinal hemorrhage such as nonischemic central RVO1. Two patients had periocular and subconjunctival hemorrhage2. SELECTED CASES REPORTS Case 2 A 21-year-old white female presented for evaluation of low visual acuity OD for 1 week. Visual acuity (VA) was 20/400 and 20/20 corrected with -9.00 and -7.50 diopters (D).Past medical history was unremarkable. Fundus examination disclosed a CNV secondary to high myopia in her right eye and left eye with normal findings. Intravitreal injection of 1.25 mg bevacizumab was performed OD. Thirty hours after injection, the patient called the retina specialist complaining about severe epistaxis, which lasted 6 hours and had a volume of about 400 ml. She was submitted to a nasal endoscopy and no nasal vascular alteration was found. Case 3 A 71-year-old white female presented for evaluation of

“Bevacizumab (Avastin®, Genentech Inc., San Francisco, USA) is a full length humanized monoclonal antibody that binds to all subtypes of vascular endothelial growth factor A (VEGF-A) and therefore inhibits new blood vessel formation” eye pain OS for one year. She recalled being diagnosed for RVO 2 years prior and treated with panretinal photocoagulation. Since then, the patient has been taking timolol 0.5% plus brimonidine 0.2% twice a day. Past medical history was positive for HBP (35 years previously) and DM type 2 for 25 years under control with insulin. She denied use of oral anticoagulants or other systemic abnormalities. On eye examination, VA was 20/60 OD and hand motions OS. Intraocular pressures were 18/43mmHg, and there was diffuse iris and angle neovascularization OS. Fundus examination OS was not possible due to lens opacity. After obtaining informed consent, the patient was submitted to intracameral injection of 2.5 mg bevacizumab through a limbal incision, and there was no conjunctival touch as the eye was fixated with a cotton tip placed 180 degrees from the superior limbal incision. On the first post-operative day, the conjunctiva was within normal limits, except for diffuse perilimbal hyperemia. However, on the 7th post-operative day the patient returned complaining of sudden ocular hemorrhage OS (Figure 1). On examination, there was diffuse conjunctival hemorrhage along with inferior palpebral bleeding bruise. Measured intraocular pressure OS was 35 mmHg. Case 9 An 82-year-old white female presented with symptoms of low vision OS for 2 months. She recalled vision loss OD 10 years previously, being diagnosed then with wetAMD. The patient was pseudophakic OU, and VA was counting fingers OD and 20/200 OS. Fundus examination

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FIGURE 1: Case 3. Palpebral bleeding bruise (Left) associated with significant subconjunctival hemorrhage (Right) which began on the seventh day after intracameral bevacizumab injection

FIGURE 2: Case 9. Fundus photography (FP) and fluorescein angiography (FA) of the left eye showing a subfoveal occult choroi-

dal neovascularization (CNV) with a small pigment epithelium detachment (PED) temporal to the lesion (Left). Large subretinal hemorrhage temporal to the fovea overlying the PED shown by FP and FA on the first day after the second 2.50mg intravitreal bevacizumab injection (Right)

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TABLE 1 â&#x20AC;&#x201C; CHARACTERISTICS OF PATIENTS

TYPE OF HEMORRHAGE

AGE

SEX

TYPE OF EYE UNDERLYING DISEASE NEOVASCULARIZATION

POH

IOP (MMHG)

OF ONSET OF HEMOROF ADMINIS- NO INJECRHAGE (DAYS SURGERY ROUTETRATION TIONS AFTER INJECTION)

Systemic hemorrhage 1

Metrorrhagia

CRVO

Epistaxis

Myopia

Optic disc Laser photocoaguneovascularization lation one year ago

intravitreal

Choroidal neovascularization myopic

intravitreal

none

Periocular hemorrhage 3 4

Subconjunctival plus palpebral Subconjunctival plus palpebral

71 78

F F

OS OD

PDR AMD

Iris neovascularization

none

intracameral

Choroidal neovascularization - classic

Previous subconjunctival hemorrhage fellow eye

intravitreal

intracameral

Intraocular hemorrhage 5

Iris melanoma

Ciliary body neoplasia

myopia -4.00 OU

lesion resection

Subretinal hemorrhage

AMD

Choroidal neovascularization - occult

none

intravitreal

Subretinal hemorrhage, VH

AMD

Choroidal neovascularization - occult

none

intravitreal

Subretinal hemorrhage, VH

AMD

Choroidal neovascularization - occult

none

intravitreal

Subretinal hemorrhage, VH

AMD

Disciform scar Choroidal neovascu- fellow eye - pseularization - occult dophakic

Subretinal hemorrhage

AMD

Choroidal neovascularization - occult

none

intravitreal

Subretinal hemorrhage

AMD

Choroidal neovascularization - occult

none

intravitreal

Subretinal hemorrhage

AMD

Choroidal neovascularization - occult

pseudophakic

intravitreal

Subretinal hemorrhage

AMD

Choroidal neovascularization - classic

pseudophakic

intravitreal

Subretinal hemorrhage

AMD

Subretinal hemorrhage

AMD

Diffuse intraretinal hemorrhage, CRVO nonischemic-like

AMD

Choroidal neovascularization - classic/ myopia -2.00 OU juxtafoveal scar fellow Choroidal neovascu- Disciform -pseudophakic larization - occult eye both eyes Choroidal neovascularization - occult

none

POH: past ocular history; PMH: past medical history; IOP: intraocular pressure; F: female; M: male; OD: right eye; OS: left eye; CRVO: central retinal vein occlusion; PDR: proliferative diabetic retinopathy; DM: diabetes mellitus; HBP: high blood pressure; AMD: age-related macular degeneration; VH: vitreous hemorrhage; OU: both eyes

TABLE 2 - HYPOTHETICAL MECHANISMS OF OCULAR HEMORRHAGE AFTER INTRAOCULAR BEVACIZUMAB INJECTION RELATED TO THE DISEASE

Related to the procedure: injection & surgery

by VEGF reduction Related to the drug Non-VEGF-mediated

MECHANIC CNV CONTRACTION WITH VASCULAR INJURY Hypotension with choroidal vascular rupture Ciliary body or choroidal trauma Trauma by the flow of drug fluid Retinal vessel touch by long injection needle Palpebral hemorrhage by blepharostat Lack of VEGF promotes platelet loss Vascular endothelial cells apoptosis by VEGF reduction Coagulation cascade alterations/ reduced tissue factor expression Systemic high blood pressure Direct bevacizumab injury to platelet

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FIGURE 3: Case 14. Fundus photography (FP), fluorescein angiography (FA), and optic coherence tomography (OCT) of the left eye

showing an extra-foveal classic choroidal neovascularization (CNV) secondary to myopia (Left). Intravitreal injection of 1.25 mg bevacizumab was performed, and after 60 days, reactivation of the CNV was seen with subretinal hemorrhage located above and under the fovea (Right).

FIGURE 4: Case 16. Right eye fundus photography (FP) and fluorescein angiography (FA) indicate a small juxta-foveal classic cho-

roidal neovascularization (CNV) (Left). FP on the fifth post-operative day revealed diffuse intraretinal hemorrhages and few peripapillary cotton-wool spots (Top right). FA confirmed the areas of hemorrhage and retinal ischemia (Bottom right).

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OS disclosed a subfoveal occult CNV with a small PED temporal to the lesion (Figure 2, left), while OD there was a large disciform scar. She was treated with intravitreal bevacizumab (2.5 mg). She returned for the one-month follow-up visit with vision improvement, where visual acuity was 20/100 OS. She underwent a second intravitreal injection of 2.5 mg bevacizumab, and she was discharged from the operating room without an eye patch. On the first postinjection day, she reported a sudden severe loss of vision OS, where measured VA was counting fingers OS. There was a large subretinal hemorrhage temporal to the fovea overlying the PED (Figure 2, right). The patient was submitted for pars plana vitrectomy, subretinal 25 micrograms tPA injection and intravitreal injection of C3F8 gas. For the next six months, the patient underwent two additional intravitreal injections of 2.5 mg bevacizumab, VA recovered to 20/50 OS, and there was absorption of the subretinal hemorrhage and regression of the CNV. Case 14 A 28-year-old white male first presented with decrease in visual acuity OS. Ophthalmic examination disclosed an extra-foveal classic CNV secondary to myopia of -2.00 OS, where VA was 20/50 (Figure 3, left). The patient underwent an intravitreal injection of 1.25 mg bevacizumab OS. He recalled vision improvement, where measured VA was 20/20 with correction OS. Two months after intravitreal injection, he returned for ophthalmic examination due to a sudden vision loss OS. VA was counting fingers OS and fundus examination disclosed reactivation of the CNV with subretinal hemorrhage located above and under the fovea (Figure 3, right). The patient recently underwent a second intravitreal injection of 2.5 mg bevacizumab OS. Case 16 A 73-year-old white female presented with decreased vision for 1 month in OD. Past ocular history was unremarkable, while she recalled a 10-year history of HBP under control. VA was 20/60 OD, and fluorescein angiography disclosed a small classic juxta-foveal CNV OD (Figure 4, left). She underwent an uneventful intravitreal injection of 2.5 mg bevacizumab OD. On the first post-operative day, the eye and retinal examination were unremarkable OD. On the fifth post-operative day the patient complained of severe visual loss OD, VA was 20/200 OD with correction. Fundus examination revealed diffuse intraretinal hemor-

“VEGF-A plays a key role in the pathogenesis of neovascular retinal diseases increasing vascular permeability as well as leading to subretinal fluid accumulation and formation of new vessels” rhages and few peripapillary cotton-wool spots. Fluorescein angiography OD confirmed the areas of hemorrhage and retinal ischemia (Figure 4, right). DISCUSSION VEGF-A plays a key role in the pathogenesis of neovascular retinal diseases increasing vascular permeability as well as leading to subretinal fluid accumulation and formation of new vessels. However, VEGF-A also participates actively in various tissue physiological processes such as wound healing and maintenance of the intact microvascular endothelial cells. In the physiology of the normal retina, the participation of the VEGF-family has been suggested by the presence of three VEGF-receptors within the vascular retinal elements and by the evidence of production of VEGF by various retinal cells including pericytes, ganglion cells, endothelial cells, Müller cells and RPE-cells. In the retina, VEGF has been found to exert several functions such as vasodilation/ flow, survival factor for endothelium cells, neuroprotector for retinal and brain neurons, physiological responses to ischemia, and fenestration factor in the choriocapillaries.18, 19 Various hypotheses may be proposed as the possible mechanism of hemorrhage after VEGF-therapy involving different systems such as disturbance of the coagulation cascade, VEGF-related endothelial cell survival, and alterations of systemic HBP (Table 2). First, changes in systolic blood pressure is a reasonable explanation for bleeding events after bevacizumab administration, since this is a wellknown complication related to systemic endovenous beva-

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â&#x20AC;&#x153;In summary, we presented sixteen cases of systemic and ocular hemorrhage after local administration of the full-length anti-VEGF mAb. The incidence of bleeding events was 0.7%, which is higher than with other selective anti-VEGF agents such as pegaptanib, but such high risk of hemorrhage has also been described with full pan VEGF inhibitorsâ&#x20AC;? cizumab treatment for cancer patients.20, 21 In our study, only 44 % of patients had positive history of previously diagnosed HBP. Second, in recent years, novel mechanisms at the molecular biology level have been intensely investigated to explain how the blockage of VEGF itself can induce bleeding events. In this context, anti-VEGF drugs may cause endothelial cell apoptosis, thereby providing a weakening of the small vessel wall that renders the capillaries susceptible to rupture and blood leak.22 Third, hemorrhage may be related to the VEGF-dependent interference of coagulation cascade and tissue factor production. During wound healing, platelets have been shown to secrete VEGF in these areas.23 In turn, platelets express VEGF receptors, thereby creating positive feedback. The final loop maintains the VEGF-induced expression of tissue factor as well as the formation of thrombin and fibrin.24, 25 As another mechanism of anti-VEGF-induced bleeding, anti-VEGF mAbs can induce thrombocytopenia. Such observation has been supported by studies showing that platelets take up bevacizumab, and there is a reduction in the stimulatory activity of platelets on endothelial cells through VEGF, thereby disturbing platelet-endothelial cell homeostasis.22, 26, 27 Indeed, the large variety of well-demonstrated mechanisms may imply that VEGF inhibition exposes the eye and other organs to a higher susceptibility of hemorrhage.

Indeed, major oncology trials provided important data on the risks of systemic hemorrhage after endovenous application of bevacizumab in humans. In those major studies with patients with various types of cancers, the episodes of systemic hemorrhage after endovenous bevacizumab administration manifested in a variety of severities in organs such as gastrointestinal (~10%), hematologic (~40%, severe in 5%), mucocutaneous (up to 40%, most common epistaxis), or neuronal ~10%. 28 Considerable evidence supports the theory that small but clinically relevant concentrations of bevacizumab may reach the systemic circulation after intraocular administration. Physiological VEGF-A levels in the systemic circulation are about < 80pg/ml.29 Csaky et al. injected 1.25mg bevacizumab intravitreally and determined drug levels of approximately 100,000pg/ml for up to 4 weeks in the circulating blood30, corresponding to a thousand times higher than the normal circulatory VEGF levels. In our current study, two cases of epistaxis and metrorrhagia were encountered in patients without any systemic coagulation disorders to predispose the abnormality. Although no direct causeeffect relationship can be established for anti-VEGF as the source of those bleedings, hemorrhage from mucocutaneous membranes and epistaxis are the most commonly encountered types of bleedings after endovenous bevacizumab use. In addition, patient 3 developed a periocular hemorrhagic event after intracameral injection without any conjunctival manipulation. This observation may imply that for case 3 there may have been decreased periocular VEGF levels. In this context, these findings suggest that the transient reduction in circulatory VEGF levels encountered in patients treated with bevacizumab may cause systemic side effects in other tissues. In contrast to the systemic profile, hemorrhagic complications related to the use of intraocular anti-VEGF drugs including bevacizumab have been studied little so far.31,32 In an internet-published survey of 5228 patients after intravitreal bevacizumab, increased subretinal hemorrhage or new episodes were found in only 0.06% of patients.33 In addition, few consecutive case series and case reports have revealed episodes of metrorrhagia, diffuse intraretinal hemorrhage, or severe subretinal hemorrhage after intravitreal injections of bevacizumab. On the other hand, by combining the data of the two large trials that analyzed the use of intraocular ranibizumab, MARINA and ANCHOR, it is evident that there are significantly higher rates of nonocular hemorrhage in the

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ranibizumab group (4.2% for control vs 7.8% in the ranibizumab group).17 The leading causes of hemorrhage described were epistaxis, 1.8% in the ranibizumab group (0.3 mg and 0.5 mg groups combined), vaginal hemorrhage in 0.6%, hematoma in 1.5% and ecchymosis in 1.3% of patients. Such variety of bleeding events and sources of information may mean that there is such risk of hemorrhagic events after intraocular anti-VEGF administration. Subretinal, vitreal or subconjunctival hemorrhages after intravitreal injections may be related to the procedure itself as well as the drug or the anticoagulation status of the patient. In our case series, four (25%) of the patients reported the use of anti-coagulation drugs. Two recent case series on the use of anti-VEGF in AMD indicated that there is no higher risk of hemorrhage in patients taking oral anticoagulation or antiplatelet therapy.34, 35 Charles et al. presented a subanalysis of patients on warfarin maintenance in the Lucentis study trials.36, 37 The authors also concluded that intraocular injections in warfarin-treated patients are unlikely to cause ocular hemorrhages and recommend the maintenance of anticoagulation in order to minimize the risk of cardiovascular side effects. We agree that anticoagulants should not be discontinued before intravitreal injection of anti–vascular endothelial growth factor agents. We base this belief on the likelihood that systemic morbidity and mortality from thromboembolic events far outweigh the consequences of the exceptionally rare problem of uncontrollable intraocular bleeding. Progresses in small-incision injection and surgical techniques may also lessen the potential hemorrhagic ocular risks of retinal surgery for the anticoagulated patient, thus warranting the continuation of anticoagulation in the perioperative period. The list of intraocular hemorrhages in our case series included vitreous hemorrhages, diffuse retinal hemorrhage,

and subretinal hemorrhages. Subretinal hemorrhage is a known complication after therapies for CNV, and as a rule, they occur in occult types of CNV and are associated with rupture of a RPE-tear on various days or weeks after therapy. One recent case series showed ten episodes of subretinal hemorrhage in patients with large occult CNV, as 40% of the patients initially showed no sign of hemorrhage.14 Herein, we presented 12 patients who developed subretinal hemorrhages from day one to 81 days after intravitreal bevacizumab injection. Most of the patients had occult type CNV with subsequent RPE-tear. However, 2 patients who developed subretinal hemorrhage initially, presented with classic type CNV, which is an unusual pathology as a source of retinal hemorrhage. In one case, the patient had a small classic CNV with development of diffuse intraretinal hemorrhages five days after intravitreal injection of bevacizumab. Similar to this patient, one recent case reported by Lee and Koh showed diffuse intraretinal hemorrhages not related to diabetic retinopathy after intravitreal bevacizumab injection in a patient with PDR, who underwent pars plana vitrectomy 15. Based on those findings, it is suggested that anti-VEGF inhibition is a predisposing factor for hemorrhage in a retina/eye with a risky neovascular pathology. In summary, we presented sixteen cases of systemic and ocular hemorrhage after local administration of the fulllength anti-VEGF mAb. The incidence of bleeding events was 0.7%, which is higher than with other selective antiVEGF agents such as pegaptanib, but such high risk of hemorrhage has also been described with full pan VEGF inhibitors. This risk may even increase with more potent and longer lasting novel drugs, e.g., VEGF-trap or siRNA, thus demanding a close follow-up in future trials. Overall, we propose that ocular bleedings are rare but important events in the era of anti-VEGF therapy. ■

Acknowledgments Financial support: Fundação de Amparo à Pesquisa do Estado de São Paulo (Fapesp) and Pan-American Association of Ophthalmology/ Pan-American Ophthalmological Foundation. Contributions of Authors: Design (MH, ER) and conduct of the study (MH, ER); collection (ER, OM, HS, MM, FP, JD, LH, CM), management (ER, OM, HS, MM, JPD, LH, CM), analysis (ER, OM, HS, MM, FP, JD, LH, CM), and interpretation of the data (ER, OM, HS, MM, FP, JD, LH, CM); and preparation (MH, ER, MF), review (MH, ER, OM, HS, MM, FP, JD, LH, CM, MF) or approval of the manuscript (MH, ER, OM, HS, MM, FP, JD, LH, CM, MF).

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