A r q u i v o s b r a s i l e i r o s d e

78 01publicação oficial do conselho brasileiro de oftalmologiaJaneiro/fevereiro 2015

issn 0004-2749versão impressa

Strabismus results in patients with myelomeningocele

Recombinant tissue plasminogen activator in rabbits

Choroidal thickness pediatric population

One-year follow-up of Tranilast® in pterygium surgery

Anesthetic approaches for intravitreal injections

indexada nas bases de dados

medline | embase | isi | scielO

Arquivos b

rasileiros de Oftalm

ologia | jan-fev

20

15 | v

.78

n.1 p.1-6

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AnúnciosSegundo informações do Fabrício,

os anúncios serão definidos em janeiro

Frequency of publication: Bimonthly Arq Bras Oftalmol. São Paulo, v. 78, issue 1, pages 1-66, Jan/Feb. 2015

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Publisher: Ipsis Gráfica e Editora S.A. Divulgation: Brazilian Council of OphthalmologyCirculation: 7.900 copies

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Editorial BoardNationalAna Luísa Höfling-Lima (São Paulo-SP)André Augusto Homsi Jorge (Ribeirão Preto-SP)André Messias (Ribeirão Preto-SP)Andrea Zin (Rio de Janeiro-RJ)Antonio Augusto Velasco e Cruz (Ribeirão Preto-SP)Ayrton Roberto B. Ramos (Florianópolis-SC)Breno Barth (Natal-RN)Cristina Muccioli (São Paulo-SP)Denise de Freitas (São Paulo-SP)Eduardo Cunha de Souza (São Paulo-SP)Eduardo Ferrari Marback (Salvador-BA)Érika Hoyama (Londrina-PR)Fábio Ejzenbaum (São Paulo-SP)Flávio Jaime da Rocha (Uberlândia-MG)João Antonio Prata Jr. (Uberaba-MG)João Borges Fortes Filho (Porto Alegre-RS)João J. Nassaralla Jr. (Goiânia-GO)João Luiz Lobo Ferreira (Florianópolis-SC)José Beniz Neto (Goiânia-GO)José Paulo Cabral Vasconcellos (Campinas-SP)Keila Monteiro de Carvalho (Campinas-SP)Lisandro Sakata (Curitiba-PR)Luiz V. Rizzo (São Paulo-SP)Marcelo Francisco Gaal Vadas (São Paulo-SP)

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Contents

OffiCiAl PuBliCAtiON Of thE BrAziliAN COuNCil Of OPhthAlmOlOgy (CBO) iSSN 0004-2749(Printed version)

iSSN 1678-2925(Electronic version)

Frequency of publication: Bimonthly Arq Bras Oftalmol. São Paulo, v. 78, issue 1, pages 1-66, Jan/Feb. 2015

PUBLICAÇÃO OFICIAL DOCONSELHO BRASILEIRO

DE OFTALMOLOGIA

EditorialV Peer review Avaliação por pares Bruno Machado Fontes

Original Articles1 Preoperative tranilast as adjunctive therapy to primary pterygium surgery with a 1-year follow-up Terapia auxiliar com o tranilast pré-operatório na cirurgia do pterígio primário com um ano de seguimento Gildásio C. Almeida Junior, Luciano Arakawa, Dalísio de Santi Neto, Patrícia Maluf Cury, Acácio A. S. Lima Filho, Sidney J. F. Sousa, Milton R. Alves, Reinaldo Azoubel

6 Subconjunctival and topical application of recombinant tissue plasminogen activator in rabbits Uso tópico e subconjuntival de ativador de plasminogênio tecidual recombinante em coelhos José Ricardo de Abreu Reggi, Richard Yudi Hida, Milton Massato Hida, Maria Cristina Nishiwaki-Dantas, Hisashi Suzuki

10 Approach of Turkish ophthalmologists to micronutrition in age-related macular degeneration Abordagem dos oftalmologistas turcos em relação a micronutrição na degeneração macular relacionada à idade Muhammed Şahin, Harun Yüksel, Alparslan Şahin, Abdullah Kürşat Cingü, Fatih Mehmet Türkcü, Zeynep Gürsel Özkurt, İhsan Çaça

15 Surgical results of strabismus correction in patients with myelomeningocele Resultados cirúrgicos da correção do estrabismo em pacientes com mielomeningocele Dayane Cristine Issaho, Marcia Keiko Uyeno Tabuse, Nilce Tiemi Shiwaku Kamida, Monica Fialho Cronemberger

19 mini-flared Kelman tip, reverse tip, and sidewinder tip with torsional phaco: a prospective randomized comparative study Faco torsional utilizando as ponteiras Kelman mini-flared, reversa e sidewinder: um estudo prospectivo comparativo randomizado Wilson Takashi Hida, Patrick Frensel Tzelikis, Celso Takashi Nakano, Antonio Francisco Pimenta Motta, Milton Ruiz Alves

23 choroidal thickness measurement in healthy pediatric population using cirrus hD optical coherence tomography Medida da espessura da coroide na população pediátrica saudável usando tomografia de coerência óptica Cirrus HD Aylin Tenlik, Fatma B. Gürağaç, Emre Güler, Mehmet Serdar Dervişoğulları, Yüksel Totan

27 Comparison of 3 different anesthetic approaches for intravitreal injections: a prospective randomized trial Comparação de três abordagens anestésicas diferentes para injeções intravítreas: um estudo prospectivo e randomizado Gabriel Costa de Andrade, André Correa Maia de Carvalho

32 Survey: technique of performing intravitreal injection among members of the Brazilian retina and vitreous Society (SBrv) Survey: técnica para realização de injeção intravítrea pelos membros da Sociedade Brasileira de Retina e Vítreo (SBRV) Helio F. Shiroma, Michel E. Farah, Walter Y. Takahashi, Andre M. V. Gomes, Mauro Goldbaum, Eduardo Buchele Rodrigues

36 Evaluation of a simulation tool in ophthalmology: application in teaching funduscopy Avaliação do uso de um instrumento de simulação em oftalmologia: aplicação no ensino da fundoscopia Joice Elise Androwiki, Isaac Assis Scravoni, Lucas Holderegger Ricci, Djalma José Fagundes, Caroline Amaral Ferraz

40 Ocular diseases at geriatric clinics in rio de Janeiro: social and epidemiological considerations among patients with motor locomotion deficit Morbidades oculares em clínicas geriátricas do Rio de Janeiro: considerações sociais e epidemiológicas associados a indivíduos com déficit de locomoção Nadyr A. Damasceno, Marcelo Palis Ventura, Eduardo F. Damasceno

Case Reports44 recurrent myopic foveoschisis: resolution after internal limiting membrane removal Isquise miópica recorrente: resolução após remoção da membrana limitante interna Renato Antunes Schiave Germano, Leandro Cabral Zacharias, Walter Yukiko Takahashi

47 internal eye wall resection of uveal tumors: long-term evaluation Ressecção em bloco de tumores uveais: avaliação de longo prazo Carlos Augusto Moreira Jr., Carlos Augusto Moreira Neto

50 Case report: pneumatic retinopexy for the treatment of progressive retinal detachment in senile retinoschisis Relato de caso: retinopexia pneumática no tratamento do descolamento de retina associado à retinosquise senil Ana Claudia de F. Suzuki, Leandro Cabral Zacharias, Tatiana Tanaka, Diego Neves Rocha, Walter Y. Takahashi

53 An uncommon ocular manifestation of Sweet syndrome: peripheral ulcerative keratitis and nodular scleritis Uma manifestação ocular rara de síndrome de Sweet: ceratite ulcerativa periférica e esclerite nodular Ahmet Burak Bilgin, Pınar Tavas, Elif Betul Turkoglu, Hatice Deniz Ilhan, Serap Toru, Kadri Cemil Apaydin

Review Articles56 Birdshot retinochoroidopathy review Revisão sobre retinocoroidopatia do tipo “birdshot” Clovis Arcoverde Freitas-Neto, Sutasinee Boonsopon, Swetha Dhanireddy, Armin Maghsoudlou, Sukhum Silpa-archa, C. Stephen Foster

Letters to the Editor62 Measurement of choroid thickness in pregnant women using enhanced depth imaging optical coherence tomography Medição da espessura da coroide em gestantes utilizando tomografia de coerência óptica com profundidade de imagem aprimorada Saban Gonul, Banu Turgurt Ozturk, Suleyman Okudan

63 Instructions to Authors

V

Editorial

http://dx.doi.org/10.5935/0004-2749.20150001

Peer reviewAvaliação por pares

Bruno Machado Fontes

In this issue of ABO (Arquivos Brasileiros de Oftalmologia) we formally acknowledge and express our grati-tude to the voluntary hard and substantial work, commitment and proficiency of our peer reviewers. We could not thank them enough for their immense cooperation to our journal and, why not, visual sciences. That said, we could state that the essential impartiality and quality of scientific publishing is provided by peer reviewers(1-7).

Peer review is defined as the “critical assessment of manuscripts submitted to journals by experts who are not part of the editorial staff” by the International Committee of Medical Journal Editors. Journal’s editors may not have accurate expertise to provide complete and impartial reviews of all themes considered for publication. Reviewers are chosen based on their knowledge about a subject or subspecialty. Peer review aims to improve science writing and editing, and medical publications deeply rely on its quality. They help editors to decide whether to publish a manuscript and provide critical feedback aiming to raise the quality of the manuscript’s final version. Considering that a reviewer delay can potentially affect the career of younger colleagues, who are relying on a publication for promotion or tenure, reviewers work carries a “great power” and is associated to a huge responsibility(8,9).

Properly conducted peer review offers a great chance to learn from others experience and improve quality and safety of health care with the best available scientific discoveries and proper analysis. Reviewers check for inconsistencies, biases, wrong methodology and frauds. Incorrect reviews may lead to erroneous editorial decisions and good science might be rejected for bad reasons (even manuscripts that later resulted in a Nobel Prize have been rejected for publication)(9). On the other hand, imprecise, misleading and partial data can be printed and negatively impact our patients. Clinical decisions are affected based in published results, having a direct impact on patient care(10,11).

There are no “formal training” programs for peer reviewers. Hence, although universally used, peer review is time-consuming, imperfect, largely subjective, present low reproducibility even under optimal research conditions and may fail to notice important deficiencies. Why does it happen? First of all, we have to state that medicine is very complex, and few (if any) outcome have a single sufficient and necessary cause. Besides that, many methodological biases (e.g.: sample selection, data extraction and analysis, statistical analysis, etc…) may affect decision making and lead to error. Also the competitiveness in research (“publish or perish”) and limited grant funding opportunities may induce one to publish results from a single study into multiple (redundant) publications, plagiarize, fabricate or fraud scientific information(1,2,5,7).

Reviewers are more likely to accept to evaluate a manuscript when the paper represents an opportunity to learn something new, its data is relevant and contribute to their area of expertise. A sense of professional duty, part of academic role and the reputation of the journal are also key factors. The most motivating incentives included free access to the journal, annual acknowledgement of reviewers published on the journal, feedback about the outcome of the manuscript submission and the quality of their reviews, and the appointment of the best reviewers to the journal’s editorial board. Lack of time is the major factor in the decision to decline. Others reasons include conflict of interests and a tight deadline to complete the review(3).

Receiving adequate peer review for manuscripts is really a great challenge, can affect quality and result in publication delay. Most skilled reviewers are those with a respectable track record of own publications in high-quality periodicals, expertise in epidemiology or statistics, current involvement in research, affiliation to a University hospital and several reviewer contributions(8). It is not easy to find! The exponential growth of manus-cripts submitted for publication overburdens the capability of available qualified referees and challenges the maintenance of quality on their evaluations and respect timelines(7).

We have the privilege of counting with the contribution of world renowned specialists, who makes valuable revisions. We strongly support this formal recognition of their contribution and respectfully express our thankfulness for sharing your valuable time with ABO and its readers.

Submitted for publication: December 13, 2014 Accepted for publication: December 15, 2104

Associate Editor, ABO Arquivos Brasileiros de Oftalmologia, Rio de Janeiro, RJ, Brazil.

Conflict of interest: None.

Corresponding author: Bruno Machado Fontes. Av. Ataulfo de Paiva, 135 - cj.1418 - Rio de Janeiro, RJ - 20780-020 - Brazil - E-mail: fontesbrunom@gmail.com

Peer review

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Abrahão LucenaAdem TurkAfsun SahinAlexandre VenturaAlfredo AndradeAline C. F. LuiAlparslan SahinAltan GoktasAmelia Fernandes NunesAmelia KamegasawaAna Catarina Delgado SouzaAna Laura MouraAna Luisa Lima-FarahAna Tereza MoreiraAndre MessiasAndre RomanoAndrea ZinAndrew EisemanAntonio Augusto Velasco CruzAntonio MachoAntonio Marcelo CasellaAylin KiliçAyrton RamosBruna Lana DuccaBruna V VenturaBruno DinizCaio RegatieriCari Pérez-VivesCarlos ArceCarlos Augusto Moreira Jr.Carlos Eduardo Leite ArietaCarlos Roberto NeufeldCarolina GracitelliCarolina Maria ModuloCaroline Amaral FerrazCélia Simões Cardoso de Oliveira SathlerCelso MoritaChristiane Rolim de MouraCigdem AkdagCintia de PaivaClovis Arcoverde FreitasDácio CostaDaniel CecchettiDaniel LavinskyDaniel Meira-FreitasDaniel VasconcellosDaniel WasilewskiDavi ArafDavid GuytonDavid SmadjaDenise Fornazari de OliveiraDora VenturaEduardo Alonso GarciaEduardo Amorim NovaisEduardo Cunha SouzaEduardo DibEduardo França DamascenoEduardo MarbackEduardo RodriguesElcio H SatoElisabeth Nogueira MartinsElizabeth Lin

Emilio DoddsEmmerson BadaroEneas Bezerra GouveiaEnyr Saran ArcieriEnzo FulcoEric AndradeEsin Sögütlü SariEvandro LucenaFabiana ValeraFabiano CadeFabio CasanovaFabio EjzenbaumFábio Henrique FerrazFabio Jose Mariotoni BronzattoFabio KanadaniFabiola MurtaFabricio FonsecaFausto UnoFernando ChahudFernando OréficeFernando ProcianoyFernando TrindadeFernando ZanettiFlávia Augusta Attié de CastroFlavio HiraiFlavio MaccordFlávio ParanhosFlavio RochaFrancisco IrochimaFrancisco Max DamicoFrederico GuerraGuilherme CastelaGustavo Amorim NovaisGustavo BonfadiniGustavo Viani ArrudaGustavo VictorHarley E. A. BicasHélio Angotti-NetoHelio ShiromaHeloisa Andrade MaestriniHeloisa NascimentoHüseyin BayramlarInês LaínsIuuki TakasakaJack ShaoJackson Barreto Jr.Jair Giampani JuniorJarbas CastroJern Yee ChenJim SchwiegerlingJoana FerreiraJoão Antonio Prata JrJoão Borges Fortes FilhoJoão Carlos Miranda GoncalvesJoao CrispimJoão Luiz Lobo FerreiraJoao Marcello FurtadoJoao Marcelo LyraJoão Paulo Fernandes FelixJonathan LakeJorge MitreJose Aparecido da Silva

RevieweR Full Name

Fontes BM

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José Augusto CardilloJosé BenizJosé Luiz LausJosé Paulo VasconcellosJuliana SallumKatharina MessiasKátia BottósKátia dos SantosKeila Monteiro de CarvalhoKenzo HokazonoKimble MatosLarissa CoppiniLaurentino BiccasLeandro Cabral ZachariasLeonardo HuebLeonardo Provetti CunhaLiang Shih JungLigia FendiLiliane Andrade Almeida KanecadanLisa B. ArbisserLisandro SakataLucas ViannaLuciana Castro LavigneLuciano SimãoLuciene FernandesLuis BrennerLuis Eduardo Rebouças de CarvalhoLuis NominatoLuiz Felipe LynchLuiz Guilherme FreitasLuiz HagemannLuiz Henrique LimaLuiz TeixeiraLuiz VieiraM Cristina Nishiwaki DantasManuel ZegarraMarcella SalomãoMarcelo CasellaMarcelo da CostaMarcelo F. Gaal VadasMarcelo HatanakaMarcelo Jordão SilvaMarcelo Palis VenturaMarcelo SilvaMarcia Beatriz TartarellaMarcia MotonoMarcio MendesMarco BoniniMarcony SanthiagoMaria Antonia SaornilMaria de Lourdes Motta Moreira Villas BoasMaria Emília Xavier dos Santos AraújoMaria HaddadMaria Kiyoko OyamadaMaria Regina ChalitaMariluze SardinhaMário Junqueira NóbregaMarlon Moraes IbrahimMarta Halfeld Ferrari Alves LacordiaMartin BerraMauricio Abujamra NascimentoMauricio Bastos PereiraMauricio MaiaMauro Silveira de Queiroz CamposMauro WaiswolMirella Gualtieri

Moacyr Pezati RigueiroMonica AlvesMonica CronembergerMonica de Andrade MorrayeMoyses ZajdenweberMuhammet Kazim ErolMurat GunayMurilo AbudMyrna SantosNelson SabrosaNewton Kara-JuniorOsman CekicPablo ChiaradiaPatricia AkaishiPatricia NovitaPatrick Frensel TzelikisPaula Delegrego BorbaPaula Yuri SacaiPaulo FadelPaulo PierrePaulo SchorPaulo Sérgio de Moraes BarrosPedro CarricondoPeter Mc GannonPeter ReinachPhilipp AlbrechtPriscila NovaesPriscilla Ballalai BordonRafael FurlanettoRamon Coral GhanemRemzi KaradagRenata PortellaRenato DamascenoRicardo Paletta GuedesRicardo Salles CauduroRicardo SuzukiRichard HidaRobert Montés-MicoRoberta CostaRoberto Galvão-FilhoRoberto MarbackRoberto Pinto CoelhoRodrigo Brant FernandesRodrigo CaladoRodrigo EspindolaRodrigo JorgeRony Carlos PretiRosane FerreiraRubens NetoRubens SiqueiraRui SchimitiRupal TrivediSaban GonulSebastião CronembergerSergio BurnierSergio KwitkoSeydi OkumusSeyhan DikciSheau HuangSidney Faria e SousaSimone Haber Duellberg Von Faber BisonSolange SalomãoSomaia MitneTammy H OsakiTiago ArantesTiago Cavalcanti

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RefeRenCeS 1. Stahel PF, Moore EE. Peer review for biomedical publications: we can improve the system.

BMC Med. 2014;26;12(1):179. 2. Kadar N. Peer review of medical practices: missed opportunities to learn. Am J Obstet

Gynecol. 2014;211(6):596-601. 3. Tite L, Schroter S. Why do peer reviewers decline to review? A survey. J Epidemiol

Community Health. 2007;61(1):9-12. 4. Jefferson T, Alderson P, Wager E, Davidoff F. Effects of editorial peer review: a systematic

review. JAMA. 2002;287(21):2784-6. 5. Székely T, Krüger O, Krause ET. Errors in science: the role of reviewers. Trends Ecol Evol.

2014;29(7):371-3.

6. Hopewell S, Collins GS, Boutron I, Yu LM, Cook J, Shanyinde M, et al. Impact of peer review on reports of randomised trials published in open peer review journals: retros-pective before and after study. BMJ. 2014;349:g4145.

7. Gasparyan AY. Peer review in scholarly biomedical journals: a few things that make a big difference. J Korean Med Sci. 2013;28(7):970-1.

8. Gasparyan AY, Kitas GD. Best peer reviewers and the quality of peer review in biome-dical journals. Croat Med J. 2012;53(4):386-9.

9. Kotsis SV, Chung KC. Manuscript rejection: how to submit a revision and tips on being a good peer reviewer. Plast Reconstr Surg. 2014;133(4):958-64.

10. Moylan EC, Harold S, O’Neill C, Kowalczuk MK. Open, single-blind, double-blind: which peer review process do you prefer? BMC Pharmacol Toxicol. 2014;15:55.

11. Kara-Junior N. Medicina baseada em evidências. Rev Bras Oftalmol. 2014;73(1):5-6.

Tiago Santos PrataTuba CelikTuncay KusbeciUgur AcarVanessa GerenteVera Regina Cardoso CastanheiraVinícius GhanemViral JuthaniVirgilio Centurion

Virginia Laura Lucas TorresVital CostaWalter BloiseWener CellaWesley Ribeiro CamposWilliam MielerWilson Takashi HidaYasin ÇınarZelia M Correa

Original Article

1Arq Bras Oftalmol. 2015;78(1):1-5http://dx.doi.org/10.5935/0004-2749.20150002

InTRODUCTIOnRecurrence is the most common complication of pterygium

sur gery and a cause of patient discontent; these are primary chal-lenges for this surgery(1). Many approaches, including beta therapy, antimetabolic agents, and subconjunctival bevacizumab, have been proposed to prevent recurrence. However, these treatments are often associated with complications(2-6).

Tranilast inhibits the growth of pterygium-derived cells(7); the-refore, its use may reduce the recurrence of pterygium. Tranilast, N-[3,4-dimethoxycinnamonyl]-anthranilic acid, is an antiallergy drug that was first used to prevent bronchial asthma and allergic rhinitis.

ABSTRACTPurpose: To determine the efficacy of tranilast as an adjunctive therapy in con-junctival autograft. Methods: Twenty-nine patients were randomly allocated to the Tranilast Group (n=15) or the Control Group (n=14). The Tranilast Group received a subconjuncti-val injection of 0.5% tranilast 30 days prior to surgery. Conjunctival autograft was performed in both groups using fibrin sealant and 0.02% subconjunctival mitomycin C at the end of the surgery. After the resection of the pterygium, immunohistochemistry was performed with 100 cells to identify epithelial cells positive for transforming growth factor-β (TGF-β). Subjective symptoms were evaluated using a 5-point scale, and the recurrence rate was assessed. Results: Both groups showed improvements in their symptoms and similar clinical results. Compared with the Control Group, the Tranilast Group failed to show a de-creased recurrence rate (p=0.59). However, the number of epithelial cells expressing TGF-β was lower in the Tranilast Group (5 cells; 95% CI: 2.56-13.15; Control Group, 16 cells, 95% CI: 11.53-24.76; p=0.01). Minimal but reversible complications, including glaucoma secondary to corticosteroids and granuloma, occurred during the study. Conclusion: Tranilast was effective in decreasing the number of pterygium epi-thelial cells expressing TGF-β.

Keywords: Transforming growth factor beta 1; Pterygium/therapy; Recurrence; Au to grafts; Anti-allergic agents/therapeutic use; Transplantation, autologous; Con-junctiva/surgery

RESUMOObjetivo: Determinar a eficácia do tranilast, como terapia auxiliar no transplante autólogo de conjuntiva. Métodos: Vinte e nove pacientes foram randomizados em dois grupos: Grupo Tratado (15) e Grupo Controle (14). Trinta dias antes da cirurgia, o Grupo Tratado recebeu uma injeção subconjuntival de tranilast a 0,5%. O transplante autólogo de conjuntiva foi realizado em ambos os grupos, usando-se a cola de fibrina e a mitomicina 0,02% subconjuntival, ao final da cirurgia. Cada paciente foi examinado por 12 meses de acom-panhamento. A imuno-histoquímica foi realizada, mediante um total de 100 células, a fim de que se contassem as células epiteliais positivas, para o fator de crescimento transformador beta (TGF-β), após a cirurgia do pterígio. Os sintomas subjetivos foram avaliados usando-se uma escala de cinco pontos, e a taxa de recorrência foi avaliada. Resultados: Os 2 grupos apresentaram melhora dos sintomas e com resultados clínicos similares. Quando comparado com o Grupo Controle, o Grupo Tratado falhou em mostrar uma diminuição da taxa de recorrência (p=0,59). Entretanto o número de células epiteliais expressando o TGF-β foi menor no Grupo Tratado (5 células; 95% CI=2,56-13,15; Grupo Controle, 16 células; 95% CI: 11,53-24,76, p=0,01). Complicações mínimas, mas reversíveis, ocorreram durante o estudo, incluindo glaucoma secundário ao uso de corticoide e granuloma. Conclusão: O tranilast foi efetivo em diminuir o número células epiteliais do pterígio expressando o TGF-β.

Descritores: Fator de crescimento transformador beta 1; Pterígio/terapia; Recidiva; Autoen-xertos; Antialérgicos/uso terapêutico; Transplante autólogo; Túnica conjuntiva/cirurgia

Recent studies have shown that tranilast has an antifibrotic effect, inhibiting the proliferation of fibroblasts and their subsequent trans-formation into myofibroblasts(8). Furthermore, tranilast has been asso-ciated with decreases in posterior capsule opacification after cataract surgery and inhibition of scaring after glaucoma filtering surgery(9,10).

The present study aimed to determine the efficacy of tranilast for preventing pterygium recurrence. In addition, this study aimed to evaluate the symptoms and presence of transforming growth factor-β (TGF-β) in excised tissues when 0.5% tranilast was adminis-tered via subconjunctival injection prior to surgery as adjunctive the-rapy in conjunctival autograft (CAU) for cases of primary pterygium.

Preoperative tranilast as adjunctive therapy to primary pterygium surgery with a 1-year follow-upTerapia auxiliar com o tranilast pré-operatório na cirurgia do pterígio primário com um ano de seguimento

Gildásio c. alMeida Junior1, luciano arakawa1, dalísio de santi neto2, Patrícia MaluF cury2, acácio a. s. liMa Filho3, sidney J. F. sousa4, Milton r. alves5, reinaldo azouBel6

Submitted for publication: August 5, 2014 Accepted for publication: November 11, 20141 Department of Surgery, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto,

SP, Brazil.2 Department of Pathology, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto,

SP, Brazil.3 Department of Ophthalmology, Paulista School of Medicine (EPM), Federal University of São Paulo

(UNIFESP), São Paulo, SP, Brazil.4 Department of Ophthalmology, University of São Paulo (USP), Ribeirão Preto, SP, Brazil.5 Department of Ophthalmology, University of São Paulo (USP), São Paulo, SP, Brazil.6 Deparftment of Anatomy, Histology and Embryology, Faculdade de Medicina de São José do Rio

Preto, São José do Rio Preto, SP, Brazil.

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

Disclosure of potential conflict of interest: None of the authors have any potential conflict of interest to disclose.

Corresponding author: Gildasio Castello de Almeida Junior. D’Olhos Unidade Redentora. Rua Raul Silva, 559 - São José do Rio Preto, SP - 15015-020 - Brazil - E-mail: gcaj@vitavisum.com.br

This study protocol was registered as a clinical trial with the U.S. National Institutes of Health (#NCT01003613). The authors certify that the protocol for the research project conformed to the provisions of the Declaration of Helsinki of 1995 (as revised in Edinburgh 2000).

Approved by the following research ethics committee: Ethics Committee of FAMERP (#30492009)

Preoperative tranilast as adjunctive therapy to primary pterygium surgery with a 1-year follow-up

2 Arq Bras Oftalmol. 2015;78(1):1-5

MeTHODSThis prospective, randomized control trial included 50 patients

who underwent primary pterygium treatment at the Hospital de Base (HB) of the Medical School in São José do Rio Preto between June and December 2010.

The inclusion criteria were pterygium with a horizontal length of >2 mm measured from the anatomic limbus and subjective eye symptoms (irritation, burning, excessive tearing, dry eye sensation, foreign body sensation, and hyperemia). The exclusion criteria were a lack of connective tissue, history of eye trauma, glaucoma, dysfunc-tional tear syndrome, rosacea, neurotrophic keratopathy, systemic or topical use of immunosuppressive drugs, age

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Both groups used 0.1 mL mitomycin C (0.2 mg/mL) in the sub-tenonian region near the upper and lower conjunctive areas of the donor conjunctiva, and there were no complications during the first 12 months. Recurrence occurred in 2 CG patients and 1 TG patient after a year (p=0.59). The TG patient and 1 CG patient presented with small (0.5 mm) fibrovascular invasions in the limbal region. The other CG patient was diagnosed with conjunctival recurrence.

None of the patients presented with symblepharon. Both groups showed significant improvement in subjective symptoms at the end of the 12-month follow-up period, but there were no significant differences in the 6 subjective symptoms between the 2 groups (Figures 2 and 3).

The percentage of cells expressing TGF-β in TG (mean: 7.85%; range: 2.56-13.15%) was lower than that in CG (mean: 18.14%; range: 11.53-24.56%, p=0.01; Figure 4). Figure 5 shows how calculations for the expressed TGF-β cells were performed using images from a patient in CG. The esthetic results were very similar between the 2 groups (Figure 6).

DISCUSSIOnThe recurrence rates in this study, 6.66% for TG and 14.28% for

CG, were similar to other reports using different preoperative and in-traoperative regimens with adjuvant mitomycin C. Recurrence rates of 4.54% and 5.4% have been reported in 2 separate studies(15,16). Another study reported a recurrence rate of 15% after 4 years of follow-up(17).

The mean age of the patients in this study was 46.43 years for CG and 44.73 for TG. The difference in mean age may explain the higher recurrence rate in our study compared with the patients treated in another study who had a mean age of 60 years(15) because the recur-rence rate of pterygium is higher in younger individuals(18).

In a previous study, the 4-year recurrence rate of CAU alone was shown to be 15%, whereas the recurrence rate after the application of mitomycin C on bare sclera alone was 38%(17). In the current study, CAU was combined with mitomycin C in an attempt to combine and enhance the effects of each treatment.

However, it is important to note that the number of samples in each group was too small to determine the efficacy of tranilast. Fur-thermore, the loss to follow-up was very high (Figure 1), and the po-wer of the study for the variable recurrence was approximately 50%.

Anduze(19) also examined the effect of 0.1 mL of mitomycin C (0.2-0.4 mg/mL) applied directly under the conjunctival flaps posto-peratively using a similar procedure to that used in the current study.

Table 1. Preoperative characteristics of the 2 groups of patients who completed the study

Control group Tranilast group p-value

n 14 15

Gender (male/female) 8/6 5/10

Laterality (right/Left) 9:5 9:6

Age (years) 46.43 ± 13.12 (38.85-54.01) 44.73 ± 12.16 (38-51.47) 0.74

Horizontal length (mm) 3.82 (3.14-4.49) 3.30 (2.87-3.72) 0.25

Vertical length (mm) 5.30 (4.5-6.09) 4.80 (4.22-5.37) 0.22

Pterygium Tan Grading

T1 atrophic 0 (0%) 0 (0%)

T2 intermediate 3 (21.43%) 2 (13.33%)

T3 fleshy 11 (78.57%) 13 (86.67%)

Time (months) 12.71 (12.24-13.19) 12.93 (12.49-13.38) 0.45

Pterygium Tan Grading(11): Grade 1 (atrophic) - episcleral vessels under the body of the pterygium are clearly observed; Grade 3 (trophic) - episcleral vessels under the body of the pterygium are entirely obscured; and Grade 2 (intermediate) - types of pterygium that do not fit into 1 of the 2 categories described above.

figure 1. Flow diagram for the included patients during each step of the study.

Preoperative tranilast as adjunctive therapy to primary pterygium surgery with a 1-year follow-up

4 Arq Bras Oftalmol. 2015;78(1):1-5

The mechanism of action of tranilast differs from that of mi-tomycin C. Tranilast is safe to use even when the 2 agents are used concurrently, as observed in the present study. Tranilast can inhibit the proliferation and chemotaxis of pterygium-derived fibroblasts(7), as well as collagen synthesis of keloid fibroblasts(21).

There were some concerns in the present study regarding the toxicity of mitomycin, especially for late postoperative complications. However, no complications associated with its use were observed. One patient in CG lost the graft during the early postoperative period, which was possibly due to scratching of the eye. Other complications were granuloma formation and increased eye pressure secondary to corticosteroids.

One case report, in which tranilast ophthalmic solution was used, reported its effectiveness in preventing pterygium recurrence and inhibiting symblepharon and granulomas without adverse reac-tions(22). However, few studies reported in the literature have assessed both the preoperative and postoperative symptoms associated with pterygium surgery. In the present study, there were no significant differences in the symptoms between the groups and the symptoms typically disappeared 30 days postoperatively (Figures 2 and 3).

TGF-β, which is present in the epithelial cells, stromal cells, vas-cular endothelial cells, and vascular basal membrane of pterygium tissue, is a multifunctional protein that regulates cell migration, proliferation, differentiation, and apoptosis of many cell types(23). In the normal conjunctiva, positive immunolabeling for TGF-β is much weaker than in pterygium tissue(24). The present study demonstrated moderate expression of TGF-β in pterygium epithelial cells in CG compared with expression in TG (Figure 4).

Although a previous study found that an increase in TGF-β levels in the pterygium was comparable with that in normal conjunctiva(25), the immunohistochemical analysis reported here was similar to the findings of that study, showing that TGF-β was mainly expressed in the pterygium epithelial cells (Figure 5). The numbers of stained epithelial cells were significantly different between the 2 groups (p=0.01; Figure 4). Therefore, tranilast inhibits the secretion of TGF-β1 from conjunctival cells(26).

To the best of our knowledge, this study is the first to report sub-conjunctival injection of tranilast 30 days prior to pterygium surgery. Tsuji et al.(22) described other options, that include similar administra-tion such as the administration of mitomycin C in the postoperative period, that may be viable.

Based on the above findings, we consider that tranilast ophthal-mic solution administered by conjunctival injection before pterygium surgery may effectively decrease TGF-β in epithelial pterygium tissue. In contrast, we routinely use topical steroids and topical antibiotics after most eye surgeries. Therefore, we cannot ignore the possibility that steroids affected the postoperative outcome because they also have strong anti-inflammatory effects, and theoretically, could reduce recurrence after pterygium excision. However, pterygium recurrence

figure 2. Subjective symptoms before and after surgery in patients in the tranilast group (TG).

figure 3. Subjective symptoms before and after surgery in patients in the control group (CG).

figure 4. Expression of TGF-β in the epithelial cells of the pterygium in the control group (CG) compared with the tranilast group (TG).

Rubinfeld et al.(6) described 10 cases with severe complications that were associated with mitomycin C use after pterygium surgery. The safe dosage of mitomycin C is lower than 0.3 mg/mL(20), and it appears that the drug’s effective concentration overlaps with the concentration capable of causing adverse reactions.

figure 5. A) Positive immunohistochemical staining for TGF-β in the cytoplasmic membrane (arrows), with predominance in the superficial and middle portions of the conjunctival epithelium of the pterygium. The basal portion of the epithelium is scar-cely marked [frozen slides with focal artifacts (star). Magnification: 400×]. B) Negative immunohistochemical staining for TGF-β. The cytoplasmic membrane was not stained. [frozen slides. Magnification: 400×].

A B

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5Arq Bras Oftalmol. 2015;78(1):1-5

often occurs with topical steroids, suggesting that their an ti-in -flammatory effect is insufficient to prevent recurrence completely.

This study has some limitations, including the absence of a con-trol injection of the tranilast vehicle. TGF-β may interact directly or indirectly during the pathogenesis of pterygium, though this remains to be proven(24).

Subconjunctival tranilast was effective in decreasing the expression of TGF-β in pterygium epithelial cells.

RefeRenCeS 1. Hirst LW. The treatment of pterygium. Surv Ophthalmol. 2003;48(2):145-80. 2. Donnenfeld ED, Perry HD, Fromer S, Doshi S, Solomon R, Biser S. Subconjunctival

mi tomycin C as adjunctive therapy before pterygium excision. Ophthalmology. 2003; 110(5):1012-6.

3. Shenasi A, Mousavi F, Shoa-Ahari S, Rahimi-Ardabili B, Fouladi RF. Subconjunctival bevacizumab immediately after excision of primary pterygium: the first clinical trial. Cornea. 2011;30(11):1219-22.

4. Amano S, Motoyama Y, Oshika T, Eguchi S, Eguchi K. Comparative study of intraope-rative mitomycin C and beta irradiation in pterygium surgery. The British journal of oph thalmology. 2000;84(6):618-21.

5. Akarsu C, Taner P, Ergin A. 5-Fluorouracil as chemoadjuvant for primary pterygium surgery: preliminary report. Cornea. 2003;22(6):522-6.

6. Rubinfeld RS, Pfister RR, Stein RM, Foster CS, Martin NF, Stoleru S, et al. Serious compli-cations of topical mitomycin-C after pterygium surgery. Ophthalmology. 1992;99(11): 1647-54.

7. Isaji M, Kikuchi S, Miyata H, Ajisawa Y, Araki-Inazawa K, Tsukamoto Y, et al. Inhibitory effects of tranilast on the proliferation and functions of human pterygium-derived fibroblasts. Cornea. 2000;19(3):364-8.

8. Suzawa H, Kikuchi S, Ichikawa K, Koda A. Inhibitory action of tranilast, an anti-allergic drug, on the release of cytokines and PGE2 from human monocytes-macrophages. Jpn J Pharmacol. 1992;60(2):85-90.

9. Chihara E, Dong J, Ochiai H, Hamada S. Effects of tranilast on filtering blebs: a pilot study. J Glaucoma. 2002;11(2):127-33.

10. Tobari I, Iwaki Y, Miyake K. Effect of tranilast eyedrops in preventing posterior capsule opacification: preliminary report. J Cataract Refract Surg. 1999;25(10):1394-9.

11. Tan DT, Chee SP, Dear KB, Lim AS. Effect of pterygium morphology on pterygium recur-rence in a controlled trial comparing conjunctival autografting with bare sclera excision. Archives of ophthalmology. 1997;115(10):1235-40.

12. Koranyi G, Seregard S, Kopp ED. Cut and paste: a no suture, small incision approach to pterygium surgery. The British journal of ophthalmology. 2004;88(7):911-4.

13. Sebban A, Hirst LW. Pterygium recurrence rate at the Princess Alexandra Hospital. Aust N Z J Ophthalmol. 1991;19(3):203-6.

14. Lim-Bon-Siong R, Valluri S, Gordon ME, Pepose JS. Efficacy and safety of the ProTek (Vifilcon A) therapeutic soft contact lens after photorefractive keratectomy. American journal of ophthalmology. 1998;125(2):169-76.

15. Ayala M. Results of pterygium surgery using a biologic adhesive. Cornea. 2008;27(6): 663-7.

16. Koranyi G, Seregard S, Kopp ED. The cut-and-paste method for primary pterygium surgery: long-term follow-up. Acta Ophthalmol Scand. 2005;83(3):298-301.

17. Koranyi G, Artzen D, Seregard S, Kopp ED. Intraoperative mitomycin C versus autolo-gous conjunctival autograft in surgery of primary pterygium with four-year follow-up. Acta ophthalmologica. 2012;90(3):266-70.

18. Mutlu FM, Sobaci G, Tatar T, Yildirim E. A comparative study of recurrent pterygium surgery: limbal conjunctival autograft transplantation versus mitomycin C with con-junctival flap. Ophthalmology. 1999;106(4):817-21.

19. Anduze AL. Pterygium surgery with mitomycin-C: ten-year results. Ophthalmic surge-ry and lasers. 2001;32(4):341-5.

20. Chen CW, Huang HT, Bair JS, Lee CC. Trabeculectomy with simultaneous topical application of mitomycin-C in refractory glaucoma. Journal of ocular pharmacology. 1990;6(3):175-82.

21. Suzawa H, Kikuchi S, Arai N, Koda A. The mechanism involved in the inhibitory action of tranilast on collagen biosynthesis of keloid fibroblasts. Jpn J Pharmacol. 1992;60(2): 91-6.

22. Tsuji A, Kawai K, Fan H, Nakagawa Y, Suzuki T. Case in which tranilast ophthalmic solu-tion was thought to be effective for the prevention of symblepharon and recurrence after pterygium surgery. Tokai J Exp Clin Med. 2011;36(4):120-3.

23. Miyazono K, Ten Dijke P, Ichijo H, Heldin CH. Receptors for transforming growth factor-beta. Advances in immunology. 1994;55:181-220.

24. Kria L, Ohira A, Amemiya T. Immunohistochemical localization of basic fibroblast growth factor, platelet derived growth factor, transforming growth factor-beta and tumor necrosis factor-alpha in the pterygium. Acta histochemica. 1996;98(2):195-201.

25. Bianchi E, Scarinci F, Grande C, Plateroti R, Plateroti P, Plateroti AM, et al. Immunohis-tochemical profile of VEGF, TGF-beta and PGE(2) in human pterygium and normal conjunctiva: experimental study and review of the literature. International journal of immunopathology and pharmacology. 2012;25(3):607-15.

26. Ochiai H, Ochiai Y, Chihara E. Tranilast inhibits TGF- A1 secretion without affecting its mRNA levels in conjunctival cells. The Kobe journal of medical sciences. 2001;47(5): 203-9.

figure 6. The upper 3 pictures are from a patient in the tranilast group (TG) and the lower 3 pictures are from a patient in the control group (CG). (A) Before surgery, (B) 3 months after surgery, and (C) 6 months after surgery. (D) Before surgery, (E) 6 months after surgery, and (F) 12 months after surgery.

A

D

B

e

C

f

Original Article

6 Arq Bras Oftalmol. 2015;78(1):6-9 http://dx.doi.org/10.5935/0004-2749.20150003

InTRODUCTIOnThe development of exuberant fibrinous exudation or inflamma-

tion is a rare but serious complication after ocular surgery. It can cause numerous sequelae including membranes, anterior or posterior synechiae, secondary glaucoma, and pupillary block. Previous stu dies showed that recombinant tissue plasminogen activator (r-TPA) is effective and safe for improving the clinical course of fibri-nous related complications in cases of traumatic hyphema(1-3), severe post cataract fibrinous membranes in pediatric(4), fibrin formation after cataract surgery(4-6), glaucoma surgery(7-9), subretinal hemorrhage(10), and endophthalmitis(11).

Intracameral r-TPA has been shown to be effective for fibrin de-gradation. However, the effectiveness of topical(12), intravitreous(13), and subconjunctival(7,9) r-TPA remains controversial. Most studies re garding absorption or anterior chamber dosing of r-TPA were non-quan titative. To the best of our knowledge, no study has com-pared in tracameral, subconjunctival and topical application of r-TPA using the same quantitative methods.

Therefore, the purpose of this study was to quantify fibrin degra-dation products (FDP) after topical and subconjunctival administration of r-TPA in rabbits.

MeTHODSThis prospective double-blind experimental study was perfor-

med in the Setor de Técnica Cirúrgica da Santa Casa de São Paulo under veterinary supervision. It was approved by the Animal Ethical Committee and Institutional Board of the Hospital das Clínicas and the Faculdade de Medicina da Universidade de São Paulo. All proce-dures followed proper legislation for the protection of animals (EU Directive 2010/63/EU) and adhered to the Association of Research in Vision and Ophthalmology (ARVO) statement for the Use of Animals in Ophthalmic and Vision Research.

Twenty-five New Zealand male rabbits weighing 3.5 to 4.0 kg were enrolled in this study. All rabbits underwent an ocular exami-nation and slit lamp documentation (Nikon, FS3 slit lamp, Japan). All rabbits with ocular abnormalities were excluded from the study.

Anesthesia was induced in each rabbit using intramuscular in jection of a mixture of 0.3 mL/kg tiletamine hydrochloride and zo la zepam (Zoletil 50®, Laboratoire Virbac, France). General anes-thesia was achieved with an intramuscular injection of a mixture of 0.3 mL/kg tiletamine hydrochloride and zolazepam, and a mixture of 0.4 mL/kg fentanyl and droperidol (Innovar-Vet®, MTC Pharmaceu-ticals, Ontario, Canada).

Subconjunctival and topical application of recombinant tissue plasminogen activator in rabbitsUso tópico e subconjuntival de ativador de plasminogênio tecidual recombinante em coelhos

José ricardo de aBreu reGGi1, richard yudi hida1,2, Milton Massato hida3, Maria cristina nishiwaki-dantas1, hisashi suzuki2

Submitted for publication: June 30, 2014 Accepted for publication: November 10, 20141 Department of Ophthalmology, Santa Casa de São Paulo, São Paulo, SP, Brazil.2 Department of Ophthalmology, University of São Paulo (USP), São Paulo, SP, Brazil.3 Department of Ophthalmology, Universidade Estadual Paulista “Júlio de Mesquita Filho” (UNESP),

Botucatu, SP, Brazil.

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

Disclosure of potential conflicts of interest: None of the authors have any potential conflicts of interest to disclose.

Corresponding author: Richard Yudi Hida. Rua Afonso de Freitas, 488/61 - São Paulo, SP - 04006-052 - Brazil - E-mail: ryhida@gmail.com

ABSTRACTPurpose: To quantify fibrin degradation products after topical and subconjunctival administration of recombinant tissue plasminogen activator in rabbits.Methods: Fibrin formation was induced in the anterior chamber in 25 rabbits. Subsequently, five rabbits received an injection of r-TPA (positive control) in the anterior chamber, another 10 received a subconjunctival injection of r-TPA, and the remaining 10 received instillations of topical r-TPA. Afterwards, samples of aqueous humor were collected and semi-quantitative analysis of fibrin degradation products (FDP) was performed. Results: No statistical differences were noted between the treatment and control groups at any time point. Fibrin degradation products semi-quantification showed statistical improvement in the control group and the subconjunctival group. Conclusion: Fibrin degradation products were observed in the anterior cham-ber after subconjunctival administration of r-TPA. However, it was probably not sufficient to cause fibrin degradation. Topical r-TPA did not effectively absorb anterior chamber fibrin.

Keywords: Tissue plasminogen activator; Anterior chamber; Hyphema; Inflamma-tion; Postoperative complications; Animals; Rabbits

RESUMOObjetivo: Quantificar produtos de degradação de fibrina (PDF) após uso tópico e sub-conjunctival de ativador de plasminogênio tecidual recombinante (r-TPA) em coelhos. Métodos: Formação de fibrina foi induzida na câmara anterior em 25 coelhos. Cinco coelhos foram submetidos a injeção intracameral de r-TPA (controle positivo). Dez coelhos foram submetidos a injeção subconjuntival de r-TPA e dez coelhos foram submetidos a instilação tópica de r-TPA. Amostras de humor aquoso foram coletados e uma análise quantitativa dos produtos de degradação de fibrina foi realizada. Resultados: Não foi observado diferença estatisticamente significativa na degra-dação de fibrina em nenhum dos momentos estudados quando comparados com o controle. Porém foi observado diferença estatisticamente significante na quantificação do produtos de degradação de fibrina no grupo controle e no grupo subconjuntival. Conclusão: Produtos de degradação de fibrina foi observado nas amostras do grupo subconjunctival, porém, provavelmente não foi suficiente para degradar a fibrin presente. r-TPA tópico não foi efetivo em absorver fibrina na câmara anterior.

Descritores: Ativador de plasminogênio tecidual; Câmera anterior; Hifema; Inflama-ção; Complicações pós-operatórias; Animais; Coelhos

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After appropriate anesthesia was attained, 5.0 mL of blood was collected from the ear vein and centrifuged to isolate the plasma. Each rabbit received topical 0.5% procaine chloridrate (Anestalcon®, Alcon, São Paulo, Brazil), and then a lid speculum was used for para-centesis in the superior portion of the cornea with a 25 gauge needle. Keeping the needle in the anterior chamber, 0.1 mL of aqueous hu-mor was aspirated and 0.1 mL of plasma citrate was injected.

After 24 h, all rabbits were sedated and photographed under a slit lamp. All eyes with fibrin in the anterior chamber were graded according to the classification described by Lim et al.(14) (grade 0: no visible fibrin; grade 1: few visible fibrin filaments and clear details of the iris; grade 2: presence of a fibrin clot and blurry details of the iris; grade 3: presence of a fibrin clot, no visible details of the iris). All eyes with fibrin levels of grade 1 and 2 of fibrin in the anterior chamber were excluded from the study. Sampling calculations were based on a previous pilot study and statistical analysis was performed using the WINPEPI program with the COMPARE2 module (Version 2.68) to avoid sampling error. The sample size was increased in 20% due to possible loss to follow-up.

Rabbits were divided into three study groups: group 1 (n=5; positive control) received intracamerular injection of r-TPA; Group 2 (n=10) received subconjunctival injection of r-TPA; Group 3 (n=10) received topical r-TPA.

One eye from each rabbit in group 1 was randomly chosen (po-sitive control) to receive an injection of 0.1 mL of 0.25 µg/mL r-TPA (TPA-Alteplase®, Ophthalmos, São Paulo, Brazil) in the anterior cham-ber after instillation of topical 0.5% procaine chloridrate (Anestalcon®, Alcon, São Paulo, Brazil). The other eye from the same rabbit was in-jected with 0.1 mL balanced salt solution using the same technique.

One eye from each rabbit in group 2 was randomly chosen to receive a subconjunctival injection of 0.1 mL of 0.25 µg/mL r-TPA after instillation of topical 0.5% procaine chloridrate. The other eye was injected with 0.1 mL balanced salt solution using the same technique.

One eye from each rabbit in Group 3 was randomly chosen to receive one drop of topical r-TPA at 1 mg/mL, 9 times at intervals of every 5 min after instillation of topical 0.5% procaine chloridrate. The other eye received one drop of 0.1 mg/mL balanced salt solution in the same regimen.

Each rabbit was examined, classified, and documented under sedation using a slit lamp (Nikon, model FS3, Japan) at the moment of the procedure (M0), and 30 min (M1), 60 min (M2), 7 h (M3) and 24 h (M4) after the procedure.

After 24 h, each rabbit was euthanized with intramuscular 1 mg/kg acepromazine and intravenous 30 mg/kg thiopental sodium. All eyes underwent paracentesis and aspiration of samples of aqueous humor using a 25-gauge needle. Samples were immediately transported to our laboratory for qualitative and semi-quantitative analysis of FDP and fibrinogen using the macro-latex slide agglutination test (FDP Plas-

ma®, Diagnostica Stago Inc, France) according to the ma nufacturer`s instructions. This test involves multiple microlatex particles coated with mouse monoclonal anti-human FDP antibodies(15). Presence of FDPs causes agglutination of the latex particles as the FDPs bind to the antibodies. Then these agglutinated particles are detected visually. The detection limit of this test is 2.5 µg/mL.

Qualitatively, the agglutination pattern was interpreted as nega-tive when transparent and positive when blurred. Quantitatively, a positive agglutination pattern was interpreted as recommended in the manufacturer`s instructions.

All results were analyzed statistically with the Wilcoxon test (p0.05).

In group 3 (topical administration), no statistically significant diffe rence was noted at any time point (M1, M2, M3 and M4) compa-red to the control group (p>0.05).

Table 2 shows the results of the semi-quantification of the FDPs following the different applications of r-TPA compared to the control group.

FDP semi-quantification showed statistically significant improve-ment in groups 1 (p=0.0079) and 2 (p=0.0052), but no statistically significant difference was observed in group 3 (p=0.48).

DISCUSSIOnFibrinous exudation is a serious complication of intraocular sur-

gery and endophthalmitis. These complications can preclude fundus examination and interfere with the performance of a second inter-vention such as vitrectomy. These fibrinous membranes are usually difficult to manage with conventional steroid therapy. Typically, intrao-cular fibrin can be surgically removed, treated with an argon laser, or

Table 1. Distribution of the average and mean deviation of anterior chamber fibrin grading following criteria according to Lim et al.(14), after applica-tion of recombinant tissue plasminogen activator

examination time points

M1 M2 M3 M4

A ± SD p A ± SD p A ± SD p A ± SD p

Group intracameral Control 3.00 ± 0.00 0.06

3.00 ± 0.00 0.0079**

2.80 ± 0.45 0.0079**

2.00 ± 0.00 0.0079**

(0.25 µg/mL) r-TPA 1.80 ± 0.84 1.60 ± 0.55 1.00 ± 0.00 0.20 ± 0.45

Group subconjunctival Control 2.90 ± 0.32 0.97

2.90 ± 0.32 1.00

2.70 ± 0.48 1.00

2.10 ± 0.32 0.80

(0.25 µg/mL) r-TPA 3.00 ± 0.00 2.90 ± 0.32 2.70 ± 0.48 2.00 ± 0.67

Group topical Control 3.00 ± 0.00 1.00

3.00 ± 0.00 1.00

2.50 ± 0.53 0.74

2.20 ± 0.42 0.74

(1 mg/mL) r-TPA 3.00 ± 0.00 3.00 ± 0.00 2.60 ± 0.52 2.30 ± 0.48

r-TPA= recombinant tissue plasminogen activator; A= average; SD= standard deviation; M1= anterior chamber fibrin grading scale 30 min after r-TPA application; M2= anterior chamber fibrin grading scale 60 min after r-TPA application; M3= anterior chamber fibrin grading scale 7 h after r-TPA application; M4= anterior chamber fibrin grading scale 24 h after r-TPA application.

Subconjunctival and topical application of recombinant tissue plasminogen activator in rabbits

8 Arq Bras Oftalmol. 2015;78(1):6-9

occasionally fibrinolytic drugs such as streptokinase and urokinase are used(16,17). However, intraocular toxicity was often observed with these drugs(18).

R-TPA is a genetically cloned serine protease that promotes the degradation of fibrin only at the clot surface(19). It has minimal side effects or toxicity when applied to the eye. It is considered a clot-specific fibrinolytic agent, used for the treatment of deep vein throm bosis(20) and acute myocardial infarction(21). In ophthalmology, it was described as effective in thrombolytic therapy in patients with branch or central vein occlusion of the retina(22), glaucoma filtration surgery(23), or intracameral fibrinolysis following ocular surgery(5,6).

In our study using rabbit eyes, we found that intracamerular r-TPA (0.25 µg/1 mL) more effectively degraded anterior chamber fibrin compared to the control group. Other studies yielded similar re-sults(2,24,25) with similar control groups.

There was no statistically significant difference in the degradation of anterior chamber fibrin in rabbit eyes with subconjunctival r-TPA compared to the control group. Although some degradation pro-ducts were present in the anterior chamber, they were insufficient to indicate effective fibrin degradation. Additional studies are necessary to clarify whether a different concentration of subconjunctival r-TPA could actually increase fibrin degradation in the anterior chamber. The benefits and indications of r-TPA are evident especially in compli-cations of glaucoma surgery involving the conjunctiva(7,9,23).

Compared to the control group, there was also no statistically relevant difference in the degradation of anterior chamber fibrin in rabbit eyes following r-TPA injection at 1 mg/mL. Previous studies were controversial(12,26-28). The inefficacy of this method is probably re lated to poor penetration beyond the surface of the clot. Higher concentrations of r-TPA were not administered because toxicity to the epithelium was observed during a pilot study (data not shown).

The minimum concentration necessary to promote degradation of anterior chamber fibrin varied in previous studies. Based on these stu-dies, an approximate dose of 25 µg/1 mL is suggested to effectively degrade fibrin with no intraocular toxicity(2,3). There is no evidence of lens abnormalities in animal models following the use of this concen-tration(2,29). Other authors observed good results using 10 µg/mL r-TPA for total hyphema in rabbit eyes(30). Subconjunctival administration of r-TPA may be a novel method for promoting fibrin degradation.

The use of r-TPA in the eye has been considered safe with very few complications. The potential complications related to the use of r-TPA are corneal edema and anterior chamber turbidity, which results from immediate fibrinolysis products, prostaglandins, and leu-kocyte hydrolytic enzymes(31). Previous studies did not show clinically relevant abnormalities in the cornea, lens, or retina(2,29), intraocular

pressure changes, or an inflammatory response or rebleeding when intracameral or vitreous r-TPA was used at doses under 25 µg/1 mL. However, some studies suggested that it can increase the risk of in-traocular rebleeding, ocular toxicity, and corneal abnormalities. Our study showed promising results with a lower dose of intracameral r-TPA. However, further studies are required to determine whether higher doses could be more effective.

FDPs were observed in the anterior chamber after 0.25 µg/mL subconjunctival r-TPA; however, this dose was probably insufficient to cause fibrin degradation. Topical 1 mg/mL r-TPA did not effective degrade anterior chamber fibrin.

ACKNOWLEDGMENTDrs. Abreu Reggi and Hida contributed equally to this work and

request acknowledgement as co-first authors.

RefeRenCeS 1. Laatikainen L, Mattila J. The use of tissue plasminogen activator in post-traumatic

total hyphaema. Graefes Arch Clin Exp Ophthalmol. 1996;234(1):67-8. 2. Lambrou FH, Snyder RW, Williams GA. Use of tissue plasminogen activator in experi-

mental hyphema. Arch Ophthalmol. 1987;105(7):995-7. 3. Moon J, Chung S, Myong Y, Chung S, Park C, Baek N, et al. Treatment of postcataract

fibrinous membranes with tissue plasminogen activator. Ophthalmology. 1992;99(8): 1256-9.

4. Klais CM, Hattenbach LO, Steinkamp GW, Zubcov AA, Kohnen T. Intraocular recombi-nant tissue-plasminogen activator fibrinolysis of fibrin formation after cataract surgery in children. J Cataract Refract Surg. 1999;25(3):357-62. Comment in: J Cataract Refract Surg. 1999;25(7):880; J Cataract Refract Surg. 2000;26(1):4-5; J Cataract Refract Surg. 2000;26(1):4; author reply 5.

5. Wedrich A, Menapace R, Muhlbauer-Ries E. The use of recombinant tissue plasmino-gen activator for intracameral fibrinolysis following cataract surgery. Int Ophthalmol. 1994-1995;18(5):277-80.

6. Wedrich A, Menapace R, Ries E, Polzer I. Intracameral tissue plasminogen activator to treat severe fibrinous effusion after cataract surgery. J Cataract Refract Surg. 1997; 23(6):873-7.Comment in: J Cataract Refract Surg. 1998;24(5):575.

7. Fourman S, Vaid K. Effects of tissue plasminogen activator on glaucoma filter blebs in rabbits. Ophthalmic Surg. 1989;20(9):663-7.

8. Lundy DC, Sidoti P, Winarko T, Minckler D, Heuer DK. Intracameral tissue plasminogen activator after glaucoma surgery. Indications, effectiveness, and complications. Ophthalmology. 1996;103(2):274-82.

9. Ortiz JR, Walker SD, McManus PE, Martinez LA, Brown RH, Jaffe GJ. Filtering bleb thrombolysis with tissue plasminogen activator. Am J Ophthalmol. 1988;106(5):624-5.

10. Hattenbach LO, Klais C, Koch FH, Gumbel HO. Intravitreous injection of tissue plasmi-nogen activator and gas in the treatment of submacular hemorrhage under various conditions. Ophthalmology. 2001;108(8):1485-92.Comment in: Ophthalmology. 2002; 109(5):824; author reply 825.

11. Wu TT, Wang HH. Intracameral recombinant tissue plasminogen activator for the treat ment of severe fibrin reaction in endophthalmitis. Eye (Lond). 2009;23(1):101-7.

12. Gerding PA, Jr., Hamor RE, Ramsey DT, Vasaune S, Schaeffer DJ. Evaluation of topically administered tissue plasminogen activator for intraocular fibrinolysis in dogs. Am J Vet Res. 1994;55(10):1368-70.

13. Johnson MW, Olsen KR, Hernandez E, Irvine WD, Johnson RN. Retinal toxicity of re-combinant tissue plasminogen activator in the rabbit. Arch Ophthalmol. 1990;108(2): 259-63.

14. Lim JI, Maguire AM, John G, Mohler MA, Fiscella RG. Intraocular tissue plasminogen activator concentrations after subconjunctival delivery. Ophthalmology. 1993;100(3): 373-6.

15. Mirshahi M, Soria J, Soria C, Perrot JY, Boucheix C. A latex immunoassay of fibrin/fibrino-gen degradation products in plasma using a monoclonal antibody. Thromb Res. 1986; 44(6):715-28.

16. WuDunn D. Intracameral urokinase for dissolution of fibrin or blood clots after glauco-ma surgery. Am J Ophthalmol. 1997;124(5):693-5.

17. Bernatchez SF, Tabatabay C, Belin D. Urokinase-type plasminogen activator in human aqueous humor. Invest Ophthalmol Vis Sci. 1992;33(9):2687-92.

18. Ramsby ML, Kreutzer DL. Fibrin induction of tissue plasminogen activator expression in corneal endothelial cells in vitro. Invest Ophthalmol Vis Sci. 1993;34(11):3207-19.

19. Pennica D, Holmes WE, Kohr WJ, Harkins RN, Vehar GA, Ward CA, et al. Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli. Nature. 1983; 301(5897):214-21.

20. Milligan KS. Tissue-type plasminogen activator: a new fibrinolytic agent. Heart Lung. 1987;16(1):69-74.

21. Collen D, Bounameaux H, De Cock F, Lijnen HR, Verstraete M. Analysis of coagulation and fibrinolysis during intravenous infusion of recombinant human tissue-type plas-minogen activator in patients with acute myocardial infarction. Circulation. 1986;73(3): 511-7.

Table 2. Distribution of average and mean deviation of the dilution of a positive agglutination pattern of fibrin degradation products as determined by semi-quantification analysis using the macro-latex slide agglutination test (fDP Plasma®, Diagnostica Stago Inc., france). Semi-quantitatively, a positive agglutination pattern was interpreted as positive when the examiner visually detected agglutinated particles

Level of fDP (µg/mL)  

A ± SD p

Group intracameral Control 02.50 ± 0.00 0.0079**

(0.25 µg/mL) r-TPA 12.00 ± 4.47

Group subconjunctival Control 02.50 ± 0.00 0.0052**

(0.25 µg/mL) r-TPA 04.50 ± 1.05

Group topical Control 02.50 ± 0.00 0.48

(1 mg/mL) r-TPA 02.75 ± 0.79

r-TPA= recombinant tissue plasminogen activator; FDP= fibrinogen degradation products; A= average; SD= standard deviation; Wilcoxon test (**P

Reggi JRA, et al.

9Arq Bras Oftalmol. 2015;78(1):6-9

22. Kreutzer A, Brunner R, Schafer HJ, Sickel W, Auel H, Hossmann V. [Thrombolytic the-rapy with recombinant tissue-type plasminogen activator in patients with branch or central vein occlusion of the retina]. Fortschr Ophthalmol. 1988;85(5):511-3.German.

23. Ozment RR, Laiw ZC, Latina MA. The use of tissue plasminogen activator in experimen-tal filtration surgery. Ophthalmic Surg. 1992;23(1):22-30.

24. Johnson RN, Olsen K, Hernandez E. Tissue plasminogen activator treatment of pos-toperative intraocular fibrin. Ophthalmology. 1988;95(5):592-6.

25. Moon J, Chung S, Myong Y, Park C, Baek N, Rhee S. Treatment of postcataract fibrinous membranes with tissue plasminogen activator. Ophthalmology. 1992;99(8):1256-9.

26. Lim JI, Fiscella R, Tessler H, Gagliano DA, Chaques-Alepuz V, Mohler MA. Intraocular penetration of topical tissue plasminogen activator. Arch Ophthalmol. 1991;109(5):714-7.

27. Cellini M, Baldi A, Possati GL. Topical treatment of postvitrectomy fibrin formation with tissue plasminogen activator. Int Ophthalmol. 1994;18(6):351-3.

28. Zwaan J, Latimer WB. Topical tissue plasminogen activator appears ineffective for the clearance of intraocular fibrin. Ophthalmic Surg Lasers. 1998;29(6):476-83.

29. Snyder RW, Sherman MD, Allinson RW. Intracameral tissue plasminogen activator for treatment of excessive fibrin response after penetrating keratoplasty. Am J Ophthalmol. 1990;109(4):483-4.

30. Kim MH, Koo TH, Sah WJ, Chung SM. Treatment of total hyphema with relatively low-do se tissue plasminogen activator. Ophthalmic Surg Lasers. 1998;29(9):762-6.

31. McDermott ML, Edelhauser HF, Hyndiuk RA, Koenig SB. Tissue plasminogen activator and the corneal endothelium. Am J Ophthalmol. 1989;108(1):91-2.

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Original Article

10 Arq Bras Oftalmol. 2015;78(1):10-4 http://dx.doi.org/10.5935/0004-2749.20150004

InTRODUCTIOnAge-related macular degeneration (ARMD) is the most frequent

cause of vision loss in patients over 50 years of age in developed countries(1,2). In these populations, many factors including prolonged life expectancy, the need for independence in daily activities, and

ABSTRACTPurpose: To evaluate the knowledge and behaviors of ophthalmologists in Turkey concerning micronutrition support in patients with age related macular degenera-tion (ARMD). Methods: This study involved 1,845 ophthalmologists. A scientific poll was sent to all participants by email. The survey covered the following: demographic fea-tures, subspecialty knowledge about micronutrition preference for prescribing micronutrition to age related macular degeneration patients, and the reason for this preference. If a participant indicated that he or she prescribed micronutri-tion, the participant was also asked to indicate the source of the treatment and supplemental treatments. Results: Of 1,845 ophthalmologists, 249 responded to the survey. Of the res-pondents, 9% (22) never, 43% (107) sometimes, 37% (92) frequently, and 11% (27) always used micronutrition. The most frequent prescribing subgroup was general ophthalmology (22%), followed by the retina-uvea subspecialty (13.9%). The micronutrition prescribing ratio was 54.8% in retina-uvea specialists when the “frequent” and “always” responses were combined. There was no statistically significant difference between subgroups with respect to prescribing micronu-trition. Among the ophthalmologists prescribing micronutrition, 57.1% of them did not use the Age-Related Eye Disease Study-1 (AREDS) criteria, and only 31.3% prescribe micronutrition according to AREDS criteria. The results for the general ophthalmologist and retina-uvea specialist subgroups were similar, 56.3% vs 20.2%, and 54.1% vs 36.1%, respectively. Micronutrition was not recommended for the following reasons: expensive (55.4%), low patient expectancy (40%), no effect (30%), and low patient drug compliance (25.4%). Moreover, 55.2% of the clinicians recommended physical activities, dietary changes, and smoking cessation; 7.3% did not recommend these behavioral changes. Conclusion: This survey demonstrated that micronutrition preference in age related macular degeneration was low in ophthalmologists in Turkey. Additionally, retina specialists have a lower rate of prescribing micronutrition. Micronutrition support and behavior such as smoking cessation, dietary changes, etc. should be recommended more often to patients with age related macular degeneration.

Keywords: Macular degeneration/prevention & control; Dietary supplements; Vi -tamins/administration & dosage; Lutein/administration & dosage; Guideline as to pic/standards; Turkey

RESUMOObjetivo: Avaliar o conhecimento e comportamento dos oftalmologistas na Turquia sobre o suporte micronutricional em pacientes com degeneração macular relacionada à idade (DMRI). Método: Este estudo continha 1.845 oftalmologistas, e uma pesquisa científica foi enviado a todos os participantes por e-mail. O levantamento abrangeu as seguintes informações: características demográficas, conhecimento na subespecialidade sobre a preferência micronutricional para a prescrição micronutrientes a pacientes com degeneração macular relacionada à idade, e a razão por trás dessa preferência. Se um participante respondeu que prescreveu micronutrientes, foi solicitado que indicasse a origem do tratamento, bem como tratamentos suplementares. Resultados: Duzentos e quarenta e nove de 1.845 oftalmologistas responderam à pesquisa. Destes oftalmologistas 9% (22) nunca haviam usado micronutrição, 43% (107), utilizava eventualmente, 37% (92) usavam com frequência, e 11% (27) sempre usou. O subgrupo de prescrição mais frequente era composto por oftalmologistas gerais (22%), seguido por subespecialistas em retina e/ou úvea (13,9%). A frequência de prescrição de micronutrientes foi de 54,8% dentre os subespecialistas em retina e/ou úvea quando resultados de resposta foram combinados em “frequente” e “sempre.” Não houve diferença estatisticamente significativa entre os subgrupos com relação à prescrição de micronutrientes. Entre os oftalmologistas que prescreviam micronutrição, 57,1% deles não usavam os critérios The Age-Related Eye Disease Study-1 (AREDS) e 31,3% deles prescreviam de acordo com critérios AREDS. A utilização dos critérios teve distribuição semelhante entre os oftalmologistas gerais e os especialistas, 56,3% vs 20,2%, e 54,1% vs 36,1%, respectivamente. A micronutrição não era recomendada pelas seguintes razões: preço (55,4%), baixa expectativa de paciente (40%), nenhum efeito (30%), e baixa aderência do paciente à droga (25,4%). Além disso, 55,2% dos clínicos recomendam a atividade física, mudanças na dieta, e cessação do tabagismo; 7,3% deles não recomendam estas mudanças comportamentais. Conclusão: Este estudo demonstrou que a preferência por micronutrientes em degeneração macular relacionada à idade foi baixa dentre os oftalmologistas da Turquia. Além disso, os subespecialistas da retina têm uma menor taxa de prescrição. Apoio micronutricional e outras recomendações (cessação do tabagismo, mudanças na dieta, etc.) devem ser lembrados mais em pacientes com degeneração macular relacionada à idade.

Descritores: Degeneração macular/prevenção & controle; Suplementos dietéticos; Vitaminas/administração & dosagem; Luteína/administração & dosagem; Guias como assunto; Turquia

economic burden on family and society are related to the quality of life, and thus to severity of the disease(3,4).

Although the etiopathogenesis of ARMD is not fully understood, it indisputably appears as the combination of factors such as familial predisposition, family history, aging, and smoking(5). A limited study

Approach of Turkish ophthalmologists to micronutrition in age-related macular degeneration Abordagem dos oftalmologistas turcos em relação a micronutrição na degeneração macular relacionada à idade

MuhaMMed Şahin1, harun yüksel1, alparslan Şahin1, abdullah KürŞat Cingü1, Fatih MehMet türkcü1, zeyneP Gürsel Özkurt1, İhsan ÇaÇa1

Submitted for publication: May 29, 2014 Accepted for publication: November 6, 20141DepartmentofOphthalmology,SchoolofMedicine,DicleUniversity,Diyarbakır,Turkey.

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

Disclosure of potential conflicts of interest: None of the authors have any potential conflicts of interest to disclose.

Corresponding author: MuhammedŞahin.DicleUniversity,SchoolofMedicine-DepartmentofOphthalmology-Diyarbakır-Turkey-E-mail:drmuhammedsahin@gmail.com

Şahin M, et al.

11Arq Bras Oftalmol. 2015;78(1):10-4

on women suggested protective factors such as a healthy life style, modification of dietary habits, and improved physical activity de-crease the incidence of development of ARMD at a rate of 71%(6). In recent years, a number of alternative treatments, such as anti-VEGF therapy, have increased the hope of curing neovascular ARMD(7-9). However, important disadvantages of these treatments include their higher costs, need for reinjection, loss of workforce, and extra hours spent by the physicians. Currently, there is no curative treatment for dry type ARMD. Therefore, serious attempts have been made to protect patients from ARMD risk factors, and to prevent progression to advanced ARMD. Use of micronutrition in ARMD represents a large scientific scope, which is the subject of various investigations. However, an increasing proportion of patients using micronutrition led to an estimated expenditure of nearly 27 million dollars(10).

Conflicting results in the literature show that ophthalmologists have widely differing preferences regarding the use of dietary supple-ments. The increased vulnerability of retinal injury due to increased oxidative stress and free radical generation with aging has been demonstrated. Several studies were conducted to investigate the effect of dietary intake of anti-oxidant agents and vitamins on the retina(11-15). In the European Eye, a significant correlation was found between neovascular ARMD patients consuming a low-density diet containing lutein and zeaxanthin pigments, and subsequent cumulative visible light damage(16). The Age-related Eye Disease Stu-dy-1 (AREDS) is a comprehensive, prospective, placebo-controlled study monitoring 4757 participants. Its first results were published in 2001(17). This study demonstrated that high doses of vitamin and mineral supplements prevent progression to the advanced stages of ARMD (choroid neovascularization or central geographic atrophy) at a rate of 25%, and decrease the risk of serious vision loss. The authors of these and other studies (such as those conducted by American Academy of Ophthalmologists) have recommended micronutrition support for category 3, and 4 patients, as long as no contraindication exists. Outcomes of the AREDS 2 study were published in 2013(18); the results suggest that enrichment of the diet with lutein and zeaxan-thin has a protective role in ARMD progression.

A few published studies showed that patients receiving vitamin supplements complied poorly with the recommendations of their ophthalmologists. However, a large-scale study which evaluates the amount of supplements recommended by ophthalmologists has not been conducted yet(19-24). The primary objective of this study is to evaluate the frequency of micronutrition recommendations made by ophthalmologists to ARMD patients in Turkey, and to assess the crite-ria used by ophthalmologists when making such recommendations.

MeTHODSAfter obtaining approval of the Presidency of Ethics Committee

of the Dicle University Faculty of Medicine, questionnaire forms were sent to the email addresses of ophthalmologists. The participants were informed that the study was a scientific survey, and that the

responders and their responses would not be disclosed. The partici-pants were not allowed to change their responses after submission. The participants were free to respond or not respond to any question. The study encompassed ophthalmologists working in state hospi-tals, training and research hospitals, university hospitals, foundation hospitals, and private hospitals. Emails were sent to the participants twice, for example in June and September 2013. The first part of the 9-item questionnaire asked for demographic characteristics such as age, gender, title, and employer. The second part comprised of questions about the specialty/subspecialty, subject matter topics of interest, and ARMD (wet/dry) cases seen in practice. In the last part of the questionnaire, we asked the clinicians about their prescribing practices in ARMD patients, their use of the AREDS classification system, and the reasons for their prescribing preferences. The last part of the survey asked for the clinicians’ sources of information on micronutrition and their additional recommendations for ARMD pa-tients. The responses were tabulated in an excel format and analyzed.

STATiSTiCAL ANALySiSFor statistical analysis, all data were entered into a database in

SPSS v. 18, followed by descriptive analyses. The significance level between groups was assessed by the χ2 test; p

Approach of Turkish ophthalmologists to micronutrition in age-related macular degeneration

12 Arq Bras Oftalmol. 2015;78(1):10-4

not use AREDS criteria, and only 20.2% employed AREDS criteria for their category 3-4 patients. More than half (54.1%) of the retina-uvea specialists did not use AREDS criteria, and only 36.1% used them for their category 3-4 patients.

The responses to the question ”Why didn’t you prefer to use mi -cronutrition in ARMD?” by percent were: “it is expensive” (55.4%), “it does not satisfy the expectations of the patients (40%), “I don’t think that it is beneficial (30%), and “patient compliance is very poor” (25.4%).

Analysis of mic ronutrition use based on the employer of the participants revealed it was mostly used in private hospitals (56.6%), followed by university hospitals and foundation hospitals (51.2%), and then by state and training and research hospitals (39%), without any statistically significant difference between groups.

When asked about micronutrition information, 41% of the parti-cipants responded that they had read 2-5 articles about micronutri-tion. Of the remaining participants, 39% had read more than 5, 9% had read one, and 12% had not read any. We found no statistically significant difference between the categories of responders and the number of articles read.

We asked the participants about additional measures recommen-ded for ARMD patients. The responses included modification of only dietary habits (29.4%), quitting smoking (35.5%), increased physical activity (0.4%), and all of the above (55.2 %); 7.3% did not recommend any additional measures.

DISCUSSIOnIf prophylactic or definitive treatment of ARMD is not discovered

within the next 20 years, the incidence of ARMD is expected to rise up to nearly 50 percent in the USA and Europe(25). Introduction of new treatments for neovascular ARMD (i.e., anti-VEGF therapy) brings some important disadvantages, such as cost and interventional pro cedures requiring reinjection. In addition, currently there is no the rapy available for dry type ARMD. However, lower-cost treatment modalities which slow down progression to advanced ARMD have a crucial impact. These include micronutrition, modification of dietary habits, exercise, and smoking cessation.

In our survey we tried to investigate general perspectives, atti-tudes, and behavioral patterns of ophthalmologists in Turkey related to the use of micronutrition and recommendations offered to ARMD patients.

Retinal photoreceptors are exposed to intense oxidative stress induced by oxygen and light(26). Consequently, every night 10 % of the outer surface of the photoreceptor layer desquamates. The task of retinal pigment epithelium (RPE) is to remove desquamated debris, and to sustain nutrition of photoreceptors. With adequate nutritional support, RPE can achieve turnover of photoreceptors. Prior studies clearly demonstrate that prophylactic measures (i.e., antioxidant intake) are effective against development of ARMD.

Various studies have demonstrated that higher doses of vitamins and mineral supplements decrease the risk of ARMD in elderly popu-lations(27,28). In particular, placebo-controlled randomized double-blind studies (AREDS 1, and AREDS 2) showed that higher doses of vitamins and mineral supplements slow down progression of the disease to advanced ARMD in 25% of cases(29). Survey research in the UK revealed that almost all optometrists and ophthalmologists recommend mi-cronutrition supplements (92.8%)(20).

However, in our study we found that only about half of ophthal-mologists are in favor of micronutrition (52% in favor and 48% against). General ophthalmologists were the most common group to recommend micronutrition (26.4%), followed by professors (7.9%). The rate of micronutrition recommendation for ARMD was very low. It is possible that these rates are even lower than observed. Additio-nally, when looking at the differences between specialties, general ophthalmologists and retina-uvea specialists used micronutrition most commonly (22%, and 13.9%, respectively). However, these diffe-rences were not statistically significant. Although follow-up and treatment of ARMD patients were realized by retina specialists, our study suggests that a lower number of retina specialists preferred micronitrution.

Table 2. Distribution of participants by subspecialty

Subspecialty n %

General ophthalmology 121 48.8

Glaucoma-oculoplasty 019 07.7

Cornea-refractive surgery 026 10.5

Retina-uvea 062 25.0

Other 019 07.7

Total 247 99.6

Table 3. Prescribing rates of micronutrition according to gender and subspecialty

Recommendation of micronutrition

never n (%)

Occasionally n (%)

frequently n (%)

Always n (%)

Gender

Male 16 (6.6) 76 (31.4) 51 (21.1) 14 (5.8)

Female 05 (2.1) 30 (12.4) 38 (15.7) 12 (5.0)

Subspecialty

Retina & uvea 04 (1.6) 24 (09.8) 26 (10.6) 08 (3.3)

Other 18 (7.3) 82 (33.4) 65 (26.4) 19 (7.7)

Total 22 106 91 27

Table 4. Prescribing rates of micronutrition according to the AReDS criteria with respect to subspecialty

SubspecialtyI do not use AReDS Category 1-2 Category 3-4 Category 5

n (%) n (%) n (%) n (%)

General ophthalmology 67 (56.3) 12 (10.1) 24 (20.2) 2 (1.7)

Glaucoma & oculoplasty 12 (66.7) 03 (16.7) 02 (11.1) 0 (0.0)

Cornea & refractive surgery 16 (64.0) 03 (12.0) 02 (08.0) 0 (0.0)

Retina & uvea 33 (54.1) 02 (03.3) 22 (36.1) 0 (0.0)

Other 09 (52.9) 01 (05.9) 06 (35.3) 0 (0.0)

Total 137 (57.1) 21 (08.8) 56 (23.3) 2 (0.8)

Şahin M, et al.

13Arq Bras Oftalmol. 2015;78(1):10-4

AREDS1 and AREDS2 studies are multi-centered, placebo-con-trolled, randomized, double-blind studies concerning micronu -trition(18,30). Publication of AREDS 1 outcomes started in 2001, pu bli -cation of AREDS 2 results started in 2013. These publications contain recommendations for management of ARMD. Another study de-monstrated that patients often did not use recommended AREDS formulations at adequate doses(19). The same study indicated that patients who complied with the recommended doses correctly received those recommendations from retina specialists. According to a survey among optometrists and ophthalmologists, a relatively higher percentage of ophthalmologists used recommended AREDS formulations. However, according to the results of this survey, ophthalmologists rarely recommended micronutrition supplements containing macular carotenoids(20).

In our study however, more than half (56.3%) of the general ophthalmologists who recommended micronutrition did not use AREDS criteria. Only one fourth of the participants (20.2%) indicated that they had used AREDS criteria for category 3-4 patients. Also, a little over half (54.1%) of the retina-uvea specialists who recommen-ded micronutrition used AREDS criteria, and only 36.1 % of them responded that they had used these criteria for their category 3-4 patients. This finding demonstrates that two important groups of physicians, general ophthalmologists and retina specialists, do not use AREDS criteria. Additionally, only one third of the users of these criteria employ them for category 3-4 patients. Assuming that a number of patients did not comply adequately, it is likely that the number of patients who received appropriate AREDS-based treatment is even smaller.

According to our survey, retina specialists did not prefer micronu-trition mostly because of its higher treatment cost (67.8%) and failure to meet the expectations of the patients (39.2%). Additionally, they were not convinced of the benefits (32.