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

79 02publicação oficial do conselho brasileiro de oftalmologia

março/abril 2016

issn 0004-2749versão impressa

indexada nas bases de dados

medline | embase | isi | scielO

Retinal layer thicknesses in migraine

Straylight after PRK with and without MMC-C

Visual performance of different soft multifocal contact lenses

Herpes zoster ophthalmicus and varicella zoster virus vasculopathy

TRATAMENTO DO OLHO SECO, LUBRIFICAÇÃO E HIDRATAÇÃO.1

Referências Bibliográficas: 1. Bula do produto: Hyabak. Registro MS nº 8042140002. 2. Patente de Laboratoires Théa. 3. Snibson GR, Greaves JL, Soper ND, Tiffany JM, Wilson CG, Bron AJ. Ocular surface residence times of artificial tear solutions. Cornea. 1992 Jul;11(4):288-93. 4. Gomes JA, Amankwah R, Powell-Richards A, Dua HS. Sodium hyaluronate (hyaluronic acid) promotes migration of human corneal epithelial cells in vitro. Br J Ophthalmol. 2004 Jun;88(6);821-5.

*Conservante utilizado na maioria dos colírios

HYABAK®. Solução sem conservantes para hidratação e lubrificação dos olhos e lentes de contato. Frasco ABAK®. QUANDO SE DEVE UTILIZAR ESTE DISPOSITIVO: HYABAK® contém uma solução destinada a ser administrada nos olhos ou nas lentes de contato. Foi concebido: • Para humedecimento e lubrificação dos olhos, em caso de sensações de secura ou de fadiga ocular induzidas por fatores exteriores, tais como, o vento, o fumo, a poluição, as poeiras, o calor seco, o ar condicionado, uma viagem de avião ou o trabalho prolongado à frente de uma tela de computador. • Nos utilizadores de lentes de contato, permite a lubrificação e a hidratação da lente, com vista a facilitar a colocação e a retirada, e proporcionando um conforto imediato na utilização ao longo de todo o dia. Graças ao dispositivo ABAK®, HYABAK® permite fornecer gotas de solução sem conservantes. Pode, assim, ser utilizado com qualquer tipo de lente de contato. A ausência de conservantes permite igualmente respeitar os tecidos oculares. ADVERTÊNCIAS E PRECAUÇÕES ESPECIAIS DE UTILIZAÇÃO: • Evitar tocar nos olhos com a ponta do frasco. • Não injetar, não engolir. Não utilize o produto caso o invólucro de inviolabilidade esteja danificado. MANTER FORA DO ALCANCE DAS CRIANÇAS. INTERAÇÕES: É conveniente aguardar 10 minutos entre a administração de dois produtos oculares. COMO UTILIZAR ESTE DISPOSITIVO: POSOLOGIA: 1 gota em cada olho durante o dia, sempre que necessário. Nos utilizadores de lentes: uma gota em cada lente ao colocar e retirar as lentes e também sempre que necessário ao longo do dia. MODO E VIA DE ADMINISTRAÇÃO: INSTILAÇÃO OCULAR. STERILE A - Para uma utilização correta do produto é necessário ter em conta determinadas precauções: • Lavar cuidadosamente as mãos antes de proceder à aplicação. • Evitar o contato da extremidade do frasco com os olhos ou as pálpebras. Instilar 1 gota de produto no canto do saco lacrimal inferior, puxando ligeiramente a pálpebra inferior para baixo e dirigindo o olhar para cima. O tempo de aparição de uma gota é mais longo do que com um frasco clássico. Tapar o frasco após a utilização. Ao colocar as lentes de contato: instilar uma gota de HYABAK® na concavidade da lente. Registro MS nº 8042140002.

SEM CONSERVANTES2

HIDRATAÇÃO E CONFORTOPROLONGADO

3,4

SISTEMA ABAK

®

DERIVA DA ADIÇÃO DO “A” (SEM)

À ABREVIATURA INTERNACIONAL DE CLORETO

DE BENZALCÔNIO* “BAK”2

GOTAS ESTÉREIS2

O mais novo avanço no implante de AcrySof® IQ.

*De um total de 42 cirurgiões de catarata que testaram protótipos do sistema UltraSert™ em uma situação artifi cial, a maioria utilizou "suave” para descrever o avanço do êmbolo. Referências bibliográfi cas: 1. AcrySof® IQ Aspheric IOL with the AcrySert® pre-loaded delivery system directions for use. 2. AcrySert® delivery system prototype human factor testing, February

2015. 3. Comparative assessment of iol delivery systems. Alcon internal technical report: TDOC-0018957. Efective date 19 May 2015.

© 2015 NOVARTIS AP3 - BR1512417804 - SR AcrySof® IQ e Sistema Injetor AcrySert® MS: 80153480174 Dez/15

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Controle excepcional em um sistema injetor de uso único que proporciona:1-3

Injeção suave – o êmbolo TensionGlide™ fornece um nível de resistência consistente para injetar suavemente com uma única mão.*1,2

Incisões preservadas – o bocal depth guard preserva a arquitetura das incisões de até 2,2 mm.1,3

Implante consistente – a ponta do êmbolo do sistema injetor AcrySert® é projetada para um posicionamento preciso e seguro da lente no saco capsular.1,3

FAÇA PARTE DESSA EVOLUÇÃO

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ANUNCIO TEROLAC MARÇO 2016

quinta-feira, 10 de março de 2016 15:51:25

NEM TODAS AS LENTESDE CONTATO SÃO IGUAIS. NEM TODOS OSPACIENTES SÃO IGUAIS.

Saúde para os olhosCuidar da saúde ocular de seus pacientes a longo prazo é uma prioridade.

Atender às necessidadesdo pacienteSeus pacientes querem uma lente confortável e que mantenha os olhos saudáveis mesmo quando utilizada por muitas horas.

1. Morgan PB et al. Ocular physiology and comfort in neophyte subjects fi tted with daily disposablesilicone hydrogel contact lenses. Contact Lens & Anterior Eye 36 (2013) 118– 125. ©Johnson & Johnson do Brasil Indústria E Comércio de Produtos Para Saúde Ltda. MARÇO/2016 - ID 160311082727358.

Para mais informações sobre o produto, modo de uso, advertências etc., verifi que nas instruções de uso ou no site para profi ssionais da Johnson & Johnson Vision Care www.jnjvisioncare.com.br.

Este produto está devidamente regularizado na ANVISA.

1-DAY ACUVUE TruEye®:saúde ocular e conforto equivalentes aos dos olhos sem lentes.1

SAÚDE E CONFORTO O DIA TODO,

TODOS OS DIAS

Ocular physiology and comfort in neophyte subjects fi tted with daily disposablesilicone hydrogel contact lenses. Contact Lens & Anterior Eye 36 (2013) 118– 125. ©Johnson & Johnson do Brasil Indústria E Comércio de Produtos Para Saúde Ltda. MARÇO/2016 - ID 160311082727358.

CONFORTO O DIA TODO,

Frequency of publication: Bimonthly Arq Bras Oftalmol. São Paulo, v. 79, issue 2, pages 69-136, Mar/Apr. 2016

Continuous publication since 1938

Publisher: Ipsis Gráfica e Editora S.A. Divulgation: Brazilian Council of OphthalmologyCirculation: 9.000 copies

CODEN - AQBOAP

PUBLICAÇÃO OFICIAL DOCONSELHO BRASILEIRO

DE OFTALMOLOGIA

OffiCiAl PuBliCAtiON Of thE BrAziliAN COuNCil Of OPhthAlmOlOgy (CBO)

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

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Chief-editor: Wallace Chamon

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Cover: Slit-lamp photograph of a patient presenting bullae in the crystalline lens. Photographer: Wallace Chamon (Department of Ophthalmology, UNIFESP).

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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. 79, issue 2, pages 69-136, Mar/Apr. 2016

PUBLICAÇÃO OFICIAL DOCONSELHO BRASILEIRO

DE OFTALMOLOGIA

EditorialV What is plagiarism after all? Afinal de contas, o que é plágio? Wallace Chamon, Paulo E. C. Dantas

Original Articles69 Excimer laser phototherapeutic keratectomy in conjunction with mitomycin C in corneal macular and granular dystrophies Ceratectomia fototerapêutica com excimer laser em conjunto com mitomicina C em distrofias granular e macular da córnea Erdem Yuksel, Mehmet Ozgur Cubuk, Hulya Yazıcı Eroglu, Kamil Bilgihan

73 Short-term visual performance of soft multifocal contact lenses for presbyopia Desempenho visual de curto prazo de présbitas usando diferentes lentes de contato multifocais hidrofílicas Jennifer Sha, Ravi C. Bakaraju, Daniel Tilia, Jiyoon Chung, Shona Delaney, Anna Munro, Klaus Ehrmann, Varghese Thomas , Brien A. Holden

78 retinal nerve fiber layer, ganglion cell complex, and choroidal thicknesses in migraine Espessuras da camada de fibras nervosas retinianas, complexo de células ganglionares e coroide na enxaqueca Hatice Nur Colak, Feride Aylin Kantarcı, Mehmet Gurkan Tatar, Mehmet Eryilmaz, Hasim Uslu, Hasan Goker, Aydin Yildirim, Bulent Gurler

82 Descriptive analysis of the type and design of contact lenses fitted according to keratoconus severity and morphology Análise descritiva dos tipos e parâmetros das lentes de contato adaptadas de acordo com o grau evolutivo e a morfologia do ceratocone Letícia Helena Lunardi, Danielle Arroyo, Marcelo Vicente de Andrade Sobrinho, César Lipener, Juliana Maria da Silva Rosa

85 initial experience with ocriplasmin in the treatment of vitreomacular traction Experiência inicial com ocriplasmina no tratamento da tração vitreorretiniana José Maurício Botto de Barros Garcia, David Leonardo Cruvinel Isaac, Marcos Ávila

88 intraocular straylight before and after low myopic photorefractive keratectomy with and without mitomycin C Dispersão de luz intraocular antes e depois da ceratectomia fotorrefrativa para baixa miopia com e sem mitomicina C Andre Augusto Miranda Torricelli, Taís Renata Ribeiro Parede, Marcelo Vieira Netto, Francisco Penteado Crestana, Samir Jacob Bechara

92 The effects of delivery type and gender on intraocular pressure and central corneal thickness in newborns Os efeitos do tipo de parto e sexo sobre a pressão intraocular e espessura corneana central em recém-nascidos Zeynep Gursel Ozkurt, Selahattin Balsak, Berrin Balsak, Hande Guclu, Muhammed Sahın1, Harun Yuksel, Fatih M. Turkcu

96 Treatment success of laser therapy for retinopathy of prematurity in referred and non-referred patients O sucesso do tratamento com terapia a laser para retinopatia da prematuridade em pacientes encaminhados e não encaminhados Caner Kara, İkbal Seza Petriçli, Emre Hekimoğlu, Handan Akil, Özlem Beyazyildiz

100 Cognitive performance of primary open-angle glaucoma and normal-tension glaucoma patients Desempenho cognitivo em pacientes com glaucoma primário de ângulo aberto e glaucoma de pressão normal Mehmet Bulut, Aylin Yaman, Muhammet Kazim Erol, Fatma Kurtuluş, Devrim Toslak, Deniz Turgut Coban, Ebru Kaya Başar

105 lacrimal gland primary acinar cell culture: the role of insulin Células acinares de glândula lacrimal em cultura primária: o papel da insulina Leonardo Tannus Malki, Ana Carolina Dias, Angelica Gobbi Jorge, Carolina Maria Módulo, Eduardo Melani Rocha

Case Reports111 isolated posterior scleritis associated with tuberculosis Esclerite posterior isolada associada à tuberculose Ana Filipa Miranda, João Cardoso, Nadine Marques, Sandra Barros, Paula Telles, Nuno Campos

113 Dexamethasone 0.7 mg implants in the management of pseudophakic cystoid macular edema Implante de 0,7 mg de dexametasona no tratamento do edema macular cistóide do pseudofácico José Maurício Botto de Barros Garcia, David Leonardo Cruvinel Isaac, Marcos Pereira de Ávila

116 Assessment of surgical outcomes of limbal transplantation using simple limbal epithelial transplantation technique in patients with total unilateral limbal deficiency

Avaliação dos resultados cirúrgicos do transplante de limbo utilizando a técnica SLET (simple limbal epithelial transplantation), em pacientes com deficiência límbica total unilateral

Ana Gabriela Queiroz, Martina Maria Oiticica Barbosa, Myrna Serapião Santos, Telma Pereira Barreiro, José Álvaro Pereira Gomes

119 Bilateral acute depigmentation of the iris: a case report Despigmentação aguda bilateral da íris: um relato de caso Débora Raquel Rigon Narciso Fachin, Maria Fernanda de Paula Prestes, Angelino Julio Cariello, Mário Junqueira Nóbrega

121 Methylene blue-related corneal edema and iris discoloration Edema de córnea e descoloração de íris associados ao azul de metileno Ozgur Bulent Timucin, Mehmet Fatih Karadag, Mehmet Emin Aslanci, Mehmet Baykara

123 Panophthalmitis with orbital cellulitis following glaucoma drainage implant surgery in a pediatric patient Panoftalmite com celulite orbitária após implante de drenagem em glaucoma congênito Bruno L. B. Esporcatte, Luiz Fernando Teixeira, Christiane Rolim-de-Moura

Review Articles126 herpes zoster ophthalmicus and varicella zoster virus vasculopathy Herpes zoster ophthalmicus e vasculopatia por vírus varicella zoster Francisco Bandeira, Marina Roizenblatt, Guido Carlos Levi, Denise de Freitas, Rubens Belfort Jr.

Letters to the Editor130 Comment on: “measurement and clinical implications of choroidal thickness in patients with inflammatory bowel disease” Comentário: determinação da espessura da coroide e suas implicações clínicas em pacientes com doença inflamatória intestinal Abdullah Kaya, Yakup Aksoy, Oktay Diner, Mehmet Koray Sevinç

131 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 Eduardo Damasceno, Nadyr Damasceno

132 Acquired restrictive strabismus in infancy associated with neurofibromatosis type 2 Estrabismo restritivo adquirido na infância associado à neurofibromatose tipo 2 Vanessa Waisberg, Galton Carvalho Vasconcelos, Ana Rosa Pimentel de Figueiredo, Débora Marques de Miranda, Juliana Ferreira de Souza, Luiz Oswaldo Carneiro Rodrigues

133 Instructions to Authors

V

Editorial

http://dx.doi.org/10.5935/0004-2749.20160021

What is plagiarism after all?Afinal de contas, o que é plágio?

Wallace chamon1, Paulo e. c. Dantas2

ConCept

Plagiarism isn’t hard to define. Basically a manuscript should contain only authors’ own work, written in their own words. All other instances should comprise appropriate credit to the original authors. Different forms of plagiarism have been categorized(1). This wide-ranged spectrum varies from copying someone else’s work until the use of similar wording of previously published material.

plagiarism of Contents

Using data from one’s previous works without proper acknowledgement and credit is perhaps the most harmful form of plagiarism. It includes authorship definition, considering that in an irresponsible list of con-tributors someone will receive credit for someone else’s work(2). Although most of the time misreferencing is a consequence of careless research, it also may be used in order to hide a correct source and therefore appropriate someone’s idea.

plagiarism of form

Verbatim plagiarism and paraphrasing are among the most common forms of plagiarism(1). In the first practice, authors copy complete or partial sentences and paste in their own manuscript. Adequate referencing will not prevent verbatim, quotation marks must be included whenever the text being published contains someone else’s wording. Paraphrasing demands an extra step of changing the wording after copying someone’s idea, without proper citation of the original work. In other words, to avoid plagiarism: if the text contains someone else’s wording, it must be written as a direct quote, if it has someone else’s ideas, in different wording, it must contain proper credit. Specific algorithms have been perfected to detect verbatim, but they still fail to detect paraphrasing(3).

Although the non-native speaking author burdens a greater effort to write creatively in an original manner, especial attention should be taken to avoid the sequence of copying, pasting and paraphrasing.

self-plagiarism

Self-plagiarism accusations often lead to violent reactions from the authors, as they mistakenly assume that they are allowed to reuse their own work as if it was original. Various nuances are involved in this evaluation, including legal consequences of copyright infringement.

When self-plagiarism includes the use of data partially presented elsewhere or the data is “sliced” in different manuscripts, it creates a wrong impression of rich scientific production(4) and may provide wrong information about the prevalence of the findings. This approach has been referred to as “Salami Science”(5).

Editors often struggle with authors that replicate their work, submitting, simultaneously or not, the same manuscript to different journals. The instructions to authors of ABO - Arquivos Brasileiros de Oftalmologia, is very clear on this matter:

“Manuscripts submitted to ABO should not be simultaneously considered for publication by other journals. In addition, total or partial publication or translation for publication in another language of the manuscripts submitted to ABO should not be considered without the permission of the editors of ABO”.

Submitted for publication: April 13, 2016 Accepted for publication: April 13, 20161 Department of Ophthalmology and Visual Science, Escola Paulista de Medicina (EPM), Universidade

Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.2 Hospital de Olhos de Sorocaba (BOS), Sorocaba, SP, Brazil.

Disclosure of potential conflict of interest: No conflicts of interest.

Corresponding author: Wallace Chamon. R. Olimpíadas, 134/51 - São Paulo, SP - 04551-000 Brazil - E-mail: visus@pobox.com

What is plagiarism after all?

VI

retraCtion versus misConduCtScientific community uses retraction as a mechanism to state that a published work should not be considered

trustworthy. Retraction occurs if the work contains serious errors, plagiarism or fraud. The former may be related to an error, while the others are considered scientific misconduct.

in summaryA simple rule of only writing unpublished work in authors’ own words defines good scientific practices and should

be implemented globally.

RefeRenCeS 1. IThenticate. Research ethics: decoding plagiarism and attribution in research. [cited

2016 Apr 13]. Available from: http://cdn2.hubspot.net/hub/92785/file-318578964-pdf/ docs/ithenticate-decoding-survey-summary-092413.pdf

2. Hicks RW, Harris R. Avoid ethical misconduct in manuscript preparation. Advanced Emer-gency Nursing Journal. 2016;38(1):69-80.

3. Lykkesfeldt, J. Strategies for using plagiarism software in the screening of incoming journal manuscripts: recommendations based on a recent literature survey. Basic Clin Pharmacol Toxicol. 2016 Feb 15. doi: 10.1111/bcpt.12568. [Epub ahead of print].

4. Fanelli D, Larivière V Researchers’ Individual Publication Rate Has Not Increased in a Century. PLoS ONE. 2016;11(3):e0149504. doi:10.1371/ journal.pone.0149504

5. Huth EJ. Irresponsible authorship and wasteful publication. Ann Intern Med. 1986; 104(2):257-9.

Original Article

69Arq Bras Oftalmol. 2016;79(2):69-72http://dx.doi.org/10.5935/0004-2749.20160022

Excimer laser phototherapeutic keratectomy in conjunction with mitomycin C in corneal macular and granular dystrophiesCeratectomia fototerapêutica com excimer laser em conjunto com mitomicina C em distrofias granular e macular da córnea

erDem Yuksel1, mehmet ozgur cubuk1, hulYa Yazıcı eroglu1, kamıl bılgıhan1

Submitted for publication: October 14, 2015 Accepted for publication: December 2, 20151 Department of Ophthalmology, School of Medicine, Gazi University, Besevler, Ankara, 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.

Correspondence author: Erdem Yuksel. Gazi University. Faculty of Medicine - Department of Ophthal-mology, Ankara - Turkey - E-mail: rdmyksl@yahoo.com

ABSTRACTPurpose: To evaluate the visual outcomes, recurrence patterns, safety, and effi-cacy of excimer laser phototherapeutic keratectomy (PTK) in conjunction with mitomycin C (MMC) for corneal macular and granular diystrophies. Methods: The patients were divided into two groups. Group 1 included patients with macular corneal dystrophy (MCD) that caused superficial corneal plaque opacities, and Group 2 included patients with granular corneal dystrophy (GCD). Patients in both groups were pre-, peri-, and postoperatively evaluated. The groups were compared in terms of uncorrected visual acuity (VA), best spectacle-corrected VA, presence of mild or significant recurrence, and time of recurrence. Results: Eighteen eyes (nine with MCD and nine with GCD) of 18 patients (10 men and eight women) were included. PTK was performed for each eye that was included in this study. The mean ablation amount was 117.8 ± 24.4 µm and 83.5 ± 45.7 µm in MCD and GCD, respectively, (p=0.18). The postoperative improvement of the mean VA was similar between the two groups before recurrences (p>0.43) and after recurrences (p>0.71). There were no statistically significant differences in the recurrence rate and the recurrence-free period for any recurrence type.Conclusion: PTK was an effective, safe, and minimally invasive procedure for patients with MCD and GCD. PTK in conjunction with MMC was similarly effective for both groups in terms of recurrence and visual outcomes.

Keywords: Photorefractive keratectomy; Corneal dystrophies; Cornea physiopa-thology; Mitomycin; Visual acuity

RESUMOObjetivo: Avaliar os resultados visuais, padrões de recorrência, segurança e eficácia da ceratectomia fototerapêutica (PTK) por excimer laser em conjunto com mitomicina C (MMC) em distrofias macular e granular da córnea. Métodos: Os pacientes foram divididos em dois grupos. Grupo 1 incluiu pacientes com distrofia macular de córnea (MCD) que causaram opacidades superficiais corneanas em placa e o grupo 2 incluiu pacientes com distrofia corneana granular (GCD). Todos os pacientes em ambos os grupos foram avaliados no pré, per e pós-operatório. Os grupos foram comparados em termos de acuidade visual (VA) não corrigida, VA melhor corri-gida por óculos, presença de recorrência leve ou significativa e o tempo de recorrência. Resultados: Dezoito olhos de 18 pacientes (10 homens e 8 mulheres) foram incluídos no estudo, 9 olhos com MCD e 9 olhos com GCD. Um procedimento de PTK foi realizado em cada olho incluídos neste estudo. A quantidade média de ablação foi 117,8 ± 24,4, 83,5 ± 45,7 µm de MCD e GCD, respectivamente, (p=0,18). A melhora pós-operatória da acuidade visual média foi semelhante entre os dois grupos antes de as recidivas (p>0,43) e após as recidivas (p>0,71). Não houve diferença estatisticamente significativa na taxa de recorrência ou do período livre de recorrência para qualquer tipo de recorrência. Conclusão: PTK foi um procedimento eficaz, seguro e minimamente invasivo para pacientes MCD e GCD. PTK em conjunto com MMC é igualmente eficaz para ambos os grupos em termos de recorrência e resultados visuais.

Descritores: Ceratectomia fotorrefratica; Distrofias hereditárias da córnea; Córnea/fisiopatologia; Mitomicina; Acuidade visual

INTRODUCTIONPhototherapeutic keratectomy (PTK), approved by the Food and

Drug Administration in 1995, is popularly used for treating anterior corneal dystrophies(1). The aim of PTK is to remove opacities affecting visual acuity (VA) and to provide a smooth and stable corneal sur-face(1). Corneal stromal dystrophies are progressive diseases that appear in adolescence or later(2,3) and usually cause blurry vision and sometimes symptoms of recurrent erosions(2,3). Currently, PTK is the most commonly used to treat stromal dystrophies in the early stages and may be a significant alternative to delay the requirement for penetrating keratoplasty (PK)(4). Macular corneal dystrophy (MCD) is a rare stromal dystrophy that is characterized by superficial gray-white opacities and corneal thinning, which progressively involves the entire stroma from limbus to limbus(3). While MCD is a recessively inherited dystrophy, granular corneal dystrophy (GCD) is a slowly

progressive autosomal dominant disorder that is characterized by deposits at different depths in the corneal stroma(5,6). Although the literature has demonstrated that PTK is safe and effective for treating stromal dystrophies, recurrence of the disease and induced refractive error remain the main deficiencies of the procedure(7-9). In addition, mitomycin C (MMC), an alkylating agent, is commonly used in re-fractive excimer laser surgery to regulate corneal wound healing; it is believed that MMC can prevent or delay recurrence of the disease in corneal dystrophies(9-11).

However, there are still no studies in the literature that evaluated the effect of MMC on PTK in patients with MCD and GCD. Thus, this study aimed to evaluate the visual outcomes, recurrence patterns, safety, and efficacy of excimer laser PTK in conjunction with MMC in corneal macular and granular dystrophies and to compare the results of these two groups.

Excimer laser phototherapeutic keratectomy in conjunction with mitomycin C in corneal macular and granular dystrophies

70 Arq Bras Oftalmol. 2016;79(2):69-72

MeTHODSThe study protocol was approved by the Institutional Review Board/

Ethics Board of the Gazi University. We retrospectively reviewed the medical records of all patients with MCD or GCD who underwent PTK at the Refractive Surgery Unit of the ophthalmology department from January 2002 to December 2014. The patients were divided into two groups. Group 1 included patients with MCD that caused super-ficial corneal plaque opacities, and Group 2 included patients with GCD. The diagnoses of all patients were confirmed by DNA analysis. Patients with significant corneal thinning or edema, previous excimer laser ablation, uveitis, glaucoma, or other significant ocular surface diseases and a follow-up period of less than 6 months previous were excluded.

Patients in both groups were pre-, peri-, and postoperatively exa-mined. The preoperative examination included a complete systemic and ocular history examination and routine ocular examinations such as uncorrected distance VA (UCVA) in logarithm of the minimal angle of resolution (logMAR), best spectacle-corrected distance VA (BSCVA) in logMAR, manifest refraction, slit-lamp biomicroscopy, computeri-zed corneal topography (Sirius 3D Rotating Scheimpflug Camera-To-pography System Costruzione Strumenti Oftalmici, Florence, Italy), Goldman applanation tonometry, and indirect ophthalmoscopy. The depth of treatment and total stromal thickness were evaluated using anterior segment optical coherence tomography (Spectralis; Heidelberg Engineering, Heidelberg, Germany) and slit-lamp examination. The depth of ablation was perioperatively noted.

The postoperative evaluation included UCVA, BSCVA, manifest refraction, epithelial closure time, and recurrence of the disease. A loss of one line in BSCVA with deposits noticed during slit-lamp exa-mination was classified as a mild recurrence and recurrent opacities that caused a loss of two or more lines of BSCVA was classified as a significant recurrence.

We compared the two groups in terms of UCVA, BSCVA, presence of mild or significant recurrence, and the time of recurrence. Moreover, we calculated the safety and efficacy indices. The postoperative BSCVA/preoperative BSCVA (logMAR) ratio was defined as the safety index, and the postoperative UCVA/preoperative BSCVA (logMAR) ratio was defined as the efficacy index.

SURgICal TeChNIqUe

PTK was performed with the SCHWIND ESIRIS excimer laser (SCHWIND eye-tech solutions, Kleinostheim, Germany) under sterile conditions. After administering topical anesthesia (proparacaine 0.5%; Alcaine ophthalmic solution, Alcon, USA) to the cornea, we placed drapes and a sterile lid speculum. In eyes with a smooth epithelial surface, a transepithelial method was utilized; however, in eyes with an irregular epithelial surface, the epithelium was mechanically re-moved with a spatula followed by excimer laser ablation. An ablation zone of 6.5 mm with no transition zone was used for all eyes with a pulse rate of 200 Hz. After approximately three-quarters of the ex-pected ablation had been applied, the surgeon assessed the density and depth of the remaining diffuse stromal haze using the slit-lamp biomicroscopy. When necessary, an additional PTK was performed, and the total amount of ablation was recorded at the end of the procedure. Balanced salt solution was applied during the ablation to smooth the process. A 2.0 × 4.0-mm cellulose sponge pledget that was soaked with 0.02% (0.2 mg/mL) MMC was placed on every eye for 30 s. A 3-diopter anti-hyperopia treatment was applied after 100 microns of stromal ablation according to the manufacturer of the excimer laser.

After the procedure, a lotrafilcon A bandage contact lens (AIR-OPTIX Night & Day, Alcon, USA) was placed on the eye; patients were treated with moxifloxacin eye drops (Vigamox ophthalmic solution, Alcon, USA) five times a day, preservative-free artificial tears five times a day, and 0.01% fluorometholone (FML; Allergan, USA) eye drops four

times a day. The contact lens was removed after the epithelial defect healed. All patients were examined every 2 weeks for 1 month, every 4 weeks for 3 months, and then every 3 months.

SPSS software version 20.0 for Windows was used for statistical analysis. Snellen VA was converted to logMAR units for statistical analyses. Comparisons between groups or variables were calculated with nonparametric tests; the Mann-Whitney U test was used for unpaired samples, and the Wilcoxon test was used for paired samples. A p value of <0.05 was considered statistically significant.

ReSUlTSPReOPeRaTIve DaTa

This study analyzed 18 eyes, including nine with MCD and nine with GCD, of 18 patients (10 men and 8 women). All patients underwent PTK for the removal of diffuse stromal haze without any complica-tions; these procedures were performed in all eyes (100%) that were included in this study. The demographic and preoperative data are shown in table 1.

PeRIOPeRaTIve DaTa

The mean ablation amount was 117.8 ± 24.4 µm in MCD and 83.5 ± 45.7, µm in GCD (p=0.18). An anti-hyperopia treatment was performed in two eyes in Group 1 and two eyes in Group 2 (p=0.63).

POSTOPeRaTIve DaTa

Visual acuity

BCVA significantly improved after PTK in both groups before mild recurrences (p=0.02 for MCD; p=0.03 for GCD); however, there was no statistical difference in BCVA at the end of the follow-up period (p=0.11 and p=0.39, respectively), as shown in table 3 and figures 1 and 2. The postoperative BCVA data are defined in table 3 and graph 1. The postoperative improvement in mean VA was similar between the two groups both before recurrences (p>0.43) and after recurrences (p>0.71).

Table 1. Demographic and preoperative data of patients with MGD and GCD

MCD GCD P*

Sex (M/F) 5/4 5/4 0.56

Age 040.8 ± 17.70 024.00 ± 04.30 0.08

UCVA 000.7 ± 00.30 000.40 ± 00.29 0.04

BSCVA 000.7 ± 00.34 000.33 ± 00.31 0.05

SE (D) 0-5.9 ± 07.20 0-1.80 ± 02.40 0.16

Keratometry (D) 045.3 ± 01.80 044.50 ± 01.10 0.44

Pachymetry (mm) 456.0 ± 79.00 509.00 ± 46.40 0.16

Follow-up 022.0 ± 36.90 020.00 ± 14.10 0.54

MCD= macular corneal dystrophy; GCD= granular corneal dystrophies; UCVA= uncor-rected distance visual acuity; BSCVA= best spectacle-corrected distance visual acuity; M= men; F= female. *= the comparison of preoperative data of MGD and GCD, Mann-Whitney U test, (p>0.05) .

Table 2. Peroperative ablation amounts

MCD CGD P*

Ablation amount 117.8 ± 24.4 83.5 ± 45.7 0.18

Hymetropic ablation 2 eyes 2 eyes 0.51

MCD= macular corneal dystrophy; GCD= granular corneal dystrophies.*= the comparison of perioperative data MGD and GCD; Mann-Whitney U and Chi-square test, p>0.05.

Yuksel E, et al.

71Arq Bras Oftalmol. 2016;79(2):69-72

Mild and significant recurrences

The postoperative recurrence rates are shown in table 4. Mild recurrences occurred after 5.6 ± 1.4 months in MCD (five patients) and 6.6 ± 1.5 months in GCD (three patients); a significant recurren-ce was observed in one patient in Group 1 after 22 months and in one patient in group 2 after 20 months. Two eyes with significant recurrences demonstrated no improvement in VA after a repeat PTK.

Although an earlier and higher rate of mild recurrence was observed in MCD, there was no statistically significant difference in the recurrence rate and recurrence-free period for any recurrence type (p=0.6).

Safety and efficacy index

There was no statistical difference between the two groups in terms of efficacy and safety indices. The calculated efficacy index was 0.94 ± 0.42 in MCD and 1.2 ± 1.9 in GCD, and the safety index was 0.74 ± 0.35 in MCD and 0.92 ± 1.5 in GCD (p>0.5 and p>0.63, respectively).

Hypermetropic recurrence

The mean hyperopic shift was statistically higher in MCD (2.8 ± 3 diopters (D)) than in GCD (0.7 ± 1.3) (p=0.03), as shown in table 4. In addition, there was no correlation between the mean ablation amount and mean hyperopic shift.

DISCUSSIOnMMC is an alkylating agent that regulates corneal wound healing

and is commonly used in refractive excimer laser surgery to reduce corneal haze. Furthermore, MMC is used to prevent or delay corneal deposits in corneal dystrophies(9-11). However, there is limited knowledge regarding the recurrence of corneal deposits associated with MCD

Table 3. Preoperative and postoperative BCVA values of the two groups

Preoperative BSCVA

Postoperative BSCVA (BR)

Postoperative BSCVA (AR)

MCD 0.70 ± 0.34 0.45 ± 0.3 0.45 ± 0.25

p:0.02 p:0.1

GCD 0.33 ± 0.30 1 0.13 ± 0.27 0.25 ± 0.32

p:0.03 p:0.4

p 0.06 0.02 0.08

MCD= macular corneal dystrophy; GCD= granular corneal dystrophies; BSCVA= best spec-tacle corrected distance visual acuity in logMAR; BR= before the recurrences; AR= after recurrences Wilcoxon signed ranks test (p<0.05) Mann-Whitney U test (p>0.05).

figure 1. A) Preoperative clinical photograph showing the right eye of a patient with granular dystrophy. BSCVA (best spectacle-corrected visual acuity) was 7/10. B) Six months after PTK, a clinical photograph showing the right eye of the same patient with granular dystrophy. BSCVA was 10/10.

A B

A B

figure 2. A) Preoperative clinical photograph showing the right eye of a patient with macular dystrophy. BSCVA was 6/10. B) Six months after PTK, a clinical photograph showing the right eye of the same patient with macular dystrophy. BSCVA was 10/10.

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72 Arq Bras Oftalmol. 2016;79(2):69-72

Table 4. Postoperative recurrence rates

MCD CGD P

Mild recurrence 5 eyes of 9 (55.5%) 3 eyes of 9 (33.4%) 0.60

Time to recurrence (mild) 5.6 ± 1.4 months 6.6 ±1.5 months 0.60

Significant recurrence 1 eye of 9 (11.1%) 1 eye of 9 (11.1%) 0.60

Time to recurrence (mild) 22 months 20 months

Hymetropic shift 2.8 ± 3 D 0.7 ± 1.3 0.03

MCD= macular corneal dystrophy; GCD= granular corneal dystrophies; Mann-Whitney U test; Chi-square test (p>0.05).

BR-MCD= Before recurrences macular corneal dystrophy; BR-GCD= before recurrences granular cor-neal dystrophy; AR-MCD= after recurrences macular corneal dystrophy; AR-GCD= after recurrences granular corneal dystrophy; ASR-MCD= after significant recurrences macular corneal dystrophy; ASR-GCD= after significant recurrences granular corneal dystrophy.

Graph 1. Postoperative BCVA improvement.

and GCD after PTK in conjunction with 0.02% MMC. In MCD, intracyto-plasmic accumulations of glycosaminoglycans occur within the ke-ratocytes; in GCD, eosinophilic depositions of mutant transforming growth factor beta-induced protein (TGFBIp) extracellularly accumu-late. It is well documented that the recurrence rate of MCD is much higher and occurs earlier than in GCD after PTK treatment(12-14). Chen and Xie(12) observed that the time for development of a significant recurrence was 12.4 and 19.7 months after PTK in MCD and GCD, res-pectively. Redd et al.(14) reported a higher, milder, and more significant recurrence rate in MCD than in GCD. However, MMC was not used after PTK in these studies. MMC induces keratocyte apoptosis and might decrease or delay the accumulation of glycosamnoglycans within he keratocytes, thereby consequently decreasing the MGD re-currence rate and extending the recurrence time. We observed that the recurrence rate and time in our study were different than those in other studies. While the mild recurrence rate was 55.5% in MGD, the recur-rence rate was 33.4% in GCD, which was not statistically significant. Moreover, a significant recurrence occurred in one patient in each group (11.1%). The mean development time of mild recurrence was 5.6 ± 1.4 months in MCD and 6.6 ± 1.5 months in GCD. A significant recurrence was observed in one patient with MCD after 22 months and in one patient with GCD after 20 months.

Another important concern in corneal dystrophies is VA. Both MGD and GCD can cause blurry vision and glare. PTK can be safely and less aggressively used to improve vision and reduce glare in corneal stromal dystrophies; furthermore, it provides faster visual improvement(4). This study demonstrated comparable visual outcomes after PTK in patients with MGD and GCD. Although the preoperative BCVA was statistically higher in GCD, statistically significant visual improvement

was achieved before recurrences occurred in both groups and was not statistically different between both groups. However, there was no statistical difference between the preoperative and postoperative BCVA over a mean follow-up of 22 ± 36.9 months for MGD and 20 ± 14.1 months for GCD. The most likely cause of was the occurrence of recurrences. This outcome was comparable with a study by Hafner et al.,(15) which achieved a BCVA increment from 0.3 ± 0.2 to 0.6 ± 0.1 in MGD. Wagoner and Badr(16) also reported that BCVA increased from 20/80 to 20/30 in MCD. As in these studies, Redd et al.(14) revealed an increase in BCVA from 0.46 ± 0.25 to 0.51 ± 0.27 in MCD and GCD with PTK, although this was not statistically different.

A hyperopic shift is a well-described side effect of PTK for corneal dystrophies. In this study, the mean hyperopic shift was statistically higher in MCD (2.8 ± 3 D) than in GCD (0.7 ± 1.3) (p=0.03). An anti-hype-ropia treatment was performed in two eyes in each group.

In this study, the depth of PTK was set according to the slit-lamp findings during the treatment. If the remaining diffuse stromal haze was dense, PTK was continued until most of the opacity was cleared. As expected, the mean ablation was larger in MGD (117.8 ± 24.4 μ) than in GCD (83.5 ± 45.7 μ) because MCD involves the deeper layers of the cornea; however, there was no correlation between the mean ablation size and mean hyperopic shift.

PTK is an effective, safe, and minimally invasive procedure for pa-tients with MCD and GCD. PTK in conjunction with MMC was similarly effective in both groups in terms of recurrence and visual outcomes. The application of MMC after PTK can delay the recurrence time in MCD and avoid the requirement for keratoplasty.

RefeRenCeS 1. Rapuano CJ. Excimer laser phototherapeutic keratectomy. Int Ophthalmol Clin. 1996;

36(4):127-36. 2. Nassaralla BA, Garbus J, McDonnell PJ. Phototherapeutic keratectomy for granular

and lattice corneal dystrophies at 1,5 to 4 years. J Refract Surg. 1996;12(7):795-800. 3. Droutsas DD, Tsioulias GE, Kotsiras JE, Koufala CJ, Lambropoulos JE. Phototherapeutic

keratectomy in macular corneal dystrophy with recurrent erosions. J Refract Surg. 1996;12(2):293-4.

4. Kim EK. PTK in corneal dystrophy. Cornea. 2004;23(4):323-4. 5. Hong JP, Kim TI, Chung JL, Huang D, Cho HS, Kim EK. Analysis of deposit depth

and morphology in granular corneal dystrophy type 2 using fourier domain optical coherence tomography. Cornea. 2011;30(7):729-38.

6. Seitz B, Behrens A, Fischer M, Langenbucher A, Naumann GO. Morphometric analysis of deposits in granular and lattice corneal dystrophy: histopathologic implications for phototherapeutic keratectomy. Cornea. 2004;23(4):380-5.

7. Dinh R, Rapuano CJ, Cohen EJ, Laibson PR. Recurrence of corneal dystrophy after excimer laser phototherapeutic keratectomy. Ophthalmology. 1999;106(8):1490-7.

8. Dogru M, Katakami C, Yamanaka A. Refractive changes after excimer laser photothe-rapeutic keratectomy. J Cataract Refract Surg. 2001;27(5):686-92. Comment in: J Ca taract Refract Surg. 2002;28(2):207-8. J Cataract Refract Surg. 2002;28(5):732.

9. Ayres BD, Hammersmith KM, Laibson PR, Rapuano CJ. Phototherapeutic keratectomy with intraoperative mitomycin C to prevent recurrent anterior corneal pathology. Am J Ophthalmol. 2006;142(3):490-2.

10. Kim TI, Pak JH, Chae JB, Kim EK, Tchah H.Mitomycin C inhibits recurrent Avellino dys-trophy after phototherapeutic keratectomy. Cornea. 2006;25(2):220-3.

11. Ha BJ, Kim TI, Choi SI, Stulting RD, Lee DH, Cho HS, et al. Mitomycin C does not inhibit exacerbation of granular corneal dystrophy type II induced by refractive surface ablation. Cornea. 2010;29(5):490-6.

12. Chen M, Xie L. Features of recurrence after excimer laser phototherapeutic keratec-tomy for anterior corneal pathologies in North China. Ophthalmology. 2013;120(6): 1179-85.

13. Fagerholm P. Phototherapeutic keratectomy: 12 years of experience. Acta Ophthalmol Scand. 2003;81(1):19-32.

14. Reddy JC, Rapuano CJ, Nagra PK, Hammersmith KM. Excimer laser phototherapeutic keratectomy in eyes With corneal stromal dystrophies with and without A corneal graft. Am J Ophthalmol. 2013;155(6):1111-8.

15. Hafner A, Langenbucher A, Seitz B. Long term results of phototherapeutic keratec-tomy with 193-nm excimer laser for macular corneal dystrophy. Am J Ophthalmol. 2005; 140(3):392-6.

16. Wagoner MD, Badr IA. Phototherapeutic keratectomy for macular corneal dystrophy. J Refract Surg. 1999;15(4):481-4.

Original Article

73Arq Bras Oftalmol. 2016;79(2):73-7http://dx.doi.org/10.5935/0004-2749.20160023

InTRODUCTIOnMore than one third of the world’s population is over 40 years(1)

and is the age at which presbyopia generally begins developing. Pres byopia is an age-related condition that causes the eye to pro-gressively lose its ability to focus on near objects. The correction of presbyopia traditionally involves either multifocal or separate reading spectacles; however, there has been considerable interest in using

contact lenses because of their suitability for sports, cosmetic appeal, or simply a patient’s dislike for spectacles.

Concurrent with an aging global population, the prevalence of presbyopia is estimated to increase from 1.2 billion in 2010 to 1.8 billion in 2050(2). Accordingly, the age of the average contact lens wearer is increasing, revealing a growing market for presbyopic contact lenses(3). In an international survey conducted in 2011, Morgan et al. reported

Short-term visual performance of soft multifocal contact lenses for presbyopia Desempenho visual de curto prazo de présbitas usando diferentes lentes de contato multifocais hidrofílicas

Jennıfer sha1, ravı c. bakaraJu1,2, Danıel tılıa1 , JıYoon chung1 , shona DelaneY1, anna munro1, klaus ehrmann1,2, varghese thomas1 , brıen a. holDen1,2

Submitted for publication: August 11, 2015 Accepted for publication: November 13, 20151 Brien Holden Vision Institute, Sydney, Australia.2 School of Optometry and Vision Sciences, UNSW, Sydney, Australia.

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: Ravi C Bakaraju. Level 5, Rupert Myers NW, Gate 14, UNSW. Barker Street, Kensington, NSW 2033 - Australia - E-mail: r.bakaraju@brienholdenvision.org

Approved by the following research ethics committee: Bellberry Human Research Ethics Committee; Application number: 2013-06-304

Clinical trials registry: Australian New Zealand Clinical Trials Registry. Trial ID: ACTRN 12613001380785

ABSTRACTPurpose: To compare visual acuity (VA), contrast sensitivity, stereopsis, and subjec-tive visual performance of Acuvue® Oasys® for Presbyopia (AOP), Air Optix® Aqua Multifocal (AOMF), and Air Optix® Aqua Single Vision (AOSV) lenses in patients with presbyopia. Methods: A single-blinded crossover trial was conducted. Twenty patients with mild presbyopia (add ≤+1.25 D) and 22 with moderate/severe presbyopia (add ≥+1.50 D) who wore lenses bilaterally for 1 h, with a minimum overnight washout period between the use of each lens. Measurements included high- and low-contrast visual acuity (HCVA and LCVA, respectively) at a distance, contrast sensitivity (CS) at a distance, HCVA at intermediate (70 cm) and near (50 cm & 40 cm) distances, stereopsis, and subjective questionnaires regarding vision clarity, ghosting, overall vision satisfaction, and comfort. The test variables were compared among the lens types using repeated-measures ANOVA. Results: Distance variables (HCVA, LCVA, and CS) were significantly worse with multifocal lens than with AOSV lens (p≤0.008), except for AOMF lens in the mild presbyopia group in which no significant difference was observed (p>0.05). Mul-tifocal lenses had significantly greater HCVA at 40 cm than AOSV lens (p≤0.026). AOMF lens had greater intermediate HCVA than AOP lens (p<0.03). AOP lens de monstrated greater improvements in stereopsis than AOMF and AOSV lens in the moderate/severe presbyopia group (p≤0.03). Few significant differences in subjective variables were observed, with no significant difference in the overall vision satisfaction observed between lens types (p>0.05). The proportions of patients willing to buy AOSV, AOMF, and AOP lenses were 20%, 40%, and 50%, respectively, in the mild presbyopia group and 14%, 32%, and 23%, respectively, in the moderate/severe presbyopia group; however, these differences were not sta tistically significant (p≥0.159). Conclusions: Further development of multifocal lenses is required before signi-ficant advantages of multifocal lenses over single vision lens are observed in pa tients with presbyopia.

Keywords: Presbyopia; Contact lenses; Adaptation, ocular; Visual acuity

RESUMOObjetivo: Comparar a acuidade visual, sensibilidade ao contraste, estereopsia e de-sempenho visual subjetivo de présbitas usando lentes de contato Acuvue Oasys para presbiopia (AOP), Air Optix Aqua Multifocal (AOMF) e Air Optix Aqua Single Vision (AOSV). Método: Foi realizado estudo mascarado simples, cruzado. Vinte pacientes com pres-biopia baixa (adição ≤+1,25 D) e 22 com presbiopia média/alta (adição ≥+1,50 D) usaram cada lente bilateralmente durante 1 hora, com descanso mínimo de uma noite entre as diferentes lentes. As medições incluíram acuidade visual para distância em alto e baixo contraste (HCVA, LCVA), sensibilidade ao contraste para distância (CS), HCVA para distância intermediária (70 cm) e para perto (50 cm e 40 cm), estereopsia e questionários subjetivos sobre nitidez visual, fantasmas, satisfação visão geral e conforto. As variáveis foram comparadas entre os tipos de lentes, utilizando medidas repetidas ANOVA. Resultados: As variáveis para distância (HCVA, LCVA, CS) foram significativamente piores com as multifocais em relação a AOSV (p≤0,008), exceto para AOMF no grupo de baixa adição, que não foi significativamente diferente (p>0,05). As multifocais foram significativamente melhores do que a AOSV para HCVA em 40 cm (p≤0,026). AOMF superou AOP para HCVA intermediária (p<0,03). AOP superou AOMF e AOSV em relação à estereopsia no grupo de presbiopia médio/alto (p≤0,03). Houve poucas diferenças significativas nas variáveis subjetivas, mas a satisfação visual global não foi significativamente diferente entre as lentes (p>0,05). A disposição para comprar lentes AOSV, AOMF e AOP foi: 20%, 40%, 50%, respectivamente, no grupo de presbiopia baixa; 14%, 32%, 23% no grupo de presbiopia média/alto, mas essas diferenças não foram estatisticamente significativas (p≥0,159). Conclusões: Melhorias futuras parecem ser necessárias para produção de uma len-te multifocal que forneça aos présbitas uma vantagem significativa sobre a lente de vi são única.

Descritores: Presbiopia; Lentes de contato; Adaptação ocular; Acuidade visual

Short-term visual performance of soft multifocal contact lenses for presbyopia

74 Arq Bras Oftalmol. 2016;79(2):73-7

that patients with presbyopia represent just 16% of all contact lens wearers and of these, multifocal contact lenses were prescribed in less than a third of patients with presbyopia because the majority were prescribed lenses for either distance correction only or monovi-sion(4). In 2013-2014, the proportion of presbyopic contact lens wearers with multifocal contact lenses was reported to have increased to approximately 50%(5,6). The high proportion of presbyopic contact lens wearers prescribed single vision or monovision lenses may be related to the practitioners’ common perception that multifocal con-tact lenses are more challenging to fit to provide acceptable vision and/or the perceived visual performance by the contact lens wearers themselves(4).

Multifocal contact lenses, which use simultaneous imaging, often cause visual disturbances, such as ghosting and haloes, because the optical zones for intermediate- and near-distance focusing are posi-tioned over the pupil(7-10). These disturbances can occur at any dis-tance and are often exacerbated in low-contrast or low-illumination conditions. Such effects range from mild to severe and have been demonstrated to be associated with pupil size, lens decentration, lens design, and inherent spherical aberration(11-14).

Many currently used multifocal contact lenses are designed to satisfy the complex visual requirements of patients with presbyopia while minimizing the negative effects. Vasudevan et al.(15) reported no significant differences in the subjective and objective visual perfor-mance of three current multifocal lenses: Air Optix® Aqua Multifocal, Acuvue® Oasys® for presbyopia, and Biofinity Multifocal. However, their study only included patients with early presbyopia who were fitted with low-add lens designs.

In this study, we included patients with moderate and severe presbyopia and compared visual acuity (VA), contrast sensitivity, ste -reopsis, and subjective visual performance obtained with two commercially available multifocal lenses and one spherical lens, the latter of which served as a negative control. We further investigated factors associated with the patients’ satisfaction and willingness to buy each lens type.

MeTHODSSTUDy DeSIgN

This study was a prospective, patient-blinded, crossover clinical trial that was conducted at the Brien Holden Vision Institute, Sydney, Australia, in which lenses were worn bilaterally. Inclusion cri teria were as follows: age over 40 years; spectacle add ≥+0.75 D; as tigmatism ≤-1.00DC; and vision correctable to at least 6/12 (0.3 logMAR) or better in each eye with contact lenses. Exclusion criteria were previous corneal refrac-tive surgery or any contraindications to wearing contact lens. Study protocols and informed consent were reviewed and approved by an independent ethics committee, and the study followed the tenets of the Declaration of Helsinki. The trial was registered in the Australian New Zealand Clinical Trials Registry (ACTRN12613001380785).

Patients attended a baseline visit to determine distance refraction and spectacle add requirement. The add was defined as the mini-mum correction required to comfortably read the 20/25 paragraph (0.1 logMAR) on an MNREAD Acuity Chart card (Precision Vision, IL USA) at a distance of 40 cm in a well-lit clinical room (minimum of 350 lux at the patients’ eye position).

All patients wore Air Optix® Aqua Single Vision (AOSV) lenses as a negative control immediately following the baseline visit. Other lens types were randomized and tested during the assessment visits on different days with a minimum overnight washout period between visits. Allocated lenses were inserted, and the assessments were ini-tiated after at least 10 min to allow the patients’ vision to completely settle. Distance over-refraction was performed with loose lenses in a trial frame, with the endpoint defined as the maximum plus at which

patients deemed vision was acceptable when binocularly observing a 6/6 line (0.0 logMAR) at 6 m. Vision between the two eyes was main-tained within 4 letters to avoid modified monovision.

leNS allOCaTION PROCeDUReS

The lenses evaluated in this study were AOSV (lotrafilcon B: Alcon, USA), Air Optix® Aqua Multifocal (AOMF; lotrafilcon B: Alcon, USA), and Acuvue® Oasys® for Presbyopia (AOP, senofilcon A: Johnson & Johnson, USA).

Patients were fitted with low-, medium-, and high-add lens designs on the basis of spectacle add power in accordance with manufacturers’ fitting guides(16,17). Lenses were power matched to the patients’ sphe-rical equivalent subjective distance refraction.

vISION aSSeSSmeNTS

All vision measurements were assessed under high room illu-mination (minimum of 350 lux at the patients’ eye position), with over-refraction placed in a trial frame when found. The following variables were measured at each visit (best corrected at baseline and with test lenses at lens assessment visits): high- and low-contrast visual acuity (HCVA and LCVA, respectively) measured with a compu-terized logMAR letter chart (Test Chart 2000 Pro, Thompson Software Solutions, Hertfordshire UK) at 6 m with letters of 100% and 10% contrast, respectively; contrast sensitivity (CS) at 18 cycles/degree measured with the Pelli-Robson chart at 6 m; HCVA at 70 cm, 50 cm, and 40 cm measured with the MN Read Acuity chart; and stereopsis measured with the Stereo Fly Test Circles (Stereo Optical, Il USA) at 40 cm. HCVA at intermediate and near distances were measured on the basis of the smallest print that patients were able to comfortably read rather than the smallest print possible.

PaTIeNT qUeSTIONNaIReS

Patients completed a questionnaire relating to the performance of lenses that were worn. Variables were rated on a 1-10 numeric rating scale in 1-point steps (Table 1). Furthermore, patients were asked to indicate whether they would buy lenses (yes/no response) on the basis of their visual experience alone.

aSSeSSmeNTS Of CONTaCT leNS fIT

Lens fits were evaluated using a Zeiss SL-120 slit lamp (Carl Zeiss Meditec, Jena, Germany) with an eyepiece graticule at 10× magnifi-cation. Lenses were assessed for decentration with respect to the lim-bus (horizontal and vertical), primary gaze movement, and primary gaze lag using the graticule and lens tightness with the push-up test.

STaTISTICal aNalySeS

A minimum of 10 patients were estimated to be required to de-monstrate a statistically significant paired difference between lenses and each iteration in VA of 0.1 ± 0.1 logMAR units at a significance level of 5% and power of 80%.

Data were summarized as mean ± standard deviation for varia-bles that were measured on an interval scale and as percentages for categorical variables. Study variables were compared between lens types

Table 1. Subjective variables rated by patients

Study questionnaire

Subjective variable Anchor point 1 Anchor point 10

Vision clarity at distance/intermediate/near Blurred/hazy Clear/sharp

Magnitude of ghosting at distance/intermediate/near

No ghosting Severe ghosting

Overall vision satisfaction Unsatisfactory Satisfactory

Ocular comfort Uncomfortable Comfortable

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using repeated measures ANOVA. Associations between willingness to buy and study variables were analyzed using logistic regression with robust estimate of variance. A multiple logistic model to identify factors independently associated with the willingness to buy was created using significant variables identified by univariate analyses. Backward elimination was used to select variables that were followed by forward entry of variables. Pearson’s correlation was used to deter-mine the univariate association of overall vision satisfaction with an objective vision. Only correlations with p values ≤0.01 and R values ≥±0.3 were considered statistically significant. Post-hoc multiple com-parisons were corrected using the Bonferroni correction. All analyses were performed using SPSS 21 software (IBM, USA).

For simplicity, the scale used to rate ghosting has been revised in the analyses to be consistent with the other scales in which greater numbers are represented by higher values. This variable was referred to as “lack of ghosting” in the results section.

ReSULTSPaTIeNT DemOgRaPhICS

Demographic data are presented in table 2. Because of the low number of patients (n=9) with at least add +2.00 D, data from patients with moderate and severe presbyopia were combined for analyses. Results are summarized in tables 3 and 4.

vISUal aCUITy, CONTRaST SeNSITIvITy, aND STeReOPSIS vaRIableS IN The mIlD PReSbyOPIa gROUP

As expected, AOSV lens had the highest mean values for distance variables, i.e., HCVA, LCVA, and CS. AOSV lens was significantly better than AOP lens for all distance variables (p≤0.007), with no statistically significant difference observed compared with AOMF lens (p≥0.213) or between the two multifocal designs (p≥0.115). At the intermediate distance, AOMF lens had significantly higher HCVA values compared with AOP lens (p=0.012), with no significant differences were obser-ved between AOSV lens and either of the multifocal lenses (p≥0.058). At 50 cm, AOSV lens had significantly worse HCVA compared with AOMF lens (p=0.011), with no significant difference observed com-pared with AOP lens (p=0.302). No significant differences in HCVA were observed between AOMF and AOP lenses (p=0.115). At 40 cm, AOSV lens had significantly lower HCVA compared with both AOMF

and AOP lenses (p≤0.026), with no significant differences observed between the two multifocal designs (p=0.577). No significant diffe-rences in stereopsis were observed between the lens types (p=0.519).

Table 2. Demographic factors for patients with mild and moderate or severe presbyopia

Patient demographics

factor

Mild presbyopia

n=20

Moderate or severe presbyopia

n=22

Age (years) 49 ± 3 58 ± 6

Range (years) 45-56 47-70

Female: male (%) 60: 40 46: 54

Neophytes: experienced wearers (%) 35: 65 32: 68

Ethnicity (%) caucasian: asian: others 55: 10: 35 82: 9: 9

Myopes n=12 n=8

Refraction: spherical (dioptres) -2.31 ± 1.37 -2.34 ± 1.75

Refraction: cylinder (dioptres) -0.47 ± 0.32 -0.30 ± 0.25

Keratometry: flat power (dioptres) 43.93 ± 1.24 43.81 ± 1.13

Keratometry: steep power (dioptres) 44.41 ± 1.36 44.34 ± 1.29

Hyperopes n=8 n=14

Refraction: spherical (dioptres) 1.35 ± 0.44 1.64 ± 0.66

Refraction: cylinder (dioptres) -0.39 ± 0.35 -0.41 ± 0.32

Keratometry: flat power (dioptres) 42.86 ± 1.29 42.96 ± 1.26

Keratometry: steep power (dioptres) 43.63 ± 1.35 43.55 ± 1.29

Table 3. Mean ± SD values for acuity and stereopsis variables for each lens

Acuity and stereopsis results

Study variables AOSV AOMf AOP

Mild presbyopia group

Distance HCVA (logMAR) -0.09 ± 0.01 -0.09 ± 0.03^ -0.06 ± 0.04*

Distance LCVA (logMAR) -0.15 ± 0.07 -0.18 ± 0.08^ 0.22 ± 0.09*

Distance CS (log units) -1.16 ± 0.14 -1.07 ± 0.19^ 1.00 ± 0.17*

Intermediate HCVA (logMAR) -0.24 ± 0.14 -0.12 ± 0.15^ 0.23 ± 0.18*

Near HCVA 50 cm (logMAR) -0.47 ± 0.17 -0.32 ± 0.21* 0.40 ± 0.20*

Near HCVA 40 cm (logMAR) -0.67 ± 0.16 0.49 ± 0.21* 0.55 ± 0.21*

Stereopsis (sconds of Arc) 124 ± 93 116 ± 85 104 ± 85

Moderate and severe presbyopia group

Distance HCVA (logMAR) -0.08 ± 0.03 -0.04 ± 0.06*^ -0.02 ± 0.09*^

Distance LCVA (logMAR) -0.17 ± 0.06 -0.28 ± 0.08*^ -0.31 ± 0.12*^

Distance CS (log Units) -1.08 ± 0.13 -0.90 ± 0.18*^ -0.82 ± 0.27*^

Intermediate HCVA (logMAR) -0.35 ± 0.17 -0.12 ± 0.12*^ -0.21 ± 0.15*^

Near HCVA 50 cm (logMAR) -0.58 ± 0.17 -0.30 ± 0.18*^ -0.36 ± 0.17*^

Near HCVA 40 cm (logMAR) -0.77 ± 0.19 -0.48 ± 0.20*^ -0.52 ± 0.22*^

Stereopsis (seconds of Arc) 163 ± 176 148 ± 131 100 ± 84*^

*= indicates a significant difference the MFCL versus the single vision lens; ^= in-di cates a significant difference between MFCL types.

Table 4. Mean ± SD for subjective variables and willingness to buy (proportion of patients in each group willing to buy each test lens)

Subjective questionnaire results

Subjective variable AOSV AOMf AOP

Mild presbyopia group

Clarity of vision (distance, 1-10) 8.8 ± 1.3 8.5 ± 1.1^ 7.8 ± 1.8

Clarity of vision (intermediate, 1-10) 7.5 ± 2.0 7.9 ± 2.2^ 6.9 ± 2.3

Clarity of vision (near, 1-10) 4.9 ± 2.8 6.4 ± 2.5^ 4.9 ± 2.9

Lack of ghosting (distance, 1-10) 9.9 ± 0.4 9.7 ± 0.6^ 9.4 ± 0.9

Lack of ghosting (intermediate, 1-10) 9.2 ± 1.3 8.7 ± 2.1^ 9.1 ± 1.7

Lack of ghosting (near, 1-10) 8.6 ± 1.6 8.7 ± 2.1^ 8.8 ± 2.0

Overall visual satisfaction (1-10) 5.9 ± 2.3 7.2 ± 2.1^ 6.6 ± 2.6

Ocular comfort (1-10) 8.9 ± 1.5 8.6 ± 1.7^ 9.3 ± 0.7

Willingness to buy (% of patients) 20 40 50

Moderate and severe presbyopia group

Clarity of vision (distance, 1-10) 8.6 ± 1.3 7.6 ± 1.5* 6.0 ± 2.5*

Clarity of vision (intermediate, 1-10) 5.9 ± 2.4 7.5 ± 1.7* 6.9 ± 2.2*

Clarity of vision (near, 1-10) 3.5 ± 2.2 6.3 ± 2.3* 5.1 ± 2.5*

Lack of ghosting (distance, 1-10) 9.8 ± 0.7 8.6 ± 1.6* 7.0 ± 2.9*

Lack of ghosting (intermediate, 1-10) 8.6 ± 1.7 8.7 ± 1.9* 8.5 ± 1.6*

Lack of ghosting (near, 1-10) 8.7 ± 1.9 8.0 ± 1.8* 7.7 ± 1.8*

Overall visual satisfaction (1-10) 5.2 ± 1.9 6.0 ± 2.1* 5.3 ± 2.7*

Ocular comfort (1-10) 8.3 ± 1.7 7.8 ± 2.3* 8.8 ± 1.1*

Willingness to buy (% of patients) 14 32 23

*= indicates a significant difference the MFCL versus the single vision lens; ^= indicates a significant difference between MFCL types.

Short-term visual performance of soft multifocal contact lenses for presbyopia

76 Arq Bras Oftalmol. 2016;79(2):73-7

vISUal aCUITy, CONTRaST SeNSITIvITy, aND STeReOPSIS vaRIableS IN The mODeRaTe aND SeveRe PReSbyOPIa gROUP

HCVA, LCVA, and CS at distance were higher with AOSV lens than with AOMF and AOP lens (p≤0.008), with no significant differences observedbetween the two multifocal designs (p≥0.894). At the in-termediate distance, AOMF lens performed significantly better than AOSV and AOP lenses (p≤0.023), and AOP lens performed significan-tly better than AOSV lens (p=0.010). At both near distances, AOSV lens had signi ficantly worse HCVA than both AOMF and AOP lens (p≤0.001), while no significant differences was observed between the two multifocal designs (p≥0.329). AOP lens had significantly better improvements in stereopsis compared with other lenses (p≤0.030); however, no difference was found between AOSV and AOMF lens (p=1.00).

SUbjeCTIve vaRIableS aND wIllINgNeSS TO bUy leNS IN The mIlD PReSbyOPIa gROUP

No significant differences in most subjective variables were obser-ved between the lens types (p>0.05); however, AOMF lenses were rated as significantly more clear at near distances than AOP lens (p=0.005). AOP lens had the highest buy willingness in the mild pres-byopia group, with 50% patients expressing willingness to buy them, whereas AOSV lenses had the lowest willingness to buy; however, this difference was not statistically significant (p=0.159). The decision to buy in this group was associated with near VA at 40 cm [odds ratio (OR), 2.31; p=0.002] and overall vision satisfaction (OR, 7.16; p<0.001).

SUbjeCTIve vaRIableS aND wIllINgNeSS TO bUy leNS IN The mODeRaTe aND SeveRe PReSbyOPIa gROUP

AOSV lens was rated highest in terms of clarity and lack of ghos-ting at a distance, thereby performing significantly better than AOP lens in the former (p<0.001) and significantly better than both AOP and AOMF lenses in the latter (p≤0.010). AOSV lens was rated lowest in terms of clarity at both intermediate and near distances, with both significantly lower than AOMF lens (p≤0.039). No significant diffe-rences in any subjective variable, including overall visual satisfaction and ocular comfort, were observed between AOMF and AOP lenses (p>0.05). AOMF lens had the highest willingness to buy in the mode-rate and severe presbyopia group, whereas AOSV lens had the lowest willingness to buy; however, this trend was not statistically significant (p=0.385). The decision to buy in this group was associated with an overall vision satisfaction (OR, 2.52; p<0.001).

CORRelaTIONS beTweeN hCva aND vISION SaTISfaCTION

In the mild presbyopia group, strong correlations were observed between intermediate and near HCVA and overall vision satisfaction (-0.67≤R≤-0.62; p<0.001). In the moderate and severe presbyopia group, a weaker correlation was observed between intermediate HCVA and overall vision satisfaction (R=-0.33; p=0.007).

leNS fIT

AOMF lens had significantly more primary gaze movement than AOSV and AOP lenses (p≤0.019); however, the mean difference was not clinically relevant at 0.03 mm. No other differences in any other lens fitting measure were observed between the lens types (p>0.05).

DISCUSSIONThis study aimed to compare VA, contrast sensitivity, stereopsis,

and subjective visual performance of AOP, AOMF, and AOSV lenses in patients with presbyopia in a cross-over trial. The single vision lens, which acted as a negative control, had the best performance at distance in the majority of cases, as expected. In the mild pres-byopia group, AOMF lens was the only multifocal design that was able to match the distance performance of the single vision lens. However, while the other lens types had statistically significantly worse

HCVA at a distance compared with AOSV lens, the differences were within 1 line of letters and were not considered clinically significant. Nevertheless, differences were more apparent when observing LCVA and CS at a distance, indicating that in the majority of cases, patients with presbyopia who wear multifocal contact lenses that were used in this study experienced a degree of distance visual compromise that may not be have been apparent in high-contrast situations but may manifest in real-life, low-contrast conditions. At near distances, multifocal lenses provided better VA when compared with the single vision lens, as expected, because of its monofocal design. VA at an intermediate distance and stereopsis with AOSV lens were comparable with both AOP and AOMF lenses in the mild presbyopia group, which is likely because of the residual accommodation in younger patients with presbyopia.

Despite different optical designs, AOMF and AOP lenses similarly performed in the majority of variables. AOMF lens is a continuous aspheric, center-near lens that is designed to provide good near vi-sion through the central zone of the lens, good intermediate vision through the mid-peripheral zone, and good distance vision in the periphery. AOP is a center-distance design featuring distance and near concentric rings that are designed to provide consistent vision regardless of pupil size and also incorporating negative spherical aberration(18).

A comparison of visual performance between multifocal contact lenses and a single vision contact lens (distance corrected) has not been previously conducted, although a comparison of AOMF and AOP lenses was reported by Vasudevan et al.(15) In their study, no signi-ficant differences were observed in any objective or subjective varia-ble between the lenses; however, their study only included patients with early presbyopia who were fitted with low-add lens designs. We extended our investigation to include patients with moderate and severe presbyopia, in addition to those with early presbyopia, and observed similar performance of AOMF and AOP lenses for the majority (but not all) objective and subjective variables in both the groups under the test conditions.

Interestingly, considerably lower rates of stereopsis were achieved with multifocal designs in this study than those reported for the same designs in previous studies (21-54 seconds of arc)(15,19), even when considering only the mild presbyopia group in this study. We believe that this discrepancy may attributable to the inclusion of a wider age range of patients with presbyopia in this study who fell into the mild presbyopia group and the different evaluation methods used. However, variability in stereopsis measurements for multifocal lenses has been previously reported(15,20,21). In this study, HCVA at near distances that were recorded with all lenses were lower than pre viously reported values(15,20-25), which is primarily attributable to the differen-ce in methodology. Unlike other studies, we sought to measure the smallest paragraph that patients could “comfortably” read, which involved an additional subjective element in the objective resolution task. Given the assumption that reading speeds at near distance are maximal at 0.4-0.6 logMAR, it is expected that the values reported by patients with all test lenses converged toward 0.5 logMAR for near distances(26). Therefore, we recommend investigators pay more attention to differences between test and control subjects rather than absolute measures.

In this study, while few variables were found to differ between mul tifocal designs and AOSV lens, no significant differences in the patients’ overall satisfaction with the lenses or willingness to buy were observed. For the mild presbyopia group, the larger sample size may have led to a significant difference in the overall visual satisfaction or willingness to buy; however, differences were much smaller in the moderate and severe presbyopia group, indicating MFCL designs for this group did not overall perform substantially better than the single vision lens. In general, at least half of the patients with mild presbyopia and two-thirds of the patients with moderate or severe presbyopia were unwilling to buy the lenses that were tested in this

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77Arq Bras Oftalmol. 2016;79(2):73-7

study after wearing them for 1 h. It is clear that despite advances in multifocal technology in recent years, further improvements are still required to achieve a multifocal lens that provides significant advan-tages over a simple single vision lens, particularly in patients with moderate and severe presbyopia.

Because of the simplistic nature and short duration of this study, we did not set-up a separate experiment to validate our subjective questionnaires. This study aimed to evaluate subjective responses between different lens types. Given that the study was a randomized, cross-over trial, the reliability, content, and/or criterion bias (if any) remains constant throughout all the repeated administrations of the questionnaire. Thus, bias (if any) will be diminished when considering differences between subjective ratings with different lens types.

A secondary objective of our study was to investigate relationships between variables to determine the factors related to the pa tients’ satisfaction and willingness to buy the specific lenses. Papas et al. pre viously reported that objective findings have little value for this purpose, and clinicians should rely on subjective findings to predict success(9). We found that patients with better HCVA at intermediate, and occasionally near, distances tended to have higher satisfaction with overall vision, which in turn was a factor that influenced the patients’ willingness to buy. In this study, a 1 unit higher rating in the overall vision satisfaction produced a 7-fold increase in the willingness to buy in patients with mild presbyopia and a 2.5-fold increase in patients with moderate or severe presbyopia. In practice, clinicians commonly measure VA at 40 cm; however, our data demonstrate that measuring VA at slightly greater distances may be important in predicting patient success with multifocal contact lenses. This study was limited by the small adaptation period. While this imitates what often occurs when patients first fit multifocal contact lenses in practice, changes in lens performance may occur over 4-15 days(9,22). Longer term studies are required to determine if these study mea-sures continue to predict performance over a longer period of time.

COnCLUSIOnUnder the short-term testing conditions, both AOMF and AOP len-

ses similarly performed for the majority of acuity measurements and subjective variables. The findings of this study indicate that further improvements are required to achieve a multifocal lens that provides significant advantages over a simple single vision lens, particularly in patients with moderate and severe presbyopia.

ACKnOWLeDGMenTSThis work was conducted at the clinical research center of the Brien

Holden Vision Institute, Sydney, Australia. The research was completely supported by the Brien Holden Vision Institute. The authors extend their gratitude to Ms. Robertson, Dr. Naduvilath, and Ms. Laarakkers for their contributions in data collection and analysis and Dr. Flanagan for reviewing the manuscript.

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using schematic and physical eye models. Sydney, Australia: University of New South Wales;2010.

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Original Article

78 Arq Bras Oftalmol. 2016;79(2):78-81 http://dx.doi.org/10.5935/0004-2749.20160024

InTRODUCTIOnMigraine is a chronic disease involving both neurological and vas-

cular system abnormalities and is characterized by single-sided, epi-sodic attacks of headache. Gastrointestinal complaints and sensitivity to bright light and loud noises may accompany this headache(1), and migraine occurs most frequently between the ages of 35 and 45 years(2). Although the etiology of migraine is unknown, there are some theo-ries for its pathogenesis. At the end of the 1930s, Graham and Wolff identified a dilatation in the temporal artery during migraine attacks as a cause for the headache. Wolff advocated that the aura preceding migraine symptoms is due to vasospasms that reduce the blood flow to the brain(3).

Several studies have shown that vascular changes occur in the ocular system during migraine attacks. Cerebral blood flow in the occi-pital hemisphere has been shown to diminish during migraine attacks, especially in migraine with aura. Hypoperfusion has been reported to

affect the retina and the optic nerve, as well as result in ganglion cell loss(4). The retinal nerve fiber layer (RNFL) contains the axons of the retinal ganglion cells. Therefore, measurement of the mean peripa-pillary RNFL thickness is expected to provide benefits for monitoring the progressive loss of ganglion cells and axons in migraine patients.

Optical coherence tomography (OCT) can be used to obtain high-resolution images of the anterior and posterior segments of the eye. Today, modern technological OCT devices are employed for the in vivo quantitative measurement of the peripapillary RNFL, GCL, and choroid layer in various neuro-ophthalmological diseases. The reduction in RNFL thickness reflects the loss of ganglion cells and axons in migraine patients(4-6).

We expected the retina and optic nerve to be affected in recurrent migraine attacks with aura due to hypoperfusion. We evaluated the thicknesses of the peripapillary RNFL, ganglion cell complex, subfo-veal choroid, and choroid layer at six distinct points using spectral domain (SD)-OCT.

Retinal nerve fiber layer, ganglion cell complex, and choroidal thicknesses in migraine Espessuras da camada de fibras nervosas retinianas, complexo de células ganglionares e coroide na enxaqueca

hatıce nur colak1, ferıDe aYlın kantarcı1, mehmet gurkan tatar1, mehmet erYılmaz2, hasım uslu1, hasan goker1, aYDın YılDırım1, bulent gurler1

Submitted for publication: May 14, 2015 Accepted for publication: November 14, 20151 Department of Ophthalmology, Fatih University Medical Faculty Hospital, Istanbul, Turkey.2 Department of Neurology, Fatih University Medical Faculty Hospital, Istanbul, 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: Hatice Nur Colak. Fatih University Medical Faculty Hospital - Istanbul 34844 Turkey - E-mail: ncolak@fatih.edu.tr

ABSTRACTPurpose: To evaluate the thicknesses of the peripapillary retinal nerve fiber layer (RNFL), ganglion cell complex (GCL), and choroid layer using spectral domain optical coherence tomography (SD-OCT) for investigating the effects of vascular changes on the eye and optic nerve in patients who have migraine with aura. Methods: Forty-five patients who had migraine with aura (migraine group) and 45 healthy individuals (control group) were enrolled in the study. Age, gender, duration after migraine diagnosis, intraocular pressure, and axial length measure-ments were recorded in each case. RNFL, GCL, and choroid layer thicknesses were measured using SD-OCT in all participants.Results: The mean age was 36.1 ± 6.7 (20-45) years in the migraine group and 35.7 ± 8.6 (19-45) years in the control group. There was no significant difference in the RNFL thicknesses of the temporal and nasal quadrants (p>0.05). The RNFL thicknesses of the superior and inferior quadrants were significantly lower in the migraine group compared with those in the control group (p=0.001, p<0.01, res-pectively). Measurements for the superior and inferior GCL were not significantly different between the groups (p>0.05). Subfoveal, temporal, and nasal choroidal thickness measurements at 500 µm, 1000 µm, and 1500 µm were significantly lower in the migraine group than in the control group (p=0.001; p<0.01, respectively). Conclusions: Compared with the controls, the RNFL and choroid layer were determined to be thinner in patients who had chronic migraine with aura.

Keywords: Migraine with aura; Optic nerve; Nerve fibers/pathology; Choroid/pa-thology; Retinal ganglion cells; Eye/blood supply; Optical coherence tomography

RESUMOObjetivo: Avaliar as espessuras de camada peripapilar de fibras nervosas retinianas (RNFL), complexo de células ganglionares (GCL) e da coroide utilizando a tomografia de coerência óptica de domínio espectral (SD-OCT ), a fim de investigar os efeitos das alterações vasculares no olho e nervo óptico em pacientes que apresentam enxaqueca com aura. Métodos: Quarenta e cinco pacientes que apresentavam enxaqueca com aura (grupo enxaqueca) e 45 indivíduos saudáveis (grupo controle) foram incluídos no estudo. Idade, sexo, duração da enxaqueca, pressão intraocular e medidas de comprimento axial foram registrados em cada caso. Medidas da RNFL, GCL e espessuras da coroide foram obtidas com SD-OCT em todos os participantes.Resultados: A média da idade foi de 36,1 ± 6,7 (20-45) anos no grupo enxaqueca e 35,7 ± 8,6 (19-45) anos no grupo controle. Não houve diferença significativa em espessuras RNFL nos quadrantes temporal e nasal (p>0,05). A espessura da RNFL nos quadrantes superiores e inferiores foram significativamente menores no grupo de enxaqueca em comparação ao grupo controle (p=0,001; p<0,01). Medidas da GCL superior e inferior não mostraram diferença significativa entre os grupos (p>0,05). Espessuras subfoveais, temporais e nasais da coroide (CT ) a 500 µm, 1000 µm e 1500 µm foram significativamente menores no grupo de enxaqueca em relação ao grupo controle (p=0,001; p<0,01). Conclusões: Comparados aos controles, as espessuras da RNFL e coroide foram mais finas em pacientes que apresentavam enxaqueca crônica com aura.

Descritores: Enxaqueca com aura; Nervo óptico; Fibras nervosas/patologia; Coroide/patologia; Olho/irrigação sanguínea; Tomografia de coerência óptica

Colak HN, et al.

79Arq Bras Oftalmol. 2016;79(2):78-81

MeTHODSThis cross-sectional study included patients who were diagnosed

with migraine with aura at Fatih University Faculty of Medicine (study group), together with age-matched normal individuals (control group). Informed consent, which was obtained from all individuals, was pre-pared in accordance with the principles of the Declaration of Helsinki and was approved by the local ethics committee.

The study group was selected from patients who were diagnosed with migraine with aura (45 patients) according to the 2004 criteria of the International Headache Society (IHS)(2). A detailed anamnesis, including the history of headache, was obtained from each patient. Physical and neurological examinations were performed, and radio-logical examinations (computed tomography or magnetic resonance imaging) were performed as required. The control group in our study consisted of 45 age- and sex-matched healthy volunteers.

The inclusion criteria were as follows: age between 18 and 45 years, spherical or cylindrical refractory error less than +/–2 D, visual acuity of 20/20, intraocular pressure (IOP) <18 mmHg, cup-to-disc ratio <0.4, and no ophthalmological pathologies. The exclusion criteria were as follows: glaucoma, cataracts, previous eye surgery, systemic diseases such as diabetes, hypertension, history of prophylactic migraine treat ment, including calcium channel blocker, beta blockers, and anti-epileptics, to avoid their pharmacological effects on the retina.

Complete ophthalmological examination, including visual acuity, anterior segment, anterior chamber angle, and fundus examinations, as well as IOP measurement, central corneal thickness (CCT) measu-rement, and OCT measurements, were performed for each patient at our Ophthalmology Department. Best-corrected visual acuity was recorded using Snellen charts. Ocular axial lengths and CCT were measured using an ultrasonic biometry and pachymetry device (US-4000 Echoscan; NIDEK, Gamagori, Japan). Peripapillary RNFL, cen-tral macular thickness (CMT), GCL, and choroidal thickness (CT) were measured using an SD-OCT device (RS-3000; NIDEK). SD-OCT mea-surements were performed between 09:00-12:00 am by the same person 30 min after the dilation of the pupils with 0.5% tropicamide solution. Only the scans that had a signal strength of at least 6 or above with good reliability were included in the analysis.

The peripapillary RNFL thickness was measured by circular scanning around the optic nerve in an area with a diameter of 3.4 mm. We recor-ded the RNFL thicknesses at the superior, inferior, temporal, and nasal quadrants, and the mean RNFL thickness values. CMT was measured at the superior and inferior GCL regions. For CT analysis, measurements were performed vertically between the outer hyperreflective border of the retinal pigment epithelial layer and the choroid-sclera border, at the subfoveal area, and at six extrafoveal areas (500 µm, 1000 µm, 1500 µm nasal side of the fovea, and 500 µm, 1000 µm, and 1500 µm temporal to the fovea). Data obtained from the migraine patients were compared with those from the control group.

STaTISTICal aNalySIS

Statistical analyses were performed on NCSS (Number Cruncher Statistical System) 2007 & PASS (Power Analysis and Sample Size) 2008 Statistical Software (Kaysville, UT, USA). Along with descriptive statis-tics (mean, standard deviation, median, frequency, ratio, minimum, and maximum), Student’s t-test was used for the comparison of normally distributed variables between the two groups. A repeated measures test (repeated measures analysis of variance) was used for the com-parison of normally distributed parameters within a group, and Bonfer-roni correction was used for the evaluation of dual comparisons. The comparison of qualitative data was performed with Yates’ continuity correction test (Yates’ chi-square test with correction). Significance was evaluated at the p<0.01 and p<0.05 levels.

ReSULTSThe present study included 90 individuals; 73 (81.1%) of them were

female and 17 (18.9%) were male. The mean age of the individuals

was 35.9 ± 7.6 (19-45) years. There were 37 (82.8%) females and 8 (17.8%) males in the migraine group, and 36 (80%) females and 9 (20%) males in the control group. The mean age in the migraine group was 36.1 ± 6.5 (20-45) years and in the control group was 35.7 ± 8.6 (19-45) years. There was no significant difference between the groups with regard to age and sex (p=0.159, p=0.124, respectively).

For the migraine patients, the mean duration after diagnosis was 8.8 ± 6.9 (1-28) years, and the mean IOP in this group was 16 ± 3 (10-22) mmHg. The mean CCT measurement was 553.4 ± 31.8 (490-645) µm. The demographic and clinical characteristics of the migraine and control groups are given in table 1.

The mean CMT was 226.3 ± 12.4 µm in the migraine group and 226.6 ± 15.6 µm in the control group. The measurements of the axial length and CMT were not significantly different between the groups (p=0.907, p=0.929, respectively; Table 2). As for the measurements of the RNFL thickness, the temporal and nasal quadrant thicknesses were not statistically significantly different between the groups (p=0.298, p=0.395, respectively), whereas the mean quadrant thickness values were significantly lower in the migraine group than in the control group (p=0.016). Similarly, the superior and inferior thickness measurements were significantly lower in the migraine group than in the control group (p=0.001, p=0.001, respectively; Table 2, Figure 1).

Table 1. Demographic and clinical characteristics of the migraine group

n=45 Mean ± SD (min-max)Age (years) 036.1 ± 06.5 (20-45)

Years since diagnosis (years) 008.8 ± 06.9 (01-28)

IOP (mmHg) 016.0 ± 03.0 (10-22)

CCT (µm) 553.4 ± 31.8 (490-645)

SD= standard deviation; IOP (mmHg): intraocular pressure; CCT= central corneal thickness.

Table 2. Mean OCT analysis results of the migraine and control groups

Groups

*p value

Migraine group (n=45)

Control group (n=45)

Mean ± SD Mean ± SD

AL (mm) 023.2 ± 00.9 23.2 ± 000.8 0.907**

CMT (µm) 226.3 ± 12.4 226.6 ± 015.6 0.929**

RNLF (µm)

Mean 104.1 ± 08.4 108.7 ± 009.4 0.016**

Superior 107.0 ± 11.9 131.8 ± 018.3 0.001***

Inferior 101.6 ± 10.4 138.4 ± 017.1 0.001***

Temporal 072.9 ± 10.3 075.3 ± 011.5 0.298***

Nasal 087.9 ± 15.1 085.3 ± 014.0 0.395**

GCL (µm)

Superior GCL 104.8 ± 05.2 104.7 ± 006.2 0.927**

Inferior GCL 104.6 ± 05.3 105.2 ± 005.9 0.233**

CT (µm)

SFCT 343.0 ± 90.7 445.3 ± 101.6 0.001***

Temporal 500 µm CT 344.0 ± 90.5 433.0 ± 116.6 0.001***

Temporal 1000 µm CT 339.4 ± 97.1 425.3 ± 098.4 0.001***

Temporal 1500 µm CT 328.5 ± 97.9 0403.4 ± 098.9 0.001***

Nasal 500 µm CT 335.7 ± 89.9 435.7 ± 104.2 0.001***

Nasal 1000 µm CT 320.1 ± 90.3 417.8 ± 104.9 0.001***

Nasal 1500 µm CT 296.8 ± 88.6 385.1 ± 107.6 0.001***

*= Student’s t-test; **= p<0.05; ***= p<0.01.SD= standard deviation; AL= axial length; CMT= central macular thickness; RNFL= retinal nerve fiber layer; GCL= ganglion cell layer thickness; CT= choroidal thickness; SFCT= subfoveal choroidal thickness.

Retinal nerve fiber layer, ganglion cell complex, and choroidal thicknesses in migraine

80 Arq Bras Oftalmol. 2016;79(2):78-81

The superior and inferior GCL thickness measurements were not statistically significantly different between the two groups (p=0.907, p=0.233, respectively; Table 2; Figure 2).

As for the CT measurements, the subfoveal, temporal, and nasal CT at 500 µm, 1000 µm, and 1500 µm were significantly thinner in the migraine group than in the control group (p=0.001; Table 2, Figures 3 and 4).

DISCUSSIOnMigraine is a common neurological disease characterized by hea-

daches together with transient focal symptoms called aura observed in some patients. Migraine patients with aura reportedly have increa-sed rates of ischemic stroke, cardiac disease, intracerebral hemorrhage, and mortality(4,7). Endothelial and vascular smooth muscle dysfunction as well as hypercoagulability have been reported as possible respon-sible factors for the pathogenesis of migraine(8). Due to the transient cerebral vasospasm that occurs in migraine, fluctuations in perfusion during recurrent migraine attacks can lead to chronic retinal damage in the optic nerve head and the retina and eventually to ganglion cell death(4,9). Recurrent migraine attacks have been shown to induce chronic cerebral damage in several studies(10). Further, retinal infarcts due to the occlusion of the retinal artery have also been reported in migraine patients(11).

It has recently become possible to evaluate the thickness of the peripapillary RNFL and choroid layer using advanced OCT devices. This method has enabled the diagnosis and monitoring of various diseases. Today, RNFL analysis using OCT is commonly performed in patients with ocular hypertension and glaucoma(12,13). In our study, we compared the thicknesses of the RNFL, CMT, GCL, and choroid layer in migraine patients with aura to that in healthy individuals using SD-OCT.

In one study by Kara et al. in which Doppler ultrasound was used to demonstrate retinal vascular changes and perfusion in migraine patients, the resistance in the central retinal artery and posterior ciliary artery was found to be higher in migraine patients than in the control group(14).

In another study by Martinez et al., who compared 70 migraine patients and 53 normal individuals using OCT, the mean RNFL thickness was determined to be normal in migraine patients, but the RNFL thickness in the temporal quadrant was significantly thinner(4). Tan et al. evaluated RNFL thicknesses using laser polarimetry in their study, including 39 migraine patients, 15 with aura and 24 without aura, and 25 healthy individuals; they determined no reduction in the RNFL thickness, and they asserted that migraine had no effect on RNFL(15). Additionally, Sorkhabi et al. found that RNFL was thinner in the nasal quadrant in migraine patients(16).

In our study, while there was no statistically significant difference in the temporal and nasal quadrant RNFL thickness measurements between the groups (p>0.05), the mean RNFL thickness in migraine patients was found to be significantly lower compared with that in the control group (p<0.05). Similarly, the superior and inferior quadrant

figure 4. Choroid layer thickness measurement of a patient in the migraine group.

figure 1. Measurements of the retinal nerve fiber layer thickness in the migraine and control groups.

figure 2. Measurements of the ganglion cell complex thickness in the migraine and control groups.

figure 3. Measurements of the choroid layer thickness in the migraine and control groups.

Colak HN, et al.

81Arq Bras Oftalmol. 2016;79(2):78-81

RNFL thicknesses were significantly lower in the migraine group than in the control group (p<0.05).

Various visual complications have been reported in migraine, such as visual field defects similar to that observed in glaucoma as well as retinal vasculopathy(17). Ischemic damage causes thinning in RNFL in glaucoma, and RNFL thickness measurements are used to eva luate the glaucomatous changes. Studies have shown that the peripapillary RNFL is consistently thinner in patients with glaucoma. Kook et al. observed thinning in RNFL in patients with normal-tension glaucoma (NTG) in the superior and inferior quadrants, consistent with our observation(18). Drance et al. determined that the progression of visual field loss was faster in NTG patients who also had migraines compared with that in NTG patients who did not have migraines(19). Moreover, the reduction of RNFL thickness has also been reported in multiple sclerosis (MS), Alzheimer’s disease, and Parkinson’s di-sease(20-22). The GCL thickness could provide a better structural indica-tor of axonal loss compared with RNFL in certain optic neuropathies such as MS, non-arteritic anterior ischemic optic neuropathy, and compressive optic neuropathy. GCL analysis may provide a method for diagnosing and monitoring optic nerve disease(23).

In their study comparing female migraine patients to healthy women, Gipponi et al. did not find any difference in the foveal thickness and ma-cular volume; however, they determined that superior RNFL and GCL thicknesses were significantly reduced only in migraine patients with aura but not in those without aura(24). In our study, we did not observe a significant difference in the CMT and GCL measurements of migraine patients with aura and healthy individuals (p>0.05).

The choroid layer is the most important vascular layer of the eye. Choroidal vascular insufficiency and reduction in CT result in the dysfunction of the retinal pigment epithelium and photoreceptor layers(25,26). In migraine, which is regarded as a neurovascular disease, the choroid layer can become thinner due to reduced blood flow in the central retinal and posterior ciliary arteries(27). Diseases that affect the retina lead to reduced thickness of the choroid layer.

In their study evaluating CT in diabetic retinopathy, Regatieri et al. determined that CT can vary depending on the severity of retino-pathy caused by hypoxia in the retinal tissue, and they found that CT significantly decreased with increasing severity of retinopathy caused by hypoxia, especially in the presence of diabetic macular edema(28). Bourke et al. reported a correlation between untreated systemic hypertension and choroidopathy(29). The reduction of CT has been reported in a study with smokers, which was thought to be due to increased resistance in the retinal vasculature(30). Similarly, we observed that the subfoveal, temporal, and nasal CT measurements at 500 µm, 1000 µm, and 1500 µm were significantly lower in migraine patients compared with those in controls (p<0.01).

We found that the thicknesses of the RNFL and choroid layer were reduced in migraine patients compared with those in controls. Considering that patients with other diseases that could cause any retinal abnormalities, such as glaucoma (especially NTG) and systemic diseases, were not included in the study, this reduction is likely to be related to the migraine itself.

The limitations of our study are the exclusion of migraine patients without aura and the small number of cases in the study.

In conclusion, the RNFL and choroid layer thicknesses were determined to be thinner in migraine patients with aura compared with those in age-matched healthy subjects, and this is thought to be related to a progressive loss of ganglion cells and axons.

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Original Article

82 Arq Bras Oftalmol. 2016;79(2):82-4 http://dx.doi.org/10.5935/0004-2749.20160025

InTRODUCTIOn Keratoconus is characterized by bilateral asymmetrical non-in-

flam matory corneal ectasia that leads to central or inferotemporal stromal thinning, corneal protrusion (which may be surrounded by iron deposits in the epithelial basement membrane), and rupture of

Bowman’s layer. Irregular corneal astigmatism may result in significant visual loss in approximately 1 per 2000 individuals in the general po-pulation, with a diagnosis usually made in the second decade of life(1,2). Keratoconus morphology may be categorized as: nipple cones, 5-mm diameter, with the apex localized centrally or paracentrally

Descriptive analysis of the type and design of contact lenses fitted according to keratoconus severity and morphologyAnálise descritiva dos tipos e parâmetros das lentes de contato adaptadas de acordo com o grau evolutivo e a morfologia do ceratocone

letícıa helena lunarDı¹, Danıelle arroYo¹, marcelo vıcente De anDraDe sobrınho¹, césar lıPener1, Julıana marıa Da sılva rosa¹

Submitted for publication: March 17, 2015 Accepted for publication: December 4, 20151 Setor de Lentes de Contato e Refração, Universidade Federal de São Paulo, São Paulo, 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: Juliana Maria da Silva Rosa. Av. João Carlos Machado, 455/202 - Rio de Janeiro, RJ - 22620-081 - Brazil - E-mail: jumsrosa@gmail.com

Approved by the following research ethics committee: UNIFESP, Plataforma Brasil (CAAE: 14862113.7.0000.5505).

ABSTRACT Purpose: Keratoconus is characterized by bilateral asymmetrical corneal ectasia that leads to inferior stromal thinning and corneal protrusion. There is currently a lack of consensus regarding the most efficacious method for fitting contact lenses in patients with keratoconus, given the various topographical patterns and evolution grades observed in affected populations. The purpose of the present study was to evaluate the association between keratoconus evolution grade and topography pattern and the type and design of fitted contact lens. Methods: We performed a retrospective analysis of contact lenses fitted in a total of 185 patients with keratoconus (325 eyes). Keratoconus was classified as either grade I, II, III, or IV based on keratometry and cone morphology (nipple, oval, globus, or indeterminate) results. Results: A total of 325 eyes were evaluated in the present study. Of the 62 eyes classified as grade I, 66.1% were fitted with monocurve contact lenses. Of the 162 eyes classified as grade I and II, 51%, 30%, and 19% were fitted with adapted monocurve rigid gas-permeable contact lenses (RGPCL), bicurve lenses, and others lens types, respectively. Bicurve lenses were fitted in 52.1% and 62.2% of eyes classified as grade III and IV, respectively. Of the eyes classified as grade III and IV, monocurve and bicurve RGPCL were fitted in 26% and 55%, respectively. In eyes with oval keratoconus, 45%, 35%, and 20% were fitted with monocurve lenses, bicurve lenses, and other lens types, respectively. In eyes with round cones (nipple morphology), 55%, 30%, and 15% were fitted with bicurve lenses, monocurve lenses, and other lens types, respectively. Conclusion: Monocurve RGPCL were most frequently fitted in patients with mild to moderate keratoconus and oval cones morphology, while bicurve lenses were more frequently fitted in patients with severe and advanced keratoconus. This was probably because bicurve lenses are more appropriate for round cones due to increased corneal asphericity.

Keywords: Corneal diseases; Keratoconus; Keratoconus/classification; Contact lenses; Equipment design

RESUMOObjetivo: O ceratocone é uma ectasia corneana bilateral e assimétrica que leva a afinamento corneano inferior e protrusão da córnea, não existe consenso sobre qual é o melhor caminho para adaptar lentes de contato em pacientes com ceratocone, considerando seus diferentes padrões topográficos e graus de evolução. O objetivo desse estudo é associar o grau de evolução e padrão topográfico com o tipo/desenho da lente adaptada. Métodos: Análise retrospectiva das lentes de contato adaptadas em 185 pacientes com ceratocone (325 olhos) no Departamento de Lentes de Contato. O ceratocone foi classificado de acordo com a ceratometria em graus I, II, III e IV e de acordo com a morfologia em cone redondo, oval, globoso e indeterminado. Resultados: Foram avaliados 325 olhos. Em 66,1% dos olhos com grau I foi adaptada lente monocurva. Dos 162 olhos classificados como graus I e II foram adaptadas lentes monocurva em 51%, bicurva em 30% e outros em 19%. Em relação aos olhos grau III, em 52,1% foram adaptadas lentes bicurvas e o mesmo aconteceu em 62,2% dos olhos com grau IV. Apenas 26% dos olhos grau III ou IV receberam lentes monocurva, com necessidade de bicurvas em 55%. 45% dos cones ovais foram adaptados com lentes monocurva, 35% com bicurvas e 20% com outros tipos, enquanto 55% dos cones re-dondos foram adaptados com lentes bicurvas, apenas 30% com monocurvas e 15% com outros desenhos. Conclusão: Lentes de contato rígida gás-permeável (LCRGP) monocurvas são mais frequentemente utilizadas em ceratocones leves e moderados e em ovais, enquanto bicurvas são mais usadas para casos graves e avançados e em cones redondos.

Descritores: Doenças da córnea; Ceratocone; Ceratocone/classificação; Lentes de con tato; Desenho de equipamento

Lunardi LH, et al.

83Arq Bras Oftalmol. 2016;79(2):82-4

often displaced inferonasally; oval cones, 5 to 6-mm diameter, with inferotemporally ellipsoid profile; and globus cones, more than 6-mm diameter, occupying more than 75% of the cornea(3).

The use of rigid glass contact lenses was first described in 1888 by Adolf Fick. Contact lens fitting remains the most appropriate option for correcting refractive errors induced by keratoconus, as this approach regularizes the corneal surface, thereby ensuring ma ximum visual acuity with decreased residual aberration. Contact lenses provide superior amount and quality of vision as compared to spectacles(4,5). In their multicenter analysis of patients with keratoconus, Lass et al. reported that 74% do not require surgery and can be managed with either contact lenses (84%) or spectacles (13%), or without correction (3%)(6). Bilgin et al. reported a success rate of 98.9% in1004 patients fitted with contact lenses over a 30-year period(7).

Rigid gas-permeable contact lenses (RGPCL) remain the most com-monly used type of lens and are available in several designs, including bicurve and multicurve. The development of new lenses and designs has enabled improvements in visual acuity and either prevented or postponed the need for surgical intervention in an increased number of patients(6). However, there is currently a lack of consensus re gar ding the most efficacious method for fitting contact lenses in patients with keratoconus, given the various topographical patterns and evolution grades observed in affected populations.

The purpose of the present study was to evaluate the association between keratoconus evolution grade and topography pattern and the type and design of fitted contact lens.

MeTHODSA retrospective analysis of 185 patients with keratoconus (325 eyes)

fitted with contact lenses between 2007 and 2010 was conducted at the Contact Lens Sector, Paulista School of Medicine, Federal Uni-versity of São Paulo (EPM/UNIFESP). Diagnoses were made by the Cornea Department. Age, gender, keratometry, base curve, and lens diameter were recorded. Keratoconus was classified according to keratometry (K1) as either incipient or grade I (K<45.00 D in both meridians), moderate or grade II (K between 45.00 and 52.00 D in both meridians), advanced or grade III (K between 52.00 and 62.00 D in both meridians), and severe or grade IV (K>62.00 D in both meridians) and according to cone morphology (nipple, oval, globus, or indeter-minate). All patients were initially fitted with monocurve (spherical or aspherical) RGPCL with only one central base curve. In cases with unsuccessful initial lens fitting (due to contact lenses with excessive apical bearing, excessive peripheral seal-off, excessive pooling, or patient intolerance), the type and/or lens design was modified to one of the following: bicurve RGPCL (designed by Joseph Soper), with a characteristic variable central curve and a constant (45.00 D) intermediate curve; multicurve lens, a variation of the Soper design with 2 or more intermediate curves or aspherical flattening from the central till the peripheral curve; or multispherical lens, with a charac-te ristic single spherical central area, approximately 5 mm in size, with multiple flatter spherical peripheral curves. Adaptation with soft con tact lenses for keratoconus correction was attempted in patients that were intolerant to rigid contact lenses. Analyses for descriptive data were performed. Continuous variables are presented as means ± standard deviation. Categorical variables are presented as frequen-cies. Between-group differences were analyzed using the chi-square test. The SigmaPlot 11.0 software package was used for all statistical analyses with the significance level set to 5%.

ReSULTSA total of 325 eyes were evaluated in the present study. The ave-

rage patient age was 24.7 ± 8.5 years. Topography-derived mean K1 and K2 were 47.96 ± 6.75 and 52.43 ± 8.5, respectively. The mean base curve of soft contact lenses and RGPCL was 40.66 ± 2.84 and

48.8 ± 4.5 diopters, respectively. The mean visual acuity was 0.5 ± 0.3 (logMAR) with refraction and 0.2 ± 0.1 with contact lenses (P<0.05). The mean diameter of rigid contact lenses was 9.1 ± 4.1 mm (Table 1). Bicurve contact lenses were fitted in 138 (42.4%), monocurve lenses in 126 (38.8%), and multicurve lenses in 45 (13.8%) eyes. Soft contact lenses were fitted in 7 (2.1%); keratoconus special soft contact lenses (Perfect Keratoconus, World Vision, São Paulo, Brazil) in 2 (0.6%); multispherical (Century, Optolentes, Porto Alegre, Brazil) in 6 (1.8%); and reverse curve design contact lenses (Ultraflat, Ultralentes, Porto Alegre, Brazil) in 1 eye/s (0.3%, Table 2).

Sixty-two eyes were classified as grade I (19.07%), 97 as grade II (29.8%), 121 as grade III (37.2%), and 45 as grade IV (13.8%). Monocurve contact lenses were successfully fitted in 66.1% of patients with grade I keratoconus, and 42.3% patients with grade II keratoconus (P<0.05; Table 3). Of the 159 eyes classified as having mild (grade I) or moderate (grade II) keratoconus, monocurve RGPCL, bicurve lenses, and other lenses were fitted in 51.5%, 30%, and 19% of cases, respecti-vely (P<0.05). Monocurve RGPCL and bicurve lenses were fitted in 26% and 55% of patients with advanced (grade III) or severe (grade IV), respectively (P<0.05; Table 4).

In patients with oval cones, 45% were fitted with monocurve lenses, 35% with bicurve lenses, and 20% with other lens types. In patients with round cones (nipple morphology), 55% were fitted with bicurve lenses, 30% with monocurve lenses, and 15% with other lens types (P<0.05; Figure 1).

DISCUSSIOnRGPCL remain an excellent option for visual rehabilitation of pa-

tients with keratoconus. In the present study, the corrected visual acuity of patients fitted with contact lenses was higher than those fitted with spectacles (0.2 vs. 0.5 logMAR). No statistically significant diffe-rence in the number of eyes classified as mild, moderate, advanced, or severe was observed in the present study.

Monocurve RGPCL were more frequently fitted in patients with grades I or II (51%) than in those with grades III or IV (26%; P<0.05), while bicurve lenses were fitted in the most advanced cases of kera-toconus (30% in grades I or II and 55% in grades III or IV; P<0.05). In a retrospective study, Ghanem et al. analyzed 881 eyes with kerato-conus and concluded that the majority could be fitted with rigid mo nocurve contact lenses. However, the results of the present study

Table 1. Descriptive analysis of eyes studied and lens fitted

Number of eyes (n) 325

Patient age (years)* 24.70 ± 8.50 D

Base curve in soft contact lenses (D)* 40.66 ± 2.84 D

Base curve in rigid contact lenses (D)* 48.80 ± 4.50 D

K1 (D)* 47.96 ± 6.75 D

K2 (D)* 52.43 ± 8.51 D

Spectacle-corrected visual acuity (logMAR)* 00.50 ± 0.30 D

Contact lens-corrected visual acuity (logMAR)* 00.20 ± 0.10 D

Table 2. Design of fitted lenses

Contact lens design %

Monocurve 38.8%

Bicurve 42.4%

Multicurve 13.8%

Other 05.0%

Descriptive analysis of the type and design of contact lenses fitted according to keratoconus severity and morphology

84 Arq Bras Oftalmol. 2016;79(2):82-4

figure 1. Frequency of fitted designs according to cone morphology.

Table 4. Association between grade of keratoconus and design of fitted contact lenses

Grades I/II Grades III/IV

Monocurve 51% 26%

Bicurve 30% 55%

Other design* 19% 19%

*= hydrophilic contact lenses, keratoconus special hydrophilic contact lenses, multis-pherical lenses, and reverse curve design contact lenses.

Table 3. Association between the keratoconus evolution grade and type and design of contact lenses

Grade I Grade II Grade III Grade IV

n 62 97 121 45

% 19.07% 29.80% 37.20% 13.80%

Design n %Diameter*

(mm) n %Diameter*

(mm) n %Diameter*

(mm) n %Diameter*

(mm)

Monocurve 41 66.1% 09.20 ± 0.20 41 42.3% 09.0 ± 0.4 36 29.8% 8.9 ± 0.4 08 17.8% 8.7 ± 0.0

Bicurve 11 17.7% 09.40 ± 0.30 36 37.1% 09.3 ± 0.3 63 52.1% 9.3 ± 0.4 28 62.2% 9.2 ± 0.4

Multicurve 01 01.6% 08.7 13 13.4% 08.7 ± 0.1 22 18.1% 8.7 ± 0.0 02 20.0% 8.9 ± 0.3

Multispherical 04 06.5% 10.00 ± 0.20 02 02.0% 09.8 ± 0.0 00 00.0% - - - 00 00.0% - - -

Reverse curve 00 00.0% - - - 01 01.0% 11.0 00 00.0% - - - 00 00.0% - - -

Hydrophilic 04 06.5% 14.10 ± 0.30 03 03.1% 14.3 ± 0.3 00 00.0% - - - 00 00.0% - - -

Special hydrophilic for keratoconus 01 01.6% 14.2 01 01.0% 14.2 00 00.0% - - - 00 00.0% - - -

*= average ± standard deviation.

indicate that other designs may be more appropriate in patients with more advanced and severe keratoconus. Toric contact lenses and the “piggyback” system were reported to be more suited to central cones, while monocurve and bicurve rigid contact lenses were more suited to inferior peripheral cones(8). In addition, a separate study by the same group demonstrated that the design of contact lens used in the initial

evaluation does not provide the best fit between the lens and cornea, due to variations in corneal topography over time. The Soper-McGuire lenses have been shown to be more effective than monocurve RGP-CL in patients with advanced and central keratoconus(9).

Cone morphology may influence the fitting of different lens designs. In the present study, monocurve lenses fitted oval cones better (45%). However, a significant portion of eyes required bicurve lenses (35%). Round cones mostly required bicurve lenses in order to achieve a better standard of adaptation (55%).

COnCLUSIOnMonocurve RGPCL were more frequently fitted in patients with

mild to moderate keratoconus or with oval cone morphology, while bicurve lenses were more frequently fitted in patients with severe or advanced keratoconus, most likely as these lenses are considered the best option for patients with round cones due to increased corneal asphericity.

RefeRenCeS 1. Rabinowitz YS. Keratoconus. Surv Ophthalmol. 1998;42(4):297-319. 2. Krachmer JH, Feder RS, Belin MW. Keratoconus and related noninflammatory corneal

thinning disorders. Surv Ophthalmol. 1984;28(4):293-322. 3. Romero-Jiménez M, Santodomingo-Rubido J, Wolffsohn JS. Keratoconus: a review.

Cont Lens Anterior Eye. 2010;33(4):157-66. 4. Garcia-Lledo M, Feinbaum C, Alio JL. Contact lens fitting in keratoconus. Compr Oph-

thalmol Update. 2006;7(2):47-52. 5. Griffiths M, Zahner K, Collins M, Carney L. Masking of irregular corneal topography with

contact lenses. CLAO J. 1998;24(2):76-81. 6. Lass JH, Lembach RG, Park SB, Hom DL, Fritz ME, Svilar GM, et al. Clinical management

of keratoconus. A multicenter analysis. Ophthalmology. 1990;97(4):433-45. 7. Bilgin LK, Yilmaz S, Araz B, Yüksel SB, Sezen T. 30 years of contact lens prescribing for

keratoconic patients in Turkey. Contact Lens Anterior Eye. 2009;32(1):16-21. 8. Ghanem VC, Ghanem CC, Ghanem RC, Larinho, C. Ceratocone: correlação entre grau evo-

lutivo e padrão topográfico com o tipo de lente de contato adaptada. Arq Bras Oftalmol. 2003;66(2):129-35.

9. Ghanem CC, Alves MR. Avaliação comparativa da adaptação de lentes de contato rígidas gás-permeáveis Monocurvas e Bicurvas (desenho Soper-McGuire) em pacientes portadores de ceratocone: um estudo prospectivo e randomizado. Arq Bras Oftalmol. 2008;71(3):328-36.

Original Article

85Arq Bras Oftalmol. 2016;79(2):85-7http://dx.doi.org/10.5935/0004-2749.20160026

InTRODUCTIOnAnomalous posterior vitreous detachment (PVD) is a pathological

variant of the aging gel liquefaction process(1,2). In this variant, the vitreous gel adheres in an abnormally strong manner to the retina. Combining the current knowledge regarding PVD with advances in optical coherence tomography (OCT), a panel of specialists convened to develop a consensus classification of vitreomacular interface (VMI) disorders(3), such as vitreomacular adhesion (VMA), vitreomacular trac tion (VMT), and partial or full thickness macular hole (FTMH)(3,4-6).

VMA occurs during initial and partial PVD, when a portion of the posterior vitreous remains attached to the macula without alterating the underlying retinal contour(4). VMA may develop into VMT, with subsequent symptom development and anatomical distortion ob-served on OCT. This continuous traction may progress to FTMH or other potentially sight-threatening conditions(4-6).

In general, observation and pars plana vitrectomy have been the only treatment options for vitreomacular interface disorders. The Microplasmin for Intravitreous Injection-Traction Release without Surgical Treatment (MIVI TRUST) program, comprising two randomi-zed clinical trials, demonstrated the benefits of a single 0.125-mg in-travitreal ocriplasmin injection (JETREA; ThromboGenics, USA). Good tolerability and higher nonsurgical resolution of VMA were observed in 464 patients who were administered ocriplasmin (26.8%) than in 188 control patients who were administered the placebo (10.1%)(4,6). Supported by this data, in 2012, the US Food and Drug Administration

approved pharmacological vitreolysis as a valid therapeutic alterna-tive for symptomatic VMA(5). Ocriplasmin is a recombinant, truncated form of the human plasmin with autolytic and proteolytic activity. It mainly targets fibronectin and laminin that are abundant in vitreous gel and provides in a normal condition, a suitable attachment to the retina(6-8). The resolution of VMA has been typically observed within 28 days of ocriplasmin injection(4,6). The treatment also induced hi-gher rates of FMTH closure (40.6%) compared with the sham group (10.6%)(4). The MIVI TRUST study group results demonstrated major benefits in patients younger than 65 years, with focal adhesions (diameter ≤1500 µm), absence of epiretinal membrane, and phakic lens status(4). In this case series, we report the initial experience of in-travitreal ocriplasmin in the treatment of symptomatic VMA in Brazil.

MeTHODSThis study was a retrospective analysis of a small case series of

seven patients who were diagnosed with VMT according to the In-ternational Vitreomacular Traction study group and who were treated with ocriplasmin at the Centro Brasileiro de Cirurgia de Olhos (Goiâ-nia, GO) and Centro Brasileiro da Visão (Brasília, DF) in 2013 and 2014(3). Spectral domain OCT (SD-OCT) was performed using Spectralis (Heidelberg Engineering; Heidelberg, Germany). Following informed consent, a single 0.125-mg ocriplasmin injection was administered under sterile conditions. Snellen best-corrected visual acuity (BCVA) values were converted to logMAR units(9).

Initial experience with ocriplasmin in the treatment of vitreomacular tractionExperiência inicial com ocriplasmina no tratamento da tração vitreorretiniana

José maurícıo botto De barros garcıa1,2, DavıD leonarDo cruvınel ısaac1,2, marcos Ávıla1,2

Submitted for publication: February 24, 2015 Accepted for publication: December 2, 20151 Ophthalmology Department, Centro de Referência em Oftalmologia (CEROF), Goiânia, GO, Brazil.2 Ophthalmology Department, Universidade Federal de Goiás (UFG), Goiânia, GO, 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: José Maurício Botto de Barros Garcia. Rua 234, 38, Apto. 1.011 - Setor Leste Universitário - Goiânia, GO - 74605-150 - Brazil

ABSTRACTThis study aimed to report the clinical and structural outcomes of intravitreal ocriplasmin in the treatment of vitreomacular interface disorders in two tertiary centers in Brazil. A retrospective study was performed by reviewing medical records and spectral domain optical coherence tomography (SD-OCT) findings of seven patients who were treated with a single ocriplasmin injection. A total of 57.14% of patients achieved resolution of vitreomacular traction as evidenced by SD-OCT. Regarding our functional results, 87.71% maintained or improved visual acuity after follow-up. To the best of our knowledge, this is the first study reporting initial results of ocriplasmin therapy in Brazil.

Keywords: Vitreous body/pathology; Fibrinolytic agents/therapeutic use; Fibri-nolysin/therapeutic use; Tomography, optical coherence; Tertiary care centers

RESUMO O objetivo desse estudo é relatar os resultados iniciais, tanto do ponto de vista fun-cional quanto anatômico, no tratamento das doenças da interface vítreo-macular com a ocriplasmina em 2 serviços terciários no Brasil. Um estudo retrospectivo foi realizado através de revisão de prontuários, além de análise de achados em tomo-grafia de coerência óptica de domínio espectral (SD-OCT ) em 7 pacientes tratados com uma única injeção intravítrea de ocriplasmina. Em nosso estudo 57,14% dos pacientes apresentaram resolução da tração vítreo-macular no SD-OCT. Em relação aos resultados funcionais, 87,71% dos pacientes mantiveram, ou melhoraram sua acuidade visual durante o acompanhamento. Para nosso conhecimento, trata-se do primeiro estudo em nosso país, mostrando resultados iniciais com ocriplasmina em pacientes tratados no Brasil.

Descritores: Corpo vítreo/patologia; Fibrinolíticos/uso terapêutico; Fibronilisina/uso terapêutico; Tomografia de coerência óptica; Centros de atenção terciária

Initial experience with ocriplasmin in the treatment of vitreomacular traction

86 Arq Bras Oftalmol. 2016;79(2):85-7

ReSULTSPatient data are shown in table 1. The subjects had a median age

of 66.14 years. Six patients (85.71%) were females. Initial and final BCVA measurements ranged from 0.19 to 0.17, respectively, after a median follow-up of 70.57 days. Overall, 4 patients (57.14%) achieved anatomical resolution (Figures 1 and 2). Three patients (42.8%) were older than 65 years. One of these three patients achieved VMT release

during follow-up. All members included in this study were diagnosed with VMA or VMT, and none of them presented with epiretinal mem-brane or FTMH. Studying the 3 patients who failed to achieve anato-mical resolution, one patient exhibited a decrease in BCVA (Figure 3), 3 presented brief metamorphopsia, and one demonstrated transient conjunctival hemorrhage, flashes, and diplopia. No post-injection en dophthalmitis or retinal tears were identified.

Table 1. Demographical and clinical characteristics of the study population

Patient Sex Age eyeLens

status eRM MHfocal VMT

Broad VMT

Initial BCVA

(logMAR)

final BCVA

(logMAR)

Initial BCVA

(Snellen)

final BCVA

(Snellen)follow up

in days

VMT resolution (SD-OCT)

1 F 49 OS Phakic – – + – 0.30 0.18 20/40 20/30 28 +

2 F 74 OD PCIOL – – + – 0.10 0.00 20/25 20/20 4 +

3 F 62 OD PCIOL – – + – 0.18 0.00 20/30 20/20 40 +

4 F 79 OS PCIOL – – + – 0.30 0.30 20/40 20/40 61 –

5 F 63 OS PCIOL – – + – 0.00 0.40 20/20 20/50 28 –

6 M 72 OD PCIOL – – – + 0.30 0.18 20/40 20/30 319 –

7 F 64 OS PCIOL – – + – 0.18 0.18 20/30 20/30 14 +

PCIOL: posterior chamber intra ocular lens; logMAR: logarithm of minimum angle of resolution; OD: right eye; OS: left eye; ERM: epiretinal membrane; MH: macular hole; VMA: vitreomacular adhesion; VMT: vitreomacular traction; SD-OCT: spectral domain optical coherence tomography.

A B

figure 1. Initial Spectral Domain Optical Coherence Tomography (SD-OCT) of a 49-year-old phakic patient showing focal vitreo-macular traction (VMT) (A), with complete separation of the posterior hyaloid 4 days after ocriplasmin injection, accompanied by re-establishment of macular contours (B).

A B

figure 2. A 64-year-old patient having focal vitreo-macular traction (VMT) with subretinal fluid as observed on Cirrus Spectral Domain Optical Coherence Tomography (SD-OCT) (Carl Zeiss Meditec, USA), which was clinically managed over 58 days (A); 14 days after ocriplasmin injection, retinal anatomy was re-established (B).

A B

figure 3. A 63-year-old patient complained about significant metamorphopsia (A). Spectral Domain Optical Coherence Tomography (SD-OCT) showed persistent focal vitreo-macuolar traction (VMT), with no reported fracture in the ellipsoid segment (IS/OS) of the outer retina during the follow-up period (B); the patient experienced loss of vision from 20/20 to 20/50.

Garcia JMBB, et al.

87Arq Bras Oftalmol. 2016;79(2):85-7

DISCUSSIOnPharmacological vitreolysis has been studied as an alternative to

vitrectomy and has become a promising medical agent because of its ability to induce PVD, for its stable structure, and as a supplement to observation and vitrectomy in managing selected disorders(5-8,10). Pre-vious studies have demonstrated that appropriate patient selection is critical for improving outcomes using ocriplasmin(5-8,10).

The overall frequency of successful release (4 eyes, 57.1%) was higher in this study than in phase III clinical trials (26.5%). Three patients (42.8%) from our series were older than 65 years, which has been related to a worse prognosis following pharmacological vi-treolysis(4). Kim et al.(5), after studying a carefully selected group of 19 patients, demonstrated a separation of VMT in 42% of the patients. In a sample size of 17 patients, Singh et al.(7) reported a 47.1% resolution rate within 28 days after the injection; although this group reported predictive factors and patient enrollment similar to those reported by the MIVI TRUST group(4), they used SD-OCT instead of time domain OCT, which has an inferior resolution.

According to Singh et al.(7), almost all patients who responded to therapy had outer retinal fracture in the ellipsoid zone (IS/OS junc-tion) as observed on SD-OCT, which was probably because of the potential toxicity of the drug. Nevertheless, this did not alter the study outcomes regarding the spontaneous resolution of the symptoms or SD-OCT findings, with treatment response occurring in most patients within the first 7 days after the procedure, with further improvement during follow-up. In our group, four patients initially complained of blurred vision or reduced BCVA in the initial observation after the injection; however, no evident outer retina abnormalities could be observed on SD-OCT.

The limitations of our study include the small sample and its retrospective design. A retrospective study, which was performed with eight patients, revealed complete resolution in 62.5% after a minimum period of 1 month of observation, corroborating our results(8). It is important to highlight that this study included only a small case series, and these results cannot be directly compared with

randomized clinical trials. To the best of our knowledge, this is the first study reporting the initial data on pharmacological therapy of VMI-related diseases in Brazil.

In conclusion, in our study, 4 of 7 seven eyes achieved anatomical resolution of VMT after a single 0.125-mg ocriplasmin injection. This corroborates with phase III clinical trials that have proved the benefits of ocriplasmin, leading to a shift in treatment paradigm with respect to achieving optimal outcomes in symptomatic patients. Future and larger reports, particularly with SD-OCT, should help us understand and better explain the drug’s mechanism of action.

RefeRenCeS 1. Warrow DJ, Lai MM, Patel A, Raevis J, Berinstein DM. Treatment outcomes and

spectral-domain optical coherence tomography findings of eyes with symptomatic vitreomacular adhesion treated with intravitreal ocriplasmin. Am J Ophthalmol. 2015; 159(1):20-30ea.

2. Xu LT, Punjabi OS, Shao J, Ehlers JP, Srivastava SK, Singh RP, et al. Frequency of vitreomacular interface disease in patients presenting to a tertiary care institution. Ophthalmic Surg Lasers Imaging Retina. 2014;45(6):517-20.

3. Duker JS, Kaiser PK, Binder S, de Smet MD, Gaudric A, Reichel E, et al. The Interna-tional Vitreomacular Traction Study Group. Classification of vitreomacular adhesion, traction, and macular hole. Ophthalmology. 2013;120(12):2611-9.

4. Stalmans P, Benz MS, Gandorfer A, Kampik A, Girach A, Pakola S; et al, for the MIVI-TRUST Study Group. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular hole. N Engl J Med. 2012;367(7):606-15.

5. Kim BT, Schwartz SG, Smiddy WE, Doshi RR, Kovach JL, Berrocal AM, et al. Initial outco-mes following intravitreal ocriplasmin for treatment of symptomatic vitreomacular adhesion. Ophthalmic Surg Lasers Imaging Retina. 2013;44(4):334-43.

6. Kuppermann BD. Ocriplasmin for pharmacologic vitreolysis. Retina. 2012;32 Suppl 2:S225-8; discussion S228-31.

7. Singh RP, Li A, Bedi R, Srivastava S, Sears JE, Ehlers JP, et al. Anatomical and visual outcomes following ocriplasmin treatment for symptomatic vitreomacular traction syndrome. Br J Ophthalmol. 2014;98(3):356-60.

8. Knudsen VM, Kozak I. A retrospective study of a single practice use of ocriplasmin in the treatment of vitreomacular traction. Saudi J Ophthalmol. 2014;28(2):139-44.

9. Gregori NZ, Feuer W, Rosenfeld PJ. Novel method for analyzing snellen visual acuity measurements. Retina. 2010;30(7):1046-50.

10. de Smet MD, Jonckx B, Vanhove M, van Calster J, Stalmans P, Stassen JM. Pharmacoki-netics of Ocriplasmin in Vitreous. Invest Ophthalmol Vis Sci. 2012;53(13):8208-13.

Original Article

88 Arq Bras Oftalmol. 2016;79(2):88-91 http://dx.doi.org/10.5935/0004-2749.20160027

InTRODUCTIOnCornea laser refractive surgery has become generally accepted as

a safe approach for correcting low-to-moderate refractive errors, and satisfactory visual acuity outcomes have been widely reported(1). Ne-vertheless, the quality of vision may be altered due to changes in con-trast sensitivity, glare, and/or higher-order aberrations(2). Many previous studies have shown that corneal laser surgery impacts postoperative corneal aberrations and contrast sensitivity(3,4). Conversely, relatively little work has focused on glare, despite patients frequently reporting

ABSTRACTPurpose: To evaluate ocular straylight before and after photorefractive keratec-tomy (PRK) for low myopia with and without topical mitomycin (MMC) treatment. Methods: Patients who underwent PRK for low myopia were enrolled into the study. PRK without MMC was performed in 21 eyes (12 patients), whereas PRK with topical 0.02% MMC was performed in 25 eyes (14 patients). Both groups were treated using the NIDEK EC5000 excimer laser. Measurements were performed using the C-Quant straylight meter preoperatively and at two and four months postoperatively. Results: The mean patient age was 30 ± 4 years, and the mean spherical equivalent refractive error was -2.2 ± 0.75 D. The mean preoperative intraocular straylight values were 1.07 ± 0.10 in the PRK without MMC group and 1.07 ± 0.11 log(s) in the PRK with topical MMC group. At two months after surgery, there was a decrease in mean intraocular straylight values in both groups. However, a significant diffe-rence was only reached in the PRK with MMC group [0.98 ± 0.09 log(s), p=0.002] compared with preoperative values, which was likely due to a greater scatter of measurements in the PRK without MMC group [1.03 ± 0.13 log(s), p=0.082]. At four months postoperatively, ocular straylight values were not significantly different compared with those at baseline in either the PRK without MMC group [1.02 ± 0.14 log(s), p=0.26] or in the PRK with topical MMC group [1.02 ± 0.11 log(s), p=0.13]. Conclusion: PRK for low myopia decreases ocular straylight, and MMC applica-tion further reduces straylight in the early postoperative period. However, ocular straylight values do not significantly differ at four months after surgery compared with those at baseline.

Keywords: Photorefractive keratectomy; Myopia/surgery; Mitomycin; Wound healing

RESUMOObjetivo: Avaliar a dispersão de luz intraocular antes e depois da ceratectomia fo-torrefrativa (PRK) para baixa miopia com e sem a aplicação tópica de mitomicina C. Métodos: Pacientes submetidos à PRK para baixa miopia foram selecionados para o estudo. PRK sem MMC foi realizado em 21 olhos (12 pacientes) e PRK com MMC tópica a 0,02% foi realizado em 25 olhos (25 pacientes). Ambos os grupos foram tratados com o excimer laser da Nidek EC5000. Avaliações foram realizadas usando o medidor de dispersão de luz C-Quant no pré-operatório e com 2 e 4 meses de pós-operatório. Resultados: A média de idade dos pacientes foi 30 ± 4 anos e a média do equivalente esférico foi -2,2 ± 0,75 D. As médias da dispersão de luz intraocular no pré-operatório foram 1,07 ± 0,10 no grupo PRK sem MMC e 1,07 ± 0,11 log(s) no grupo PRK com MMC tópica. Após 2 meses da cirurgia houve uma diminuição na média da dispersão de luz intraocular em ambos os grupos. Entretanto uma diferença estatisticamente significante, comparado com os valores pré-operatórios, foi observada apenas no grupo PRK com MMC (0,98 ± 0,09 log(s), p=0,002), provavelmente devido as medidas com maior espalhamento de luz no grupo sem MMC (1,03 ± 0,13 log(s), p=0,082). Após 4 meses de pós-operatório, os valores de dispersão de luz não apresentavam diferença estatisticamente significantes quando comparados com os valores iniciais, tanto no grupo sem MMC (1,02 ± 0,14 log(s), p=0,26) quanto no grupo com MMC tópica (1,02 ± 0,11 log(s), p=0,13). Conclusão: PRK para baixa miopia diminui a dispersão de luz ocular e a aplicação de MMC contribui para uma ainda menor dispersão de luz no período pós-operatório inicial. Entretanto, quatro meses após a cirurgia a dispersão de luz intraocular não é significantemente diferente das medidas pré-operatórias.

Descritores: Ceratectomia fotorrefrativa; Miopia/cirurgia; Mitomicina; Cicatrização

this as a troubling symptom, at least in the early postoperative period, following procedures such as photorefractive keratectomy (PRK).

Disability glare is the veiling of vision due to the forward scattering of light in the eye(5,6). Straylight is a known source of disability glare(7).

The cornea can be a major contributor to total intraocular straylight(8). During corneal wound healing, most patients experience transient changes in corneal transparency(9). Injury to the epithelium and re-moval of the central epithelial basement membrane, which also occur in PRK, initiate a complex sequence of events mediated by

Intraocular straylight before and after low myopic photorefractive keratectomy with and without mitomycin C Dispersão de luz intraocular antes e depois da ceratectomia fotorrefrativa para baixa miopia com e sem mitomicina C

anDre augusto mıranDa torrıcellı1, taís renata rıbeıro PareDe1, marcelo vıeıra netto1, francısco PenteaDo crestana1, samır Jacob bechara1

Submitted for publication: June 10, 2015 Accepted for publication: November 13, 20151 Department of Ophthalmology, Faculdade de Medicina, Universidade de São Paulo, São Paulo,

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 conflict of interest to disclose.

Corresponding author: André A. M. Torricelli. Departamento de Oftalmologia, Setor de Cirurgia Refrativa - Instituto Central - 6o andar. Av. Dr. Enéas de Carvalho Aguiar, 155 - São Paulo, SP - 05403-000 - Brazil - E-mail: torricelli.andre@yahoo.com.br

Approved by the following research ethics committee: University of São Paulo Institutional Review Board (CAPPesq da Diretoria Clínica FMUSP) no 263/11.

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89Arq Bras Oftalmol. 2016;79(2):88-91

epithelial-stromal interactions(10,11). Corneal fibroblast and myofibro-blast generation, in addition to changes in the quality and quantity of extracellular matrix, are the main alterations contributing to stromal opa-city following PRK surgery(9,12). Accordingly, changes in ocular straylight were described in the early postoperative stage after PRK correction in work performed nearly two decades ago(3).

Subsequent to that study(13), the intraoperative use of topical mitomycin C (MMC) has been shown to be an effective adjunct treat-ment modulating the corneal wound healing response and resulting corneal opacity(14). The effect of MMC on cell replication and the consequent decreased cell density in the anterior stroma, along with changes in the extracellular matrix(15), likely modify ocular straylight after PRK. The current study aimed to evaluate and compare intraocu-lar straylight values in patients who underwent PRK surgery with and without topical MMC application for mild myopia and astigmatism.

MeTHODSSTUDy POPUlaTION

A total of 46 eyes of 26 patients who underwent PRK treatment were enrolled in the study. Inclusion criteria included patients between 22 and 45 years of age, stable refraction for at least one year, myopia correction of ≤3.00 diopters (D), astigmatism of ≤1.00 D, and central corneal thickness of >490 µm measured by ultrasonic pa chymetry. Exclusion criteria were as follows: presence of corneal abnormalities suggestive of keratoconus or other corneal ectatic di-seases, presence of ocular pathology (dry eye, active infection, cli ni cally significant lens opacification, or clinically significant retina pathology), and pregnancy or lactation.

A complete ophthalmologic examination, including uncorrected visual acuity, best-corrected visual acuity, manifest and cycloplegic refraction, and obtaining clinical history, was performed on all pa-tients. Tonometry, slit lamp examination, and dilated fundus exami-nation were also performed. A Colvard infrared pupillometer (Oasis Medical Inc, Glendora, CA, USA) was used to assess scotopic pupil size. Additional tests performed included ultrasonic pachymetry (Cor neo-Gage, Sonogage, Inc., Cleveland, OH), Placido-based corneal topography (EyeSys 2000, EyeSys Co., Houston, TX, USA), corneal to-mography (Orbscan IIz, Bausch & Lomb Inc, Rochester, NY, USA), and wavefront analysis (OPD-Scan; NIDEK, Gamagori, Japan).

The institutional review board approved the study, and the tenets of the Declaration of Helsinki were followed. Informed consent was obtained from all patients after detailed discussion, including alterna-tives and potential complications.

OCUlaR STRaylIghT

Undilated straylight measurements were performed preopera-tively and at two and four months postoperatively using the C-Quant straylight meter (Oculus Optikgerate GmbH, Wetzlar, Ger many), as previously described(16). The C-Quant straylight meter assesses the amount of light scattered toward the retina by a psy chophysical approach called the compensation comparison method(16,17). Briefly, the patient was presented with two alternative forced choices and was asked to choose between the stronger of two flickers presented in controlled background lighting(18). The test field was divided into halves: compensation light was presented to one (randomly cho sen) half of the test field, while no compensation light was presented to the other half. A bright, ring-shaped, flickering light source correspon-ding to a 7° scattering angle was used. When light scattering occurs in the eye, part of the flickering light from this ring also reaches the center of the retinal projection of the ring(19). As a result, two flickers are percei-ved, which differ in modulation depth: one results from straylight only, and the other is a combination of straylight and compensation light flickering in counterphase with the straylight(16). Due to a change in the average luminance of the stimulus and counterphase modulating light, the straylight value of the respective eye is approached when the halves

are balanced. The patients’ responses were recorded by a two-alternative, forced-choice procedure. A psy chometric curve was fitted to the pa-tients’ responses, from which the log (straylight parameter), estimated standard deviation (ESD), and quality factor (Q) were deduced. The measurement was conside red reliable when ESD and Q were <0.08 and >1.00(20), respectively. Straylight values are expressed as log(s). Higher values indicate more straylight.

Measurements were taken under low-mesopic conditions by the same technician. Three straylight measurements were taken per eye at each time point, and mean values were calculated and recorded for data analysis.

RefRaCTIve SURgeRy PROCeDURe

Stromal tissue ablations were performed with the NIDEK EC 5000 CXIII excimer laser system (NIDEK, Gamagory, Japan). The epithelium was mechanically removed using a blunt blade, and an optical zone of 6.0 mm with a 7.5-mm transition zone was used in all cases. When used, 0.02% MMC was applied for 30 s after tissue ablation, and the cornea was subsequently irrigated with balanced salt solution.

All eyes were treated with 0.5% moxifloxacin hydrochloride ophthal mic solution four times daily for one week after PRK. Further, 1% prednisolone acetate ophthalmic suspension was administered as one drop four times daily for the first week, three times daily for the second week, twice daily for the third week, and once daily for the last week. In addition, artificial tears were used four to eight times a day as needed after surgery. Bandage contact lenses were worn for five to seven days after surgery.

STaTISTICal aNalySIS

Statistical analysis was performed with SPSS version 20.0 software (SPSS, Inc, Chicago, IL). All datasets were tested for normality using the Kolmogorov-Smirnov test. Data are expressed as the mean ± stan-dard deviation. All data were normally distributed. The compa rison of pre-and postoperative straylight values was performed using the paired t-test, and differences between the groups were determined by the independent t-test. Correlations between ocular straylight, wavefront error, and spherical equivalent values were investigated using Pearson’s correlation analysis. A p-value of <0.05 was considered to be statistically significant.

ReSULTSA total of 46 eyes of 26 patients (21 women and 5 men) were

enrolled into the study. The mean age was 30 ± 4 years (range, 25-45 years); the mean myopic error was 1.96 ± 0.69 diopters (D) (range, -0.75 – -3.00); the mean astigmatism was 0.43 ± 0.42 D (range, 0-1.00 D); the mean spherical equivalent was -2.2 ± 0.75 D (range, 1.00-3.50 D). PRK surgery without MMC was performed in 21 eyes of 12 patients and PRK surgery with topical 0.02% MMC was performed in 25 eyes of 14 patients. The demographic and baseline clinical cha racte ristics of the patients stratified by the application of MMC are provided in table 1.

The mean preoperative intraocular straylight values were 1.07 ± 0.10 log(s) and 1.07 ± 0.11 log(s) in the PRK without MMC and PRK with topical MMC groups, respectively. During postoperative follow-up, all patients had complete epithelial healing within 5 to 7 days after surgery, and no late haze was noted after the first month. Values on pre-and postoperative ocular straylight, wavefront error, and spherical equivalent in both PRK groups are summarized in table 2. At two months after surgery, there was a decrease in the mean intraocular straylight values in both groups compared with those at baseline; however, a significant difference was observed only in the PRK with MMC group (p=0.002) and not in the PRK without topical MMC group (p=0.082). At four months after surgery, there was an increase in straylight in the PRK with topical MMC group when compared with the

Intraocular straylight before and after low myopic photorefractive keratectomy with and without mitomycin C

90 Arq Bras Oftalmol. 2016;79(2):88-91

two-month value; however, it failed to reach a significant difference (p=0.107). In the PRK without topical MMC group, the intraocular straylight value remained unchanged at four months when compa-red with the two-month value after surgery (p=0.74). In addition, at four months postoperatively, ocular straylight values were not signi-ficantly different compared with those at baseline in the PRK without MMC group (p=0.26) or the PRK with topical MMC group (p=0.13).

Regarding wavefront analyses, there was a trend toward increa-sing higher-order aberration (HOA) in both groups after surgery (Table 2) (p=0.074, PRK without MMC group at four months after sur-gery compared with baseline; p=0.037, PRK with MMC group at four months after surgery compared with baseline). However, between the groups, HOA values were not statistically significant different at any time point. Finally, no correlation was found between ocular straylight and wavefront error values and between ocular straylight values and spherical equivalent correction.

DISCUSSIOnThe current study revealed that low myopic PRK correction tends

to decrease ocular straylight values either with or without topical MMC application. In addition, straylight reduction was more pro-nounced in the early postoperative period at 2 months after PRK with MMC treatment. At four months after refractive surgery, however, such reduction was not significantly different in any of the two groups

compared with baseline values. To the best of our knowledge, no prior study has evaluated the impact of topical MMC on ocular straylight after PRK surgery.

Many structures are involved in the generation and modulation of ocular straylight, including the cornea, lens, iris, and intraocular media(21). Light scattered by lenses tends to increase with age and in-creases with cataract(19). Corneal scattered light is relatively constant(22), although it may change after corneal refractive procedures(21). Con-sidering other corneal factors that might also affect ocular straylight, Li and Wang(21) reported that central corneal thickness and anterior chamber depth have no significant association with ocular straylight.

Our findings are in agreement with previous studies that have also shown a decrease in postoperative ocular straylight values after refractive surgery(23,24). Lapid-Gortzak et al.(24) found a decrease in ocular straylight values at three months after laser in situ keratomi-leusis (LASIK) and laser-assisted subepithelial keratectomy for myopic correction. In that study, the authors referred to ocular straylight as a parameter of corneal clarity and suggested that it is correlated to the stromal cellular response to surgery. It has been recognized that the anterior stromal cell density decreases after PRK correction(15,25), and the depletion of keratocytes in the anterior stroma has been shown to be higher after MMC application(14). It is also known that stromal corneal fibroblasts and keratocytes contribute to the total amount of ocular light scattered(26). Thus, we believe that the observed changes in ocular straylight values in the early two-month period after PRK occurred due to a reduction of the anterior stromal cell density. In the PRK with MMC group, the effect was likely greater due to the inhibition of keratocyte replication by the drug(15). In that group, it is likely that at least partial recovery of stromal cell density at four months after surgery led to an increase in the intraocular straylight value compared with the two-month value. It could also be specula-ted that the higher reduction in straylight in the PRK with MMC group compared with that in the PRK without MMC group is related to a higher ablation depth (higher spherical equivalent correction)(18). However, a previous study failed to show any relationship between ocular straylight and ablation depth(21). In concordance with our fin-dings, other studies have shown that after an initial decrease, ocular straylight values slowly return to the preoperative state(23,24).

It is important to note that many previous studies found an increa-se in ocular straylight values after laser correction surgery. However, most of these investigations were based on LASIK surgery where corneal flap creation appeared to be a critical factor in increases in ocular straylight(20,21). Flap generation may lead to microfolds and par-ticles at the interface(27), which may contribute to increased ocular straylight. According to Wallau and Campos(28), eyes undergoing PRK with MMC have less higher-order aberrations and better contrast sensitivity than LASIK eyes when the level of correction is similar in both groups, emphasizing the role of the corneal LASIK flap in the quality of vision. Moreover, the level of myopic correction in previous studies was also higher(21,29), which is likely to trigger a more exube-rant wound healing response, possibly associated with generation of

Table 1. Demographic and baseline clinical data of patients in the photorefractive keratectomy (PRK) without topical mitomycin (MMC) group and the PRK with topical MMC group

Treatment group

p-valuePRK without MMC PRK with MMC

Patients (n) 12 14

Sex 11F/1M 10F/4M

Eyes (n) 21 25

Age (years) 30 ± 4 (25-34) 30 ± 5 (25-56) 0.067

Preop myopia (D)

Mean ± SD -1.47 ± 0.47 -2.37 ± 0.56 0.001

Range -0.75 to -2.0 -1.25 to -3.0

Preop astigmatism (D)

Mean ± SD -0.26 ± 0.36 -0.59 ± 0.42 0.002

Range 0 to -1.00 0 to -1.00

Preop mean keratometry (D) 42.78 ± 1.98 43.74 ± 1.24 0.072

Low-mesopic pupil size (mm) 06.02 ± 0.50 06.02 ± 00.7 0.085

Total of HOA 0.33 ± 0.10 0.32 ± 0.07 0.079

F= female; M= male; D= diopter; HOA= higher-order aberration.

Table 2. Mean values ± standard deviations of pre-and postoperative intraocular straylight [log(s)] values, wavefront error (µm), and spherical equivalent (D) after photorefractive keratectomy (PRK) without topical mitomycin C (MMC) and PRK with topical MMC

Intraocular straylight Wavefront error Spherical equivalent

PreopPostop Postop

PreopPostop Postop

PreopPostop Postop

2 months 4 months 2 months 4 months 2 months 4 monthsPRK without MMC 1.07 ± 0.10 1.03 ± 0.13 1.02 ± 0.14 0.33 ± 0.10 0.417 ± 0.127 0.388 ± 0.106 -1.63 ± 0.57 -0.37 ± 0.41 -0.05 ± 0.31

PRK with MMC 1.07 ± 0.11 0.98 ± 0.09 1.02 ± 0.11 0.32 ± 0.07 0.387 ± 0.064 0.412 ± 0.083 -2.66 ± 0.54 -0.30 ± 0.83 -0.05 ± 0.34

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myofibroblasts and greater production of disorganized extracellular matrix as well as activated keratocytes (corneal fibroblasts), thus in-creasing ocular straylight. There are several reports(13,30) of haze as a cause of increased straylight, and we agree that the development of moderate-to-severe haze is an important factor(24). In the present study, the overall low myopic correction, with and without MMC application, likely led to the faster recovery of corneal transparency.

Study limitations include the relatively small number of eyes inclu-ded in each group and the lack of ultrastructural assessment.

At four months postoperatively, which is a relatively short follow-up period, the straylight values in both the PRK with MMC group and the PRK without MMC group were similar; hence, the use of topical MMC is not likely to influence the quality of vision with regard to straylight.

Further long-term follow-up studies with confocal microscopy could advance our understanding of factors contributing to ocular straylight after laser corneal surgery(21). The present study shows that low myopic PRK correction, decreased ocular straylight at two months after surgery, and topical MMC application likely contribute to ocular straylight reduction. However, at four months after PRK surgery, this reduction appears to not be substantial. The role of ocular straylight in overall patient satisfaction following corneal laser surgical procedures remains to be elucidated.

RefeRenCeS 1. Alio JL, Muftuoglu O, Ortiz D, Artola A, Perez-Santonja JJ, de Luna GC, et al. Ten-year

follow-up of photorefractive keratectomy for myopia of less than -6 diopters. Am J Ophthalmol. 2008;145(1):29-36. Comment in: Am J Ophthalmol. 2008;145(1):1-2. Am J Ophthalmol. 2008;145(6):1109-10; author reply 1110.

2. Fan-Paul NI, Li J, Miller JS, Florakis GJ. Night vision disturbances after corneal refractive surgery. Surv Ophthalmol. 2002;47(6):533-46.

3. Myrowitz EH, Chuck RS. A comparison of wavefront-optimized and wavefront-guided ablations. Curr Opin Ophthalmol. 2009;20(4):247-50.

4. Hammond SD Jr, Puri AK, Ambati BK. Quality of vision and patient satisfaction after LASIK. Curr Opin Ophthalmol. 2004;15(4):328-32.

5. van den Berg TJ, Franssen L, Kruijt B, Coppens JE. History of ocular straylight measure-ment: A review. Z Med Phys. Feb 2013;23(1):6-20.

6. Barreto J Jr, Barboni MT, Feitosa-Santana C, Sato JR, Bechara SJ, Ventura DF, et al. In-traocular straylight and contrast sensitivity after contralateral wavefront-guided LASIK and wavefront-guided PRK for myopia. J Refract Surg. 2010;26(8):588-93.

7. van der Meulen IJ, Engelbrecht LA, van Vliet JM, Lapid-Gortzak R, Nieuwendaal CP, Mourits MP, et al. Straylight measurements in contact lens wear. Cornea. 2010;29(5): 516-22.

8. Aslam TM, Haider D, Murray IJ. Principles of disability glare measurement: an ophthal-mological perspective. Acta Ophthalmol Scand. 2007;85(4):354-60.

9. Jester JV, Moller-Pedersen T, Huang J, Sax CM, Kays WT, Cavangh HD, et al. The cellular basis of corneal transparency: evidence for ‘corneal crystallins’. J Cell Sci. 1999;112(Pt 5): 613-22.

10. Netto MV, Mohan RR, Sinha S, Sharma A, Dupps W, Wilson SE. Stromal haze, myofibro-blasts, and surface irregularity after PRK. Exp Eye Res. 2006;82(5):788-97.

11. Torricelli AA, Singh V, Agrawal V, Santhiago MR, Wilson SE. Transmission electron mi-croscopy analysis of epithelial basement membrane repair in rabbit corneas with haze. Invest Ophthalmol Vis Sci. 2013;54(6):4026-33.

12. Wilson SE. Corneal myofibroblast biology and pathobiology: generation, persistence, and transparency. Exp Eye Res. 2012;99:78-88.

13. Veraart HG, van den Berg TJ, Hennekes R, Adank AM. Stray light in photorefractive keratectomy for myopia. Doc Ophthalmol. 1995;90(1):35-42.

14. Netto MV, Mohan RR, Sinha S, Sharma A, Gupta PC, Wilson SE. Effect of prophylactic and therapeutic mitomycin C on corneal apoptosis, cellular proliferation, haze, and long-term keratocyte density in rabbits. J Refract Surg. 2006;22(6):562-74.

15. Mohan RR, Hutcheon AE, Choi R, Hong J, Lee J, Mohan RR, et al. Apoptosis, necrosis, proliferation, and myofibroblast generation in the stroma following LASIK and PRK. Exp Eye Res. 2003;76(1):71-87.

16. Franssen L, Coppens JE, van den Berg TJ. Compensation comparison method for assessment of retinal straylight. Invest Ophthalmol Vis Sci. 2006;47(2):768-76.

17. Coppens JE, Franssen L, van Rijn LJ, van den Berg TJ. Reliability of the compensation comparison stray-light measurement method. J Biomed Opt. 2006;11(3):34027.

18. Lapid-Gortzak R, van der Linden JW, van der Meulen IJ, Nieuwendaal CP, Mourits MP, van den Berg TJ. Straylight before and after hyperopic laser in situ keratomileusis or laser-assisted subepithelial keratectomy. J Cataract Refract Surg. 2010;36(11):1919-24.

19. Van Den Berg TJ, Van Rijn LJ, Michael R, Heine C, Coeckelbergh T, Nischler C, et al. Straylight effects with aging and lens extraction. Am J Ophthalmol. 2007;144(3):358-63.

20. Wang Y, Li J, Liu Y, Xie L. Intraocular straylight after thin-flap LASIK with a femtosecond laser versus a mechanical microkeratome. J Refract Surg. 2013;29(8):534-9.

21. Li J, Wang Y. Characteristics of straylight in normal young myopic eyes and changes before and after LASIK. Invest Ophthalmol Vis Sci. 2011;52(6):3069-73.

22. JK IJ, de Waard PW, van den Berg TJ, de Jong PT. The intraocular straylight function in 129 healthy volunteers; dependence on angle, age and pigmentation. Vision Res. 1990;30(5):699-707.

23. Lorente-Velazquez A, Nieto-Bona A, Collar CV, Gutierrez Ortega AR. Intraocular straylight and contrast sensitivity (1/2) and 6 months after laser in situ keratomileusis. Eye Contact Lens. 2010;36(3):152-5.

24. Lapid-Gortzak R, van der Linden JW, van der Meulen I, Nieuwendaal C, van den Berg T. Straylight measurements in laser in situ keratomileusis and laser-assisted subepithe-lial keratectomy for myopia. J Cataract Refract Surg. 2010;36(3):465-71.

25. Erie JC, Patel SV, McLaren JW, Hodge DO, Bourne WM. Corneal keratocyte deficits after photorefractive keratectomy and laser in situ keratomileusis. Am J Ophthalmol. 2006; 141(5):799-809.

26. Moller-Pedersen T, Cavanagh HD, Petroll WM, Jester JV. Stromal wound healing ex-plains refractive instability and haze development after photorefractive keratectomy: a 1-year confocal microscopic study. Ophthalmology. 2000;107(7):1235-45.

27. Charman WN. Mismatch between flap and stromal areas after laser in situ keratomi-leusis as source of flap striae. J Cataract Refract Surg. 2002;28(12):2146-52.

28. Wallau AD, Campos M. Photorefractive keratectomy with mitomycin C versus LASIK in custom surgeries for myopia: a bilateral prospective randomized clinical trial. J Refract Surg. 2008;24(4):326-36.

29. Nieto-Bona A, Lorente-Velazquez A, Collar CV, Nieto-Bona P, Mesa AG. Intraocular straylight and corneal morphology six months after LASIK. Curr Eye Res. 2010;35(3): 212-9.

30. Beerthuizen JJ, Franssen L, Landesz M, van den Berg TJ. Straylight values 1 month after laser in situ keratomileusis and photorefractive keratectomy. J Cataract Refract Surg. May 2007;33(5):779-83.

Original Article

92 Arq Bras Oftalmol. 2016;79(2):92-5 http://dx.doi.org/10.5935/0004-2749.20160028

InTRODUCTIOnIntraocular pressure (IOP) and central corneal thickness (CCT) have

been measured in term and pre-term newborns in previous studies, and are well-documented(1-5). However, no data are available on the effect of the mode of delivery on IOP and CCT or on the changes in these in the first hours of life. Birth itself, and particularly the duration of active labor until vaginal delivery (VD), is the main stressor for the infant during the peripartum period(6). This stress results in higher plasma catecholamine levels, grades of excitability, and heart rates in vaginally delivered infants(7-9). In previous adult and animal studies, physical and emotional stress have also been shown to induce eleva-tion in IOP(10-11). Thus, IOP in vaginally-delivered infants might also be affected by delivery stress.

CCT in newborns decreases during the first days of life(1,2), and the corneal endothelium is primarily responsible for the pump function.

Previous studies of mouse corneas have demonstrated that the pump function of the corneal endothelium can be enhanced by dexametha-sone(12,13). During VD, stress increases the plasma levels of catechola-mines(14-16). This increment may also activate the corneal endothelial pump system and result in thinner corneas in vaginally-delivered infants. The effect of gender on CCT in newborns has been evaluated previously, and corneas in male newborns have been found to be thicker than corneas in female newborns(1). However, the effect of gender on IOP and CCT in the first hours of life has not been analyzed.

The gold standard for IOP measurement is Goldmann applana-tion tonometry, and in many studies the measured IOP has been de-monstrated to vary with CCT(17-19). In recent studies, Tono-Pen XL and iCare have been recommended for obtaining accurate IOP measure-ments of edematous corneas(20). These methods were presumed to be less dependent on CCT due to the smaller area of applanation(21).

The effects of delivery type and gender on intraocular pressure and central corneal thickness in newbornsOs efeitos do tipo de parto e sexo sobre a pressão intraocular e espessura corneana central em recém-nascidos

zeYneP gursel ozkurt1, selahattın balsak2, berrın balsak3, hanDe guclu4, muhammeD sahın1, harun Yuksel1, fatıh m. turkcu1

Submitted for publication: August 24, 2015 Accepted for publication: January 14, 20161 Ophthalmology Department, Dicle University of Medicine, Diyarbakir, Turkey.2 Diyarbakir Education and Research Hospital, Diyarbakir, Turkey.3 Obstetrics and Gynecology Department, Diyarbakir Women’s and Children’s Diseases Hospital,

Diyarbakir, Turkey.4 Ophthalmology Department, Trakya University of Medicine, Edirne, 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: Zeynep Gursel Ozkur. E-mail: drzeynepgursel@gmail.com

Approved by the following research ethics committee: Dicle University Medical Faculty Ethics Committee for Non-Interventional Studies (August 27, 2013 #474).

ABSTRACTPurpose: To analyze intraocular pressure (IOP) and central corneal thickness (CCT) in newborns during the first 12 h of life. Methods: Forty-three newborns born by vaginal delivery (VD) and 30 newborns born by cesarean section (CS) were evaluated. IOP and CCT were measured using Tono-Pen and handheld pachymeter, respectively, at both the 5th minute after delivery and at the 12th h of life. Results: The mean IOP for the VD group was significantly higher than that of the CS group at both the 5th minute and 12th h (p=0.042 and p=0.018, respectively). In both groups, the IOP decreased by the 12th h, but the decrease was only significant for the CS group (p=0.020). The decrease in CCT over the 12 h was significant for both groups (p<0.001). In the VD and CS groups, the IOP values of the males were significantly higher than those of the females at the fifth minute only (p=0.024 and p=0.043, respectively). No other values were significantly different between the genders. Conclusions: Newborn IOP is affected by the mode of delivery and gender. A higher IOP was found in vaginally delivered newborns than in CS newborns for at least 12 h postpartum. CCT showed a significant decline within 12 h. Male newborns have significantly higher IOP values in the first minutes of life.

Keywords: Cesarean section; Delivery, obstetric; Intraocular pressure; Cornea/ana-tomy & histology; Infant; Newborn

RESUMOObjetivos: Analisar a pressão intraocular (IOP) e a espessura corneana central (CCT ) em recém-nascidos durante as primeiras 12 horas de vida. Método: Quarenta e três recém-nascidos nascidos por parto vaginal ( VD) e 30 re-cém-nascidos nascidos após cesariana (CS) foram avaliados. IOP e CCT foram medidos com Tono-Pen e Handheld Pachymeter no quinto minuto após o parto e na décima segunda hora de vida. Resultados: A média de IOP para o grupo VD foi significativamente maior do que o grupo CS tanto no quinto minuto quanto na décima segunda hora (p=0,042, p=0,018, respectivamente). Em ambos os grupos, a IOP diminuiu na décima segunda hora, mas a redução foi significativa apenas para o grupo CS (p=0,020). A diminuição da CCT nas doze horas foi significativa para ambos os grupos (p<0,001). Nos grupos VD e CS os valores de IOP dos homens foram significativamente maiores do que das mulheres apenas no quinto minuto (p=0,024 e p=0,043, respectivamente). Outros valores não foram significativamente diferentes entre os sexos. Conclusões: A IOP em recém-nascidos é afetada pela via de parto e pelo sexo. A IOP é maior em recém-nascidos de parto normal durante pelo menos 12 horas. A CCT mostra queda significativa no prazo de 12 horas. Recém-nascidos do sexo masculino têm valores de IOP significativamente mais elevados nos primeiros minutos de vida.

Descritores: Cesárea; Parto obstétrico; Pressão intraocular; Córnea/anatomia & his-tologia; Recém-nascido

Ozkurt ZG, et al.

93Arq Bras Oftalmol. 2016;79(2):92-5

In newborns, corneas are edematous, so the Tono-Pen is a suitable instrument for measuring IOP.

In this study, we prospectively studied the behavior of IOP and CCT in newborns in terms of their delivery type and gender. Our aim was to establish a standard of normality of IOP and CCT of newborns in the first 12 h of their lives.

MeTHODSThis study was approved by the institutional review board of the

hospital, and adhered to the tenets of the Declaration of Helsinki. In this prospective study, 43 right eyes of 43 infants born by VD and 30 right eyes of 30 infants born after elective cesarean section (CS) by epidural anesthesia at Diyarbakir Women’s and Children’s Diseases Hospital, were evaluated. Parental consent was obtained after the purpose and risks of the study had been fully explained.

The inclusion criteria included: infants with a gestational age between 37 and 41 weeks according to Dubowitz assessment (a method of clinical assessment in newborns from birth until five days old that includes neurological criteria for the infant’s maturity and other physical criteria to determine gestational age), and with a birth weight between 2500 g and 4000 g. Further, in the VD group, infants presented cephalically, and in the CS group, infants born after electi-ve operations, were included. The exclusion criteria were as follows: ocular abnormalities resulting in a negative red reflex; corneal and iris alterations; familial congenital glaucoma; maternal major organ dysfunction or a syndrome that can affect IOP; and complicated or assisted deliveries, general anesthesia, and the mother being given anesthetic drugs in addition to epidural anesthesia.

The ophthalmological examination included an external exami-nation, testing of pupil reactivity, and visualization of the red reflex. Measurements were performed using the smallest wire lid speculum under topical anesthesia (proparacaine hydrochloride 0.5%) in a supi-ne position. The right eyes of all the newborns were measured by the same operator. The newborn was given time to become accustomed to the speculum (quiet and still) to avoid a Valsalva-like effect. IOP and CCT were measured centrally immediately after the delivery at the fifth minute and at the 12th h of the postpartum period. IOP was deter-mined using the Tono-Pen AVIA (TPA; Reichert Inc., Depew, NY, USA). The TPA displays the mean of 10 independent readings, along with a statistical confidence index. Each series of measurements was per-formed three times, and the mean was taken into account. The mean of the measurements was accepted with a confidence index of 95%, which represents very reliable measurements. CCT was determined using the Palm Scan AP2000 Handheld Pachymeter (Micromedical Devices, Inc., Englewood, CO, USA), by determining the mean of four independent readings.

Statistical calculations were performed using the SPSS 15.0 sta-tistical package (SPSS for Windows, Chicago, IL, USA). All data are presented as the mean ± standard deviation. The distribution of the data was analyzed using the Kolmogorov-Smirnov test, and the distri-butions of IOP and CCT were found to be normal; therefore, pa rametric tests were used. Qualitative data were evaluated using the paired

samples t-test and the independent samples t-test. The Pearson test was used for correlation analysis, and a p-value of <0.05 was regarded as statistically significant.

ReSULTSIn this study, 43 right eyes of 43 infants (28 girls, 15 boys, ratio:

1.86) born by VD and 30 right eyes of 30 infants (18 girls, 12 boys, ratio: 1.5) born by CS, were evaluated. In the VD group, the mean gestational age at birth was 38.4 ± 0.63 weeks (range: 37-41 weeks), and the mean birth weight was 3199 ± 329 g (range: 2700-3900 g). In the CS group, the mean gestational age at birth was 38.4 ± 0.62 weeks (range: 37-40 weeks), and the mean birth weight was 3290 ± 349 g (range: 2770-4000 g). Differences between the two groups in terms of gestational age, birth weight, and gender were not statistically sig-nificant (p=0.957, p=0.388, and p=0.656, respectively). The mean IOP and CCT values for both groups at the fifth minute and at the 12th h of the postpartum period are shown in table 1. The independent samples t-test was used to compare the IOP and CCT values between the VD and CS groups. The IOP values of the VD group were signifi-cantly higher than those of the CS group, both at the fifth minute and at the 12th h of the postpartum period (p=0.042 and p=0.018, respectively). In the CS group, the IOPs of five newborns were above 21 mmHg at the fifth minute (range: 31-23 mmHg), and the IOP of two of these infants (40%) remained above 21 mmHg at the 12th h (23 and 28 mmHg). In the VD group, the IOPs of 16 newborns were above 21 mmHg at the fifth minute (range: 43-22 mmHg), and the IOP of five of these infants (31.25%) remained above 21 mmHg at the 12th h (range: 35-22 mmHg). The CCT differences between the two groups were not statistically significant (p=0.188 and p=0.075, respectively). We analyzed the changes in IOP and CCT between the fifth minute and 12th h in both groups, using the paired samples t-test. The CCT values for both the VD and CS groups declined significantly (p<0.001 for both groups). In the VD group, the IOP appeared to be decreased, but the difference was not statistically significant (p=0.120). Con-versely, IOP decreased significantly in the CS group (p=0.020). We analyzed the correlations between the IOP and CCT values in both delivery groups at both measurement times. In the VD group, a weak correlation was found at the fifth minute and 12th h (p=0.006, r=0.416 and p=0.000, r=0.538, respectively). However, in the CS group, no correlation was found at the fifth minute and 12th h (p=0.870, r=-0.031 and p=0.665, r=0.082, respectively).

In the VD and CS groups, we also evaluated the effect of gender on IOP and CCT both at the fifth minute and at the 12th h of the postpar-tum period. The VD group values are shown in table 2, while the CS group values are shown in table 3. In the VD and CS groups, the IOP values of the males were significantly higher than those of the fema-les at the fifth minute (p=0.024 and p=0.043, respectively). When the delivery type was not taken into account, at the fifth minute all of the males’ IOP was again significantly higher than that of the females (p=0.003). In the VD and CS groups, at the fifth minute, the CCT values of the males were not significantly different to those of the females (p=0.091 and p=0.841, respectively). Further, when the delivery

Table 1. IOP and CCT values of the VD- and CS-delivery groups at the fifth minute and at the 12th hour of the postpartum period

Measurement time Delivery type newborn numbers Mean IOP ± SD (mmHg) IOP range (mmHg) Mean CCT ± SD (µm) CCT range (µm)

5th min VD 43 21.6 ± 6.2 13-45 681 ± 55 535-789

CS 30 18.9 ± 4.6 12-31 703 ± 86 556-916

12th h VD 43 19.8 ± 5.6 11-35 595 ± 53 510-721

CS 30 16.9 ± 4.2 09-28 623 ± 80 500-820

IOP= intraocular pressure; CCT= central corneal thickness; VD= vaginal delivery; CS= cesarean section; SD= standard deviation.

The effects of delivery type and gender on intraocular pressure and central corneal thickness in newborns

94 Arq Bras Oftalmol. 2016;79(2):92-5

type was not taken into account, there was no significant differen-ce of the CCT values between the genders (p=0.360). At the 12th h, IOP values between the genders were not significantly different in the VD group, CS group, or in all of the studied newborns (p=0.386, p=0.107, and p=0.155, respectively). Similarly, at the 12th h, the CCT values between the genders were not significantly different in the VD group, CS group, or all of the studied newborns (p=0.055, p=0.811, and p=0.225, respectively).

DISCUSSIOnIn recent studies, IOP and CCT have been evaluated in pre-term

and full-term newborns. However, to the best of our knowledge, CCT and IOP values immediately after birth and after 12 h have not been studied. Therefore, the current study is the first to report the effect of the mode of delivery and gender on IOP and CCT in the first 12 h of life.

Active labor is the main cause of stress for infants during the pe ripartum period(6). The final effectors of physical and emotional stresses during birth are glucocorticoids and the main actors are ca techolamines such as adrenaline and noradrenaline. Previously published studies have shown that plasma catecholamine levels of infants born by CS are lower than those of infants born by VD(6,7). Another study identified a significant correlation between a lower plasma level of noradrenaline and poor muscle tone and/or lower grade of excitability in infants born by CS compared to infants born by VD(8). In the first minutes of life, higher heart rates have also been reported in infants born by VD compared to infants born by CS(9). Psychological stress is known to induce elevated IOP in adults(10). In our study, IOP values were significantly higher in the VD group than in the CS group at the fifth minute. The psychological stress of VD may be the cause of the higher IOP.

In the present study, IOP was also measured at the 12th h of the postpartum period. Although the IOP had decreased by the 12th h in both groups, the IOP values of the VD group were still significantly higher than those of the CS group. In a previous study, infant saliva cortisol levels were examined 72 h after birth, and higher levels were observed in the VD group than in the CS group(6). The study demons-trated that the effects of delivery stress continue for at least 72 h

postpartum. Therefore, the higher IOP in the VD group at the 12th h may have been the result of sustained higher cortisol levels.

Fetuses delivered vaginally are at greater risk of head compres-sion than those delivered by CS. The direct physical effect of vaginal birth may be the reason for this increment in IOP. Further, the in tra-cranial major venous system may be affected by the increased pres-sure around it due to the thin wall structure of the venous vessels. The effect of the mode of delivery on cerebral hemodynamics has been discussed in previous studies(22,23). Moreover, similar changes of cerebral hemodynamics have been observed in newborns delivered by VD and CS(24). Additionally, no correlation was found between the duration of labor and venous and arterial Doppler indices and ve-locities(25). These data support our theory of hormonal effects on the IOP of newborns.

In our study, at the fifth minute, IOP of males was found to be sig-nificantly higher than that of females in both delivery groups. In a pre-vious study, IOP was measured in 150 newborns between 12 and 24 h after birth, and again no significant difference was found between the genders(4). This result is similar to the results of our study, because in our study the difference between the genders was only significant at the fifth minute. At the 12th h, however, while the males’ mean IOP values appeared to be higher than those of the females in both de-livery groups, the differences were not statistically significant. As far as we know, none of the studies researching delivery stress, cerebral hemodynamics, and the IOP of newborns have evaluated the effect of gender. Further investigation is necessary to understand the reason for the higher IOP values in males.

Newborn CCT has also been evaluated in recent studies. The earliest measurements in the literature were performed at 6 h postpartum without grouping the newborns according to delivery type. The mean CCT was 647 ± 61 μm at 0-6 h postpartum and 611 ± 72 μm at 7-12 h postpartum(1). For both groups, our results were higher than those of the previous study at 0-6 h postpartum, most likely due to our earlier measurement time. The effect of gender on the CCT of newborns was evaluated in the same study, at six days postpartum. In males, the mean CCT was 631 ± 67 μm in the right eyes and 630 ± 65 μm in the left eyes, while in females, these values were 601 ± 52 μm in the right eyes and 559 ± 49 μm in the left eyes; the difference between the genders was statistically significant(1). In another study,

Table 2. IOP and CCT values of both genders at the fifth minute and at the 12th h of the postpartum period in the VD group

Measurement time Gender newborn numbers Mean IOP ± SD (mmHg) IOP range (mmHg) Mean CCT ± SD (µm) CCT range (µm)

5th min Female 28 20.1 ± 5.1 13-32 670 ± 51 535-752

Male 15 24.5 ± 7.0 17-43 700 ± 58 584-789

12th h Female 28 19.3 ± 5.0 11-32 582 ± 42 510-664

Male 15 20.9 ± 6.8 12-35 619 ± 63 518-721

IOP= intraocular pressure; CCT= central corneal thickness; SD= standard deviation; VD= vaginal delivery.

Table 3. IOP and CCT values of both genders at the fifth minute and at the 12th h of the postpartum period in the CS group

Measurement time Gender newborn numbers Mean IOP ± SD (mmHg) IOP range (mmHg) Mean CCT ± SD (µm) CCT range (µm)

5th min Female 18 17.3 ± 3.3 12-25 699 ± 75 556-916

Male 12 21.1 ± 5.4 16-31 705 ± 94 559-864

12th h Female 18 15.9 ± 3.6 12-23 626 ± 81 513-820

Male 12 18.4 ± 4.7 09-28 618 ± 82 500-817

IOP= intraocular pressure; CCT= central corneal thickness; SD= standard deviation; CS= cesarean section.

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the effect of gender was evaluated again at six days postpartum. The mean CCT of the males was again found to be higher than that of the females, but the difference was not significant(2). In our study, although the differences did not reach statistical significance, in the VD group the males’ mean CCT at both times was higher than that of the females. In the CS group, the differences between the genders were negligible. In the previous studies mentioned above, the de-livery type was not taken into account. If the newborns had been grouped according to delivery type, the results could have been more significant in the VD groups.

Previous studies have reported a decline in CCT in newborns during the first days of life(1,2). In our study, this decrease was highly significant in both the VD and CS groups. This decline is thought to be due to improving control of corneal hydration, evaporation, and cor-neal remodeling over time (2,5). Prolonged eye closure may explain the thicker corneas during the first days of life. Infants are known to have physiologic intracellular fluid excess and, after birth, sudden fluid efflux occurs from the intracellular compartment to the extracellular compartment(26). In addition to prolonged eye closure, physiologic in-tracellular fluid excess might be the cause of the edematous cornea.

The respiratory outcome in newborns is linked to fetal maturity and the mode of delivery. Infants delivered by CS have a higher inci-dence of respiratory distress than vaginally delivered infants. Active Na+ transport across the pulmonary epithelium drives liquid from the lung lumen to the interstitium, and labor is critical for the activation of the Na+ pump system. There is considerable evidence that high levels of endogenous catecholamines at birth may be important for accelerating alveolar fluid clearance by increasing its activity(27). In our study, although the differences were not statistically significant, the mean CCT was higher for the CS group than for the VD group both at the fifth minute and at the 12th h. The Na+- and K+-dependent ATPase (Na+/K+-ATPase) expressed in the basolateral membrane of corneal endothelial cells is primarily responsible for the pump function of the corneal endothelium. In two different studies of mouse corneal en-dothelial cells, dexamethasone was shown to increase Na+/K+-ATPase activity and pump function(12,13). We suggest that, like the pulmonary epithelium Na+ transport system, the corneal endothelial pump func-tion may be induced by higher endogenous plasma catecholamine levels in vaginally-delivered infants, causing thinner CCT values in the VD group than in the CS group.

To measure IOP and CCT in newborns, a protocol based on the experiences documented in previous studies was used. A previous study reported that the use of the Alfonso eyelid speculum in chil-dren can falsely elevate IOP by 4 mmHg(28). Further, topical anesthe-tics have been found to affect IOP and CCT readings(29,30). Therefore, the use of a speculum and topical anesthetic drops are limitations of our study. The small number of cases involved in our study is another limitation. Since the international gold standard for IOP measure-ment is Goldmann applanation tonometry, the use of a Tono-Pen in our study could be considered a limitation. However, Tono-Pen XL and iCare have recently been recommended for obtaining accurate IOP measurements of edematous corneas(20). These methods were presumed to be less dependent on CCT due to the smaller area of applanation(21). The duration of active labor of the deliveries was not taken into account because, in our region, most pregnant women arrive at hospital after the beginning of active labor, which is another limitation of our study.

In conclusion, IOP remains higher in vaginally-delivered infants than in infants delivered by CS for at least 12 h postpartum. Infant CCT decreases significantly over the 12 h postpartum. Vaginally-delivered infants have thinner CCT values than infants delivered by CS. The present study establishes reference values for IOP and CCT in newborns, which could be used in the early diagnosis of congenital eye disor-ders. Additionally, these data may be useful for understanding the ocular physiology of newborns. Further studies are needed to clarify the possible effects on IOP and CCT in newborns.

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Original Article

96 Arq Bras Oftalmol. 2016;79(2):96-9 http://dx.doi.org/10.5935/0004-2749.20160029

InTRODUCTIOnThe incidence of retinopathy of prematurity (ROP) has shown a

marked increase due to increasing birth rates and advances within neonatal intensive care units (NICU)(1). ROP-related vision loss, also called the “third epidemic,” is more common in developed countries, and many of these countries are establishing screening programs for its management(1,2).

Turkey, which ranks 90th in the Human Development Index based on 2013 data, is one of the countries in this group(3) and is also in the high-risk group for ROP-induced blindness(4). To address this, the Turkish Ministry of Health has launched a new national program in 2011 for ROP and planned to establish diagnostic and treatment centers across the country(5). Some of these centers are only intended

as screening centers, whereas others are to offer both diagnostic and therapeutic services.

Individual countries should evaluate their screening and treatment programs at ROP diagnosis and treatment centers, serving as referral hospitals, by comparing treatment results from referred patients and non-referred patients.

In this study, we aimed to evaluate laser therapy (LT) outcomes in patients diagnosed and followed up in our clinic and referred from other centers during a three-year follow-up period.

MeTHODSMedical records of 1,856 patients who were followed up in our

clinic due to ROP between January 2011 and December 2013 were

Treatment success of laser therapy for retinopathy of prematurity in referred and non-referred patientsO sucesso do tratamento com terapia a laser para retinopatia da prematuridade em pacientes encaminhados e não encaminhados

caner kara1, İkbal Seza Petriçli1, emre Hekimoğlu1, hanDan akıl2, Özlem beYazYılDız3

Submitted for publication: September 17, 2015 Accepted for publication: December 3, 20151 Department of Ophthalmology, Etlik Zubeyde Hanim Women’s Health Education and Research

Hospital, Ankara, Turkey.2 Department of Ophthalmology, Nevsehir State Hospital, Nevsehir, Turkey.3 Department of Ophthalmology, Samsun Training and Research Hospital, Samsun, Turkey.

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

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

Corresponding author: Caner Kara. Etlik Zubeyde Hanim Women’s Health Education and Research Hospital - Department of Ophthalmology - Yeni Etlik Caddesi, 55 - Keçiören, Ankara 06010 - Turkey - E-mail: canerkara@hotmail.com

Approved by the following research ethics committee: Etlik Zubeyde Hanim Women’s Diseases Teaching & Research Hospital Institutional Review Board (# 197).

ABSTRACTPurpose: Comparison of laser therapy (LT) outcomes in patients with retinopathy of prematurity (ROP) followed up in our clinic and referred from other centers.Methods: Medical records of 1,856 ROP patients were retrospectively evaluated, and a total of 128 patients who underwent LT were included in the study. The study population was divided into the following two groups: patients who were followed up and treated in our clinic (group 1, N=45) and patients who were referred to our clinic from other centers (group 2, N=83). Data regarding birth weight, sex, gestational age, postnatal treatment time, disease localization, and stage were analyzed and compared between the two groups. Treatment success was defined by anatomic success 6 months after treatment. Results: Patients in the referred group presented with a more advanced disease (p<0.01), a lower treatment success rate (p=0.01), and a longer time interval between diagnosis and LT (p=0.04). Conclusions: The treatment success rate of ROP was significantly lower in referred patients because of the potential delay in LT and more advanced disease at the time of treatment initiation.

Keywords: Early diagnosis; Laser coagulation; Retinopathy of prematurity/diagno-sis; Treatment outcome

RESUMOObjetivos: A comparação dos resultados da terapia a laser (LT ) em pacientes com retinopatia da prematuridade (ROP) acompanhados em nossa clínica e encaminhados por outras clínicas. Método: Os arquivos de 1.856 pacientes com ROP foram analisados retrospectivamente e um total de 128 pacientes submetidos à LT foram incluídos no estudo. A população do estudo foi dividida em dois grupos; os pacientes que foram acompanhados e tratados em nossa clínica (grupo 1, n=45) e os pacientes que foram encaminhados à nossa clínica por outros centros (grupo 2, n=83). Os dados referentes a peso de nascimento, sexo, idade gestacional, tempo de tratamento pós-natal, localização e fase da doença foram analisados e comparados entre os grupos. O sucesso do tratamento foi definido pelo sucesso anatômico no sexto mês após o tratamento. Resultados: Pacientes no grupo de pacientes encaminhados apresentaram doença mais avançada (p<0,01), taxa de sucesso inferior (p=0,01) e maior intervalo de tempo entre o diagnóstico e tratamento a laser (p=0,04). Conclusões: A taxa de sucesso do tratamento da ROP é significativamente menor em pacientes encaminhados por causa de possível atraso da LT e do estágio mais avançado da doença observado.

Descritores: Diagnóstico precoce; Fotocoagulação a laser; Retinopatia da prematu-ridade/diagnóstico; Resultado do tratamento

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97Arq Bras Oftalmol. 2016;79(2):96-9

retrospectively evaluated. A total of 128 patients who underwent LT were included in the study, which was approved by the local Ethics Committee at Etlik Zübeyde Hanım Women Diseases Training and Research Hospital.

The study population comprised two groups: the first was made up by non-referred patients who were followed up and treated in our hospital (group 1, N=45), and the second group comprised patients who were referred from peripheral centers (group 2, N=83). Data regar-ding birth weight (BW), sex, gestational age (GA), and postnatal treat-ment period with disease localization and stage were retrospectively retrieved. Treatment results were evaluated in terms of anatomic success in the sixth post-treatment month according to the criteria of the Multicenter Trial of Cryotherapy of ROP (CRYO-ROP) study(6). Although a normal view of the posterior fundus was considered to be an anatomic success, retinal detachment and macular folds were considered as anatomic failures.

Screening for ROP was performed for patients who were <32 weeks old and/or had a BW of <1,500 g in the NICU department and for patients who were >32 weeks and/or had a BW of ≥1,500 g, but with unstable clinical courses such as long-term oxygen therapy, sepsis, repeated blood transfusions, and long-term mechanical ventilation. The first examinations were performed on patients who were in their postnatal 4th week; patients who were <28 weeks old were examined in the 30th and 31st weeks. Pupillary dilation prior to examination was enabled with 0.5% tropicamide drops (Tropamide 0.5%, Bilim, Turkey) and 2.5% phenylephrine drops (Mydfirin 2.5%, Alcon, USA) given 10 min apart (three times). After pupillary dilatation, binocular indirect ophthalmoscopic (Omega 2C, Heine, Germany) examination was performed using 20 and 28 D lenses with topical anesthesia obtained by instillation of 0.5% procaine hydrochloride (Alcain 0.5%, Alcon, USA). A lid speculum and scleral indentator were used to vi-sualize the peripheral retina. On each examination, the International Classification of ROP was used to denote the zone, stage, and extent of ROP, and whether “plus disease” or aggressive posterior (AP)-ROP was present in each eye(7). Patients with significantly increased arterial tortuosity and venous dilatation in at least four quadrants of zones 1 and 2 were classified as AP-ROP. Patients without ROP were exami-ned by 2-week intervals until the vascularization had reached zone 3. Patients with ROP were examined weekly, and those who were candidates for AP-ROP were examined twice a week.

Treatments were performed according to the Early Treatment for Retinopathy of Prematurity trial recommendations (which encompass thresholds) as follows: (1) zone 1, any stage with plus disease; (2) zone 1, stage 3, with or without plus disease; (3) zone 2, stage 2 or 3 with plus disease(8). Upon informed consent, peripheral retinal ablation was performed by a 810-nm transpupillary diode laser (OcuLight® SL, Iridex, USA) on both eyes of patients for whom LT was indicated. Laser applications were carried out by a physician (EH) experienced in this field under remifentanil analgesia in the NICU(9). Upon LT, topical steroids, antibiotics, and mydriatic therapy were administered to all patients. Follow-up care was conducted on postoperative day 1 and continued on a weekly basis until complete regression of ROP. Patients who did not show any improvement in extraretinal neovas-cularization and plus disease were re-evaluated for any skip area. Additional LT was carried out in the event of a skip area.

Statistical analysis was performed using SPSS v.21.0 for Windows. Continuous variables were presented as means ± SD; categorical va-riables were indicated by numbers and percentages. The chi-square test and Fisher’s exact test were used for categorical variables. Data were tested for normality using Kolmogorov-Smirnov and Shapiro-Wilk tests; between-group differences were analyzed using appropriate parametric (t-test) and non-parametric (Mann-Whitney U) tests. Pro-bability (p) values of <0.05 were considered statistically significant.

ReSULTSLaser therapy was applied to a total of 128 (6.9%) of the 1,856

pa tients who were followed up at the eye clinic due to ROP. The

number of patients by year was evaluated, and it was observed that the number of patients peaked in 2011. After that time, a reduction was observed in the number of patients (Table 1). The majority of the treatment population consisted of patients weighing <1000 g and aged <28 weeks. The distribution of BW and GA of both groups is shown in table 2.

There was no statistically significant difference between the groups in terms of gender, GA, or BW (p>0.05). The postmenstrual age of preterm patients at the time of treatment was statistically higher in group 2 (p=0.04, Mann-Whitney U test). The distribution of the number of patients and demographic characteristics of both groups are shown in tables 1 and 2.

The overall anatomic success rate was 93.8%. The anatomic success rate observed in groups 1 and 2 was 100% and 90.4%, respectively; the difference between the groups was statistically significant (p=0.01). The groups were evaluated in terms of disease stage and location, and a statistically significant difference was found with regard to disea-se stage. Stage-3 disease was significantly more common in group 2, whereas stage-2 disease was significantly more common in group 1 (p<0.01). There was no significant difference in terms of disease loca-tion between the two groups. Disease stage and location are shown in table 3.

DISCUSSIOnIn this study, we found that the treatment success rate for ROP was

significantly reduced in referred patients, which may be due to a more

Table 1. Distribution of patients by year

Yearsnon-referred patients

n (%)Referred patients

n (%) Total

2010 05 (71.4) 02 (28.6) 007

2011 23 (34.8) 43 (65.2) 066

2012 12 (33.3) 24 (66.7) 036

2013 05 (26.3) 14 (73.7) 019

Total 45 83 128

N= number.

Table 2. Demographic characteristics of referred and non-referred patients

non-referred patients

Referred patients p value

Gender, n (%) Male 26 (37.1) 44 (62.9) 0.65***

Female 19 (32.8) 39 (67.2)

Gestational age† Mean ± SD 27.2 ± 2.4 27.7 ± 2.3 0.22***

(Range) (24.00-33.00) (23.00-34.00)

Birth weight (g) Mean ± SD 963 ± 221 1021 ± 299 0.47***

(Range) (650-1600) (570-1850)

Age at treatment† Mean ± SD 36 ± 4 38 ± 3 0.02***

(Range) (32-46) (34.0-50.0)

Additional laser N (%) 1 (14.3) 06 (85.7) 0.21***

Age at additional laser treatment†

Mean ± SD 41 41.2 ± 5.3 1.00***

(Range) - (37.1-49.7)

AP-ROP N (%) 07 (28) 18 (72.0) 0.40***

Anatomic success N (%) 45 (100) 75 (90.4) 0.03***

†= weeks; SD= standard deviation; N= number of patients; *= Chi-square test; **= Mann- Whitney U test; ***= Fisher’s exact test; AP-ROP= aggressive posterior ROP.

Treatment success of laser therapy for retinopathy of prematurity in referred and non-referred patients

98 Arq Bras Oftalmol. 2016;79(2):96-9

advanced disease in these patients and a delay in the initiation of LT. Here the anatomic success rate for referred patients was 93%; however, the anatomic success rate for non-referred patients was 100%. The overall anatomic success rate in our clinic was 96.1%, and this rate is consistent with previous studies, which have reported success rates above 90%(10-15). Thus, we found a significantly better success rate in the non-referred group.

Laser photocoagulation is performed to destruct the non-vascu-larized retina, decreasing the release of angiogenic factors and subse-quent neovascular complications(16,17). Destruction of non-vascularized retina in the treatment of ROP was initially achieved with cryotherapy(6). Later, LT proved as effective as cryotherapy in the treatment of ROP, inducing less pressure and trauma to the eye, being more effective for zone-1 and -2 diseases than cryotherapy using laser(17).

Low BW and small GA are known to be risk factors for the deve-lopment of ROP(18). Many previous studies included treatment groups mainly consisting of preterm patients weighing <1000 g and aged <28 weeks(10,19-21). In our study, consistent with previous reports, the average BW and GA in patients who received treatment were 900 g and 27 weeks, respectively; although these values were higher among referred patients, they were not statistically significant. Comparing patients with similar BW and GA, the apparent worst outcomes were observed in the group of referred patients. Differences in the treatment success rates between groups could be partially explained by the presence of advanced disease and late initiation of the treatment to the referred patients.

In this study, we showed that postnatal LT was initiated to the re-ferred group only 2 weeks later than in the non-referred group. Accor-ding to the ET-ROP and CRYO-ROP study results, the threshold ROP was set to nearly 37 weeks in patients with BWs <1,251 g(8,22). In several studies, patients were treated between 34 and 37 weeks, which may be the critical time interval for the progression of the ROP(23,24). After establishing a diagnosis of ROP and identifying an indication for treat-ment, treatment should be immediately initiated. The ET-ROP study emphasized that patients who require treatment should be treated within 48 h(8). We found that treatment timing in the non-referred patient group was consistent with many previous studies and that treatment timing in the referred patient group was approximately 2 weeks later than the average of previous studies(23,24). This situation may be a factor explaining the difference in success rate between the two groups. Treatment delay may have been caused by difficulties in terms of referring patients to experienced neonatal care units.

Another outstanding difference between the two groups was the presence of a significantly higher number of stage-3 ROP patients in the referred group. Our study showed that 71% of zone-2 patients also had findings of stage-3 ROP in the referred patient group. This proportion was found to be 29% in the non-referred patient group. Despite stage-2 patients having a treatment indication, many peri-pheral centers may not refer these patients until the development of stage-3 features, which may lead to lower success rates in the referred patient group. In a similar study, Nicoara et al.(25) reported a higher incidence of zone-2 stage-3 patients in their referred patient group

than in their local follow-up patient group. In their protocol, they clo-sely observed stage-2 and zone-2 ROP with plus disease patients, and initiated prompt treatment if they reached stage 3. However, referred zone-1 and -2 patients were already at stage 3 on first examination because of delayed referral.

We evaluated the distribution of patients by year and found that the number of patients peaked in 2011, with a gradual reduction ob-served over the following years. This could be related to the establish-ment of the national screening program in 2011, which increased the awareness of ROP. After 2011, a decrease in the number of referred patients was seen in our study. We speculate that the decline is rela-ted to the establishment of peripheral treatment centers according to the national screening program. We also observed a decrease in the number of patients who sought treatment at our clinic. New re-gulations of oxygen protocols in the NICUs for preterm patients may be a cause of this decline, and this situation merits attention.

Our results showed that differences in the treatment success rates between the groups were caused by the presence of advanced disea-se and delayed treatment in referred patients. Nevertheless, for both groups, perinatal risk factors may affect the success of the treatment.

This study has some limitations: (1) the heterogeneous structure of the referred group, (2) the lack of comparisons of perinatal risk factors of the referred and non-referred patient groups, and (3) the fact that we evaluated and treated the patients ourselves; this situation may introduce bias. However, this issue could not be mitigated because of the retrospective structure of the study.

Early diagnosis and treatment of patients is the most important step to preventing ROP-induced blindness. Every country should have a policy aiming to improve neonatal care services, increase the number of the ROP screening-treatment centers, and decrease the referral rate with a view to decreasing ROP-induced blindness.

RefeRenCeS 1. Gilbert C, Rahi J, Eckstein M, O’Sullivan J, Foster A. Retinopathy of prematurity in

middle-income countries. Lancet. 1997;350(9070):12-4. 2. Gilbert C, Fielder A, Gordillo L, Quinn G, Semiglia R, Visintin P, et al. Characteristics of

patients with severe retinopathy of prematurity in countries with low, moderate, and high levels of development: Implications for screening programs. Pediatrics. 2005; 115(5):518-25.

3. United Nations Development Programme (UNDP). 2013 Human Development Report.[cited 2015 Jan 12]. Available from: http://hdr.Undp.Org/en/2013-report

4. Gilbert C. Changing challenges in the control of blindness in children. Eye (Lond). 2007;21(10):1338-43.

5. Türkiye’de Özellikli Planlama Gerektiren Sağlık Hizmetleri 2011–2023 (Turkish). Turkish Ministry of Health, general directorate of curative services publications, Ankara, 2011.[cited 2015 Jan 12]. Available from: www.Tkhk.Gov.Tr/dosyalar/4adfd685cc544ff381e2c31fc84a14a2.Pdf

6. Multicenter trial of cryotherapy for retinopathy of prematurity. Preliminary results. Cryotherapy for retinopathy of prematurity cooperative group. Arch Ophthalmol. 1988; 106(4):471-9.

7. International Committee of Classification of Retinopathy of Prematurity Revisited. Arch Ophthalmol. 2005;123(7):991-9.

8. Early Treatment for Retinopathy of Prematurity Cooperative Group. Revised indica-tions for the treatment of retinopathy of prematurity: Results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol. 2003;121(12):1684-94.

9. Demirel N, Bas AY, Kavurt S, Celik IH, Yucel H, Turkbay D, et al. Remifentanil analgesia during laser treatment for retinopathy of prematurity: A practical approach in neona-tal intensive care unit. Am J Perinatol. 2014;31(11):983-6.

10. Axer-Siegel R, Maharshak I, Snir M, Friling R, Ehrlich R, Sherf I, et al. Diode laser treat-ment of retinopathy of prematurity: Anatomical and refractive outcomes. Retina. 2008;28(6):839-46.

11. McLoone E, O’Keefe M, McLoone S, Lanigan B. Long term functional and structural ou-tcomes of laser therapy for retinopathy of prematurity. Br J Ophthalmol. 2006;90(6): 754-9.

12. Kobylarz J, Piwowarczyk A, Romanowska-Dixon B. Diode laser photocoagulation for retinopathy of prematurity-outcomes in one-year observation. Klin Oczna. 2006; 108(1-3):36-8. Polish.

13. Good WV, Carden SM. Retinopathy of prematurity. Br J Ophthalmol. 2006;90(3):254-5. 14. Essex RW, Carden SM, Elder JE. Two-year results of laser treatment for retinopathy of

prematurity at a single neonatal intensive care unit. Clin Experiment Ophthalmol. 2005; 33(4):390-4.

Table 3. Disease stage and location of the groups

non-referred patients Referred patients

p value

n (%) n (%)

Zone 1 Zone 2 Total Zone 1 Zone 2 Total

Stage 2 5 32 37 02 20 22 <0.01*

(100) (80) (82.2) (16.7) (29) (27.2)

Stage 3 0 08 08 10 49 59 <0.01*

(0) (20) (17.8) (83.3) (71) (72.8)

N= number; *= Chi-square test.

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15. Fallaha N, Lynn MJ, Aaberg TM, Jr., Lambert SR. Clinical outcome of confluent laser photoablation for retinopathy of prematurity. J AAPOS. 2002;6(2):81-5.

16. Soh Y, Fujino T, Hatsukawa Y. Progression and timing of treatment of zone i retinopa-thy of prematurity. Am J Ophthalmol. 2008;146(3):369-74.

17. O’Keefe M, Kirwan C. Screening for retinopathy of prematurity. Early Hum Dev. 2008; 84(2):89-94.

18. Avery GB, Glass P. Retinopathy of prematurity: Progress report. Pediatr Ann. 1988;17(8): 528-33.

19. Dhawan A, Dogra M, Vinekar A, Gupta A, Dutta S. Structural sequelae and refractive outcome after successful laser treatment for threshold retinopathy of prematurity. J Pediatr Ophthalmol Strabismus. 2008;45(6):356-61.

20. Wani VB, Sabti KA, Kumar N, Raizada S, Kandari JA, Harbi MA, et al. Structural and func-tional results of indirect diode laser treatment for retinopathy of prematurity from 1999 to 2003 in kuwait. Clin Ophthalmol. 2013;7:271-8.

21. Sahni J, Subhedar NV, Clark D. Treated threshold stage 3 versus spontaneously regres-sed subthreshold stage 3 retinopathy of prematurity: A study of motility, refractive, and anatomical outcomes at 6 months and 36 months. Br J Ophthalmol. 2005;89(2): 154-9.

22. Palmer EA. Costenbader lecture. The factor of time in retinopathy of prematurity. J AAPOS. 2006;10(6):500-6.

23. Axer-Siegel R, Snir M, Cotlear D, Maayan A, Frilling R, Rosenbaltt I, et al. Diode laser treatment of posterior retinopathy of prematurity. Br J Ophthalmol. 2000;84(12):1383-6.

24. Kieselbach GF, Ramharter A, Baldissera I, Kralinger MT. Laser photocoagulation for re-tinopathy of prematurity: Structural and functional outcome. Acta Ophthalmol Scand. 2006;84(1):21-6.

25. Nicoara SD, Cristian C, Irimescu I, Stefanut AC, Zaharie G. Diode laser photocoagula-tion for retinopathy of prematurity: Outcomes after 7 years of treatment. J Pediatr Ophthalmol Strabismus. 2014;51(1):39-45.

XIV Congresso Internacional de Catarata e Cirurgia Refrativa

X Congresso Internacional de Administração em Oftalmologia

III Congresso Internacional de enfermagem em Oftalmologia

1 a 4 de junho de 2016Parque Anhembi

São Paulo - SP

informações: Site: www.brascrs2016.com.br

Original Article

100 Arq Bras Oftalmol. 2016;79(2):100-4 http://dx.doi.org/10.5935/0004-2749.20160030

RESUMOObjetivos: Avaliar as diferenças de desempenho cognitivo entre pacientes com glau -coma primário de ângulo aberto (POAG), glaucoma de pressão normal (NTG) e controle de indivíduos saudáveis (C). Métodos: Um total de 60 pessoas (20 POAG, 20 NTG e 20 indivíduos saudáveis) foram incluídos neste estudo. Um exame oftalmológico detalhado foi realizado em todos os participantes. Um sistema de tomografia de coerência óptica de domínio espectral (SD-OCT ) foi utilizado para medir as espessuras da camada de células ganglionares plexiforme interna (GC-IPL) e da camada de fibras nervosas da retina (RNFL). Para avaliar o desempenho cognitivo de todos os participantes, foi realizado pelo mesmo neurologista um exame neurológico detalhado, incluindo mini-exame do estado mental (MMSE). Resultados: Não houve diferenças significativas entre os grupos em termos de idade (p=0,348) e sexo (p=0,935). Espessuras médias da RNFL foram significativamente di ferentes, sendo 85,2 ± 14,7, 76,8 ± 10,3 e 91,4 ± 7,7 µm nos grupos POAG, NTG e controles, respectivamente (p<0,001). As espessuras médias da GC-IPL observadas foram 77.5 ± 9.7 μm no grupo POAG, 73,4 ± 7,8 µm no grupo NTG e 78,8 ± 3,8 µm nos controlos. As diferenças entre os grupos não foram estatisticamente significantes (p=0,085). Graduações do MMSE foram 26,1 ± 1,4, 25,7 ± 2,3 e 28,8 ± 0,9 nos grupos POAG, NTG e controles, respectivamente. Houve diferenças significativas entre os três grupos (p<0,001). Houve diferença significativa entre NTG e saudáveis (p<0,001). Houve diferença significativa entre POAG e saudáveis (p=0,001). Não houve diferença significativa entre o POAG e NTG (p=0,595). Conclusões: Parecem haver fatores de risco semelhantes no glaucoma e nos distúrbios neurodegenerativos que causam deterioração no desempenho cognitivo. Comparando a baixa graduação do MMSE de pacientes com POAG e NTG com controles saudáveis referenda nossa hipótese. Consequentemente recomenda-se que um neurologista também examine os pacientes de glaucoma.

Descritores: Glaucoma de ângulo aberto; Glaucoma de baixa tensão; Transtornos cog-nitivos; Demencia

ABSTRACTPurpose: To assess cognitive performance differences among primary open-angle glaucoma (POAG) patients, normal-tension glaucoma (NTG) patients, and healthy control (C) subjects. Methods: A total of 60 participants (20 POAG, 20 NTG, and 20 C subjects) were included in this study. A detailed ophthalmologic examination was performed on all participants. A spectral domain-optical coherence tomography (SD-OCT) system was used to measure the ganglion cell-inner plexiform layer (GC-IPL) and retinal nerve fiber layer (RNFL) thicknesses. To assess the cognitive performance of all participants, detailed neurological examinations, including the mini-mental state examination (MMSE), were performed by the same neurologist. Results: There were no significant differences among the groups in terms of age (p=0.348) or gender (p=0.935). The mean RNFL thicknesses were significantly diffe rent among the groups (85.2 ± 14.7, 76.8 ± 10.3, and 91.4 ± 7.7 µm in the POAG, NTG, and C subjects, respectively; p<0.001). The mean GC-IPL thicknesses were 77.5 ± 9.7 µm in the POAG group, 73.4 ± 7.8 µm in the NTG group, and 78.8 ± 3.8 µm in the C group. Differences among the groups were not statistically significant (p=0.085). MMSE scores were 26.1 ± 1.4, 25.7 ± 2.3, and 28.8 ± 0.9 in the POAG, NTG, and C groups, respectively. There were significant differences among the three groups (p<0.001). Specifically, there were significant differences between the NTG and C groups (p<0.001), and between the POAG and C groups (p=0.001). There was no significant difference between the POAG and NTG groups (p=0.595). Conclusions: There appear to be similar risk factors in glaucoma and neurodege-nerative disorders that cause deterioration in cognitive performance. Comparing the low MMSE scores of the POAG and NTG patients with the scores of healthy C participants supports our hypothesis. Consequently, it is recommended that a neurologist should also examine glaucoma patients.

Keywords: Glaucoma, Open-angle; Low-tension glaucoma; Cognition disorders; Dementia

InTRODUCTIOnGlaucoma is characterized by a progressive loss of retinal ganglion

cells (RGCs) and atrophy of the optic nerve, leading to a characteris-tic pattern of visual field loss(1). It is the leading cause of irreversible visual loss worldwide(2), and without treatment, glaucoma can cause blindness(3). Primary open-angle glaucoma (POAG) is the most common type of glaucoma(4). While the pathogenesis of POAG is not yet known, there are several known risk factors, one of which is elevated intrao-

cular pressure (IOP)(5). To decrease the IOP with this treatment slows down the progression of the disease(1). However, visual loss may still continue despite reducing the IOP in some patients(1).

Another type of glaucoma is normal-tension glaucoma (NTG), in which there is optic nerve degeneration without IOP elevation. Patients with statistically normal IOP who develop the characteristic changes of progressive retinal nerve fiber layer (RNFL) loss, RGC loss, and visual field defects are grouped as having NTG, an important

Cognitive performance of primary open-angle glaucoma and normal-tension glaucoma patientsDesempenho cognitivo em pacientes com glaucoma primário de ângulo aberto e glaucoma de pressão normal

mehmet bulut1, aYlın Yaman2, muhammet kazım erol1, Fatma kurtuluş2, Devrım toslak1, Denız turgut coban1, ebru kaya başar3

Submitted for publication: August 24, 2015 Accepted for publication: January 7, 20161 Ophthalmology Department, Antalya Training and Research Hospital, Antalya, Turkey.2 Neurology Department, Antalya Training and Research Hospital, Antalya, Turkey.3 Department of Animal Science Biometry and Genetics Unit, Faculty of Agriculture, Akdeniz Uni-

versity, Akdeniz, 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: Muhammet Kazim ErolD. Meydan kavağı mah. Avni tolunay cad. Yerge daran sit. C blok d: 22 - Muratpaşa, Antalya - Turkey - E-mail: muhammetkazimerol@gmail.com

Approved by the following research ethics committee: Antalya Training and Research Hospital (# 2014-163).

Bulut M, et al.

101Arq Bras Oftalmol. 2016;79(2):100-4

subset of open-angle glaucoma (OAG)(6). POAG and NTG patients form the subgroups of OAG patients.

Dementia, which affects 24 million people worldwide, with dou-ble the number of affected people every 20 years, is an important health problem for the aging population(7). It is a term used to des-cribe a group of conditions that can affect a person’s ability to think, remember, understand, make judgments, communicate, and interact socially(8). Alzheimer-type dementia (ATD) is known as the most wi-despread form of dementia and is an important health problem in every country(9). It is a progressive neurodegenerative disorder cha-racterized by cognitive deterioration and deterioration in memory, changes in personality, behavioral disturbances, and impaired ability to perform the activities of daily life(10).

Glaucoma and dementia (especially ATD) share several features. Both become more severe with advanced age, and they occur more frequently in women than in men(11,12). Common genetic risk factors have been reported in ATD and glaucoma, and similar pathological changes in the optic nerves of glaucoma patients and the brains of patients with ATD have been demonstrated(13). At the molecular level, caspase activation was shown in a rat study of chronic ocular hyper-tension to induce abnormal amyloid precursor protein formation, which is the key event in the pathogenesis of ATD(14).

Both ATD and glaucoma demonstrate early structural changes in the visual cortex and lateral geniculate nucleus. Both diseases affect magnocellular visual processing(15). Spectral domain-optical coheren-ce tomography (SD-OCT) can demonstrate these early changes, so it is reasonable to use OCT when assessing for cognitive decline in glaucoma patients to analyze the possible correlations between OCT measures and cognitive parameters.

Although several clinical studies have demonstrated an increased prevalence of glaucoma in dementia patients(16), large population-based studies have not revealed an association between glaucoma and de-mentia(17). Since there have been very few studies of the relationship between glaucoma and dementia, more studies are necessary to firmly establish this relationship. Since the MMSE is one of the most frequen-tly used screening tools for the assessment of cognitive function, the aim of our study was to determine whether there are differences among the POAG, NTG, and control (C) groups in terms of MMSE scores, and also to assess the relationship between the MMSE scores and SD-OCT parameters.

MeTHODSThe study was performed in compliance with the Helsinki Decla-

ration and with the approval of the Ethics Committee of the Antalya Education and Research Hospital. A total of 60 people, including 20 POAG patients (aged between 44 and 73 years), 20 NTG patients (aged between 45 and 73 years), and 20 healthy C participants (aged between 47 and 69 years), participated in this study, and the age and gender proportions of the groups were similar. We recruited our patients in the hospital outpatient setting. C subjects meeting the inclusion criteria were recruited in the same setting from the neurology and ophthal-mology outpatient clinics. Glaucoma patients were taking at least one topical medication (beta-blockers, carbonic anhydrase inhibitors, prostaglandin analogs, sympathomimetic drugs, and parasympatho-mimetic drugs). All of our participants had graduated from elementary school. Since most of the subjects in the patient and C groups had attained this level of education, illiterate subjects and high school and university graduates were excluded to provide homogeneity. The majority of the subjects were on a similar level of socioeconomic sta-tus. Patients who had neurological diseases that could have affected cognitive performance, such as ATD, vascular dementia, and mild cog-nitive impairment (MCI), were excluded from this study. None of the patients had subjective complaints concerning cognitive impairment. Further, at the time of the study, none of the participants had been using systemic medications that could have affected cognition such

as benzodiazepines, opiates, tricyclic antidepressants, anticonvulsants, and dopamine agonists, etc. Subjects who did not meet these criteria were excluded. Subjects with moderate-severe depression and chronic systemic diseases such as diabetes mellitus, arthritis, hypertension, heart disease, stroke, and cancer were excluded. Additionally, patients who smoked cigarettes, had a best-corrected visual acuity of less than 1.0 according to Snellen chart, or had eye diseases other than glauco-ma that could have affected RNFL and ganglion cell-inner plexiform layer (GC-IPL) thicknesses, such as macular degeneration and optic neuropathy, were excluded from this study.

OPhThalmOlOgICal examINaTION

All participants in this study underwent an ophthalmological exa-mination including visual acuity assessment with a Snellen chart, IOP with Goldman’s applanation tonometer after application of a local anesthetic (hydrochloric proxymetacaine 0.5%), measurement of cen-tral corneal thickness (CCT) with an optic pachymeter (Lenstar LS 900; Haag-Streit, Koeniz, Switzerland), slit-lamp-assisted biomicroscopy of the anterior and posterior segments of the eye, gonioscopy, and photography of the fundus (Visucam NM-FA; Carl Zeiss Meditec Inc., Oberkochen, Germany). SD-OCT (Cirrus HD OCT model 5000; Carl Zeiss Meditec Inc., Dublin, CA, USA) was used to measure the GC-IPL (macu-lar cube 512 × 128) and RNFL (optic disc cube 200 × 200) thicknesses. The examination was concluded with a check of the visual fields using a static perimeter apparatus type Octopus 900 (Haag-Streit). These examinations were used for the glaucoma diagnosis and classification. The diagnostic criteria for POAG were high IOP (>21 mmHg, corrected by corneal thickness), normal iridocorneal open angle, glaucomatous changes in the visual field with optic nerve cupping, and the absence of other optic neuropathies. Except for evidence of high IOP (≤21 mmHg), we used the same diagnostic criteria of POAG to diagnose NTG. All POAG and NTG diagnoses were applied according to the guidelines of the European Glaucoma Society(18).

NeUROlOgICal examINaTION Detailed neurological examination, including the MMSE test which

evaluates cognitive function, was applied to all participants. All of the patients had intact neurological examination findings, including those of the motor, sensory, and cerebellar systems and the cranial nerves, except for the optic nerve. The MMSE is the most commonly used test for evaluating cognitive function and scanning for dementia. Orientation, attention, memory, language, and shape copying are evaluated in this test. The maximum number of points is 30. The study for the validity and reliability of the MMSE in Turkey was performed by Güngen(19) and his associates in 2002, and the cut-off value was determined to be 23/24. This test is affected by education, and is considered to be reliable for identifying the degree of mild dementia. There is also a modified version for uneducated people. The MMSE is used for both diagnosis and treatment follow-up. Long-term memory, short-term memory, attention span, calculation, the naming of items, performance of a task with three steps, reading, writing, and assem-bling abilities are all measured in this test.

STaTISTICal aNalySIS All statistical analyses were performed using IBM SPSS 20 for Windows

(IBM Corp., Armonk, NY, USA). IOP, CCT, mean deviation (MD), RNFL thickness, GC-IPL thickness, and MMSE scores were compared among the groups. The normality and variance homogeneity assumptions of the continuous variables for the parametric methods were evaluated by the Shapiro-Wilks and Levene’s tests, respectively. The IOP and CCT were provided normality and homogeneity of varian ce assumptions. For this reason, the one-way analysis of variance (ANOVA) test was used to compare the differences among the three groups for each variable. Non-parametric tests, including the Kruskal-Wallis H test and the Mann-Whitney U test, were used for the other variables, which were

Cognitive performance of primary open-angle glaucoma and normal-tension glaucoma patients

102 Arq Bras Oftalmol. 2016;79(2):100-4

not provided assumptions for the parametric tests (RNFL thickness, GC-IPL thickness, MD, and MMSE scores). Correlations among the va-riables were assessed using Spearman’s correlation coefficients. P<0.05 was regarded as statistically significant.

ReSULTS The mean ages of group one (POAG), group two (NTG), and group

three (C) were 59.8 ± 10.1, 61.9 ± 9.8, and 60.1 ± 8.5 years, respectively. There were no significant differences with regard to age among the groups (p=0.348). All subjects involved in the study were Caucasian. There were 11 males and nine females in the POAG group, 11 males and nine females in the NTG group, and 10 males and 10 females in the C group (p=0.935) (Table 1). The mean IOP value was 16.2 ± 2.9 mmHg in the POAG group, 14.7 ± 1.9 mmHg in the NTG group, and 14.8 ± 2.9 mmHg in the C group (p=0.270).

The CCT was 545.6 ± 29.7 µm in the POAG group, 519 ± 25.7 µm in the NTG group, and 551.9 ± 26.2 µm in the C group. The differences observed between the NTG group and the two other groups were statistically significant (p<0.001). When we compared the groups pairwise, we found statistically significant differences between the NTG and POAG groups (p=0.001), and the NTG and healthy C groups (p<0.001). The MD in the worse eye was 4.8 ± 3.1 dB in the POAG group, 7.9 ± 3.8 dB in the NTG group, and 1.2 ± 1.1 dB in the C group; there were significant differences among the three groups (p<0.001). The MD in the better eye was 3.5 ± 2.1 dB in the POAG group, 4.6 ± 3.1 dB in the NTG group, and 0.7 ± 0.7 dB in the C group; there were significant differences among the three groups (p=0.001). The IOP, CCT, MD in the worse-eye, and MD in the better-eye measurement values, are shown in table 1.

Among the POAG patients, three were taking beta-blockers, se-ven were taking prostaglandin analogs, four were taking beta-blockers plus carbonic anhydrase inhibitors, two were taking beta-blockers plus prostaglandin analogs, two were taking beta-blockers plus sympa-thomimetic drugs, one was taking beta-blockers plus carbonic anhydrase inhibitors as well as parasympathomimetic drugs, and one was taking beta-blockers plus carbonic anhydrase inhibitors plus sympathomimetic drugs. Among the NTG patients, three were taking beta-blockers, eight were taking prostaglandin analogs, two were taking sympathomimetic drugs, two were taking beta-blockers plus carbonic anhydrase inhibitors, four were taking beta-blockers and prostaglandin analogs, and one was taking beta-blockers plus sympathomimetic drugs.

The mean RNFL thickness measurements were 85.2 ± 14.7 µm for the POAG group, 76.8 ± 10.3µm for the NTG group, and 91.4 ± 7.7 µm for the C group; statistically significant differences were found among the three groups (p<0.001). When the groups were compared pairwise, statistically significant differences were found between the NTG and POAG groups (p=0.034), and the NTG and C groups (p<0.001). The

difference between the POAG and C groups was not statistically sig-nificant (p=0.102). These measurements are shown in table 2.

The mean GC-IPL measurement was 77.5 ± 9.7 µm in the POAG group, 73.4 ± 7.8 µm in the NTG group, and 78.8 ± 3.8 µm in the con-trol group. No statistically significant difference could be found when all the groups were compared with each other (p=0.085). However, when the groups were compared pairwise, the difference between the NTG and C groups was statistically significant (p=0.023). When we compared the POAG group with the NTG and C groups separately, no significant differences were found (p=0.143 and p=0.714, respectively). The above measurements are shown in table 2.

The MMSE scores were 26.1 ± 1.4 in the POAG group, 25.7 ± 2.3 in the NTG group, and 28.8 ± 0.9 in the C group. When all three scores were compared together, the differences between the mea-surements were statistically significant (p<0.001). The measurements are shown in table 2. When the scores were compared pairwise, a statistically significant difference was found between both the NTG and C groups, and the POAG and C groups; however, the difference was not statistically significant between the NTG and POAG groups. The measurements are shown in table 3. A significant correlation was not found between the MMSE scores and either the RNFL (p=0.385) or GC-IPL (p=0.813) thicknesses.

DISCUSSIOnIn the present study, it was necessary to determine if there were

any differences in the MMSE scores (same age and gender) of the three groups (20 POAG, 20 NTG, and 20 healthy C participants). In this study, the hypothesis was that lower cognitive scores in glaucoma patients were anticipated. The pathogenesis of the dementia group diseases, such as ATD and MCI, which cause lower MMSE scores, is similar to that of glaucoma. Since both diseases have noticeable neuron loss, it evident that there is a relationship of some kind.

Studies have shown a higher incidence of glaucoma among ATD patients. In a previous study, the rate of glaucoma was found to be 25.9% in ATD patients and 5.2% in controls(17). Tamura et al. found that 23.8% of patients with ATD had glaucoma, while only 9.9% of the age-matched controls had glaucoma(1). From these data, it was proposed that the optic nerve of patients with ATD may be less resis-tant to elevated IOP(15). Based on this proposition, we suspected that in the early stages of ATD, lower IOP may cause glaucomatous optic neuropathy; therefore, the NTG patients could be expected to attain

Table 1. Demographic and clinical characteristics of patients and control subjects

POAG n=20

nTG n=20

Control n=20 p value

Age+ (years) 059.8 ± 10.1 061.9 ± 9.8 060.1 ± 08.5 0.348

Sex (M/F)* 11/9 11/9 10/10 0.935

TO+ 015.5 ± 1.9 016.2 ± 2.9 14.8 ± 2.9 0.270

CCT+ 545.6 ± 29.7 519.0 ± 25.7 551.9 ± 26.2 <0.001

MD worse eye** 4.8 ± 3.1 7.9 ± 3.8 01.2 ± 1.1 <0.001

MD better eye** 3.5 ± 2.1 4.6 ± 3.1 00.7 ± 0.7 <0.001

POAG= primary open-angle glaucoma; NTG= normotensive glaucoma; M= male; F= female; TO= tension ocular; CCT= central corneal thickness; MD= mean defect; += one-way ANOVA test with Bonferroni correction; *= Chi-square test; **= Kruskal-Wallis test.

Table 2. Comparison of the mean RnfL, GC-IPL, and MMSe complex among the POAG, nTG, and control groups

POAG n=20

nTG n=20

Control n=20 p value

RNFL (mean)* 85.2 ± 14.7 76.8 ± 10.3 91.4 ± 7.7 <0.001

GC-IPL (mean)* 77.5 ± 09.7 73.4 ± 07.8 78.8 ± 3.8 <0.085

MMSE* 26.1 ± 01.4 25.7 ± 02.3 28.8 ± 0.9 <0.001

RNFL= retinal nerve fiber layer; GC-IPL= ganglion cell-inner plexiform layer; MMSE= mini-mental state examination; POAG= primary open-angle glaucoma; NTG= normotensive glaucoma; *= Kruskal-Wallis test.

Table 3. Pairwise comparison of the MMSe scores between the control subjects and the POAG and nTG patients

Control (n=20) MMSE: 28.8 ± 0.9

POAG (n=20) MMSE: 26.1 ± 1.4

p=0.001*

NTG (n=20) MMSE: 25.7 ± 2.3

p<0.001*

MMSE= mini-mental state examination; POAG= primary open-angle glaucoma; NTG= normotesive glaucoma; *= Mann-Whitney U test.

Bulut M, et al.

103Arq Bras Oftalmol. 2016;79(2):100-4

lower MMSE scores. However, we did not find a significant difference in the MMSE scores between the POAG and NTG groups.

Few studies have explored cognitive impairment in glaucoma patients. Yochim et al. found cognitive impairment in 44% of 41 older glaucoma patients(20). Similarly, we found lower MMSE scores in the glau coma patients than in the healthy C group. Hagerman et al. found that 32% of patients with low vision had cognitive impairment as determined by the MMSE(21). In contrast, Cumurcu et al. showed no significant differences in the MMSE score among pseudoexfoliative glaucoma patients, POAG patients, and healthy controls(22).

The dementia group of disorders (ATD, vascular dementia, mixed dementia) causes cognitive impairment(23). The MMSE is used to eva-luate the cognitive condition of a person and scanning of dementia. Personal orientation, attention to detail, language ability, and the copying of shapes are evaluated in this test, and 30 is the maximum possible score. Further, general cognitive function can be assessed with the MoCA (Montreal Cognitive Assessment), which provides a more comprehensive assessment than MMSE. Executive function, short-term memory, attention, language skills, and visuospatial pro-cessing are the categories included in the MoCA test(24). Since the educational level of our patients was low, we could not perform the MoCA test in the present study. In our study, we found statistically significant different MMSE scores among the three groups (26.1 ± 1.4 in the POAG group, 25.7 ± 2.3 in the NTG group, and 28.8 ± 0.9 in the C group; p<0.001). Similarly, Jefferis et al. found lower MMSE scores in glaucoma patients as opposed to healthy controls(25). Since MMSE requires intact vision for eight of the 30 points, they also studied the MMSE scores of their subjects by extracting the part of the MMSE that requires intact vision. At this time, they found no significant difference in the MMSE scores between the glaucoma patients and healthy controls. In our study, we excluded patients with vision less than 1.0 according to Snellen chart, to minimize the effect of vision on MMSE scores.

Although we excluded patients with vision less than 1.0 accor-ding to the Snellen chart, vision may still have affected the MMSE scores in glaucoma patients, since glaucoma affects the magnocellular visual pathway. Visual function mediated by this part of the brain is difficult to assess by conventional ophthalmological examination. Motion process and contrast sensitivity are parts of these visual pro-cesses(26). In addition, ATD patients may have structural defects in the magnocellular visual pathway even in the absence of plaques and neurofibrillary tangles in these brain areas(27).

In our study, we found that the mean thicknesses of RNFL and GC-IPL in both the glaucoma groups were thinner, as expected, compared with the normal C group. These results are consistent with those of previous studies(27,28). The CCT values were found to be significantly thinner in the NTG group than in the other groups (p<0.05). These results are also consistent with those from the available literature(29). We did not find any significant correlations between the MMSE score and either the RNFL or GC-IPL thicknesses. The literature did not re-veal any studies with similar glaucoma and dementia parameters for glaucoma patients. In some studies performed on dementia-group diseases causing cognitive impairment, a significant correlation was found between the MMSE score and RNFL thickness(30,31). In addition, in a study by Bayhan et al., a significant correlation was(32) found between the MMSE score and the mean GC-IPL thickness. Conversely, in another study, no correlation was found between the MMSE score and RNFL thickness(33).

To minimize the effects of vision on the MMSE score, because we did not include patients with a visual acuity of less than 1.0, most of our patients had early-stage glaucoma. Since POAG patients are at an earlier stage of glaucoma than NTG patients, even though the GC-IPL and RNFL thicknesses were lower in these two groups than in the C group, this difference was not statistically significant. We found that NTG patients had lower MMSE scores than POAG patients. We believe that although there was no statistically significant difference

of the MMSE scores between the NTG and POAG patients, the lower values of MMSE in NTG patients might be attributed to the later stage of glaucoma in those patients. Figure 1 shows a box plot graph of the MMSE scores in each group.

Some research has shown that glaucoma has some of the same characteristics as ATD, which is the most common cause of dementia(1). They are both chronic neurodegenerative diseases that are closely related to aging, and both progress very slowly. Recently, Yoneda et al.(34) suggested that beta-amyloid and tau (neurofibrillary tangles), which have significance in ATD pathology, may also have important roles in glaucoma pathology. They also found a significant decrease in the levels of beta-amyloid and a significant increase in the level of tau in the vitreous of glaucoma patients when compared with that in the vitreous of a healthy control group. In a previous study, when ATD patients were compared with a control group, a significant decrease was found in the beta-amyloid levels of the cerebrospinal fluid, as well as a significant increase in the level of tau(35). Based on these findings, the neurodegenerative process causing neuron loss in glaucoma may have a mechanism similar to the process causing the same pathology in ATD. In addition, it was found that beta-amyloid accumulates in the RGCs of rats with glaucoma induced for experimental purposes(14). In another experimental glaucoma study performed on rats, a hypothesis was proposed that chronic beta-amyloid neurotoxicity at the molecular level causes the death of retinal neurons and is similar to the death of neurons in the brains of ATD patients(36).

There were some limitations in this study. The number of subjects (60) was relatively low, and the glaucoma drugs used by the patients were not taken into account. Although all the patients in this study had good visual acuity, we could not confirm the effect of visual function on the MMSE scores. The absence of complete neuropsy-chologic data is another limitation. Unfortunately, we were unable to perform more sensitive tests to evaluate the cognitive status of the patients, such as the MoCA, due to the low educational level of the participants. This could be considered a limitation of our study. Un-doubtedly, longitudinal studies should be performed to obtain more data on this topic. A strength of this study is that the neurologist who performed the neurologic examinations on the patients was com-pletely unaware of the ophthalmological diagnoses of the patients.

In conclusion, since the glaucoma group of diseases and the de-mentia group of diseases share similar neurodegenerative processes affecting cognitive impairment, our findings support our hypothesis. Since glaucoma patients have lower cognitive performance, glaucoma can take place in the group of neurodegenerative diseases. Therefore, it is incumbent upon the ophthalmologist to refer glaucoma patients to a neurologist.

MMSE= mini-mental state examinationfigure 1. Box plot graph of MMSE scores in each group.

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104 Arq Bras Oftalmol. 2016;79(2):100-4

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Original Article

105Arq Bras Oftalmol. 2016;79(2):105-10http://dx.doi.org/10.5935/0004-2749.20160031

InTRODUCTIOnThe condition of lacrimal glands (LG) is influenced by compo-

nents of the immune, neural, and endocrine systems(1-5). Insulin is thought to be of major importance, based on observations related to its deprivation in diabetes mellitus (DM), on LG, tear film, and ocular surface in humans, animal models, and in culture(6-8). Lacrimal gland acinar cell (LGAC) culture is an appropriate model for improving the understanding of the influence of insulin on these cells.

In previous studies, the culture of LGACs from different species was performed over an average period of 21 days(9,10). Several attempts to enhance the growth of acinar cells in culture have been made, but after a span of approximately 3 weeks, LGACs exhibited decreased viability, with high numbers of apoptotic cells(11-14).

Exocrine acinar cells are fragile, post-mitotic epithelial cells with marked polarity. This indicates that the apical and basal sides are clearly positioned but also that intracellular organelles are located at one or the other pole, depending on their cellular functions. Thus, an ade-quate extracellular matrix and other specific ingredients are needed in the culture media to mimic in vivo conditions(15,16). The handling during isolation and culture procedure of LGACs should be gentle

ABSTRACTPurpose: The goal of the present study was to establish a protocol for primary culture of lacrimal gland acinar cells (LGACs) and to assess the effect of adding insulin to the culture media. Methods: LGACs were isolated and cultured from lacrimal glands of Wistar male rats. The study outcomes included cell number, viability, and peroxidase release over time and in response to three concentrations of insulin (0.5, 5.0, and 50.0 μg/mL). Results: In LGAC primary culture, cells started to form clusters by day 3. There was a time-response pattern of peroxidase release, which rose by day 6, in response to carbachol. Culture viability lasted for 12 days. An insulin concentration of 5.0 μg/mL in the culture medium resulted in higher viability and secretory capacity.Conclusions: The present method simplifies the isolation and culture of LGACs. The data confirmed the relevance of adding insulin to maintain LGACs in culture.

Keywords: Acinar cells; Lacrimal gland; Lacrimal apparatus; Insulin; Peroxidase; Cell Count; Regenerative medicine; Tissue engineering; Animals; Rats, Wistar

RESUMOObjetivo: O objetivo do estudo foi estabelecer um protocolo de cultura primária para o isolamento de células acinares da glândula lacrimal (CAGL) e avaliar a relevância de insulina no meio de cultura. Métodos: CAGL foram isoladas e cultivadas a partir das glândulas lacrimais de ratos Wistar machos. Os parâmetros analisados foram: o número de células, viabilidade e secreção da peroxidase ao longo do tempo e em resposta a três concentrações de insulina (0,5; 5,0 e 50,0 μg/ml). Resultados: Na cultura primária de CAGL as células passaram a se agrupar por volta do dia 3. A secreção de peroxidase em resposta ao carbacol aumentou no dia 6. O período de cultura viável foi limitado à 12 dias. Insulina à 5,0 μg/ml no meio de cultura resultou em viabilidade e capacidade secretora maior. Conclusão: o estudo descreveu um método para simplificar o isolamento e cultivo de CAGL. Os dados apresentados confirmam a importância da insulina na manutenção da cultura de CAGL.

Descritores: Células acinares; Glândula lacrimal; Aparelho lacrimal; Insulina; Pero-xidase; Contagem de células; Medicina regenerativa; Engenharia tecidual; Animais; Ratos Wistar

and kept to a minimum to avoid disturbing this organization and de creasing cell viability. Changes in culture medium, temperature, and time of handling decreases the amount and viability of isolated LGACs, resulting in unsatisfactory isolation and cell culture viability(9).

Rat LG acinar cells have to be handled carefully from isolation to culture. Also, a series of steps and parameters are necessary to se-parate acinar cells from the other LG cells (i.e., ductal, myoepithelial, endothelial, and neuronal cells and leukocytes)(17). To achieve this, it is necessary to apply binders and digestive enzymes. The selected cell populations are submitted to gradient centrifugation and filtering to isolate the target cells. The difficulty of this procedure not only pertains to cell isolation but also to obtaining good viability (higher than 80% of the total number of cells) to ensure a large population of target cells with preserved secretory activity(17).

Previous studies have focused on the aspects of LGACs in primary culture, applying standard amounts of insulin in the culture media(12,18). The aims of this study were to determine the optimal conditions for establishing a line of primary LGACs in culture and to study the effect of insulin in variable concentrations in the culture medium on acinar cell growth, secretory function, and viability.

Submitted for publication: June 19, 2015 Accepted for publication: January 22, 20161 Department of Ophthalmology, Otorhinolaryngology and Head & Neck Surgery. Faculdade de

Medicina de Ribeirão Preto (FMRP), Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil.

Funding: This study was supported by CAPES, CNPq, FAPESP, FAEPA, NAP-FTO USP.

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

Corresponding author: Eduardo Melani Rocha. Department of Ophthalmology. Otorhinolaryngology and Head & Neck Surgery. Faculdade de Medicina de Ribeirão Preto - Universidade de São Paulo - Av. Bandeirantes, 3.900 - Ribeirão Preto, SP - 14049-900 - Brazil - E-mail: emrocha@fmrp.usp.br

Approved by the following research ethics committee: CETEA-FMRP. 076/2004.

Lacrimal gland primary acinar cell culture: the role of insulinCélulas acinares de glândula lacrimal em cultura primária: o papel da insulina

leonarDo tannus malkı1, ana carolına Dıas1, angelıca gobbı Jorge1, carolına marıa móDulo1, eDuarDo melanı rocha1

Lacrimal gland primary acinar cell culture: the role of insulin

106 Arq Bras Oftalmol. 2016;79(2):105-10

MeTHODSaNImalS aND STUDy DeSIgN

Male Wistar rats (Rattus norvegicus, 8 weeks old) were euthanized to obtain LGACs. The study protocols and the project followed the guidelines of the Association of Research in Vision and Ophthalmo-logy (ARVO) and were approved by the Ethics Committee on Animal Experimentation (CETEA) of the Faculty of Medicine of Ribeirão Preto, Universidade de São Paulo (FMRP-USP) (Process # 076/2004).

LGs were removed under intraperitoneal anesthesia with xylazine 15 mg/kg and ketamine 150 mg/kg. After harvesting LGs, the animals were euthanized by an excess of anesthesia. For each experiment, three animals were sacrificed, using both LGs of each animal, in a total of 15 experiments. Experiments with a cell viability of ≥80% after isolation and transfer of LGACs to culture plates were conside-red reproducible for data collection. A summary of the study flow is presented in figure 1.

All glassware and surgical instruments were cleaned with Extran MA 02 neutral (Merck KGaA, Darmstadt, Germany) and washed in Milli-Q® water (Thermo Fisher Scientific Inc, Barnstead Nanopure, Waltham, MA, USA) prior to sterilization and use for tissue harvesting, reagent preparation, and cell isolation.

meDIUm, ReageNTS, aND SUbSTRaTeS

The culture medium was prepared based on the culture media used for LGAC cultures, as previously described(9,15,17), and was applied for LGAC isolation, cell manipulation, and cell culture.

For the preparation of the medium, 250 mL of low glucose (1 g/L) Dulbecco’s Modified Eagles Medium (DMEM) (Invitrogen, Camirillo, CA) was supplemented with gentamicin 25 µg/mL, putrescine 1.0 mM, redu-ced glutathione 10 µg/mL, ascorbic acid 50 µg/mL, dexamethasone 10 µg/mL, insulin 5.0 µg/mL, selenium 5.0 ng/mL, transferrin 5.0 µg/mL, and carbachol 100 μM (Sigma–Aldrich, St. Louis, MO, USA). The rea-gents were carefully weighed (Bioprecisa, FA 2104N, PR, Brazil) and mixed under aseptic conditions in a fume hood (Nuaire, NU-425, USA) (Table 1).

After buffering the pH to 7.6 (Model 215, Denver Instrument Com-pany, USA), the culture medium was filtered with disposable 22-µm sterile filters (Corning Inc, NY, USA) connected to a vacuum pump.

Epithelial growth factor (EGF) was added (Sigma-Aldrich, St. Louis, MO) at a concentration of 10 ng/mL. The medium was stored at 4°C and removed 30 min prior to use to warm it up slowly to room temperature.

As specifically mentioned in the assays described below, the me-dium was supplemented with fetal bovine serum (FBS) (Invitrogen, Camirillo, CA, USA) or variable concentrations of insulin and carbachol (Sigma-Aldrich, St. Louis, MO, USA).

Cell ISOlaTION

After removal, each LG had its capsule gently removed and were washed in sterile petri plates (Techno Plastic Products TPP, Switzerland) with 1.0 mL of defined culture medium with 10 µL soybean trypsin inhibitor (Sigma–Aldrich, St. Louis, MO, USA). The glands were trans-ferred to a new sterile petri plate (35 × 10 mm) (Corning, NY, USA) containing Hanks› balanced solution without Ca2+ and Mg2+ (HBSS, Invitrogen Camirillo, CA, USA), cut into small pieces, transferred to a 15-mL Falcon-type tube (Techno Plastic Products TPP, Switzerland), and shaken in HBSS with 0.5 M EDTA at 5 rpm for 15 min at room temperature (Arsec OSC1, Cotia, SP, Brazil). The glandular tissue was sedimented for 15 min and gassed with 95% O

2 and 5% CO

2 for 15 s.

After discarding the supernatant, the tissue was transferred to a spinner flask (Bellco Glass, Inc., NJ) with 5.0 mL culture medium with 10 µL hyaluronidase (150 U/mL), 25 µL collagenase (300 U/mL), and 25 µL DNAse (4 U/mL) (Sigma-Aldrich, St. Louis, MO, USA). Enzymatic digestion was performed using a magnetic stirrer (model 78 HW-I, Biomixer, Jiangsu, China) at 60 rpm at 37°C for 60 min. LGACs were separated by subsequent filtration with 100-µm and 70-µm cell strainers (BD Bioscience, NJ, USA). The decanted cells formed a pellet and were ready to culture.

flOw CyTOmeTRy

After centrifugation at 5000 rpm for 15 min at room temperature (Eppendorf 5417 R, Hamburg, Germany), the pellet had clearly se-gregated into two phases: a thick, light brown phase on the bottom and a light red phase on the top (Figure 2). Samples of 10 µL of LGAC suspension (n=3) were gently obtained by aspiration with a micropi-pette, (Eppendorf, Hamburg, Germany) without mixing the phases, and diluted in a phosphate buffer. These samples were subjected to flow cytometry, using fluorescence-activated cell sorting (FACS) in triplicate samples (BD FACS Array FACS Diva version 6.1.1 software, BD Bioscience, NJ, USA) to confirm the predominance of LGAC upon iso-lation. Rabbit IgG antibody against the cell membrane water channel aquaporin-5 (Anti-AQP5, Sc-28628, Santa Cruz Biotechnologies, Santa Cruz, CA, USA) was applied because its expression in LGs is limited to acinar cells(19).

The following conditions were compared: cells obtained from the bottom and cells obtained from the top of the pellet, following cell separation and centrifugation. The “bottom cells” were assumed to be acinar cells (heavier), and the “top cells” were assumed to be fibroblasts, myoepithelial, and endothelial cells (lighter)(15). The per-centage of acinar cells (positive for aquaporin-5) was compared in samples from the bottom and top of the pellet.

Samples of LGAC suspension were blocked with autologous rat serum and incubated for 1 h with the primary antibody (Anti-AQP5) at 4 µg/mL, followed by 30 min of exposure to the secondary antibody (goat anti-rabbit IgG-FITC, Sc-2012 Santa Cruz Biotechnologies, Santa Cruz, CA, USA) at 2.5 µg/0.5 mL, as previously described(18).

Cell CUlTURe

The acinar cells were cultured in 24-well culture plates (Techno Plastic Products TPP, Switzerland) pre-coated with MatrigelTM (BD Bioscience, NJ, USA). To each well, 200 µL of cell suspension (an average of 3 × 105 cells) and 300 µL of culture medium were added.

Other culture approaches were attempted, including leaving the plastic bottom without any coating or coating with poly-L-lysine or fibronectin (Sigma-Aldrich, St. Louis, MO, USA) instead of Matrigel.

Table 1. Composition of the supplemented low-glucose DMeM used in the primary culture of LG acinar cells

Suplement final concentration

Putrescin 01.0 mM

Reduced glutathione 10.0 mg/ML

Ascorbic acid 50.0 mg/ML

Dexamethasone 10.0 mg/ML

Insulin 05.0 mg/ML

Selenium 05.0 mg/ML

Transferrin 05.0 mg/ML

figure 1. Schematic study design showing the steps involved in and timing of the evaluation of LGAC growth in primary culture.

Malki LT, et al.

107Arq Bras Oftalmol. 2016;79(2):105-10

A B C D e

figure 2. Illustrative photos of the key steps involved in LGAC primary culture. A) Rat exorbital lacrimal gland isolated (arrow). B) Lacrimal gland cutting in a Petri dish and embedding of small fragments in culture medium. C) Enzymatic digestion of the lacrimal gland on a magnetic stirrer using a spinner flask. D) Lacrimal gland cell pellet after centrifugation (arrow). E) LGAC counting and viability testing using a Neubauer chamber and trypan blue after isolation.

figure 3. A) A low amount of aquaporin-5-positive LGACs (3%) was observed in the supernatant. B) A higher amount of positive cells (20%) was observed in the pellet (arrow), indicating the efficiency of the isolation method.

A

B

Cultures were terminated at specific time points. The medium was replaced by 300 µL of culture medium containing trypsin (1.0 mg/mL) and EDTA (0.4 mg/mL) (Sigma-Aldrich, St. Louis, MO, USA) and incubated at 37°C and 95% O

2 and 5% CO

2 for 45 min (Nuaire,

N4750 G, USA). Prior to and after culture termination, cell counting and viability

were performed by analyzing 10 μL of cell suspension in culture medium mixed with 10 µl of 2% trypan blue (Sigma-Aldrich, St. Louis, MO, USA) using a Neubauer chamber (Optik Labor, Germany).

As mentioned above, data on cell numbers and cell viability of primary culture LGACs cultivated under different conditions were obtained. Culture media and cells were stored separately at -80°C (So-Low-Ultra-Low Freezer, Cincinnati, OH, USA) for subsequent bio-chemical analysis.

PeROxIDaSe aCTIvITy aSSay

A peroxidase activity assay was performed with aliquots of 50 µL of LGAC primary culture samples using a commercial kit for peroxida-se (Invitrogen Camirillo, CA, USA) according to the manufacturer›s protocol (n=5 wells for each condition; samples tested in duplicates). Light absorbance was observed using a spectrophotometer (Spec-traMax M5, San Diego, California, USA).

To assess the influence of insulin, levels of insulin in the cultu-re medium during the culture process were maintained as usual (5.0 μg/mL), 10 times higher (50 μg/mL), or 10 times lower (0.5 μg/mL).

Further, 100 mM carbachol was added to the culture medium 20 min prior to culture termination to compare peroxidase secretory capacity over time and in response to different insulin concentrations in the culture media.

Image CaPTURe aND STORage

Cell culture digital image capturing was performed using inverted microscopes (Olympus, model BX60F5, MA, USA; Labomed model LX500 Labo, Breukhoven, Netherlands). Macroscopic images were taken with a digital camera (Sony DSC-HX9V, Sony Inc, Japan).

STaTISTICS

The data are presented as mean ± standard error (SE). Descriptive and comparative statistic calculations (non-parametric Kruskal-Wallis test) were performed using GraphPad Prism 5.0 (San Diego, CA, USA).

ReSULTSAnalysis of LGAC populations isolated and separated by FACS

from the two pellet layers (top and bottom) showed that the cells isolated from the bottom layer represented 20% acinar cells on average; meanwhile, samples from aliquots obtained from the top of the pellets had less than 3% cells positive for aquaporin-5 (acinar cells), confirming the efficiency of the method of cell isola-tion (Figure 3).

By the fourth day, Matrigel proved to be a superior substrate for LGAC growth with respect to cell shape and number of viable cells compared with plastic, poly-L-lysine, and fibronectin (Figure 4). The

figure 4. Counts of LG acinar cells in primary culture on four conse-cutive days, using supplemented low-glucose DMEM. Comparative analysis of four substrates: plastic, poly-L-lysine, fibronectin, and Matrigel at day 0 (black columns) and day 4 (white columns) (n=3 wells/condition).

Lacrimal gland primary acinar cell culture: the role of insulin

108 Arq Bras Oftalmol. 2016;79(2):105-10

cells growing on Matrigel were larger, and the number of cells was similar compared with that at day 0.

The time length of the survival curve of LGACs in primary culture with supplemented low-glucose DMEM on Matrigel-covered culture plates was evaluated. The mean levels, as measured every 3 days, revealed a higher number and proportion of viable cells at day 3, with a continuous decline until day 12 (Figure 5).

Daily observation of LGACs in culture by microscopy revealed, from the third to the fourth day, the wave front of cell proliferation; it was also possible to observe cells attaching to each other, forming clusters similar to acinar units, and in certain cells, structures compa-tible with secretory granules were observed in the cytoplasm. Longer periods of LG culture revealed different morphologic types of cells in parallel with a reduction in the number of acinar cells between days 21 and 28 of culture, suggesting the proliferation of residual myoepi-thelial and mesenchymal cells (Figure 6).

To investigate the secretory capacity of the isolated acinar cells in culture, the peroxidase activity was measured in the supernatant prior to and after stimulation with 100 µL of 100 mM carbachol. The data showed that the peroxidase secretion, as measured in the medium at days 3 and 6, was efficiently stimulated by carbachol. However, these returned to non-stimulated levels (indifferent to cholinergic stimulation) by day 9 (Figure 7A).

To determine changes in cell proliferation due to changes in the concentration of insulin in the supplemented low-glucose DMEM, analysis of cell count and viability in experiments using three different insulin concentrations (0.5, 5.0, and 50.0 μg/mL) was performed. The data showed that at day 0 and day 3, there was no change in cell number or cell viability; however, at day 6, the acinar cells exposed to lower insulin concentrations began to decline in viability, and after day 9, both the number of cells and viability of the culture using supplemented low-glucose DMEM with 0.5 and 50.0 μg/mL of insulin presented relatively lower numbers (Figure 8).

Comparative analysis of the secretory activity under different insu-lin conditions was performed by stimulation with 100 µL of 100 mM carbachol for 30 min and evaluating the peroxidase activity in samples obtained from the supernatant from cultures with three different con-centrations of insulin (0.5, 5.0, and 50 μg/mL) every 3 days (from day 0 to day 12). The data showed that insulin at a concentration of 5.0 μg/mL supported a higher peroxidase secretion from LGAC, measured by its acti-vity in the culture medium, than insulin at a concentration of 0.5 μg/mL; this finding was most remarkable at day 3. The decline in peroxidase secretion over the 12 days was more prominent in the hypoinsulinic me-dium (0.5 μg/mL) and similar between the standard and hyperinsulinic media (5.0 and 50.0 μg/mL, respectively; Figure 7 B).

DISCUSSIOnThe present study introduced a feasible protocol for the isolation

and culture of LGACs. Moreover, it elucidated aspects pertaining to the

figure 5. Microscopic aspects of LG acinar cells in culture on day 4. A) The wave front of cell proliferation by the third day (100x magnification). B) LG cells forming clusters similar to acinar units (arrow) by the third day (200x magnification). C) Structures compatible with secretory granules in the cytoplasm (arrow) were observed on the fifth day (200x magnification). D) Different morphologic types of LG cells, suggesting the proliferation of remaining myoepithelial and mesenchymal cells by the third week (400x magnification).

A B C D

figure 6. Counts of LG acinar cells in primary culture over a span of 12 days, using supplemented low-glucose DMEM and Matrigel substrate; comparative analysis of cell number (A) and viability (B) every 3 days, from the seeding day (0) until day 12 (n=3 wells/condition).

A

B

longevity of primary culture and the influence of insulin on culture maintenance.

This information contributes to the understanding of the role of LG homeostasis, its relationship with the endocrine system, and the potential effects of LG on the ocular surface.

The cell isolation procedure in this report included a reduction of several of the usual steps, such as repeated washings and centrifuga-tions, and the use of Ficoll to isolate LGAC, as previously described(17). The simplified procedure did not compromise the purity of LGAC cells and helped to increase the longevity of the primary culture, compatible with recently published protocols(10,11). Our hypothesis is that reduced manipulation during isolation contributes markedly to improving and extending cell viability and behavior during culture.

Moreover, removal of the fibrous capsular tissue that surrounds LGs proved to be a crucial step for optimizing isolation of LGACs and thus successful culture.

An increase in both the number of living cells and cell viability with insulin at 5.0 μg/mL was observed from the third to the ninth day

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109Arq Bras Oftalmol. 2016;79(2):105-10

of cultivation, compared with day 0 (seeding), as well as with lower or higher doses of insulin, indicating a key role of insulin in a certain range for the homeostasis and proliferation of LGAC(8,20).

The trend to form clusters after the third day revealed that these cells show polarity, as previously observed(15). In some of the experi-ments, the cell culture was extended to investigate the behavior of LGACs in culture plates.

The method for isolating LGAC is efficient with respect to excluding most other cell types, as observed in the flow cytometry assay with aquaporin-5, where the number of AQP5-positive LGACs was subs-tantially higher. The fact that more than 60% of the cells had not been detected by flow cytometry may be explained by a weak antibody affinity. Immunocytochemistry analyses at different stages of serial cultures could give an indication of cell lines involved during culture(18).

Fibroblasts appeared by the third week of culture. None of these obser vations had been registered in our previous experiments or re-ported by other authors in studies using shorter culture periods(10,17,18,21).

The use of a combination of quinolone (ofloxacin) and amino-glycoside (gentamicin) was effective in terms of preventing contami-nation of the culture. One of the experiments failed because of the presence of filamentous fungi. It is assumed that an anti-fungal drug is necessary to prevent this issue.

None of the assays achieved cell culture confluence; therefore, neither passages nor sub-cultures were performed.

A relevant item that has not been highlighted previously with respect to maintaining LGAC cultures is the addition of carbachol in doses one thousand times less (100 μM) than those used to stimulate secretion. It is probably necessary to support these cells through neurotrophic pathways, as recently observed in embryonic salivary acinar cells, to enhance growth and differentiation(22).

Higher doses of carbachol (100 mM) were useful to confirm the se-cretory capacity of LGACs in culture. The secretory product evaluated was the enzyme peroxidase, which is present in tears and is linked to defense functions(23,24). Our observations revealed a time-depen-dent secretory capacity of these cells in culture with a decline after day 6, which also depended on insulin levels. Higher levels of insulin in the medium did not improve or extend the period of peroxidase secretion, which may be explained by faster consumption of glucose and/or achieving the limit of cell-specific metabolic activity.

In conclusion, this study introduced a method for simplifying isolation of LGACs using a cell strainer and a cell spin flask. In the culture method, we highlighted the importance of Matrigel as a culture substrate and low concentration of carbachol in the medium to maintain cell tropism. Also, most importantly, we identified the requirement for and the key concentration of insulin in the culture medium to maintain LGAC growth and secretory function. Improved understanding of culture methods can help develop strategies to restore post-mitotic injured tissues in the context of regenerative medicine, specifically in tissue engineering.

RefeRenCeS 1. Wilson SE. Lacrimal gland epidermal growth factor production and the ocular surfa-

ce. Am J Ophthalmol. 1991;111(6):763-5. 2. Pflugfelder SC. Tear fluid influence on the ocular surface. Adv Exp Med Biol. 1998;438:

611-7. 3. Alves M de C, Carvalheira JB, Modulo CM, Rocha EM. Tear film and ocular surface

changes in diabetes mellitus. Arq Bras Oftalmol. 2008;71(6 Suppl):96-103. 4. Jorge AG, Módulo CM, Dias AC, Braz AM, Filho RB, Jordão AA Jr., et al. Aspirin prevents

diabetic oxidative changes in rat lacrimal gland structure and function. Endocrine. 2009;35(2):189-97.

5. Kelleher RS, Hann LE, Edwards JA, Sullivan DA. Endocrine, neural, and immune con-trol of secretory component output by lacrimal gland acinar cells. J Immunol. 1991; 146(10):3405-12.

6. Dogru M. Tear secretion and tear film function in insulin dependent diabetics. Br J Ophthalmol. 2000;84(10):1210. Comment in: Br J Ophthalmol. 2000;84(1):19-21.

7. Modulo C, Jorge A, Dias A, Braz AM, Bertazolli-Filho R, Jordão AA Jr., et al. Influence of insulin treatment on the lacrimal gland and ocular surface of diabetic rats. Endocrine. 2009;36(1):161-8.

figure 8. The effect of insulin concentration in the supplemented low-glucose DMEM media on LGAC proliferation in primary culture, using Matrigel substrate over a span of 12 days. Comparative analysis of cell number (A) and viability (B) in response to three concentrations of insulin in the medium (0.5, 5.0, and 50.0 μg/mL) was evaluated. The culture was discontinued at the indicated days (0 through 12), and cell counting and viability testing was performed (n=3/condition) using a Neubauer chamber and trypan blue staining (black filled bars, 5.0 μg/mL insulin; white filled bars, 0.5 μg/mL insulin; grey filled bars, 50.0 μg/mL of insulin).

A

B

figure 7. Peroxidase activity in the culture medium using Matrigel substrate of LG acinar cells in primary culture from day 0 to 12. A) The culture medium containing the standard insulin concentration (5.0 μg/mL) was collected at the indicated days, prior to and 30 min after incubation with 100 mM carbachol. Peroxidase activity was analyzed as described in the methods (n = 2-4 samples/condition). B) The effect of insulin concentration on secretory activity over a period of 12 days in response to 100 mM carbachol stimulation. LGACs were cultured using three concentrations of insulin (0.5, 5.0, and 50.0 μg/mL). The culture media was collected on the indicated days (days 0-12) and peroxidase activity was measured (n=3/condition in duplicates) as described in the methods section (black filled bars, 5.0 μg/mL insulin; white filled bars, 0.5 μg/mL insulin; grey filled bars, 50.0 μg/mL of insulin).

B

A

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110 Arq Bras Oftalmol. 2016;79(2):105-10

8. Hann LE, Kelleher RS, Sullivan DA. Influence of culture conditions on the androgen control of secretory component production by acinar cells from the rat lacrimal gland. Invest Ophthalmol Vis Sci. 1991;32(9):2610-21.

9. Oliver C, Waters JF, Tolbert CL, Kleinman HK. Growth of exocrine acinar cells on a re constituted basement membrane gel. In Vitro Cell Dev Biol. 1987;23(7):465-73.

10. Schrader S, Kremling C, Klinger M, Laqua H, Geerling G. Cultivation of lacrimal gland acinar cells in a microgravity environment. Br J Ophthalmol. 2009;93:(8)1121-5.

11. Schrader S, Wedel T, Kremling C, Laqua H, Geerling G. Amniotic membrane as a carrier for lacrimal gland acinar cells. Graefes Arch Clin Exp Ophthalmol. 2007;245(11):1699-704.

12. Andersson SV, Edman MC, Bekmezian A, Holmberg J, Mircheff AK, Gierow JP. Cha-racterization of beta-hexosaminidase secretion in rabbit lacrimal gland. Exp Eye Res. 2006;83(5):1081-8.

13. Selvam S, Thomas PB, Trousdale MD, Stevenson D, Schechter JE, Mircheff AK, et al. Tissue-engineered tear secretory system: functional lacrimal gland acinar cells cul-tured on matrix protein-coated substrata. J Biomed Mater Res B Appl Biomater. 2007; 80(1):192-200.

14. Tiwari S, Ali MJ, Balla MM, Naik MN, Honavar SG, Reddy VA, et al. Establishing human lacrimal gland cultures with secretory function. PLoS One. 2012;7(1):e29458.

15. Oliver C. Isolation and maintenance of differentiated exocrine gland acinar cells in vitro. In vitro. 1980;16(4):297-305.

16. Dartt DA. Neural regulation of lacrimal gland secretory processes: relevance in dry eye diseases. Prog Retin Eye Res. 2009;28(3):155-77.

17. Hann LE, Tatro JB, Sullivan DA. Morphology and function of lacrimal gland acinar cells in primary culture. Invest Ophthalmol Vis Sci. 1989;30(1):145-58.

18. Ueda Y, Karasawa Y, Satoh Y, Nishikawa S, Imaki J, Ito M. Purification and characterization of mouse lacrimal gland epithelial cells and reconstruction of an aci-narlike structure in three-dimensional culture. Invest Ophthalmol Vis Sci. 2009;50(5): 1978-87.

19. Matsuzaki T, Suzuki T, Koyama H, Tanaka S, Takata K. Aquaporin-5 (AQP5), a water channel protein, in the rat salivary and lacrimal glands: immunolocalization and effect of secretory stimulation. Cell Tissue Res. 1999;295(3):513-21.

20. Alves M, Cunha DA, Calegari VC, Saad MJ, Boschero AC, Velloso LA, et al. Nuclear factor-kappaB and advanced glycation end-products expression in lacrimal glands of aging rats. J Endocrinol. 2005;187(1):159-66.

21. You S, Kublin CL, Avidan O, Miyasaki D, Zoukhri D. Isolation and propagation of me-senchymal stem cells from the lacrimal gland. Invest Ophthalmol Vis Sci. 2011;52(5): 2087-94.

22. Knox SM, Lombaert IM, Reed X, Vitale-Cross L, Gutkind JS, Hoffman MP. Parasympa-thetic innervation maintains epithelial progenitor cells during salivary organogenesis. Science. 2010;329(5999):1645-7. Comment in: Science. 2010; 329(5999):1610-1.

23. Bromberg BB. Autonomic control of lacrimal protein secretion. Invest Ophthalmol Vis Sci. 1981;20(1):110-6.

24. Bromberg BB, Cripps MM, Welch MH. Peroxidase secretion by lacrimal glands from juvenile F344 rats. Invest Ophthalmol Vis Sci. 1989;30(3):562-8.

Simpósio do Instituto Penido Burnier

11 de junho de 2016Instituto Penido Burnier

Campinas - SP

informações: E-mail: penido@penidoburnier.com.br

Case Report

111Arq Bras Oftalmol. 2016;79(2):111-2http://dx.doi.org/10.5935/0004-2749.20160032

InTRODUCTIOnPosterior scleritis is an ocular inflammatory disorder that is pre-

dominantly idiopathic, autoimmune, or rarely, infective(1,2). Anterior and posterior scleritis due to Mycobacterium tuberculosis are rare but have been reported in the literature(3); however, to our knowledge, isolated posterior scleritis associated with tuberculosis (TB) has only been described twice(1,4).

We report a patient with posterior scleritis associated with latent TB without associated uveitis, anterior scleritis, keratitis, or any other previous ocular disease history.

CASe RePORTA previously healthy 43-year-old woman presented with com-

plaints of painful reduced visual acuity and periorbital edema in her left eye of 4 days’ duration. Ophthalmological examination showed best corrected visual acuity (BCVA) in the right and left eyes of 6/6 and 6/60, respectively, and left eye proptosis, with no conjunctival or ciliary hyperemia and no anterior chamber reaction. Fundoscopy was unremarkable in the right eye, while the left eye showed choroidal folds, optic disc edema, and exudative inferior retinal detachment.

Orbital computerized tomography (CT) scan and magnetic re-sonance imaging revealed a left eye choroidal and transscleral mass

spreading to the Tenon’s space, along with thickening of the optic papilla (Figure 1).

Macular optical coherence tomography (OCT) showed edema with neurosensory retinal detachment in the left eye. B-scan ultra-sonography (Figure 2) revealed sclerochoroidal thickening and the presence of sub-Tenon’s space fluid (T-sign).

On fluorescein angiography, we found disc staining and multiple early pinpoint retinal pigment epithelial leaks (Figure 3).

The patient was treated for posterior scleritis with oral predniso-lone 1 mg/kg body weight once daily. After 2 weeks of treatment, an improvement in pain was noted by the patient, along with BCVA of 6/60 in the left eye with improvement of the macular OCT edema; ho-wever, on fundoscopy, worsening of the optic disc edema was found. The orbital CT scan and B-scan ultrasonography revealed identical results. Etiological investigation showed negative anti-HIV antibody test, C-reactive protein level of 0.3 mg/dL, elevated sedimentation rate (59 mm), negative rapid plasma reagin and treponema pallidum hemagglutination test, normal angiotensin-converting enzyme (25 UI/L), negative cytoplasmic and perinuclear anti-neutrophil cytoplasmic antibodies, negative Borrelia burgdorferi and Toxoplasma gondii IgG and IgM, and negative rheumatoid factor and antinuclear antibodies. The chest radiograph was normal and the patient denied any respiratory symptoms or recent travel in TB-endemic regions. The

Isolated posterior scleritis associated with tuberculosisEsclerite posterior isolada associada à tuberculose

ana fılıPa mıranDa1, João carDoso1, naDıne marques1, sanDra barros1, Paula telles1, nuno camPos1

Submitted for publication: March 23, 2015 Accepted for publication: May 2, 20151 Department of Ophthalmology, Hospital Garcia de Orta, Almada, Portugal.

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

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

Corresponding author: Ana Filipa Miranda. Av. Torrado da Silva, 2.801-951 - Almada - Portugal - E-mail: anafbmiranda@gmail.com

ABSTRACTOcular tuberculosis (TB) is considered to be rare, although its incidence has varied widely over time and in different populations. Latent TB is diagnosed when a person is infected with Mycobacterium tuberculosis but does not have active TB. During the last decade, interferon-gamma release assay tests have been developed that allow identification of patients with latent TB infection with better specificity than the tuberculin skin test and can differentiate between infection and prior vaccina-tion. Although rare, tuberculous scleritis should be considered in the differential diagnosis of posterior scleritis. Here we describe a patient with posterior scleritis and severe visual loss associated with latent TB without uveitis, anterior scleritis, keratitis, or any other previous ocular disease history. The patient responded well to a combined treatment of antitubercular therapy and oral corticosteroids.

Keywords: Scleritis/diagnosis; Tuberculosis, ocular/diagnosis; Eye infections, bac-terial; Mycobacterium tuberculosis

RESUMOA tuberculose (TB) ocular foi considerada rara, embora a sua incidência tenha variado significativamente ao longo do tempo e nas diferentes populações. A TB latente é diagnosticada quando alguém é infetado com Mycobacterium tuberculosis sem possuir doença ativa. Durante a última década, testes tendo por base interferon gamma release assay foram desenvolvidos, permitindo a identificação de pacientes com infeção por tuberculose latente com maior especificidade que o teste tuberculínico e diferenciar infeção e vacinação prévia. Embora rara, a esclerite tuberculosa deve ser tida em consideração no diagnóstico diferencial de esclerite posterior. Reportamos um paciente com esclerite posterior e baixa grave de acuidade visual associada a TB latente, sem uveíte, esclerite anterior, ceratite ou história de doença ocular prévia. O paciente respondeu favoravelmente a um tratamento combinado de fármacos antituberculose e corticoides orais.

Descritores: Esclerite/diagnóstico; Tuberculose ocular/diagnóstico; Infecções oculares bacterianas; Mycobacterium tuberculosis

Isolated posterior scleritis associated with tuberculosis

112 Arq Bras Oftalmol. 2016;79(2):111-2

patient had a positive result for the purified protein derivative (PPD) skin test (17 mm induration under corticotherapy 80 mg/day) and interferon-gamma release assay (IGRA), which is a more specific test. Antitubercular chemotherapy was started in combination with the oral corticosteroids, and was a combination of rifampicin 10 mg/kg, isoniazid 5 mg/kg, and pyrazinamide 25 mg/kg. The oral prednisolo-ne treatment was given for 10 weeks, and the antitubercular therapy for 9 months. After 10 weeks of treatment, the patient recovered a visual acuity of 6/6 in the left eye, the optic disc edema and choroidal folds disappeared, and the orbital CT scan (Figure 4) and B-scan ultra-sonography were normal. The patient has since remained asympto-matic for a period of 18 months.

DISCUSSIOn

This case report is an example of a patient with latent TB and seve-re posterior scleritis, with no signs of anterior segment involvement.

Some authors have suggested that infection due to TB should be considered as a possible cause of scleritis if the investigation reveals a positive PPD skin test, particularly if the scleral inflammation does not respond adequately to standard corticosteroid treatment(5). Given the worsening of the optic disc edema, no im provement of the BCVA, orbital CT scan, and B-scan ultrasonography with oral corticosteroids, and the positive results from the PPD skin and IGRA tests, we assumed that TB was the causative agent of the posterior scleritis, and started antitubercular therapy. An intraocular sample to confirm the diagnosis of Mycobacterium tuberculosis infection was not performed as the patient responded well to the combined treatment of oral corticosteroids and antitubercular therapy. In our investigation, we could not establish the presence of any connec-tive tissue disorder in our patient, and she has had no recurrences in the 18 months of follow-up, which suggests a non-connective tissue disorder as an etiology. Some authors consider a therapeu-tic trial to be justified in patients with severe sight-threatening intraocular inflammation and latent TB infection(6). Furthermore, the addition of antitubercular therapy to corticosteroids in uveitis patients with latent/manifested TB has been shown to reduce the recurrences of uveitis(7).

The difficulty in optic neuropathy screening in this patient led our infectious diseases specialists to not use ethambutol as part of the antitubercular regimen.

In conclusion, posterior scleritis associated with TB can present with no signs of anterior segment involvement, and responds well to a combination treatment of antitubercular therapy and oral corti-costeroids. Oral corticosteroids, given without antitubercular drugs, are likely to worsen the disease in these patients. The establishment of the diagnosis is very important for well-directed therapy, visual re covery, and no recurrences.

RefeRenCeS

1. Chen FK, White A, Harney BA. Systemic tuberculosis presenting with bilateral visual loss. Br J Ophthalmol. 2010;94(12):1686-7.

2. Gupta A, Gupta V, Pandav SS, Gupta A. Posterior scleritis associated with systemic tuberculosis. Indian J Ophthalmol. 2003;51(4):347-9.

3. Thompson MJ, Albert DM. Ocular Tuberculosis. Arch Ophthalmol. 2005;123(6):844-9. 4. Velasco e Cruz AA, Chahud F, Feldman R, Akaishi PM. Posterior scleral tuberculoma:

case report. Arq Bras Oftalmol. 2011;74(1):53-4. 5. Keino H, Watanabe T, Taki W, Nakashima C, Okada AA. Clinical features and visual outco-

mes of Japanese patients with scleritis. Br J Ophthalmol. 2010;94(11):1459-63. 6. La Distia Nora R, van Velthoven ME, Ten Dam-van Loon NH, Misotten T, Bakker M, van

Hagen MP, Rothova A. Clinical manifestations of patients with intraocular inflamma-tion and positive QuantiFERON-TB gold in-tube test in a country nonendemic for tu berculosis. Am J Ophthalmol. 2014;157(4):754-61.

7. Bansal R, Gupta A, Gupta V, Dogra MR, Bambery P, Arora SK. Role of anti-tubercular the-rapy in uveitis with latent/manifest tuberculosis. Am J Ophthalmol. 2008;146(5):772-9.

figure 1. CT scan of the patient showing a transscleral mass on the left eye.

figure 2. B-scan ultrasonography showing T-sign on the left eye of the patient.

figure 3. Fluorescein angiography with multiple early pinpoint retinal pig ment epithelial leaks.

figure 4. Normal orbital CT scan of the patient 10 weeks after treat ment.

Case Report

113Arq Bras Oftalmol. 2016;79(2):113-5http://dx.doi.org/10.5935/0004-2749.20160033

InTRODUCTIOnPseudophakic cystoid macular edema (PCME), or Irvine-Gass syn-

drome, is a common complication following cataract surgery(1). It was first described in 1953 by Irvine, and in 1966, Gass and Norton pu-blished an angiographic study of its characteristics(1,2). The incidence of clinical (symptomatic) PCME has been greatly reduced because of its advances in surgical techniques (approximately 0.1%-2.35%), and most cases of PCME have spontaneous resolution(2). Majority of patients remain asymptomatic without active inflammation on fundus examination and optical coherence tomography (OCT)(3). However, subclinical PCME is detected in almost 30% of patients with postsur-gical angiography and a further 11%-41% patients with OCT(4).

The pathogenesis of PCME remains obscure. Most investigators agree that inflammation is the main etiologic factor in the develop-ment of PCME(5). Inflammatory mediators disrupt the blood-aqueous barrier (BAB) and blood-retinal barrier (BRB), leading to an amplifica-tion of retinal permeability and the development of PCME(2,5).

No recent significant studies have been conducted to establish the best therapeutic options for treating this disorder(4). Non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids represent the most common first-line treatments(4,6). Antiangiogenic therapy, sub cu-

taneous injections of interferon α2a, hyperbaric therapy, and vitrecto-my are also therapeutic options(4,5). The dexamethasone implant (DEX implant; Ozurdex; Allergan, USA) is a 0.7 mg biodegradable intravitreal implant that delivers dexamethasone into the vitreous and retina. The drug acts on all inflammatory mediators and has been approved by the US Food and Drug Administration (FDA) for the treat ment of macular edema (ME) secondary to retinal vein occlusion (RVO) and for non-infectious posterior uveitis(4). The DEX implant has also been indicated for the treatment of diabetic ME in patients who are pseu-dophakic or are phakic and scheduled for cataract surgery(4).

In this study, we describe a case series of six patients who were previously diagnosed with PCME and treated with DEX implants.

CASe RePORTThis is a retrospective small case series of six patients who were

diagnosed with PCME and treated with DEX implants at the Centro Brasileiro de Cirurgia de Olhos (Goiânia, Goiás, Brazil) and Centro Bra sileiro da Visão (Brasília, Distrito Federal, Brazil) between 2013 and 2015. Spectral domain OCT (SD-OCT) was performed with a Spectralis instrument (Heidelberg Engineering, Heidelberg, Germany) during

Dexamethasone 0.7 mg implants in the management of pseudophakic cystoid macular edemaImplante de 0,7 mg de dexametasona no tratamento do edema macular cistóide do pseudofácico

José maurícıo botto De barros garcıa1,2, DavıD leonarDo cruvınel ısaac1,2, marcos Pereıra De Ávıla1,2

ABSTRACTPseudophakic cystoid macular edema (PCME) is a common complication follo-wing cataract surgery. Although majority of patients with PCME remain asympto-matic, it remains an important cause of vision loss after cataract surgery. The pathogenesis of PCME remains unclear, but most authors agree that inflammation plays a major role in its development. There is no standard algorithm for treatment procedures for PCME. A biodegradable 0.7 mg dexamethasone intravitreal implant can be used to deliver medication into the posterior segment of eyes. This drug acts on all inflammatory mediators and has been approved for the treatment of macular abnormalities secondary to retinal vein occlusion and for non-infectious posterior uveitis. In this case series, we report six patients who presented with PCME and were treated with a 0.7 mg dexamethasone intravitreal implant. Fa-vorable anatomical outcomes were demonstrated by spectral domain-optical coherence tomography images.

Keywords: Macular edema/etiology; Macular edema dexamethasone implants/drug therapy; Dexamethasone/administration & dosage; Visual acuity/physiology

RESUMOO edema macular cistóide do pseudofácico (PCME) é uma frequente complicação no acompanhamento pós-operatório da cirurgia de catarata. Embora a maioria dos pacientes apresente-se sem sintomas, PCME ainda permanece como importante causa de baixa visão após facectomia. Sua patogênese ainda permanece obscura, porém, autores sugerem que fatores que promovem maior inflamação possuem papel fundamental em sua origem. Não há um algoritmo padrão no manejo do PCME. O implante biodegradável de dexametasona 0,7 mg surgiu como possível arma terapêutica, após aplicação intra-vítrea. Essa droga consegue agir sobre me-diadores inflamatórios, além de já ter sido aprovada no tratamento do edema de macula secundário à oclusões venosas da retina, e uveítes posteriores de origem não infecciosa. Na seguinte série de casos, relatamos a evolução de 6 pacientes com PCME, submetidos a terapia com implante de dexametasona 0,7 mg. A melhora anatômica foi documentada com imagens de SD OCT.

Descritores: Edema macular/etiologia; Edema macular/quimioterapia; Dexameta-sona/administração & dosagem; Acuidade visual/fisiologia

Submitted for publication: May 11, 2015 Accepted for publication: July 21, 20151 Ophthalmology Department, Centro de Referência em Oftalmologia, Goiânia, GO, Brazil.2 Ophthalmology Department, Universidade Federal de Goiás, Goiânia, GO, Brazil.

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

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

Corresponding author: José Maurício Botto de Barros Garcia. Rua 234, 38/1011 - Setor Leste Universitário - Goiânia, GO - 74605-150 - Brazil - E-mail: zemauricio20@hotmail.com

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114 Arq Bras Oftalmol. 2016;79(2):113-5

pre- and post-procedure visits to evaluate macular status (Table 1). The first-li ne approach in all patients was a topical combination of NSAIDs and corticosteroids for a course of 3 months, what did not result in the clinical resolution of the described cases. Mild glaucoma had been previously diagnosed in two of the patients (Figures 1, 2, and 3). The patients ranged in age from 64 to 74 years (median: 69.75). Three of the patients were men (50.0%). The follow-up period after the procedure ranged from 48 to 201 days. The initial central retinal thickness (CRT) on SD-OCT ranged from 406 to 773 µm (median 542.5), and the final CRT ranged from 218 to 288 µm (median: 219.5). No patient presented significant changes in intraocular pressure du-ring the follow-up period.

DISCUSSIOnThe pathogenesis of PCME remains unclear, but it is generally

agreed that inflammation plays a major role in its development(2,4,5,7). Breakdown of the BAB and BRB may be associated with diabetes and glaucoma(2). Patients with diabetes, particularly those with diabetic retinopathy, are at an increased risk of developing PCME(8). In gene-ral, cataract surgery results in intraocular inflammation produced by inflammatory mediators that cause increased expression of vascular endothelial growth factor (VEGF), which potently induces increased permeability of the perifoveal capillary net and breakdown of the

BRB(5). However, to date, no studies have shown increased ocular VEGF levels in patients with PCME in the absence of ischemic ocular disease(2).

The DEX implant has been approved by the US FDA for the treat-ment of ME secondary to RVO, for non-infectious posterior uveitis and for the treatment of diabetic ME in patients who are pseudophakic or are phakic and scheduled for cataract surgery(4).

Dexamethasone has a six-fold more potent anti-inflammatory pro file than triamcinolone acetonide(8). A phase II study on the dexa-methasone drug delivery system conducted a subgroup analysis that included patients with PCME and patients with uveitis(4,9). A visual gain of at least 15 ETDRS letters was reported at the 90-day follow-up in 53.8% of the patients who were treated with 0.7 mg intravitreal dexa-methasone implants(9). In the EPISODIC study, cases of ocular hyper-tension were reported but were controlled with pressure-lowering me dications. No filtering surgery was required(4). In our group of pa tients, including two with previously diagnosed glaucoma, there was no need to change their current therapies.

In conclusion, when considering the relationship between in-flammation and the development of PCME, it is reasonable to hypo-thesize that DEX implants may offer a promising treatment option for patients who develop PCME following cataract surgery. Controlled studies with larger sample sizes should be performed to confirm these preliminary findings.

Table 1. Patient demographics and treatment history

PatientAge

(years) Gender eyefollow-up after Ozurdex® (days)

Initial SD-OCT (CRT)

final SD-OCT (CRT)

Initial BCVA (Snellen)

final BCVA (Snellen)

1 64 M OS 091 496 µm 252 µm 20/200 20/30

2 68 F OD 064 529 µm 227 µm 20/200 20/50

3 69 M OD 195 406 µm 218 µm 20/80 20/30

4 74 F OS 080 556 µm 216 µm 20/60 20/30

5 70 M OS 048 773 µm 221 µm 20/50 20/30

6 74 F OS 201 556 µm 288 µm 20/60 20/30

SD-OCT= spectral domain optical coherence tomography; BCVA= best-corrected visual acuity; CRT= central retinal thickness.

figure 1. A patient with mild glaucoma and PCME following cataract surgery. Top: FA demonstrates hyperfluorescence with a petaloid aspect in the late frames, and the SD-OCT displays cystic abnormalities, as well as subretinal fluid. Bottom: The patient returned with significantly reduced ME in the SD-OCT. PCME= pseudophakic cystoid macular edema; SD-OCT= spectral domain optical coherence tomography; ME= macular edema; FA= fluorescein angiogram.

Garcia JMBB, et al.

115Arq Bras Oftalmol. 2016;79(2):113-5

figure 2. The patient underwent cataract surgery 10 years ago in the OD. Top: FA and SD-OCT before DEX implantation. Bottom: Six months after DEX implantation, late frame FA and SD-OCT showed a reduction of the central retinal thickness of 302 µm. SD-OCT= spectral domain optical cohe-rence tomography; DEX= dexamethasone; FA= fluorescein angio gram.

figure 3. Patient with mild glaucoma under timolol 0.5% BID. A) Infrared photograph. B) Petaloid aspect in central macula displayed in FA of OD. C) SD-OCT de-monstrating ME before DEX implantation. D) SD-OCT 195 days after the procedure, with no signs of ME. SD-OCT= spectral domain optical coherence tomography; ME= macular edema; DEX= dexamethasone; FA= fluorescein angiogram; BID= twice daily.

A B C D e f

RefeRenCeS 1. Irvine SR. A newly defined vitreous syndrome following cataract surgery. Am J Ophthal-

mol. 1953;36(5):599-619. 2. Guo S, Patel S, Baumrind B, Johnson K, Levinsohn D, Marcus E, et al. Management of

pseudophakic cystoid macular edema. Surv Ophthalmol. 2015;60(2):123-37. 3. Kiernan DF HS. Controversies in the management of Irvine-Gass syndrome. Ophthal-

mic Surg Lasers Imaging Retina. 2013;44(6):522-7. 4. Bellocq D KJ, Burillon C, Voirin N, Dot C, Souied E, Conrath J, et al. Effectiveness and

sa fety of dexamethasone implants for post-surgical macular oedema including Irvine-Gass syndrome: the EPISODIC study. Br J Ophthalmol. 2015;99(7):979-83.

5. Arevalo JF, Maia M, Garcia-Amaris RA, Roca JA, Sanchez JG, Berrocal MH, et al. Intravitreal bevacizumab for refractory pseudophakic cystoid macular edema: the Pan-American Collaborative Retina Study Group results. Ophthalmology. 2009;116(8):1481-7.

6. Dutra Medeiros M NR, Garcia-Arumi J, Mateo C, Corcostegui B. Dexamethasone in-travitreal implant for treatment of patients with recalcitrant macular edema resulting from Irvine-Gass syndrome. Invest Ophthalmol Vis Sci. 2013;54(5):3320-4.

7. Brynskov TLC, Halborg J, Kemp H, Sorensen TL. Longstanding refractory pseudophakic cystoid macular edema resolved using intravitreal 0.7 mg dexamethasone implants. Clin Ophthalmol. 2013;7:1171-4.

8. Khurana RN PJ, Porco TC, Wieland MR. Dexamethasone intravitreal implant for pseu-dophakic cystoid macular edema in patients with diabetes. Ophthalmic Surg, Lasers Imaging Retina. 2015;46(1):56-61.

9. Williams GA, Haller JA, Kuppermann BD, Blumenkranz MS, Weinberg DV, Chou C, et al. Dexamethasone posterior-segment drug delivery system in the treatment of macular edema resulting from uveitis or Irvine-Gass syndrome. Am J Ophthalmol. 2009; 147(6):1048-54.

Case Report

116 Arq Bras Oftalmol. 2016;79(2):116-8 http://dx.doi.org/10.5935/0004-2749.20160034

InTRODUCTIOnThe ability to maintain the balance between cell death and the

regeneration of the corneal surface depends on the reserve of stem cells located in the limbal region(1). Injury to these cells can result from mechanical or chemical damage causing total or partial limbal stem cell deficiency, unilaterally or bilaterally. This deficiency can cause va rious signs and symptoms, including corneal neovascularization and conjunctivalization, loss of the Vogt palisades, irregularity of the corneal epithelium, presence of goblet cells on impression cytology of the cornea, and decreased visual acuity.

Different surgical techniques have been proposed for the treat-ment of ocular surface diseases caused by limbal stem cell de ficiency(2) (Table 1). In the case of unilateral presentation, the pro cedure of choice is conjunctival limbal autograft transplantation (CLAU), which involves the removal and transplantation of two fragments taken 90° (or three clock hours) from the limbus and adjacent conjunctiva of the healthy donor eye. In bilateral limbal stem cell deficiency, the most frequently indicated procedure is a heterologous transplant or limbal allograft, which involves the donation of the limbus and conjunctiva from the eye of either a human leukocyte antigen (HLA)-compatible relative [known as a living related conjunctival limbal allograft (LR-CLAL)] or a non-compatible donor, either live

ABSTRACTThis study aimed to evaluate the effectiveness of the novel simple limbal epithe-lial transplantation (SLET) technique, which reduces the risk of iatrogenic limbal stem cell deficiency in the donor eye. Four patients with total unilateral limbal stem cell deficiency received a limbal graft, measuring 4 mm × 2 mm, from the contralateral healthy eye in a single surgical procedure. The graft was divided into 10-20 pieces and distributed on the corneal surface. At 6-month follow-up, a completely avascular corneal epithelial surface was obtained in two patients, and there was improvement in visual acuity in one patient. The limbal grafts did not adhere to the cornea in one patient. No serious complications related to the surgery were observed in this study.

Keywords: Burns; Limbus corneae; Transplantation; Autologous; Epithelial cells/transplantation

RESUMOEste trabalho tem como objetivo avaliar a eficácia de uma nova técnica cirúrgica denominada SLET (simple limbal epithelial transplantation), um procedimento promissor que reduz os riscos de indução de deficiência límbica iatrogênica no olho doador. Quatro pacientes com deficiência límbica total unilateral, secundária a queimadura química, receberam um enxerto de células límbicas, medindo 4 mm x 2 mm, do olho contralateral sadio, em apenas um tempo cirúrgico. Este foi divido em 10 a 20 fragmentos e distribuído sobre a superfície da córnea. Após 6 meses de cirurgia, superfície corneana totalmente epitelizada e avascular foi obtida em dois pacientes. Houve melhora da acuidade visual em um paciente. Não houve aderência dos enxertos de limbo na córnea em um paciente. Nenhum paciente apresentou efeitos colaterais graves decorrentes do procedimento cirúrgico.

Descritores: Queimaduras; Limbo da córnea; Transplante; Transplante autólogo; Células epiteliais/transplante

[living conjunctival limbal allograft (CLAL)] or cadaveric [cadaveric limbal allograft (c-KLAL)](3,4). Although rare, there is a potential risk of iatroge nic limbal stem cell deficiency for the donor eye if a large amount of tissue is removed(5).

Another technique for treatment is cultivated limbal epithelial transplantation (CLET), which involves the minimal removal of limbic tissue, measuring approximately 2 mm, from the donor eye to be expanded ex vivo onto a scaffold as an amniotic membrane, which is then transplanted onto the recipient eye. However, the cost of es-tablishing and maintaining a stem cell laboratory is extremely high, restricting the availability of this technique to major research centers.

More recently, a new technique called simple limbal epithelial transplantation (SLET) was proposed for limbal autografts. SLET invol-ves the removal of a 4 mm × 2 mm limbal tissue graft from the donor eye. One of the benefits of SLET is a reduced risk of iatrogenic limbal stem cell deficiency in the donor eye that may occur during CLAU. In addition, SLET can be performed in a single surgical procedure and does not require a laboratory for cell expansion, thereby reducing the costs of surgery.

This case series evaluates the short-term results of limbal trans-plantation using SLET in patients with unilateral total limbal stem cell deficiency.

Assessment of surgical outcomes of limbal transplantation using simple limbal epithelial transplantation technique in patients with total unilateral limbal deficiency Avaliação dos resultados cirúrgicos do transplante de limbo utilizando a técnica SLET (simple limbal epithelial transplantation), em pacientes com deficiência límbica total unilateral

ana gabrıela queıroz1, martına marıa oıtıcıca barbosa1, mYrna seraPıão santos2, telma Pereıra barreıro2, José Álvaro Pereıra gomes2

Submitted for publication: October 30, 2014 Accepted for publication: March 17, 20151 Cornea Section, Department of Ophthalmology, Universidade Federal de São Paulo (UNIFESP),

São Paulo, SP, Brazil.2 Department of Ophthalmology, Universidade Federal de São Paulo (UNIFESP), São Paulo, 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 conflictof interest to disclose.

Corresponding author: Ana Gabriela Queiroz. Rua Júlio de Castilhos, 64/901 - Rio de Janeiro - RJ - 22081-025 - Brazil - E-mail: anagabiqueiroz@yahoo.com.br

Approved by the following research ethics committee: University of São Paulo (UNIFESP), São Paulo (SP), Brazil. Number of research project (CAAE): 30939914.2.0000.5505.

Queiroz AG, et al.

117Arq Bras Oftalmol. 2016;79(2):116-8

MeTHODSFour patients diagnosed with unilateral total limbal stem cell

de ficiency due to ocular burn were selected for inclusion in this case series. The diagnosis was defined on the basis of clinical criteria, inclu-ding loss of the Vogt palisades, irregularity of the corneal epithelium, superficial corneal vascularization, persistent epithelial defect, and corneal conjunctivalization.

The procedure was performed under peribulbar anesthesia in the recipient eye and topical anesthesia in the donor eye. In the donor eye, a 4 mm × 2 mm section of limbal tissue was marked with a te-cidual pen (Codman 38). Excision of the corneal-scleral conjunctiva and limbal tissue was performed. In the recipient eye, 360° peritomy and superficial keratectomy with the removal of the abnormal epi-thelium and fibrovascular pannus were performed (Figure 1). Then amniotic membrane(8) attached to the underlying corneal stroma was transplanted using a fibrin tissue adhesive (Evicel®, Johnson & Johnson, Somervile, NJ, USA). The limbal graft was divided into 10 to 20 equal pieces, which were placed on the amniotic membrane with the epithelial side up, in a circular fashion, while avoiding the visual axis. At the end of the surgical procedure, a soft contact lens was placed on the recipient eye and was followed by overnight patching.

Postoperatively, antibiotics eye drops (moxifloxacin 5 mg/mL eye drops, Vigamox®, Alcon Labs, Brazil) were prescribed for instillation four times a day together with topical steroid (prednisolone acetate 1% eye drops, Pred Fort®, Alcon Labs, Brazil) instillation six times a day. Patients were evaluated on days 1, 7, 15, and 30 and then monthly for until 6-month follow-up.

ReSULTSThe demographic and clinical characteristics of patients are des-

cribed in table 1. At 6-month follow-up, a completely epithelialized and avascular corneal surface was observed in two patients (50%, cases 1 and 2; Figure 2). Visual acuity improved from hand motion (HM) to 20/80 vision (Case 2) in one patient. The other patients did not have any change in the final visual acuity because of the presen-ce of stromal opacity in the visual axis. In one patient, there was no adherence of the amniotic membrane and limbal cornea fragments (Case 3). Another patient (Case 4) had a recurrence of corneal neovas-cularization and persistent epithelial defect after 6-months follow-up. None of the patients developed any infectious complications resul-ting from the surgical procedure (Table 2).

DISCUSSIOnDespite good results with the conventional technique for limbal

autograft transplantation (CLAU), the SLET technique may be increa-

A

D

B

e

C

f

figure 2. Series of photographs of two patients who successfully underwent SLET. (A) Preoperative appearance of case 1: male, after 6 years of an acid corneal burn in the left eye, with unilateral total limbal stem cell deficiency. (B) Postoperative appearance of case 1 (30-day follow-up): total corneal epithelialization. (C) Postoperative appearance of case 1 (90-day follow-up): total corneal epithelialization, superficial vascularization 12 to 24 hours and some fragments of limbal graft in absorption. (D) Preoperative appearance of case 2: Female patient, after 30 years of an alkali corneal burn, with unilateral total limbal stem cell deficiency. (E) Postoperative appearance of case 2 (60-day follow-up): total corneal epithelialization. (F) Postoperative appearance of case 2 (180-day follow-up): total corneal epithelialization, avascular cornea, and some fragments of limbal graft in absorption.

Table 1. Comparison of the SLeT, CLeT, and CLAU surgical techniques for limb transplant(10)

SLeT CLeT CLAU

Surgical time One Two One

Interval between surgical time None Two weeks None

Size of donor tissue (mm) 2 2 10-20

Conjunctival donor tissue No No Yes

Stem cell laboratory No Yes No

Amniotic membrane Yes Yes No

Site of transplantation Over entire cornea

Over entire cornea

Only over the limbo

Possibility of causing limbal stem cell deficiency in the donor eye

No No Yes

Favorable outcome Waiting 50%-100% 77%-100%

SLET= simple limbal epithelial transplantation; CLET= cultivated limbal epithelial trans-plantation; CLAU= conjunctival autograft transplantation.

Table 2. Clinical and demographic characteristics of patients with limbal stem cell deficiency who underwent SLeT

CaseAge

(years) Sex eyeDuration

(years)Ocular

surgery Initial VA final VA

1 38 M L 6 CLAU HM HM

2 55 F R 30 No CF at 1 m 20/80

3 74 M R 10 No CF at 2 m CF at 2 m

4 14 M R 5 Eyelid reconstruction

HM HM

SLET= simple limbal epithelial transplantation; L= left eye; R= right eye; M= male; F= female; CLAU= conjunctival autograft transplantation; VA= visual acuity; HM= hand movements; CF at 1 m= counting fingers at 1 meter; CF at 2 m= counting fingers at 2 meter.

singly used when considering the associated reduction in the risk of iatrogenic limbal stem cell deficiency in the donor eye. Techniques involving cell therapy represent a major advance in the treatment of ocular surface diseases. Studies have suggested that transplantation of limbal stem cells that are expanded ex vivo (CLET) is safer for the donor eye because it requires lesser tissue and has better long-term results because of the higher number of cultivated limbal cells that are transplanted(9,10). However, the costs of installing and maintaining

figure 1. Clinical photographs showing the surgical technique of simple limbal epi-thelial transplantation (SLET). (A) 360° peritomy was performed. (B) The fibrovascular pannus is excised from the recipient cornea. (C) A human amniotic membrane graft is placed on the bare ocular surface and secured to it with fibrin glue. (D, E) The donor limbal tissue is cut into small pieces. (F, G) The small limbal transplants are transferred to the recipient eye and fixed in place with fibrin glue. (H) A soft bandage contact lens is placed on the recipient eye.

A

e

B

f

C

G

D

H

Assessment of surgical outcomes of limbal transplantation using simple limbal epithelial transplantation technique in patients with total unilateral limbal deficiency

118 Arq Bras Oftalmol. 2016;79(2):116-8

a stem cell laboratory restrict the use of the procedure to major research centers.

The SLET technique described in this case series presents the advantages of CLAU, including a single surgical procedure and the nonrequirement for a stem cell laboratory, in addition to the same advantages as CLET, related to the use of lower amounts of donor tissue (Table 1 compares CLAU, CLET, and SLET techniques).

In this case series, we observed good results in two out of four (50%) of patients. However, no substantial improvement in visual acuity was observed because of the underlying corneal opacity. There-fore, the next step for visual rehabilitation in these patients is corneal transplantation.

Case 1 had a history of failed limbal transplantation (CLAU). It could possibly be considered that this surgery interfered with the outcome; however, the fact that CLAU failed and conjunctivalizations recurred and that SLET was associated with previous 360° peritomy and keratectomy make such a possibility unlikely.

Among the two cases in which we were unsuccessful, one case presented an early complication, including limbo-conjunctival frag-ments and amniotic membrane detachment, and the second case showed graft failure and recurrence of corneal neovascularization. The failure in the first case can be explained by a problem with the biologi-cal adhesive used or traumatic displacement of the graft. In the second case, there may have been damage or failure of the transplanted limbal epithelial stem cells. In addition, it is possible that, as with any surgical procedure, the learning curve has influenced our results.

Considering the first results of SLET published by Sangwan et al.(7) and the satisfactory initial results we obtained in two of our four cases, it seems that the SLET technique may be a good alternative in

treating total limbal stem cell deficiency. In conclusion, these results suggest the need for larger studies to observe the long-term outco-mes and to confirm the effectiveness of the SLET technique.

RefeRenCeS 1. Cotsarelis G, Cheng SZ, Dong G, Sun TT, Lavker RM. Existence of slow-cycling limbal

epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells. Cell. 1989;57:201-9.

2. Sheraz M. Daya, FACP, FACS, Clara C. Chan, FRCSC, Edward J. Holland. Cornea Society Nomenclature for Ocular Surface Rehabilitative Procedures. Cornea. 2011;30:1115-9.

3. Kenyon KR, Tseng SC. Limbal autograft transplantation for ocular surface disorders. Ophthalmology. 1989;96:709-22.

4. Barreiro TP, Santos MS, Vieira AC, de Nadai Barros J, Hazarbassanov RM, Gomes JA. Comparative study of conjunctival limbal transplantation not associated with the use of amniotic membrane transplantation for treatment of total limbal deficiency secundary to chemical injury. Cornea. 2014;33(7):716-20.

5. Miri A, Said DG, Dua HS. Donor site complications in autolimbal and living related allolimbal transplantation. Ophthalmology. 2011;118:1265e71.

6. Gomes JA, Pazos HS, Silva AB, Cristovam PC, Belfort Júnior R. Transplantation of alloge-nic limbal epithelial stem cells cultivated ex vivo on amniotic membrane: case report]. Arq Bras Oftalmol. 2009;72(2):254-6.

7. Sangwan VS, Basu S, MacNeil S, Balasubramanian D. Simple limbal epithelial trans-plantation (SLET): a novel technique for the treatment of unilateral limbal stem cell deficiency. Br J Ophthalmol. 2012;96:931-4.

8. Gomes JAP, Komagome, CM, Santos, Chaves AP, Cunha C, Freitas D (1999). Membrana amniótica nas cirurgias reconstrutivas da superfície ocular nas ceratoconjuntivites cicatriciais. Arq Bras Oftalmol. 1999;62(5):562-76.

9. Santos MS, Gomes JA, Hofling-Lima AL, Rizzo LV, Romano AC, Belfort R Jr. Survival ana lysis of conjunctival limbal grafts and amniotic membrane transplantation in eyes with total limbal stem cell deficiency. Am J Ophthalmol. 2005 Aug;140(2):223-30.

10. Ang LP, Sotozono C, Koizumi N, Suzuki T, Inatomi T, Kinoshita S. A comparison between cultivated and conventional limbal steam cell transplantation for Stevens-Johnson Syndrome. Am J Ophthalmol. 2007;143:178-80.

Case Report

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InTRODUCTIOn Bilateral acute depigmentation of the iris (BADI) is a rare disorder

with unknown etiology. It was described for the first time in Turkey in 2006(1). It occurs more frequently in middle-aged women and is cha-racterized by asymptomatic, bilateral, symmetrical, and simultaneous iris depigmentation with focal or diffuse stromal atrophy(2,3).

Although BADI is not usually associated with atrophy of the iris pigmented epithelium, pigment dispersion in the anterior chamber and pigment deposition in the trabecular meshwork have been re-ported. The prognosis is generally good and repigmentation can occur spontaneously(3-5).

Here we describe a case of BADI and discuss its main clinical aspects and differential diagnosis.

CASe RePORTA 26-year-old emmetropic woman presented to our clinic after

no ticing spontaneous iris color change over the past 2 months. Her personal and family medical histories were negative for eye diseases.

Visual acuity was 20/20 and intraocular pressure was 12 mmHg (at 10:00 am) in both eyes. Biomicroscopy revealed extensive bilate-ral stromal iris atrophy (Figures 1 and 2). The transillumination test was negative and the lens showed no abnormalities. Gonioscopy showed an open iridocorneal angle with a heavily pigmented trabe-cular meshwork. The dilated fundus examination was unremarkable in both eyes.

Her serology tests were negative for herpes simplex IgM (herpes simplex IgG positive), hepatitis B and C, and toxoplasmosis. The tuber-culin sensitivity test was non-reactive (0 mm).

There was no detectable change in the clinical examination after 10 months of follow-up, with maintenance of the pattern of bilateral stromal iris atrophy without any transillumination defects (Figures 3 and 4).

DISCUSSIOnBADI is a rare disease with unknown etiology and pathophysio-

logy. The largest published case series of BADI enrolled 26 patients and revealed a previous history of upper respiratory tract infection in 35.8%(5). The authors also suggested an association of BADI with cy tomegalovirus infection(5). Another study suggested a possible re -l a tionship with the herpes simplex virus and varicella zoster virus(1). Non-infectious etiologies like iris ischemia and neurotrophic mecha-nisms have also been proposed(3); however, no causative agents have been confirmed yet.

Despite the lack of clinical change after 10 months of follow-up in the case described in this report, other studies have shown that there could be spontaneous resolution over time(3,5).

The differential diagnosis of BADI includes Fuchs heterochromic uveitis, herpetic iridocyclitis, pigment dispersion syndrome, and pseudoexfoliation syndrome(6).

Bilateral acute depigmentation of the iris: a case reportDespigmentação aguda bilateral da íris: um relato de caso

Débora raquel rıgon narcıso fachın1, marıa fernanDa De Paula Prestes2, angelıno Julıo carıello1, mÁrıo Junqueıra nóbrega1,3

Submitted for publication: January 21, 2015 Accepted for publication: March 11, 20151 Department of Ophthalmology, Hospital de Olhos Sadalla Amin Ghanem, Joinville, SC, Brazil.2 Universidade de Joinville (UNIVILLE), Joinville, SC, Brazil.3 Department of Ophthalmology, Universidade de Joinville (UNIVILLE), Joinville, SC, Brazil.

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

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

Corresponding author: Débora Raquel Rigon Narciso Fachin. Rua Camboriú, 35 - Joinville, SC - 89216-222 - Brazil - E-mail: deboranarciso@hotmail.com

ABSTRACTBilateral acute depigmentation of the iris (BADI) is a new clinical entity of unknown etiology and is characterized by bilateral, symmetrical, and simultaneous depig-mentation of the iris with focal or diffuse stromal atrophy; this condition generally has a good prognosis. We present a case of a 26-year-old woman who noted a spontaneous change in the iris color in both eyes in the last 2 months. The oph thal mological findings were atrophy of the iris stroma and pigmentation of the trabecular meshwork, without affecting the pigmented epithelium of the iris. Her intraocular pressure was normal and the visual acuity was 20/20 in both eyes.

Keywords: Iridocyclitis; Iris; Iris diseases; Pigment epithelium of eye; Pigmentation disorders; Eye color

RESUMOA despigmentação aguda bilateral da íris (DABI) é uma nova entidade clínica carac-terizada pela despigmentação bilateral, simétrica e simultânea da íris, com atrofia focal ou difusa do seu estroma, geralmente com bom prognóstico. Apresentamos o caso de uma mulher de 26 anos de idade que procurou atendimento médico em nosso serviço com queixa de mudança espontânea na cor da íris de ambos os olhos nos últimos dois meses. Os achados oftalmológicos observados durante o exame clínico foram atrofia do estroma da íris e pigmentação da malha trabecular, sem afetar o epitélio pigmentado da íris. A pressão intraocular era normal e acuidade visual de 20/20 em ambos os olhos.

Descritores: Iridociclite; Íris; Doenças da íris; Epitélio pigmentado ocular; Transtornos da pigmentação; Cor de olho

Bilateral acute depigmentation of the iris: a case report

120 Arq Bras Oftalmol. 2016;79(2):119-20

figure 1. Diffuse bilateral iris atrophy in the right eye.

figure 2. Diffuse bilateral iris atrophy in the left eye.

figure 3. Aspect of the right eye after 10 months.

figure 4. Aspect of the left eye after 10 months.

Fuchs heterochromic uveitis is bilateral only in 5%-10% of cases and generally presents with stellate keratic precipitates, mild intrao cular inflammation, and cataract(5). Herpetic iridocyclitis generally ma nifests as a unilateral hypertensive acute anterior uveitis in pa tients with decreased corneal sensitivity. A subsequent positive tran sillu mination test may be observed as a sequela of the posterior iris pig ment epi-thelium atrophy(7).

The pigment dispersion and pseudoexfoliation syndromes exhibit typical bilateral, irreversible, posterior iris pigment epi-thelium defects and a positive transillumination test on slit lamp exa mination(8).

The diagnosis of BADI is based on clinical features and may be chal-lenging due to its rarity and the paucity of noted signs and symptoms. Nonetheless, the clinical findings described in this case were different from those observed in all the entities mentioned above. We believe that the prevalence of this disease may be higher than previously thought and that documenting periodical iris images may help in the diagnosis of suspected cases.

Maestrini et al.(2) described the first Brazilian case of this disease; however, as pointed by experts in this pathology in a letter to the editor(9), deeper analysis of the case demonstrated that the characte-ristics were closer to another pathological condition called bilateral acute iris transillumination (BAIT). This disorder usually shows atonic dilated pupils and diffuse iris transillumination defects and has a

higher incidence of IOP elevation(10). Thus, we believe that our report is the first described case of BADI in Brazil.

RefeRenCeS 1. Tugal-Tutkun I, Urgancioglu M. Bilateral acute depigmentation of the iris. Graefe’s Arch

Clin Exp Ophthalmol. 2006;244(6):742-6. 2. Maestrini HA, Maestrini AA, Machado DO, Santos DV, Almeida HG. Bilateral acute de-

pigmentation of the iris (BADI): first reported case in Brazil. Arq Bras Oftalmol. 2013; 76(1):42-4. Comment in: Arq Bras Oftalmol. 2014;77(3):201.

3. Barraquer F, Mejía LF. Bilateral acute depigmentation of the iris: first report on the American continent and 5 years follow-up of two patients. J Emmetropia [Internet]. 2012[cited 2014 Jun 21];3(3):118-22. Available from: http://www.journalofemmetropia.org/2171-4703/v3n3/v3-3-02.pdf

4. Portmann A, Gueudry J, Siahmed K, Muraine M. [Bilateral acute depigmentation of the iris syndrome]. J Fr Ophthamol. 2010;34(5):309-12.

5. Tugal-Tutkun I, Araz B, Taskapili M, Akova YA, Yalniz-Akkaya Z, Berker N, et al. Bilateral acute depigmentation of the iris: report of 26 new cases and four-year follow-up of two patients. Ophthalmology. 2009;16(8):1552-7.

6. Goktas A, Goktas S. Bilateral acute depigmentation of the iris first misdiagnosed as acute iridocyclitis. Int Ophthalmol. 2011;31(4):337-9.

7. Siverio Junior CD, Imai YD, Cunningham ET Jr. Diagnosis and management of herpetic anterior uveitis. Int Ophthalmol Clin. 2002;42(1):43-8.

8. Niyadurupola N, Broadway DC. Pigment dispersion syndrome and pigmentary glau-coma - a major review. Clin Experiment Ophthalmol. 2008;36(9):868-82.

9. Gonul S, Bozkurt B. Bilateral acute depigmentation of the iris (BADI): first reported case in Brazil. Arq Bras Oftalmol. 2014;77(3):201. Comment on: Arq Bras Oftalmol. 2013;76(1):42-4.

10. Tugal-Tutkun I, Onal S, Garip A, Taskapili M, Kazokoglu H, Kadayifcilar S, Kestelyn P. Bila-teral acute iris transillumination. Arch Ophthalmol. 2011;129(10):1312-9.

Case Report

121Arq Bras Oftalmol. 2016;79(2):121-2http://dx.doi.org/10.5935/0004-2749.20160036

InTRODUCTIOnSeveral dyes are used to stain the anterior capsule during cata-

ract surgery, including indocyanine green, sodium fluorescein, rose bengal, gentian violet, and trypan blue(1). Trypan blue (0.025%) is ge nerally considered safer than other dyes because it does not cause postoperative inflammation, endothelial dysfunction, residual staining of the anterior chamber, or iris staining(2). The use of inappro-priate dyes or dyes at inappropriate concentrations may result in se-vere ocular toxicity(3,4). We report a case of inadvertent administration of 1% methylene blue for capsule staining during cataract surgery. Limited effects of methylene blue toxicity were observed contrary to expectations with no evidence of bullous keratopathy(5,6). We discuss the possible reasons for the limited toxic effects observed following the administration of 1% methylene blue into the anterior chamber.

CASe RePORT We report a case of inadvertent injection of 0.1-0.2 ml of 1%

methylene blue into the anterior chamber instead of 0.025% trypan blue for anterior capsule staining during phacoemulsification in a 70-year-old female patient with a mature cataract in the left eye. On injection of the dye into the anterior chamber, the administering surgeon observed that the blue dye was darker than normal and the cornea was gradually staining blue. When it was understood that the incorrect dye had been used to stain the anterior capsule on questioning the nurse, the area was copiously irrigated with balanced salt solution for approximately 30 min using an anterior chamber maintainer (ACM). After the capsule was stained and the setting

became sufficiently transparent, surgery proceeded without further complications, and a foldable acrylic intra ocular lens was implanted in the capsular bag. The following day, eye examination revealed +3 diffuse corneal edema, a visual acuity of approximately 0.05, and an intraocular pressure of 14 mmHg. Hourly topical steroid and antibio-tic therapies were initiated. After one week, eye examination findings persisted. Eye examination at one month revealed +1 central corneal edema and 3/10 visual acuity (Figures 1 and 2). On eye examination at 24 months, corneal edema had almost entirely resolved, although subtle stromal haze and iris discoloration persisted, and the central corneal thickness had thickened (560/510 µm) compared with that of her right eye (Figures 3 and 4).

DISCUSSIOnMethylene blue and trypan blue, which are used in the operating

theatre, are generic brands stored in multiple-use bottles. Methylene blue is maintained in the operating theatre for multiple uses, inclu-ding skin marking during eyelid surgery (blepharoplasty) and scleral marking during scleral buckling. Trypan blue is commonly used to stain the anterior capsule in challenging cataract cases. Trypan blue selectively stains the basal membrane of the anterior capsule. Methy-lene blue stains the anterior capsule in a similar manner.

The effects of inadvertent intraocular injection of methylene blue have not been discussed in detail in previous literature. A number of studies have performed intrachamber administration of various dyes to establish the safety and efficacy of dye injections(3,4). These studies demonstrated no corneal endothelial damage on the intrachamber

Methylene blue-related corneal edema and iris discolorationEdema de córnea e descoloração de íris associados ao azul de metileno

ozgur bulent tımucın1, mehmet fatıh karaDag1, mehmet emın aslancı2, mehmet baYkara2

Submitted for publication: March 11, 2015 Accepted for publication: May 2, 20151 Department of Ophthalmology, Istanbul Hospital, Van, Turkey.2 Department of Ophthalmology, School of Medicine, Uludag University, Bursa, 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: Ozgur Bulent Timucin. Van Özel İstanbul Hastanesi. Oftalmoloji Bölümü - Merkez/Van - 65100 - Turkey - E-mail: bulenttimucin@gmail.com

ABSTRACTWe report the case of a 70-year-old female patient who developed corneal edema and iris discoloration following the inadvertent use of 1% methylene blue instead of 0.025% trypan blue to stain the anterior capsule during cataract phacoemulsi-fication surgery. Copious irrigation was performed upon realization of incorrect dye use. Corneal edema and iris discoloration developed during the early posto-perative period and persisted at 24-months follow-up. However, keratoplasty was not required. The intracameral use of 1% methylene blue has a cytotoxic effect on the corneal endothelium and iris epithelium. Copious irrigation for at least 30 min using an anterior chamber maintainer may improve outcomes.

Keywords: Phacoemulsification; Corneal edema; Iris; Methylene blue; Anterior eye segment; Drug effects; Adverse effects; Ophthalmic solutions; Case reports

RESUMOPaciente do sexo feminino com 70 anos de idade desenvolveu edema da córnea e des-coloração da íris após o uso inadvertido de 1% de azul de metileno em vez de 0,025% de azul tripano para corar a cápsula anterior do cristalino durante a cirurgia de catarata por facoemulsificação. Foi realizada irrigação abundante quando detectou-se que o corante incorreto tinha sido usado. Edema da córnea e descoloração íris que ocorreu no período pós-operatório precoce persistiu durante 24 meses de seguimento; no entanto, a ceratoplastia não foi necessária. O uso intracameral de 1% de azul de metileno tem efeitos citotóxicos sobre o endotélio da córnea e epitélio da íris. A irrigação abundante durante pelo menos 30 minutos, utilizando um mantenedor de câmara anterior pode resultar em um prognóstico melhor.

Descritores: Facoemulsificação; Edema da córnea; Segmento anterior do olho; Íris/efei-tos de drogas; Azul de metileno/efeitos adversos; Soluções oftálmicas; Relatos de casos

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122 Arq Bras Oftalmol. 2016;79(2):121-2

injection of 0.05 ml of 0.2% methylene blue for 1 min by transmission electron microscopy. Corneal endothelial toxicity begins to occur with intrachamber administration of 0.5% methylene blue(3). A con-centration of 0.1% is sufficient to stain the anterior capsule without causing ocular toxicity or staining of adjacent structures(3).

We identified similar publications in the literature reporting the inadvertent use of methylene blue and found one case that develo-ped bullous keratopathy after persistent corneal edema, resulting in keratoplasty, and one case that developed persistent corneal edema and endophthalmitis with progression to corneal failure(5,6). Based on previously reported cases, we predicted the definitive develop-ment of bullous keratopathy because of endothelial insufficiency in this case. However, we determined bullous keratopathy had not developed and that a functional level of vision had been preserved after a 24-month follow-up period. Copious irrigation of the anterior chamber using ACM may have protected against the expected deve-lopment of bullous keratopathy. The anterior chamber was irrigated throughout the surgery using a 20-G ACM attached to a balanced salt solution bottle. In contrast to previously reported similar cases, irrigation of the anterior chamber using ACM for at least 30 min may have protected the corneal endothelium in our case. We believe that the cornea may have been partially protected by the treatment me-thod utilized in this case, a clinical scenario that may be encountered by any surgeon. However, this explanation for the improved outco-me in this case requires validation in experimental animal models. Therefore, ACM may be an important tool in the management of inadvertent intraocular injection of toxic dyes by facilitating anterior

figure 1. Central corneal edema on postoperative day 1.

figure 2. Persistent central corneal edema and iris discoloration at one month postoperatively.

figure 3. Complete resolution of corneal edema clinically observed at 24 months postoperatively.

figure 4. Complete resolution of corneal edema clinically observed at 24 months postoperatively.

chamber washout and reducing iatrogenic injury of the iris and cor-neal endothelium.

A number of minor precautionary measures in the operating room may help avoid the inadvertent use of methylene blue instead of trypan blue, including labeling methylene blue bottles in an obvious manner, the use of different cap colors, and storing methylene blue in a different location to trypan blue.

RefeRenCeS 1. Dada VK, Sharma N, Sudan R, Sethi H, Dada T, Pangtey MS. Anterior capsule staining

for capsulorhexis in cases of white cataract: comparative clinical study. J Cataract Refract Surg. 2004;30(2):326-33.

2. Marback EF, Freitas LL, Fernandes FP, Branco BC, Belfort R Jr. Anterior capsule staining using 0.025% trypan blue in cataracts without red reflex.  Arq Bras Oftalmol. 2001; 64(4):333-5.

3. Chang YS, Tseng SY, Tseng SH, Chen YT, Hsiao JH. Comparison of dyes for cataract surgery. Part 1: cytotoxicity to corneal endothelial cells in a rabbit model. J Cataract Refract Surg. 2005;31(4):792-8.

4. Chang YS, Tseng SY, Tseng SH. Comparison of dyes for cataract surgery. Part 2: efficacy of capsule staining in a rabbit model. J Cataract Refract Surg. 2005;31(4):799-804.

5. Lim AK, Ulagantheran VV, Siow YC, Lim KS. Methylen blue related sterile endophthal-mitis. Med J Malaysia. 2008;63(3):249-50.

6. Brouzas D, Droutsas D, Charakidas A, Malias I, Georgiadou E, Apostolopoulos M, et al. Severe toxic effect of methylene blue 1% on iris epithelium and corneal endothelium. Cornea. 2006;25(4):470-1.

Case Report

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InTRODUCTIOnPrimary congenital glaucoma (PCG) is the most frequent childhood

glaucoma and an important cause of blindness. Surgical manage-ment of PCG is challenging because of an elevated risk of complica-tions and failure of surgery as a result of anatomical factors related to ocular enlargement and aggressive healing(1).

Goniotomy and trabeculotomy are the first-line surgical inter-ventions for PCG; however, approximately 15%-20% of PCG cases are refractory to these techniques(2). When angle procedures fail, more invasive surgeries are required to reduce the intraocular pressure (IOP), such as trabeculectomy or insertion of a glaucoma drainage implant(3).

Here we present an atypical case of panophthalmitis with orbital cellulitis following treatment with an Ahmed™ glaucoma valve (AGV) implant.

CASe RePORTThe patient was a 15-month-old male child who presented to the

ophthalmologic emergency room of Hospital São Paulo with severe edema and erythema affecting the superior eyelid of the left eye. The mother had observed moderate hyperemia and purulent eye discharge associated with prostration and low fever over a period of 2 days previously. Examination was limited due to a lack of coopera-tion. Routine ophthalmological evaluation performed a week earlier had been unremarkable.

According to the parents, the patient had a history of blepharos-pasm, epiphora, and photophobia in both eyes since birth and had been diagnosed with PCG at 2 months of age. All information related to previous ophthalmological history was collected from medical re-

ABSTRACTHere we report a case of childhood glaucoma refractory to angle and trabeculec-tomy surgery. The patient was treated with an Ahmed™ drainage implant that was subsequently complicated by rapid-onset panophthalmitis and orbital cellulitis. Intravenous and intravitreal antibiotic therapy was initiated and the drainage tube was removed. The infectious process resolved within 3 weeks; however, phthisis bulbi developed subsequently.

Keywords: Glaucoma/congenital; Glaucoma drainage implant; Endophthalmitis/surgery; Panophthalmitis/surgery; Orbital cellulitis

RESUMORelato de um caso de uma criança portadora de glaucoma congênito primário, refratário a cirurgias angulares e trabeculectomias prévias, submetido à implante de drenagem do tipo Ahmed®. O paciente evoluiu com panoftalmite e celulite orbitária de aparecimento súbito, sendo submetido à remoção do tubo e antibioticoterapia endovenosa e intravítrea. O processo infeccioso foi resolvido em três semanas, porém o olho evoluiu para phthisis bulbi.

Descritores: Glaucoma/congênito; Implantes para drenagem de glaucoma; Endoftal-mite/cirurgia; Panoftalmite/cirurgia; Celulite orbitária

cords (Pediatric Glaucoma Nucleus - Federal University of São Paulo). Initial examination under anesthesia revealed buphthalmos [axial length: 22.43 mm, oculus dexter (OD); 23.99 mm, oculus sinister (OS)], corneal enlargement [13 mm, oculus uterque (OU)] with important haze and an elevated IOP (OD: 24 mmHg/OS: 28 mmHg). Trabeculo-tomy was subsequently performed on both eyes.

In order to manage IOP during the first year, other surgeries were attempted on both eyes, including trabeculotomy (OS), combined trabeculotomy and trabeculectomy (OD), and trabeculectomy (OU). All surgeries were uneventful.

One month prior to this presentation to the emergency room, the patient presented with bilateral increases in axial length (OD, 28.60 mm; OS, 28.76 mm) and an elevated IOP. No filtration bleb was observed in the OS during ophthalmological examination under anesthesia. Subsequently, uneventful AGV implantation was perfor-med (FP7 model, New World Medical Inc., Rancho Cucamonga, CA). The parents stated that moxifloxacin 0.5% (4 times/day for 10 days) and prednisolone acetate 1% (5 times/day for 4 weeks) had been adequately instilled in the OS during the postoperative period.

Prompt hospitalization was recommended in light of the initial pediatric examination. Blood samples were collected for culture and empirical intravenous antibiotic treatment with vancomycin (60 mg/kg/ day) and cefepime (150 mg/kg/day) was initiated. Computed tomo-graphy of the orbit and ocular ultrasonography were performed.

Computed tomography suggested infiltration of the periorbitary tissue, generalized scleral thickening, and increased density of the postseptal fat (Figure 1). Ultrasonography findings included low-am-plitude mobile echoes, vitreous membranes, and thickening of the retina and choroid (Figure 2).

Panophthalmitis with orbital cellulitis following glaucoma drainage implant surgery in a pediatric patientPanoftalmite com celulite orbitária após implante de drenagem em glaucoma congênito

bruno l. b. esPorcatte1, luız fernanDo teıxeıra1, chrıstıane rolım-De-moura1

Submitted for publication: March 30, 2015 Accepted for publication: June 6, 20151 Department of Ophthalmology, Escola Paulista de Medicina, Universidade Federal de São Paulo,

São Paulo, SP, Brazil.

Funding: This study was supported by Coordenação de aperfeiçoamento de pessoal de nível superior (CAPES).

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

Corresponding author: Bruno L. B. Esporcatte. Rua Botucatu, 821 - 2o andar - São Paulo, SP - 04023-062 - Brazil - E-mail: bruno_esporcatte@yahoo.com.br

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124 Arq Bras Oftalmol. 2016;79(2):123-5

DISCUSSIOnSatisfactory success rates with the AGV to control IOP in pediatric

glaucoma have been reported(3). Infectious events in patients treated with glaucoma drainage implants are rare. In 2 long-term studies comparing outcomes following the use of Ahmed™ and Baerveldt™ glaucoma devices, the incidence of endophthalmitis in adult patients was 0.8% and 2%, respectively, with no significant difference obser-ved between implants(4,5).

There have been few reports describing similar complications in childhood glaucoma. A retrospective review of patients treated with AGVs by Al-Torbak et al. reported endophthalmitis in 4.4% of children (5/113 eyes) and 0.9% (4/429 eyes) of adults(6). The time course for the development of endophthalmitis ranged from 4 weeks to 12 months, with a median time of 7 months postoperatively(7).

Lack of compliance with postoperative care recommendations, including the avoidance of eye rubbing and non-adherence to to-pical treatments, may increase the risk of early infection in children. Generally, incisions heal insufficiently during the first postoperative month and conjunctival dehiscence allows ocular infiltration of bac-terial agents through the ocular surface(8).

The most frequently isolated organisms in cases of endophthal-mitis following the insertion of glaucoma drainage implants in chil-dren are Haemophilus influenzae, Streptococcus pneumoniae, or both. These organisms are components of the normal bacterial flora of the conjunctiva and upper respiratory tract(8). Orbital cellulitis in children is typically secondary to sinusitis, with Staphylococcus aureus and Streptococcus pyogenes isolated in 75% of cases(9).

S. epidermidis is capable of forming biofilms, a characteristic of bacteria highly resistant to antibiotic treatment and found on the surface of prosthetic medical devices. The formation of biofilms has reportedly been observed on intraocular lenses, scleral buckles, cor-neal sutures, stents, and glaucoma tubes(10).

Antibiotic regimens are typically initiated with broad-spectrum agents to cover gram-positive and gram-negative organisms known to cause postoperative endophthalmitis. In a retrospective study, Miller et al. demonstrated that 100% of the S. epidermidis strains isolated from vitreous samples were sensitive to vancomycin and 68% were sensitive to fourth-generation fluoroquinolones(11).

The recommendation of removing glaucoma shunt devices from eyes with endophthalmitis is controversial(6,12). In the present case, we decided to remove the AGV due to the presence of purulent material surrounding the plate. The prognosis of endophthalmitis ranges from recovery to previous visual acuity to progression to phthisis bulbi.

figure 1. Orbital computed tomography demonstrated proptosis, inflammation of the extraconal fat, scleral thickening, and diffuse purulent collection surrounding the Ahmed™ glaucoma valve implant (arrow).

figure 2. B-scan ultrasonography demonstrated vitreous opacities.

figure 3. Clinical progression after glaucoma drainage device removal and antibiotic therapy, showing the regression of the eyelid edema. A) At presentation. B) One day postoperatively. C and D) Two days postoperatively. E) Seven days postoperatively. F) Fifteen days postoperatively.

A

D

B

e

C

f

The patient was examined under anesthesia on the same day. Perioperative observations revealed a swollen, tense, and hyperemic superior eyelid. The OS was proptotic. The conjunctiva was chemotic and had significant hyperemia (3+/4), the cornea was diffusely hazy, and the anterior chamber had a large hypopyon. Neither the lens nor the ocular fundus could be visualized.

The previous surgical site was explored. Purulent material sur-rounding the valve was observed. The plate was removed and sent for bacterial culture analysis. Abundant irrigation with balanced saline solution was performed. A 30-gauge needle was introduced through the pars plana and a 0.3-ml specimen was obtained from the vitreous and used to directly inoculate culture media. Vancomycin (2.5 mg/0.1 ml) and ceftazidime (2.5 mg/0.1 ml) were injected intravitreally and into the subtenon space.

Although repeated cultures from blood and vitreous samples were negative, cultures from the removed tube revealed infection with Staphylococcus epidermidis sensitive to amikacin, cefalotin, line-zolid, rifampicin, and vancomycin.

The patient completed 8 days of treatment with intravenous van-comycin and cefepime during the hospital stay, topical gatifloxacin 5 times/day for 2 weeks, and 10 days of treatment with oral amoxicilin/clavulanate potassium at home. Complete regression of eyelid ede-ma was observed after 15 days of treatment (Figure 3). Unfortunately, the OS subsequently progressed to phthisis bulbi.

Esporcatte BLB, et al.

125Arq Bras Oftalmol. 2016;79(2):123-5

Severe infections, such as orbital cellulitis, in pediatric cases re-quire prompt hospitalization and initiation of intravenous antibiotic treatment because of the risk of posterior spread into the cavernous sinus. Parents should be informed of all surgical risks, complications, and warning signs to allow for early evaluation. Postoperative infec-tious events with prosthetic materials should be communicated to hospital infection committees and device manufacturers.

RefeRenCeS 1. Ou Y, Caprioli J. Surgical management of pediatric glaucoma. Dev Ophthalmol. 2012;

50:157-72. 2. Tanimoto SA, Brandt JD. Options in pediatric glaucoma after angle surgery has failed.

Curr Opin Opthalmol. 2006;17(2):132-7. 3. Morad Y, Donaldson CE, Kim YM, Abdolell M, Levin AV. The Ahmed drainage implant

in the treatment of pediatric glaucoma. Am J Ophthalmol. 2003;135(6):821-9. 4. Christakis PG, Tsai JC, Kalenak JW, Zurakowski D, Cantor LB, Kammer JA, Ahmed II.

The Ahmed versus Baerveldt study: three-year treatment outcomes. Ophthalmology. 2013;120(11):2232-40.

5. Barton K, Feuer WJ, Budenz DL, Schiffman J, Costa VP, Godfrey DG, Buys YM; Ahmed

Baerveldt Comparison Study Group. Three-year treatment outcomes in the Ahmed Baerveldt comparison study. Ophthalmology. 2014;121(8):1547-57

6. Al-Torbak AA, Al-Shahwan S, Al-Jadaan I, Al-Hommadi A, Edward DP. Endophthalmitis associated with the Ahmed glaucoma valve implant. Br J Ophthalmol. 2005;89(4):454-8.

7. Wentzloff JN, Grosskreutz CL, Pasquale LR, Walton DS, Chen TC. Endophthalmitis after glaucoma drainage implant surgery. Int Ophthalmol Clin. 2007;47(2):109-15.

8. Gedde SJ, Scott IU, Tabandeh H, Luu KK, Budenz DL, Greenfield DS, Flynn HW Jr. Late endophthalmitis associated with glaucoma drainage implants. Ophthalmology. 2001; 108(7):1323-7.

9. Botting AM, McIntosh D, Mahadevan M. Paediatric pre- and post-septal peri-orbital infections are different diseases. A retrospective review of 262 cases. Int J Pediatr Otorhinolaryngol. 2008;72(3):377-83.

10. Hou W, Sun X, Wang Z, Zhang Y. Biofilm-forming capacity of Staphylococcus epider-midis, Staphylococcus aureus, and Pseudomonas aeruginosa from ocular infections. Invest Ophthalmol Vis Sci. 2012;53(9):5624-31.

11. Miller DM, Vedula AS, Flynn HW Jr, Miller D, Scott IU, Smiddy WE, Murray TG, Venkatraman AS. Endophthalmitis caused by Staphylococcus epidermidis: in vitro antibiotic suscepti-bilities and clinical outcomes. Ophthalmic Surg Lasers Imaging. 2007;38(6):446-51.

12. Park SS, Rabowsky J. Early postoperative endophthalmitis after pars plana Ahmed val-ve placement with persistent extraocular infection. Ophthalmic Surg Lasers Imaging. 2007;38(5):404-5.

11o Simpósio Internacional de Glaucoma da UnICAMP

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São Paulo - SP

informações: Tel.: (11) 5575-0254

Site: www.simposioglaucomaunicamp.com.brE-mail: atendimento3@creativesolution.com.br

Review Article

126 Arq Bras Oftalmol. 2016;79(2):126-9 http://dx.doi.org/10.5935/0004-2749.20160038

InTRODUCTIOnVaricella zoster virus (VZV), a ubiquitous human alpha-herpes virus,

is a member of the Herpesviridae family(1). Following primary infection with VZV (chicken pox), the immune response protects against reinfection on re-exposure to VZV. However, when cell-mediated immunity declines through aging or immunosuppression, VZV can reactivate in the sensory ganglia, causing herpes zoster (HZ), which is the secondary (recurrent) form of the disease(2,3).

Age also appears to be important in the natural history of HZ infection. It is known, for example, that HZ affects >50% of individuals by 80 years of age(4) and that there is an increased prevalence of impaired immunity due to systemic disorders or immunosuppressive therapy(5,6). Considering that the number of people aged ≥60 years is projected to double over coming decades, the number of HZ cases is also expected to increase substantially.

A diagnosis of HZ is primarily based on the history and clinical findings(7), with laboratory confirmation unnecessary in all but specific patient populations(8). Definitive proof of HZ requires viral antigen detection using direct fluorescent antibody or polymerase chain reaction (PCR). The virus can be detected in cutaneous lesions, cerebrospinal fluid (CSF), bronchoalveolar lavage fluid, saliva, and aqueous humor, as well as in blood, corneal, retinal, and vitreous fluids(9-13). Although direct fluorescent antibody is more frequently used for the diagnosis of VZV, it is less specific and sensitive than

ABSTRACTHerpes zoster (HZ) corresponds to the reactivation of varicella zoster virus (VZV). Among adults, the ophthalmic division of the trigeminal nerve is one of the most common sites of involvement. Vasculopathy caused by HZ is associated with significant morbidity and mortality, affecting structures such as the brain, which can lead to stroke. In this review, we analyzed the epidemiological and clinical aspects of the vascular involvement of VZV, focusing on the peculiarities of its association with ocular HZ. A review of the available literature indicated that ocular involvement of HZ was a risk factor for vasculopathy after adjusting for age, sex, body mass index, smoking, indicators of metabolic syndrome, and vascular and heart diseases. Considering the severity of this complication, vascular disease mediated by VZV requires early diagnosis and aggressive treatment. Finally, the anti-HZ vaccine has been recommended as a prophylactic measure in the elderly, but it should be used with caution in immunocompromised individuals.

Keywords: Herpesvirus 3, human; Herpes zoster ophthalmicus; Stroke; Herpes zoster vaccine

RESUMOHerpes zoster (HZ) corresponde à reativação do vírus varicela zoster (VVZ) e, entre os adultos, o envolvimento da divisão oftálmica do nervo trigêmeo é um dos locais mais comuns A vasculopatia associada ao HZ é uma complicação dotada de grande morbimortalidade e afeta diferentes estruturas, favorecendo, inclusive o acidente vascular cerebral. Nesta revisão analisamos aspectos epidemiológicos e clínicos da vasculopatia mediada pelo VZV, bem como as peculiaridades relacionadas com o HZ ocular. De acordo com dados disponíveis na literatura, o acometimento ocular pelo HZ mostrou ser um fator de risco para vasculopatia após se ajustar para idade, sexo, índice de massa corporal, tabagismo, indicadores da síndrome metabólica, doença vascular e cardiopatias. Em face da gravidade dessa complicação, a doença vascular mediada pelo VZV requer diagnóstico precoce e tratamento agressivo. A vacina anti-HZ tem sido recomendada profilaticamente em idosos, mas deve ser usada com cautela em indivíduos imunocomprometidos.

Descritores: Herpervirus humano 3; Herpes zoster oftálmico; Acidente vascular ce-re bral; Vacina contra herpes zoster

PCR, and even less effective for early diagnosis. PCR of the CSF can detect VZV within 1 week of infection onset and can remain positive for 14-50 days(10,14).

HZ ophthalmicus (HZO) is 20 times more common when com-pared with either mandibular or maxillary infection(2,15), being exceeded only by thoracic zoster(16). As shown in table 1, there are several potential complications associated with HZO, and these can affect either the skin, anterior ocular segment, optic nerve, retina, or central nervous system(7). HZ infection can also occur in the absence of cuta-neous involvement(17,18), as is seen in zoster sine herpete.

HZO is a serious and unpredictable disease that should always be treated with nucleoside analogs at the first sign of infection, prefera-bly within 72 h of prodromal symptoms(19,20). Early acyclovir treatment (800 mg, five times a day) can reduce acute pain and the incidence of eye complications from 50% to 20%-30%(21). Valacyclovir (1000 mg t.i.d.) and famciclovir (500 mg t.i.d.), which are therapeutically equivalent, can also be used, and published recommendations on the manage-ment of HZ agree that antiviral therapy with either drug is preferable to acyclovir(20,22). Valacyclovir and famciclovir provide higher plasma concentrations of the acyclic nucleoside analog required to inhibit VZV, thus reducing acute viral shedding and minimizing neural dama-ge. Further, these drugs have simpler dosing regimens and are asso-ciated with higher treatment adherence. Foscarnet is an alternative treatment option in special cases(23).

Herpes zoster ophthalmicus and varicella zoster virus vasculopathyHerpes zoster ophthalmicus e vasculopatia por vírus varicella zoster

francısco banDeıra1, marına roızenblatt1, guıDo carlos levı2, Denıse De freıtas1,3, rubens belfort Jr.1,3

Submitted for publication: October 15, 2015 Accepted for publication: January 7, 20161 Department of Ophthalmology and Visual Science, Escola Paulista de Medicina (EPM), Universidade

Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.2 Sociedade Brasileira de Imunização, São Paulo, SP, Brazil.3 Instituto da Visão, São Paulo, 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 conflict of interest to disclose.

Corresponding author: Francisco Bandeira. Universidade Federal de São Paulo. Departamento de Oftalmologia. Rua Botucatu, 821, 2o andar - São Paulo, SP - 04023-062 - Brazil

E-mail: franciscobandeira@me.com

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127Arq Bras Oftalmol. 2016;79(2):126-9

In addition to antiviral therapy, corticosteroid eye drops are re-commended for severe inflammation caused by HZO, such as uveitis, and an oral corticosteroid may eventually be required(24). Moreover, oral or topical corticosteroids in combination with oral antivirals are the treatment of choice for recurrent and chronic HZO(25). However, the role of steroids in the management of HZ is controversial(24), and the results of a systematic review of their efficacy are awaited. There fore, the use of corticosteroids to treat HZ without concomitant antiviral therapy is not recommended(23).

Following HZO, ocular complications associated with poor visual outcomes include acute corneal lesions, retinitis, optic neuritis, and uvei-tis(26). Patients may also develop postherpetic neuralgia, scleritis, or ocular palsies(27). Overall, these may cause permanent visual loss and substantial health care utilization. Moreover, diseases in immunocom-promised patients are unpredictable and associated with unfavorable outcomes(28).

vZv vaSCUlOPaThy

HZ infections were first discovered to be associated with neurologic VZV vasculopathy in 1919, when it was described as a late contra-lateral hemiplegia following stroke(29). Since then, there have been numerous reports of infarcts in the cerebrum, cerebellum, midbrain, and pons after HZ or varicella infection(30). More recently, active viral

infection has been shown in large and small arteries of patients with VZV vasculopathy(31), leading to the clinical spectrum expanding beyond typical hemiplegia to include other signs and symptoms, such as headache, fever, cognitive changes, transient ischemic attacks (TIAs), temporal arteritis(32), and focal neurologic deficits(17) (Table 2). However, specific vascular involvement varies widely, and associated TIAs may also evolve into a variety of vascular events, including single, bilateral, or multiple ischemic/hemorrhagic infarcts; aneurysms; cere-bral or subarachnoid hemorrhages(33-35); or infarcts of the basal ganglia or internal capsule(36).

The mean time from onset of HZ to vasculopathy is unclear, and although it is typically described as 5-12 weeks(37,38), it can range from a day to 2.5 years(14,38,39). The diagnosis of VZV vasculopathy differs from that for either HZ or HZO infection in that it is based not only on clinical signs but also on the results of imaging and serological examinations. The criteria for magnetic resonance imaging rely on the identification of deep-seated infarcts at the junction of the gray and white matter. Magnetic resonance angiography can also show focal stenosis and beading(14,34), with multiple segmental narrowing of any artery on the ipsilateral side to the affected dermatome(35,40).

Screening for VZV vasculopathy is performed using either anti-VZV testing [immunoglobulin (Ig) M and IgG] or PCR of the CSF and serum. Nagel et al.(14) compared the sensitivities of these testing methods for VZV vasculopathy and found that only 30% of subjects had DNA positive for VZV in the CSF, whereas 93% had anti-VZV IgG in the CSF, indicating the significant superiority of VZV antibody testing.

VZV vasculopathy should be suspected in patients presenting with a recent episode of HZ and stroke(s) of undetermined origin, particu-larly if the patient is immunocompromised. In addition, considering that 30% of patients have neither a rash nor CSF pleocytosis(14), the absence of a rash or the presence of normal CSF should not exclude the possibility of VZV vasculopathy. Recently, there have been reports of similar vascular events due to herpes simplex virus type 2 (HSV-2), and this should be considered in the differential diagnosis. Testing the CSF for HSV-2 DNA can help to differentiate one etiology from the other(41).

The vasculopathy mechanism was proposed initially as a varicella infection leading to a granulomatous angiitis(39,42,43). However, recent developments have shown evidence of direct VZV infection via ophthalmic branches the trigeminal nerve(44,45), which leads to trans-mural spread from the adventitia and later disruption of the internal elastic lamina, intimal hypertrophy, and proinflammatory conditions - all of which are related to an increased risk of thrombotic events(16). Large and/or small vessels can be affected(46), in 50% of the cases both vessels are involved(16). (Figure 1).

Originally, the mechanism underlying vasculopathy was believed to be a result of varicella infection causing a granulomatous angiitis(39,42,43). However, recent developments have shown that there is direct VZV infection via the ophthalmic branches of the trigeminal nerve(44,45), which subsequently causes transmural spread from the adventitia that disrupts the internal elastic lamina, causes intimal hyper trophy, and promotes inflammatory conditions, all of which

Table 1. Acute and chronic features of herpes zoster ophthalmicus

Ocular structure

Clinical features

Acute Chronic

Lids and ocular adnexa

Hyperemia Lagophthalmos

Edema Allodynia

Rash Ptosis

Cicatricial skin changes

Loss of lashes

Conjunctiva Conjunctivitis (pseudomembranous/membranous/follicular)

Symblepharon

Hypoesthesia

Ulcers

Hemorrhages

Cornea Punctate epithelial Corneal mucous plaques

Keratitis Disciform keratitis

Pseudodendrites Neurotrophic keratitis

Ulcers Exposure keratitis

Stromal infiltrates

Endotheliitis

Sclera Episcleritis Scleral atrophy and thinning

Scleritis

Uvea Uveitis Paralytic mydriasis

Hyphema Iris atrophy

Hypopyon Posterior synechiae

Retina Retinitis Cystoid macular edema

Acute retinal necrosis Retinal detachment

Progressive outer retina Retina atrophy

Necrosis

Optic nerve Optic neuritis Optic atrophy

Papillitis

Orbit and brains

Paralysis of eye movement Strabismus

Diplopia

Vasculitis

Table 2. Warning signs and symptoms of zoster vasculopathy

Alert signs and symptomsHeadaches

Fever

Mental status changes

Aphasia

Ataxia

Hemianopia

Hemisensory loss

Monocular visual loss

Acute hemiplegia

Herpes zoster ophthalmicus and varicella zoster virus vasculopathy

128 Arq Bras Oftalmol. 2016;79(2):126-9

increase the risk of thrombotic events(14). Large or small vessels can be affected(46), and both vessels are involved in 50% of reported cases (14).

hZO aND vaSCUlOPaThy: RISk aNalySIS

Major studies have been conducted to assess the relative risk of ischemic, thrombotic, or general vascular events related to zoster infections. Most agree there is a defined and significant risk among them(37,38,47,48), with general risk ratios ranging from 1.31 to 2.27(37,47,48). The risk ratios in these studies were extremely sensitive to the period after the zoster infection, zoster dermatome, treatment, and patient age at the time of infection.

When data obtained from patients with HZO were crossed with those of patients with vasculopathy events, the hazard ratios signi-ficantly increased(38). A comparison between 658 patients with HZO with 1,974 controls showed that there was a mean 4.52-fold increased risk of stroke. Kang et al.(47) and Langan et al.(37) reported mean increa-sed hazard risks of 4.59-and 3.38-fold, respectively, when they analyzed only patients with HZO. Overall, the evidence indicates that the first year after zoster infection is critical, being associated with the greatest increased risk of stroke among patients with both HZ and HZO. The ma-ximal risk appears to fall within the first 3 months after zoster infection, when the mean risk ratios for HZ and HZO range from 0.99-fold(37) to 2.27-fold(48) and from 0.82-fold(37) to 4.52-fold(38), respectively.

Multifocal temporal arteritis is another possible presentation of VZV vasculopathy. Termed multifocal VZV vasculopathy, it presents with the same clinical signs, symptoms, and laboratory findings as giant cells arteritis (GCA) and should be considered in cases of classic GCA where the temporal artery biopsy is negative(49).

Prompt diagnosis of VZV vasculopathy is imperative not only be-cause it is a life-threatening condition with a mortality rate of 25%(50) if left untreated but also because the prognosis is benign when treated with intravenous acyclovir(51). Treatment typically involves 10-15 mg/kg of intravenous acyclovir three times daily for 10-14 days, with 1 mg/kg of prednisone administered intravenously or orally according to se-verity(34,35). In most reports, corticosteroid use has resulted in either improvement or maintenance of the prognosis(52) (Table 3)(53,54).

COMMenTAlthough the risk for VZV vasculopathy is often high in patients with

HZO(37,38,48,55), several risk factors need to be considered when making an assessment. These include age, sex, body mass index, smoking status, and cholesterol levels, as well as the presence of comorbid hypertension, diabetes, and vascular and heart diseases. The absence of an adjusted analysis in some reports(38,48) may also have resulted in

bias, such as selection based on the records of compatible treatments for HZ(48), or public medical records, which both may lead to misclassi-fication of zoster types(37,38). Thus, it is not currently possible to confirm whether these risk factors increase the severity of HZ vasculopathy, whether patients with HZ vasculopathy have a higher incidence of these risk factors, whether these are also risk factors for HZ vasculo-pathy, or whether there is any correlation between them.

Notwithstanding the disagreement among authors over whether the risk of VZV complications is directly attributable to VZV infection or whether they are merely independent vascular diseases associated with post-zoster infection, the severity of VZV vasculopathy should bring our attention to the need for a more aggressive HZ vaccination program. Indeed, HZ is preventable with vaccine administration(55), yet several authors only advocate HZ vaccination for patients with one episode of HZO(56), based on the rationale that most of these patients are older than 50 years and are already at an increased risk of vascular disease(57,58). However, this neglects the facts that prior vaccination reduces morbidity associated with HZ and is well tolerated(59). In general, primary care physicians usually recommend vaccination, but ophthalmologists may also need to play their role in preventing HZO. In the US, the cost of HZ vaccination was approxi-mately $150 in 2009 (60), which limits general access. Although oral prophylaxis is routinely prescribed with either acyclovir or valacyclo-vir, no evidence-based guidelines have been produced that support the prolonged use of suppressive antivirals for chronic HZO and its complications(61).

Despite the possible benefits of vaccination and its good safety profile, complications have been reported(62). Demyelinating central nervous system diseases are perhaps the most widely reported, and optic neuritis is the most prominent, with symptom onset ranging from several hours after vaccination to as late as 3 weeks. Although the prog-nosis has been mostly good, several cases of poor visual outcomes have been reported(63). Other autoimmune diseases must also be considered in the differential diagnosis(64), including multiple sclerosis and neuromyelitis optica.

In this review, we analyzed the epidemiologic and clinical concepts of VZV infection and vasculopathy, and the peculiarities in relation to HZO. It is clear that VZV vasculopathy and HZO are related and that patients who present with HZO are at higher risk of developing VZV. However, making a diagnosis of VZV is not always easy, and it is essen-tial that we educate the ophthalmology community on the systemic risks of VZV infections, particularly of stroke in patients with HZO. This is important because proper treatment with currently available antivirals can prevent death and provide better outcomes.

Preventing HZ vasculopathy is a controversial issue because it is not very prevalent. Nevertheless, a relative consensus agrees that vaccination may be important in preventing vascular events such as TIAs and strokes(37,57). In addition, because patients with HZO are already at an increased risk for vasculopathy, efforts should be made to reduce risk factors, including lifestyle habits such as smoking cessation as well as controlling obesity, cholesterol, and diabetes. Moreover, making a diagnosis of VZV vasculopathy is often complicated by the fact that neu rologic disease can develop weeks or months after an episode of herpes zoster; that not all patients have a history of rash or chickenpox; that vasculopathies of other origins produce the same clinical, CSF, and imaging abnormalities; and that virological analysis is often limited(14).

The considerations outlined in this review indicate the importance of ophthalmologists in the management of HZO. Follow-up visits for these patients must be frequent, and clinicians should be vigilant for symptoms of VZV vasculopathy. Ophthalmologists should be alert to the onset of neurological signs and instruct patients to report any changes because early systemic antiviral therapy is frequently asso-ciated with a good prognosis.

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Table 3. Therapeutic approaches for herpes zoster ophthalmicus

Drugs

Details

Dosing Indication

Acyclovir 800 mg PO 5 times a day for 7-10 days All cases of HZO

10-15 mg/kg IV t.i.d for 10-14 days Severe HZO

Valacyclovir 1000 mg PO t.i.d for 7 days All cases of HZO

Famciclovir 500 mg t.i.d PO for 7 days All cases of HZO

Foscarnet 40 mg/kg t.i.d to 100 mg/kg b.i.d Resistant HZO

#= must always be combined with antiviral; HZO= herpes zoster ophthalmicus; PO= per os.

figure 1. Physiopathology of herpes zoster ophthalmicus and vasculopathy.

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35. Nagel MA, Gilden D. Update on varicella zoster virus vasculopathy. Curr Infect Dis Rep. 2014;16(6):407.

36. Miravet E, Danchaivijitr N, Basu H, Saunders DE, Ganesan V. Clinical and radiological features of childhood cerebral infarction following varicella zoster virus infection. Dev Med Child Neurol. 2007;49(6):417-22.

37. Langan SM, Minassian C, Smeeth L, Thomas SL. Risk of stroke following herpes zoster: a self-controlled case-series study. Clin Infect Dis. 2014;58(11):1497-503. Comment in: Clin Infect Dis. 2014;59(8):1185; Clin Infect Dis. 2014;58(11):1504-6.

38. Lin HC, Chien CW, Ho JD. Herpes zoster ophthalmicus and the risk of stroke: a popu-lation-based follow-up study. Neurology. 2010;74(10):792-7. Comment in: Neurology. 2010;74(10):788-9.

39. Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, Mahalingam R, Cohrs RJ. Neurologic complications of the reactivation of varicella-zoster virus. N Engl J Med. 2000;342(9):635-45. Comment in: N Engl J Med. 200;344(1):65-6; N Engl J Med. 2001; 344(13):1019-20; author reply 1021-2.

40. MacKenzie RA, Forbes GS, Karnes WE. Angiographic findings in herpes zoster arteritis. Ann Neurol. 1981;10(5):458-64.

41. Snider SB, Jacobs CS, Scripko PS, Klein JP, Lyons JL. Hemorrhagic and ischemic stroke secondary to herpes simplex virus type 2 meningitis and vasculopathy. J Neurovirol. 2014;20(4):419-22.

42. Filloux F, Townsend J. Herpes zoster ophthalmicus with ipsilateral cerebellar infarction. Neurology. 1985;35(10):1531-2.

43. Verghese A, Sugar AM. Herpes zoster ophthalmicus and granulomatous angiitis. An ill-appreciated cause of stroke. J Am Geriatr Soc. 1986;34(4):309-12.

44. Kleinschmidt-DeMasters BK, Gilden DH. The expanding spectrum of herpesvirus infections of the nervous system. Brain Pathol. 2001;11(4):440-51.

45. Nagel MA, Traktinskiy I, Azarkh Y, Kleinschimidt-DeMasters B, Hedley-Whyte T, Russman A, et al. Varicella zoster virus vasculopathy: analysis of virus-infected arteries. Neurology. 2011;77(4):364-70.

46. Nagel MA. Varicella zoster virus vasculopathy: clinical features and pathogenesis. J Neu rovirol. 2014;20(2):157-63.

47. Kang JH, Ho JD, Chen YH, Lin HC. Increased risk of stroke after a herpes zoster attack: a population-based follow-up study. Stroke. 2009;40(11):3443-8.

48. Sreenivasan N, Basit S, Wohlfahrt J, Pasternack B, Munch TN, Nielsen LP, et al. The short- and long-term risk of stroke after herpes zoster - a nationwide population-based cohort study. PLoS One. 2013;8(7):e69156.

49. Mathias M, Nagel MA, Khmeleva N, Boyer PJ, Choe A, Durairaj VD, et al. VZV multifocal vasculopathy with ischemic optic neuropathy, acute retinal necrosis and temporal artery infection in the absence of zoster rash. J Neurol Sci. 2013;325(1-2):180-2.

50. Hilt DC, Buchholz D, Krumholz A, Weiss H, Wolinsky JS. Herpes zoster ophthalmicus and delayed contralateral hemiparesis caused by cerebral angiitis: diagnosis and manage-ment approaches. Ann Neurol. 1983;14(5):543-53.

51. Gilden DH, Lipton HL, Wolf JS, Akenbrandt W, Smith JE, Mahalingam R, et al. Two patients with unusual forms of varicella-zoster virus vasculopathy. N Engl J Med. 2002; 347(19):1500-3.

52. Nagel M, Ortiz GA. Does herpes zoster ophthalmicus increase the risk of stroke? Neu-rology. 2010;74(10):788-9.

53. Arvin A, Abendroth A. VZV: immunobiology and host response. In: Arvin A, Campa-delli-Fiume G, Mocarski E, Moore PS, Roizman B, Whitley R, Yamanish K, editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis [Internet]. Cambridge: Cam-bridge University; 2007. [cited 2016 Jan 21]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK47434/

54. Eaglstein WH, Katz R, Brown JA. The effects of early corticosteroid therapy on the skin eruption and pain of herpes zoster. JAMA. 1970;211(10):1681-3.

55. Yawn BP, Saddier P, Wollan PC, St Sauver JL, Kurland MJ, Sy LS. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc. 2007;82(11):1341-9.

56. Grose C. Stroke after varicella and zoster ophthalmicus: another indication for treatment and immunization. Pediatr Infect Dis J. 2010;29(9):868-9.

57. Breuer J, Pacou M, Gautier A, Brown MM. Herpes zoster as a risk factor for stroke and TIA: A retrospective cohort study in the UK. Neurology. 2014;83(2):e27-33.

58. Cohen EJ. Prevention of herpes zoster: we need to do better. JAMA Ophthalmol. 2013;131(3):396-8.

59. Sanford M, Keating GM. Zoster vaccine (Zostavax): a review of its use in preventing herpes zoster and postherpetic neuralgia in older adults. Drugs Aging. 2010;27(2): 159-76.

60. Gilden D, Cohrs RJ, Mahalingam R, Nagel MA. Varicella zoster virus vasculopathies: di-verse clinical manifestations, laboratory features, pathogenesis, and treatment. Lancet Neurol. 2009;8(8):731-40.

61. Sackel DJ, Castano E, Cohen EJ. Physician survey for study of suppressive antiviral treatment to reduce chronic ocular disease and postherpetic neuralgia after herpes zoster Ophthalmicus. Eye Contact Lens. 2014;40(4):200-6.

62. Gagliardi AM, Gomes Silva BN, Torloni MR, Soares BG. Vaccines for preventing herpes zoster in older adults. The Cochrane Database Syst Rev. 2012;10:CD008858. Comment in: Sao Paulo Med J. 2014;132(4):255; Am Fam Physician. 2013;88(9):578; Evid Based Med. 2013;18(5):e43.

63. Stubgen JP. A literature review on optic neuritis following vaccination against virus infections. Autoimmun Rev. 2013;12(10):990-7.

64. Han SB, Hwang JM, Kim JS, Yang HK. Optic neuritis following Varicella zoster vaccination: Report of two cases. Vaccine. 2014;32(39):4881-4.

Letters to the Editor

130 Arq Bras Oftalmol. 2016;79(2):130 http://dx.doi.org/10.5935/0004-2749.20160039

Comment on: “measurement and clinical implications of choroidal thickness in patients with inflammatory bowel disease”

Comentário: determinação da espessura da coroide e suas implicações clínicas em pacientes com doença inflamatória intestinal

Dear Editor:We read with great interest the article titled, “measurement and

clinical implications of choroidal thickness in patients with inflamma-tory bowel disease”. In their study, the authors investigated the rela-tionship between inflammatory bowel diseases (IBD) and choroidal thickness (CT). Although CT was not found to be associated with IBD, the authors state high measurements as an indicator of ileal invol-vement in Crohn’s disease. However, we have doubts regarding the accuracy of this hypothesis. IBD are well-known to be associated with anterior segment uveitis. If a cross-reaction between antigens against the ileal endothelium and choroid was present, a clinical presentation of uveitis would be expected, as in Vogt-Koyanagi-Harada syndrome. However, there was no report of such a presentation in their study.

In their study, decreased choroid thickness in patients with the Crohn’s disease was found to be associated with colonic involvement.

The mean CT in patients with ileal involvement was 324.7 with colonic involvement of 140.0. As ulcerative colitis (UC) is a disease of the colon, CT in patients with UC would be expected to be approximately 140 μm if the hypothesis of their study was correct. However, the mean CT in patients with UC was measured as approximately 300 μm, similar to measurements in patients with the Crohn’s disease with ileal involvement. Therefore, we do not agree there could be an association between CT and ileal involvement. Further, as manual measurement of CT is not objective, we believe errors may have been introduced by incorrect measurements by the operators.

Abdullah Kaya1, Yakup Aksoy2, Oktay Diner3,

Mehmet Koray Sevinç4

Submitted for publication: November 18, 2015 Accepted for publication: December 2, 20151 Department of Ophthalmology, Anıttepe Military Dispansery, Ankara, Turkey.2 Department of Ophthalmology, Girne Military Hospital, Girne, Cyprus.3 Department of Ophthalmology, Erzurum Military Hospital, Erzurum, Turkey.4 Department of Ophthalmology, Beytepe Military Hospital, Ankara, Turkey.

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

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

Corresponding author: Abdullah Kaya. Department of Ophthalmology. Anıttepe Military Dispansery, Ankara - Turkey - E-mail: abdullahkayamd@gmail.com

RefeRenCeS 1. Onal IK, Yuksel E, Bayrakceken K, Demir MM, Karaca EE, Ibis M, et al. Measurement and

clinical implications of choroidal thickness in patients with inflammatory bowel disease. Arq Bras Oftalmol. 2015;78(5):278-82.

Letters to the Editor

131Arq Bras Oftalmol. 2016;79(2):131http://dx.doi.org/10.5935/0004-2749.20160040

Evaluation of a simulation tool in ophthalmology: application in teaching funduscopyAvaliação do uso de um instrumento de simulação em oftalmologia: aplicação no ensino da fundoscopia

Dear Editor:I read with interest the study with the above title by Androwiki,

which reported regarding the funduscopy simulator device, that pu-blished in the ABO February 2015 edition(1). My team and I published a similar article entitled “Teaching ophthalmology at university medical undergraduate course: comparative study of direct ophthalmoscopy between conventional ophthalmoscope and wide field ophthal-moscope (panoptic) as evaluation method” in Revista Brasileira de Oftalmologia(2).

We agree with the authors that teaching funduscopy through a new type of device is feasible; however, some considerations are required. a) In ophthalmology, the teaching of the beginners may be com -

plicated by eye fundus difficulties, such as high-refraction errors, small pupils, and lens opacities. The same difficulties are faced among physicians in other specialties(2,4).

b) Limitations with simulators are known in several subspecialties (mainly surgical ones); however, in this particular study, the association with a wide-field direct ophthalmoscope could facilitate this type of teaching(2,3).

Eduardo Damasceno1

Nadyr Damasceno2

Submitted for publication: November 30, 2015 Accepted for publication: December 2, 20151 School of Medicine, Universidade Federal Fluminense (UFF), Niteroi, RJ, Brazil.2 Hospital Naval Marcílio Dias, Rio de Janeiro, RJ, 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: Eduardo F. Damasceno. Rua Marques do Paraná, 303 - Niteroi, RJ -

20520-060 - Brazil - E-mail: e_damasceno@yahoo.com

RefeRenCeS 1. Androwiki JE, Scravoni IA, Ricci LH, Fagundes DJ, Ferraz C A. Evaluation of a simulation

tool in ophthalmology: application in teaching funduscopy. Arq Bras Oftalmol. 2015; 78(1):36-9.

2. Damasceno EF, Damasceno NA, Costa Filho AA. Ensino de oftalmologia na gradua-ção médica: Estudo comparativo de aprendizado na oftalmoscopia direta com oftalmoscópio convencional e de campo amplo (Panoptic). Rev Bras Oftalmol. 2009; 68(4):231-6.

3. McComiskie JE, Greer RM, Gole GA. Panoptic versus conventional ophthalmoscope. Clin Experiment Ophthalmol. 2004;32(3):238-42.

4. Lippa LM. Medical student education. Ophthalmology. 2006;113(5):890-1.

Letters to the Editor

132 Arq Bras Oftalmol. 2016;79(2):132 http://dx.doi.org/10.5935/0004-2749.20160041

Acquired restrictive strabismus in infancy associated with neurofibromatosis type 2Estrabismo restritivo adquirido na infância associado à neurofibromatose tipo 2

Dear Editors:We would like to add some new information regarding the pa-

tient described in the paper entitled, “Surgical treatment of acquired restrictive strabismus in infancy: case report”, published in Arquivos Brasileiros de Oftamologia in 2009(1). We stated that the diagnosis in the reported case was unclear despite extensive investigations.

After surgical treatment of acquired restrictive strabismus, the child described remained stable with no other symptoms for appro-ximately 7 years. By the age of 14 years, he developed left hand palsy

and skin tumors. One year later, he started experiencing the begin-nings of a hearing loss. Magnetic resonance imaging (MRI) of the brain revea led bilateral tumors indicative of vestibular schwannoma (Figure 1).

Subsequently, the patient was referred to the Neurofibromatosis Reference Center of the Universidade Federal de Minas Gerais for further evaluation. Diagnosis of neurofibromatosis type 2 (NF2) was then established according to MRI demonstrating bilateral vestibular schwannomas associated with cutaneous schwannomas.

NF2 is a dominant, autosomal disease characterized by bilateral vestibular schwannomas with multiple nervous system and skin tumors and is often associated with ocular abnormalities. Although classically considered a disease of adults, the initial signs and symptoms of NF2 may be evident in childhood and often goes unre cognized(2). Diagnosis is difficult in the majority of cases because of its rarity. Initial manifestations of NF2 differ between children and adults. The first sign of disease severity in patients with early-onset NF2 predomi-nantly comprise ocular presentations and weakness in lower motor neuron extremities as opposed to impairment of the eighth nerve in cases of late disease onset(3).

Approximately 50% of NF2 patients present with strabismus, ty pically associated with tumors and palsies of cranial nerves III, IV, and VI(4). Although restrictive strabismus is not commonly reported in patients with NF2, it is possible that it was associated with early onset of NF2 in our patient.

Vanessa Waisberg1, Galton Carvalho Vasconcelos1,

Ana Rosa Pimentel de Figueiredo1, Débora Marques de Miranda2,

Juliana Ferreira de Souza3, Luiz Oswaldo Carneiro Rodrigues3

Submitted for publication: September 29, 2015 Accepted for publication: January 23, 20161 Departamento de Oftalmologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.2 Departamento de Pediatria, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.3 Departamento de Clinica Médica, Universidade Federal de Minas Gerais, Belo Horizonte, MG,

Brazil.

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

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

Corresponding author: Vanessa Waisberg. Av. Brasil, 691 - 4o andar - Belo Horizonte, MG - 30140-000 - Brasil - E-mail: vanessawaisberg@hotmail.com

RefeRenCeS 1. Damasceno JV, Vasconcelos GC, Figueiredo AR, Almeida HC. [Surgical treatment of

acquired restrictive strabismus in infancy: case report]. Arq Bras Oftalmol. 2009;72(1): 119-22. Portuguese.

2. Evans DG, Birch JM, Ramsden RT. Paediatric presentation of type 2 neurofibromatosis. Arch Dis Child. 1999;81(6):496-9.

3. Bosch MM, Boltshauser E, Harpes P, Landau K. Ophthalmologic findings and a long-term course in patients with neurofibromatosis type 2. Am J Ophthalmol. 2006; 141(6):1068-77.

4. Feucht M, Griffiths B, Niemüller I, Haase W, Richard G, Mautner VF. Neurofibromatosis 2 leads to higher incidence of strabismological and neuro-ophthalmological disorders. Acta Ophthalmol. 2008;86(8):882-6.

figure 1. Magnetic resonance imaging with gadolinium demonstrating bilateral ves-tibular schwannomas with size predominance on the right side.

133Arq Bras Oftalmol. 2016;79(2):133-6

Instructions Authors

instruCtions to autHors

• Scope and policy• Methods• Types of Manuscripts• Editorial Process• Manuscript Preparation

ABO-ARQUIVOS BRASILeIROS De OfTALMOLOGIA (ABO, ISSN 0004-2749 - printed version and ISSN 1678-2925 - online version) is the official bimonthly publication of the Brazilian Council of Ophthal-mology (Conselho Brasileiro de Oftalmologia - CBO). The purpose of the journal is to publish scientific studies in Ophthalmology, Visual Sciences, and Public Health, encouraging research, as well as qualifi-cation and updating of the professionals involved in this field.

MeTHODSOriginal manuscripts are accepted only in English. Manuscripts

are grouped into one of the following categories, based on the me-thodology used:

ClINICal STUDIeS

Descriptive or analytical studies involving humans or evaluating the literature relevant to humans.

ePIDemIOlOgICal STUDIeS

Analytical studies involving results from human populations.

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Editorials are contributed by invitation and should be related to to pics of current interest, preferentially related to articles published in the same issue of ABO (title, maximum of 1,000 words, 2 figures or tables, and 10 references).

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Original articles present complete experiments with results that have never been published before (title, structured abstract, maximum of 3,000 words, 7 figures or tables, and 30 references). The evaluation of the manuscripts will be based on the following priorities:

1. New and relevant information based on a study that uses appro-priate methodology.

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Letters to the editor are considered for publication if they contain comments related to manuscripts previously published in ABO or, exceptionally, the results of original studies with insufficient content to be submitted as Original Article. These letters should present new information or new interpretation of existing information. When the content of the letter refers to an article previously published in ABO, such article should be mentioned in the first paragraph of the letter and included in its reference list. In these cases, the letters will be linked to the article, and the authors of the article will have their right of reply guaranteed in the same issue. Congratulation letters will not be published (title, maximum of 700 words, 2 figures or tables, and 5 references).

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Review articles follow the editorial line and are accepted only by invitation from the editor. Suggestions of topics for review articles should be sent directly to the editor, but manuscripts cannot be sent without an invitation (title, unstructured abstract, maximum of 4,000 words, 8 figures or tables, and 100 references).

eDITORIAL PROCeSSManuscripts will only be considered for publication if they meet

all the journal’s requirements. The editorial office will inform the authors if their manuscript fails to meet such requirements. Upon notification, the corresponding author will have 30 days to make the necessary changes in the manuscript. If the deadline is not met, the manuscript will be excluded from the editorial process.

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134 Arq Bras Oftalmol. 2016;79(2):133-6

nuscript is 30 days after the authors are informed of the need to make changes in their manuscript. Manuscripts will be excluded from the process if authors fail to meet this deadline. The ultimate publication will be based on the final approval of the editors.

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The corresponding author should complete and submit the Au-thor Contribution Statement as a supplementary document.

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bellow before submitting your work: • CONSORT (Controlled and randomized clinical trials) • STARD (Diagnostic instruments or techniques) • PRISMA (Systematic reviews and meta-analyses) • STROBE (Observational studies)

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2. Abstract and Keywords. Structured abstract (Objective, Metho-ds, Results, Conclusions) with no more than 300 words. Unstructured abstract with no more than 150 words. Five keywords in English listed by the National Library of Medicine (MeSH - Medical Subject Headings).

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6. References. Citations (references) of authors in the text should be numbered sequentially in the same order as they are cited and identified using superscript Arabic numerals. References should be in accordance with the format suggested by the International

135Arq Bras Oftalmol. 2016;79(2):133-6

Committee of Medical Journal Editors (ICMJE), based on the exam-ples below.

The titles of the journals should be abbreviated according to the style provided by the List of Journal Indexed in Index Medicus of the National Library of Medicine.

The names of all authors should be cited for references with up to six authors. For studies with seven or more authors, cite only the first six authors followed by et al.

Examples of references:

Journal ArticlesCosta VP, Vasconcellos JP, Comegno PEC, José NK. O uso da mitomi cina C em cirurgia combinada. Arq Bras Oftalmol. 1999;62(5):577-80.

BooksBicas HEA. Oftalmologia: fundamentos. São Paulo: Contexto; 1991.

Book ChaptersGómez de Liaño F, Gómez de Liaño P, Gómez de Liaño R. Exploración del niño estrábico. In: Horta-Barbosa P, editor. Estrabismo. Rio de Janeiro: Cultura Médica; 1997. p. 47-72.

AnnalsHöfling-Lima AL, Belfort R Jr. Infecção herpética do recém-nascido. In: IV Congresso Brasileiro de Prevenção da Cegueira; 1980 Jul 28-30, Belo Horizonte, Brasil. Anais. Belo Horizonte; 1980. v.2. p. 205-12.

DissertationsSchor P. Idealização, desenho, construção e teste de um ceratômetro cirúrgico quantitativo [dissertation]. São Paulo: Universidade Federal de São Paulo; 1997.

Electronic DocumentsMonteiro MLR, Scapolan HB. Constrição campimétrica causada por vigabatrin. Arq Bras Oftalmol. [online journal]. 2000 [cited 2005 Jan 31]; 63(5): [about 4 p.]. Available at:http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0004-27492000000500012&lng=pt&nrm=iso

7. Tables. Tables should be numbered sequentially using Arabic nu-merals in the order they are mentioned in the text. All tables should have a title and a heading for all columns. Their format should be simple, with no vertical lines or color in the background. All ab-breviations (even if previously defined in the text) and sta tistical tests should be explained below the table. The bibliographical source of the table should also be informed when the table is extracted from another study.Do not include tables in the main document of the manuscript, they should be uploaded as supplementary documents

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9. Abbreviations and Acronyms. Abbreviations and acronyms should be preceded by the spelled-out abbreviation on first mention and in the legends of tables and figures (even if they have been pre-viously mentioned in the text). Titles and abstracts should not contain abbreviations and acronyms.

10. Units of Measurement: Values of physical quantities should be used in accordance with the standards of the International System of Units.

11. Language. Texts should be clear to be considered appropriate for publication in a scientific journal. Use short sentences, written in a direct and active voice. Foreign words should be in italics. Thera-peutic agents should be mentioned by their generic names with the following information in parentheses: trade name, manufacturer’s name, city, state and country of origin. All instruments or apparatus should be mentioned including their trade name, manufacturer’s name, city, state and country of origin. The superscript symbol of trademark ® or™ should be used in all names of instruments or trade names of drugs. Whenever there are doubts about style, terminology, units of measurement and related issues, refer to the AMA Manual of Style 10th edition.

12. Original Documents. Corresponding authors should keep the original documents and the letter of approval from the Research Ethics Committee for studies involving humans or animals, the con-sent form signed by all patients involved, the statement of agreement with the full content of the study signed by all authors and the state-ment of conflict of interest of all authors, as well as the records of the data collected for the study results.

13. Corrections and Retractions. Errors may be noted in published manuscripts that require the publication of a correction. However, some errors pointed out by any reader may invalidate the results or the authorship of a manuscript. If substantial doubt arises about the honesty or integrity of a submitted manuscript, it is the editor’s responsibility to exclude the possibility of fraud. In these situations, the editor will inform the institutions involved and the funding agen-cies about the suspicion and wait for their final decision. If there is confirmation of a fraudulent publication in ABO, the editor will act in compliance with the protocols suggested by the International Com-mittee of Medical Journal Editors (ICMJE) and by the Committee on Publication Ethics (COPE).

CHeCKLISTBefore submitting their manuscript, authors should make sure

that all the following items are available: □Manuscript prepared in accordance with the instructions to

authors. □Maximum number of words, tables, figures, and references

according to the type of manuscript. □ Title page including the clinical trial registration number is not

included in the main document □ No figures and tables are included in the main document of

the manuscript. □ All figures and tables were uploaded separately as supple-

mentary documents. □ Author Contribution Statement completed and saved as a

digital file to be sent as a supplementary document. □ Form for Disclosure of Potential Conflicts of Interest of all

authors completed and saved as digital files to be sent as supplementary documents.

□ Digital version of the report provided by the Institutional Re-view Board containing the approval of the project to be sent as a supplementary document.

136 Arq Bras Oftalmol. 2016;79(2):133-6

LIST Of WeBSITeSAuthorship Principles according to the iCMJEhttp://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-role-of-authors-and-contributors.html

Authors’ Participation Formhttp://www.cbo.com.br/site/files/Formulario Contribuicao dos Autores.pdf

CONSOrT (Consolidated Standards of reporting Trials) http://www.consort-statement.org/consort-statement/

STArD (Standards for the reporting of Diagnostic accuracy studies) http://www.stard-statement.org/

PriSMA (Preferred reporting items for Systematic reviews and Meta-Analyses) http://www.prisma-statement.org/index.htm

STrOBE (Strengthening the reporting of Observational studies in Epidemiology) http://www.strobe-statement.org/

Online interface for submission of manuscripts to ABOhttp://www.scielo.br/ABO

international Committee of Medical Journal Editors (iCMJE)http://www.icmje.org/

uniform requirements for manuscripts submitted to biomedical journalshttp://www.nlm.nih.gov/bsd/uniform_requirements.html

Declaration of helsinkihttp://www.wma.net/en/30publications/10policies/b3/index.html

Principles of the Association for research in vision and Ophthal-mology (ArvO)http://www.arvo.org/About_ARVO/Policies/Statement_for_the_Use_of_Animals_in_Ophthalmic_and_Visual_Research/

World association of medical editors: conflict of interest in peer- reviewed medical journalshttp://www.wame.org/about/wame-editorial-on-coi

Form for Disclosure of Potential Conflicts of interesthttp://www.icmje.org/coi_disclosure.pdf

u.S. national institutes of healthhttp://www.clinicaltrials.gov

australian and new zealand clinical trials registryhttp://www.anzctr.org.au

international Standard randomised Controlled Trial Number - iSrCTNhttp://isrctn.org/

university hospital medical information network clinical trials registry - uMiN CTrhttp://www.umin.ac.jp/ctr/index.htm

Nederlands Trial registerhttp://www.trialregister.nl/trialreg/index.asp

registros Brasileiros de Ensaios Clínicoshttp://www.ensaiosclinicos.gov.br/

meSh - medical Subject headingshttp://www.ncbi.nlm.nih.gov/sites/entrez?db=mesh&term=

DecS - health Sciences Keywords in Portuguesehttp://decs.bvs.br/

Format suggested by the international Committee of Medical Journal Editors (iCMJE)http://www.nlm.nih.gov/bsd/uniform_requirements.html

list of Journal indexed in index Medicushttp://www.ncbi.nlm.nih.gov/journals

AMA Manual of Style 10th editionhttp://www.amamanualofstyle.com/

Protocols of the international Committee of Medical Journal Editors (iCMJE)http://www.icmje.org/recommendations/browse/publishing-and-editorial-issues/scientific-misconduct-expressions-of-concern-and-retraction.html

Protocols of the Committee on Publication Ethics (COPE)http://publicationethics.org/resources/flowcharts

Chief Executive Officer: Fernando Steven Ullmann;Commercial Director: Helen Suzana Perlmann; Art Director: Elza Rudolf;

Publishing, Printing and CTP: Ipsis Gráfica e Editora S.A.Frequency of publication: Bimonthly; Circulation: 9.000 copies

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