Visually Evoked Potentials and Malingering Diagnosis Toxic

issn 0004-2749 versão impressa A r q u i v o s b r a s i l e i r o s d e

publicação oficial do conselho brasileiro de oftalmologia SETEMBRO/OUTUBRO 2016 79 05

Visually evoked potentials and malingering diagnosis Toxic anterior segment syndrome following DALK Bilateral angle-closure glaucoma and Wegener’s polyangiitis Comparison of gas and air in DMEK Amblyopia

indexada nas bases de dados medline | embase | isi | L SciE O Anúncio CBO 2017 21X28 cm.pdf 1 24/10/2016 16:44:16

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1. AcrySof® IQ PanOptix™ IOL Directions for Use. 2. PanOptix™ Diffractive Optical Design. Alcon internal technical report: TDOC-0018723. Effective date 19 Dec 2014. 3. Charness N, Dijkstra K, Jastrzembski T, et al. Monitor viewing distance for younger and older workers. Proceedings of the Human Factors and Ergonomics Society 52nd Annual Meeting, 2008. http://www. academia.edu/477435/Monitor_Viewing_Distance_for_Younger_and_Older_Workers. Accessed April 9, 2015. 4. Average of American OSHA, Canadian OSHA and American Optometric Association Recommendations for Computer Monitor Distances. *Instruções de uso: DFU PanOptix, DFU Zeiss AT Lisa tri, DFU PhysIOL FineVision. Registro da Anvisa nº 80153480180 © 2016 Novartis AP3:BR1605480447-SR-MAI/2016

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Alcon 2016 - Panoptix - Anuncio 210x280-1605480447.indd 1 12/05/2016 16:43:15 OFFIcIaL PUbLIcaTIon oF THe BRaZILIan CoUncIL oF OpHTHaLMoLoGY (CBO) PUBLICAÇÃO OFICIAL DO CONSELHO BRASILEIRO ISSN 0004-2749 DE OFTALMOLOGIA Continuous publication since 1938 (Printed version) CODEN - AQBOAP ISSN 1678-2925 (Electronic version)

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Frequency of publication: Bimonthly Arq Bras Oftalmol. São Paulo, v. 79, issue 5, pages 285-356, Sep/Oct. 2016

Contents

Editorial V Crosslinking enters public health armamentarium in Brazil Crosslink torna-se disponível no sistema de saúde pública do Brasil Wallace Chamon

original Articles 285 Corneal structure in tilted disc syndrome Estrutura da córnea na síndrome de disco inclinado Abuzer Gunduz, Nihat Polat, Tongabay Cumurcu, ErsinErsan Demirel, Ercan Özsoy 289 Microbiological and epidemiological study of infectious keratitis in children and adolescents Estudo microbiológico e epidemiológico da ceratite infecciosa em crianças e adolescentes Maria Cecilia Zorat Yu, Ana Luisa Höfling-Lima, Guilherme Henrique Campos Furtado 294 Dysfunction in the fellow eyes of strabismic and anisometropic amblyopic children assessed by visually evoked potentials Alterações dos potenciais visuais evocados nos olhos contralaterais de crianças com ambliopia estrabísmica e anisometrópica Eric Pinheiro Andrade, Adriana Berezovsky, Paula Yuri Sacai, Josenilson Martins Pereira, Daniel Martins Rocha, Solange Rios Salomão

Comparison of 20% sulfur hexafluoride with air for intraocular tamponade in Descemet membrane 299 endothelial keratoplasty (DMEK) Comparação de hexafluoreto de enxofre a 20% com ar para tamponamento intraocular na ceratoplastia endotelial de membrana Descemet (DMEK) Benjamin Botsford, Gustavo Vedana, Leslie Cope, Samuel C. Yiu, Albert S. Jun 303 Pattern-reversal visual evoked potentials as a diagnostic tool for ocular malingering Potenciais visuais evocados por padrões reversos como uma ferramenta diagnóstica de simulação Tarciana de Souza Soares, Paula Yuri Sacai, Adriana Berezovsky, Daniel Martins Rocha, Sung Eun Song Watanabe, Solange Rios Salomão 308 Subfoveal choroidal thickness changes after intravitreal bevacizumab therapy for central serous chorioretinopathy Alterações da espessura subfoveal coroide após terapia com bevacizumab para coriorretinopatia serosa central Cihan Ünlü, Gurkan Erdogan, Tugba Aydogan Gezginaslan, Betul Ilkay Sezgin Akcay, Esra Kardes, Tahir Kansu Bozkurt 312 Comparison of central corneal thickness estimated by an ultrasonic pachymeter and non-contact specular microscopy Comparação da espessura central de córnea estimada por um paquímetro ultrassônico e por um microscópio especular sem contato Sadık Görkem Çevik, Rahmi Duman, Mediha Tok Çevik, Sertaç Argun Kıvanç, Berna Akova-Budak, Irfan Perente, Resat Duman 315 is there a relationship between outer retinal destruction and choroidal changes in cone dystrophy? Existe uma relação entre a destruição da retina externa e alterações da coroide em distrofia de cones? Onder Ayyildiz, Gokhan Ozge, Murat Kucukevcilioglu, Cem Ozgonul, Tarkan Mumcuoglu, Ali Hakan Durukan, Fatih Mehmet Mutlu 319 Evaluation of inner segment/outer segment junctions in different types of epiretinal membranes Avaliação da junção segmento interno/segmento externo em diferentes graus de membranas epirretinianas Rukiye Aydın, Eyyup Karahan, Mahmut Kaya, Taylan Ozturk, Kubra Serefoglu Cabuk, Nilufer Kocak, Suleyman Kaynak 323 repeatability of contrast sensitivity testing in patients with age-related macular degeneration, glaucoma, and cataract Reprodutibilidade dos escores de sensibilidade ao contraste em pacientes com degeneração macular relacionadas à idade, glaucoma e catarata Selcuk Kara, Baran Gencer, Ismail Ersan, Sedat Arikan, Omer Kocabiyik, Hasan Ali Tufan, ArzuTaskiran Comez Case Reports 328 Coexistence of optic pit and coloboma of iris, lens, and choroid: a case report Coexistência de fosseta óptica e coloboma de íris, cristalino e coroide: um primeiro relato de caso Ramazan Özelce, Vuslat Gürlü, Hande Güçlü, Sadık Altan Özal 330 Toxic anterior segment syndrome following deep anterior lamellar keratoplasty Síndrome tóxica do segmento anterior após transplante lamelar anterior profundo Neslihan Sevimli, Remzi Karadag, Ozgur Cakici, Huseyin Bayramlar, Seydi Okumus, Unsal Sari 333 Adenoid cystic carcinoma of the lacrimal sac: case report Carcinoma adenóide cístico do saco lacrimal: relato de caso Antonio Ramos, Carmen Del Pozo, Ana Chinchurreta, Fernando García, Mercedes Lorenzo, Saturnino Gismero 336 Bilateral acute angle-closure glaucoma as a first presentation of granulomatosis with polyangiitis (Wegener’s) Glaucoma de ângulo fechado bilateral agudo como uma primeira apresentação da granulomatose com poliangeíte (de Wegener) Alper Mete, Sabit Kimyon, Oguzhan Saygili, Can Pamukcu, Kıvanç Güngör 339 Management of necrotizing scleritis after pterygium surgery with rituximab Tratamento com rituximabe de esclerite necrosante após cirurgia de pterigeo Tania Sales de Alencar Fidelix, Luis Antonio Vieira, Virginia Fernandes Moca Trevisani 342 Nonarteritic anterior ischemic optic neuropathy following pars plana vitrectomy for macular hole treatment: case report Neuropatia óptica isquêmica anterior não arterítica pós vitrectomia pars plana para tratamento do buraco macular: relato de caso Leonardo Provetti Cunha, Luciana Virgínia Ferreira Costa Cunha, Carolina Ferreira Costa, Mário Luiz Ribeiro Monteiro

review Articles 346 Amblyopia: neural basis and therapeutic approaches Ambliopia: bases neurais e intervenções terapêuticas Caio César Peixoto Bretas, Renato Nery Soriano

letters to the Editor 352 retinal nerve fiber layer, ganglion cell complex, and choroidal thicknesses in migraine Espessuras da camada de fibras nervosas, do complexo de células ganglionares e da coroide na migrânea Salih Uzun, Emre Pehlivan

353 instructions to Authors Editorial

Crosslinking enters public health armamentarium in Brazil Crosslink torna-se disponível no sistema de saúde pública do Brasil

Wallace Chamon*

Brazilian health system, named SUS (Sistema Único de Saúde or Unique Health System) was created in 1990, based on constitutional principles set in 1988 and, in its basic values, states that health is a fundamental human right, and the State must provide the necessary conditions for it(1). Six years after being cleared by Brazilian go- vernment as a valid medical treatment(2), crosslinking (CXL) became available to all Brazilian citizens or residents, as well as foreigners, regardless their visa status(3-5). Other agencies, such as Ontario Health Technology Advisory Committee (OHTAC), have made similar suggestions a few years ago(6). The rationale for this new approval is the cost of the treatment and its efficacy in avoiding keratoplasties(7), considering that one-third of keratoplasties is consequent to keratoconus in Brazil(3,8-10). Brazilian public health system spent US$ 2,738,869 in 4,234 keratoplasties for keratoconus, in 2014; an average of US$ 647,00 per procedure. The estimated cost for CXL is US$ 92,00 and the estimate total expenditure in CXL for the next five years is US$ 1,113,251 (US$ 1.00 = R$ 3.20, October 29, 2106)(3). Brazilian SUS has still a lot to improve in order to accomplish its mission. Therefore, supplementary private health providers are mainstream for almost one third of the population. Surprisingly, CXL is not yet provided by health insurances or health maintenance organizations, which do not offer nor reimburse the procedure(11). Although the real prevalence of keratoconus using newer diagnostic tools is yet to determined, it should be at least 54:100,000(12) which would lead to approximately 110,400 patients with keratoconus and 4,000 new cases per year, in Brazil. We still don’t know the natural history of keratoconus in order to determine what percentage of patients will undergo keratoplasty, but with a failure rate between 8 to 10%, CXL will prevent at least 90% of the keratoplasties in keratoconus patients, if patients are diagnosed early enough(13). Crosslinking isn’t a risk-free procedure but so far it has been shown to present fewer and less severe complications compared to keratoplasty. Early diagnosis became the most important link in the chain to prevent keratoplasties in patients with keratoconus. Careful follow-up of early diagnosed patients will allow preventive measures to halt its progression, such as orientation about eye rubbing and, if progression is detected, CXL. It is our medical duty to inform the society of the existence of treatment for keratoconus that may halt its progression and, therefore, avoid the need of keratoplasty.

References 4. Brasil. Qualidade e eficiência do Sistema Único de Saúde -SUS. Diário Oficial da União [Internet]. 2002; 168(1):84. [citado 20156 Out 10]. Disponível em: http://pesquisa. 1. Brasil. Lei n. 8.080, de 19 de setembro de 1990. Dispõe sobre as condições para a in.gov.br/imprensa/jsp/visualiza/index.jsp?jornal=1&pagina=84&data=30/08/2002 promoção, proteção e recuperação da saúde, a organização e o funcionamento dos serviços correspondents e dá outras providências [Internet]. Diário Oficial da União, 5. Brasil. Secretaria de Ciência, Tecnologia e Insumos Estratégicos. Portaria n. 30, de 20 20 de setembro de 1990. [citado 2016 Out 12]. Disponível em: http://www.planalto. de setembro de 2016. Torna pública a decisão de incorporar o crosslinking corneano gov.br/ccivil_03/leis/L8080.htm para o tratamento da ceratocone, no âmbito do Sistema Único de Saúde- SUS. Diario 2. Schaefer T, relator. Processo-Consulta CFM n. 1923/10- Parecer CFM n. 30/10. Proce- Oficial da União [Internet]. 2016/;183(1):41. [citado 2016 Out 12]. Disponível em: dimento de cross-linking para ceratocone [Internet]. Salvador (BA): Conselho Federal http://pesquisa.in.gov.br/imprensa/jsp/visualiza/index.jsp?jornal=1&pagina=41&da de Medicina; 2010. [citado 2016 Out 10]. Disponível em: http://www.portalmedico. ta=22/09/2016 org.br/pareceres/CFM/2010/30_2010.htm 6. Ontario Health Technology Advisory Committee. Collagen cross-linking using ribo- 3. Comissão Nacional de Incorporação de Tecnologias no SUS. Crosslinking corneano flavin and ultraviolet-a for corneal thinning disorders. Ontario: OHTAC; 2011. [cited para ceratocone [Internet]. Brasilia (DF): Ministério da Saúde; 2016. [citado 2016 Out 12]. 2015 Set 1]. Available from: http://www.hqontario.ca/en/ohtac/tech/pdfs/2011/ Disponível em: http://conitec.gov.br/images/Consultas/Relatorios/2016/Relatorio_ rev_CXL_November.pdf Crosslinking_Ceratocone_CP13_2016.pdf 7. Sandvik GF, Thorsrud A, Råen M, Østern AE, Sæthre M, Drolsum L. Does Corneal colla-

Submitted for publication: October 28, 2016 Disclosure of potential conflicts of interest: Author declares having received research grants, fees Accepted for publication: October 31, 2016 for lectures and advisory board fees from Abbott Vision. * Department of Ophthalmology and Visual Sciences, Escola Paulista de Medicina (EPM), Universidade Corresponding author: Wallace Chamon. R. Olimpíadas, 134/51 - São Paulo, SP - 04551-000 - Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil. Brazil - Phone: +55(11) 4171-2000 - E-mail: [email protected]

http://dx.doi.org/10.5935/0004-2749.20160082 V Crosslinking enters public health armamentarium in Brazil

gen cross-linking reduce the need for keratoplasties in patients with keratoconus? 11. Agência Nacional de Saúde Suplementar. Rol de procedimentos e eventos em saúde Cornea. 2015;34(9):991-5. 2016. Anexo I [Internet]. Brasília, DF. [citado 2016 Jul 21]. Disponível em: http://www. 8. Flores VG, Dias HL, de Castro RS. [Penetrating keratoplasty indications in Hospital das ans.gov.br/images/stories/Plano_de_saude_e_Operadoras/Area_do_consumidor/ Clínicas-UNICAMP]. Arq Bras Oftalmol. 2007;70(3):505-8. rol/ROL2016_listagem_procedimentos.pdf 9. Adam Netto A, Botelho CA, Felicissimo LC. Indications and epidemiological profile of 12. Kennedy RH, Bourne WM, Dyer JA. A 48-year clinical and epidemiologic study of patients submitted to keratoplasty. Rev Bras Oftalmol. 2014;73(3):162-6. keratoconus. Am J Ophthalmol. 1986;101(3):267-73. 10. Neves RC, Boteon JE, Santiago AP. Indications for penetrating corneal graft at the 13. Pron G, Ieraci L, Kaulback K. Collagen cross-linking using riboflavin and ultraviolet-a São Geraldo Hospital of Minas Gerais Federal University. Rev Bras Oftalmol. 2010; for corneal thinning disorders: an evidence-based analysis. Ont Health Technol Assess 69(2):84-8. Ser. 2011;11(5):1-89.

VI Original Article

Corneal structure in tilted disc syndrome Estrutura da córnea na síndrome de disco inclinado

Abuzer Gunduz1, Nihat Polat1, Tongabay Cumurcu1, ErsinErsan Demirel1, Ercan Özsoy1

ABSTRACT RESUMO Purpose: To evaluate the central corneal thickness (CCT), corneal volume (CV), Objetivo: Avaliar a espessura central da córnea (CCT), o volume de córnea (CV), e and anterior and posterior corneal surfaces using the Scheimpflug imaging system a superfície corneana anterior e posterior utilizando sistema de imagem Scheimpflug in patients diagnosed with tilted disc syndrome (TDS). em pacientes com diagnóstico de síndrome do disco inclinado (TDS). Methods: The study group (Group 1) and the control group (Group 2) comprised Métodos: O grupo de estudo (grupo 1) e o grupo controle (grupo 2) consistiu de 35 35 eyes of 35 age-, sex-, and refraction-matched cases. All cases underwent a full olhos de 35 pacientes pareados por idade, sexo e refração em cada grupo. Todos os ophthalmic examination that included cycloplegic refraction, axial ocular length casos foram submetidos a um exame oftalmológico completo incluindo refração measurement, and Scheimpflug imaging. sob cicloplegia, medida do comprimento axial ocular e avaliação por Scheimpflug. Results: The mean age was 34.68 ± 15.48 years in Group 1 and 34.11 ± 12.01 Resultados: A idade média foi de 34,68 ± 15,48 anos no grupo 1 e 34.11 ± 12,01 years in Group 2 (p=0.864). The gender distribution was 18 males and 17 females anos no grupo 2 (p=0,864). A distribuição por sexo foi de 18 homens e 17 mulheres in Group 1 and 16 males and 19 females in Group 2 (p=0.618). All subjects were do grupo 1 e 16 homens e 19 mulheres no grupo 2 (p=0,618). Todos os indivíduos Caucasian. The spherical equivalent was 3.62 ± 1.75 D in Group 1 and 3.69 ± 1.51 D eram caucasianos. O equivalente esférico foi 3,62 ± 1,75 D no Grupo 1 e 3,69 ± 1,51 D in Group 2 (p=0.850). There was no significant difference in age, sex, race, or no Grupo 2 (p=0,850). Não houve diferença significativa entre os dois grupos para spherical equivalent between groups. There was no significant difference in mean idade, sexo, raça e equivalente esférico. Não houve diferença significativa entre os dois keratometric value and CV3 (the CV in the central 3 mm) between groups (p=0.232 grupos para o valor médio ceratométrico e CV3 (o volume da córnea na central 3 mm) and 0.172, respectively). There were statistically significant differences in CCT, CV5, (p=0,232, p=0,172, respectivamente). Houve diferença estatisticamente significativa and CV7 (CV in the central 5 and 7 mm3, respectively) and total CV between groups entre os dois grupos para CCT, CV5, CV7 (volume de córnea na região central 5 e 7 mm, (p=0.008, 0.003, 0.023, and 0.019, respectively). The values of all parameters were respectivamente) e CV total (p=0,008, p=0,003, p=0,023 e p=0,019, respectivamente). lower in the study group than in the control group. There was also a statistically Os valores do grupo de estudo foram menores do que o grupo controle para todos os significant difference in the anterior elevation parameters of the cornea between parâmetros. Houve também diferença estatisticamente significativa entre os dois groups (p<0.05). The mean values of Group 1 were higher than those of Group 2. grupos nos parâmetros elevação anterior da córnea (p<0,05). Os valores médios do There were statistically significant differences in the two parameters referring to grupo 1 foram maiores do que o grupo 2. Não houve diferença entre os dois grupos the posterior elevation of the cornea between the two groups (p<0.05). para os dois parâmetros referentes à elevação posterior da córnea (p<0,05). Conclusion: The results of this study showed that eyes with TDS have thinner CCT, Conclusões: Nosso estudo mostrou que os olhos com TDS apresentam CCT mais lower CV, and different anterior corneal curvature than normal eyes. fina, menor volume da córnea e alterações na curvatura corneana anterior quando comparados aos olhos normais. Keywords: Corneal topography; Cornea/pathology; Optic disk/abnormalities; Diag Descritores: Topografia da córnea; Córnea/patologia; Disco óptico/anormalidades; Téc nostic techniques, ophthalmological nicas de diagnóstico oftalmológico

INTRODUCTION to be mainly corneal in origin, is the main cause of poor vision in TDS (5) Tilted disc syndrome (TDS) is a nonhereditary syndrome characte patients . Another study reported clinically significant lenticular astig- rized by a congenital optic disc abnormality with an elevation of the matism in these cases(3). A marked relationship between abnormal superotemporal part and depression of the inferonasal part of the corneal configuration and abnormal optic discs has been reported disc, leading to an oblique orientation of its longitudunal axis that in the literature. Another study reported that the orientation of the affects males and females equally(1,2). Situs inversus (oblique orienta- long axis of the optic disk could indicate the corneal astigmatism tion of retinal vascular structures), myopic astigmatism, peripapillary axis(6), and Pakravan et al.(7) reported an inverse correlation between atrophy, ectasic inferonazal fundus, inferior retinal pigment epithe- the optic disk area and central corneal thickness (CCT). lium, and choroid thinning are frequently present in these cases(1,2). The Scheimpflug imaging system (Pentacam) provides data on the These findings can be associated with bitemporal hemianopsia, elevation of the anterior and posterior corneal aspects, and pachymetric central retinal vein thrombosis, peripapillary subretinal hemorrhage, measurements without making contact with the ocular surface using macular neurosensory retinal detachment, and secondary choroidal a procedure that is easy to perform and repeatable. The Scheimpflug neovascularization(3,4). Myopic astigmatism, which has been reported imaging system also provides user-independent high reliability(8).

Submitted for publication: December 4, 2014 Funding: No specific financial support was received for this study. Accepted for publication: May 27, 2016 Disclosure of potential conflicts of interest: None of the authors have any potential conflict of 1 Department of Ophthalmology, School of Medicine, Inonu University, Malatya, Turkey. interest to disclose. Corresponding author: Abuzer Gunduz. Inonu University School of Medicine. Malatya 44280 - Turkey - E-mail: [email protected] Approved by the following research ethics committee: Malatya Clinical Studies Ethic Committee (#2012/57)

http://dx.doi.org/10.5935/0004-2749.20160083 Arq Bras Oftalmol. 2016;79(5):285-8 285 Corneal structure in tilted disc syndrome

The aim of this study was to evaluate the detailed structure of the rected visual acuity (BCVA), cornea and anterior segment evaluation cornea in patients with a diagnosis of TDS using the Scheimplug with a slit lamp, and intraocular pressure (IOP) measurements. Only imaging system and to compare these data with those of a normal patients with no pathology were included in the study. All eyes were population. The difference between this study and other previous evaluated with the Scheimpflug imaging system (Oculus Optikgerate studies is the use of the Scheimpflug imaging system to evaluate the GmbH, Wetzlar, Germany) and axial length measurement and cyclo- anterior and posterior surfaces and the volume of the cornea in detail. plegic refraction were performed with an auto kerato-refractometer (KR-8900; Topcon Corporation, Tokyo, Japan) 45 min after administration of 1% cyclopentolate hydrochloride drops at 10-min intervals. METHODS Both groups consisted of patients with no systemic disease who The study protocol was approved by the Ethics Committee of had not used any systemic or topical drugs in the last 3 months. Pa- Inonu University (Malatya, Turkey). All patients participated in the study tients who underwent ocular surgery, had a history of contact lens voluntarily. Information and consent forms were obtained from the use, had ocular trauma, or had symptoms of ocular allergy or dry eye patients and volunteers in the control group. were excluded from the study. Eyes with a corrected visual acuity of This was a cross-sectional study conducted between May 2012 less than 0.5 on a standard ophthalmic examination and eyes with an and December 2012 that included one eye from each participant. axial length (ALX) of less than 22.0 mm or more than 26.0 mm were The eye with a spherical equivalent closer to the control group in also excluded. bilateral cases was chosen. Patients diagnosed with TDS and control cases were recruited from approximately 1350 patients who pre- Pentacam measurements sented to the Department of Ophthalmology, School of Medicine, All measurements were obtained under standard dim light con- Inonu University. The patients and controls were aged 18-60 years ditions and without dilation. The instrument automatically starts the with no ocular or corneal pathology or history of ocular surgery, use measurement once correct alignment with the corneal apex and of any topical or systemic drugs in the last 3 months, or systemic di- focus is achieved. One measurement with the Scheimpflug imaging sorder (diabetes mellitus, rheumatologic diseases, Down syndrome, system takes approximately 2 s, during which time the Scheimpflug pregnancy) that could affect the eyes. The cases were evaluated as camera captures 25 images by rotating 360 degrees around the opti two groups in the study. Power analysis showed that the minimum cal axis of the eye. Three images were evaluated and the one with number of cases for each group was 32. the best quality was recorded for each eye. CCT measurements and The study group (Group 1) consisted of 35 eyes of 35 patients anterior and posterior elevation maps were obtained with this ins- with TDS. The following criteria were used for a diagnosis of TDS: trument. Once the screening was completed, the Pentacam software elevation of the superotemporal part and backwards dislocation automatically recorded the CCT, corneal volume (CV), the volumes of of the inferonasal part of the optic disc, oblique orientation of the 3, 5, and 7 mm3 (CV3, CV5, and CV7, respectively), and mean kerato- longitudinal axis of the optic disc, the presence of retinal pigment metry (mK) values. The data obtained from the anterior and posterior (8) epithelium and choroidal atrophy together with inferonasal peripa maps were evaluated as reported by Uçakhan et al. . Accordingly, pillary atrophy (Figure 1). The fundus of all study participants was the Max AE5, Max AD5, AER, and AEDD parameters were calculated photographed. from the anterior corneal maps and the Max PE5, Max PD5, PER, and The control group (Group 2) consisted of 35 eyes of 35 age- and PEDD parameters from the posterior corneal maps. These parameters sex-matched healthy patients chosen according to spherical equiva were then used to evaluate the anterior and posterior aspects of the lents. We made sure that the cycloplegic refraction spherical equi- cornea. These abbreviations of the indices are explained in table 1. valent value (calculated by adding half the minus astigmatism value Axial length measurements to the spherical value) of the control group was similar to that of the study group. Also, the same exclusion criteria were used for the Proparacaine HCl 0.5% drops (Alcaine; Alcon-Couvreur NV, Puurs, control group and the study group. Belgium) were used for topical corneal anesthesia before measure- An ophthalmologist performed standard ophthalmic examina- ment of axial length (Alx). by ultrasound using a Biovision A-Scan tions of participants in both groups that included refraction, best cor- V-Plus Echograph (Biovision, Milpitas, CA, USA) equipped with an 8-MHz linear probe. The average of 10 Alx measurements was used for analysis.

Statistical analysis SPSS software version 18.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. The Shapiro-Wilk test was used to determine whether the distribution of values was normal. The independent sample t-test was used for normally distributed values and the Mann-Whitney U test was used for non-normally distributed values. The chi-square test was used to compare the ratio of males to females between the groups. An α-value of 0.05 indicated a type I error. A probabilit y (p) value of >0.05 was considered statistically significant.

RESULTS There were 18 males and 17 females in group 1 and 16 males and 19 females in group 2. Table 2 presents the age, BCVA, IOP, sex, axial length, and spherical equivalent values of the patients. There were no statistically significant differences in age, gender, axial length, or spherical equivalent values between two groups (p=0.864, 0.618, 0.234, and 0.850, respectively). The CCT and mK value were obtained directly from the Scheimpflug F igure 1. An optic disc image of a 32-year-old male TDS patient with a spherical equi imaging system and the CV3, CV5, CV7, and total CV data were com- valent of -3.25 diopter pared between the two groups. As presented in table 3, there were

286 Arq Bras Oftalmol. 2016;79(5):285-8 Gunduz A, e t a l .

no significant differences in mK values between the two groups The anterior corneal values calculated from the anterior maps ob- (p=0.232). There was also no statistical difference in CV of the central tained via the Scheimpflug imaging system are presented in table 4. 3-mm3 volume between the two groups (p=0.172). However, there There were statistically significant differences in the Max AE5, Max were statistically significant differences in CCT, CV5, CV7, and total AD5, AER, and AEDD parameters between the two groups that showed CV values between the groups (p=0.008, 0.003, 0.023, and 0.019, res elevation of the anterior cornea (p=0.001, 0.001, 0.001, and 0.001, res pectively). The values for all three parameters were lower in the study pectively). The mean values of these four parameters were greater in group than in the control group. the study group than in the control group. The values calculated from the posterior surface maps of the cornea obtained via the Scheimpflug imaging system showing elevation of the posterior cornea are shown in table 5. There were statistically Table 1. Abbreviations MaxAE5 The maximum elevation value above the BFS at the central 5.0 mm of the anterior elevation map obtained by Table 3. Comparison of the corneal central thickness (CCT) and mean moving the cursor to the highest point keratometry value and the CV3, CV5, CV7 and CV data that show on the anterior elevation map. the corneal volume obtained directly from the Pentacam between groups MaxAD5 The maximum depression value below the BFS at the central 5.0 mm of the Group 1 (n=35) Group 2 (n=35) anterior elevation map obtained by Pentacam data (Mean ± SD) (Mean ± SD) p-value moving the cursor to the lowest point Mean K 040.91 ± 14.66 043.93 ± 12.96 0.232* on the anterior elevation map. CCT, μm 517.06 ± 36.31 542.66 ± 41.33 0.008*

AER (anterior elevation ratio) Obtained from the anterior elevation 3 data. The maximum elevation value CV3, mm 003.75 ± 00.27 003.86 ± 00.37 0.172* above the BFS at the central 5.0 mm of CV5, mm3 011.00 ± 00.77 011.59 ± 00.79 0.003* the anterior elevation map divided by CV7, mm3 023.86 ± 01.86 024.83 ± 01.60 0.023* the BFS (AER Z MaxAE5/BFS). CV, mm3 057.92 ± 04.25 060.40 ± 04.30 0.019* AEDD (anterior elevation depression Obtained from the anterior elevation difference) data. The highest minus lowest value *= statistically significant; n= number; SD= standard deviation; K= keratometry; CCT= above and below the best-fit sphere central corneal thickness; CV3= corneal volume in 3 mm3; CV5= corneal volume in 5 mm3; (BFS) (AEDD Z MaxAE5 _ MaxAD5). CV7= corneal volume in 7 mm3; CV= total corneal volume. MaxPD5 The maximum depression value below the BFS at the central 5.0 mm3 of the posterior elevation map obtained by moving the cursor to the lowest point Table 4. Comparison of the Max AE5, Max AD5, AER, and AEDD on the posterior elevation map. values that were obtained from the anterior elevation map from the Pentacam and that showed the corneal anterior elevation between MaxPE5 The maximum elevation value above the two groups the BFS at the central 5.0 mm3 of the posterior elevation map obtained by Group 1 (n=35) Group 2 (n=35) moving the cursor to the highest point Pentacam data (Mean ± SD) (Mean ± SD) p-value on the posterior elevation map. Max AE5, μm -12.22 ± 06.66 -07.51 ± 4.23 0.001* PEDD (posterior elevation depression Obtained from the posterior elevation Max AD5, μm -13.11 ± 06.68 0-8.31 ± 5.17 0.001* difference) data. The highest minus lowest value above and below the BFS (PEDD = AER -01.42 ± 00.95 -00.96 ± 0.62 0.001* MaxPE5 - MaxPD5). AEDD, μm -24.80 ± 11.82 -15.02 ± 9.00 0.001* PER (posterior elevation ratio) Obtained from the posterior elevation *= statistically significant; n= number; SD= standard deviation; MaxAE5= the maxi- data. The maximum elevation value mum elevation value above the BFS at the central 5.0 mm3 of the anterior elevation 3 above the BFS at the central 5.0 mm of map; MaxAD5= the maximum depression value below the BFS at the central 5.0 mm3 the posterior elevation map divided by of the anterior elevation map; AER= anterior elevation ratio obtained from the the BFS (PER = MaxPE5/BFS). anterior elevation data; AEDD= anterior elevation depression difference obtained from the anterior elevation data.

Table 2. Age, sex, axial length and cycloplegic spherical equivalent Table 5. Comparison of the Max AE5, Max AD5, AER, and AEDD va- mean values of the study subjects lues that were obtained from the posterior elevation map from the Group 1 (n=35) Group 2 (n=35) Pentacam and that showed the corneal posterior elevation between the two groups Patient (Mean ± SD) (Mean ± SD) p-value Group 1 (n=35) Group 2 (n=35) Age, years 34.68 ± 15.48 34.11 ± 12.01 0.864 Pentacam data (Mean ± SD) (Mean ± SD) P BCVA 9/10 10/10 0.963 Max PE5, μm -26.28 ± 15.56 -19.74 ± 11.40 0.066* IOP 16 17 1 Max PD5, μm -29.17 ± 13.15 -24.51 ± 12.32 0.140* Sex PER -04.21 ± 02.45 -02.88 ± 01.51 0.001* Male, n (%) 18 (51.42%) 16 (45.71%) 0.618 PEDD, μm -54.77 ± 27.06 -43.17 ± 20.83 0.048* Female, n (%) 17 (48.57%) 19 (54.28%) *= statistically significant. n, number; SD= standard deviation; MaxPD5= the maximum ALX, mm 23.50 ± 0.38 23.39 ± 0.41 0.234 depression value below the BFS at the central 5.0 mm3 of the posterior elevation map; MaxPE5= the maximum elevation value above the BFS at the central 5.0 mm3 of the Spheric equivalent, D 03.62 ± 1.75 03.69 ± 1.51 0.850 posterior elevation map; PER= posterior elevation ratio obtained from the posterior n= number; SD= standard deviation, BCVA= best corrected visual acuity; IOP= intraocular elevation data; PEDD= posterior elevation depression difference obtained from the pressure; ALX= axial length; mm= millimeter; D= diopter. posterior elevation data.

Arq Bras Oftalmol. 2016;79(5):285-8 287 Corneal structure in tilted disc syndrome

significant differences in the PER and PEDD parameters between the cases. Prior studies only evaluated refractive and pachymetric mea- two groups (p=0.001 and 0.048, respectively), while there were no surements of the cornea. The Scheimpflug imaging system uses the significant differences in Max PE5 and Max PD5 values between the elevation-based tomography principle and therefore provides accu- two groups (p=0.066 and 0.14, respectively). rate and reliable data on the actual shape of the cornea, independent of position, orientation and axis(18). It therefore enables a much more detailed evaluation of the cornea than do refractive or ultrasonogra- DISCUSSION phic pachymetry measurements. There is a relationship between the optic disc and cornea, which There were some limitations to this study. The main limitations are the anterior and posterior windows of the sclera to the outside. were the small number of cases and the lack of blinding during the A marked relationship between abnormal optic disc shape and abnor examinations. Multicenter studies with larger patient cohorts may mal corneal configuration has been reported in the literature(6). Thick provide more valuable results. Another limitation was that the study corneas have been shown to be present with optic disc drusen, and control groups consisted of Caucasians only. Thus, future studies indicating a relationship between development of the optic nerve of multiracial study groups will provide more valuable information. head and corneal thickness(9). These findings indicate that factors that In conclusion, we performed a detailed evaluation of the cornea play roles in corneal development also play roles in optic disc deve- in eyes with TDS and found that CCT was lower, the cornea volume lopment. A previous study reported a relationship between cornea was decreased especially in the peripheral regions, and there were and optic disc dimensions and that the larger the cornea, the larger important changes, especially in the anterior corneal elevation in the optic disc(10). Another study found a reverse relationship between eyes with TDS, as compared to normal eyes. The decreased peripheral CCT and the optic nerve area in primary open angle glaucoma pa- CV together with anterior corneal elevation in TDS cases can cause tients and this relationship was shown to result in larger optic nerve serious problems during refractive surgery procedures resulting in areas with thinner corneas(11). CV loss. We therefore feel that the cornea should be evaluated more TDS is a congenital optic disc anomaly that affects the anterior carefully in eyes with TDS before refractive surgery. Repeating this and posterior segments of the eye. A significant relationship has been study with a larger cohort could reinforce the results. found between an abnormal optic disc shape and abnormal corneal structure in TDS cases(6). Another study found no statistically significant relationship between CCT values of TDS patients and normal REFERENCES controls(12). However, they found that the CCT was 6-µm thicker in TDS . 1 Apple DJ, Rabb MF, Walsh PM. Congenital anomalies of the optic disc. Surv Ophthalmol. patients than in the control group. Dehghani et al.(4) also found no 1982;27(1):3-41. 2. Young SE, Walsh FB, Knox DL. The tilted disc syndrome. Am JOphthalmol. 1976;82(1): statistically significant relationship in corneal thickness between the 16-23. TDS and control groups, although CCT values were greater in TDS ca- 3. Gündüz A, Evereklioğlu C, Er H, Hepşen İF. Lenticular astigmatism in tilted disc syn- ses. In contrast, we found significantly smaller CCT values in eyes with drome. J Cataract Refract Surg. 2002;28(10):1836-40. TDS than in those in the control group (517.06 ± 36.31 vs. 542.66 ± 4. Dehghani C, Nowroozzadeh MH, Shankar S, Razeghinejad MR. Ocular refractive and 41.33 microns, respectively, p=0.008). We believe that the difference biometric characteristics in patients with tilted disc syndrome. Optometry. 2010;81(12): 688-94. in CCT between our study and these previous reports is due to the 5. Bozkurt B, Irkec M, Gedik S, Orhan M, Erdener U.Topographical analysis of corneal technique used to measure corneal thickness and racial differences astigmatism in patients with tilted-disc syndrome.Cornea. 2002;21(5):458-62. of the included subjects. The A-scan ultrasound used in the literature 6. Jonas JB, Kling F, Grundler AE. Optic disc shape, corneal astigmatism, and amblyopia. is highly user-dependent compared to the Pentacam system, which Ophthalmology. 1997;104(11):1934-7. can also influence the results(13).The technique used in the present 7. Pakravan M, Parsa A, Sanagou M, Parsa CF. Central corneal thickness and correlation study provides more reliable results in this respect. Studies have also to optic disc size: a potential link for susceptibility to glaucoma. Br J Ophthalmol. 2007; (14,15) 91(1):26-8. shown that CCT can vary between subjects of different races . 8. Uçakhan ÖÖ, Cetinkor V, Özkan M, Kanpolat A. Evaluation of Scheimpflug imaging The parameters for evaluation of CV were also checked in this parameters in subclinical keratocunus, keratocunus, and normal eyes. J Cataract Refract study. There was no difference in the CV3 value while there were Surg. 2011;37(6):1116-24. statistically significant differences in the CV5, CV7, and CV values 9. Dohadwala AA, Damji KF. Familial occurrence of artefactual ocular hypertension from between the two groups, which indicated that CV is decreased and thick corneas and of primary open angle glaucoma in a French Canadian kindred. Ophthalmic Genet. 2000;21(1):1-7. the cornea is thinner in eyes with TDS. We therefore believe that the 10. Jonas JB, Konigsreuther KA. Macrodiscs in eyes with flat and large corneas. Ger J Ophthal- lower volume in the peripheral cornea than in the central cornea in mol. 1994;3(3):179-81. TDS cases can increase the risk of ectasia following refractive surgery. 11. Insull E, Nicholas S, Ang GS, Poostchi A, Chan K, Wells A. Optic disc area and correla- Current technology has facilitated the detection of ectasia of the tion with central corneal thickness, corneal hysteresis and ocular pulse amplitude in anterior and posterior aspects. Identification of elevations of the an- glaucoma patients and controls. Clin Experiment Ophthalmol. 2010;38(9):839-44. terior and posterior corneal surfaces is especially important for refrac- 12. Ornek K, Ozdemir M. Central corneal thickness in tilted disc syndrome. Optom Vis Sci. 2008;85(5):E350-52. tive surgery. It has also been reported that elevation of the posterior 13. Kuerten D, Plange N, Koch EC, Koutsonas A, Walter P, Fuest M.Central corneal thickness cornea is important for early detection of keratoconus in addition to determination in corneal edema using ultrasound pachymetry, a Scheimpflug camera, anterior corneal elevation(16,17). We found a significant difference in an- and anterior segment OCT. Graefes Arch Clin Exp Ophthalmol. 2015;253(7):1105-9. terior curvature changes of the cornea between the control and TDS 14. Yo C, Ariyasu RG. Racial differences in central corneal thickness and refraction among groups in this study. We also found changes in elevation of the pos- refractive surgery candidates. J Refract Surg. 2005;21(2):194-7. 15. Aghaian E, Choe JE, Lin S, Stamper RL.Central corneal thickness of Caucasians, Chinese, terior corneal surface, although these changes were not as significant Hispanics, Filipinos, African Americans, and Japanese in a glaucoma clinic. Ophthal- as those in the anterior surface. Since this is the first study to compare mology. 2004;111(12):2211-9. the degree of elevation of the anterior and posterior cornea in TDS 16. Piñero DP, Alió JL, Alesón A, Escaf Vergara M, Miranda M. Corneal volume, pachymetry, cases, we were unable to compare our data with other data sets in and correlation of anterior and posterior corneal shape in subclinical and different the literature. However, we believe these corneal elevations could be stages of clinical keratoconus. J Cataract Refract Surg. 2010;36(5):814-25. important in TDS patients who are candidates for refractive surgery. 17. Nilforoushan MR, Speaker M, Marmor M, Abramson J, Tullo W, Morschauser D, Latkany R. Comparative evaluation of refractive surgery candidates with Placido topography, The main difference of this study from others in the literature is Orbscan II, Pentacam, and wavefront analysis. J Cataract Refract Surg. 2008;34(4):623-31. the use of the Scheimpflug imaging system to evaluate the anterior 18. Miháltz K, Kovács I, Takács A, Nagy ZZ.Evaluation of keratometric, pachymetric, and and posterior surfaces, and volumes of the cornea in detail in TDS elevation parameters of keratoconic corneas with pentacam.Cornea. 2009;28(9):976-80.

288 Arq Bras Oftalmol. 2016;79(5):285-8 Original Article

Microbiological and epidemiological study of infectious keratitis in children and adolescents Estudo microbiológico e epidemiológico da ceratite infecciosa em crianças e adolescentes

Maria Cecilia Zorat Yu1, Ana Luisa Höfling-Lima1, Guilherme Henrique Campos Furtado2

ABSTRACT RESUMO Purpose: To analyze epidemiological and microbiological aspects of microbial Objetivos: Descrever o perfil epidemiológico e microbiológico de ceratite microbiana keratitis in children and adolescents. em crianças e adolescentes. Methods: This retrospective cohort study was conducted at the Department Métodos: Estudo retrospectivo tipo coorte, utilizando fichas laboratoriais de pa of Ophthalmology and Visual Science, Escola Paulista de Medicina, Universidade cientes, atendidos no Departamento de Oftalmologia e Ciências Visuais - Escola Federal de São Paulo, between July 15, 1975, and December 31, 2010. We analyzed Paulista de Medicina - Universidade Federal de São Paulo, entre 15 de julho de 1975 corneal samples from 859 patients with clinical suspicion of infectious keratitis, a 31 de dezembro de 2010. Foram comparados pacientes com ceratite bacteriana comparing epidemiological and microbiological characteristics of bacterial keratitis e não bacteriana (não viral). Entre os pacientes com ceratite bacteriana, foram with those of non-bacterial and non-viral keratitis. We also compared Gram-positive compar ados aqueles em que a ceratite foi causada por bactérias Gram positivas and Gram-negative pathogens in patients with bacterial keratitis. We created a e Gram negativas. O perfil de sensibilidade dos microrganismos bacterianos aos susceptibility profile of the bacterial microorganisms studied. antimicrobianos também foi estudado. Results: Of the 859 patients, 346 (40.3%) showed positive culture results for Resultados: Foram analisadas amostras corneanas de 859 pacientes com suspeita non-viral microorganisms. Teenagers (13-18 years) made up the group with the clínica de ceratite infecciosa, na faixa etária estudada. Destes, 346 (40,3%) apresen- highest number of patients with keratitis (164, 47.4%). The most frequent risk taram resultados de culturas positivas para microrganismos não virais. Adolescentes factors for keratitis were trauma (33.5%) and previous ocular surgery (24.9%). (13 a 18 anos) compuseram o grupo com maior número de pacientes com ceratite Gram-positive bacteria (71.8%) were the most often isolated, with coagulase-ne (164-47,4%). Os principais fatores de risco foram trauma (33,5%) e cirurgias oculares gative Staphylococcus (23.8%) the most prevalent microorganism. Logistic regres- prévias (24,9%). Bactérias Gram positivas foram isoladas com maior frequência (71,8%), sion analysis showed age (p=0.002), topical antimicrobial drug use (p=0.01), and sendo prevalente o patógeno Staphylococcus coagulase negativo (23,8%). De acordo trauma due to non-chemical burns (p=0.005) were risk factors for non-bacterial com a análise de regressão logística, idade (p=0,002), uso tópico de drogas antimi- keratitis. Age (p=0.01) was also a risk factor for Gram-negative bacterial keratitis. crobianas (p=0,01) e trauma por queimadura não química (p=0,005) foram fatores Conclusion: Our study showed that in the age range studied, the prevalence of predisponentes para ceratite não bacteriana. Idade (p=0,01) também foi fator de risco keratitis caused by Gram-negative bacteria or by the non-viral microorganisms para ceratite causada por bactérias Gram negativas. evaluated increases with age. Previous use of topical antimicrobial drug and trauma Conclusões: Nosso estudo mostrou que quanto maior a idade, na faixa etária es due to non-chemical burns are associated with non-bacterial keratitis. Knowledge tudada, maior a probabilidade da ceratite ser causada por bactérias Gram negati of the risk factors and the microorganisms involved may help improve treatment vas e/ou por outros microrganismos não virais avaliados. O uso tópico de drogas of keratitis in children and adolescents and minimize visual impairment. antimicrobianas prévias e trauma devido à queimadura não química predispõe à ceratite não bacteriana. O conhecimento dos fatores de risco e dos microrganismos envolvidos resultarão em tratamento específico da ceratite em crianças e adolescentes, com menores danos visuais. Keywords: Keratitis/microbiology; Keratitis/epidemiology; Eye infections; Chil- Descritores: Ceratite/microbiologia; Ceratite/epidemiologia; Infecções oculares; Crian dren; Adolescent ça; Adolescente; Infecções oculares

INTRODUCTION than 20/200(4-7). Infectious keratitis are more prevalent in tropical de- Infectious keratitis is rare but potentially serious disease found veloping countries with poor healthcare systems than in developed mainly in young people. It is a preventable cause of visual impairment, countries(3,8-21). similar to including amblyopia in children and mono-or bilateral The diagnosis of keratitis is usually clinical and the treatment is blindness (1-3). empirical, with the application of broad-spectrum topical antimicro- More than one-third of eye injuries among children and adolescents bial agents until identification of the etiologic agent is completed. result from their natural curiosity, immature motor skills, and tendency However, few studies have investigated the causative agents and risk to imitate adult behavior without assessing the risks relevant to their factors of infectious keratitis in children and adolescents. actions. Although infectious keratitis is not common in this age group, The purpose of this study was to investigate the epidemiological it is potentially devastating as approximately, considering thet 30% of and microbiological findings of infectious keratitis in patients up to young victims of serious eye injuries end up with visual acuity lower 18 years of age attending a tertiary referral center. In addition, the

Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil. o 2 Corresponding author: Maria Cecilia Zorat Yu. Rua Pedro de Toledo, 669 - 4 andar - São Paulo, SP Departamento de Infectologia, Escola Paulista de Medicina (EPM), Universidade Federal de São 04023-062 - Brazil - E-mail: [email protected] Paulo (UNIFESP), São Paulo, SP, Brazil. Approved by the following research ethics committee: Universidade Federal de São Paulo (# 16206).

http://dx.doi.org/10.5935/0004-2749.20160084 Arq Bras Oftalmol. 2016;79(5):289-93 289 Microbiological and epidemiological study of infectious keratitis in children and adolescents

risk factors associated with the presence of bacterial keratitis and Acanthamoeba spp. with 23 (23.7%) of these patients testing positive. non-bacterial non-viral keratitis were analyzed, as well as the in vitro Overall, 4% and 6.6% of all patients tested positive for fungi and susceptibility profile of the bacterial isolates. Acanthamoeba spp., respectively. A total of 344 microorganisms were isolated from the 309 positive METHODS bacterial cultures (71.8% Gram-positive and 28.2% Gram-negative). The most prevalent bacteria were coagulase-negative Staphylococcus This retrospective cohort study assessed microbial keratitis in pa- (23.8%), Staphylococcus aureus (20.9%), and Pseudomonas spp. (14.2%) tients up to 18 years old in the period from July 15, 1975, to December (Table 2). Polymicrobial cultures accounted for 9.5% of the positive 31, 2010. All data included in the laboratory records of patients with cultures. clinical suspicion of keratitis were evaluated at the Ocular Microbiolo- gy Laboratory, Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil. The variables studied included age, sex, Table 1. Frequency of ocular antecedents among patients aged from affected eye, use of contact lenses, use of topical medications, ocular 10 days to 18 years with keratitis antecedents, comorbidities, and previous ocular surgery. The in vitro E ye history Total (%) susceptibility profiles of the bacteria were identified, and the annual Ocular antecedent incidence of infectious keratitis and the prevalence of etiologic agents were also evaluated. The local Ethics Committee approved this study. Use of topical medications 148 (42.8) All subjects underwent sample collection from corneal ulcers by Trauma 116 (33.5) an ophthalmologist. The corneal scraping was performed using to- Prior eye surgery 086 (24.9) pical anesthesia with proxymetacaine (5 mg/ml) or, when necessary, Use of contact lenses 063 (18.2) narcosis in the operating room. We inoculated the collected material Conjunctivitis 024 (06.9) in solid (blood agar, chocolate agar and Sabouraud agar; Oxoid Ltd., Comorbidities 020 (05.8) Basingstoke, UK) and liquid (brain heart infusion and thioglycolate; Oxoid Ltd.) culture media(22-24). The material was placed in a transport Congenital glaucoma 013 (03.8) medium containing saline and sterile distilled water and was subse- Keratitis 011 (03.2) quently inoculated on plates with soy agar culture media (semi-defi- Keratoconus 008 (02.3) ned), supplemented with 20 µl of inactivated Escherichia coli when an Herpes 007 (02.0) (24) infection with the protozoan Acanthamoeba spp. was suspected . In Atopy 003 (00.9) our laboratory, the routine practice of this specific culture began in Blepharitis 003 (00.9) 1987 with the identification and subsequent publication of the first cases of keratitis caused by Acanthamoeba spp. in Brazil(25). Mainte- Endophthalmitis 002 (00.6) nance of the inoculated culture media, and isolation and identifica- Stye 002 (00.6) tion of bacteria, fungi, and the protozoan Acanthamoeba spp. were Proptosis 002 (00.6) performed according to standard microbiology procedures(22-24,26). Nodular degeneration Salzmann 001 (00.3) The assessment of bacterial susceptibility to antimicrobial agents Entropion 001 (00.3) commonly used in ophthalmology was performed by using the Microphthalmos 001 (00.3) Kirby-Bauer agar-diffusion test according to the guidelines of the National Committee for Clinical Laboratory Standards (NCCLS; Phila- Trachoma 001 (00.3) delphia, PA, USA) until 2004, and, subsequently, by the Clinical and Laboratory Standards Institute (CLSI; Philadelphia, PA, USA). Categorical variables were analyzed using the chi-square test. Table 2. Prevalence of bacteria isolated from keratitis samples among patients aged from 10 days to 18 years Continuous variables were analyzed using Student’s t test. A p value <0.1 was considered significant. Logistic regression was used with a Bacteria Total (%) p value <0.05 considered significant. MedCalc software version 11.6.1(27) Coagulase-negative Staphylococcus 82 (23.8) (MedCalc, Ostend, Belgium) was used for the statistical analysis. Staphylococcus aureus 72 (20.9) Pseudomonas spp. 49 (14.2) RESULTS Streptococcus pneumonia 31 (09.0) Between July 1975 and December 2010, a total of 859 patients with Streptococcus viridans 28 (08.1) clinical suspicion of keratitis aged 0-18 years were assessed. From these Corynebacterium spp. 21 (06.1) patients, 346 eyes from 346 patients [197 (56.9%) boys] with positive Moraxella spp. 16 (04.6) cultures for bacteria, fungi and/or the protozoan Acanthamoeba spp. were included in the study. Serratia spp. 10 (02.9) The right eye was more commonly affected, in 184 (53.2%) of Haemophilus spp. 08 (02.3) patients. The age ranged from 10 days to 18 years with a mean of 12 Streptococcus spp.* 08 (02.3) ± 4.7 years. We divided the patients according to age: there were 5 Unidentified Gram- bacilli 03 (00.9) (1.4%) newborns (0-28 days), 47 (13.6%) infants (29 days to 2 years), 57 Unidentified Gram+ bacilli 03 (00.9) (16.5%) pre-school age children (3-6 years), 73 (21.1%) school children Enterobacter spp. 03 (00.9) (7-12 years), and 164 (47.4%) adolescents (13-18 years). Thus, the most prevalent age group was the adolescents. Proteus spp. 03 (00.9) Topical medication was used at the time of sample collection in Klebsiella spp. 02 (00.6) 42.8% of the patients. Antimicrobial drugs accounted for 71.6% of Acinetobacter spp 01 (00.3) the topical medications used (Table 1). Major antecedents included Bacillus circulans 01 (00.3) trauma in 33.5% of patients, previous eye surgery in 24.9%, and the use Citrobacter spp 01 (00.3) of contact lenses in 18.2% (Table 1). Cancer was the major comorbidity found, in seven of the patients, accounting for 2% of the study patients. Neisseria spp 01 (00.3) Bacterial cultures were requested for all 346 patients and 309 Nocardia asteroides 01 (00.3) (89.3%) tested positive. There were 317 requests for fungal cultures, Total 344 with 14 (4.4%) testing positive and 97 requests for the protozoan *= Streptococcus spp.: gamma-hemolytic (4), spp. (3) and beta-hemolytic (1).

290 Arq Bras Oftalmol. 2016;79(5):289-93 Yu MCZ, e t a l .

Thirteen filamentous fungi and one yeast, Rhodotorula rubra, were xacin and resistance lower than 6% to gentamicin, tobramycin, and identified. Filamentous fungi included Fusarium solani species com- polymyxin B. plex (64.3%), Aspergillus flavus species complex, Scedosporium apios- We analyzed the annual incidence of cases of keratitis in children permum, Penicillium spp. (7.1% each) and one unidentified. and adolescents and the respective identification of microorganisms All of the Gram-positive cocci were vancomycin-susceptible. over the study period. The percentage of fungal infections remained Methicillin-susceptible Staphylococcus showed resistance lower than stable throughout the study period, with positivity ranging from 1.8% 10% to first generation cephalosporins, aminoglycosides, and fluoro to 16.6%. The prevalence of infections with Acanthamoeba spp. ranged quinolones, and resistance lower than 20% to trimethoprim-sulfa from 1.8% to 11.1%. Bacterial infections were always the most common, methoxazole. Methicillin-resistant Staphylococcus showed significant with the prevalence in cultures ranging from 10% to 100%. resistance to most antimicrobials apart from the most recent gene- Univariate analysis comparing patients with bacterial and rations of fluoroquinolones.Streptococcus pneumoniae showed no non-bacterial keratitis showed the following significant variables for resistance to penicillin. non-bacterial keratitis: age (p=0.001), the use of antimicrobial drugs Enterobacteriaceae showed full susceptibility to amikacin, ceftria (p=0.02), and non-chemical or physical burns (p=0.004). In the mul- xone, ciprofloxacin, chloramphenicol, gentamicin, moxifloxacin, and tivariate analysis, age (odds ratio [OR] 1.19; 95% confidence interval [C] I ofloxacin, whereas tobramycin and trimethoprim-sulfamethoxazole 1.09-1.31), use of antimicrobial drugs (OR 2.50; 95%CI 1.19-5.23), and showed 5.6% and 12.5% resistance, respectively. Pseudomonas aerugi physical burn injuries (OR 17.29; 95%CI 2.40-124.57) were associated nosa showed 100% susceptibility to amikacin, ciprofloxacin, and oflo with non-bacterial keratitis (fungal or Acanthamoeba spp.) (Table 3).

Table 3. Univariate and multivariate analyses comparing bacterial versus non-bacterial keratitis among patients aged from 10 days to 18 years Bacterial keratitis Non-bacterial keratitis (N=309) (N=37) p-value Odds ratio 95%CI p-value Variables Age, years 10.0 ± 6.0 14.6 ± 3.4 0.001 1.19 1.09 - 1.31 0.0002 Male sex 179 (57.9) 18 (48.6) 0.370 Affected right eye 166 (53.7) 18 (48.6) 0.680 Eye history Atopy 003 (01.0) 00 (00.0) 0.740 Blepharitis 003 (01.0) 00 (00.0) 0.740 Keratitis 008 (02.6) 01 (02.7) 0.610 Keratoconus 008 (02.6) 01 (02.7) 0.610 Conjunctivitis 023 (07.4) 01 (02.7) 0.470 Endophthalmitis 002 (00.6) 00 (00.0) 0.510 Congenital glaucoma 013 (04.2) 00 (00.0) 0.420 Herpes 006 (02.0) 01 (02.7) 0.760 Stye 002 (00.6) 00 (00.0) 0.510 Proptosis 002 (00.6) 00 (00.0) 0.510 Antimicrobial use 088 (28.5) 18 (48.6) 0.020 02.50 1.19 - 5.23 0.0100 Injury Vegetable 041 (13.2) 00 (00.0) 0.040 Mechanical 015 (04.8) 01 (02.7) 0.860 Metal 015 (04.8) 03 (08.1) 0.650 Chemical burn 003 (01.0) 00 (00.0) 0.740 Non-chemical burn 002 (00.6) 03 (08.1) 0.004 17.29 2.40 - 124.57 0.0050 Prior eye surgery Corneal transplantation 036 (11.6) 07 (18.9) 0.320 Postoperative complications 015 (04.8) 01 (02.7) 0.510 Removal of corneal foreign body 007 (02.3) 01 (02.7) 0.680 Suture 004 (01.3) 02 (05.4) 0.250 Eyelid correction 002 (00.6) 00 (00.0) 0.510 Tumor excision 002 (00.6) 00 (00.0) 0.510 Coating 002 (00.6) 00 (00.0) 0.510 Blepharorrhaphy 002 (00.6) 00 (00.0) 0.510 Antiglaucoma tube insertion 002 (00.6) 00 (00.0) 0.510 Type of contact lenses Soft 029 (09.4) 07 (18.9) 0.130 Rigid 006 (01.9) 00 (00.0) 0.850 Therapeutic 003 (01.0) 00 (00.0) 0.740 Comorbidities Cancer 007 (02.3) 00 (00.0) 0.760 Chemo or radiation therapy 002 (00.6) 00 (00.0) 0.510 Data are presented as mean ± standard deviation or n (%).

Arq Bras Oftalmol. 2016;79(5):289-93 291 Microbiological and epidemiological study of infectious keratitis in children and adolescents

In univariate analysis that compared patients according to whether Childhood keratitis differs from adult keratitis in several respects, the keratitis was caused by Gram-negative or by Gram-positive bacteria, including possible reluctance of the child to undergo the clinical age (p=0.01) was found to be statistically significant. Indeed, log istic examination and sample collection, and the information-gathering re regression showed age (OR 1.06; 95%CI 1.01-1.11) to be a risk factor garding triggering factors and inflammation, which is apparently more for keratitis caused by Gram-negative bacteria in the (Table 4). intense in children(3,15). Among teenagers, contact lenses are becoming increasingly popular as a refractive error correction device, for esthetic reasons. The association between the use of contact lenses and in- DISCUSSION fectious ulcers is well established. Microbial keratitis and its sequelae are important causes of ocular During the period analyzed, 10.1% of keratitis cases occurred in morbidity and blindness in developing countries. Microbial keratitis the age group up to 18 years, mostly among male adolescents. These is characterized by inflammation of the cornea, usually with stromal data corroborate previous studies in which keratitis in children and infiltration, and is considered an ophthalmic emergency that requires adolescents accounted for 11% to 13.1% of all ophthalmologic visits(3,8). immediate attention. Keratitis can progress rapidly with corneal des- Our study found that age, the use of topical antimicrobial drugs, truction that causes permanent visual dysfunction. and prior physical burns were associated with fungal and Acantha- In the literature, childhood is defined as the period of growth from moeba spp. keratitis. Age was also associated with keratitis caused birth to puberty. However, the definition of the limits of chronological by Gram-negative bacteria. As far as we know, no previous study has adolescence is controversial. For the World Health Organization, the analyzed this subject. age is between 10 and 19 years whereas for the United Nations Organi- In our series, the use of topical medication was present in 42.8% zation, it is between 15 and 24 years. In Brazil, the Child and Adolescent of patients at the time of laboratory evaluation. Other authors have Statute, law 8.069 of 1990, considers a child to be a person under 12 already indicated the use of empirical medication at the time of years old and defines adolescence as the age range 12-18 years(28). sample collection in 48% to 67.1% of patients with clinical suspicion

Table 4. Univariate and multivariate analyses comparing keratitis caused by Gram-negative bacteria with that caused by Gram-positive bacteria among patients aged from 10 days to 18 years Gram-positive bacteria Gram-negative bacteria (N=213) (N=86) p-value Odds ratio 95%IC p-value Variables Age, years 9.9 ± 5.5 11.6 ± 5.2 0.01 1.06 1.01-1.11 0.01 Male sex 118 (55.4) 55 (63.9) 0.22 Right eye affected 118 (55.4) 41 (47.6) 0.28 Eye history Atopy 03 (01.4) 00 (00.0) 0.64 Blepharitis 02 (00.9) 01 (01.2) 0.64 Keratitis 07 (03.3) 01 (01.2) 0.53 Keratoconus 05 (02.3) 02 (02.3) 0.68 Conjunctivitis 17 (08.0) 06 (07.0) 0.96 Congenital glaucoma 11 (05.2) 01 (01.2) 0.20 Herpes 06 (02.8) 00 (00.0) 0.26 Stye 02 (00.9) 00 (00.0) 0.91 Use of antimicrobial 67 (31.5) 19 (22.1) 0.14 Injury Vegetable 30 (14.1) 11 (12.8) 0.91 Mechanical 10 (04.7) 04 (04.6) 0.77 Metal 07 (03.3) 07 (08.1) 0.13 Non-chemical burn 03 (01.4) 00 (00.0) 0.64 Chemical burn 00 (00.0) 02 (02.3) 0.15 Prior eye surgery Corneal transplantation 24 (11.3) 11 (12.8) 0.86 Postoperative complications 15 (07.0) 00 (00.0) 0.02 Removal of corneal foreign body 06 (02.8) 01 (01.2) 0.66 Suture 02 (00.9) 00 (00.0) 0.91 Comorbidity Tumor 05 (02.3) 02 (02.3) 0.68 Type of contact lenses Soft 25 (11.7) 04 (04.6) 0.10 Rigid 03 (01.4) 02 (02.3) 0.95 Therapeutic 01 (00.5) 02 (02.3) 0.41 Data are presented as mean ± standard deviation or n (%).

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of keratitis(3,9,16). As they are already widespread, the use of antibiotics from physical burns were predisposing factors for non-bacterial ke can inhibit bacterial growth, favoring the appearance of other mi- ratitis . Age was associated with Gram-negative keratitis. croorganisms. This factor was statistically significant in the group of patients with non-bacterial keratitis and may be considered as a ACKNOWLEDGMENTS predisposing factor. A history of trauma was the most common antecedent found The authors thank Prof Dr Annette Silva Foronda for her contribution in our study as cause of keratitis in the age range studied, affecting on identifying the Acanthamoeba spp. positive cultures. 33.5% of patients. Trauma has been reported as the major risk factor for keratitis in several published studies, accounting for 21.2% to 58.8% REFERENCES of cases(8-18,29). . 1 Whitcher JP, Srinivasan M. Corneal ulceration in the developing world-a silent epidemic. In our study, 18.2% of patients had a history of using contact lenses. Br J Ophthalmol. 1997;81(8):622-3. Soft lenses were the most commonly used type. More than 90% of 2. Passos RM, Cariello AJ, Yu MC, Hofling-Lima AL. Microbial keratitis in the elderly: a patients with a positive culture for Acanthamoeba spp. were contact 32-year review. Arq Bras Oftalmol. 2010; 73(4):315-9. lens users and all were adolescents. As has been said, the association 3. Hsiao CH, Yeung L, Ma DH, Chen YF, Lin HC, Tan HY, et al. Pediatric microbial keratitis between the use of contact lenses and infectious ulcers is well es in Taiwanese children: a review of hospital cases. Arch Ophthalmol. 2007;125(5):603-9. tablished. Several authors have reported the use of contact lenses, 4. World Health Oorganization (WHO). Global data on visual impairments 2010. Geneve: especially orthokeratology, as a predisposing factor for keratitis in World Health Organization; 2012. (3,8-10,14,17,19,20,30) 5. Sofi RA, Wani JS, Keng MQ. Profile of children with ocular trauma. JK-Practitioner. 2014; children and adolescents . The use of this type of lens is 17(1-3):44-50. not common in Brazil. 6. Serrano JC, Chalela P, Arias JD. Epidemiology of childhood ocular trauma in a northeastern Comorbidities were present in 5.8% of the study patients; this was Colombian region. Arch Ophthalmol. 2003;121(10):1439-45. lower than rates reported in previous studies(3,8-14). Cancer was the 7. Sociedade Brasileira de Pediatria (SBP). Problemas oftalmológicos mais frequentes main comorbidity, present in 2% of our records. This percentage was em pediatria [Internet]. São Paulo: SBP; 2013. [citado 2013 Fev 7]. Disponivel em: lower than the rate of 3.8% reported by Onakpoya et al.(11). Other www.intranet.sbp.com.br. ocular antecedents found in our study have been reported by several 8. Ormerod LD, Murphree AL, Gomez DS, Schanzlin DJ, Smith RE. Microbial keratitis in (3,10,11,19) children Ophthalmology. 1986;93(4):449-55. authors, citing similar percentages . 9. Clinch TE, Palmon FE, Robinson MJ, Cohen EJ, Barron BA, Laibson PR. Microbial kera- The prevalence of microorganisms responsible for microbial keratitis titis in children. Am J Ophthalmol. 1994;117(1):65-71. in children and adolescents varies in different regions of the world(3). 10. Cruz OA, Sabir SM, Capo H, Alfonso EC. Microbial keratitis in childhood. Ophthalmo- Microbial cultures were positive in 40.3% of the study sample, whereas logy. 1993;100(2):192-6. in the literature positivity has ranged from 33% to 87%(3,8-10,12-18,20,29). 11. Onakpoya OH, Adeoye AO. Childhood eye diseases in southwestern Nigeria: a tertiary Polymicrobial isolates accounted for 9.5% of positive cultures in our hospital study. Clinics. 2009;64(10):947-52. 12. Kunimoto DY, Sharma S, Reddy MK, Gopinathan U, Jyothi J, Miller D, et al. Microbial study. In previous studies, the positivity of polymicrobial cultures has keratitis in children Ophthalmology. 1998;105(2):252-7. (3,8-10,12,14) varied from 6.9% to 27% . As observed in other studies, the 13. Vajpayee RB, Ray M, Panda A, Sharma N, Taylor HR, Murthy GV, et al. Risk factors for pe- inherent difficulty in getting corneal samples from patients, the use of diatric presumed microbial keratitis: a case-control study. Cornea. 1999;18(5):565-9. antimicrobials, improper corneal sampling, and microorganisms with 14. Al Otaibi AG, Allam K, Damri AJ, Shamri AA, Kalantan H, Mousa A. Childhood microbial slow growth on culture media may account for the low positivity rate keratitis. Oman J Ophthalmol. 2012;5(1):28-31. observed in our study(3,15). 15. Chirinos-Saldaña P, Lucio VMB, Hernandez-Camarena J, Navas A, Ramirez-Miranda A, The presence of Gram-positive bacteria in keratitis in this study was Vizuet-Garcia L, et al. Clinical and microbiological profile of infectious keratitis in chil (3,8,9,12-17,19,20,29) dren. BMC Ophthalmology. 2013;13(54):1-6. 71.8%, similar to the level previously reported elsewhere . 16. Maidana E, Gonzalez R, Melo Junior LA, Souza LB. [Infectious keratitis in children: an Of the identified etiologic agents, the most common was coagula epidemiological and microbiological study in a university hospital in Asuncion-Pa se-negative Staphylococcus, which was isolated from 23.8% patients; raguay]. Arq Bras Oftalmol. 2005;68(6):828-32. Portuguese. this was followed by Staphylococcus aureus (20.9%) and Pseudomonas 17. Song X, Xu L, Sun S, Zhao J, Xie L. Pediatric microbial keratitis: a tertiary hospital study. spp. (14.2%). These results were similar to those observed in the elderly Eur J Ophthalmol. 2012;22(2):136-41. population in a previous study conducted in our institution(2). 18. Tabbara KF, Badr IA. Changing pattern of childhood blindness in Saudi Arabia. Br J Ophthalmol. 1985;69(4):312-5. Methicillin-resistant Staphylococcus spp. showed a trend of resis- 19. Wong VW, Lai TY, Chi SC, Lam DS. Pediatric ocular surface infections: a 5-year review tance to most antimicrobials, something that has also been observed of demographics, clinical features, risk factors, microbiological results, and treatment. (15,19,20,29) by other authors , whereas coagulase-negative Staphylococcus, Cornea. 2011;30(9):995-1002. Streptococcus spp., and enterobacteria showed good susceptibi lity to 20. Hong J, Chen J, Sun X, Deng SX, Chen L, Gong L. Paediatric bacterial keratitis cases the majority of antimicrobial drugs tested. Streptococcus pneumoniae in Shangai: microbiological, profile, antibiotic susceptibility and visual outcomes. Eye strains showed no resistance to penicillin. Pseudomonas aeruginosa (Lond). 2012;26(12):1571-8. strains showed no resistance to ciprofloxacin and low resistance to 21. Parmar P, Salman A, Kalavathy CM, Kaliamurthy J, Thomas PA, Jesudasan CA. Microbial keratitis at extremes of age. Cornea. 2006;25(2):153-8. polymyxin B, gentamicin, and tobramycin, in contrast to the study 22. Tabbara KF, Hyndiuk RA, editors. Infections of the eye. 2nd ed. Boston: Little Brown; by Moreno-Andrade et al., who reported 100% resistance to this an 1996. timicrobial(29). 23. Höfling-Lima AL, Moeller CT, Freitas D, Martins EN. Manual de condutas em oftalmo- The positivity of fungal infection among children and adolescents logia. São Paulo: Atheneu; 2008. was 4% in our study, whereas the positivity for fungal infection in pre- 24. Foronda AS. Observações sobre amebas de vida livre potencialmente patogênicas viously published studies has ranged from 4% to 48.7%(3,8-10,12-14,16,17,19). [tese]. São Paulo: Universidade de São Paulo; 1979. Fusarium solani complex was the most commonly isolated fungus, as 25. Nosé W, Sato EH, Freitas D, Ribeiro MP, Foronda AS, Kwittko S, et al. Úlcera de córnea (3,10,17) por Acanthamoeba: quatro primeiros casos no Brasil. Arq Bras Oftalmol. 1988;51:223-6. was the case in other previous studies . 26. Koneman EW, Allen SD, Janda WM, Schreckenberger PC, Winn Jr WC. Color Atlas and Keratitis caused by the protozoan Acanthamoeba spp. showed textbook of diagnostic microbiology. 5th ed. Philadelphia, New York: Lippincott; 1997. 6.6% positivity in the present study, which again is similar to previous 27. Software MS. MedCalc 11.6.1. Belgica 1993 - 20131993 [cited 2013 02/07Feb 7]. Available studies(3,9,12,19). It is noteworthy that all patients with positive culture from: www.medcalc.org/. for Acanthamoeba spp. were adolescents and that 91.3% had a history 28. Einsenstein E. Adolescência: definições, conceitos e critérios. Adolesc Saúde. 2005; of using contact lenses. It is likely that increasing the frequency of 2(2):6-7. use of contact lenses by teenagers increases the risk of adolescents 29. Moreno-Andrade A, Ramirez-Miranda AJ, Navas A, Hernandez-Camarena JC, Vizuet-García L, Gaona-Juárez C, et al. Clinical and microbiological profile of infectious keratitis in developing corneal ulcers by Acanthamoeba spp. children. Seattle (USA): ARVO; 2013. In conclusion, we found that the risk factors for infectious keratitis 30. Young AL, Leung KS, Tsim N, Hui M, Jhanji V. Risk factors, microbiological profile, and in children and adolescents were noticeably the same as those obser treatment outcomes of pediatric microbial keratitis in a tertiary care hospital in Hong ved in adults. We found that age, the use of antimicrobials, and injuries Kong. Am J Ophthalmol. 2013;156(5):1040-4.

Arq Bras Oftalmol. 2016;79(5):289-93 293 Original Article

Dysfunction in the fellow eyes of strabismic and anisometropic amblyopic children assessed by visually evoked potentials Alterações dos potenciais visuais evocados nos olhos contralaterais de crianças com ambliopia estrabísmica e anisometrópica

Eric Pinheiro Andrade1, Adriana Berezovsky1, Paula Yuri Sacai1, Josenilson Martins Pereira1, Daniel Martins Rocha1, Solange Rios Salomão1

ABSTRACT RESUMO Purpose: To evaluate visual acuity and transient pattern reversal (PR) visual Objetivo: Avaliar a acuidade visual e os potenciais visuais evocados transientes por evoked potentials (VEPs) in the fellow eyes of children with strabismic and/or reversão de padrões no olho contralateral de crianças com ambliopia estrabísmica anisometropic amblyopia. e/ou anisometrópica. Methods: Children diagnosed with strabismic and/or anisometropic amblyopia Métodos: Foram avaliados os potenciais visuais evocados de crianças com amblio- were recruited for electrophysiological assessment by VEPs. Monocular grating pia estrabísmica e/ou anisometrópica. As acuidades visuais monoculares de grades and optotype acuity were measured using sweep-VEPs and an Early Treatment e de optotipos foram mensuradas utilizando o PVE de varredura e a tabela EDTRS, Diabetic Retinopathy Study chart, respectively. During the same visit, transient respectivamente. Na mesma visita, foram registrados os PVERP transients de cada PR-VEPs of each eye were recorded using stimuli subtending with a visual angle of olho usando estímulos de ângulo visual de 60’; 15’ e 7,5’. Parâmetros de amplitude 60’, 15’, and 7.5’. Parameters of amplitude (in μV) and latency (in ms) were deter- (em microvolts) e latência (em milissegundos) foram determinados para os registros mined from VEP recordings. dos potenciais visuais evocados. Results: A group of 40 strabismic and/or anisometropic amblyopic children Resultados: Um grupo de 40 crianças amblíopes estrábicas e/ou anisometrópicas (22 females: 55%, mean age= 8.7 ± 2.2 years, median= 8 years) was examined. (22 meninas - 55%, media idade= 8,7 ± 2,2, mediana= 8) foi examinado. Um grupo A control group of 19 healthy children (13 females: 68.4%, mean age= 8.2 ± 2.6 de 19 crianças saudáveis (13 meninas 68,4%, media idade= 8,2 ± 2,6, mediana= 8) de years, median= 8 years) was also included. The fellow eyes of all amblyopes had controle também foi incluído. A acuidade visual por optotipos foi significativamente significantly worse optotype acuity (p=0.021) than the control group, regardless pior (p=0,021) nos olhos contralaterais de todos os amblíopes, quando comparado of whether they were strabismic (p=0.040) or anisometropic (p=0.048). Overall, com o grupo controle, independentemente se estrábico (p=0,040) ou anisometrópico grating acuity was significantly worse in the fellow eyes of amblyopes (p=0.016) (p=0,048). No geral, a acuidade visual por grades foi significativamente pior nos olhos than in healthy controls. Statistically prolonged latency for visual angles of 15’ and contralaterais dos amblíopes (p=0,016), quando comparados com o grupo controle. Foi 7.5’ (p=0.018 and 0.002, respectively) was found in the strabismic group when encontrada latência estatisticamente prolongada para ângulos visuais de 15’ (p=0,018) compared with the control group. For the smaller visual stimulus (7.5’), statistically e 7,5’ (p=0,002) no grupo estrábico, quando comparado com o grupo controle. Para o prolonged latency was found among all fellow eyes of amblyopic children (p<0.001). menor estímulo visual (7,5’) foi encontrada latência estatisticamente prolongada nos Conclusions: The fellow eyes of amblyopic children showed worse optotype and olhos contralaterais de todas crianças amblíopes (p<0,001). grating acuity, with subtle abnormalities in the PR-VEP detected as prolonged Conclusões: Os olhos contralaterais de crianças amblíopes mostraram pior acuidade latencies for smaller size stimuli when compared with eyes of healthy children. visual de optotipo e de resolução de grades, com alterações sutis nos PVERP, detectadas These findings show the deleterious effects of amblyopia in several distinct visual pelas latências prolongadas para estímulos de menor tamanho, quando comparados functions, mainly those related to spatial vision. com os olhos de crianças saudáveis. Estes resultados mostram os efeitos deletérios da ambliopia em várias funções visuais distintas, principalmente relacionadas à visão espacial. Keywords: Visual acuity; Evoked potentials, visual; Electrophysiology; Amblyopia; Descritores: Acuidade visual; Potenciais visuais evocados; Eletrofisiologia; Ambliopia; Refractive errors; Child Erros de refração; Criança

INTRODUCTION eye(2-4). In strabismus, a new fixation point is formed mainly for esotro Amblyopia is a developmental disorder that occurs when the pia and creates new connections with the visual cortex. As the den- visual input from the two eyes is poorly correlated during early de sity of retinal ganglion cells decreases and the center of receptive velopment. Such poor correlation may be due to a chronically blurred fields becomes larger as they move away from the fovea, visual acuity image in one eye (anisometropia), a turned eye (strabismus), or de- in this new setting is limited and the “good” eye image suppresses privation of one or both eyes(1). visualization by the eye with poorer acuity to avoid diplopia and ge In anisometropic amblyopia, the connections between the retina neration of amblyopia(5). and cortex do not form an accurate cortical topographic map, as in Amblyopia onset usually occurs within the first 3 years of life and a normal subject, which results in widespread visual loss in the affected is thought to reflect alterations in the properties of neurons in early

Submitted for publication: January 12, 2016 Funding: No specific financial support was received for this study. Accepted for publication: May 30, 2016 Disclosure of potential conflicts of interest: None of the authors have any potential conflict of 1 Department of Opththalmology and Visual Sciences, Escola Paulista de Medicina (EPM), Univer- interest to disclose. sidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil. Corresponding author: Eric Pinheiro de Andrade. Rua Catão, 804/61 - São Paulo, SP - 05049-000 - Brazil - E-mail: [email protected] Approved by the following research ethics committee: Federal University of São Paulo (approval no 0503/08).

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cortical areas, possibly even as early as the lateral geniculate nucleus. Norcia and Tyler in 1999. The stimuli were phase-reversal sine-wave Accordingly, sensory deficits include loss of visual acuity, stereopsis, gratings presented on a 29 x 38-cm, high-resolution, monochromatic, position acuity, and contrast sensitivity, particularly at high spatial video monitor. The mean luminance was maintained at 140 cd/m² frequencies(6). throughout the session. Responses were obtained from electroen- Several different treatments have been proposed for amblyopia cephalogram (EEG) electrodes attached to the scalp with electrode therapy over the last century. Of these, patching therapy has been cream and cotton pads. used to treat amblyopia for several years, even though this therapeutic The EEG was recorded from two bipolar placements positioned at O1 option has many shortcomings and compliance is poor because of the (left occiput) and O2 (right occiput), 2-3 cm to the left and right of a difficulty of forcing a child to wear a patch combined with the impaired ground electrode placed 1 cm above the inion on the midline. A revision experienced by the child when the patch is in place. Moreover, the ference electrode was placed at the vertex (Cz). Differences in electric use of full-time occlusion can cause psychophysical dysfunction in the potentials were amplified (gain= 10,000; -3 dB cutoff at 1 and 100 Hz). fellow eye; therefore, partial occlusion is more beneficial(7). The stimuli were presented at a constant average luminance of Physiological and electrophysiological parameters are markedly 120.97 to 142.35 cd/m2, contrast of 80%, and temporal modulation attenuated in the amblyopic eye, mainly the amplitude of small rate of 6Hz (12 reversals/s). The subject was positioned at a distance of pattern elements of the transient pattern reversal visual evoked po- 30 to 150 cm from the monitor (depending on the quality of fixation tentials (PR-VEPs). A small, but statistically significant, increase in the and age) and visual attention was drawn to small toys and objects latency of the transient PR-VEP also occurs in the amblyopic eye(8). shown in the center of the monitor. While the amblyopic eye has been overly studied(2-11) in children with Fixation was maintained during each trial with small toys presen- strabismic and anisometropic amblyopia, there are few studies about ted hanging in front of the TV monitor and small music boxes to focus the fellow eye(11-15). the infant’s attention. When the subject was alert and fixated on the In the present study, the hypothesis that fellow eyes of children monitor (judged by the position of the image of the monitor cente- with amblyopia are not fully normal was tested by visual acuity mea red in the subject’s pupil), the observer began recording the EEG from sured behaviorally with an optotype chart, grating acuity measured two channels that were adaptively filtered (bandpass) in real time electrophysiologically by sweep-VEP, and by assessment of the inte- (sampling rate = 397 Hz) to isolate the VEPs. The amplitude and phase grity of the maculo-occipital pathway tested by electrophysiological of the first and second harmonics of the stimulus frequency were parameters of transient PR-VEP. calculated for each channel. The test was performed in a dark room so that the primary cues for accommodation were provided by the display. Grating acuity was measured by sweeping spatial frequency METHODS at a fixed contrast of 80%. Ten linearly-spaced spatial frequencies at The main outcome measures of this prospective cross-sectional 1/s were presented starting at a low spatial frequency. Patterns were observational study were optotype acuity, grating acuity, and PR-VEP temporally alternated in counterphase with a temporal modulation parameters of amplitude and latency. The study protocol was appro- of 6.6 Hz for all tests. ved by the Committee of Ethics in Research of the Federal University Three to 12 repetitions of the sweep were obtained and the vectors of São Paulo (approval number 0502/08) and conducted in accor- were averaged. Grating acuity was estimated with an automated al dance with the tenets of the Declaration of Helsinki, and informed gorithm, which performs a linear fit and extrapolation to zero ampli- consent was obtained from the parents of each child before testing. tude for the final descending limb of the function related to the VEPs Children with anisometropic and/or strabismic amblyopia who in the second harmonic amplitude to the linear spatial frequency. participated in the study were recruited from pediatric private practi- A signal-to-noise ratio (SNR) at peak mean amplitude of 3:1 was requi- ce and the Strabismus Section of the Department of Ophthalmology red. In all cases, two thresholds (one for each channel) were obtained. and Visual Sciences, Federal University of São Paulo. Inclusion criteria The final acuity score was calculated in logMAR using the results of were a previous diagnosis of amblyopia by ophthalmic examination, the better threshold channel with the highest SNR. inter-ocular acuity difference of at least two lines using the conventional printed Snellen chart, best optical correction, and normal fun- PR-VEPs dus. Anisometropia was determined by one or more of the following: PR-VEPs of each eye were recorded with natural pupils and the a difference of at least 1.00 diopter (D) in the spherical component; participant using the best optical correction. During the examination, a difference of 0.75 D in the cylindrical component; or a spherical each patient remained comfortably seated and the scalp was cleaned equivalent difference of more than 1.50 D. The exclusion criteria with Nuprep® abrasive gel (DO Weaver & Co., Aurora, CO, USA). Each were the presence of any other eye condition that could decrease channel was processed using gold disk electrodes (Grass Model visual acuity; any neurological disease; or a history of seizures or use F-E5GH; Astro-Med, Inc., West Warwick, RI, USA) that were placed accor of anti-seizure medication. ding to the 10-20 system of electro-encephalography. One active The type of occlusion therapy was noted for each participant electrode was placed 2 cm above the inion (Oz), a reference electrode as full-time (patching during all awake hours) or part-time (patching was placed on the forehead (FP ), and a ground electrode was placed during part of awake hours), the eye to be patched (if alternate or not), z at the vertex (Cz). Each electrode was fixed in position with EC2 con- and the compliance of the prescribed patching. ductive paste (Astro-Med, Inc.) and an elastic band. A comprehensive ophthalmic examination, which included an The screen of the stimulator had a visual field of 17° × 17° and external eye examination, ocular motility assessment, biomicroscopy, consisted of a black and white checkerboard pattern with subten- cycloplegic refraction, and fundus assessment with indirect binocular ding visual angles of 7.5’, 15’, and 60’. The temporal frequency was set ophthalmoscopy, was performed before electrophysiological testing at 1.9 Hz. Maximum contrast (100%) and constant luminance were by a pediatric ophthalmologist. used. The occipital responses were recorded using the UTAS E-3000 system (LKC Technologies Inc., Gaithesburg, MD, USA). An average Optotype acuity of 100 individual responses to the PR-VEPs were recorded from each The optotype acuity of each eye was measured, with best optical eye. Latencies of the largest positive peak (P100) were determined in correction, using an ETDRS “tumble E” retro-illuminated chart pre- ms. Peak-to-peak amplitude was defined as the difference between sented at a distance of 4 m. Visual acuity scores are presented as the the peaks of N75 and P100 in µV. A representative PR-VEP waveform logarithmic minimum angle of resolution (logMAR). is shown in figure 1.

Grating acuity measured by sweep VEPs Statistical analysis Grating acuity of each eye was measured using the PowerDiva All statistical analyses were performed using Stata: Data Analysis (digital infant vision assessment) sweep-VEP system developed by and Statistical Software version 12 (StataCorp LP, College Station, TX,

Arq Bras Oftalmol. 2016;79(5):294-8 295 Dysfunction in the fellow eyes of strabismic and anisometropic amblyopic chil dren assessed by visually evoked potentials

USA). The following statistical models were used: the Student’s t-test, one-way analysis of variance (ANOVA), the paired t-test, the Pearson correlation coefficient, and multiple linear regression analysis. When there was no normal distribution of variables, the nonparametric Mann-Whitney and Kruskal-Wallis ANOVA tests were used. A probability (p) value of ≤0.05 with a two-tailed rejection region, according to the common general pattern in medical and biological areas, was considered statistically significant.

RESULTS A group of 40 amblyopic children, consisting of 18 boys (45%) and 22 girls (55%), was tested. The mean age of the children was 8.7 ± 2.2 (range, 6-14) years. Amblyopia was considered as strabismic in 21 (52.5%) children, anisometropic in 15 (37.5%), and a mix of both in four (10%). The demographic and clinical features of these patients F igure 1. A representative transient PR-VEP waveform of a 9-year-old healthy girl. are shown in table 1. Full-time occlusion therapy of the fellow eye was

Table 1. Demographic and clinical features of amblyopic children ID Gender Age Amblyopia group Ocular motility Refraction Patching 01 Female 08 Mix Esotropia OD: -2.00 -2.00 @ 010º Yes 02 Male 06 Mix Esotropia OD: +3.00 -0.00 @ 000º Yes 03 Female 07 Mix Esotropia OD: +3.75 -0.00 @ 000º Yes 04 Male 12 Mix Esotropia OD: +0.50 +0.75 @ 010º Pretreat 05 Female 08 Anisometropia Orthoposition OD: -1.50 -0.50 @ 180º No 06 Male 07 Anisometropia Orthoposition OD: 0.00 -2.00 @ 005º Yes 07 Male 10 Anisometropia Orthoposition OD: +0.50 +0.25 @ 100º Pretreat 08 Female 07 Anisometropia Orthoposition OD: +1.50 -2.00 @ 10º No 09 Male 07 Anisometropia Orthoposition OD: +1.00 +0.50 @ 170º No 10 Female 09 Anisometropia Orthoposition OD: +1.50 -0.00 @ 000º No 11 Male 07 Anisometropia Orthoposition OD: +1.50 -0.00 @ 000º No 12 Male 07 Anisometropia Orthoposition OD: +1.50 -0.00 @ 000º No 13 Female 07 Anisometropia Orthoposition OD: -0.25 -2.25 @ 005º No 14 Female 06 Anisometropia Orthoposition OD: -10.50 -3.00 @ 180º Yes 15 Female 07 Anisometropia Orthoposition OD: -6.50 -1.00 @ 035º Yes 16 Female 09 Anisometropia Orthoposition OD:-6.50 -5.50 @ 010º Yes 17 Male 08 Anisometropia Orthoposition OD:+2.00 -0.00 @ 000º Yes 18 Female 09 Anisometropia Orthoposition OD: +0.50 -0.50 @ 180º Yes 19 Female 08 Anisometropia Orthoposition OD: -1.00 -1.00 @ 180º Pretreat 20 Female 10 Strabismus Esotropia OD: +0.75 +0.50 @ 180º No 21 Male 12 Strabismus Esotropia OD: +0.75 +0.75 @ 090º Pretreat 22 Female 07 Strabismus Esotropia OD: +8.50 -0.00 @ 000º Yes 23 Male 14 Strabismus Esotropia OD: +1.50 +1.00 @ 180º No 24 Female 07 Strabismus Exotropia OD: +1.00 -0.00 @ 000º Pretreat 25 Female 12 Strabismus Esotropia OD: 0.00 -1.00 @ 180º No 26 Male 08 Strabismus Esotropia OD: +1.75 +1.25 @ 060º Pretreat 27 Male 07 Strabismus Esotropia OD: +1.00 -0.00 @ 000º No 28 Female 07 Strabismus Esotropia OD: +1.50 +0.75 @ 095º No 29 Male 07 Strabismus Esotropia OD: +4.50 +2.25 @ 015º No 30 Female 08 Strabismus Esotropia OD: +4.75 +2.25 @ 110º Pretreat 31 Male 08 Strabismus Esotropia OD: +1.50 -0.00 @ 000º Pretreat 32 Male 10 Strabismus Esotropia OD: +6.00 +1.00 @ 95º Yes 33 Female 09 Strabismus Exotropia OD: +1.75 -0.00 @ 000º Yes 34 Female 06 Strabismus Esotropia OD: +3.50 +0.75 @ 100º Yes 35 Female 13 Strabismus Esotropia OD: +1.00 -0.00 @ 000º Pretreat 36 Female 08 Strabismus Esotropia OD: +2.00 +2.50 @ 105º Yes 37 Male 13 Strabismus Esotropia OD: +2.25 -3.75 @ 175º Pretreat 38 Male 13 Strabismus Esotropia OD: +0.75 -0.00 @ 000º No 39 Male 11 Strabismus Esotropia OD: +0.75 -0.00 @ 000º Pretreat 40 Female 09 Strabismus Esotropia OD: +4.25 +0.75 @ 075º Yes ID= identification; OD= right eye; OS= left eye.

296 Arq Bras Oftalmol. 2016;79(5):294-8 Andre ad EP, e t a l .

ongoing in 15 (37.5%) children at the time of examination, whereas and the eye with better vision of the control children (open symbols) 14 (35.0%) children had never had previous patching therapy and for grating acuity. 11 (27.5%) have had it previously, but it had been discontinued before the examinations. Pattern reversal transient visually evoked potentials The control group consisted of 19 healthy children with normal P100 latency ophthalmic exam results, consisting of six males (31.6%) and 13 females (68.4%) with a mean age of 8.2 ± 2.6 (range, 5-15) years. The There was a statistically prolonged latency of visual stimuli of 15’ demographic and clinical features of this group are shown in table 2. (p=0.018, 106.81 ± 7.99 ms, median 106.00 ms) and 7.5’ (p=0.002, 112.93 ± 11.38 ms, median 110.00 ms) of the fellow eyes in the strabismic group, Visual acuity as compared to the control group (101.42 ± 5.46 ms, median 102.50 ms for visual stimulus of 15’, and 103.21 ± 6.82 ms, median 104.00 ms for Optotype acuity visual stimulus of 7.5’). For the smaller visual stimulus, a statistically Optotype acuity ranged from 0.00 (20/20) to 0.24 (20/34) logMAR prolonged latency was also found in all amblyopic children (p<0.001, in the fellow eye of amblyopic children and from 0.00 (20/20) to 0.00 110.89 ± 11.42 ms, median 109.50 ms) (Figures 3, 4, and 5). (20/20) logMAR in those of the control group. Overall, optotype acuity Regarding occlusion, there was no statistically significant diffe- was significantly worse (p=0.021) in the fellow eyes of all amblyopic rence between control group and fellow eyes at 60’ and 15’ compared patients than in the control group (0.04 ± 0.07 logMAR, median 0.0 to those with occlusion, without occlusion, and previously treated. logMAR vs. 0.0 ± 0.0 logMAR, median 0.0 logMAR, respectively). The The fellow eyes showed prolonged latencies for stimuli at 7.5’ in the same trend was found in the strabismic group (p=0.040, 0.04 ± 0.08 group previously treated (p<0.05), as compared to controls. logMAR, median 0.0 logMAR) and the anisometropic group (p=0.048, Comparing the N75-P100 amplitude of the fellow eyes with that 0.04 ± 0.07 logMAR, median 0.0 logMAR). Optotype acuity was signi- of the control group, there were no differences between any stimuli ficantly better in control eyes than in fellow eyes in the groups with and groups, including occlusion therapy. and without occlusion therapy (p<0.05, both).

Grating acuity DISCUSSION Grating acuity ranged from -0.01 (20/19) to 0.21 (20/32) logMAR in For several decades, the fellow eye of amblyopic patients was con the fellow eyes of amblyopic children and from 0.01 (20/20) to 0.20 sidered unchanged due to presenting normal optotype acuity. An in- (20/31) logMAR in those of the control group. Grating acuity was also teresting finding of this study was that optotype acuity was worse in significantly worse (p=0.016) in fellow eyes of all amblyopic subjects the fellow eyes of amblyopic patients than in those of healthy controls. than in the control group (0.07 ± 0.05 logMAR, median 0.07 logMAR vs. These results were similar in patients with anisometropic amblyopia 0.05 ± 0.04 logMAR, median 0.05 logMAR, respectively). Regarding as well as strabismic amblyopia. occlusion, the control group had significantly better optotype acuity than the fellow eyes in the group without occlusion (p<0.05). Figure 2 shows the individual scores of optotype (A) and grating acuity (B) for the fellow eyes of amblyopic children (filled symbols) A and a randomly selected eye of the control group for optotype acuity

Table 2. Demographic and clinical features of the control group ID Gender Age Ocular motility Refraction 01 Female 08 Orthophoria OD: +0.75 -0.00 @ 000º 02 Male 08 Orthophoria OD: +1.25 -0.00 @ 000º 03 Female 05 Orthophoria OD: +1.50 -0.00 @ 000º 04 Female 12 Orthophoria OD: -2.25 -0.00 @ 000º 05 Female 07 Orthophoria OD: +7.25 +1.50 @ 100º 06 Male 10 Orthophoria OD: +5.25 +2.75 @ 095º 07 Female 09 Orthophoria OD: +0.50 -0.00 @ 000º B 08 Female 08 Orthophoria OD: +1.75 -0.00 @ 000º 09 Female 07 Orthophoria OD: +0.50 +0.25 @ 060º 10 Male 06 Orthophoria OD: +1.00 -0.00 @ 000º 11 Female 07 Orthophoria OD: +1.50 -0.00 @ 000º 12 Female 06 Orthophoria OD: +1.00 -0.00 @ 000º 13 Male 08 Orthophoria OD: +1.00 -0.00 @ 000º 14 Female 11 Orthophoria OD: +0.75 -0.00 @ 000º 15 Female 05 Orthophoria OD: +1.50 -0.00 @ 000º 16 Male 09 Orthophoria OD: +1.50 -3.00 @ 180º 17 Male 05 Orthophoria OD: +1.50 -0.00 @ 000º 18 Female 15 Orthophoria OD: +0.50 -0.00 @ 000º 19 Female 10 Orthophoria OD: +0.75 -0.00 @ 000º F igure 2. Individual scores of optotype (A) and grating acuity (B) of the fellow eyes of ID= identification; OD= right eye; OS= left eye. amblyopic children and the better-vision eye of control children.

Arq Bras Oftalmol. 2016;79(5):294-8 297 Dysfunction in the fellow eyes of strabismic and anisometropic amblyopic chil dren assessed by visually evoked potentials

than those of the control group. The small patient cohort was a limitation to the present study, thus a larger sample of cases may provide different results. Grating acuity may be overestimated by sweep VEP, especially with lower visual acuity(12). By comparing the values of the contralateral eye of all amblyopes (N=40), we found statistically worse values than those of control group. This fact confirms the hypothesis that the fellow amblyopic eye is not completely normal. As indicated by the results of latency and amplitude of PR-VEPs of the fellow eyes in this study, only patients with strabismic amblyopia showed increased P100 latency for the smaller visual stimuli, as compared to the control group. Although few studies have evaluated the parameters of PR-VEPs BAE= best acuity eye; *= statistically significant difference. in the fellow eyes of patients with amblyopia, Mendonça et al.(16) F igure 3. P100 latency of the amblyopic group. reported a case of mixed amblyopia in an 11-year-old child with delayed P100 latency in the amblyopic and fellow eyes to stimuli at 60’, 30’, and 15’. This finding was attributed to the loss of contrast sensitivity at high spatial frequencies, which can be intensified in anisometropic amblyopia. However, patching therapy for amblyopia, particularly occluding the fellow eye, can have a negative effect, as shown in animal experiments, in which monocular deprivation has the greatest effect on the primary visual cortex rather than the retina and geniculate lateral body(13). It is worthwhile to note that about one-third of the children in the current study were receiving patching therapy and another third had discontinued patching therapy. Occlusion, somehow, may have contributed to the results of the sound eye, especially in the parvocellular pathway. When compared to healthy children, the fellow eyes of amblyopic children showed worse optotype and grating acuity, with subtle BAE= best acuity eye; *= statistically significant difference. abnormalities in the PR-VEP detected as prolonged latencies for F igure 4. P100 latency of the strabismic amblyopic group. smaller size stimuli, especially in children with a history of therapy at the time of the exam. These findings confirm those of previous studies showing that the fellow eyes of amblyopic patients were not fully normal and patching therapy can cause physiological defects in sound eyes.

REFERENCES . 1 Allen B, Spiegel DP, Thompson B, Pestilli F, Rokers B. Altered white matter in early visual pathways of humans with amblyopia. Vision Res. 2015;114:48-55. 2. Kiorpes L, Kiper DC, O’Keefe LP, Cavanaugh JR, Movshon JA. Neuronal correlates of amblyopia in the visual cortex of macaque monkeys with experimental strabismus and anisometropia. J Neurosci. 1998;18(16):6411-24. 3. Kiorpes L, McKee SP. Neural mechanisms underlying amblyopia. Curr Opin Neurobiol. 1999;9(4):480-6. 4. Birch EE. Amblyopia and binocular vision. Progr Retin Eye Res. 2013;33:67-84. 5. Daw NW. Visual development. New York: Spring Science; 2006. BAE= best acuity eye; *= statistically significant difference. 6. Levi DM, Knill DC, Bavelier D. Stereopsis and amblyopia: a mini-review. Vision Res. F igure 5. P100 latency of the anisometropic amblyopic group. 2015;114:17-30. 7. Mendonça RH, Abbruzzese S, Bagolini B, Nofroni I, Ferreira EL, Odom JV. Visual evoked potential importance in the complex mechanism of amblyopia. Int Ophthalmol. 2013; 33(5):515-9. 8. Oner A, Coskun M, Evereklioglu C, Dogan H. Pattern VEP is a useful technique in mo Deficits in visual function of fellow eyes have been studied for nitoring the effectiveness of occlusion therapy in amblyopic eyes under occlusion more than three decades. Kandel et al.(13) unjustifiably classified the therapy. Doc Ophthalmol. 2004;109(3):223-7. sound eye of amblyopic patients as normal based on the finding that 9. Hess RF, Thompson B. Amblyopia and the binocular approach toits therapy. Vision these eyes have reduced contrast sensitivity, low visual acuity, and Res. 2015;114:4-16. 10. Sokol S. Abnormal evoked potential latencies in amblyopia. Br J Ophthalmol. 1983;67(5): horizontal eccentric fixation when compared to normal eyes with 310-4. normal binocular fixation. 11. Brémond-Gignac D, Copin H, Lapillonne A, Milazzo S, European Network of Study A retrospective study evaluating visual acuity and the maturation and Research in Eye Development. Visual development in infants: physiological and of the fellow eye was conducted by reviewing the medical records of pathological mechanisms. Curr Opin Ophthalmol. 2011;22(1):S1-S8. 112 children with unilateral amblyopia secondary to anisometropia, 12. Ridder III WH, Rouse MW. Predicting potencials acuities in amblyopes. Doc Ophthalmol. (11) 2007;114(4):135-45. strabismus, or both conditions with previous patching therapy . Cor- 13. Kandel GL, Grattan PE, Bedell HE. Are the dominant eyes of amblyopes normal? Am J roborating the findings of this past study, the current study found sta- Optom Physiol Opt. 1980;57(1):1-6. tistically worse optotype acuity of the fellow eyes than of eyes of the 14. Varadharajan S, Hussaindeen JR. Visual acuity deficits in the fellow eyes of children control group, especially among patients with strabismic amblyopia. with unilateral amblyopia. J AAPOS. 2012;16(1):41-5. Different results were observed when analyzing grating acuity, 15. Leguire LE, Rogers GL, Bremer DL. Amblyopia: The normal eye is not normal. J Pediatr Ophthalmol Strabismus. 1990;27(1): 32-8. where the strabismic and anisometropic amblyopia groups showed 16. Mendonça RH, Ferreira EL. Visual evoked potentials (VEP) and visual acuity improve- similar results to the control group. However, when we analyzed the ment after cytidine 52-diphosphocholine (CDP-Choline) therapy in amblyopic patient. results of all amblyopes, significantly worse values were observed Rev Bras Oftalmol. 2012;71(5):328-30.

298 Arq Bras Oftalmol. 2016;79(5):294-8 Original Article

Comparison of 20% sulfur hexafluoride with air for intraocular tamponade in Descemet membrane endothelial keratoplasty (DMEK) Comparação de hexafluoreto de enxofre a 20% com ar para tamponamento intraocular na ceratoplastia endotelial de membrana Descemet (DMEK)

Benjamin Botsford1, Gustavo Vedana2, Leslie Cope3, Samuel C. Yiu2, Albert S. Jun2

ABSTRACT RESUMO

Purpose: To compare the effect of 20% sulfur hexafluoride (SF6) with that of air Objetivo: Comparar as taxas de descolamento do botão endotelial com o uso de gás on graft detachment rates for intraocular tamponade in Descemet membrane hexafluoreto de enxofre a 20% (SF6) em relação ao ar para o tamponamento intraocular endothelial keratoplasty (DMEK). na ceratoplastia endotelial da membrana de Descemet (DMEK). Methods: Forty-two eyes of patients who underwent DMEK by a single surgeon Métodos: Quarenta e dois olhos foram operados com a técnica de DMEK por um único (A.S.J.) at Wilmer Eye Institute between January 2012 and 2014 were identified; cirurgião (A.S.J.) no Wilmer Eye Institute entre janeiro de 2012 a 2014. Os primeiros 21 received air for intraocular tamponade and the next consecutive 21 received 21 olhos receberam ar para o tamponamento intraocular após o enxerto do botão

SF6. The main outcome measure was the graft detachment rate; univariate and endotelial e os 21 olhos seguintes receberam SF6. O desfecho primário medido foi a multivariate analyses were performed. taxa de descolamento do botão endotelial por análise univariada e multivariada.

Results: The graft detachment rate was 67% in the air group and 19% in the SF6 Resultados: A taxa de descolamento do botão endotelial foi de 67% no grupo que group (p<0.05). No complete graft detachments occurred, and all partial detachments recebeu ar vs 19% no grupo que recebeu SF6 (p<0,05). Não houve nenhum descolamento underwent intervention with injection of intraocular air. The percentages of eyes total de botão e todos os parciais foram tratados com injeção de ar intraocular. Não with 20/25 or better vision were not different between the groups (67% vs. houve diferença estatística significativa entre os grupos em relação a AV de 20/25 ou 71%). Univariate analysis showed significantly higher detachment rates with air melhor (67% vs 71%). A análise univariada demonstrou maior taxa de descolamento tamponade (OR, 8.50; p<0.005) and larger donor graft size (OR, 14.96; p<0.05). com o tamponamento por ar intraocular (OR 8,50, p<0,005) e com botões doadores Multivariate analysis with gas but not graft size included showed that gas was an maiores (OR 14,96, p<0,05). Na análise multivariada, incluindo gás, mas não o ta- independent statistically significant predictor of outcome (OR, 6.65; p<0.05). When manho do botão doador, o tipo de gás usado permaneceu sendo um fator preditivo graft size was included as a covariate, gas was no longer a statistically significant independente e estatisticamente significativo para o desfecho primário, com OR de predictor of detachment but maintained OR of 7.81 (p=0.063) similar to the results 6,65 (p<0,05). Porém, quando o tamanho do botão doador foi incluso como cova of univariate and multivariate analyses without graft size. riável, o gás perdeu a sua significância como preditor de descolamento, mantendo o Conclusion: In comparison with air, graft detachment rates for intraocular tam- OR de 7,81 (p=0,063), semelhante as análises univariada e multivariada excluindo o tamanho do botão doador. ponade in DMEK were significantly reduced by 20% SF6. Conclusão: O uso de gás hexafluoreto de enxofre a 20% (SF6) para o tamponamento intraocular reduz a taxa de descolamento do botão endotelial quando comparado ao uso de ar no DMEK. Keywords: Descemet membrane; Descemet stripping endothelial keratoplasty/ Descritores: Lâmina limitante posterior; Ceratoplastia endotelial com remoção da instrumentation; Sulfur hexafluoride/administration & dosage; Endotamponade; lâmina limitante posterior/instrumentação; Hexafluoreto de enxofre/administração Visual acuity & dosagem; Tamponamento interno; Acuidade visual

INTRODUCTION higher-order aberrations, and provide more immunogenic tissue that (1-5) Descemet membrane endothelial keratoplasty (DMEK) is an attracti- could possibly precipitate graft rejection . Although DMEK has been ve alternative to corneal transplantation for patients with endothelial shown to have quicker and more pronounced visual rehabilitation dysfunction. The procedure involves transplantation of a graft con- than DSEK(1), the different techniques and learning curve of DMEK sisting of donor endothelium and Descemet membrane (DM) that have limited widespread adoption of this approach. replaces the host endothelium and DM. This procedure offers certain One of the most important challenges facing DMEK is preventing advantages over Descemet stripping (automated) endothelial kera- postoperative graft detachment, which is the most frequent compli- toplasty (DS(A)EK) in which the graft includes portions of stromal cation of the procedure. Detachment rates reported in the literature tissue that may distort the corneal architecture, produce more vary, with one recent multicenter study reporting rates of 34.6%(6).

Submitted for publication: January 18, 2016 Funding: This study was supported by grants from the J. Willard and Alice S. Marriott Foundation, Accepted for publication: April 14, 2016 Edward Colburn, Lorraine Collins, Richard Dianich, Mary Finegan, Barbara and Peter Freeman, 1 Tufts University School of Medicine, Boston, MA, United States. Stanley Friedler, MD, Ida Jeffries, Herbert Kasoff, Diane Kemker, James Lamson, Jean Mattison, 2 Wilmer Eye Institute, Johns Hopkins Medical Institutions, Baltimore, MD, United States. Florenz Ourisman, Lee Silverman, and Norman Tunkel, PhD (all to ASJ). 3 Oncology Center-Biostatistics/Bioinformatics, Johns Hopkins University, Baltimore, Maryland, United Disclosure of potential conflicts of interest: None of the authors have any potential conflict of States. interest to disclose. Corresponding author: Albert S. Jun. 400 N. Broadway, Smith 5011 - Wilmer Eye Institute, Johns Hopkins Medical Institutions - Baltimore, MD 21231 - USA - E-mail: [email protected] Approved by the following research ethics committee: Johns Hopkins Medicine Institutional Review Board (# IRB00061877).

http://dx.doi.org/10.5935/0004-2749.20160086 Arq Bras Oftalmol. 2016;79(5):299-302 299 Comparison of 20% sulfur hexafluoride with air for intraocular tamponade in Des cemet membrane endothelial keratoplasty (Dmek)

These detachments may necessitate postoperative intervention in of surgery and postoperative day 1 and included 10-minute upright volving reinjection of intraocular air. periods hourly while awake and every 2-3 hours overnight on the Although some surgeons use air for tamponade during the pro- night of surgery and the next night. For postoperative days 2 and 3, 2 cedure, longer-acting inert gases, such as sulfur hexafluoride (SF6), hours of supine positioning were interspersed with 1 hour of upright have been explored for this application recently. SF6 has a higher light activity and no overnight positioning, and for postoperative buoyancy and a longer half-life than those of air(7), which possibly pro- days 4 and 5, 2 hours of supine positioning were interspersed with 2 vides advantages for maintaining graft attachment postoperatively. hours of upright light activity and no overnight positioning. Starting

A recent study of 44 patients who underwent DSEK compared SF6 at the postoperative day 1 visit, standard postoperative topical corti- with air for graft attachment and noted that, although patients who costeroids and antibiotics were applied to the operated eye. received air had five graft detachments, there were no detachments (8) ollow up reported in the group that received SF6 . Additionally, Guell et al., re- F - cently demonstrated reduced detachment rates with SF from those 6 The patients’ follow-up information was obtained at 1 day, 1 week, with air in their series, and no effect on corneal endothelial cell counts (9) and 1 month postoperatively. BSCVA measurements postsurgically was observed . In the present study, we compared graft detachment were taken from approximately 6 months after intervention (range, rates between SF and air for intraocular tamponade in DMEK. 6 4-7 months). No complete graft detachments occurred, and all partial detachments identified in data collection underwent intervention METHODS with reinjection of intraocular air. A retrospective chart review was performed to evaluate patients Statistical analyses who underwent DMEK by a single surgeon (A.S.J.) at the Wilmer Eye Institute of Johns Hopkins Hospital between January 2012 and Analyses using the two-tailed Student’s t-test and chi-squared December 2014. Forty-two eyes were identified; 21 received air for tests were performed. Additionally, we performed univariate and intraocular tamponade and 21 received SF6. Approval from the Insti- multivariate analyses to evaluate the association between measured tutional Review Board of Johns Hopkins University was obtained, and variables and graft detachment rates. Analyses were performed in the the study was conducted in concordance with the ethical principles R statistical computing environment using the glm() function with established in the Declaration of Helsinki. the option, “family=‘binomial’.” P<0.05 was considered to indicate Data on patient demographics, preoperative and postoperative statistical significance. intraocular pressure (IOP), best spectacle corrected visual acuity (BSCVA), graft detachment, and donor tissue were collected from the patients’ operative and follow-up notes and from tissue bank infor- RESULTS mation. BSCVA was measured using the Snellen chart, and IOP was Forty-two eyes were included; 21 received air and the next 21 measured using Goldmann applanation tonometry. The indication consecutive eyes received SF6 for intraocular tamponade. Table 1 for all operations was bullous keratopathy caused by Fuchs’ endo- summarizes the baseline characteristics for each group. The preo- thelial dystrophy. perative BSCVA values were significantly different between the two

groups (Group 1 (air): logMAR, 0.33 ± 0.15; Group 2 (SF6): logMAR, Surgical procedure 0.48 ± 0.21 (p=0.014), with no significant differences in the other Operations were performed under sub-Tenon anesthesia by a preoperative measures. single surgeon (A.S.J.). Initial steps of the procedure were performed For other ocular comorbidities, one patient in group 1 had diabe- by making a 2.75-mm clear corneal keratome incision and included tic macular edema, one patient in group 1 had epiretinal membranes scoring of the DM at the same size as the planned graft, removal of in both eyes, one in group 1 had a history of optic neuritis, two pa- the DM, and scraping of the peripheral recipient stromal bed. All tients in group 2 were glaucoma suspects, and one patient in group patients underwent an intraoperative inferior peripheral iridectomy. 2 had mild amblyopia OS. In 32 of the 42 cases, combined phacoemulsification with intraocular lens (IOL) implantation was performed before any steps of the DMEK procedure.

Sterile 20% SF6 gas mixed with air was prepared as follows: 100% Table 1. Baseline characteristics filtered SF6 gas was drawn up from the tank into a syringe and diluted Group 1 (air) Group 2 (SF6) to 20% with filtered air. Using a stop-cock, the 20% SF6 gas was distri- o buted into 1-cc syringes with capped 30-gauge intraocular cannulas. N of eyes/patients 21/17 21/16 Preparation and insertion of donor tissue was performed as pre- Age (years) viously described(10). In brief, standard intravenous tubing (part num- (Mean ± SD) 62.90 ± 7.50 63.50 ± 5.60† ber MX451FL; Smiths Medical, Dublin, OH) was cut approximately 2 Sex inches from the Luer lock and attached to an Alcon B IOL cartridge (Alcon, Fort Worth, TX). Trephination was performed on pre-dissected (% male) 29% 25% DMEK donor tissue obtained from Lions VisionGift (Portland, OR) with (% female) 71% 75% sizes ranging from 7.75 to 8.5 mm depending on the recipient’s cor- Preoperative BSCVA (logMAR) neal size. Donor tissue was stained with trypan blue and placed into (Mean ± SD) 00.33 ± 0.15 00.48 ± 0.21† the IOL cartridge. After the graft was inserted and unfolded, the eye Donor age was completely filled with either air or a 20% SF6 mixture. Following a 10-minute waiting period, a small amount of gas was released to (Mean ± SD) 68.70 ± 4.80 65.70 ± 5.80† reduce the IOP to approximately 10-20 mmHg by palpation. The Donor endothelial cell count patient was then discharged home and instructed to remain in the (Mean ± SD) 2852 ± 239 2808 ± 401 supine position as follows: for air, the supine period was continuous Death to transplant (days) until 6 pm on postoperative day 2 and included 10-minute upright periods hourly while awake and every 2 hours overnight on the night (Mean ± SD) 04.30 ± 1.10 04.60 ± 1.60† †p<0.05= for all other baseline characteristics; p>0.05. of surgery only; for SF6, the supine period was continuous for the day

300 Arq Bras Oftalmol. 2016;79(5):299-302 Botsford B, e t a l .

Operative characteristics In multivariate analysis (Table 4) with gas included but not graft size, gas remained an independent statistically significant predictor Table 2 summarizes operative measurements and information. of detachment (air: OR, 6.65; p=0.020). When graft size was included Eighty-six percent of the air cases were combined with CE/IOL, and as a covariate, gas was no longer a statistically significant predictor 67% of the SF6 cases were combined with CE/IOL. There was a significant difference in graft size between the groups (group 1, 8.4 ± 0.2 mm; of detachment but maintained OR of 7.81 (p=0.063), similar to results group 2, 8.1 ± 0.2 mm (p=0.000010). of univariate and multivariate analyses without graft size. No other factor in this analysis was significant. Visual outcomes The mean change in BSCVA was -0.24 ± 0.19 inches in group 1 DISCUSSION and -0.39 ± 0.17 inches in group 2 (p=0.011). However, there was no In this study, we compared the outcomes of 42 eyes that underwent significant difference in the percentages of eyes with 20/25 or better DMEK at our institution, 21 with 20% SF6 and 21 with 100% air used BSCVA between the groups (67% vs. 71%). for intraocular tamponade, and focused on detachment and intervention rates. We demonstrated a lower detachment rate when SF Graft detachment rate 6 was used, and no significant differences in other outcome measures No complete graft detachments occurred. Intervention involving were observed. reinjection of intraocular air occurred in 67% of the eyes in group 1 (air) Complication rates with DMEK have improved over the years with and in 19% in group 2 (SF6) (p=0.0020). All cases of partial detachment refinements in surgical technique and increased surgical experience. were deemed appropriate for reinjection of air. Graft detachment rates have dramatically improved. An important criterion to consider, however, is the surgeon’s determination of which Other complications detachments require intervention. A recent series by Terry using SF6 There was one case of pupillary block in group 1 on postoperative for DMEK demonstrated a 6% graft rebubbling rate, although a 47% day 1 and one occurrence in group 2 on postoperative day 2. There graft detachment rate as measured by optical coherence tomogra- was no significant difference in IOPs on the first day between the phy (OCT) was reported (11). Their rebubbling criteria were separation groups (Table 2). No graft rejections or failures were noted. of donor Descemet membrane causing central corneal edema affec- In univariate analysis (Table 3), the gas used was the most signifi- ting vision and/or evidence of progressive separation of the graft cant factor predicting graft detachment (odds ratio, 8.50; p=0.0031). over successive visits. Guell et al. noticed a similar rebubbling rate but Graft size was also significant (odds ratio, 14.96; p=0.043). stated that they also had detachments that did not fit their criteria for rebubbling(9). In our study, all of the partial graft detachments were determined to fit our criteria for rebubbling, which included central Table 2. Surgical outcomes corneal edema affecting vision. There are limited data on whether Group 1 Group 2 p-value more aggressive intervention is necessary or beneficial to long-term (air) (SF ) (Group 1 vs. Group 2) vision recovery, and currently the decision to intervene is at the 6 surgeon’s discretion. Combined with CE/IOL In our experience, the incorporation of SF6 coincided with the (%) 86 67 0.150000 transition to smaller trephine size (8.0 mm). Both smaller trephine

Post-op BSCVA (logMAR) size and use of SF6 correlated with reduced risk of detachment in the (Mean ± SD) 00.10 ± 0.12 00.09 ± 0.10 0.900000 univariate analysis (Table 3). Multivariate analysis with both variables included was, therefore, partially confounded. However, comparison Graft Size (mm) of the detachment rates between eyes with the same graft size but (Mean ± SD) 08.40 ± 0.20 08.10 ± 0.20 0.000010 that had received SF6 or air suggests a benefit for the former. For Detachment rate example, 8.5-mm grafts showed detachments rates of 68% for group (%) 67 19 0.002000 1 (13/19) and 20% for group 2 (1/5). For graft sizes of ≤8.0 mm, the Pre-op IOP detachment rates were 50% for group 1 (1/2) and 19% for group 2 (3/16). However, the coinciding changes in smaller graft size from 8.5 (Mean ± SD) 13.10 ± 3.20 14.50 ± 3.10 0.160000 to 8.0 mm with the introduction of SF6 led to only two eyes in our IOP POD#1 series receiving both 8.0-mm graft size and air, which made a more (Mean ± SD) 18.80 ± 9.50 16.40 ± 4.00 0.300000 robust analysis difficult. The high odds ratio for reduced detachment

rate with SF6 use and the significance from univariate and multivariate analyses with graft size removed strongly suggest that the gas used is a significant factor affecting detachment rate. Additionally, the gas Table 3. Univariate analysis of effect on graft detachment rate Odds ratio LCB† UCB‡ p-value Patient age 00.98 0.89 001.08 0.6900 Table 4. Effect of air on detachment rate determined by multivariate analysis Patient sex 01.50 0.39 005.77 0.5600 with and without graft size included IOP Pre-op 00.81 0.65 001.00 0.0560 Odds ratio LCB† UCB‡ P-value Pre-op BSCVA 00.07 0.00 002.46 0.1400 Graft size excluded Change VA 09.12 0.30 278.31 0.2000 Gas used (Air) 6.65 1.35 32.83 0.020 Gas used 08.50 2.06 035.08 0.0031 Graft Size Included Graft size (mm) 14.96 1.09 205.56 0.0430 Gas used (Air) 7.81 0.90 67.95 0.063 Death to transplant (days) 01.02 0.66 001.59 0.9200 Graft size 0.60 0.01 60.66 0.830 Pre-op endothelial cell density 01.00 1.00 001.00 0.8100 †LCB= lower border of 95% confidence interval;‡ UCB= upper border of 95% confi- †LCB= lower border of 95% confidence interval;‡ UCB= upper border of 95% confidence dence interval. No other factors from univariate analysis were statistically significant interval. on multivariate analysis.

Arq Bras Oftalmol. 2016;79(5):299-302 301 Comparison of 20% sulfur hexafluoride with air for intraocular tamponade in Des cemet membrane endothelial keratoplasty (Dmek)

used had a much more statistically significant effect than did graft 3. Rudolph M, Laaser K, Bachmann BO, Cursiefen C, Epstein D, Kruse FE. Corneal higher-order size when both were included in the multivariate model. However, aberrations after Descemet’s membrane endothelial keratoplasty. Ophthalmology. because our study design was retrospective, and changes in graft 2012;119(3):528-35. 4. Anshu A, Price MO, Price FW Jr. Risk of corneal transplant rejection significantly re- size coincided with the change from air to SF6, our analysis could not duced with Descemet’s membrane endothelial keratoplasty. Ophthalmology. 2012; determine the relative contribution of these two factors. 119(3):536-40. An additional concern with use of SF6 is potential toxicity to the 5. Price MO, Giebel AW, Fairchild KM, Price FW Jr. Descemet’s membrane endothelial corneal endothelium(12). Although the gas is thought to be inert, keratoplasty: prospective multicenter study of visual and refractive outcomes and increased buoyancy and longevity of the gas may have mechanical endothelial survival. Ophthalmology. 2009;116(12):2361-8. Comment in: Ophthalmology. effects on the endothelial surface(13). A recent in vitro study, however, 2010;117(7):1459-60; author reply 1460. 6. Monnereau C, Quilendrino R, Dapena I, Liarakos VS, Alfonso JF, Arnalich-Montiel F, et found no significant difference between 6SF and air on endothelial cell (14) al. Multicenter study of descemet membrane endothelial keratoplasty: First case series counts or toxicity of corneal endothelial cells . Additionally, Guell et al. of 18 surgeons. JAMA Ophthalmology. 2014;132(10):1192-8. Comment in: JAMA found no difference in endothelial cell counts between use of SF6 or Ophthalmol. 2015;133(6):725. JAMA Ophthalmol. 2015;133(6):724-5. air ≤3years after DMEK(9). 7. Thompson JT. Kinetics of intraocular gases. Disappearance of air, sulfur hexafluoride, and perfluoropropane after pars plana vitrectomy. Arch Ophthalmol. 1989;107(5): One weakness of our study was that the SF6 procedures followed the air procedures chronologically because detachment rates have 687-91. been found to diminish with experience of the surgeon(15). However, 8. Acar BT, Muftuoglu O, Acar S. Comparison of sulfur hexafluoride and air for donor the reduction in detachment rates from the first 21 to the next 21 attachment in Descemet stripping endothelial keratoplasty in patients with pseudo- phakic bullous keratopathy. Cornea. 2014;33(3):219-22. consecutive eyes was dramatic, and detachment rates were equiva- 9. Guell JL, Morral M, Gris O, Elies D, Manero F. Comparison of sulfur hexafluoride 20% lent between those in the first half of air cases and those in the second versus air tamponade in descemet membrane endothelial keratoplasty. Ophthalmology. half. Although technical improvement of the surgeon may account 2015;122(9):1757-64. 10. Kim EC, Bonfadini G, Todd L, Zhu A, Jun AS. Simple, inexpensive, and effective injector for some of this difference, SF6 was found to have a substantial impact on maintaining graft adherence and preventing graft detachment for descemet membrane endothelial keratoplasty. Cornea. 2014;33(6):649-52. post-surgery without any significant differences in other outcome 11. Terry MA, Straiko MD, Veldman PB, Talajic JC, VanZyl C, Sales CS, et al. Standardized DMEK technique: reducing complications using prestripped tissue, novel glass injector, measures in our study. Randomized prospective studies could further and Sulfur Hexafluoride (SF6) Gas. Cornea. 2015;34(8):845-52. address this important question. 12. Landry H, Aminian A, Hoffart L, Nada O, Bensaoula T, Proulx S, et al. Corneal endothelial toxicity of air and SF6. Invest Ophthalmol Vis Sci. 2011;52(5):2279-86. 13. Green K, Cheeks L, Stewart DA, Norman BC. Intraocular gas effects on corneal endothelial REFERENCES permeability. Lens Eye Toxic Res. 1992;9(2):85-91. . 1 Goldich Y, Showail M, Avni-Zauberman N, Perez M, Ulate R, Elbaz U, et al. Contralateral 14. Schaub F, Simons HG, Roters S, Heindl LM, Kugler W, Bachmann BO, et al. [Influence of eye comparison of descemet membrane endothelial keratoplasty and descemet stripping 20% sulfur hexafluoride (SF6) on human corneal endothelial cells: An in vitro study]. automated endothelial keratoplasty. Am J Ophthalmol. 2015;159(1):155-9 e1. Ophthalmologe .2016;113(1):52-7. German. 2. Guerra FP, Anshu A, Price MO, Giebel AW, Price FW. Descemet’s membrane endothelial 15. Dapena I, Ham L, Droutsas K, van Dijk K, Moutsouris K, Melles GR. Learning Curve in keratoplasty: prospective study of 1-year visual outcomes, graft survival, and endothe- Descemet’s Membrane Endothelial Keratoplasty: First series of 135 consecutive cases. lial cell loss. Ophthalmology. 2011;118(12):2368-73. Ophthalmology. 2011;118(11):2147-54.

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302 Arq Bras Oftalmol. 2016;79(5):299-302 Original Article

Pattern-reversal visual evoked potentials as a diagnostic tool for ocular malingering Potenciais visuais evocados por padrões reversos como uma ferramenta diagnóstica de simulação

Tarciana de Souza Soares1, Paula Yuri Sacai1, Adriana Berezovsky1, Daniel Martins Rocha1, Sung Eun Song Watanabe1, Solange Rios Salomão1

ABSTRACT RESUMO Purpose: To investigate the contributions of transient pattern-reversal visual evoked Objetivo: Investigar a contribuição dos potenciais visuais evocados por padrões reversos potentials in the diagnosis of ocular malingering at a Brazilian university hospital. no diagnóstico de simulação de baixa de visão em um hospital universitário do Brasil. Methods: Adult patients with suspected malingering in one or both eyes were Métodos: Um grupo de pacientes adultos com suspeita de simulação de baixa de referred for visual evoked potential testing. Data from patients’ medical records visão em um ou ambos os olhos foi avaliado e os dados analisados retrospecti were reviewed and analyzed retrospectively. Data analysis included the distance vamente. Foram medidos: acuidade visual de optotipos informada para longe optotype visual acuity based on a ETDRS retro-illuminated chart and the transient utilizando a tabela ETDRS, parâmetros dos potenciais visuais evocados por padrões pattern-reversal visual evoked potential parameters of latency (milliseconds) and reversos de latência (milissegundos) e amplitude (microvolts) para o componente amplitude (microvolts) for the P100 component, using checkerboards with visual P100 com estímulos de ângulos visuais de 15’ e 60’. A motivação do paciente para subtenses of 15’ and 60’. Motivations for malingering were noted. a simulação foi anotada. Results: The 20 subjects included 11 (55%) women. Patient ages ranged from Resultados: Os participantes foram 20 indivíduos com 11 (55%) do sexo feminino. A 21 to 61 years (mean= 45.05 ± 11.76 years; median= 49 years). In 8 patients (6 idade variou de 21 a 61 anos (média= 45,05 ± 11,76 anos; mediana= 49 anos). Em 8 women), both eyes exhibited reduced visual acuity with normal pattern-reversal pacientes (6 mulheres) ambos os olhos tinham acuidade visual reduzida com parâme- visually evoked potential parameters (pure malingerers). The remaining 12 pa- tros dos potenciais visuais evocados por padrão reverso normais para ambos os olhos tients (7 men) exhibited reduced vision in only 1 eye, with simulated reduced (simuladores puros). Uma subsérie separada de 12 pacientes (7 homens) tinha visão vision in the contralateral eye (exaggerators). Financial motivation was noted in reduzida em apenas um olho e estavam simulando redução da visão no outro olho 18 patients (9 men). (exacerbadores). A motivação financeira foi observada em 18 pacientes (9 homens). Conclusion: Normal pattern-reversal visually evoked potential parameters with Conclusões: Parâmetros dos potenciais visuais evocados por padrões reversos nor- suspected ocular malingering were observed in a 20 patient cohort. This electro- mais foram encontrados neste grupo de 20 pacientes com suspeita de simulação. Esta physiological technique appeared to be useful as a measure of visual pathway técnica eletrofisiológica pode ser útil como uma medida da integridade do sistema integrity in this specific population. visual nesta população de doentes. Keywords: Evoked potentials, visual/physiology; Malingering; Pattern recogni- Descritores: Potenciais evocados visuais/fisiologia; Simulação de doença; Reconhe- tion, visual; Vision disorders; Visual acuity cimento visual de modelos; Transtornos da visão; Acuidade visual

INTRODUCTION cution, escape from military service, compensation from social security agencies or insurance companies, and/or access to unnecessary free Functional vision loss (FVL) is a condition in which the patient’s (7,8) subjective visual symptoms do not corroborate the results of a clini- medications or medical equipment . In contrast, patients with psy cal examination and diagnostic workup(1). In general, FVL is a clinical chogenic disorders tend to seek sympathy, family assistance, or social adjustment, and such cases usually present evidence of previous emo- diagnosis made when the physician demonstrates that the patient’s tional trauma or stressful life events prior to the symptoms onset(7). visual acuity (VA) is better than alleged(2). The terminology associated A comprehensive examination must be performed to rule out with this condition varies considerably, and includes descriptors such organic causes of vision loss(9). Measurement of visual function is as non-organic visual loss, psychogenic visual loss, malingering, hys (1,3,4) a valuable step toward objectively explaining a patient’s report of terical visual loss, and ocular conversion reaction . Decreased visual loss with no visible damage, and defending against subjec- VA, one of the most common functional complaints, may be either tive decision-making(10). The visual evoked potential (VEP) test has psychogenic or caused by malingering; with the former, subjects are been used to evaluate functionality of the visual pathway, and the unconscious of dissembling, whereas with the latter, subjects cons- pattern-reversal (PR)-VEP has been used as an objective assessment ciously dissemble the disease(5). of VA. Previous studies have used the PR-VEP to objectively assess the In order to distinguish between a potential psychogenic disorder visual pathway by comparing the results achieved with normative and malingering, it is important to conduct a thorough search for amplitude and latency values(11). evidence and establish a well-documented understanding of the The present study investigated the contributions of pattern-re patient’s context(6). Malingering usually occurs when the patient seeks versal transient VEPs to diagnose malingering in patients treated at a benefits associated with illness such as an evasion of criminal prose- university hospital in Brazil.

Submitted for publication: October 20, 2015 Funding: No specific financial support was available for this study. Accepted for publication: May 15, 2016 Disclosure of potential conflicts of interest: None of the authors have any potential conflicts of 1 Laboratório de Eletrofisiologia Visual Clínica, Departamento de Oftalmologia e Ciências Visuais, interest to disclose. Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Corresponding author: Solange Rios Salomão. Depto. de Oftalmologia e Ciências Visuais. Rua Botucatu, SP, Brazil. 821 - São Paulo, SP - 04023-062 - Brazil - E-mail: [email protected] Approved by the following research ethics committee: Escola Paulista de Medicina, Universidade Federal de São Paulo - UNIFESP (#04171712.3.0000.5505).

http://dx.doi.org/10.5935/0004-2749.20160087 Arq Bras Oftalmol. 2016;79(5):303-7 303 Pattern-reversal visual evoked p otentials as a diagnostic tool for ocular malingering

METHODS and pinhole correction were used when necessary. Each score was This retrospective study was performed in the Laboratory of recorded as the 4-m logarithm of the minimum angle of resolution Clinical Electrophysiology of Vision, Universidade Federal de São Paulo (logMAR) acuity. (UNIFESP), Hospital São Paulo, São Paulo, Brazil. This study’s procedures complied with the tenets of the Declaration of Helsinki, and the Statistical analysis study’s protocol was approved by the UNIFESP Committee on Ethics An unpaired t-test was used to compare age distributions between in Research. male and female subjects, and a p value ≤0.05 was considered to be All participants were asked about their clinical histories, with an statistically significant. emphasis on the visual loss characteristics (e.g., bilateral or unilateral) and onset (e.g., sudden or progressive). In an attempt to gather detai- RESULTS led information about the motivation for FVL, questions were asked regarding medical leave from work, financial compensation for work The study subjects comprised 20 adults, including 11 (55%) wo- accidents, and eventual use of medications for psychiatric disorders. men, with ages ranging from 21 to 61 years (mean= 45.05 ± 11.76 The inclusion criteria were (1) unexplained visual loss according to years; median= 49 years). The age distributions of men and women findings from a previous ophthalmic exam (including visual acuity, were similar; men’s ages ranged from 21 to 58 years (mean= 44.44 ± refraction, biomicroscopy, intraocular pressure, direct and indirect 11.91 years; median= 49 years), and women’s ages ranged from 30 fundoscopy evaluations) and (2) an age of ≥18 years. The exclusion to 61 years (mean= 45.54 ± 12.19 years; median= 49 years). A total of criterion was the presence of neurological disorders that might affect 39 eyes were tested (1 female subject had a right ocular prosthesis). VEP recording (e.g., epilepsy, intracranial tumor). Figure 1 shows the distributions of individual PR-VEP parameters (P100 latency and amplitude) for 8 patients who met the criteria for Procedures malingering. The demographics, complaints of visual loss, informed optotype acuities, and motivations for FVL are listed in table 1. Infor- Pattern-reversal visual evoked potential (PR-VEP) med optotype acuity ranged from no light perception (NLP) to 20/50. Transient PR-VEP recording was performed according to the Previous ocular or head trauma was present in 3 cases. Two female recommendations of the International Society for Clinical Electro- patients had no apparent cause of malingering; these cases most physiology of Vision (ISCEV)(12). PR-VEPs of each eye were obtained likely involved psychogenic functional visual loss, and one patient using electroencephalograph electrodes placed according to the (patient #4) was referred for psychiatric assessment. 10-20 system. The active, reference, and ground electrodes were Twelve patients had an organic background for visual loss in 1 placed at Oz, Fpz, and Cz, respectively. Pattern-induced visual stimu eye and complained of visual loss in the contralateral eye; accor- lation was provided by a pattern generator monitor with a mean dingly, they were classified as exaggerators. Table 2 presents the luminance of 50 cd/m². The reversal frequency of the frame-locked demographics, visual loss complaints, informed optotype acuities, pattern was 1.9 Hz. At the viewing distance used in this study (100 cm), and motivations of this particular group. For these 12 patients, the the display screen subtended angles of 17° x 17° at the eye. Black individual parameters (P100 latency and amplitude) of the eye without and white checks with visual subtenses of 15’ and 60’ were used as an organic background for visual loss are shown in figure 2. All pa- stimuli, and the spatial frequency in the 45º direction was calculated tients in this group had a financial motivation for their visual loss. for both sizes of stimuli using a previously described formula(13). The Visual acuity in the malingering eye ranged from 20/63 to NLP. In 5 spatial frequencies (cycles/degree) were 0.44 and 1.79 for larger and cases, ocular trauma was the organic cause that led to malingering smaller checks, respectively. These spatial frequencies corresponded of the contralateral eye in an attempt to achieve personal gains from to checkerboard resolution visual acuity thresholds of approximately social security agencies. Representative PR-VEP data from both eyes 20/1400 for larger checks and 20/300 for smaller checks. Because the of a 32-y ear-old man with a subjective VA of 20/250 in the right eye resolution acuity thresholds could exceed the optotype acuity scores and ability to count fingers with the left eye are presented in figure 3. by up to 1 octave, the minimum visual acuity required to evoke res- The subject had experienced blunt trauma to his left eye and was ponses to the larger and smaller checks would be 20/700 and 20/150, suing his former employer for compensation benefits regarding his respectively. The contrast was set to maximum, and the luminance workplace injury. remained constant. Occipital responses were averaged using the UTAS E-3000 system (LKC Technologies, Inc., Gaithersburg, MD, USA). The average response DISCUSSION to 100 reversals was analyzed. Latencies (ms) of the major positive com- In this cohort of patients from a public hospital in Brazil, transient ponent (P100) and the negative peaks (N75 and N135) were deter- PR-VEP testing was found to be highly sensitive for the identification mined for both stimuli. The P100 latency was compared with normal and diagnosis of pure malingering(5), as all eyes tested under the sus- values obtained in our laboratory after setting the 97.5th percentile as picion of malingering yielded normal PR-VEP amplitudes and laten- the upper limit of normal(14). The Amplitude (µV) was defined as the cies. A normal VEP result indicates a normal visual pathway with no difference in potential between the N75 and P100 peaks. For each eye organic cause of vision loss, and consequently, suggests malingering and using the two checkerboard sizes, VEPs were classified as normal, because of a specific motivation. It is important, however, to note that reduced amplitude, prolonged latency, and non-recordable. Normal normal subjects might have employed changes in accommodation, PR-VEP parameters (P100 latency and amplitude) for both stimulus a lack of attention, or meditation to consciously alter their VEPs to sizes and in both eyes were indicative of malingering. mimic significant visual or neurological lesions(5,15-18). For example, a To improve accuracy and compliance, a direct observation of the patient might not focus on the center of the screen or might close examined eye was performed, during which the subject was conti- his/her eyes too frequently. However, these artifacts were controlled nuously asked to pay attention to the center of the stimulus monitor. through a careful observation of patient behavior during testing, as In addition, evaluations were performed by experienced examiners described in another report(19). In some cases, mainly those of patients and the developing average waveform was carefully observed. who reported a lack of light perception, the use of flash VEPs might be considered to avoid the requirement for constant and steady eye Visual acuity testing fixation. However, flash VEPs are not sensitive to image blurring. The participants’ best corrected visual acuity was measured using The majority of subjects in this study reported financial moti- a retro-illuminated ETDRS Chart with Tumble “E” optotypes; glasses vations for their reported ocular malingering (90%). As in previous

304 Arq Bras Oftalmol. 2016;79(5):303-7 Soares TS, e t a l .

F igure 1. Transient pattern-reversal visual evoked potential parameters for check sizes of 15’ and 60’, demonstrating P100 latency (upper panels) and P100 amplitude (lower panels). Data were obtained from 8 patients with functional visual loss who were characterized as malingerers. Closed symbols represent right eye data; open symbols represent left eye data. Dotted lines indicate the lower and upper limits of normal as was determined in our own laboratory.

Table 1. Clinical characteristics of patients with malingering and normal VEP parameters in both eyes ID Sex Age (years) Complaint of visual loss Cause VA RE VA LE Motivation 1 F 33 Binocular None HM 20/160 Psychogenic 2 M 58 Binocular Corneal burn RE 20/160 20/50 Financial 3 F 57 Binocular Bilateral diabetic retinopathy HM 20/125 Financial 4 F 36 Binocular None 20/200 NLP Psychogenic 5 F 56 Right eye Acute myocardial infarct 20/160 20/125 Financial 6 M 32 Left eye Blunt trauma LE 20/250 CF Financial 7 F 60 Binocular None 20/160 20/125 Financial 8 F 49 Binocular Head trauma with retinal detachment LE 20/125 20/200 Financial ID= identification; VA= visual acuity; F= female; M= male; RE=right eye; LE= left eye; HM= hand motion; NLP= no light perception; CF= counting fingers.

Table 2. Clinical characteristics of 12 patients classified as exaggerators, with unilateral organic lesion: 9 malingering of the contralateral eye and 3 exaggerators of ipisilateral eye (patients 3, 7 and 9) ID Sex Age VA RE VA LE Complaint VEP RE VEP LE Motivation Ocular findings 01 F 34 NLP 20/630 Binocular Non- detactable Normal Financial Retinal atrophy post uveitis in RE 02 F 34 20/320 NLP Binocular Normal Non-detectable Financial Infantile cataract in LE 03 F 30 20/400 20/32 Monocular Normal Normal Financial Penetrating ocular trauma in RE 04 F 51 Prosthesis 20/63 Monocular N/A Normal Financial Ocular prosthesis in RE 05 M 37 HM LP Binocular Normal Non-detectable Financial Macular scar post-chorioretinitis in LE 06 M 52 NLP CF Monocular Non-detectable Normal Financial RCVO in RE 07 M 21 NLP 20/20 Binocular Normal Normal Financial Penetrating ocular trauma in RE 08 M 52 NLP 20/100 Binocular Non-detectable Normal Financial Phthisis bulbi in RE 09 M 48 HM 20/160 Binocular Non-detectable Normal Financial Retinal detachment in LE 10 F 61 NLP 20/400 Binocular Non-detectable Normal Financial Penetrating ocular trauma in RE 11 M 51 NLP 20/125 Binocular Non-detectable Normal Financial Blunt ocular trauma in RE 12 M 49 NLP 20/80 Binocular Non-detectable Normal Financial Penetrating ocular trauma in RE ID= identification; VA= visual acuity; F= female; M= male; RE= right eye; LE= left eye; NLP= no light perception; HM= hand motion; LP= light perception; CF= counting fingers; VEP= visual evoked potential; N/A= non-applicable; RCVO= retinal central vein occlusion.

Arq Bras Oftalmol. 2016;79(5):303-7 305 Pattern-reversal visual evoked p otentials as a diagnostic tool for ocular malingering

studies, reliable PR-VEP data could be recorded in all patients with psychological and social motivations as the major reasons for malin no observable physical damage to the anterior visual system who gering(22). PR-VEP testing assesses the integrity of visual stimulus were included in the present study(9,20,21). An earlier study of 4 children conduction through the visual pathway, and a normal PR-VEP is with functional visual losses and normal PR-VEP results reported thought to indicate pathway integrity; in addition, it is possible to

F igure 2. Transient pattern-reversal visual evoked potential parameters for check sizes of 15’ and 60’, demonstrating P100 latency (upper panels) and P100 amplitude (lower panels). Data obtained from 12 patients with functional visual loss who were characterized as malingerers and had one eye with an organic background. Data were obtained from the exaggerator eyes. Dotted lines indicate the lower and upper limits of normal as was determined in our own laboratory.

F igure 3. Transient pattern-reversal visually evoked potentials of the right and left eyes in a 32-year-old male (patient #6) with informed visual acuity of 20/250 in the right eye, the ability to count fingers with the left eye, and financial motivation.

306 Arq Bras Oftalmol. 2016;79(5):303-7 Soares TS, e t a l .

infer whether the informed acuity is or is not reliable. However, mild 4. Hamilton R, Bradnam MS, Dutton GN, Lai Chooi Yan AL, Lavy TE, Livingstone I, et al. losses in visual acuity should be interpreted in light of clinical findings Sensitivity and specificity of the step VEP in suspected functional visual acuity loss. Doc Ophthalmol. 2013;126(2):99-104. from an ophthalmic exam that includes careful anamnesis and detailed 5. Gundogan FC, Sobaci G, Bayer A. Pattern visual evoked potentials in the assessment semiology. Furthermore, patients with a true reduction in visual of visual acuity in malingering. Ophthalmology. 2007;114(12):2332-7. acuity might exhibit normal VEP responses and could therefore be 6. Bass C, Halligan P. Factitious disorders and malingering: challenges for clinical assessment considered false dissemblers. and management. Lancet. 2014;383(9926):1422-32. Comment in: Lancet. 2014;383 If the results of conventional tests are equivocal or an objective (9926):1368-9. 7. Nicholson TR, Kanaan RA. Conversion disorder. Psychiatry. 2009;8(5):164-9. assessment of the visual system functional integrity is required, VEP 8. Incesu AI, Sobaci G. Malingering or simulation in ophthalmology-visual acuity. Int J testing can offer a more direct assessment of visual pathway integrity, Ophthalmol, 2011;4(5):558-66. particularly in the context of a simulated severe visual acuity loss such 9. Xu S, Meyer D, Yoser S, Mathews D, Elfervig JL. Pattern visual evoked potential in the as that of light perception. Although the current study was not de- diagnosis of functional visual loss. Ophthalmology. 2001;108(1):76-81. signed to measure objective visual acuity using ISCEV transient VEPs, 10. Bobak P, Khanna P, Goodwin J, Brigell M. Pattern visual evoked potentials in case of ambiguous acuity loss. Doc Ophthalmol. 1993;85(2):185-92. such measurements could be reliably achieved using the previously 11. Jeon J, Oh S, Kyung S. 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Pattern-reversal visually evoked po The major limitations of the present study were its retrospective tentials in healthy adults [abstract]. Invest Ophthalmol Vis Sci. 2006;47:5368. design and its basis on a medical chart review; accordingly, the study 15. Bumgartner J, Epstein C. Voluntary alteration of visual evoked potentials. Ann Neurol. 1982;12(5):475-8. lacked follow-up data that could confirm the subjects’ malingering 16. Tan CT, Murray NM, Sawyers D, Leonard TJ. Deliberate alteration of the visual evoked statuses. Furthermore, subject cooperation during the examination potential. J Neurol Neurosurg Psychiatry. 1984;47(5):518-23. might have affected the PR-VEP outcomes. In this case series, many 17. Lovasik JV, Spafford M, Szymkiw M. Modification of pattern reversal VERs by ocular of the contributing factors associated with malingering, such as accommodation. Vision Res. 1985;25(4):599-608. pre-existing trauma, physical illness, and pursuit of social benefits, 18. 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Diagnosis and management of functional visual deficits. Curr Treat Options formance of three visual evoked potential-based methods to estimate visual acuity. Neurol. 2006;8(1):45-51. Doc Ophthalmol. 2013;126:45-56. 2. Chen CS, Lee AW, Karagiannis A, Crompton JL, Selva D. Practical clinical approaches 24. Perlman I, Segev E, Mazawi N, Merhav-Armon T, Lei B, Leibu R. Visual evoked cortical to functional visual loss. J Clin Neurosci. 2007;14(1):1-7. potential can be used to differentiate between uncorrected refractive error and macular 3. Lessel S. Nonorganic visual loss: what’s in a name? Am J Ophthalmol. 2011;151(4):569-71. disorders. Doc Ophthalmol. 2001;102:41-62.

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Arq Bras Oftalmol. 2016;79(5):303-7 307 Original Article

Subfoveal choroidal thickness changes after intravitreal bevacizumab therapy for central serous chorioretinopathy Alterações da espessura subfoveal coroide após terapia com bevacizumab para coriorretinopatia serosa central

Cihan Ünlü1, Gurkan Erdogan1, Tugba Aydogan Gezginaslan1, Betul Ilkay Sezgin Akcay1, Esra Kardes1, Tahir Kansu Bozkurt1

ABSTRACT RESUMO Purpose: To evaluate subfoveal choroidal thickness (SFCT) changes after in- Objetivo: Avaliar as alterações da espessura da coroide subfoveal (SFCT) após travitreal bevacizumab (IVB) therapy for central serous chorioretinopathy (CSC) terapia com bevacizumab (IVB) para coriorretinopatia serosa central (CSC) usando using enhanced depth imaging spectral-domain optical coherence tomography tomografia de coerência óptica de domínio espectral com profundidade apri (EDI-OCT). morada (EDI-OCT). Methods: In this retrospective study, we assessed the medical records of patients Métodos: Neste estudo retrospectivo, foram avaliados prontuários de pacientes com with CSC who received IVB (IVB group) or who were observed without intervention CSC que receberam IVB (grupo IVB) ou que foram apenas observados, sem intervenção (control group). SFCT was measured using EDI-OCT. The main outcome measure (grupo controle). SFCT foi medido por meio de EDI-OCT. O desfecho principal avaliado was the change in SFCT. foi a mudança na SFCT. Results: Twenty-one eyes were included in the IVB group and 16 eyes were Resultados: Houve 21 olhos no grupo IVB e 16 olhos no grupo de controle. Todos os included in the control group. All patients showed resolution of neurosensory pacientes apresentaram resolução de descolamento neurossensorial e melhora na detachment and improvement in vision. In the IVB group, the mean SFCT was visão. No grupo IVB, a SFCT media foi 315 µm no início e diminuiu para 296 µm na visita 315 µm at baseline, which decreased to 296 µm at the most recent visit. In the mais recente. No grupo controle, a SFCT média foi 307 µm no início e diminuiu para control group, the mean SFCT was 307 µm at baseline, which decreased to 266 µm na visita mais recente. Embora tenha havido uma diminuição significativa na 266 µm at the most recent visit. Although there was a significant decrease in the SFCT média para o grupo controle, a diminuição não foi significativa para o grupo IVB mean SFCT for the control group, the decrease was not significant for the IVB group (41 µm contra 19 µm, p=0.003 vs p=0.071). (41 vs 19 µm, p=0.003 vs p=0.071). Conclusões: A SFCT diminuiu em ambos os grupos após a remissão da doença. Conclusions: SFCT decreased in both groups with remission of the disease. Contudo, a diminuição foi significativamente maior no grupo de controle. Em termos However, the decrease was significantly greater in the control group. In terms of de resultados anatômicos e funcionais, a injeção de IVB não foi promissora. anatomic and functional outcomes, IVB injection is not promising. Keywords: Intravitreal injection; Bevacizumab; Central serous chorioretinopathy; Descritores: Injeções intravítreas; Bevacizumab; Coriorretinopatia serosa central; Co Choroid; Optical coherence tomography roide; Tomografia de coêrencia óptica

INTRODUCTION have showed that the choroid is very thick in patients with CSC, which (9-11) Central serous chorioretinopathy (CSC) is an idiopathic condition might indicate the crucial role of the choroid in CSC . characterized by the development of a well-circumscribed, serous Although most cases with CSC may resolve spontaneously detachment of the sensory retina in the posterior pole. Although without any intervention, treatment may be required in chronic and the pathogenesis of CSC has been extensively studied, it still remains recurrent cases and in acute cases who need prompt restoration of controversial(1-3). The primary pathology may involve dysfunction of vision due to occupational or other needs. Several treatment options the retina pigment epithelium (RPE) or choriocapillaris hyperpermea are now available, including pharmacological treatment with aceta- bility or both. Gass postulated that choriocapillaris hyperpermeabi- zolamide, nonsteroidal anti-inflammatory drugs, argon laser photo- lity was the cause of CSC. Later, studies using indocyanine green coagulation of the leaking site, and photodynamic therapy with verte- angiography (ICGA) showed multiple areas of choroidal vascular porfin. It is well known that vascular endothelial growth factor (VEGF) is hyperpermeability, vascular dilatation, filling delay in the choroidal related to vascular permeability(12). Anti-VEGF agents may reduce cho- arteries and choriocapillaris, and punctate hyperfluorescent spots(4-8). roidal hyperpermeability. Recently, several reports have demonstrated These angiographic findings strongly support the theory of Gass, acceptable outcomes after intravitreal anti-VEGF agent (ranibizumab which suggests that the primary pathology underlying CSC involves and bevacizumab) injection in patients with CSC(12-18). choroidal vascular changes. Recent studies using enhanced depth Conventional OCT devices have limited ability for choroidal ima- imaging spectral-domain optical coherence tomography (EDI-OCT) ging due to low penetration and high light scattering at the level of

Submitted for publication: January 27, 2016 Funding: No specific financial support was available for this study. Accepted for publication: April 14, 2016 Disclosure of potential conflicts of interest: None of the authors have any potential conflicts of 1 Opthalmology Department, Ümraniye Training and Research Hospital, İstanbul, Turkey. interest to disclose. Corresponding author: Cihan Ünlü. Bengisu evleri sitesi D2/2 Bengisu cad. Aşağı Dudullu mah. Ümraniye, İstanbul, Turkey - E-mail: [email protected] Approved by the following research ethics committee: Ümraniye Training and Research Hospital, İstanbul, Turkey.

308 Arq Bras Oftalmol. 2016;79(5):308-11 http://dx.doi.org/10.5935/0004-2749.20160088 Ünlü C, e t a l .

the RPE. Spaide introduced the EDI-OCT technique, which improved (logMAR) for analysis. The primary outcome measures were changes imaging of the choroid. Since this landmark study, an increasing in SFCT and BCVA. Descriptive statistics methods such as the mean, number of investigators have studied choroidal thickness in several standard deviation, and median were used to analyze the data. Nor- diseases of the eye(9,19-21). In this study, we aimed to evaluate the cho- mally distributed data were analyzed using Student’s t-test between roidal thickness changes after intravitreal bevacizumab (IVB) injection groups and paired sample t-tests within each group. Non-normally in patients with CSC and compare the results with those of control distributed data were analyzed using the Mann-Whitney U-test patients who did not receive any treatment for CSC. This finding may between groups and the Wilcoxon signed-rank test within each group. help to elucidate the pathophysiology of CSC. Fisher’s exact test was used to compare percentages. For all tests, p<0.05 was considered to be statistically significant. METHODS This study followed the tenets of the Declaration of Helsinki. This RESULTS retrospective comparative study was approved by the local ethics The study included 37 eyes of 37 patients. The mean age of the committee (Ümraniye Training and Research Hospital, İstanbul, patients was 44.7 ± 9.4 years (range, 24-64 years). Twenty-six patients Turkey). Written informed consent, explaining all potential risks and (70%) were male, and 11 patients (30%) were female. The mean possible benefits of the IVB injection and the off-label nature of this follow-up time was 9.4 ± 8.4 months (range, 3-30 months). There were therapy, was obtained from all patients who received the IVB injection. 21 patients in the IVB group and 16 patients in the control group. The The charts of patients who were diagnosed with unilateral CSC demographic characteristics of the groups are summarized in table 1. were reviewed. The diagnosis of CSC was established by the presence No significant differences were detected between the two groups. of serous macular detachment on dilated fundus examination, fluo- The mean SFCT and the mean BCVA at baseline and the final visits rescein leakage on fluorescein angiography (FA), and corresponding for both groups are summarized in table 2. Figures 1 and 2 show a subretinal fluid accumulation as evidenced by OCT. Each of the patients had a history of comprehensive ocular examinations, including best-corrected visual acuity (BCVA) on a Snellen chart, intraocular Table 1. Demographic characteristics of the groups pressure measurement, biomicroscopic examination, dilated retinal IVB (n=21) Control (n=16) examination, and OCT examinations. All eyes were examined with mean ± SD mean ± SD p value the RTVue-100 OCT device (Optovue Inc., Fremont, CA, USA). The charts of the patients were excluded from this study if the patients Patient age (years) 46.2 ± 8.2 42.70 ± 10.60 a0.269 had a history of previous chorioretinal disease, history of intraocular Duration of CSC episode (weeks) 11.3 ± 5.3 10.94 ± 06.02 b0.540 surgery, previous photodynamic therapy, or intravitreal anti-VEGF Follow-up time (months) (median) 10.2 ± 9.5 (6.0) 08.40 ± 07.00 (3.5) b0.404 therapy, glaucoma, high myopia with a refractive error <-6.0, or other eye diseases that could compromise visual acuity. Patients with sys- n (%) n (%) temic diseases that could have affected the choroidal thickness such Gender as diabetes mellitus or malignant hypertension were also excluded. Female 04 (19.0%) 7 (43.8%) c0.151 Patients who were included in this study were followed up for at Male 17 (81.0%) 9 (56.2%) least 3 months. Patients who were treated with an intravitreal injection of 0.05 ml CSC= central serous chorioretinopathy; IVB= intravitreal bevacizumab. a= Student’s t-test; b= Mann-Whitney U-test; c= Fisher’s exact test. (1.25 mg) of bevacizumab (Avastin®) were grouped as the IVB group, and patients who were only observed without any treatment were grouped as the control group. We administered IVB injections to the Table 2. The mean subfoveal choroidal thickness and the mean BCVA acute patients with CSC who were eager to receive this treatment at baseline and at the final visit for both groups due to occupational needs or excessive discomfort because of the decreased vision. IVB injection was performed through the pars plana IVB (n=21) Control (n=16) into the vitreous cavity under strict aseptic conditions. Eyes were mean ± SD (median) mean ± SD (median) p value injected less than 2 weeks after diagnosis in our clinic. The control BCVA group was observed without any treatment. a Subfoveal choroidal thickness (SFCT) measurements were obtained Baseline 0.49 ± 0.23 (0.50) 0.45 ± 0.21 (0.5) 0.709* by the EDI-OCT technique previously described by Spaide(18). SFCT Final 0.70 ± 0.26 (0.70) 0.86 ± 0.27 (1.0) a0.021* was defined as the vertical distance from the hyperreflective line of bp 0.001** 0.001** Bruch’s membrane to the inner surface of the observed sclera under Difference 0.22 ± 0.21 (0.20) 0.41 ± 0.31 (0.5) a0.046* the center of the fovea. Baseline and final SFCT measurements were obtained for the IVB and control groups. Final SFCT measurements logMAR BCVA for comparison between the groups were performed at the final visit Baseline 0.37 ± 0.24 (0.30) 0.39 ± 0.22 (0.3) a0.709* at the end of the follow-up period. Final 0.19 ± 0.21 (0.15) 0.10 ± 0.19 (0.0) a0.021* At all follow-up visits, patients were examined with slit-lamp bp 0.001** 0.001** examination and OCT. FA was performed at the discretion of the a examiner. The BCVA was obtained in all patients. Re-injection was Difference 0.17 ± 0.21 (0.11) 0.29 ± 0.27 (0.3) 0.110* performed in some of the patients if sustained, and reaccumulated SFCT subretinal fluid was associated with moderate-to-severe vision loss. Baseline 315.05 ± 56.96 (304.0) 306.69 ± 50.64 (303.5) c0.646* Re-injections were performed at least 2 months following the pri- Final 295.86 ± 52.95 (287.0) 265.69 ± 40.90 (254.5) c0.067* mary injection. dp 0.071 0.003** Statistical analysis Difference 019.19 ± 46.10 (011.0) 041.00 ± 46.92 (035.0) a0.290* Statistical analyses were performed using Number Cruncher BCVA= best-corrected visual acuity; IVB= intravitreal bevacizumab; logMAR= logarithm of Statistical System 2007 and Power Analysis and Sample Size 2008 the minimum angle of resolution; SFCT= subfoveal choroidal thickness. *= p<0.05; **= p<0.01. Statistical Software (Utah, USA). Visual acuity measurements were a= Mann-Whitney U-test; b= Wilcoxon signed-rank test; c= Student’s t-test; d= Paired converted into the logarithm of the minimum angle of resolution sample test.

Arq Bras Oftalmol. 2016;79(5):308-11 309 Subfoveal choroidal thickness change s after intravitreal bevacizumab therapy for central s erous chorioretinopathy

with verteporfin, and intravitreal injection of anti-VEGF agents, have been applied with variable success rates. In this study, we aimed to demonstrate the effect of IVB therapy on the choroid, which plays a vital role in the pathogenesis of CSC. There have been many theories concerning the pathogenesis of CSC. RPE dysfunction or defect has been blamed in the development of serous retinal detachment in CSC(22,23). Gass proposed that CSC was the result of choroidal vascular hyperpermeability(1). Later studies using ICGA supported the theory of Gass and demonstrated evi dence of hyperpermeability from the choriocapillaries(24,25). Increased hydrostatic pressure from choroidal vascular hyperpermeability may F igure 1. Baseline enhanced depth imaging spectral-domain optical coherence tomography imaging of a patient with acute central serous chorioretinopathy. The subfoveal cause leaks from the level of the RPE and subsequent serous retinal (25) choroidal thickness was 395 µm. detachment . Based on this knowledge, choroidal vascular abnormalities seem to play a key role in the pathogenesis of CSC as the underlying mechanism. Using EDI-OCT, Imamura et al., demonstrated the presence of a thick choroid in patients with CSC(9). Increased choroidal thickness in patients with unilateral CSC has been shown not only in the affected eyes but also in the unaffected fellow eyes(10). In the present study, the baseline mean SFCTs were 315 ± 57 µm in the IVB group and 307 ± 51 µm in the control group, which are greater than that of the normal population [unpublished data: we had previously evaluated 412 eyes of 206 normal Turkish subjects with a mean age of 45 years and found a mean SFCT of 254.4 ± 43.1 µm (range, 122-426 µm)], which supports the presence of a thick F igure 2. Final enhanced depth imaging spectral-domain optical coherence tomogra- choroid in patients with CSC. This finding is consistent with the results phy imaging of a patient with acute central serous chorioretinopathy. The subfoveal choroidal thickness was 328 µm. from a previous study by Kim et al., in which the SFCT of normal individuals was found to be 266 ± 55 µm(10). In the present study, after a mean follow-up period of 10 months, the mean SFCT decreased to 296 ± 53 and 266 ± 41 µm in the IVB and control groups, respectively, representative case at the baseline and final visits, respectively. All and the mean BCVA levels increased to 0.70 and 0.86 in the IVB and patients showed complete resolution of neurosensory detachment control groups, respectively. According to these results, better visual and improvement in vision at the final visit after the follow-up period. acuity is associated with thinner SFCT. This decrease can be interpre- In the IVB group, the mean SFCT was 315 ± 57 µm at the baseline ted as an approach toward the normal physiological state for SFCT, visit, which decreased to 296 ± 53 µm at the final visit after a mean which was associated with better visual acuity in the control group. follow-up period of 10.2 months. In the control group, the mean Bevacizumab is a full-length monoclonal antibody that selecti SFCT was 307 ± 51 µm at the baseline visit, which decreased to 266 ± vely bonds with VEGF. Since 2005, it has been used in ophthalmology 41 µm at the final visit after a mean follow-up period of 8.4 months. to treat various conditions, including neovascular age-related macu- The mean SFCT at the baseline and final visits did not significantly lar degeneration, diabetic macular edema, retinal vein occlusions, differ between the groups. Although there was a significant decrease and neovascular glaucoma(26). Variable outcomes have been reported in the mean SFCT for the control group, no significant decrease was on the use of bevacizumab in CSC(13,16), and the mechanism of action found for the IVB group (41 vs 19 µm, p=0.003 vs p=0.071). The mean of bevacizumab in CSC is unknown. Choroidal ischemia may cause BCVA levels in the IVB group at the baseline and final visits were 0.49 an increase in the concentration of VEGF and subsequent choroidal (logMAR 0.37) and 0.70 (logMAR 0.19), respectively. In contrast, the hyperpermeability, which results in a thickened choroid in CSC. At mean BCVA levels in the control group at the baseline and final visits this point, some benefits of an anti-VEGF agent may be proposed were 0.45 (logMAR 0.39) and 0.86 (logMAR 0.10), respectively. The on the basis of choroidal ischemia and hyperpermeability as the mean BCVA at the baseline visit was similar for both groups, and pathogenesis of CSC(12-14). However, no studies have demonstrated the mean BCVA increased significantly in both groups (p=0.001). an increased level of VEGF in CSC until now. Conversely, Lim et al., However, the increase in the mean BCVA was significantly greater for repor ted no significant difference in the VEGF levels in the aqueous the control group (0.41; logMAR 0.29) than for the IVB group (0.22; humor of patients with CSC compared with a control group(27). In logMAR 0.17; p<0.05 for BCVA), and the mean final BCVA of the con- addition, the optimal dosage of IVB for CSC has not been formally trol group was significantly greater than that of the IVB group [0.86 evaluated. We have used a dosage of 1.25 mg in 0.05 ml, which is the (logMAR 0.10) vs 0.70 (logMAR 0.19 p<0.05]. typical dosage of bevacizumab used in other well-studied disease Twenty-eight patients (76%) had total and nine patients (24%) states(28-29). Furthermore, there are still some controversies about the had near-total resolution of subretinal fluid at the end of the acute nature of the disease. It is not yet understood whether the resolution CSC episode; only 12 of 16 patients (75%) in the observation group of subretinal fluid is due to IVB or the natural history of the disease. had complete resolution, and only 16 of 21 patients (76%) in the IVB In the present study, the effect of bevacizumab injection was not group had complete resolution. The resolution rates were similar in promising compared with observation in terms of the functional and both groups, and re-injection was performed on five patients in the structural outcomes. This finding supports the literature, which indi- IVB group (n=21). No treatment complications were observed during cates no beneficial effect of anti-VEGF agents in CSC(16). the follow-up period. Since the introduction of EDI-OCT by Spaide et al., this technique has been used by many authors to evaluate the choroidal thickness in various diseases and conditions such as age-related macular dege DISCUSSION neration, high myopia, and CSC(9,18). Increased choroidal thickness No established treatment modalities exist for CSC. Various treat- was demonstrated in both eyes of patients with unilateral active ments, including topical or systemic carbonic anhydrase inhibitors, CSC(10), and changes in choroidal thickness have been shown to be laser photocoagulation to the leaking site, photodynamic therapy closely related to choroidal vasculature(30). However, it remains unclear

310 Arq Bras Oftalmol. 2016;79(5):308-11 Ünlü C, e t a l .

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Arq Bras Oftalmol. 2016;79(5):308-11 311 Original Article

Comparison of central corneal thickness estimated by an ultrasonic pachymeter and non-contact specular microscopy Comparação da espessura central de córnea estimada por um paquímetro ultrassônico e por um microscópio especular sem contato

Sadık Görkem Çevik1, Rahmi Duman2, Mediha Tok Çevik3, Sertaç Argun Kıvanç4, Berna Akova-Budak4, Irfan Perente5, Resat Duman2

ABSTRACT RESUMO Purpose: To compare central corneal thickness (CCT) measurements of healthy Objetivo: Comparar as medidas de espessura central corneana (CCT) de indivíduos individuals obtained with ultrasonic pachymetry (UP) and non-contact specular saudáveis obtidos pela paquimetria ultrassônica (UP) e microscopia especular sem microscopy (NCSM). contato (NCSM). Method: In total, 148 eyes of 74 subjects with no ocular or systemic diseases Método: Cento e quarenta e oito olhos de 74 indivíduos que não tinham doenças were included in the study. Central corneal thickness measurements of all patients oculares ou sistêmicas foram incluídos no estudo. Medidas da espessura central performed with UP and NCCM were compared. corneana de todos os pacientes foram comparadas entre UP (SP 100, Tomey, Nagoya, Japão) e do NCSM (NSP-9900, Konan Medical, Inc., Hyogo, Japão). Results: A total of 74 subjects (38 females) were included in this study. The mean age was 45.2 ± 18.4 (range 12-85) years. The mean central corneal thickness of all Resultados: Um total de 74 indivíduos (38 mulheres) foram incluídos neste estudo. 148 eyes was 546.9 ± 40 μm with UP and 510.8 ± 42 μm with NCSM. The mean A idade média foi de 45,2 ± 18,4 (variação 12-85) anos. A medida média da espessura central corneal thickness measured with NCSM was 35 μm thinner than that central corneana de todos os 148 olhos foi 546,9 ± 40 μm com UP e 510,8 ± 42 μm com NCSM. A espessura central corneana média avaliada pelo NCSM foi de 35 μm measured with UP (p<0.001). A high degree of agreement was found between mais fina do que a UP (p<0,001). Foi encontrado um elevado grau de concordância the two methods (r=0.942, p<0.001). entre os dois métodos (r=0,942, p<0,001). Conclusions: Our results suggest that NCSM measures thinner corneas than UP Conclusões: Nossos resultados sugerem que a microscopia especular sem contato and that the correction formula we identified should be applied when comparing mede córneas mais finas em comparação com a UP e que o fator de correção identi between these two devices. ficado deve ser aplicado ao fazer comparações entre esses dois aparelhos. Keywords: Cornea/pathology; Corneal pachymetry; Microscopy/methods; Cornea/ Descritores: Córnea/patologia; Paquimetria corneana; Microscopia/métodos; Cór anatomy & histology; Comparative study nea/anatomia & histologia; Estudo comparativo

INTRODUCTION 2015. Full ophthalmological examination was performed before The measurement of central corneal thickness plays an important measuring pachymetry. The patients with ocular diseases (corneal role in the prognosis and treatment of many corneal diseases and scar, cataract, glaucoma and keratoconus, or retinal disease), history glaucoma. It is also critical for refractive surgery management(1,2). of contact lens wear, dry eye, any systemic diseases, or a history of Central corneal thickness (CCT) can be measured using an ultrasonic previous ocular surgery were excluded from the study. Patients with pachymeter (UP) or with specular microscopy, corneal topography best-corrected visual acuity of 20/20 were included. screening, confocal microscopy, optical coherence tomography, In order to avoid the potential effect of epithelial compression and the Scheimpflug imaging method(3). Many modern contact and on consecutive measurements at the same location, CCT measure- non-contact pachymetry measurement methods have been descri- ments were first taken via non-contact specular microscope NSP-9900 bed; however, UP is still considered the gold standard(4). (Konan Medical, Inc., Hyogo, Japan). At the second stage of the study, In this study, we aimed to compare CCT of healthy individuals mea CCT measurement was performed using an ultrasound pachymeter sured by UP and non-contact specular microscopy (NCSM) and to SP-100 (Tomey, Nagoya, Japan), which operates at 20 MHz, for mea determine the average difference between the two measurements. suring thicknesses in the range of 150 to 1200 μm with calibration at speeds ranging from 1400 to 2000 m/s(5). Topical anesthetic drops (0.5% proparacaine hydrochloride Alcaine®, Alcon) were instilled in METHODS all patients 1.5 to 2 minutes(6) before UP measurements. We evaluated 148 eyes from 74 healthy subjects who consented NCSM and UP measurements were taken three times in the center to participation in this study. The study was conducted in the Şevket of the cornea. For both measurements, average values were taken to Yılmaz Training and Research Hospital between March, 2015 and June, compare pachymetry values.

Submitted for publication: August 4, 2015 Funding: No specific financial support was available for this study. Accepted for publication: May 20, 2016 Disclosure of potential conflicts of interest: None of the authors have any potential conflict of 1 Department of Ophthalmology, Şevket Yılmaz Education and Training Hospital, Bursa, Turkey. interest to disclose. 2 Department of Ophthalmology, Kocatepe University, Afyon, Turkey. 3 Corresponding author: Sadık Görkem Çevik. Şevket Yılmaz Education and Training Hospital. Bursa Department of Ophthalmology, Düziçi State Hospital, Osmaniye, Turkey. 16310 - Turkey - E-mail: [email protected] 4 Department of Ophthalmology, Uludag University, Bursa, Turkey. 5 Department of Ophthalmology, Beyoglu Goz Education and Training Hospital, Istanbul, Turkey. Approved by the following research ethics committee: Şevket Yılmaz Training and Research Hos pital (#2015/13-05).

312 Arq Bras Oftalmol. 2016;79(5):312-4 http://dx.doi.org/10.5935/0004-2749.20160089 Çevik SG, et al.

All measurements were taken by one of the two authors (SGÇ or RD) DISCUSSION in the afternoon, between 14:00 and 16:00 during a single visit. The stu- CCT is a parameter that has a very wide range of applications for dy was planned and conducted in accordance with the Helsinki De- diagnosis and treatment of ocular diseases. In particular, when con claration. A patient consent form was obtained from all participants. sidering the clinical impact of the smallest changes in refractive sur gery and glaucoma follow-up, the importance of measuring CCT in Statistical analysis the most reliable way cannot be understated(1,4,7). Descriptive statistics included mean, standard deviation, minimum Although UP is the gold standard method, several non-contact values, and maximum values. The distribution of the variables was measurement methods are sometimes preferred to ensure accurate measured with the Kolmogorov Simirnov test. In the analysis of the measurement, need for contact with the cornea, and the capability to repeated measurements, a Wilcoxon test was used. A chi square test make measurements on multiple areas simultaneously(8,9). On the other was utilized in the analysis of qualitative data. When chi square test hand, UP is currently the cheapest and most widely used method for conditions were not met a Fischer test was applied. Intra-class analysis CCT measurement. In this study, we compared UP, which only measures was undertaken for correlation. The changes across measurements corneal thickness, and NCSM, which has the capacity to evaluate the were assessed using Bland-Altman graphics. For the analyses, the SPSS endothelium and measure CCT at the same time. 22.0 program was used. There are many studies in the literature comparing CCT measu rements methods and devices for normal corneas. Most of these studies reported that UP measurements were thicker than NCSM RESULTS measurements(10-13). Modis et al. examined 73 eyes from 44 patients One hundred and forty-eight eyes from 74 patients (36 (49%) (mean age 66 years) with normal corneas comparing three different males, 38 (51%) females) were assessed in this study. The mean age devices: NCSM (Topcon SP-2000P; Topcon Corporation, Tokyo, Japan), of participants was 45.2 ± 18.4 (12-85) years. The mean CCT measu- UP (AL-1000; Tomey, Erlangen, Germany), and contact specular mi- rement of all 148 eyes was 546.9 ± 40 μm with UP and 510.8 ± 42 μm croscope (CSM) (EM-1000; Tomey, Tokyo, Japan). The normal mean CCT was measured as 542 ± 46 µm with NCSM, 570 ± 42 µm with with NCSM. Ultrasonic pachymetry and NCSM measurement results UP, and 638 ± 43 µm with CSM. The NCSM measurement was found were around the equality line shown in figure 1. The mean CCT was to be significantly lower than the UP measurement(10). Al-Ageel and 35 μm thicker in the UP group and the difference between groups Al Muammar reported that CCT was significantly thinner when mea was statistically significant (p<0.001). sured with specular microscope (SM) (511.9 ± 38.6) (SP-2000P, Topcon Among the 148 eyes, corneal thickness measured with NCSM Corporation, Tokyo, Japan) than when measured with UP (533.3 ± and UP devices showed significant and strong correlation (r=0.942/ 37.9) (SP-3000, Tomey Corporation, Nagoya, Japan) and that the two p<0.001). In all 148 eyes, the NCSM device measured corneal thickness instruments were in good correlation while measuring 94 normal as significantly (p<0.001) more thin than the UP device. eyes of 47 patients, with a mean age of 33 years(12). In a multicenter The equation, y=32.2 + 0.99x (R²=0.887), was attained via a re study in Japan, both Orbscan and UP measurements were significan- gression model according to the CCT measurements with NCSM tly higher than NSCM (SP-2000P, Topcon Corporation, Tokyo, Japan) (x) and UP (y). The assumption that the values taken with the NCSM measurements and ultrasonic pachymetry correlated with NCSM(13). device will be 32 units lower than the UP per measurement has been In contrast, Khaja et al. reported lower values when comparing mea- proven to be a strong premise. Figure 2 presents the Bland-Altman surements made by UP vs. SM. The authors compared CCT measure- plot demonstrating good agreement between the UP and NCSM ments of 4 different devices in 32 healthy eyes of 32 subjects (mean methods for measurement of CCT. age: 31 years). The authors compared, UP, slit-lamp optical coherence

F igure 1. Scatter plots between central corneal thickness measurements (microns) F igure 2. Bland-Altman plot showing the correlation between central corneal thickness acquired with non-contact specular microscope NCSM and ultrasound pachymetry (microns) acquired with non-contact specular microscope NCSM and ultrasound (UP) showing a linear regression of y=31.22 + 0.99x. pachymetry (UP).

Arq Bras Oftalmol. 2016;79(5):312-4 313 Comparison of c entral c orneal thi ckness estimated by an ultrasonic pa chymeter and non-c ontact spe cular mi croscopy

tomography (OCT), SM (Konan Medical Corporation, Fairlawn, NJ, evaluate CCT and intraocular pressure (IOP) from the former CCT and USA), and Orbscan, and found that the mean CCT was 557 ± 49.92 µm IOP history. As mentioned by Bourges et al.(21), we also believe that on SM and 548 ± 48.68 µm on UP. However, they did not find this diffe- reproducibility and interchangeability in methods without contact to rence significant. This was in contrast with our findings, although it is the cornea, in relation to ultrasound pachymetry, may allow for the possible that our studies limited sample size may have influenced our non-contact devices to become gold standards for measuring CCT. findings. It has also been reported that UP correlates with SM(14). Wu et al. measured the CCT of 322 eyes in 173 normal subjects using the Konan non-contact specular microscope to determine whether this method REFERENCES was reliable or not and was able to confirm this method’s efficacy(15). 1. Doughty MJ, Zaman ML. Human corneal thickness and its impact on intraocular pressure measures: A review and meta-analysis approach. Surv Ophthalmol. 2000;44(5): Differences in measurement between UP and NCSM devices may be 367-408. caused by the different working systems of each device. In cases of 2. Ge L, Yuan Y, Shen M, Tao A, Wang J, Lu F. The role of axial resolution of optical cohe- ultrasound pachymetry, the exact posterior corneal reflection point is rence tomography on the measurement of corneal and epithelial thicknesses. Invest not known; it may be located between the Descemet membrane and Ophthalmol Vis Sci. 2013 28;54(1):746-55. the anterior chamber(16). One other factor potentially influencing CCT 3. Çakıcı Ö. Santral corneal kalınlıgının klinik önemi ve santral kornea kalınlıgI ölçüm measurement is tear film. Some authors have claimed that tear film yöntemlerinin karsılastırılması. J Clin Exp Invest. 2014;5(1):153-8. 4. Lackner B, Schmidinger G, Pieh S, Funovics MA, Skorpik C. Repeatability and repro- thickness might be added into corneal thickness when non-contact ducibility of central corneal thickness measurement with Pentacam, Orbscan, and optical devices measure CCT; however, tear film is compressed by ultrasound. Optom Vis Sci. 2005;82(10):892-9. the pachymeter probe when using UP(17-19). Reproducibility of the 5. Queirós A, González-Méijome JM, Fernandes P, Jorge J, Almeida JB, Parafita MA. Accu- applications is also important, and some studies have shown that the racy and repeatability of a new portable ultrasound pachymeter. Ophthalmic Physiol reproducibility of the optical devices is high(20,21). However, with UP, Opt. 2007;27(2):190-3. it is difficult to maintain the same points and the perpendicularity of 6. Nam SM, Lee HK, Kim EK, Seo KY. Comparison of corneal thickness after theinstillation of topical anesthetics: proparacaine versus oxybuprocaine. Cornea. 2006;25(1):51-4. the ultrasound probe in sequential measurements. 7. Shetgar AC, Mulimani MB. The central corneal thickness in normal tension glaucoma, Measuring corneal thickness remains a challenge for several primary open angle glaucoma and ocular hypertension. J Clin Diagn Res. 2013;7(6): devices and methods. In one study, De Bernado et al. using Topcon 1063-7. SP3000 specular microscopy, recorded thinner measurements than 8. Marsich MW, llimore MA. The repeatability of corneal thickness measures. Cornea. 2000; an Oculus Pentacam(22). In another study, the Pentacam and SP2000P 19(6):792-5. Topcon NCSM were compared and the measurements obtained with 9. Miglior S, Albe E, Guareschi M, Mandelli G, Gomarasca S, Orzalesi N. Intraobserver and interobserver reproducibility in the evaluation of ultrasonic pachymetry measure the SP2000P were significantly smaller than those obtained with ments of central corneal thickness. Br J Ophthalmol. 2004 88(2):174-7. (19) the Pentacam . Fujioka et al. compared the Pentacam with NCSM 10. Módis L Jr, Langenbucher A, Seitz B. Corneal thickness measurements with contact (Noncon Robo; Konan medical, Japan). Measurements taken with and noncontact specular microscopic and ultrasonic pachymetry. Am J Ophthalmol. NCSM (552.04 ± 42.95 µm) were significantly smaller than those 2001;132(4):517-21. obtained with the Pentacam (559.49 ± 38.44 µm)(23). Other studies 11. Bovelle R, Kaufmann SC, Thompson HW, Hamano H. Corneal thickness measurements with the Topcon SP-2000P specular microscope and an ultrasound pachymeter. Arch have measured CCT with the Konan NCSM; however, to the best of our Ophthalmol. 1999;117(7):868-70. knowledge this study examines the greatest number of healthy eyes 12. Al-Ageel S, Al-Muammar AM. Comparison of central corneal thickness measurements while comparing CCT measurements for UP and NCSM. by Pentacam, noncontact specular microscope, and ultrasound pachymetry in normal In this study, one of the aims was to provide a regression formula to and post-LASIK eyes. Saudi J Ophthalmol. 2009;23(3-4):181-7. translate one measurement into another. We detected a strong and 13. Suzuki S, Oshika T, Oki K, Sakabe I, Iwase A, Amano S, et al. Corneal thickness mea- meaningful correlation between NCSM and the gold standard, UP. surements: scanning-slit corneal topography and noncontact specular microscopy versus ultrasonic pachymetry. J Cataract Refract Surg. 2003;29(7):1313-8. We found a difference of 32 units between measurements of the two 14. Khaja WA, Grover S, Kelmenson AT, Ferguson LR, Sambhav K, Chalam KV. Comparison devices, which may exist on the grounds of the change in possible of central corneal thickness: ultrasound pachymetry versus slit-lamp optical coheren- reference points. We also think that a regression model can be used ce tomography, specular microscopy, and Orbscan. Clin Ophthalmol. 2015;9:1065-70. to convert the measurements of both devices and thus established 15. Wu Q, Duan X, Jiang Y, Qing G, Jiang B, Shi J. [Normal value of the central corneal the equation y=32.2 + 0.99x. This conversion may help assess patients thickness measured by non-contact specular microscope]. Yan Ke Xue Bao. 2004; who are referred to a clinic that uses a different measurement device 20(4):229-32. Chinese. 16. Nissen J, Hjortdal JO, Ehlers N, Frost-Larsen K, Sørensen T. A clinical comparison of (e.g., UP is used and NCSM measurements from other clinic have to optical and ultrasonic pachometry. Acta Ophthalmol Scan. 1991;69(5):659-63. be converted). However, this does not mean that these measurement 17. Kim HY, Budenz DL, Lee PS, Feuer WJ, Barton K. Comparison of central corneal thickness methods are interchangeable. Bourges et al. reported that non-contact using anterior segment optical coherence tomography vs ultrasound pachymetry. Am methods are reproducible and interchangeable with each other; J Ophthalmol. 2008;145(2):228-32. however, interchangeability with UP has been found to be limited(21). 18. Bayhan HA, AslanBayhan S, Can I. Comparison of central corneal thickness measurements with three new optical devices and a standard ultrasonic pachymeter. Int J In conclusion, in this study we obtained thinner CCT measure- Ophthalmol. 2014;7(2):302-8. ments with NCSM compared to UP, widely regarded to be the gold 19. Uçakhan OO, Ozkan M, Kanpolat A. Corneal thickness measurements in normal and standard. We think the differences between the devices is due to the keratoconic eyes: Pentacam comprehensive eye scanner versus noncontact specular different reference points these devices use for the measurements. microscopy and ultrasound pachymetry. J Cataract Refract Surg. 2006;32(6):970-7. In addition, the impact of the drops used for anesthesia and the refe- 20. Muscat S, McKay N, Parks S, Kemp E, Keating D. Repeatability andreproducibility of rence points taken from the posterior cornea for the measurements corneal thickness measurements by optical coherence tomography. Invest Ophthal- mol Vis Sci. 2002;43(6):1791-5. could not be precisely explained. 21. Bourges JL, Alfonsi N, Laliberté JF, Chagnon M, Renard G, Legeais JM, et al. Average These results confirm that SM measures significantly thinner 3-dimensional models for the comparison of Orbscan II and Pentacam pachymetry corneas compared to UP. This could be due to the fact that the two maps in normal corneas. Ophthalmology. 2009;116(11):2064-71. machines measure different corneal points. This means that it is 22. De Bernardo M, Borrelli M, Mariniello M, Lanza M, Rosa N. Pentacamvs SP3000P hard to estimate which of the two systems generates more accurate specular microscopy in measuring corneal thickness. Cont Lens Anterior Eye. 2015; results in finding the closest value to the real value of CCT. The re- 38(1):21-7. 23. Fujioka M, Nakamura M, Tatsumi Y, Kusuhara A, Maeda H, Negi A. Comparison of Pen- gression formulas given in this study could help more easily translate tacam Scheimpflug camera with ultrasound pachymetry and noncontact specular one measurement into another and this helps us to compare and microscopy in measuring central corneal thickness. Curr Eye Res. 2007;32(2):89-94.

314 Arq Bras Oftalmol. 2016;79(5):312-4 Original Article

Is there a relationship between outer retinal destruction and choroidal changes in cone dystrophy? Existe uma relação entre a destruição da retina externa e alterações da coroide em distrofia de cones?

Onder Ayyildiz1, Gokhan Ozge1, Murat Kucukevcilioglu1, Cem Ozgonul2, Tarkan Mumcuoglu1, Ali Hakan Durukan1, Fatih Mehmet Mutlu1

ABSTRACT RESUMO Purpose: The aim of the present study was to use enhanced depth imaging Objetivo: O objetivo deste estudo foi a utilização de imagens de tomografia de optical coherence tomography (EDI-OCT) to investigate choroidal changes in coerência óptica com profundidade aprimorada (EDI-OCT) para investigar alte patients with cone dystrophy (CD) and to correlate these findings with clinical rações da coroide em pacientes com distrofia de cones (CD) e correlacionar esses and electroretinography (ERG) findings. achados com os achados clínicos e de eletrorretinografia (ERG). Methods: This case-control study included 40 eyes of 20 patients with CD Métodos: Este estudo de caso-controle incluiu 40 olhos de 20 pacientes com and 40 eyes of 40 age- and refraction-matched healthy individuals. Choroidal CD e 40 olhos de 40 indivíduos saudáveis com idades e refração pareados. As thickness (CT) measurements were obtained under the foveal center and at 500 medidas da espessura da coroide (CT) foram obtidas sob o centro foveal e a and 1,500 µm from the nasal and temporal regions to the center of the fovea, 500 µm e 1.500 µm de distância do centro da fóvea, nas regiões nasais e tem- respectively. EDI-OCT and ERG data were analyzed, and the correlations of CT porais. Dados de EDI-OCT e ERG foram analisados e as correlações do CT com with the best-corrected visual acuity (BCVA) and the central foveal thickness a acuidade visual melhor corrigida (BCVA) e da espessura foveal central (CFT) (CFT) were evaluated. foram realizadas. Results: The mean subfoveal CTs in the CD and control groups were 240.70 ± 70.78 Resultados: As CTs subfoveais médias nos grupos CD e controle foram 240,70 ± and 356.18 ± 48.55 µm, respectively. The subfoveal CT was significantly thinner 70,78 µm e 356,18 ± 48,55 µm, respectivamente. A CT subfoveal foi significativa- in patients with CD than in the controls (p<0.001). The patients with CD also had mente mais fina em pacientes com CD do que nos controles (p<0,001). Os com significantly thinner choroids than the controls at each measurement location CD pacientes apresentaram também coroides significativamente mais finas do relative to the fovea (p<0.001). The subfoveal CT in the CD group correlated with que os controles, em cada local de medição em relação à fóvea (p<0,001). A CT CFT (p=0.012), but no significant correlation was found between the subfoveal subfoveal no grupo CD se correlacionou com o CFT (p=0,012), mas nenhuma CT and BCVA or photopic ERG responses. correlação significativa foi encontrada entre a CT subfoveal e a acuidade visual Conclusions: The present study demonstrated a significant thinning of the ou respostas fotópicas da ERG. choroid in patients with CD. EDI-OCT is a useful technique for describing the Conclusões: O presente estudo demonstrou um afinamento significativo da choroidal changes occurring in CD. Future studies investigating the association coroide em pacientes com CD. A EDI-OCT é uma técnica útil para descrever as between choroidal changes and outer retinal destruction or the disease stage mudanças que ocorrem na coroide de pacientes com CD. Futuros estudos in may provide a better understanding of the pathophysiology of CD. vestigando a associação entre as alterações da coroide e a destruição da retina externa ou estágio da doença irão proporcionar uma melhor compreensão da fisiopatologia da CD. Keywords: Choroid; Fovea centralis; Retinal dystrophies; Retinal cone photore- Descritores: Coroide; Fóvea central; Distrofias retinianas; Células fotorreceptoras ceptor; Tomography, optical coherence; Electroretinography retinianas cones; Tomografia de coerência óptica; Eletrorretinografia

INTRODUCTION for cone dysfunction(2). The retinal pathology of CD occurs mainly Cone dystrophy (CD) is an inherited retinal disease characterized between the photoreceptor outer segment and retinal pigment epi by the deterioration of the cone cells responsible for central and color thelium (RPE) layer(1). Alterations in the retinal structure were pre vision(1). Progressive vision loss, decreased color vision, photophobia, viously demonstrated in patients with CD using spectral-domain and nystagmus are common clinical features of CD. Full-field electro- optical coherence tomography (SD-OCT)(3), and some investigators retinography (ERG) reveals reduced single and flicker cone responses have observed reduced neuroretinal thickness in the fovea centralis under photopic conditions and normal rod responses under scotopic and macula using SD-OCT(3). Enhanced depth imaging (EDI) is a tech conditions. ERG is a more sensitive technique and can be used to diag- nique that can be utilized to examine both the retina and choroid nose CD earlier than is possible using current diagnostic techniques(1). using specific focusing techniques and an SD-OCT device(4). Images A variety of mechanisms, such as defective outer segment mor- acquired with EDI-OCT not only have an improved ability to visualize phogenesis, protein transport along the cilium, phototransduction, the deeper ocular structures and the choroid; they also allow the or cellular interaction, have been suggested as being responsible thickness and contour of the choroid to be assessed(5).

Submitted for publication: February 17, 2016 Funding: No specific financial support was available for this study. Accepted for publication: April 14, 2016 Disclosure of potential conflicts of interest: None of the authors have any potential conflicts of 1 Department of Ophthalmology, GATA Medical School, Ankara, Turkey. interest to disclose. 2 Department of Ophthalmology, Van Military Hospital, Van, Turkey. Corresponding author: Onder Ayyıldız. Department of Ophthalmology. GATA Medical School. Ankara 06010 - Turkey - E-mail: [email protected] Approved by the following research ethics committee: GATA Medical School (# 2015-KAEK-45).

http://dx.doi.org/10.5935/0004-2749.20160090 Arq Bras Oftalmol. 2016;79(5):315-8 315 Is there a relationship between outer ret inal destruction and choroidal changes in cone dystrophy ?

Most inherited retinal dystrophies lead to damage of the outer retinal structures and RPE. Several studies have demonstrated that a loss of photoreceptor and RPE cells leads to secondary choroidal thinning and atrophy(4,5). The pathogenesis of photoreceptor cell deterioration and RPE dysfunction in CD remains unclear, and knowledge on the changes in the choroid in retinal dystrophies is limited. To the best of our knowledge, no published study has yet examined the choroidal A alterations in a large group of patients with CD using EDI-OCT. The aims of this case-control study were to image and describe the choroidal changes occurring in patients with CD using EDI-OCT, to compare the results with those from age- and refraction-matched healthy controls, and to correlate these outcomes with the best-cor rected visual acuity (BCVA) and ERG responses.

METHODS B This diagnostic case-control study was approved by the insti tutional review board at GATA Medical School (# 2015-KAEK-45) F igure 1. Measurement of choroidal thickness with enhanced depth imaging optical and was performed at GATA Medical School between March and coherence tomography. The upper yellow line indicates the retinal pigment epithelium/ December 2015. Informed consent was obtained from each subject, Bruch’s membrane interface, and the lower yellow line indicates the sclerochoroidal and all study procedures adhered to the tenets of the Declaration interface. (A) Healthy control with a choroid of normal thickness and (B) cone dystrophy patient with choroidal thinning. of Helsinki. Twenty patients with CD were enrolled, and 40 healthy age- and refraction-matched volunteers without CD or other ocular diseases were included for comparison purposes as a control group. Data recorded for all subjects included Snellen BCVA, intraocular ± 11.14 years (range, 18-55 years); the mean spherical equivalent pressure, biomicroscopy, fundoscopy, refractive error, and EDI-OCT (SE) was -0.70 ± 1.67 diopters (range, -3.50 to +2.50); and the mean (Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany) fin- BCVA was 0.27 ± 0.19. All patients were phakic with clear lenses. The dings as well as demographic data such as age and sex. The diagnos- control group included 40 individuals (21 men and 19 women; 40 tic criteria for CD were as follows: decreased cone cell function with eyes) with no abnormalities of the anterior segment and fundus. The relatively normal rod cell function in full-field ERG (RetiScan System; Roland Consult, Wiesbaden, Germany); a history of progressive visual mean age in the control group was 24.50 ± 3.50 years (range, 18-32 loss, photophobia, nystagmus, or poor color vision; and fundoscopic years); the mean SE was 0.06 ± 0.82 diopters (range, -1.50 to +1.25); findings in the macula with non-specific changes to the characteristic and the mean BCVA was 0.95 ± 0.07. The study group and the control RPE lesions of the bull’s eye and reduced neuroretinal thickness in the group differed significantly in terms of BCVA (p<0.001), whereas the fovea and macula in OCT. All patients with CD underwent color vision age and SE differences were not statistically significant (p=0.74 and testing and full-field standard ERG. Some of the patients with CD also p=0.12, respectively; Table 1). underwent visual field testing, fluorescein angiography, and fundus The mean CFT measured 152.58 ± 57.14 µm in the CD group and autofluorescence imaging. 219.35 ± 14.74 µm in the control group. CFT was significantly thinner All subjects were examined using EDI-OCT imaging with pupil in patients with CD than in controls (p<0.001; Table 1). In addition dilation. All EDI-OCT images were obtained by the same experienced to the significant difference in CFT between the groups, the mean technician in ambient lighting in the afternoon. The OCT device was subfoveal CTs in the CD and control groups were 240.70 ± 70.78 and positioned sufficiently close to the eye to obtain an inverted image. 356.18 ± 48.55 µm, respectively. The subfoveal CT was also significan- Each section was obtained using automatic eye-tracking software, tly thinner in patients with CD than in controls (p<0.001; Figure 2). and 100 averaged images were taken to improve the signal-to-noise The CT measurements taken at 1,500 and 500 µm from the nasal ratio. A horizontal image across the fovea was obtained for each region, and 500 and 1,500 µm from temporal region to the center of subjec t. The choroidal thickness (CT) measurement was performed the fovea were, respectively, 190.80 ± 79.17, 235.68 ± 77.66, 243.48 manually in a vertical direction from RPE/Bruch’s membrane interface ± 72.24, and 221.13 ± 63.14 µm in the CD group and 325.18 ± 54.28, to the sclerochoroidal interface (Figure 1). The choroid was indepen- 336.70 ± 43.31, 330 ± 55.38, and 372.38 ± 41.83 µm in the control dently measured by two blinded observers (OA and GO) at the foveal group (Figure 2). The patients with CD had significantly thinner CTs center and at 500 and 1,500 µm from the nasal and temporal regions compared with the controls at each measurement location relative to the center of the fovea, respectively. The measurement locations to the fovea (p<0.001). were determined according to the cone cell density in the retina(6). The mean BCVAs for the CD and control groups were 0.27 ± 0.19 Data analysis was performed using SPSS for Windows 16.0 softwa- and 0.95 ± 0.07, respectively (p<0.001). Best corrected visual acuity re package (SPSS, Inc., Chicago, IL, USA). The data were expressed as correlated weakly with CFT in the CD group (Pearson’s r=0.552, percentage values or as group mean and standard deviation values. p<0.001) and no correlation was found between BCVA and other fac- The t-test was used to compare continuous variables with normal dis- tors, such as the subfoveal CT and photopic ERG responses (Table 2). In tribution, and the Mann-Whitney U-test was used to compare non- the same group, subfoveal CT correlated weakly with CFT (Pearson’s normally distributed continuous variables. The chi-square test was r=-0.396, p=0.012) and no significant correlation was found between used for the comparison of discrete variables. Pearson correlations the subfoveal CT and BCVA or the photopic ERG responses. were performed to explore the correlations among BCVA, central foveal thickness (CFT), subfoveal CT, and photopic ERG responses in DISCUSSION the CD group. A p-value<0.05 was accepted as statistically significant. Previous histopathological studies have established choriocapillaris degeneration, photoreceptor loss, and RPE deterioration in RESULTS eyes with various dystrophies(7,8). The photoreceptor layer and RPE are A total of 20 patients (12 men and 8 women; 40 eyes) with a the major sites of structural impairment as discerned by SD-OCT in diagnosis of CD were included in the study. The mean age was 28 patients with CD. Some investigators have observed reduced neuro-

316 Arq Bras Oftalmol. 2016;79(5):315-8 Ayyildiz O, e t a l .

Table 1. Characteristics of the individuals retinal structures in the fovea show a smaller reduction in the retinal (3) Cone dystrophy (n=20) Control (n=40) p value thickness and better VA . In this case-control study, the patients with CD demonstrated sig- Age (years) 28.00 ± 11.14 024.80 ± 03.50 0.740 nificantly thinner CTs than healthy controls at each measurement lo- Gender (M/F) 12/8 21/19 0.460 cation relative to the fovea. The significance of the choroidal thinning Visual acuity 0.27 ± 00.19 000.95 ± 00.07 <0.001 observed in CD is unclear. It may be related to the characteristic pho- SE (Dpt) -0.70 ± 01.67 000.06 ± 00.82 0.120 toreceptor degeneration of CD, which could cause choroidal thinning. A similar thinning of the choroid has been reported in patients Photopic A Amp (mV) 9.72 ± 07.01 N/A N/A with other inherited retinal dystrophies and in animal models(4,5,10). Photopic B Amp (mV) 28.49 ± 21.77 N/A N/A Destruction of the RPE cells has been reported in animal models 30 Hz Amp (mV) 6.01 ± 05.64 N/A N/A of disease responsible for secondary choriocapillaris atrophy(5,11). A CFT (µm) 152.58 ± 57.14 216.35 ± 14.74 <0.001 requirement for vascular endothelial growth factor, which is produced by RPE cells, has been demonstrated for choroidal maintenance; M= male; F= female; SE= spherical equivalent; Dpt= diopter; Amp= amplitude; Photopic (4,12) A= electroretinogram photopic A wave; Photopic B= electroretinogram photopic B wave; therefore, this growth factor may play a role in choroidal thinning . 30 Hz= electroretinogram 30-Hz wave; N/A= not applicable; CFT= central foveal thickness. The retinas, and especially the photoreceptor cells, are the most metabolically active tissues in the body, and their oxygen consumption is faster than that seen in other tissues(13). Progressive destruction of the outer segment of the retina in retinal dystrophies may reduce the demand for oxygen and other metabolic nutrients. Impaired oxygenation and a reduced nutrient supply may thus contribute to the reduction in retinal and choroidal blood flow. Reductions in retinal and choroidal circulation and volume have previously been shown to occur in hereditary retinal disorders and in animal models of disease(4,14,15). Consequently, the choroidal thinning observed in our patients may be a manifestation of decreased choroidal blood flow and may indicate reduced oxygen dependence in the retina. We found no significant correlation between BCVA and subfoveal CT in the patients with CD in our study. Previous studies that examined the choroid using EDI-OCT for a variety of other inherited retinal disorders also revealed no relationship between choroidal thinning and BCVA(4,5,7). Interestingly, the subfoveal CT correlated with CFT in the current study. On the contrary, Dhoot et al.(4) and Yeoh et al.(5) found no F igure 2. The mean CT measurements. The mean CTs in the CD group were significantly (5) thinner in each measurement location than those in the control group (p<0.001). CD= correlation between CT and CFT. Yeoh et al. reported alterations in cone dystrophy; CT= choroidal thickness; SCT= subfoveal choroidal thickness; 500 and the choroid in eyes with inherited retinal disorders, and they analyzed 1,500 N= choroidal thickness 500 and 1,500 µm from the nasal region to the center of CT with focal retinal thinning using EDI-OCT; however, they did not the fovea, respectively; 500 and 1,500 T= choroidal thickness 500 and 1,500 µm from correlate the results with those of age-matched healthy controls. In the the temporal region to the center of the fovea, respectively. present study, we determined a diffuse thinning of the choroid and a break of the choroidal contour in relation to the outer retinal damage in patients with CD; these features were correlated with CFT. In CD, only the cone responses are diminished in the standard Table 2. Pearson correlations in the cone dystrophy group (p values) full-field ERG. ERG is more sensitive and can be used to diagnose CD Photopic Photopic 30 Hz earlier than is possible with current SD-OCT techniques(1). Cho et al.(1) BCVA CFT SCT A Amp B Amp Amp reported a correlation between central retinal thinning and BCVA as BCVA 1 <0.001 0.770 0.180 0.23 0.77 well as the electrophysiological function, in eyes with CD. However, CFT <0.001 1 0.012 0.680 0.57 0.77 in our study, no significant correlation was found between retinal dysfunction on ERG and any of the other variables, such as BCVA, SCT 0.770 0.012 1 0.360 0.27 0.08 CFT, or CT (Table 2). Demonstration of a relationship among these Photopic A Amp 0.180 0.680 0.360 1 N/A N/A parameters may require studies on a larger population. Photopic B Amp 0.230 0.570 0.270 N/A 1 N/A The limitations of this study are the lack of genetic investigation, 30 Hz Amp 0.770 0.770 0.080 N/A N/A 1 the small sample size, and its cross-sectional nature. We did not assess the various retinal and choroidal layers, and nor did we measure the BCVA= best-corrected visual acuity; CFT= central foveal thickness; SCT= subfoveal choroidal thickness; Photopic A= electroretinogram photopic A wave; Photopic B= electroretinogram choroidal blood flow. A prospective longitudinal assessment of the photopic B wave; 30 Hz= electroretinogram 30-Hz wave; Amp= amplitude; N/A= not applicable. outer retinal injury in patients with CD and the relationship with choroidal alterations may contribute further to our understanding of the pathogenesis of CD. In conclusion, patients with CD showed significantly thinner cho- retinal and retinal thickness in the fovea, with this reduced thickness roids than individuals in the control group. BCVA and the subfoveal predominantly localized to the outer layers(3,9). In agreement with the- CT correlated with CFT in these patients; however, BCVA did not cor- se previous findings, we found a significant decrease in CFT in eyes relate with the subfoveal CT. A long-term study with more subjects with CD (Table 1). In addition, BCVA and the subfoveal CT correlated may establish a correlation between the disease stage and the extent with the thinning of these retinal layers (Table 2). and pattern of choroidal thinning. Visual acuity (VA) is determined by the number of preserved cones in the fovea(3). The neuroretinal thickness in the fovea is not REFERENCES the only determining factor for VA as VA also depends on the extent 1. Cho SC, Woo SJ, Park KH, Hwang JM. Morphologic characteristics of the outer retina of the preservation of the photoreceptors and of the contour of the in cone dystrophy on spectral-domain optical coherence tomography. Korean J outer retinal layer-RPE complex(3). Eyes with better preserved neuro- Ophthalmol. 2013;27(1):19-27.

Arq Bras Oftalmol. 2016;79(5):315-8 317 Is there a relationship between outer ret inal destruction and choroidal changes in cone dystrophy ?

2. Lima LH, Sallum JM, Spaide RF. Outer retina analysis by optical coherence tomogra- 9. Wolfing JI, Chung M, Carroll J, Roorda A, Williams DR. High resolution retinal imaging phy in cone-rod dystrophy patients. Retina. 2013;33(9):1877-80. of cone-rod dystrophy. Ophthalmology. 2006;113(6):1014-9. 3. Zahlava J, Lestak J, Karel I. Optical coherence tomography in progressive cone dystro- 10. May CA, Horneber M, Lutjen-Drecoll E. Quantitative and morphological changes of phy. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2014;158(4):628-34. the choroid vasculature in RCS rats and their congenic controls. Exp Eye Res. 1996; 4. Dhoot DS, Huo S, Yuan A, Xu D, Srivistava S, Ehlers JP, et al. Evaluation of choroidal 63(1):75-84. thickness in retinitis pigmentosa using enhanced depth imaging optical coherence 11. Korte GE, Reppucci V, Henkind P. RPE destruction causes choriocapillary atrophy. tomography. Br J Ophthalmol. 2013;97(1):66-9. Invest Ophthalmol Vis Sci. 1984;25(10):1135-45. 5. Yeoh J, Rahman W, Chen F, Hooper C, Patel P, Tufail A, et al. Choroidal imaging in 12. Saint-Geniez M, Kurihara T, Sekiyama E, Maldonado AE, D’Amore PA. An essential role inherited retinal disease using the technique of enhanced depth imaging optical for RPE-derived soluble VEGF in the maintenance of the choriocapillaris. Proc Natl coherence tomography. Graefes Arch Clin Exp Ophthalmol. 2010;248(12):1719-28. Acad Sci USA. 2009;106(44):18751-6. 6. Jonas JB, Schneider U, Naumann GO. Count and density of human retinal photore- 13. Caprara C, Grimm C. From oxygen to erythropoietin: relevance of hypoxia for retinal ceptors. Graefes Arch Clin Exp Ophthalmol. 1992;230(6):505-10. development, health and disease. Prog Retin Eye Res. 2012;31(1):89-119. 7. Chhablani J, Nayaka A, Rani PK, Jalali S. Choroidal thickness profile in inherited retinal 14. May CA, Narfstrom K. Choroidal microcirculation in Abyssinian cats with hereditary diseases in Indian subjects. Indian J Ophthalmol. 2015;63(5):391-3. rod-cone degeneration. Exp Eye Res. 2008;86(3):537-40. 8. Voo I, Glasgow BJ, Flannery J, Udar N, Small KW. North Carolina macular dystrophy: 15. Langham ME, Kramer T. Decreased choroidal blood flow associated with retinitis Clinicopathologic correlation. Am J Ophthalmol. 2001;132(6):933-5. pigmentosa. Eye (Lond). 1990;4(Pt 2):374-81.

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318 Arq Bras Oftalmol. 2016;79(5):315-8 Original Article

Evaluation of inner segment/outer segment junctions in different types of epiretinal membranes Avaliação da junção segmento interno/segmento externo em diferentes graus de membranas epirretinianas

Rukiye Aydın1, Eyyup Karahan2, Mahmut Kaya3, Taylan Ozturk3, Kubra Serefoglu Cabuk4, Nilufer Kocak3, Suleyman Kaynak3

ABSTRACT RESUMO Purpose: This study was conducted to evaluate the relationships of inner/outer Objetivo: Este estudo foi realizado para avaliar a relação entre a interrupção da junção segment (IS/OS) junction disruption, macular thickness, and epiretinal membrane segmento interno/segmento externo (IS/OS), espessura macular e grau de membrana (ERM) grade with best-corrected visual acuity (BCVA), as well as the relationship epirretiniana (ERM), com a melhor acuidade visual corrigida (BCVA), e a relação entre a between IS/OS junction disruption and ERM grade. interrupção da junção IS/OS com a severidade da ERM. Methods: Fifty-four eyes of 54 patients with different grades of ERM were retrospec- Métodos: Cinquenta e quatro olhos de 54 pacientes com diferentes graus de ERM foram tively reviewed. Patients were classified into three groups by ERM grade according avaliados retrospectivamente. ERMs foram classificadas, de acordo com as estrias de to retinal striae and vessel distortion: grade/group 1, visible membranes without retina e a distorção dos vasos, em 3 grupos: grupo 1 foram membranas visíveis sem estrias retinal striae or vessel distortion; grade/group 2, mild to moderate macular striae retinianas ou distorção dos vasos, grupo 2 membranas com estrias maculares discretas or vessel straightening; and grade/group 3, moderate to severe striae and vascular a moderadas ou retificação dos vasos, e grupo 3 membranas com estrias moderadas a straightening. Correlations of BCVA with age, central retinal thickness, ERM grade, graves e retificação vascular. A correlação da BCVA com a idade, espessura central da and IS/OS disruption as well as of IS/OS disruption, central macular thickness, and retina, severidade da ERM e interrupção da junção IS/OS foram avaliadas. A relação BCVA with ERM grade were evaluated. de interrupção da junção IS/OS, a espessura macular central e acuidade visual com a Results: Twenty-nine (53.7%) eyes exhibited IS/OS junction disruption. Groups severidade da ERM também foram avaliadas. 1 and 2 differed significantly with respect to BCVA (p=0.038), but groups 2 and 3 Resultados: Vinte e nove olhos (53,7%) apresentavam interrupção da junção IS/OS. did not (p=0.070). Central macular thickness was significantly greater in group 2 A BCVA foi diferente entre ERMs grupo 1 e grupo 2 (p=0,038), a diferença entre o grupos than in group 1 (p=0.031) and in group 3 than in group 2 (p=0.033). Groups 1 and 2 e 3 não foi estatisticamente significativa (p=0,070). A espessura macular central foi 2 differed significantly in terms of IS/OS disruption (p=0.000), but groups 2 and 3 estatisticamente maior no grupo 2, quando comparado ao grupo 1 (p=0,031) e maior did not (p=0.310). no grupo 3 quando comparado ao grupo 2 (p=0,033). A diferença entre o grupo 1 e Conclusions: The IS/OS junction appears to be disrupted during the early stages grupo 2 em relação à interrupção da junção IS/OS foi estatisticamente significativa of ERM. Grade 3 ERM is associated with a significantly higher incidence of IS/OS (p=0,000), ao passo que a diferença entre o grupo 2 e do grupo 3 não foi estatistica- disruption. mente significativa (p=0,310). Conclusões: As junções IS/OS parecem estar interrompidas nos estágios iniciais da ERM. O grau 3 de ERM têm uma maior incidência significativa de interrupção da junção IS/OS. Keywords: Epiretinal membrane; Retinal photoreceptor cell inner segment; Diag- Descritores: Membrana epirretiniana; Segmento ınterno das células fotorreceptoras nostic techniques, ophthalmologic; Tomography, optical coherence/methods da retina; Técnicas de diagnóstico oftalmológico; Tomografia de coerência óptica

INTRODUCTION of this layer reflects an anatomical disruption of the retinal photo- (4,5) Epiretinal membrane (ERM) is a type of nonvascular fibrocellular receptors . Studies involving SD-OCT in patients with ERM have proliferation that develops on the surface of the internal limiting mem shown that visual acuity deteriorates as a result of IS/OS junction brane and causes retinal wrinkling and distortion. Spectral domain disruption(6-10), and that there is thickening of the central macula(8-12) optical coherence tomography (SD-OCT) has yielded unpreceden- and outer retina(11,12). In support of this, Oster et al.(13) found that the ted details about ERM, the retinal structure, the overlying vitreous IS/OS junction was a more useful predictor of poor visual acuity when layer, and has reliably resolved details of individual retinal layers(1-3). compared with central macular thickness. One layer that is clearly delineated by SD-OCT represents the junction Currently, both preoperative and postoperative IS/OS disruption between the photoreceptor’s inner and outer segments (IS/OS are known to lead to visual acuity deterioration in eyes with ERM; junction). In normal eyes, this junction is visible as a hyperreflective however, very little information is currently available about the rela line immediately above the retinal pigment epithelium. Disruption tionship between IS/OS disruption and the ERM grade. Furthermore,

Submitted for publication: February 2, 2016 Funding: No specific financial support was available for this study. Accepted for publication: May 15, 2016 Disclosure of potential conflicts of interest: None of the authors have any potential conflicts of 1 Department of Ophthalmology, Faculty of Medicine, Medipol University, Istanbul, Turkey. interest to disclose. 2 Department of Ophthalmology, Faculty of Medicine, Sifa University, Izmir, Turkey. o 3 Corresponding author: Mahmut Kaya. Mithatpasa Cad. 2. Karatas, N 338, D:12 - Konak, Izmir Department of Ophthalmology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey. Turkey - E-mail: [email protected] 4 Department of Ophthalmology, Bağcılar Training and Research Hospital, Istanbul, Turkey. Approved by the following research ethics committee: Istanbul Medipol University Research Ethics Committee (#264/2015).

http://dx.doi.org/10.5935/0004-2749.20160091 Arq Bras Oftalmol. 2016;79(5):319-22 319 Evaluation of inner smeg ent/outer smeg ent junctions in different types of e pir etinal m embranes

the ERM grade during which IS/OS disruption begins has yet to be Next, we measured several variables from the SD-OCT images. discerned. In this study, we evaluated the relationships of IS/OS Foveal thickness, which was calculated using a caliper feature on the disruption, macular thickness, and ERM grade with visual acuity. Addi SD-OCT instrument with manual correction as needed, was deter- tionally, we evaluated the relationship between IS/OS disruption and mined as an average of the values from both horizontal and vertical ERM grade. scans. The photoreceptor IS/OS layer was evaluated for 500 µm in either direction of the fovea on both horizontal and vertical scans, and METHODS a diagnosis of a disrupted IS/OS junction was based on the absence and/or irregularity of the aforementioned hyperreflective line (Figure 2 Data of patients with different ERM grades who had undergone SD-OCT scanning (HRA-2; Heidelberg Engineering, Heidelberg, Ger A, B). One observer (R.A.), who was blinded to the clinical findings of the many) were retrospectively reviewed, in accordance with the tenets patients (e.g., visual acuity and ERM grade), measured the retinal layer of the Declaration of Helsinki. Only patients with primary ERM were thickness and assessed the status of the IS/OS junction. included in the study. We excluded patients with primary vitrecto Correlations of BCVA with age, central retinal thickness, ERM grade, my and ocular disorders associated with ERM, such as uveitis, and and IS/OS disruption were evaluated using linear regression analysis. patients with macular disorders and/or significant cataracts that In addition, eyes were divided into three groups with respect to ERM blocked the visualization of ERM during fundoscopy and SD-OCT grade: group 1, eighteen (33.3%) eyes with grade 1 ERM; group 2, 21 scans. The final study group was comprised of a total of 54 eyes of (38.9%) eyes with grade 2 ERM; and group 3, 15 (27.8%) eyes with 54 patients. We obtained each patient’s age, sex, and best-corrected grade 3 ERM. The relationships of IS/OS disruption, central macular visual acuity (BCVA) from medical records. thickness, and BCVA with the ERM grade were also evaluated through All patients underwent SD-OCT evaluations involving horizontal linear regression analysis. and vertical scans performed at maximal resolution through the fovea. Patients also underwent fundus imaging via color fundus photo Statistical analysis graphy (Topcon, Paramus, NJ, USA) to visualize details of the fundus. For each patient, the ERM severity was graded on fundus images SPSS version 11.6 (SPSS, Inc., Chicago, IL, USA) was used for the sta using a three-step scale as described previously(13). Grades 1, 2, and tistical analysis. Visual acuity values weres converted to logMAR units 3 ERM were defined as a visible membrane without retinal striae or for the statistical analyses. In addition to the linear regression analyses vessel distortion, mild to moderate macular striae or vessel straightening, mentioned above, a one-way analysis of variance with a post-hoc and moderate to severe striae and vascular straightening, respecti Tukey’s test was used to compare the three groups with respect to vely (Figure 1 A, B, and C, respectively). A single observer (S.K.) who BCVA and central macular thickness. Categorical variables were com was blinded to the visual acuity and SD-OCT scan data graded all pared between the groups with the χ2 test. A P value <0.05 was con fundus images. sidered statistically significant.

A B C

F igure 1. Fundus grading of the epiretinal membrane (ERM). A) Example of a grade 1 ERM with minimal retinal surface changes. B) Early macular striae are visible in a grade 2 ERM. C) A combination of large macular striae and prominent vascular straightening are seen in a grade 3 ERM.

A B

F igure 2. A) Example of an intact inner segment/outer segment (IS/OS) junction. B) Example of a disrupted IS/OS junction (arrow).

320 Arq Bras Oftalmol. 2016;79(5):319-22 Aydın R, e t a l .

RESULTS cause longstanding morphological changes in the retina can lead to Of the 54 patients, 20 (37.0%) were men and 34 (63.0%) were women. irreversible functional damage. Extensive studies of the integrity of The mean age of the patients was 67.9 ± 9.2 years (range: 41-84 years). the photoreceptor IS/OS line have demonstrated a significant asso- In addition, the mean logMAR visual acuity and mean central retinal ciation between an intact IS/OS line and better postoperative BCVA (6,7,10,14) (6) thickness were 0.4 ± 0.32 (range: 0.0-2.0) and 462.6 ± 119.8 µm (range: after successful removal of an ERM . Inoue et al. evaluated the 271-877 µm), respectively. Twenty-nine (53.7%) of the eyes exhibited prognostic value of IS/OS line integrity and observed significantly IS/OS disruption. Notably, the correlation of age with BCVA was not better postoperative BCVA in patients with an intact IS/OS junction 2 pre-operation. Furthermore, using preoperative SD-OCT scans, Cobos significant (r =0.018, p=0.334). However, BCVA exhibited significant (15) correlations with central retinal thickness (r2=0.531, p=0.000), IS/OS et al. observed significantly better postoperative BCVA in eyes disruption (r2=0.304, p=0.000), and ERM grade (r2=0.287, p=0.000). The with an intact IS/OS junction, compared to eyes with an irregular or disrupted IS/OS junction. characteristics and clinical data of the patients are shown in table 1. In another study of 41 patients who underwent surgery for ERM, The three groups, stratified according to ERM grade, were com- potential prognostic factors that may influence functional outcomes pared with respect to age, sex, BCVA, central macular thickness, and were investigated. Notably, the baseline CRT and appearance of IS/OS disruption. Age and sex were found to be similar among the the foveal contour did not significantly influence distance and near groups (p=0.519 and p=0.300, respectively). In terms of BCVA, groups visual acuity outcomes at 3-month follow-up. However, patients with 1 and 2 differed significantly (p=0.038), whereas the difference a continuous or interrupted IS/OS line exhibited significant impro- between groups 2 and 3 was not statistically significant (p=0.070). Cen- vements in distance and near visual acuity at 3 months, as well as a tral macular thickness was significantly greater in group 2 compared significantly higher rate of improvements in both distance and near to group 1 (p=0.031) and in group 3 compared to group 2 (p=0.033). visual acuity, compared to patients with a nearly absent IS/OS line(7). IS/OS distortion was observed in two (11.1%) of the eyes in group Suh et al.(8) evaluated 101 eyes of 101 patients with idiopathic ERM 1, 14 (66.7%) of the eyes in group 2, and 13 (86.7 %) of the eyes in who underwent PPV for ERM removal. OCT-detected photoreceptor group 3. The difference in IS/OS disruption between groups 1 and 2 disruption, which was potentially irreversible, was found to be a good was found to be statistically significant (p=0.000), whereas the predictor of poor visual outcomes in eyes with idiopathic ERM. The difference between groups 2 and 3 was not significant (p=0.310). authors postulated that early membrane removal might prevent Characteristics of the three groups are shown in table 2. additional photoreceptor damage in ERM patients with photoreceptor disruption. In the present study, the central macular thickness increased significantly as the ERM grade increased. In addition, differences DISCUSSION in IS/OS disruption rates and BVCA were only significant between Retinal traction caused by an ERM leads to morphological changes patients with grade 1 and grade 2 ERM. We believe that these findings that affect the entire retina, including the photoreceptor layer, rather suggest the presence of IS/OS disruption, even at early stages of ERM, than merely the superficial layers. This characteristic is important be and indicate that the main disruption occurs between grades 1 and 2. Mitamura et al.(10) used OCT to evaluate 70 eyes of 70 consecutive patients who underwent vitrectomy for idiopathic ERM; evaluations Table 1. Characteristics of patients classified according to epiretinal were conducted before and at 3 and 6 months after surgery. In that membrane grade study, the preoperative IS/OS junction grade correlated significantly Group 1 (n=18) Group 2 (n=21) Group 3 (n=15) P value with BCVA at 6 months. However, central foveal thickness did not correlate with BCVA between 3 and 6 months. Massin et al.(16) also re- Age (years) 066.20 ± 11.20 067.80 ± 08.50 070.00 ± 007.50 0.519* ported that the preoperative macular thickness did not correlate with Sex (%) the postoperative BCVA. In our study, the correlation of CMT with BCVA Male/female 37.8/62.2 33.3/66.7 41.70/58.30 0.300* was stronger than the correlation of IS/OS with BCVA. Interestingly , the IS/OS disruption rate and mean BCVA did not differ between BCVA 000.20 ± 00.14 000.42 ± 00.22 000.64 ±000.43 0.000* grade 2 and 3 ERMs, whereas the mean CMT was higher in grade 3 CMT (µm) 383.20 ± 81.60 465.50 ± 87.10 554.00 ± 135.60 0.000* ERMs relative to grade 2 ERMs. IS/OS junction (%) Suh et al.(8) reported that 12 of 37 eyes (32.40%) with a postopera Disrupted/Intact 11.1/88.9 66.7/33.3 86.70/13.30 0.000* tively disrupted IS/OS junction possessed an intact preoperative IS/OS junction; in contrast, only 5 of the 64 eyes (7.81%) with an intact *= statistically significant; BCVA= best-corrected visual acuity; CMT= central macular thickness; IS/OS= inner segment/outer segment. IS/OS junction exhibited a preoperatively disrupted IS/OS junction. As we think that IS/OS disruption begins during the early stages of ERM, we suggest that early membrane removal should be considered to prevent additional photoreceptor damage in patients with ERM. Table 2. Comparison of BCVA, CMT, and IS/OS disruption between We must note some limitations of the present study. Notably, the groups study featured a retrospective design and lacked a control group. In Mean P value addition, only a small number of patients were included, and this might BCVA (logMAR) have affected the reliability of the statistical analysis. In conclusion, the IS/OS junction appears to be disrupted during Group 1 - Group 2 0.20 ± 0.14 - 0.42 ± 0.22 0.038* the early stages of ERMs. Grade 3 ERMs had a significantly higher inci- Group 2 - Group 3 0.42 ± 0.22 - 0.64 ± 0.43 0.070* dence of IS/OS disruption, a finding that suggested by the poorer sur- CMT (µm) gical outcomes reported in other studies. Future prospective studies Group 1 - Group 2 383.2 ± 81.6 - 465.5 ± 087.1 0.031* with larger sample sizes are needed to determine the relationship between the IS/OS junction and ERM development. Group 2 - Group 3 465.5 ± 87.1 - 554.0 ± 135.6 0.033* Disrupted IS/OS junction (%) REFERENCES Group 1 - Group 2 11.1 - 66.7 0.000* . 1 Legarreta JE, Gregori G, Knighton RW, Punjabi OS, Lalwani GA, Puliafito CA. Three-di Group 2 - Group 3 66.7 - 86.7 0.310* mensional spectral-domain optical coherence tomography images of the retina in the *= statistically significant; BCVA= best-corrected visual acuity; CMT= central macular presence of epiretinal membranes. Am J Ophthalmol. 2008;145(6):1023-30. thickness; IS/OS= inner segment/outer segment. 2. Koizumi H, Spaide RF, Fisher YL, Freund KB, Klancnik JM Jr, Yannuzzi LA. Three-dimensional

Arq Bras Oftalmol. 2016;79(5):319-22 321 Evaluation of inner smeg ent/outer smeg ent junctions in different types of e pir etinal m embranes

evaluation of vitreomacular traction and epiretinal membrane using spectral-domain 10. Mitamura Y, Hirano K, Baba T, Yamamoto S. Correlation of visual recovery with presence optical coherence tomography. Am J Ophthalmol. 2008;145(3):509-17. of photoreceptor inner/outer segment junction in optical coherence images after 3. Marmor MF, Choi SS, Zawadzki RJ, Werner JS. Visual insignificance of the foveal pit: epiretinal membrane surgery. Br J Ophthalmol. 2009;93(2):171-5. reassessment of foveal hypoplasia as fovea plana. Arch Ophthalmol. 2008;126(7):907-13. 11. Watanabe A, Arimoto S, Nishi O. Correlation between metamorphopsia and epiretinal . 4 Inoue M, Watanabe Y, Arakawa A, Sato S, Kobayashi S, Kadonosono K. Spectral-domain membrane optical coherence tomography findings. Ophthalmology. 2009;116(9): optical coherence tomography images of inner/outer segment junctions and macular 1788-93. hole surgery outcomes. Graefes Arch Clin Exp Ophthalmol. 2009;247(3):325-30. 12. Arichika S, Hangai M, Yoshimura N. Correlation between thickening of the inner and 5. Baba T, Yamamoto S, Arai M, Arai E, Sugawara T, Mitamura Y, et al. Correlation of visual outer retina and visual acuity in patients with epiretinal membrane. Retina. 2010;30(3): recovery and presence of photoreceptor inner/outer segment junction in optical co 503-8. herence images after successful macular hole repair. Retina. 2008;28(3):453-8. 13. Oster SF, Mojana F, Brar M, Yuson RM, Cheng L, Freeman WR. Disruption of the photo 6. Inoue M, Morita S, Watanabe Y, Kaneko T, Yamane S, Kobayashi S, et al. Inner segment/ receptor inner segment/outer segment layer on spectral domain-optical coherence outer segment junction assessed by spectral-domain optical coherence tomography tomography is a predictor of poor visual acuity in patients with epiretinal membranes. in patients with idiopathic epiretinal membrane. Am J Ophthalmol. 2010;150(6):834-9. Retina. 2010;30(5):713-8. 7. Falkner-Radler CI, Glittenberg C, Hagen S, Benesch T, Binder S. Spectral-domain optical coherence tomography for monitoring epiretinal membrane surgery. Ophthalmology. 14. Kim JH, Kim YM, Chung EJ, Lee SY, Koh HJ. Structural and functional predictors of visual 2010;117(4):798-805. outcome of epiretinal membrane surgery. Am J Ophthalmol. 2012;153(1):103-10. 8. Suh MH, Seo JM, Park KH, Yu HG. Associations between macular findings by optical 15. Cobos E, Arias L, Ruiz-MorenO JM, Rubio MJ, Garcia-Bru P, Caminal JM, et al. Preoperative coherence tomography and visual outcomes after epiretinal membrane removal. Am study of the inner segment/outer segment junction of photoreceptors by spectral-do- J Ophthalmol. 2009;147(3):473-80. main optical coherence tomography as a prognostic factor in patients with epiretinal 9. Michalewski J, Michalewska Z, Cisiecki S, Nawrocki J. Morphologically functional membranes. Clin Ophthalmol. 2013;7:1467-70. correlations of macular pathology connected with epiretinal membrane formation in 16. Massin P, Allouch C, Haouchine B, Metge F, Paques M, Tangui L, et al. Optical coherence spectral optical coherence tomography. Graefes Arch Clin Exp Ophthalmol. 2007;245(11): tomography of idiopathic macular epiretinal membranes before and after surgery. 1623-31. Am J Ophthalmol. 2000;130(6):732-9.

IV Congresso Internacional de Estética Periocular XXV Congresso Internacional de Oculoplástica

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322 Arq Bras Oftalmol. 2016;79(5):319-22 Original Article

Repeatability of contrast sensitivity testing in patients with age-related macular degeneration, glaucoma, and cataract Reprodutibilidade dos escores de sensibilidade ao contraste em pacientes com degeneração macular relacionadas à idade, glaucoma e catarata

Selcuk Kara1, Baran Gencer1, Ismail Ersan1, Sedat Arikan1, Omer Kocabiyik1, Hasan Ali Tufan1, ArzuTaskiran Comez1

ABSTRACT RESUMO Purpose: To analyze the intrasession and intersession repeatability of contrast Objetivo: Analisar a reprodutibilidade intrassessão e intersessão das medidas de sensitivity (CS) measurements in patients with glaucoma, cataract, or age-related sensibilidade ao contraste (CS) em pacientes com degeneração macular relacionada macular degeneration (AMD) and healthy controls. à idade (AMD), glaucoma e catarata. Methods: CS measurements were performed using the OPTEC-Functional Vision Método: As medidas de CS foram feitas pelo OPTEC-Funcional Visão Analyzer (FVA), Analyzer (FVA), which uses a standardized and closed (view-in) system. Measu- que utiliza um sistema padronizado e fechado de avaliação da acuidade visual. rements for patients with glaucoma, cataract, or AMD and healthy controls were Medidas em pacientes com AMD, glaucoma, catarata e nos controles saudáveis repeated within 30 minutes (intrasession) and during two sessions (intersession), foram repetidas no prazo de 30 minutos (intrassessão) em duas visitas (intersessão), separated by one week to one month. Test-retest reliability and correlation were separadas por uma semana a um mês. A confiabilidade e correlação teste-reteste measured using the intraclass correlation coefficient (ICC) and coefficient of foram calculados por meio do coeficiente de correlação intraclasse (ICC) e coeficiente repeatability (COR). de reprodutibilidade (COR). Results: Ninety subjects (90 eyes) with visual acuity of 0.17 logMAR or higher in Resultados: Noventa olhos de 90 indivíduos foram recrutados com acuidade visual the cataract group or 0.00 logMAR in the other groups were included. During the de 0,17 logMAR ou melhor em catarata e 0,00 logMAR nos outros grupos. A confiabili- first session, the ICC values were 0.87, 0.90, 0.76, and 0.69, and COR values were dade da CS na primeira visita dos grupos normal, glaucoma, catarata e AMD foram, 0.24, 0.20, 0.38, and 0.25 for the control, glaucoma, cataract, and AMD groups, respectivamente, ICC 0,87; 0,90; 0,76; 0,69, e COR 0,24; 0,20; 0,38; 0,25. Os índices de respectively. The reliability scores significantly improved during the second session, confiabilidade foram significativamente melhorados nas segundas visitas, exceto no except in the glaucoma group. There was an acceptable floor effect and no ceiling grupo glaucoma. Houve um efeito chão aceitável e nenhum efeito teto em frequências effect at higher frequencies in the glaucoma and AMD groups. mais altas nos grupos glaucoma e AMD. Conclusion: In subjects with good visual acuity, the FVA system is useful for eva Conclusões: Em indivíduos com boa acuidade visual, o sistema FVA de avaliação da luating CS and demonstrates good repeatability, as shown by ICC and COR. Because CS é útil e apresenta boa confiabilidade, como mostrado pelas análises de ICC e COR. there is no ceiling effect, this system is beneficial for evaluation of early changes Por não apresentar efeito teto, este sistema parece ser benéfico para a avaliação das in CS, particularly in patients with glaucoma or AMD. alterações precoces de CS, especialmente no glaucoma e AMD. Keywords: Macular degeneration; Contrast sensitivity; Glaucoma; Age effect; Re Descritores: Degeneração macular; Sensibilidade de contraste; Glaucoma; Fator producibilit y of results idade; Reprodutibilidade dos testes

INTRODUCTION detection of eye diseases and measurement of functional vision(6,10-12). Contrast sensitivity (CS) is the ability to recognize small differen- CS decreases in all stages of glaucoma and age-related macular ces in luminance or differentiate two objects from each other and degeneration (AMD) have been documented using different testing the background(1,2). CS is an important part of functional vision that methods(7,12-15). Glaucoma, cataract, and AMD patients suffer from is related to many activities of daily living and measuring it is one of problems in vision-related activities of daily living and the inability to the best ways to assess vision quality(3-5). Despite having normal visual recognize targets in real world, which can be better identified by CS acuity measured by a Snellen chart, the satisfaction with the results tests than by visual acuity tests(14,16-18). The increasing importance of of refractive surgery may vary relative to CS, and some eye diseases visual quality and the need for accurate measurement of visual acuity cause isolated loss of CS(4,6-8). Snellen acuity tests have a limited abi- has led to more interest in CS tests(12,19-21). lity to detect fine changes in contrast because high contrast letters There are several clinical tests for measuring CS with letters or (black on white) are used(9). Also, recent advances in knowledge gratings(5,22-26). A limitation of CS tests is low reliability associated with about refractive surgery, optical tissues, and glaucoma and macular varying environmental conditions and the subjective nature of the diseases revealed that the Snellen acuity test is inadequate for early tests. In particular, CS tests that use charts may be affected by ina-

Submitted for publication: May 21, 2015 Funding: No specific financial support was available for this study. Accepted for publication: May 20, 2016 Disclosure of potential conflicts of interest: None of the authors have any potential conflict of 1 Department of Ophthalmology, Faculty of Medicine, Canakkale Onsekiz Mart University, Canakkale, interest to disclose. Turkey. Corresponding author: Selcuk Kara. Canakkale Onsekiz Mart Universitesi Tip Fakultesi, Goz Hastalıkları AD - Canakkale - 17000 - Turkey - E- mail: [email protected] Approved by the following research ethics committee: Canakkale Onsekiz Mart University (#050. 99-151).

http://dx.doi.org/10.5935/0004-2749.20160092 Arq Bras Oftalmol. 2016;79(5):323-7 323 Repeatability of contrast sensitivity testing in patients with age-r elated macular degene ration, glaucoma, and cata ract

dequate or uneven lighting, fading, the subject’s learning curve, and subjects had normal findings on a comprehensive eye examination reflections(2,3). The Functional Acuity Contrast Test (FACT) assesses five (including anterior segment biomicroscopy and fundoscopy of the spatial frequencies (1.5, 3, 6, 12, and 18 cycles per degree (cpd)) and macula and optic nerve) and IOP <21 mmHg. 9 levels of contrast for each frequency. FACT uses a small increment A closed-system CS testing device, the OPTEC-FVA (Stereo Optical (0.15 log unit) and a forced-choice method with three options(2). Co, Inc., Chicago, IL, USA), was used to examine CS values under daytime Although the FACT test has greater reliability compared with other without glare. Figure 1 shows the FVA CS testing device. The FVA has CS testing methods, administration of the CS test in a closed system, rotating slide packages for other visual functions, including visual with charts on the screen inside the device, with a Functional Visual acuity, disability glare, and stereo and color vision. The CS testing Acuity (FVA) device has additional advantages. These advantages device contains the FACT chart, which uses three orientations for the include the ability to display contrast charts in a random order and gratings: oriented vertically or tilted 15º to the right or left. Subjects the administration of the test with standardized lighting, which is identified the orientation of each grating and were required to guess difficult to maintain under other conditions(3,27). A CS test is expected when they could not determine the orientation of gratings. to have a good reliability to differentiate a small loss or detect real The CS testing device controls light levels with sensors to achieve progression, which can be better achieved by a closed test system, consistent conditions for each test. This device supplies a target lu 2 which has inherently stable testing conditions. minance level of 85 cd/m for daytime conditions in compliance with To the best of our knowledge, there has been little research pu- the American National Standards Institute (ANSI). It evaluates spatial blished about the comparative reliability of these devices for healthy frequencies using sine-wave grating charts of 1.5, 3, 6, 12, and 18 cpd. controls and patients with eye disease. This study investigates the Figure 2 presents the sine-wave gratings charts for the frequencies repeatability of the closed system FVA CS test in control subjects and that the CS testing device used. Contrast was defined according to the Michelson formula (C = [Lmaximum − Lminimum]/[Lmaximum + Lminimum], in patients with glaucoma, cataracts and good Snellen visual acuity, (2) or age-related macular degeneration (AMD). C: Contrast, L: Luminance) . CS was measured during two sessions separated by at least one week and up to one month (intersession).

METHODS This prospective, observational study included patients with glaucoma, cataracts, or AMD and healthy control subjects. All subjects were recruited from the Eye Clinic at Canakkale Onsekiz Mart Uni- versity. Written informed consent was obtained from all participants following a comprehensive explanation of the study. The research was approved by the local clinical research ethics committee and complied with the tenets of the Helsinki Declaration. The study included subjects between 40 and 70 years old to facilitate enrollment of subjects with best corrected visual acuity (BCVA) of 0.00 logMAR for the groups without cataracts. One eye of each patient was included in the study. Subjects were not eligible to be included if they had ocular diseases other than glaucoma, cataracts, or AMD, refractive error <-3 or >3 diopters (D) sphere or >2.00 D cylin- der, or a history of previous eye surgery or laser treatment. Patients with psychiatric or neurologic disorders, poor compliance during the CS test, or who used systemic or ocular medications could affect CS were excluded. All patients underwent an ophthalmic examination, including auto refractometry, BCVA evaluation, anterior segment biomicroscopy, funduscopy, and IOP, measured with a Goldmann applanation tonometer (GAT). The glaucoma group included subjects who were diagnosed with primary open-angle glaucoma (POAG) or normotensive glauco ma (NTG). The inclusion criteria for patients with POAG were the cha- F igure 1. The functional vision analyzer contrast sensitivity test device. racteristic visual field loss, glaucomatous optic neuropathy (having rim thinning or notching, retinal nerve fiber layer defects, or disc hemorrhage and disc asymmetry between the eyes ≥0.2), and intrao cular pressure (IOP) >21 mmHg. The inclusion criteria for patients with NTG were visual field loss, glaucomatous optic neuropathy, and IOP ≤21 mmHg. Glaucomatous visual field defects, which were repeatable in at least two standard automated perimetry evaluations, included at least one of the following: nasal step, arcuate scotoma, paracentral scotoma, or temporal wedge. All glaucoma patients had a grade 3 or 4 open angle according to the Shaffer Classification System(29) and a mean deviation no worse than -6 dB. In the cataract group, only eyes with a BCVA of 0.17 logMAR or better and a nuclear sclerosis of less than grade 2 were included. Nuclear sclerosis was graded by the slit-lamp method according to the Lens Opacities Classification System III(28). The inclusion criteria for the AMD group were retinal pigment epithelial abnormalities in the form of hypopigmentation or hyperpigmentation, without evidence of active choroidal neovascularization, and no prior treatment with any anti-vascular endothelial growth factor injections. The control F igure 2. Sine-wave grating charts in the view-in contrast sensitivity test device.

324 Arq Bras Oftalmol. 2016;79(5):323-7 Kara S, e t a l .

At each session, two measurements taken 30 minutes apart (intra- Table 1. Test-retest reliability of the contrast sensitivity test in the session). All tests were performed with the optimum refractive cor- groups of control, glaucoma, cataract, and age-related macular degeneration groups rection and a natural pupil. All the subjects performed the CS test for 1st session 2nd session Intersession the first time during our study, and each test lasted approximately 10 Spatial minutes. The CS measurements were obtained by a single operator frequency (cpd) ICC COR ICC COR p-value ICC COR who was blinded to the patient’s group. Control All the CS values were converted to logarithmic values. The group test-retest reliability of the CS test was examined using the intraclass 1.5 0.86 0.19 0.91 0.13 0.92 0.14 correlation coefficient (ICC) and the coefficient of repeatability (COR) and the corresponding 95% confidence interval (CI). The ICC was cal- 3 0.86 0.18 0.89 0.16 0.95 0.10 culated with absolute agreement. The COR is calculated as 1.96 times 6 0.83 0.23 0.87 0.20 0.042*a 0.91 0.16 the standard deviation of the difference between the test and retest 12 0.91 0.23 0.96 0.15 0.043*b 0.94 0.18 scores. An ICC value of 1.0 and a COR value of 0.0 represent perfect 18 0.87 0.38 0.96 0.18 0.94 0.23 test-retest reliability(2). Reliability analyses were performed within in dividual sessions and between sessions for all groups. Possible floor Mean 0.87 0.24 0.92 0.16 0.93 0.16 and ceiling effects were evaluated by calculating the percentage of Glaucoma subjects with lowest and highest test scores, respectively, for each of group the four tests at each spatial frequency and within each group. 1.5 0.92 0.14 0.83 0.22 0.96 0.10 Spearman rank-order correlations were used to investigate the 3 0.80 0.24 0.92 0.15 0.95 0.11 possible correlation between age and changes in CS score. The Wil 6 0.85 0.22 0.94 0.14 0.461a 0.86 0.20 coxon and Mann-Whitney U-tests were used to compare CS scores b between groups. The Bonferroni correction, which applies a statistical 12 0.95 0.20 0.97 0.11 0.194 0.96 0.15 significance level of 1/n times the “p” value (n= the number of com- 18 0.98 0.18 0.98 0.18 0.98 0.19 parisons), was used to test for multiple comparisons to ensure that an Mean 0.90 0.20 0.93 0.16 0.94 0.15 (30) appropriate level of significance was applied to the individual tests . Cataract Statistical analysis was performed using SPSS software (Windows group version 19.0; SPSS, Inc., Chicago, IL, USA), and statistical significance 1.5 0.86 0.22 0.88 0.17 0.94 0.14 was defined as p<0.05. 3 0.84 0.23 0.94 0.14 0.96 0.10 6 0.86 0.25 0.93 0.18 0.043* a 0.96 0.14 RESULTS 12 0.56 0.56 0.85 0.37 0.043*b 0.81 0.34 The analysis was included 90 eyes of 90 Caucasian subjects, including healthy control (n=30; mean ± standard deviation age 47.1 18 0.70 0.67 0.92 0.33 0.96 0.22 ± 6.7 years; 15 males), glaucoma (n=13; age 59.6 ± 4.1 years; 8 males), Mean 0.76 0.38 0.90 0.24 0.93 0.19 cataract (n=29; age 56.3 ± 5.2 years; 14 males), and AMD (n=18; age AMD 59.9 ± 4.6 years; 9 males) groups. group The test-retest reliability of the CS test, including ICC and COR, is 1.5 0.72 0.17 0.88 0.14 0.93 0.09 shown in table 1. The reliability of the CS test in the control, glaucoma, 3 0.74 0.19 0.84 0.16 0.91 0.10 cataract, and AMD groups were good at the first session (ICC: 0.87 a [95% CI 0.84 -0.9], 0.90 [CI 0.84 -0.96], 0.76 [CI 0.65 -0.87], and 0.69 6 0.62 0.23 0.80 0.23 0.043* 0.88 0.13 [CI 0.59 -0.79], respectively; and COR 0.24, 0.20, 0.38, and 0.25, respecti- 12 0.83 0.18 0.90 0.20 0.141b 0.90 0.15 vely). However, at the second session, statistically significant increases 18 0.56 0.50 0.90 0.32 0.68 0.42 were found in the reliability of the CS test, except in the glaucoma Mean 0.69 0.25 0.86 0.21 0.86 0.18 group (ICC: 0.92 [CI 0.88 -0.96], p=0.042; 0.93 [CI 0.88 -0.98], p=0.461; AMD= age-related macular degeneration; ICC= Intraclass correlation coefficient; COR= coeffi 0.90 [CI 0.86 -0.94], p=0.043; and 0.86 [CI 0.82 -0.9], p=0.043; and COR cient of repeatability; cpd= cycle per degree. of 0.16, 0.16, 0.24, and 0.21 in the control, glaucoma, cataract, and *= statistically significant p<0.05. AMD groups, respectively). a= p-value of Wilcoxon signed-rank test for ICC of 1st and 2nd sessions. Figure 3 illustrates the mean CS score for all groups as a function b= p-value of Wilcoxon signed-rank test for COR of 1st and 2nd sessions. of spatial frequency. The CS scores for the AMD group were significantly lower than for those in the control group at all frequencies (significance of Bonferroni correction 0.012, p<0.001). In the glaucoma group, except at a frequency of 1.5 cpd, the CS scores were significantly lower compared with control group (significance of Bonferroni correction 0.012, p<0.012). There was also a statistically significant correlation between age and changes in CS scores of subjects at all spatial frequencies (1st session p<0.001, r=-0.399, -0.484, -0.484, -0.386, and -0.395 at 1.5, 3, 6, 12, and 18 cpd, respectively; 2nd session p<0.001, r=-0.424, -0.450, -0.495, -0.432, and -0.444 at 1.5, 3, 6, 12, and 18 cpd, respectively). Table 2 summarizes the results of the analysis of possible floor and ceiling effects at each spatial frequency and for each group. There was a prominent floor effect at the highest frequency (18 cpd) in all groups. In healthy eyes, a floor effect, except in the second test, only occurred at 18 cpd. However, in the glaucoma group, the floor effect was greatest for the first two tests and decreased for the last F igure 3. Contrast sensitivity for the control, glaucoma, cataract, and age-related macular CS tests. There was no ceiling effect in the glaucoma or AMD groups degeneration (AMD) groups as a function of spatial frequency.

Arq Bras Oftalmol. 2016;79(5):323-7 325 Repeatability of contrast sensitivity testing in patients with age-r elated macular degene ration, glaucoma, and cata ract

Table 2. The floor and ceiling effect for each spatial frequency and group were better at the second session (0.86-0.94) than the first session (measured by the percentage of maximum and minimum CS scores in the (0.69-0.90) in all groups. Furthermore, the CORs improved at the control (n=30), glaucoma (n=13), cataract (n=29), and AMD (n=18) groups) second session (first session 0.20-0.38; second session 0.16-0.24). Percentage with the Percentage with the There may be a learning effect, which possibly arises from cognitive minimum CS score for maximum CS score for abilities or getting familiar with the test procedure during the repea each spatial frequency (%) each spatial frequency (%) ted tests. It has been reported that using letter charts for CS tests Test Group 1.5 3 6 12 18 1.5 3 6 12 18 result in learning effects according to variable abilities to recognize 1 Control 0.0 0.0 0.0 0.0 06.7 06.7 3.3 03.3 0.0 0.0 letters. The FACT charts that use sine-wave gratings eliminate these problems(2,31). However, subjects high probability of correct guessing Glaucoma 0.0 0.0 0.0 7.7 46.1 00.0 0.0 00.0 0.0 0.0 with the FACT charts, so repetitive tests are needed to reduce this Cataract 0.0 0.0 0.0 3.6 25.0 07.1 3.6 00.0 0.0 0.0 effect(27,31). Subjects’ responses may become more reliable after learning AMD 0.0 0.0 0.0 0.0 16.7 00.0 0.0 00.0 0.0 0.0 the FVA CS test procedure so it is important to conduct multiple CS 2 Control 0.0 0.0 0.0 6.7 10.0 10.0 6.7 10.0 3.3 0.0 tests to obtain more reliable clinical results. It has been well documented that the spatial and temporal Glaucoma 0.0 0.0 0.0 7.7 38.4 00.0 0.0 00.0 0.0 0.0 types of CS decrease in people with glaucoma(11,32,33). Grating CS tests Cataract 0.0 0.0 0.0 0.0 28.6 03.6 7.1 10.7 0.0 0.0 are promising for the detection of early glaucoma and its progres- AMD 0.0 0.0 0.0 5.6 22.2 00.0 0.0 00.0 0.0 0.0 sion(32,34). Klein et al.(17) suggested that spatial CS were a sensitive 3 Control 0.0 0.0 0.0 0.0 06.7 10.0 6.7 10.0 0.0 3.3 indicator of early glaucomatous loss in the presence of cataracts. Although visual acuity was good, the CS of the eyes with glaucoma Glaucoma 0.0 0.0 0.0 0.0 30.7 00.0 0.0 00.0 0.0 0.0 was significantly less than among healthy subjects except at 1.5 cpd Cataract 0.0 0.0 0.0 3.6 25.0 00.0 0.0 07.1 3.6 0.0 (p<0.012). This result was compatible with that previously reported AMD 0.0 0.0 0.0 0.0 33.3 00.0 0.0 00.0 0.0 0.0 by Onal et al.(7) using the FACT wall chart. The authors suggested that 4 Control 0.0 0.0 0.0 0.0 10.0 06.7 6.7 06.7 0.0 3.3 the FACT chart was useful for early diagnosis of patients with glau- Glaucoma 0.0 0.0 0.0 0.0 23.1 00.0 0.0 00.0 0.0 0.0 coma, accompanied by a short-wavelength automated perimetry. This may be associated with early degeneration in the magnocellular Cataract 0.0 0.0 0.0 7.1 32.1 00.0 0.0 00.0 0.0 0.0 ganglion cells, which are important for CS, in glaucoma(35). AMD 0.0 0.0 0.0 5.6 22.2 00.0 0.0 00.0 0.0 0.0 The CS of eyes with AMD was worse than among healthy subjects AMD= age-related macular degeneration; CS= contrast sensitivity. at all frequencies (p<0.001), similar to previous studies(6,36). As there are limited options for treatment of AMD, early detection of the disease and prevention of progression are very important. Visual discomfort in performing daily activities often occurs in patients with AMD even though they have a BCVA of 0.00 logMAR on Snellen charts. This vi at any of the tested frequencies. In healthy and cataract eyes, a low sion quality loss is seen in early AMD before any detectable retinal ceiling effect (3.3%-10%), with a slight decrease during the last two changes occur(18,37). CS reduction in AMD patients becomes more evi tests, was detected. dent and uncomfortable under conditions of low illumination, which provides a low contrast environment(16). DISCUSSION It was reported previously that the closed system FACT chart had a lower ceiling effect than the wall chart test, which might increase This study showed that the FVA CS test has good reliability, as shown its ability to detect small changes. In our study, no ceiling effect was by ICC and COR analysis. The CS test is useful for patients with good visual acuity who have healthy eyes without glaucoma, cataracts, or observed in eyes with glaucoma or AMD using the FVA closed system CS test, and the ceiling effect was acceptable in healthy and cataract AMD. Although there are other commercially available CS tests using (3) letters, symbols, or sine-wave gratings, these tests are not clearly stan- eyes . Even after a gap of at least one week between the first and dardized for performing a common CS evaluation such as visual field second CS tests, the ceiling effect in normal and cataract eyes tended analyses(2,23). Sine-wave gratings permit sensitive testing of individual to decrease. These results suggest that the FACT chart in a closed visual channels and are part of spatial frequency for evaluating CS system has the potential to detect small decreases in high CS scores function in vision science(12). The FACT chart also uses sine-wave gra- in healthy, cataract, and AMD eyes and otherwise healthy eyes with tings, which have been chosen at given luminance and glare levels early stages of glaucoma. A more pronounced floor-effect emerged in for the ANSI by the United States Food and Drug Administration(5). glaucoma and AMD eyes at higher frequencies, which may represent Although the FACT chart is a modified version of the Vistech, it uses the effects of early retinal or ganglion cell defects on the loss of CS. smaller increments (0.15 log units) and subjects must choose from It is critical to know if the patients are affected by glaucoma, three options. Previous CS studies with sine-wave gratings reported catarac ts, or AMD in their daily lives when considering treatment insufficient scores for reliability analyses (ICC 0.28-0.64 and COR 0.26- options. CS has become more important for quality of life assessments, 0.58)(2). Despite having poor reliability with FACT wall charts, closed which have been receiving increase attention in recent years(37-39). systems using the standard FACT luminance and glare values were CS is involved with differentiating low-contrast objects, such as hu- reported to exactly match the ANSI standards, thereby providing man faces, and recognizing movement(37,40). Because of the close better reliability(3, 27). Hohberger et al.(27) reported average reliability relationship between CS and the ability to perform activities of daily coefficients of 0.80-0.96 for each cpd with an OPTEC 6500 CS test. living, despite normal BCVA, CS testing is a useful clinical method to Using the same device, Hong et al.(3) reported ICC 0.85 and COR 0.20, assess how ocular disease affects what patients can do. The present which are comparable to our results with the FVA closed system CS study found that FVA closed system CS evaluation provided reliable test (intersession ICC 0.86-0.94 and COR 0.16-0.19). results with an easy method and standardized luminance. Previous studies with FACT charts in closed systems omitted any It should be noted that there are several limitations of this study. comparison with earlier and latter CS test scores that might have ex The numbers of patients with eye disease and healthy controls were plained possible improvements in test reliability. We think that such small. Reliability was evaluated by only two sessions with CS test each, comparisons are important to establish a reliable clinical application so more sessions are required to strengthen the results. In addition, of the CS test. In this study, the mean ICCs of the closed system CS test the interval between sessions varied from one week to one month.

326 Arq Bras Oftalmol. 2016;79(5):323-7 Kara S, e t a l .

CS measures visual quality and can provide detailed information 17. Klein J, Pierscionek BK, Lauritzen J, Derntl K, Grzybowski A, Zlatkova MB. The effect by spatial frequency assessment. Thus, it can be used to detect early of cataract on early stage glaucoma detection using spatial and temporal contrast sensitivity tests. PLoS One. 2015;10(6):e0128681. subclinical findings or changes during treatment for visual-sys 18. Bansback N, Czoski-Murray C, Carlton J, Lewis G, Hughes L, Espallargues M, et al. tem-relat ed eye diseases. However, to differentiate healthy from Determinants of health related quality of life and health state utility in patients with abnormal characteristics and to detect real disease progression, the age related macular degeneration: the association of contrast sensitivity and visual CS test must have strong clinical reliability. In this study, we found acuity. Qual Life Res. 2007;16(3):533-43. good reliability of the FVA closed system CS test in all groups and 19. Söğütlü Sari E, Kubaloğlu A, Unal M, Liorens DP, Koytak A,Ofluoglu AN, et al. Penetra- reliability improved during the second session. Therefore, to get more ting keratoplasty versus deep anterior lamellar keratoplasty: comparison of optical and visual quality outcomes. Br J Ophthalmol. 2012;96(8):1063-7. reliable results, repeated measurements are needed. Although, there 20. Karakus SH, Basarir B, Pinarci EY, Kirandi EU, Demirok A. Long-term results of half-dose was an acceptable floor-effect with the closed system test in patients photodynamic therapy for chronic central serous chorioretinopathy with contrast with glaucoma and AMD, we found no ceiling effect; consequently, the sensitivity changes. Eye (Lond). 2013;27(5):612-20. view-in test has potential to detect fine changes at high frequencies. 21. Gertnere J, Solomatin I, Sekundo W. Refractive lenticule extraction (ReLEx flex) and In summary, to the best of our knowledge, this is the first study wavefront-optimized Femto-LASIK: comparison of contrast sensitivity and high-order aberrations at 1 year. Graefes Arch Clin Exp Ophthalmol. 2013;251(5):1437-42. reporting the repeatability of FACT test scores using a closed system 22. Thayaparan K, Crossland MD, Michael D, Rubin GS. Clinical assessment of two new in patients with AMD and glaucoma. Hopefully, the reliability of this contrast sensitivity charts. Br J Ophthalmol. 2007;91(6):749-52. FACT will encourage clinicians to incorporate contrast sensitivity 23. Keane PA, Patel PJ, Ouyang Y, Chen FK, Ikeji F, Walsh AC, et al. Effects of retinal morpho- into their thorough evaluation of the early changes that accompany logy on contrast sensitivity and reading ability in neovascular age-related macular glaucoma, cataract, and AMD. degeneration. Invest Ophthalmol Vis Sci. 2010;51(11):5431-7. 24. Haughom B, Strand T-E. Sine wave mesopic contrast sensitivity - defining the normal range in a young population. Acta Ophthalmol. 2013;91(2):176-82. REFERENCES 25. Li JH, Feng YF, Zhao YE, Zhao YY, Lin L. Contrast visual acuity after multifocal intrao cular lens implantation: aspheric versus spherical design. Int J Ophthalmol. 2014; 1. Miller D, Schor P, Magnante P. Optics of the normal eye. In: Yanoff M, Duker JS, editor. 7(1):100-3. Ophthalmology. China: Elsevier; 2014. p. 38-45. 26. Haymes SA, Roberts KF, Cruess AF, Cruess AF, Nicolela MT, LeBlanc RP, et al. The letter 2. Richman J, Spaeth GL, Wirostko B. Contrast sensitivity basics and a critique of curren- contrast sensitivity test: clinical evaluation of a new design. Invest Ophthalmol Vis tly available tests. J Cataract Refract Surg. 2013;39(7):1100-6. Sci. 2006;47(6):2739-45. 3. Hong YT, Kim SW, Kim EK, Kim T. Contrast sensitivity measurement with 2 contrast 27. Hohberger B, Laemmer R, Adler W, Juenemann AG, Horn FK. Measuring contrast sensitivity tests in normal eyes and eyes with cataract. J Cataract Refract Surg. 2010; sensitivity in normal subjects with OPTEC 6500: influence of age and glare. Graefes 36(4):547-52. Arch Clin Exp Ophthalmol. 2007;245(12):1805-14. 4. Nielsen E, Hjortdal J. Visual acuity and contrast sensitivity after posterior lamellar kera 28. Chylack LT Jr, Wolfe JK, Singer DM, Leske MC, Bullimore MA, Bailey IL, et al. The Lens toplasty. Acta Ophthalmol. 2012;90(8):756-60. Opacities Classification System III. The Longitudinal Study of Cataract Study Group. Arch 5. Ginsburg AP. Contrast sensitivity: determining the visual quality and function of ca Ophthalmol. 1993;111(6):831-6. taract, intraocular lenses and refractive surgery. Curr Opin Ophthalmol. 2006;17(1):19-26. 29. Shaffer RN. Primary glaucomas. Gonioscopy, ophthalmoscopy and perimetry. Trans 6. Aslam T, Mahmood S, Balaskas K, Patton N, Tanawade R, Tan S, et al. Repeatability of Am Acad Ophthalmol Otolaryngol. 1960;64:112-27. visual function measures in age-related macular degeneration. Graefes Arch Clin Exp 30. Armstrong RA, Davies LN, Dunne MC, Gilmartin B. Statistical guidelines for clinical Ophthalmol. 2014;252(2):201-6. studies of human vision. Ophthalmic Physiol Opt. 2011;31(2):123-36. 7. Onal S, Yenice O, Cakir S, Temel A. FACT contrast sensitivity as a diagnostic tool in 31. Bühren J, Terzi E, Bach M, Wesemann W, Kohnen T. Measuring contrast sensitivity under glaucoma: FACT contrast sensitivity in glaucoma. Int Ophthalmol. 2008;28(6):407-12. different lighting conditions: comparison of three tests. Optom Vis Sci. 2006;83(5): 8. Zhang J, Zhou YH, Li R, Tian L. Visual performance after conventional LASIK and 290-8. wavefront-guided LASIK with iris-registration: results at 1 year. Int J Ophthalmol. 2013; 32. Lundh BL. Central and peripheral contrast sensitivity for static and dynamic sinusoidal 6(4):498-504. gratings in glaucoma. Acta Ophthalmol. 1985;63(5):487-92. 9. Ginsburg AP. Contrast sensitivity and functional vision. Int Ophthalmol Clin. 2003; 33. McKendrick AM, Sampson GP, Walland MJ, Badcock DR. Contrast sensitivity changes 43(2):5-15. due to glaucoma and normal aging: low-spatial-frequency losses in both magno- 10. Lahav K, Levkovitch-Verbin H, Belkin M, Glovinsky Y, Polat U. Reduced mesopic and cellular and parvocellular pathways. Invest Ophthalmol Vis Sci. 2007;48(5):2115-22. photopic foveal contrast sensitivity in glaucoma. Arch Ophthalmol. 2011;129(1):16-22. 34. Ansari EA, Morgan JE, Snowden RJ. Psychophysical characterisation of early functional 11. Yenice O, Onal S, Incili B, Temel A, Afşar N, Tanrıdag. Assessment of spatial-contrast loss in glaucoma and ocular hypertension. Br J Ophthalmol. 2002;86(10):1131-5. function and short-wavelength sensitivity deficits in patients with migraine. Eye (Lond). 35. Sun H, Swanson WH, Arvidson B, Dul MW. Assessment of contrast gain signature in 2007;21(2):218-23. inferred magnocellular and parvocellular pathways in patients with glaucoma. Vision 12. Richman J, Lorenzana LL, Lankaranian D, Dugar J, Mayer J, Wizov SS, et al. Importance Res. 2008;48(26):2633-41. of visual acuity and contrast sensitivity in patients with glaucoma. Arch Ophthalmol. 36. Patel PJ, Chen FK, Rubin GS, Tufail A. Intersession repeatability of contrast sensitivity 2010;128(12):1576-82. scores in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2009;50(6): 13. Hawkins AS, Szlyk JP, Ardickas Z, Alexander KR, Wilensky JT. Comparison of contrast 2621-5. sensitivity, visual acuity, and Humphrey visual field testing in patients with glaucoma. 37. Scilley K, Jackson GR, Cideciyan AV, Maguire MG, Jacobson SG, Owsley C. Early J Glaucoma. 2003;12(2):134-8. age-related maculopathy and self-reported visual difficulty in daily life. Ophthalmo- 14. Faria BM, Duman F, Zheng CX, Waisbourd M, Gupta L, Ali M, et al. Evaluating contrast logy. 2002;109(7):1235-42. sensitivity in Age-related macular degeneration using a novel computer-based test, 38. Browne C, Brazier J, Carlton J, Alavi Y, Jofre-Bonet M. Estimating quality-adjusted life the Spaeth/Richman contrast sensitivity test. Retina. 2015;35(7):1465-73. years from patient-reported visual functioning. Eye (Lond). 2012;26(10):1295-301. 15. Stangos N, Voutas S, Topouzis F, Karampatakis V. Contrast sensitivity evaluation in eyes 39. Wei H, Sawchyn AK, Myers JS, Katz LJ, Moster MR, Wizov SS, Steele M, Lo D, Spaeth GL. predisposed to age-related macular degeneration and presenting normal visual acuity. A clinical method to assess the effect of visual loss on the ability to perform activities Ophthalmologica. 1995;209(4):194-8. of daily living. Br J Ophthalmol. 2012;96(5):735-41. 16. Puell MC, Barrio AR, Palomo-Alvarez C, Gómez-Sanz FJ, Clement-Corral A, Pérez-Carrasco 40. Rubin GS, Bandeen-Roche K, Huang GH, Muñoz B, Schein OD, Fried LP, West SK. The MJ. Impaired mesopic visual acuity in eyes with early age-related macular degenera association of multiple visual impairments with self-reported visual disability: SEE tion. Invest Ophthalmol Vis Sci. 2012;53(11):7310-4. project. Invest Ophthalmol Vis Sci. 2001;42(1):64-72.

Arq Bras Oftalmol. 2016;79(5):323-7 327 Case Report

Coexistence of optic pit and coloboma of iris, lens, and choroid: a case report Coexistência de fosseta óptica e coloboma de íris, cristalino e coroide: um primeiro relato de caso

Ramazan Özelce1, Vuslat Gürlü1, Hande Güçlü1, Sadık Altan Özal1

ABSTRACT RESUMO A 42-year-old woman was admitted to our clinic with a complaint of glare in both Uma mulher de 42 anos de idade foi internada em nossa clínica com queixa de ofus eyes. Biomicroscopic examination of both the eyes revealed iris and lens colobomas camento em ambos os olhos. O exame biomicroscópico revelou coloboma de íris e in the inferior quadrant. Fundus examination of the right eye revealed an oval and cristalino no quadrante inferior em ambos os olhos. O exame de fundo do olho direito gray inferotemporal optic pit and two choroid colobomas in the inferior quadrant. revelou um fosseta óptica oval e acinzentada na região inferotemporal e dois colobomas In the left eye, two choroid colobomas were detected that were inferior to the coroide no quadrante inferior. No olho esquerdo, dois colobomas de coroide foram optic nerve head. Furthermore, a 21-year-old man presented to our clinic for a detectados inferiormente à da cabeça do nervo óptico. Outro homem de 21 anos routine ophthalmologic examination. Bilateral biomicroscopic examination was apresentou-se em nossa clínica para um exame oftalmológico de rotina. O exame normal. Fundus examination of the left eye revealed an oval and gray inferotem- biomicroscópico foi normal, bilateralmente. O exame de fundo do olho esquerdo poral optic pit and a choroid coloboma that was inferior to the optic nerve head. revelou uma fosseta oval e acinzentada de nervo óptico óptico inferotemporal e um Here we describe optic pits co-occurring with iris, lens, and choroidal colobomas. coloboma coroide inferior à cabeça do nervo óptico. Nestes relatos nós descrevemos On the basis of these cases, a defect in the closure of the embryonic fissure is the fossetas ópticas ocorrendo simultaneamente com colobomas de íris, cristalino, e co most plausible etiology of the optic pit. roide. Com base nestes casos, o defeito no fechamento da fissura embrionária é uma provável etiologia da fosseta óptica. Keywords: Coloboma; Eye abnormalities; Optic nerve abnormalities; Iris abnorma Descritores: Coloboma; Anormalidades do olho; Nervo óptico/anormalidades; Íris/ lities; Choroid abnormalities; Lens, crystalline abnormalities anormalidades; Coroide/anormalidades; Cristalino/anormalidades

INTRODUCTION was 18 mmHg. Fundus examination of the right eye revealed an oval Optic pit is a congenital anomaly of the optic nerve head that and gray inferotemporal optic pit and two choroid colobomas (one may cause acquired or congenital vision loss and serous macular de- was 2-disc size and an anteriorly located one was 8-disc size, exten- tachment(1). It usually occurs unilaterally and temporally on the optic ding to the equator) in the inferior quadrant (Figure 2 A). Under the disc, is round and gray, and may coexist with the cilioretinal artery. In left optic disc was a 4-disc-sized choroid coloboma that was covered the early phase, the optic pit is hypofluorescent on fundus fluorescein with a membrane with a 1-optic disc-sized hole. A second 7-disc-sized angiography (FFA); however, it is hyperfluorescent in the late phase(2). coloboma was detected at the anterior of the coloboma, and pig- Here we report two cases of co-occurring optic pit and uveal ment alterations were observed around both (Figure 2 B). No retinal coloboma, including the first published case of an optic pit accompa detachment was found, and the bilateral maculae were normal. In the nied by a unilateral iris, lens, and choroid coloboma. right eye, the optic pit revealed hypofluorescence in the early phase and relative hyperfluorescence in the late phase of FFA, as did the bilateral choroid colobomas (Figure 3). Results of optical coherence CASE 1 tomography (OCT) of the optic pit are shown in figures 3 C and 3 D. A 42-year-old woman was admitted with a complaint of glare in both the eyes. On ophthalmic examination, her best corrected visual acuity (BCVA) was 20/20 in both the eyes. Biomicroscopic examination CASE 2 of the right eye revealed iris and lens colobomas in the inferior qua- A 21-year-old man presented at our clinic for a routine bilateral drant, pigment precipitates on the lens, and posterior subcapsular ophthalmologic examination. His BCVA was 20/20 in the right eye cataract (Figure 1 A). In the left eye, there was an iris coloboma in the and 20/50 in the left eye, with a refraction of -4.00. Bilateral biomicros- inferonasal quadrant and iris septa near the limbus that connects the copic examination was normal. Intraocular pressure was 12 mmHg iris tissue, pigment precipitates on the lens, and a lens coloboma in in the right eye and 9 mmHg in the left eye. Fundus examination of the inferonasal quadrant (Figure 1 B). Bilateral intraocular pressure the left eye revealed an oval and gray inferotemporal optic pit and a

Submitted for publication: July 13, 2015 Funding: No specific financial support was available for this study. Accepted for publication: October 29, 2015 Disclosure of potential conflicts of interest: None of the authors have any potential conflicts of 1 Ophthalmology Department, Trakya University, Edirne, Turkey. interest to disclose. Corresponding author: Ramazan Özelce. Fatih Mah - Fatma Memik Sok. Ece Sitesi B Blok Daire:4 Edirne - 22100 - Turkey - E-mail: [email protected]

328 Arq Bras Oftalmol. 2016;79(5):328-9 http://dx.doi.org/10.5935/0004-2749.20160093 Özelce R, et al.

A B A B C

F igure 1. A) Iris coloboma of the right eye, case 1. B) Iris coloboma of the left F igure 3. A) Hypofluorescent optic pit and choroidal coloboma in the early phase eye, case 1. of FFA of the right eye, case 1. B) Relatively hyperfluorescent optic pit and choroidal coloboma in the late phase of FFA of the right eye, case 1. C) Colorless image of the right fundus captured by OCT and a red arrow cross the optic pit, case 1. D) A deep optic pit is seen in the horizontal section of an OCT image of the right eye, case 1.

A B

F igure 2. A) Optic pit and choroidal colobomas of the right eye, case 1. B) Choroi F igure 4. Optic pit and small choroidal coloboma inferior to optic nerve dal colobomas of the left eye inferior to the optic nerve, case 1. head, case 2.

choroid coloboma with half the size of an optic disc that was inferior coloboma. Choroidal coloboma in the first patient had a hole in it, but to the optic nerve head. Additionally, two cilioretinal arteries were retinal detachment was absent. Overall, a very small number of cases detected, one of which transited through the optic pit (Figure 4). The have been published regarding the co-occurrence of optic pits and macula was normal, and there was no retinal detachment in the left choroidal colobomas(4-7), and to the best of our knowledge, this is the eye. The fundus of the right eye was normal. first published description of optic pit accompanied by iris, lens, and choroid coloboma. On the basis of these cases, a defect in the closure DISCUSSION of the embryonic fissure appears to be the most plausible etiology of the optic pit. Two hypotheses have been proposed for optic pit development. The first proposes developmental anomaly of the primordial optic nerve(3), whereas the second attributes optic pit development to the REFERENCES (4-7) incomplete closure of the embryonic fissure . The coexistence of . 1 Corbett JJ, Savino PJ, Schatz NJ, Orr LS. Cavitary developmental defects of the optic disc. optic pits and uveal colobomas supports the latter hypothesis. Because Visual loss associated with optic pits and colobomas. Arch Neurol. 1980;37(4): 210-3. of the defective closure of the embryonic fissure, colobomas may arise 2. Brown GC, Shields JA, Goldberg RE. Congenital pits of the optic nerve head II. Clinical anywhere from the optic nerve head to the pupil. After invagination of studies in humans. Ophthalmology. 1980;87(1):51-65. the primary optic vesicle, the distal portion approaches the proximal 3. Gass JD. Serous detachment of the macula secondary to congenital pit of the optic nerve head. Am J Ophthalmol. 1969;67(6):821-41. part, thus creating the optic cup. Abnormal closure of the inner layer of 4. Singerman LJ, Mittra RA. Hereditary optic pit and iris coloboma in three generations the optic cup leads to chorioretinal coloboma, and the closure defect of a single family. Retina. 2001;21(3):273-5. (8) of the distal end of the embryonic fissure causes iris coloboma . 5. Brown GC, Augsberger JJ. Congenital pits of the optic nerve head and retinochoroi- Cases of optic pit co-occurring with serous macular detachment, dal colobomas. Can J Ophthalmol. 1980;15(3):144-6. choroidal coloboma, or retinochoroidal coloboma have been reported, 6. Gotsis S, Koutsandrea C, Apostopoulos M, Theodosiadis G. [Optic disk and choroidal both unilaterally(6,7) and bilaterally(5). One report described a 2-year-old coloboma]. J Fr Ophthalmol. 1989;12(10):683-5. French. patient with aniridia and with an optic pit in one eye and a morning 7. Saatci AO, Kocak N, Soylev FM. Unilateral coexistent optic pit and choroidal coloboma. glory anomaly in the other(9). The optic pit and iris coloboma develo- Neuroophthalmology. 2002;28(1):41-3. (4) 8. Pagon RA. Ocular coloboma. Surv Ophthalmol. 1981;25(4):223-36. ping in three generations of the same family have also been reported . 9. Traboulsi EI, Jurdi-Nuwayhid F, Torbey NS, Frangieh GT. Aniridia, atypical iris defects, Here we described a case of optic pit co-existing with iris, lens, and cho- optic pit and the morning glory disc anomaly in a family. Ophthalmic Paediatr Genet. roidal colobomas and a case of optic pit co-occurring with choroidal 1986;7(2):131-5.

Arq Bras Oftalmol. 2016;79(5):328-9 329 Case Report

Toxic anterior segment syndrome following deep anterior lamellar keratoplasty Síndrome tóxica do segmento anterior após transplante lamelar anterior profundo

Neslihan Sevimli1, Remzi Karadag2, Ozgur Cakici1, Huseyin Bayramlar2, Seydi Okumus3, Unsal Sari2

ABSTRACT RESUMO We present the case of a 31-year-old patient with toxic anterior segment syn- Apresentamos o relato de uma paciente com 31 anos de idade, que desenvolveu drome (TASS) that developed after undergoing deep anterior lamellar keratoplasty síndrome tóxica do segmento anterior (TASS) após o procedimento de transplante (DALK). She had keratoconus, and despite wearing hard contact lenses for many lamelar anterior profundo (DALK). Ela apresentava ceratocone e, apesar de ter usado years in the left eye, her vision had deteriorated; therefore, DALK was performed lentes de contato rígidas por muitos anos no olho esquerdo, apresentou deterioração on this eye. The preoperative visual acuity (VA) was finger counting at 3 m. Routine da visão nesse olho que foi submetido a procedimento DALK. A acuidade visual DALK was performed using the “big-bubble” technique. The corneal entry incision (VA) era de conta dedos a três metros. O procedimento DALK de rotina foi realizado was hydrated at the end of the surgery, which was terminated by air injection utilizando técnica de bolha grande (Big Bubble). A incisão de entrada da córnea into the anterior chamber. On postoperative day 1, VA was at the level of hand foi hidratada ao final da cirurgia que foi terminada com a injeção de ar na câmara movements, and the cornea was edematous. Topical high-dose dexamethasone anterior. No primeiro dia de pós-operatório a VA era de percepção de movimentos da and oral steroids were initiated considering the diagnosis of TASS. Subsequently, mão e a córnea estava edemaciada. Dexametasona tópica em alta dose e esteróides the patient’s VA increased, and the corneal edema decreased. We believe that the orais foram iniciadas ao se considerar o diagnóstico de TASS. Acreditamos que o uso use of re-sterilized cannulas may have been the likely cause of TASS. Although de cânulas reesterilizadas podem ter sido a causa provável da TASS. A VA melhorou DALK can be performed without interfering with the anterior chamber, one should e o edema da córnea do diminuiu durante a evolução. Embora o procedimento keep in mind that TASS may occur in response to the solution used to hydrate the DALK foi realizado sem interferir com câmara anterior, deve-se ter em mente que incision site and the air injected into the anterior chamber. TASS pode ocorrer com a solução utilizada para hidratar o local da incisão e o ar injetado na câmara anterior. Keywords: Keratoplasty; Anterior eye segment/pathology; Keratoconus; Corneal Descritores: Ceratoplastia; Segmento anterior do olho/patologia; Ceratocone; Trans transplantation plante de córnea

INTRODUCTION CASE REPORT Toxic anterior segment syndrome (TASS) is an acute and nonin A 32-year-old female patient consulted our clinic due to decrea fectious inflammation of the anterior segment. Most cases have been sed vision in her left eye. She was being followed for bilateral kera- reported as occurring after cataract surgery(1). Anterior segment toconus, and she had undergone penetrating keratoplasty in the inflammation usually occurs within 12-48 h after surgery, and the right eye. On examination, her visual acuity was 20/100 in the right symptoms include decreased visual acuity, increased intraocular eye and 3-m finger counting in the left eye, with a Snellen chart. The pressure, corneal edema, anterior chamber (AC) inflammation, fibrin patient had been using a hard contact lens in her left eye; however, formation, hypopyon, and fixed pupils. The vitreous body is not in- no improvement had been seen in her visual acuity, and the patient fected in this syndrome(2). had to undergo DALK in her left eye. The surgery was performed under Various contaminants, usually from surgical equipment or sup- general anesthesia, and topical anesthetic drops were not used, plies, including denatured ophthalmic viscosurgical devices (OVDs), although 10% povidone/iodine was used topically at the beginning preservatives, talc material in surgical gloves, topical ophthalmic of the surgery. Descemet’s membrane was detached using the ointment, inappropriately reconstituted intraocular preparations, “big-bubble” method during surgery. A microvitreoretinal (MVR) knife heat-stable endotoxins, and detergents have all been suspected as was used to reduce the AC pressure, and disposable trephine and causes of TASS(1-3). Further, cataract surgery(1-3), iris-supported phakic in- punch systems were used once to prepare the recipient bed and traocular lenses (IOLs)(4), penetrating keratoplasty(5), and Descemet’s donor cornea, respectively, and were discarded after use. The donor stripping automated endothelial keratoplasty (DSAEK)(6) have all cornea was sutured to the recipient bed with continuous suture, 360° been speculated as causing TASS. Most cases of TASS can be success- around, using 10/0 nylon after the endothelium was stripped. Then, fully treated with topical steroids and nonsteroidal anti-inflammatory the incision site was hydrated with balanced salt solution (BSS), air agents(3). To our knowledge, TASS the following DALK case has not was let into the AC (the bubble occupied 50% of the AC), and the been previously reported in the literature. operation was terminated. The air did not appear to have caused In this case report, we present a case of TASS following uncom- pupillary block. The BSS brand that we used was Ringer’s lactate, plicated DALK. which had not been used in any other prior surgery. No other drug

Submitted for publication: July 13, 2015 Funding: No specific financial support was available for this study. Accepted for publication: November 6, 2015 Disclosure of potential conflicts of interest: None of the authors have any potential conflicts of 1 Department of Ophthalmology, Istanbul Medeniyet University Goztepe Research and Training interest to disclose. Hospital, Istanbul, Turkey. 2 Corresponding author: Remzi Karadag. Department of Ophthalmology. School of Medicine. Istanbul Department of Ophthalmology, Istanbul Medeniyet University School of Medicine, Istanbul, Turkey. Medeniyet University - Goztepe, Istanbul - Turkey - E-mail: [email protected] 3 Department of Ophthalmology, Gaziantep University School of Medicine, Gaziantep, Turkey.

330 Arq Bras Oftalmol. 2016;79(5):330-2 http://dx.doi.org/10.5935/0004-2749.20160094 Seviml N, et al.

was topically or intracamerally applied, and moxifloxacin eye drops (0.1 ml) and dexamethasone solution (0.4 ml) were subconjunctivally A injected. Ointments were not used at the end of the surgery. Up to this point, we had been using the cannulas that have also been used for viscoelastic injection, a couple of times. To clean them, we routinely wash out the cannulas with distilled water, pass 10 ml of air with an injector through the lumen, and put them in the autoclave immediately after use to avoid waste sedimentation in the lumen. We do not use enzymatic or other cleaning detergents or an ultrasonic bath. During the postoperative course, topical loteprednol etabo- nate, antibiotic eye drops, and artificial tears drops were initiated. One day postoperatively, the patient had a moderately painful eye; her visual acuity was at the level of hand movements, and there was edema in the cornea. The pupil was mid-dilated, and light reactions were weak. There was no hypopyon in the AC, and no vitreous pathology on ultrasonography. Topical high-dose dexamethasone was initiated, and samples from the solution and donor cornea were sent to a microbiology laboratory. Oral steroids were started because the symptoms did not regress with treatment, and pupillary membrane B formation occurred despite treatment (Figure 1 A, B). There were no microorganisms in the cultures. At the follow-up visits, visual acuity increased, and the corneal edema and membrane formation decreased. Treatment was gradually discontinued. At the 18-month follow up, spectacle-corrected visual acuity was 4/10 with a Snellen chart, the cornea was clear, the pupil was mid-dilated, and iris pigments were present on the crystalline lens (Figure 2). We investigated the medical records and found that there had been no other cases of TASS at our institute over the same period (1 month before and after). In fact, we have not encountered more than three cases of TASS over the last year.

DISCUSSION TASS is an acute inflammation in the AC, and increasing rates F igure 1. A) Severe postoperative corneal edema; B) 5 days postoperatively, the corneal edema and pupillary membrane formation decreased. of TASS diagnosis have recently been found(1-3). It is important to differentiate TASS from postoperative endophthalmitis(7). Clinically, TASS occurs during the early postoperative period, with symptoms usually beginning within 12-48 h after surgery(1-3,7). However, it has been reported that early-onset endophthalmitis cases may be seen due to the presence of Staphylococcus epidermidis and Bacillus cereus similarly, which are also seen in TASS(3). Inflammation is restricted to the AC in TASS, and AC reaction, fibrin formation, hypopyon, and corneal edema are observed in this syndrome(8). TASS often occurs due to contamination of the surgical instruments used during surgery, OVDs, improper intraoperative drugs, or talc material in gloves(1-3,7). The most widely known risk factor is the procedures applied during sterilization(9). Maier et al. detected sterile keratitis in 24 patients following penetrating keratoplasty during the postoperative period. TASS was diagnosed, and they reported that the trephine system was responsible for the development of TASS(5). In a previous study, TASS was detected in three patients with foldable iris-fixated phakic IOLs. These patients were successfully treated with intensive topical steroids. They also reported that endotoxins in OVDs may cause TASS(4). Sorkin and Varssano reported a case of TASS following DSAEK, phacoemulsification, and IOL implantation. F igure 2. Slit-lamp image at 18 months follow up. The patient was successfully treated with cycloplegic and topical steroids(6). There have been reports of TASS following penetrating keratoplasty(5) and DSAEK(6) in the literature, but there has never been a occurred from the first incision. We used a re-sterilized cannula for reported case of TASS following DALK. In our case, TASS occurred hydrating the incision with BSS and letting air into the AC, and we following uncomplicated DALK. In contrast to penetrating kerato- believe that this cannula was the cause of the development of TASS. plasty and DSAEK, entry into the AC is extremely rare in DALK. The The small amount of liquid used to inflate the incision can escape purpose of entering the AC is to open a side-port with an MVR knife into the AC. If a cannula is used without sterilization or is not cleaned to reduce the AC pressure, thus allowing the side-port to be hydrated with plenty of fluids, particles remaining in the cannula could cause with BSS solution and letting some air into the AC. In our case, we TASS. The same situation applies during the process of letting air into used disposable MVR blades. Therefore, we do not believe that TASS the AC. These processes are the final stages of the operation, so if any

Arq Bras Oftalmol. 2016;79(5):330-2 331 Toxic an terior segmen t syndrome following deep an terior lamellar kera toplasty

particles enter the AC during these processes, they will not be remo- 2. Centers for Disease Control and Prevention (CDC). Toxic anterior segment syndrome ved, and may lead to a reaction. TASS is mostly reported after cataract after cataract surgery--Maine, 2006. MMWR Morb Mortal Wkly Rep. 2007;29;56(25): surgery(1-3). There is plenty of irrigation from phaco equipment during 629-30. 3. Holland SP, Morck DW, Lee TL. Update on toxic anterior segment syndrome. Curr Opin phacoemulsification, and more fluid is used during this surgery. The- Ophthalmol. 2007;18(1):4-8. refore, even if there are particles in the cannula, they may be cleaned 4. van Philips LA. Toxic anterior segment syndrome after foldable artiflex iris-fixated phakic or diluted with more liquid, thus lowering the risk of a reaction. intraocular lens implantation. J Ophthalmol. 2011;2011:982410. Contact with the AC is relatively lesser during DALK than during 5. Maier P, Birnbaum F, Böhringer D, Reinhard T. Toxic anterior segment syndrome other similar procedures. This contact is during the final stages of following penetrating keratoplasty. Arch Ophthalmol. 2008;126(12):1677-81. the operation, and thus, it is important to use a new cannula, or if it 6. Sorkin N, Varssano D. Toxic anterior segment syndrome following a triple descemet’s stripping automated endothelial keratoplasty procedure. Case Rep Ophthalmol. is absolutely necessary to re-use it, it should be cleaned by passing 2012;3(3):406-9. plenty of fluids through it. 7. Gopal L, Vijaya L. Toxic anterior segment syndrome. Br J Ophthalmol. 2013;97(8):953. 8. Choi JS, Shyn KH. Development of toxic anterior segment syndrome immediately after uneventful phaco surgery. Korean J Ophthalmol. 2008;22(4):220-7. REFERENCES 9. Cutler Peck CM, Brubaker J, Clouser S, Danford C, Edelhauser HE, Mamalis N. Toxic 1. Mamalis N, Edelhauser HF, Dawson DG, Chew J, LeBoyer RM, Werner L. Toxic anterior anterior segment syndrome: Common causes. J Cataract Refract Surg. 2010;36(7): segment syndrome. J Cataract Refract Surg. 2006;32(2):324-33. 1073-80.

XX Congresso da Sociedade Brasileira de Uveítes

9 a 11 de março de 2017 Espaço de Eventos Unimed Belo Horizonte - MG

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332 Arq Bras Oftalmol. 2016;79(5):330-2 Case Report

Adenoid cystic carcinoma of the lacrimal sac: case report Carcinoma adenóide cístico do saco lacrimal: relato de caso

Antonio Ramos1, Carmen Del Pozo1, Ana Chinchurreta1, Fernando García1, Mercedes Lorenzo1, Saturnino Gismero1

ABSTRACT RESUMO Lacrimal sac tumors are rare with a clinical presentation that typically includes Tumores do saco lacrimal são raros. A apresentação clínica muitas vezes mostra uma obstruction of the lacrimal drainage system and epiphora as the most frequent obstrução no sistema de drenagem lacrimal sendo a epífora o sinal mais frequente. Car symptom. Cribriform adenoid cystic carcinoma (ACC) is the most common malig- cinoma adenóide cístico cribriforme (ACC) é o tumor epitelial maligno mais comum nant epithelial tumor of the lacrimal gland and minor salivary glands; however, its da glândula lacrimal e glândulas salivares menores, mas a sua ocorrência no aparelho occurrence in the lacrimal drainage apparatus is extremely rare. Given the rarity of de drenagem lacrimal é extremamente rara. Infelizmente, devido a raridade destes ACC, definitive diagnosis is almost invariably late conferring a poor prognosis. Herein tumores, o diagnóstico preciso é quase sempre atrasado, o que por sua vez leva a we report the case of a 41-year-old woman with primary ACC of the lacrimal sac um pior prognóstico. Nós relatamos o caso de uma mulher de 41 anos de idade, com and describe the ophthalmological examination, diagnosis, and multidisciplinary ACC primário do saco lacrimal e analisamos o exame oftalmológico, diagnóstico e treatment of this rare type of tumor. tratamento multidisciplinar deste tipo de tumor. Keywords: Carcinoma; Adenoid cystic/diagnosis; Lacrimal apparatus diseases; Eye Descritores: Carcinoma adenoide cístico/diagnóstico; Carcinoma adenoide cístico/ neoplasms terapia; Doenças do aparato lacrimal; Neoplasias oculares

INTRODUCTION In August 2013, the patient was re-attended complaining of Lacrimal sac tumors are rare with a typically non-specific presen- pain in the right canthus and mucosanguineous secretions from the tation. As the most common signs of lacrimal sac tumors are epiphora lacrimal punctum in response to pressure. A new DCG was performed or presence of a mass, the process can be incorrectly diagnosed as demonstrating a filling defect in the sac without passage of contrast dacryostenosis or chronic dacryocystitis (DC)(1-4). Consequently, defi- into the distal duct. Orbital magnetic resonance imaging identified nitive diagnosis is delayed leading to worsened prognosis(5). a solid-cystic lesion measuring 17 × 17 × 13 mm in the right lacrimal Adenoid cystic carcinoma (ACC) is an extremely rare form of sac seen extending towards the orbit and infiltrating the extraconal malignant epithelial neoplasia of the lacrimal sac. However, it is the fatty tissue (Figure 1). Right dacryocystectomy was performed follo- most common type of malignant epithelial tumor of the lacrimal and wing observation of a gelatinous mass infiltrating the lacrimal sac and minor salivary glands(6,7). To date, 11 cases of ACC of the lacrimal sac eroding the surrounding bony structures. Pathologic examination have been reported in literature (Table 1). demonstrated ACC with a predominantly cribriform pattern infiltra- We report the case of a 41-year-old woman with a right lacrimal ting the muscle and bone tissue with additional perineural infiltration sac ACC with a follow-up duration of 24 months post surgery. (Figure 2). In the extension study, no signs of tumor spread were evident. Further intervention with right lateral rhinotomy located the CASE REPORT mass to the canthal area. The tumor planes were dissected and an A 41-year-old Caucasian woman presented to our department in osteotomy was performed from the canthal ligament to the orbital August 2012 with a 2-year history of lacrimation and pain affecting floor. The orbital floor was reconstructed before tension-free closure the medial canthus of the right eye. The lacrimal drainage system was and approximation of the rhinotomy flap. Pathological examination permeable; however, reflux of mucopurulent material was observed. of the dissected tissues confirmed the existence of ACC. Following Dacryocystography (DCG) demonstrated a patent pathway with for- surgery, the patient had a favorable clinical course. A multidisciplina- ced passage of contrast from the lacrimal sac. Tumoral pathology was ry approach was established, and the patient received 33 sessions of not suspected, and the patient was diagnosed with dacryocystitis radiotherapy with no signs of recurrence observed after a follow-up and started on topical and systemic antibiotic treatment accordingly. for 2 years.

Submitted for publication: July 24, 2015 Funding: No specific financial support was available for this study. Accepted for publication: November 9, 2015 Disclosure of potential conflicts of interest: None of the authors have any potential conflict of 1 Department of Ophthalmology, Costa del Sol Hospital, Marbella, Malaga, Spain. interest to disclose. Corresponding author: Antonio Ramos. Department of Ophthalmology. Hospital Costa del Sol. Autovia A-7 Km 187 - Marbella, Málaga 29603 - Spain - E-mail: [email protected]

http://dx.doi.org/10.5935/0004-2749.20160095 Arq Bras Oftalmol. 2016;79(5):333-5 333 Adenoid cystic c arcinoma of the l acrimal sac: ce as report

Table 1. Summary of previously reported clinical cases Age Sex Side Presentation Treatment Recurrence Follow-up interval Author 62 F Right 2 years epiphora. Lacrimal sac Enbloc excision of the tumor with No 14 months L. Miller et al.(8) mass (without data specification) exenteration of the orbit, radical maxillectomy, and ethmoidectomy. 57 F Left Epiphora and swelling of the Orbital exenteration. Further Lung metastases 48 months after C. Kincaid et al.(3) left lower lid (without data treatment: CT. after 2 years. which she was lost specification) to follow-up. 38 F Not specified Not specified Surgery No 60 months A. Stefanyszyn et al.(1)

51 F Not specified Not specified Not specified No 60 months A. Stefanyszyn et al.(1) 64 F Not specified Not specified Not specified No 60 months A. Stefanyszyn et al.(1) 41 M Left 1 month epiphora and lacrimal Surgery and RT No 12 months R. Parnel l et al.(9) sac mass 72 M Right 1 year epiphora and lacrimal Orbital exenteration and RT for Lung metastases 192 months DN. Parmar et al.(2) sac mass pulmonary metastases after 16 years

62 F Not specified Epiphora, epistaxis and nasal Surgery and RT Not specified Not specified O. Choussy et al.(10) obstruction (without data specification) 74 M Right Tearing associated with a Exclusive RT No Death at 30 months A. Montalban et al.(5) palpable mass in the internal canthus (without data specification) 48 F Not specified Mass Globe sparring surgery, RT, and CT Metastatic disease Death at 48 months T. El-Sawy et al.(11) 70 M Not specified Mass Globe sparring surgery, RT, and CT No 6 months T. El-Sawy et al.(11) F= female; M= male; RT= radiotherapy; CT= chemotherapy.

DISCUSSION Epiphora is the most common clinical sign of lacrimal sac tumors(1-4). These tumors may also present as masses in the canthal area. Sangui- neous discharge (spontaneous or on lacrimal sac irrigation), epistaxis, pain, and skin ulceration are all highly suspicious of malignancy. Pathologically, lacrimal sac tumors can be divided into epithelial tumors, mesenchymal tumors, lymphomatous lesions, melanoma, and neuronal tumors. Inflammatory lesions are not true neoplasms but appear as masses in the lacrimal sac with similar symptoms(1). The most common malignant tumors affecting the lacrimal sac are of the epithelial type, with squamous subtype having the highest incidence within this group. ACC is an extremely unusual entity in the lacrimal drainage system(1,2,4). ACC is slow-growing(6,7) but has a tendency for perineural invasion and spread to adjacent tissues, such as the bone(4,8). Local recurrence is frequently observed several years after surgical excision. Although a late finding, hematogenous metastases are possible and(7) most commonly affect the lungs. Local lymph node involvement is rare(5-7). From a histological standpoint, there are three types of ACC: cribriform, tubular, and solid. Cribriform pattern foci are generally constant even when a different histological tumor type predominates. The cribriform pattern is the most common and associated with the best prognosis, whereas the solid type is less frequent but has a poorer prognosis(3,7,8). The most appropriate approach to the management of lacrimal sac tumors depends more on the tumoral size and the general condition of the patient rather than the histological type(5). The classi cal treatment of malignant lacrimal sac tumors has been complete excision of the tumor and lacrimal drainage system, including the canaliculi and nasolacrimal duct, followed by radiotherapy and/or adjuvant chemotherapy(1,9). At present, a multidisciplinary approach to (11) disease treatment is essential in obtaining the best clinical outcomes . F igure 1. Solid-cystic lesion occupying the right lacrimal sac region consistent The need to perform orbital exenteration versus more conservative with a neoplastic process.

334 Arq Bras Oftalmol. 2016;79(5):333-5 Ramos A, et al.

CONCLUSION Lacrimal sac tumors should be considered in any case of epiphora or dacryocystitis that does not improve with dacryocystorhinostomy. Imaging studies are required to rule out the presence of a lacrimal drainage system tumor. The finding of a mass or gelatinous tissue during dacryocystorhinostomy may require termination of the procedure or performance of a biopsy and imaging studies to rule out the existence of neoplasia(11). Ophthalmologists should be aware of the characteristic triad of primary lacrimal sac tumors, which includes the clinical findings of persistent dacryocystitis or epiphora, an irreducible mass, and abnormal dacrycystography. Delayed diagnosis may worsen the prognosis of this rare type of malignant tumor.

REFERENCES 1. Stefanyszyn MA, Hidayat AA, Jacob J, Flanagan JC. Lacrimal sac tumors. Ophthal Plast Reconstr Surg. 1994;10(3):169-84. 2. Parmar DN, Rose GE. Management of lacrimal sac tumors. Eye (Lond). 2003;17(5): 599-606. F igure 2. Presence of basophilic mucoid material in pseudocystic areas (hematoxylin-eosin 3. Kincaid MC, Meis JM, Lee MW. Adenoid cystic carcinoma of the lacrimal sac. Ophthal- stain, ×20 times magnification). mology. 1989;96(11):1655-8. 4. Ni C, D’Amico DJ, Fan CQ, Kuo PK. Tumors of the lacrimal sac: a clinicopathological ana lysis of 82 cases. Int Ophthalmol Clin. 1982;22(1):121-40. 5. Montalban A, Liétin B, Louvrier C, Russier M, Kemeny JL, Mom T, et al. Malignant surgery should always be evaluated individually, as exenteration lacrimal sac tumors. Eur Ann Otorhinolaryngol Head Neck Dis. 2010;127(5):165-72. (2) 6. Chawla B, Kashyap S, Sen S, Bajaj MS, Pushker N, Gupta K, et al. Clinicopathologic does not ensure a better prognosis and causes substantial facial review of epithelial tumors of the lacrimal gland. Ophthal Plast Reconstr Surg. 2013; disfigurement that may lead to severe psychological and psychiatric 29(6):440-5. disorders. 7. Lukšić I, Suton P, Macan D, Dinjar K. Intraoral adenoid cystic carcinoma: is the presence Following appropriate treatment, patients must undergo life- of perineural invasion associated with the size of the primary tumor, local extension, long follow-up given the high rate of local recurrence of lacrimal surgical margins, distant metastases, and outcome? Br J Oral Maxillofac Surg. 2014;52(3): sac tumors(11). Because of the poor specificity of clinical symptoms, 214-8. 8. Miller CL, Offutt WN, Kielar RA. Adenoid cystic carcinoma of the antrum and epiphora. clinicians must have a high degree of suspicion to arrive at a prompt Am J Ophthalmol. 1977;83(4):582-6. definitive diagnosis. Lacrimal sac tumors should be considered in any pa- 9. Parnell JR, Mamalis N, Davis RK, Flaharty PM, Anderson RL. Primary adenoid cystic car- tient with chronic epiphora or dacryocystitis who does not respond cinoma of the lacrimal sac: report of a case. Ophthal Plast Reconstr Surg. 1994;10(2): to standard treatments. Radiological studies with DCG, Computed 124-9. Tomography (CT)-DCG, CT, and magnetic resonance imaging are 10. Choussy O, Babin E, Delas B, Bailhache A, François A, Marie JP, et al. Les tumeurs malignes (1,5) primitives des voies lacrymales. Ann Otolaryngol Chir Cervicofac. 2007; 124(6):309-13. essential in ruling the possibility of a lacrimal sac tumor . In any case, 11. El-Sawy T, Frank SJ, Hanna E, Sniegowski M, Lai SY, Nasser QJ, et al. Multidisciplinary pathological examinations are required for a definitive diagnosis of management of lacrimal sac/nasolacrimal duct carcinomas. Ophthal Plast Reconstr lacrimal sac tumor(4). Surg. 2013;29(6):454-7.

XIII Congresso Sul-Brasileiro de Oftalmologia

31 de março a 1o de abril de 2017 Sede da Associação Catarinense de Medicina Florianópolis - SC

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Arq Bras Oftalmol. 2016;79(5):333-5 335 Case Report

Bilateral acute angle-closure glaucoma as a first presentation of granulomatosis with polyangiitis (Wegener’s) Glaucoma de ângulo fechado bilateral agudo como uma primeira apresentação da granulomatose com poliangeíte (de Wegener)

Alper Mete1, Sabit Kimyon1, Oguzhan Saygili1, Can Pamukcu2, Kıvanç Güngör1

ABSTRACT RESUMO We report a case of bilateral acute angle-closure glaucoma in a patient with Relatamos um caso glaucoma bilateral agudo de ângulo fechado em um paciente undiagnosed granulomatosis with polyangiitis (Wegener’s). A 59-year-old man sem diagnóstico prévio de granulomatose com poliangeíte (Wegener). Um homem presented with a severe headache, ocular pain, blurred vision, shortness of de 59 anos apresentou-se com uma forte dor de cabeça, dor nos olhos, visão turva, breath, and mild fever. Clinical examination revealed conjunctival chemosis, dificuldade em respirar e febre baixa. Observamos quemose conjuntival, edema da corneal edema, and shallow anterior chambers. Closed angles were observed córnea e câmara anterior rasa. A gonioscopia demonstrou ângulos fechados bila bilaterally on gonioscopy. The patient was treated with intravenous mannitol, teralmente. Ele foi tratado com manitol intravenoso, acetazolamida oral, olho e oral acetazolamide, and anti-glaucomatous eye drops. Over the following two colírios antiglaucomatosos. Durante os dois dias seguintes a sua visão melhorou e days, his vision improved and intraocular pressures decreased. Subsequently, laser as pressões intra-oculares diminuíram. A seguir, foram realizadas iridotomias a laser iridotomies were performed bilaterally and the patient attended consultations bilateralmente e ele foi referido para os departamentos de doenças pulmonares, with our departments of respiratory medicine, nephrology, and rheumatology nefrologia e reumatologia. Ele foi diagnosticado com poliangeíte granulomatosa. and was subsequently diagnosed with granulomatosis with polyangiitis. Bilateral Glaucoma bilateral agudo de ângulo fechado é uma entidade clínica muito rara e sua acute angle-closure glaucoma is a very rare ocular manifestation of granuloma associação com a granulomatose de Wegener é desconhecida e deve acrescentar-se tosis with polyangiitis. The association of this clinical entity with Wegener’s à lista de manifestações oculares de granulomatose com poliangeíte. granulomatosis remains unknown. Keywords: Glaucoma, angle-closure/diagnosis; Acute disease/diagnosis; Granu- Descritores: Glaucoma de ângulo fechado/diagnóstico; Doença aguda/diagnóstico; lomatosis with polyangiitis/diagnosis; Vasculitis Granulomatose com poliangiíte/diagnóstico; Vasculite

INTRODUCTION immediately referred to the Ophthalmology Department, Gaziantep Granulomatosis with polyangiitis (Wegener’s) predominantly University for further evaluation and treatment. affects the upper and lower respiratory tracts, lungs, and kidneys and On initial examination, his best-corrected visual acuity (BCVA) was represents a rare multisystem necrotizing granulomatous vasculitis 20/200 in both eyes (OU). IOPs were measured using an applanation of small-sized vessels. Central nervous system, cutaneous, heart, tonometer and recorded as 43 mmHg and 47 mmHg in the right and gastrointestinal tract, orbital, and ocular involvement may also be left eye, respectively. On slit-lamp examination we observed bilateral observed(1). Ocular or orbital involvement in granulomatosis with conjunctival chemosis, mild corneal edema, shallow anterior chambers, polyangiitis is reportedly occurs in 20-50% of patients(2,3). and immature senile cataracts. On gonioscopy, we observed angle Bilateral acute angle-closure (AAC) glaucoma is a very rare clinical closure in the superior and lateral quadrants (Shaffer Classification, entity that is generally caused by the use of various topical or syste- Grade 0), and Grade 1 angle closure in the inferior and medial quadrants. mic medications, many of which are known to cause pupillary dilata There was no evidence of previous angle closure glaucoma, such as tion, emotional stress, dim illumination, surgical anesthesia, viral iris atrophy or glaucomflecken. He had no previous glaucoma-related infections, systemic vasculitis, and subarachnoid hemorrhage(4-7). To medical history. We initially planned treatment with timolol maleate, our knowledge, this is the first reported case of granulomatosis with 0.5% twice daily; brimonidine, 0.15% twice daily; pilocarpine, 1% polyangiitis presenting with bilateral acute angle-closure glaucoma. four times daily; oral acetazolamide, 250 mg four times daily; and 350 ml mannitol, 20% intravenously. Six hours later, IOPs dropped to 28 mmHg bilaterally. The following day, we continued topical CASE REPORT anti-glaucomatous medication and oral acetazolamide. His BCVA A 59-year-old Caucasian man presented to a local ophthalmo- improved to 20/30 and 20/40 in the right and left eye, respectively. logist with acute bilateral onset of ocular pain, blurred vision, and a His IOP dropped to 19 mmHg and 20 mmHg in the right and left severe headache. He was diagnosed with bilateral AAC glaucoma and eyes, respectively. On slit-lamp examination, we observed resolution

Submitted for publication: September 22, 2015 Funding: No specific financial support was available for this study. Accepted for publication: December 2, 2015 Disclosure of potential conflicts of interest: None of the authors have any potential conflict of 1 Department of Ophthalmology, School of Medicine, Gaziantep University, Gaziantep, Turkey. interest to disclose. 2 Department of Ophthalmology, Hatem Private Hospital, Gaziantep, Turkey. Corresponding author: Alper Mete. Gaziantep University. School of Medicine - Department of Ophthalmology - Gaziantep 27310 - Turkey - E-mail: [email protected]

336 Arq Bras Oftalmol. 2016;79(5):336-8 http://dx.doi.org/10.5935/0004-2749.20160096 Mete A, et al.

of the mild corneal edema, reduction in conjuctival chemosis, and ground glass opacities with nodular consolidation in the right upper improved anterior chamber depth which continued to be shallow lobe. Enlarged bilateral axillary, paratracheal, and carinal lymph nodes peripherally (Figure 1). Undilated fundus examination demonstrated were also noted (Figure 2 A, B). Subsequently, he was evaluated by normal optic discs and maculae in both eyes. Subsequently, YAG laser our departments of rheumatology and nephrology. Abdominal CT iridotomies were performed 36 hours after the initial examination. and ultrasonography revealed bilateral cysts within the kidney paren- On the third day, IOPs were 11 mmHg in the right eye and 13 mmHg chyma. Pathological examination of a kidney biopsy specimen was in the left eye with topical and oral anti-glaucomatous medication. reported as consistent with focal and segmental glomerulosclerosis Therefore, oral acetazolamide was stopped at this time. (FSGS) with chronic tubulointerstitial changes. Additional laboratory The patient reported a one-week duration of shortness of breath and mild fever at the initial presentation. We therefore arranged a evaluations revealed the presence of autoantibodies to neutrophil consultation with our department of respiratory medicine on the cytoplasmic components (cytoplasmic anti-neutrophil cytoplasmic first day of hospitalization. Laboratory examinations and radiological antibodies, C-ANCA) with proteinase-3 (PR3) specificity. Granuloma- evaluations were planned by the same department. Serological exa- tosis with polyangiitis (Wegener’s) was diagnosed accordingly and mination demonstrated an elevated erythrocyte sedimentation rate, treatment with cyclophosphamide and prednisolone was initiated. proteinuria, and elevated levels of C-reactive protein, urea, and creati The patient attended a follow-up visit one week later and reported nine. Chest radiography and computed tomography (CT) revealed complete resolution of his ocular symptoms. His BCVA had improved

A B

C D

E F

G H

F igure 1. A, B) Sirius topography revealed narrow angles in both eyes on the second day. C, D) Slit-lamp examination of both eyes on the second day. E, F) Slit-lamp examination of both eyes following laser iridotomy. G, H) B-scan ultrasonography of both eyes on the second day.

Arq Bras Oftalmol. 2016;79(5):336-8 337 Bilateral acute angle-closure glaucoma as a first presentation of granulomatosis with polyangiitis (Wegener ’s)

A B C

F igure 2. A) Chest radiography revealed bilateral opacities consistent with focal consolidation. B) Chest CT demonstrated ground glass opacities with focal regions of consolidation in the right upper lobe. C) Chest CT at 3 months after systemic cyclophosphamide and prednisolone therapy demonstrated complete resolution of nodular opacities in the right upper lobe.

to 20/20 and 20/25 in the right and left eye, respectively. IOPs were or fundus examination. Therefore, we believe AAC glaucoma in our 15 mmHg in the right eye and 16 mmHg in the left eye. Openings patient was most likely due to the development of mydriasis. created by laser iridotomy were seen to be patent. Gonioscopy An accurate diagnosis of granulomatosis with polyangiitis is de revealed angles open to the scleral spur bilaterally. All systemic pendent on comprehensive clinical examinations and supporting symptoms continued to gradually improve with systemic treatment pathology evaluations. Early diagnosis and treatment of granuloma- (Figure 2 C). tosis with polyangiitis may prevent the development of serious asso ciated complications. To the best of our knowledge, this is the first DISCUSSION report of bilateral AAC glaucoma as the initial presenting symptom of granulomatosis with polyangiitis. The findings in the present case Granulomatosis with polyangiitis, formerly known as Wegener’s demonstrate AAC glaucoma as a rare but significant manifestation of granulomatosis, commonly involves the upper and lower respira- granulomatosis with polyangiitis. tory tracts and kidneys. Ocular or orbital manifestations are present in approximately one-tenth of patients with granulomatosis with polyangiitis(8). Ocular involvement can range from mild conjunctivitis REFERENCES and episcleritis to more severe inflammation with peripheral ulserati- 1. Newman NJ, Slamovits TL, Friedland S, Wilson WB. Neuro-ophthalmic manifestations ve keratitis, scleritis, uveitis, and retinal vasculitis. Orbital involvement of meningocerebral inflammation from the limited form of Wegener’s granulomatosis. Am J Ophthalmol. 1995;120(5):613-21. may cause proptosis, diplopia, restrictive myopathy, and compressive 2. Bullen CL, Liesegang TJ, McDonald TJ, DeRemee RA. Ocular complications of (8) optic neuropathy, as a consequence of orbital inflammation . Ocular Wegener’s granulomatosis. Ophthalmology. 1983;90(3):279-90. or orbital manifestations may result from a variety of pathologies, 3. Haynes BF, Fishman ML, Fauci AS, Wolff SM. The ocular manifestations of Wegener’s including focal vasculitis of small-sized vessels, granulomatous in- granulomatosis. Fifteen years experience and review of the literature. Am J Med. flammation, vascular thrombosis, hemorrhage, or as a consequence 1977;63(1):131-41. (9) 4. Hunter TG, Chong GT, Asrani S, Allingham RR, Blumberg DM. Simultaneous bilateral of chronic inflammation or ischemia . AAC glaucoma has been pre- angle closure glaucoma in a patient with giant cell arteritis. J Glaucoma. 2010;19(2): (4-6) viously reported to be associated with other vasculitides . The exact 149-50. mechanisms underlying the association between AAC glaucoma 5. Yao J, Chen Y, Shao T, Ling Z, Wang W, Qian S. Bilateral acute angle closure glaucoma and systemic vasculitis are yet to be elucidated. Choroidal ischemia as a presentation of vogt-koyanagi-harada syndrome in four chinese patients: a small case secondary to vasculitis may cause choroidal thickening of an already series. Ocul Immunol Inflamm. 2013;21(4):286-91. 6. Kranemann CF, Buys YM. Acute angle-closure glaucoma in giant cell arteritis. Can J narrow angle, which may then precipitate an acute episode of glau- Ophthalmol. 1997;32(6):389-91. coma. Previous studies have reported that a 20% increase in choroidal 7. Ceruti P, Morbio R, Marraffa M, Marchini G. Simultaneous bilateral acute angle-closure thickness is sufficient to result in a forward shift of the iris against glaucoma in a patient with subarachnoid hemorrhage. J Glaucoma. 2008;17(1):62-6. the cornea and acute development of glaucoma(10). Alternatively, iris 8. Perez VL, Chavala SH, Ahmed M, Chu D, Zafirakis P, Baltatzis S et al. Ocular manifesta- sphincter ischemia secondary to vasculitis, AAC glaucoma, or increa tions and concepts of systemic vasculitides. Surv Ophthalmol. 2004;49(4):399-418. 9. Pakrou N, Selva D, Leibovitch I. Wegener’s granulomatosis: ophthalmic manifestations sed sympathetic output due to pain related to vasculitis may cause and management. Semin Arthritis Rheum. 2006;35(5):284-92. (6) mydriasis and precipitate acute glaucoma . In the present case, we 10. Quigley HA, Friedman DS, Congdon NG. Possible mechanisms of primary angle closure did not observe choroidal thickening on B-Scan ultrasonography and malignant glaucoma. J Glaucoma. 2003;12(2):167-80.

338 Arq Bras Oftalmol. 2016;79(5):336-8 Case Report

Management of necrotizing scleritis after pterygium surgery with rituximab Tratamento com rituximabe de esclerite necrosante após cirurgia de pterigeo

Tania Sales de Alencar Fidelix1, Luis Antonio Vieira1, Virginia Fernandes Moca Trevisani1

ABSTRACT RESUMO The authors present a case of necrotizing scleritis after pterygium excision Os autores apresentam um caso de sucesso no tratamento com rituximabe de successfully treated with rituximab after attempts with high doses of corticos esclerite necrosante após cirurgia de pterígio refratário a altas doses de corticoste- teroids and immunosuppressive drugs. A literature review revealed case roides e drogas imunossupressoras. Uma revisão da literatura direcionada ao uso de reports and a phase I/II dose-ranging randomized clinical trial using rituximab rituximabe para tratamento de esclerites necrosantes revelou relatos de casos e um for necrotizing scleritis with or without association with autoimmune disease. estudo clínico randomizando fase I/II. Este é o único caso descrito de rituximabe para This is the only case report on rituximab treatment for necrotizing scleritis after o tratamento de esclerite necrosante pós cirúrgica. O uso de anticorpo anti-CD20 pterygium surgery. In cases with refractoriness to immunosuppressive drugs, a pode ser uma opção em casos refratários aos imunossupressores no tratamento da CD20 antibody can be used. esclerite necrosante pós-cirúrgica. Keywords: Scleritis; Pterygium/surgery; Rituximab/therapeutic use; Antibodies, Descritores: Esclerite; Pterígio/cirurgia; Rituximabe/uso terapêutico; Anticorpos mo monoclonal/administration and dosage noclonais/administração & dosagem

INTRODUCTION necrosis. Complete hematology and immunology profiles for rheu- Scleritis is currently recognized as a heterogeneous group of matoid arthritis, antinuclear antibody (ANA), and anti-neutrophil cy diseases characterized by inflammation of the sclera, which may toplasmic antibodies (ANCA) were determined, which showed that be caused by a local or systemic infection, an immune-mediated only ANA was positive and extractable nuclear antigen antibodies disease, or a primary manifestation of an acquired connective tissue (ENA) were negative. Serology tests, such as venereal disease resear ch disorder or vasculitic disease, often signaling a life-threatening situa laboratory test, Treponema pallidum hemagglutination assay, and tion(1,2). Surgically induced necrotizing scleritis (SINS) occurs after tuberculin test, were all negative. ocular surgeries for cataract extraction, trabeculectomy, strabismus, She was further evaluated in the Rheumatology Department and pterygium retinal detachment(3). because of generalized pain and ANA positivity. Combined with la The diagnosis and treatment of these special cases using immu- boratorial analysis showing normal renal, hematological, and hepatic nosuppressive patch grafts or amniotic membrane grafts should be functions and negativity for anti-double stranded DNA (dsDNA), prompt(4). Immunosuppressive agents used to treat these conditions ANCA, ENA, rheumatoid factor, and anti-cyclic citrullinated peptide include azathioprine, cyclophosphamide, tacrolimus, and high-dose antibody (anti-CCP), a diagnosis of fibromyalgia and SINS was made, pulse methylprednisolone(4). Although other biological agents can be and the patient was promptly treated with high-dose corticoste- used, particularly for the treatment of necrotizing scleritis, which po- roids. However, 1 month later, she presented with aggravated scleral tentially represents vasculitis, rituximab is generally recommended thinning; thus, immunosuppressive agents (2 mg/kg of azathioprine for the treatment of systemic vasculitis(5). and 1 g/m2/month of intravenous cyclophosphamide) were added to corticosteroid therapy for 12 months. However, remission was not achieved and necrotizing scleritis of the right eye continued. There CASE REPORT fore, rituximab treatment was initiated, which resulted in improve- Our patient was a 51-year-old woman who presented with a ment after the first cycle of two infusions of 1 g each administered 2 chief complaint of redness and pain affecting both eyes. She pre- weeks apart. Visual acuity was preserved in the left eye but decreased viously underwent (2-3 months before) pterygium excision using from 20/20 to 20/160 in the right eye. The prednisone dose was the bare sclera technique, without the use of adjunctive irradiation tapered off, and after 3 months, the patient was free from all drugs or mitomycin C. An ophthalmological examination revealed bilateral (Figures 1-4). She has remained symptom-free for 6 months after the conjunctival hyperemia and scleral thinning with peripheral corneal second rituximab cycle. The laboratory workup was repeated twice, ulcers measuring 5 × 2 mm in the right eye and nasal scleral thinning and ANA was the only altered parameter with a 1/320 speckled pat- with peripheral corneal swelling in the left eye that further promoted tern, and ENA remained negative. There was no symptom that could scleral thinning, staphyloma formation, and subsequent ulcerative be attributed to a collagen disease.

Submitted for publication: August 5, 2015 Funding: No specific financial support was received for this study. Accepted for publication: December 9, 2016 Disclosure of potential conflicts of interest: The authors declare no potential conflict of interest. 1 Departamento de Oftalmologia e Ciências Visuais, Universidade Federal de São Paulo (UNIFESP), Corresponding author: Tania Fidelix. TSA Reumatologia. Rua Barão do Triunfo, 156 - São Paulo, São Paulo, SP, Brazil. SP 04602-000 - Brazil - E-mail: [email protected]

http://dx.doi.org/10.5935/0004-2749.20160097 Arq Bras Oftalmol. 2016;79(5):339-41 339 Management of necrotizing scleritis after pterygiu m surgery with rituximab

F igure 1. Right eye before rituximab. Conjunctival and scleral nasal hyperemia with local F igure 3. Right eye after rituximab. Sectoral scleral thinning with no signs of active thinning and a peripheral corneal ulcer. inflammation.

F igure 2. Left eye before rituximab. Conjunctival hyperemia, scleral thinning, and asso F igure 4. Left eye after rituximab. Diffuse redness with improvement in sectoral scleral ciated scleral staphyloma with necrotic ulceration. inflammation. Scleral thinning remained.

DISCUSSION Medical management of SINS after pterygium surgery includes The local and systemic treatment of scleritis has recently under- immunosuppression with the oral steroids methylprednisolone + gone significant changes. These changes include more aggressive cyclophosphamide or tacrolimus for patients who do not respond and early treatment of patients to maintain vision and achieve rapid to cyclophosphamide and azathioprine(4). Surgical intervention in the remission. form of patch grafts of scleral, corneal, or amniotic membranes(10) has Increased use of combination immunosuppressive therapy and also been reported. biological agents in patients with severe and refractory ocular inflam- Autoimmunity or hypersensitivity is now well accepted as an matory disease has contributed to modifications in the prognosis of etiological factor in the development of SINS. Immune complexes these conditions1. have been found in and around episcleral vessel walls by immuno- Scleral necrosis and melting may occur after pterygium surgery fluorescence techniques, and systemic immunosuppressive regimes due to the use of adjunctive irradiation(6) and mitomycin C(7), although have been successful in the treatment of SINS(3,10). Clinical or serolo- the use of these gents reportedly contributes to prolonged inhibition gical markers of connective tissue disorders are present in as many as of wound healing. In addition, excessive cauterization during the 62% of cases. Our patient was ANA-positive without evidence of any bare sclera technique may cause scleral necrosis(8). According to a associated connective tissue disorder. The search for an associated review by Doshi et al.(9), the technique used for pterygium surgery can autoimmune disease was exhaustive and included tests for anti-CCP, alter the risk of necrotizing or even infectious scleritis. In 203 cases, ENA panel, complement system proteins, and anti-dsDNA. These SINS occurred in 17.2% and scleritis in 68.8% of cases that underwent tests were performed on more than two occasions, particularly for the bare sclera technique, as in our case. ANA and the ENA panel, because it was important to exclude the

340 Arq Bras Oftalmol. 2016;79(5):339-41 Fidelix TSA, et al.

possibility of an autoimmune disease associated with ANA positivity, 2. Foster CS. Ocular manifestations of the potentially lethal rheumatologic and vascu- such as systemic lupus erythematosus or systemic vasculitis. litic disorders. J Fr Ophtalmol. 2013;36(6):526-32. 3. Galanopoulous A, Snibson G, O’Day J. Necrotising anterior scleritis after pterygium In this case, the scleritis was refractory to classical immunosup- surgery. Aust NZ J Ophthalmol. 1994;22(3):167-73. pressive therapy, although all recommended steps, including high 4. Beardsley RM, Suhler EB, Rosenbaum JT, Lin P. Pharmacotherapy of scleritis: current prednisone doses, azathioprine and cyclophosphamide (12 pulses), paradigms and future directions. Expert Opin Pharmacother. 2013;14(4):411-24. were attempted. 5. Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair A review of the literature for studies of biologic therapy for scleri- EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp tis revealed case reports and a randomized clinical trial of necrotizing D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U; scleritis treated with rituximab after immunosuppressive therapy, RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated (11,12) which achieved good responses . vasculitis. N Engl J Med. 2010;363(3):221-32. Comment in: Nat Rev Rheumatol. 2010; Rituximab is a chimeric anti-CD20 monoclonal antibody that 6(10):556; N Engl J Med. 2010;363(21):2072-3; author reply 2073-4; Curr Rheumatol Rep. continues to increase in popularity for the treatment of ocular in- 2010;12(6):395-8; N Engl J Med. 2010;363(21):2072-3; author reply 2073-4. flammatory diseases and intraocular lymphoma(13). SINS should be 6. Mackenzie FD, Hirst LW, Kynaston B, Bain C. Recurrence rate and complications after considered as a differential diagnosis in patients with scleritis or scle- beta-irradiation for pterygium. Ophthalmology. 1991;98(12):1776-81. Comment in: Ophthalmology. 1992;99(6):841. Ophthalmology. 1992;99(6):841-2. ral melting following pterygium surgery, particularly after radiation 7. Rubenfeld RS, Pfister RS, Stein RM, Foster CS, Martin NF, Stoleru S, et al. Serious compli- or mitomycin C therapy. Evidence of a connective tissue disease may cations of topical mitomycin-C after pterygium surgery. Ophthalmology. 1992;99(11): or may not be found on clinical examination or laboratory inves- 1647-54. tigations, although it remains uncertain whether an autoimmune 8. Alzagoff Z,Tan DT, Chee SP. Necrotising scleritis after bare sclera excision of ptery- disease is present before or is unleashed by the section of sclera. gium. Br J Ophthalmol. 2000;84(9):1050-2. 9. Doshi RR, Harocopos JH, Schwab IR, Cunningham Jr ET. The spectrum of postopera- Therefore, it is important to be alert to the risks of scleritis after such tive scleral necrosis. Surv Ophthalmol. 2013;58(6):620-33. surgical procedures, particularly those that can lead to the damage 10. O’Donoughue E, Lightman S, Tuft S, Watson P. Surgically induced necrotizing scle- of avascular tissue, such as sclera, because the risks of necrosis and rokeratitis (SINS)-precipitating factors and response to treatment. Br J Ophthalmol. infections are considerably increased. Early diagnosis and prompt 1992;76(1):17-21 immunosuppr ession is required for the successful management of 11. Suhler EB, Lim LL, Beardsley RM, Giles TR, Pasadhika S, Lee ST, et al. Rituximab therapy this complication(4). The CD20 antibody rituximab is now an option for refractory orbital inflammation: results of a phase 1/2, dose-ranging, randomized clinical trial. JAMA Ophthalmol. 2014;132(5):572-578. that can be used for the treatment of these special cases. 12. Joshi L, Tanna A, McAdoo SP, Medjeral-Thomas N, Taylor SR, Sandhu G, et al. Long- term outcomes of rituximab therapy in ocular granulomatosis with polyangiitis: impact on localized and nonlocalized disease. Ophthalmology. 2015;122(6):1262-8. REFERENCES 13. Shetty RK, Adams BH, Tun HW, Runyan BR, Menke DM, Broderick DF. Use of rituximab 1. Wakefield D, Di Girolamo N, Thurau S, Wildner G, McCluskey P. Scleritis: immunopa- for periocular and intraocular mucosa-associated lymphoid tissue lymphoma. Ocul thogenesis and molecular basis for therapy. Prog Retin Eye Res. 2013;35:44-62. Immunol Inflamm. 2010;18(2):110-2.

XXIII Congresso Norte Nordeste de Oftalmologia

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Arq Bras Oftalmol. 2016;79(5):339-41 341 Case Report

Nonarteritic anterior ischemic optic neuropathy following pars plana vitrectomy for macular hole treatment: case report Neuropatia óptica isquêmica anterior não arterítica pós vitrectomia pars plana para tratamento do buraco macular: relato de caso

Leonardo Provetti Cunha1,2, Luciana Virgínia Ferreira Costa Cunha2, Carolina Ferreira Costa2, Mário Luiz Ribeiro Monteiro3

ABSTRACT RESUMO Herein, we report a case of nonarteritic anterior ischemic optic neuropathy Nosso objetivo é descrever a ocorrência de neuropatia óptica isquêmica anterior (NAION) following uneventful pars plana vitrectomy for macular hole treatment. não-arterítica (NOIA-NA) após vitrectomia posterior para tratamento do buraco A 56-year-old previously healthy woman presented with a full-thickness macular macular. Uma mulher de 56 anos de idade previamente hígida apresentou buraco hole in right eye (OD) and small cup-to-disc ratios in both eyes. Five days after macular de espessura total no olho direito (OD) e uma relação escavação disco surgery, she noticed sudden painless loss of vision in OD and was found to have pequena em ambos os olhos. No quinto dia de pós-operatório ela notou uma perda an afferent pupillary defect and intraocular pressure of 29 mmHg. Fundus exami- visual súbita e indolor OD associado a presença de um defeito pupilar aferente nation showed right optic disc edema and the resolution of a macular hole with relativo e pressão intraocular de 29 mmHg neste mesmo olho. A avaliação do fundo an inferior altitudinal visual field defect. Erythrocyte sedimentation rate, C-reactive de olho revelou a presença de edema de disco óptico e buraco macular fechado OD protein levels, and general physical examination findings were normal. She was associado a presença de defeito de campo visual altitudinal inferior. A velocidade de treated with hypotensive eyedrops and oral prednisone, resulting in mild visual hemossedimentação e a dosagem da proteína C reativa foram normais, assim como improvement and a pale optic disc. A combination of face-down position and o exame físico geral. A paciente foi tratada com colírios hipotensores e prednisona increased intraocular pressure due to a small optic disc cup were considered oral e evoluiu com discreta melhora visual e palidez de disco óptico. Acreditamos que as potential mechanisms underlying NAION in the present case. Vitreoretinal a combinação de posição de cabeça virada para baixo associado a um aumento da surgeons should be aware of NAION as a potentially serious complication and pressão intraocular em um paciente com relação escavação disco pequena são os be able to recognize associated risk factors and clinical findings. possíveis mecanismos para a ocorrência de NOIA-NA neste presente caso. Os cirurgiões de retina e vítreo devem estar atentos a esta possível grave complicação e reconhecer os seus fatores de risco relacionados assim como sua apresentação clinica. Keywords: Optic neuropathy, ischemic/diagnosis; Papilledema; Retinal perfora- Descritores: Neuropatia óptica isquêmica/diagnóstico; Papiledema; Perfurações re tions/therapy; Vitrectomy; Visual fields tinianas/terapia; Vitrectomia; Campos visuais

INTRODUCTION study documenting the occurrence of nonarteritic anterior ischemic Pars plana vitrectomy (PPV) with perimacular traction removal optic neuropathy (NAION) following uncomplicated PPV. The exact and facedown intraocular gas tamponade have demonstrated utility incidence of NAION, however, may be underestimated as optic disc in treating idiopathic full-thickness macular holes (FTMH). Despite evaluations are usually impaired by the presence of intraocular gas great advances in surgical technique over the last few years with the during the early postoperative period. achievement of good anatomical and functional outcomes, FTMH Here, we aimed to report the incidence of NAION following une- surgical treatment remains associated with a number of ocular com- ventful PPV for idiopathic FTMH treatment and discuss the potential plications, including retinal detachment, retinal tears, enlargement mechanisms underlying this serious postoperative complication. of the hole, macular phototoxicity, postoperative intraocular pressure (IOP) elevation, and cataracts(1,2). Furthermore, visual field (VF) CASE REPORT defects associated with peripapillary retinal nerve fiber layer (RNFL) thickness reduction, optic neuropathy, and optic disc pallor may A 56-year-old previously healthy woman reported a 6-month occur after otherwise uncomplicated surgery for macular hole treatment. history of progressive visual decline in her right eye (OD). Her past Although various underlying mechanisms, including optic nerve medical history was unremarkable, with no history of stroke, myo- and retinal ischemia, have been proposed, the exact cause remains cardial infarction, dyslipidemia, sleep apnea syndrome, or smoking. unclear(3-5). Visual loss from optic neuropathy following uncompli- Best-corrected visual acuity (VA) was 20/200 in OD, 20/20 in the left cated PPV for idiopathic FTMH treatment is a rare and potentially eye (OS). Slit lamp examination was normal; the patient was phakic, devastating complication(3,5,6). Previous studies(5) have been unable to and the anterior chamber angle was wide open in both eyes on fully elucidate the mechanisms underlying visual loss, with only one gonioscopy. IOP was 18 mmHg in OD and 19 mmHg in OS. Fundus

Submitted for publication: August 24, 2015 Funding: No specific financial support was available for this study. Accepted for publication: February 12, 2016 Disclosure of potential conflicts of interest: None of the authors have any potential conflict of 1 Universidade Federal de Juiz de Fora, Juiz de Fora, MG, Brazil. interest to disclose. 2 Hospital de Olhos Juiz de Fora, Juiz de Fora, MG, Brazil. 3 Corresponding author: Leonardo Provetti Cunha. Av. Barão Rio Branco, 4.051 - Juiz de Fora, MG Universidade de São Paulo, São Paulo, SP, Brazil. - 36021-630 - Brazil - E-mail: [email protected]

342 Arq Bras Oftalmol. 2016;79(5):342-5 http://dx.doi.org/10.5935/0004-2749.20160098 Cunha LP, et al.

examination revealed normal optic nerves with a cup-to-disc ratio of DISCUSSION 0.2, partial posterior vitreous detachment, and a macular hole in OD NAION is the most common optic neuropathy in patients >50 years (Figure 1 A), and was normal in OS. Optical coherence tomography old; it is thought to be a multifactorial disease involving an ischemic (OCT) showed a full-thickness macular hole with overlying operculum process resulting from microvascular occlusion or hypoperfusion of (Figure 1 B). Under retrobulbar anesthesia, she underwent an une- the blood supply to the optic nerve head, resulting in sudden visual ventful 25-gauge posterior PPV with posterior hyaloid separation loss associated with pale optic disc edema. followed by internal limiting membrane (ILM) staining with brilliant Taban et al. described two cases of NAION after uncomplicated vi- blue G (OphthalmosTM, Brazil) for 30 s. Subsequently, intraocular forceps trectomy for macular hole and epiretinal membrane(6): A 65-year-old were used to circumferentially peel ILM around the macular hole. A phakic hypertensive and diabetic woman and a 94-year-old aphakic few self-limited, small, superficial, pre-retinal hemorrhages occurred hypertensive man. Both patients developed sudden visual loss and in the peeled macular area. Then, fluid-air exchange and air-gas optic disc edema in the operated eye approximately 1 month after exchange with 20% SF6 were performed. No hyper- or hypotensive vitrectomy, with NAION subsequently diagnosed. The present case events were observed intraoperatively. The patient was instructed to differs because the patient was younger and had no systemic risk maintain a face-down position for 5 days postoperatively. factors such as hypertension or diabetes mellitus. Furthermore, she The initial postoperative VA was 20/400, with an IOP of 10 mmHg presented with visual loss soon after surgery, which reinforces the in the operative eye. On the fifth postoperative day, the patient noti- role of PPV in the development of NAION. ced sudden painless vision loss, with the VA reduced to finger coun- More recently, Bansal et al. retrospectively reviewed 7 patients who ting at 1 meter in OD. On examination, she had a right relative affe- underwent PPV for primary regmatogenous retinal detachment with rent pupillary defect with an IOP of 29 mmHg in OD. Her right optic subsequent development of optic neuropathy, with comparison to nerve was edematous (Figure 2 A). OCT imaging of the macular area 42 age- and gender-matched patients undergoing similar surgery. revealed macular hole closure (Figure 2 B). Automated perimetry was Despite the apparent lack of structural findings early in the postope- obtained on the 14th post-operative day and demonstrated a diffuse rative period, all 7 patients eventually developed optic nerve pallor, a reduction of sensitivity with an inferior altitudinal defect (Figure 3). relative afferent pupillary defect, and VF defects. The authors further The erythrocyte sedimentation rate (ESR) was 20 mm/h, C-reactive performed a review of 37 previously reported eyes with VF defect protein (CRP) was <0.3 mg/l, and the patient denied any symptoms after PPV and found that none had documented disc edema despite suggestive of giant cell arteritis (GCA). A fixed combination of timolol the authors positing ischemia as a potential cause. While the authors maleate 0.5% and brimonidine tartrate 0.2% (Combigan®) twice daily indicated that the presence of an intraocular gas bubble precluded for OD was initiated in combination with 80 mg of prednisone orally a detailed assessment of the optic nerve head during the postopera- for 7 days with subsequent dose tapering. Three months later, the tive period, they postulated that post-vitrectomy optic neuropathies best-corrected visual acuity was 20/160-1O D. The right optic nerve are more consistent with posterior ischemic optic neuropathy, similar was pale, and the macular hole remained closed (Figure 4). to those seen after spine surgery(5). The present case in addition to

A B

F igure 1. A) Preoperative fundus retinography demonstrating normal optic nerves with a small cup-to-disc ratio and macular hole affecting the right eye. The green square represents the area of the macular hole (6 × 6 mm) on optical coherence tomography (OCT). The central green horizontal line represents the OCT scan through the center of the fovea. B) OCT (horizontal scan) of the same eye demonstrating a full-thickness macular hole with overlying operculum.

A B C

F igure 2. A) Fundus retinography demonstrating optic disc edema affecting the right eye 7 days after surgery. B) Fundus retinography of same eye. C) Optical coherence tomography (horizontal scan) demonstrating complete closure of the macular hole.

Arq Bras Oftalmol. 2016;79(5):342-5 343 No narteritic a nterior ischemic optic n europathy following pars plana vitrectomy for macular hole treatme nt: case report

F igure 3. Automated Humphrey visual field (24-2) of the right eye, 14 days after the procedure, revealing diffuse depression and an inferior altitudinal defect that was more pronounced in the inferior nasal quadrant.

A B

F igure 4. A) Fundus retinography demonstrating optic disc pallor in the right eye 3 months after surgery. B) Optical coherence tomography (horizontal scan) of the same eye demonstrating complete closure of the macular hole with foveal depression recovery.

those described by Bansal et al.(5) indicate that optic neuropathy with While the exact mechanisms underlying the development of optic disc edema (anterior ischemic optic neuropathy) may, in fact, optic neuropathy after PPV have yet to be fully elucidated, a combi- occur. Furthermore, we agree with Taban et al.(6) that visibility is diffi- nation of factors may have contributed to the occurrence of NAION cult early during the post-operative period due to the presence of after posterior vitrectomy in the present case. We believe the com- an intraocular gas bubble. Accordingly, the occurrence of optic disc bination of face-down position and increased IOP during the posto- edema may be an under-reported phenomenon. perative period of macular hole surgery may play an important role

344 Arq Bras Oftalmol. 2016;79(5):342-5 Cunha LP, et al.

in the development of NAION(7). One possible explanation is that the creased the incidence of VF defects after macular hole surgery from blood flow to the optic nerve head, which is dependent on perfusion 24% to 4%(10). pressure, may have been impaired. Ocular perfusion pressure is the Bansal et al. posited that reduced ocular perfusion due to intrao difference between mean arterial blood pressure and IOP or venous perative systemic hypotension may be a risk factor for the develop pressure. Since both IOP and venous pressure are increased in the ment of optic neuropathy after PPV(5). That explanation, however, prone position, the combination of these two events may precipitate is also difficult to reconcile with the findings of the present case as ischemia of the anterior portion of the optic nerve, resulting in NAION. visual loss clearly developed within 5 days of surgery. A final possi- Although we documented only a moderate increase in IOP in the bility is that the occurrence of NAION in the present case may have present case, IOP may have reached a much higher level before exa- been a coincidental event unrelated to surgery asNAION is the most mination and thereby contributed to the development of NAION(8). common optic neuropathy in patients in the sixth decade of life. The association between face-down position and increased IOP is However, we consider this possibility s very unlikely. well described, notably in low-light conditions, and can be used in cli- In conclusion, we believe the combination of face-down positio- nical practice as a provocative test for angle-closure glaucoma(7). The ning and increased IOP with other risk factors, such as a small optic exact mechanism underlying IOP elevation is not completely unders- disc cup, may have predisposed the present case to NAION after tood, but it may be related to forward movement of the lens in the apparently uneventful posterior vitrectomy for macular hole treat- prone position, particularly when associated with mydriasis, possibly ment. Vitreoretinal surgeons should be aware of this potentially se- leading to anterior chamber angle closure and impaired aqueous rious complication and recognize its risk factors and clinical findings. humor out-flow. Therefore, we believe a combination of such factors may have contributed to IOP elevation in the present case. REFERENCES Other factors may contribute to the occurrence of NAION after . 1 Jackson TL, Donachie PH, Sallam A, Sparrow JM, Johnston RL. United Kingdom National vitreoretinal surgery, e.g., posterior vitreous detachment, indicating Ophthalmology Database study of vitreoretinal surgery: report 3, retinal detachment. that direct mechanical trauma to the optic disc during separation of Ophthalmology. 2014;121(3):643-8. the posterior hyaloid may lead to damage to the retinal arterioles, 2. Gupta OP, Weichel ED, Regillo CD, Fineman MS, Kaiser RS, Ho AC, et al. Postoperative nerve fiber layer, or retina(6,9). Parsa and Hoyt posited that the vitreous complications associated with 25-gauge pars plana vitrectomy. Ophthalmic Surg Lasers Imaging. 2007;38(4):270-5. adhesion over the optic disc and peripapillary retina may be parti- 3. Ezra E, Arden GB, Riordan-Eva P, Aylward GW, Gregor ZJ. Visual field loss following cularly strong over the cupless disc, with stretching and elongation vitrectomy for stage 2 and 3 macular holes. Br J Ophthalmol. 1996;80(6):519-25. during posterior vitreous detachment breaking the cytoskeleton in 4. Williams JM, Jacobson Sr DM. Visual field loss after vitreous surgery. Arch Ophthalmol. older and less distensible axons, leading to axoplasmic accumulation 1997;115(3):434-5. and axonal atrophy in the prelaminar sites of separation(9). In the 5. Bansal AS, Hsu J, Garg SJ, Sivalingam A, Vander JF, Moster M, et al. Optic neuropathy after vitrectomy for retinal detachment: clinical features and analysis of risk factors. present case, the posterior hyaloid was adhered to the peripapillary Ophthalmology. 2012;119(11):2364-70. area, indicating the traction induced during aspiration of the poste- 6. Taban M, Lewis H, Lee MS. Nonarteritic anterior ischemic optic neuropathy and rior cortical vitreous may have resulted in axonal damage. However, ‘visual field defects’ following vitrectomy: could they be related? Graefes Arch Clin Exp this is less likely as visual loss was present on the first and not the fifth Ophthalmol. 2007;245(4):600-5. postoperative day in the present case. 7. Hyams SW, Friedman Z, Neumann E. Elevated intraocular pressure in the prone posi tion. A new provocative test for angle-closure glaucoma. Am J Ophthalmol. 1968;66(4): Another possible explanation for NAION after macular hole repair 661-72. is indirect mechanical trauma induced by high infusion pressure 8. Torricelli A, Reis AS, Abucham JZ, Suzuki R, Malta RF, Monteiro ML. Bilateral nonarteritic during air-fluid exchange. However, in our patient, a system that anterior ischemic neuropathy following acute angle-closure glaucoma in a patient constantly monitors air pressure infusion was used (The Constella- with iridoschisis: case report. Arq Bras Oftalmol. 2011;74(1):61-3. tion® Vision System, Alcon Laboratories) and the target pressure was 9. Parsa CF, Hoyt WF. Nonarteritic anterior ischemic optic neuropathy (NAION): a misnomer. Rearranging pieces of a puzzle to reveal a nonischemic papillopathy caused by vitreous set at 30 mmHg, which is the standard for the majority of vitrectomy separation. Ophthalmology. 2015;122(3):439-42. surgeries, making this hypothesis less feasible. Indeed, Hirata et al. 10. Hirata A, Yonemura N, Hasumura T, Murata Y, Negi A. Effect of infusion air pressure on demonstrated that reduced air pressure infusion to 30 mmHg de- visual field defects after macular hole surgery. Am J Ophthalmol. 2000;130(5):611-6.

Arq Bras Oftalmol. 2016;79(5):342-5 345 Review Ar ticle

Amblyopia: neural basis and therapeutic approaches Ambliopia: bases neurais e intervenções terapêuticas

Caio César Peixoto Bretas1, Renato Nery Soriano2

ABSTRACT RESUMO Abnormalities in visual processing caused by visual deprivation or abnormal Anormalidades nos processamentos visuais causadas por privação visual ou in binocular interaction may induce amblyopia, which is characterized by reduced teração binocular anormal podem gerar ambliopia, caracterizada por redução visual acuity. Occlusion therapy, the conventional treatment, requires special da acuidade visual. A terapia de oclusão (tratamento convencional) necessita de attention as occlusion of the fellow normal eye may reduce its visual acuity and cuidados especiais, pois a oclusão do olho normal (não-amblíope) pode reduzir a impair binocular vision. Besides recovering visual acuity, some researchers have acuidade visual do mesmo e prejudicar a visão binocular. Além de recuperar a acuidade recommended restoration of stereoacuity and motor fusion and reverse suppression visual, alguns pesquisadores alertam para a necessidade em potencial de se restau- in order to prevent diplopia. Recent studies have documented that the amblyopic rar a estereoacuidade e a fusão motora, bem como reverter a supressão a fim de visual cortex has a normal complement of cells but reduced spatial resolution and a impedir diplopia. Estudos recentes revelam que nos córtices visuais de amblíopes há disordered topographical map. Changes occurring in the late sensitive period uma quantidade normal de células, mas com resolução espacial reduzida e mapa selectively impact the parvocellular pathway. Distinct morphophysiologic and topográfico desorganizado. Alterações ocorridas durante o período crítico tardio do psychophysical deficits may demand individualization of therapy, which might desenvolvimento visual humano impactam seletivamente a via parvocelular. Déficits provide greater and longer-lasting residual plasticity in some children. morfofisiológicos e psicofísicos distintos podem exigir programas de tratamento potencialmente seletivos e poderiam explicar a plasticidade residual maior e mais duradoura em algumas crianças. Keywords: Amblyopia; Visual acuity; Neural plasticity; Visual cortex Descritores: Ambliopia; Acuidade visual; Plasticidade neuronal; Córtex visual

INTRODUCTION vision in 20- to 70-year-old patients(9). The incidence is 1% to 5% in (12) Visual processing occurs as neural coding is transmitted from children , and it accounts for about 60% of vision disorders in preschool (13) cells of the lateral geniculate nucleus of the thalamus to the primary and school-age children . visual cortex (V1, the striate cortex). This is located in the occipital Despite the high incidence of amblyopia in children and the fact lobe calcarine sulcus (Broadmann area 17), where inhibitory and exci- that it affects their cognitive development, school performance, so- (13,14) tatory binocular convergence occurs(1). Cortical synaptic connections cial integration, and future profession , its neural basis is relatively integrate a fragmented representation of a scene or object, creating poorly understood. Investigations have produced apparently conflicting (1,9,15,16) a recognizable visual perception(2). Color and form are perceived results . Studies in the last two years have suggested that it is through the ventral pathway (parvocellular cells) in the temporal lobe, essential to discover when the visual deficit took place, that is, in the (17) while localization and motion are processed through the dorsal pathway early sensitive period versus late sensitive period to prescribe pro- (magnocellular cells) in the parietal lobe(3). per treatment. Morphophysiologic changes associated with abnormalities of Based on the most recent advances in understanding the neural visual processing may generate amblyopia, characterized by reduced basis of amblyopia, the present article reviews clinical and neurophy visual acuity and contrast sensitivity either uni- or bilaterally. Patients siologic aspects related to its causes, symptoms, and therapeutic with amblyopia also present with deficits in binocular vision, color, approaches. and form perception (parvocellular pathway), motion perception (magnocellular pathway), and contour integration. There may be Causes abnormal function of the fellow normal eye as well. Overall, there is Ametropia, anisometropia, and strabismus(18) during childhood are diminished capacity to generate a tridimensional representation of the most common causes of amblyopia. They result in an abnormal the world adequate to coordinate manipulation (eye-hand coordina- visual experience that impairs visual development and processing. tion), reading, and visual decision making(4-8). Development of the visual system is completely dependent on visual Amblyopia has no detectable organic cause(9) but occurs as a result stimuli(16) that induce elaboration of neural circuits(19). Maturation of of visual deprivation (congenital cataracts; ametropia) and/or abnor- neural circuits begins at birth, with an early sensitive period at 4 to 18 mal binocular interaction (strabismus; anisometropia)(10). Amblyopia months(17) and a late sensitive period to about 7 years of age(15,17). After is the main source of preventable child blindness(11) and of monocular that, there is a significant reduction in neuroplasticity. Until the end of

Submitted for publication: July 11, 2016 Funding: No specific financial support was available for this study. Accepted for publication: August 28, 2016 Disclosure of potential conflicts of interest: None of the authors have any potential conflict of 1 Faculdade de Medicina, Universidade Federal de Juiz de Fora (UFJF), Governador Valadares, MG, interest to disclose. Brazil. 2 Corresponding author: Renato Nery Soriano. Setor de Fisiologia e Biofísica. Departamento Núcleo de Fisiologia e Biofísica, Departamento de Ciências Básicas da Vida, Universidade Federal de Ciências Básicas da Vida. Universidade Federal de Juiz de Fora, Governador Valadares, de Juiz de Fora (UFJF), Governador Valadares, MG, Brazil. MG - 35010-177 - Brazil - E-mail: [email protected]

346 Arq Bras Oftalmol. 2016;79(5):346-51 http://dx.doi.org/10.5935/0004-2749.20160099 Bretas CCP, Soriano NR

the late sensitive period(17) (Table 1), there is macular maturation, optic Congenital cataracts (20) nerve myelination, fusion of images for binocular vision , formation Congenital cataracts cause significant visual deficiency and gene of the ocular dominance columns in V1 by competition, and matura- rate visual deprivation. If cataracts are not surgically treated, they can tion of binocular connections by cooperation among afferents from lead to amblyopia(32). This, however, is a less frequent cause(18). both eyes(21). Once past this period, even if the cause of the deficit is corrected, an 8- to 10-year-old child is likely to have persistent reduction Congenital ptosis in visual acuity and contrast sensitivity(22). Congenital ptosis (blepharoptosis) refers to an upper eyelid posi Ametropia tioned lower than normal, narrowing the vertical dimension of the (33) The most common ametropias are hyperopia, myopia, and astig palpebral cleft . Visual deprivation and consequently amblyopia may matism. Hyperopia is characterized by a refractive error produced occur if the pupil is covered by the upper eyelid. Studies have shown by a shorter than normal ocular axial length. There is an imbalance that 6% of patients with congenital ptosis develop amblyopia(34,35), between refractive capacity and the anteroposterior length of the called stimulus deprivation amblyopia. eye(22,23). In a study performed on 37 children 5 to 8 years of age with bilateral hyperopia and esotropic amblyopia, it was found that hype- Diagnosis ropia in the amblyopic eyes was more severe than that of the fellow The diagnosis of amblyopia is challenging since there is no specific (24) eye . In contrast to hyperopia, myopia is a refractive error occurring test to detect it, and it depends on the child’s ability to cooperate, po- (22) when the anteroposterior ocular axial lenght is longer than normal . tentially compromising the diagnostic process(35). The Snellen chart for Astigmatism, on the other hand, is detected when the vertical diopter (22) visual acuity, together with its successors are the main instruments value differs from the horizontal value . Astigmatism is the most used to evaluate visual acuity, that is, high contrast, black-and-white common refractive error associated with amblyopia(12) as it substan recognition acuity. tially affects visual system development(25). The term meridional amblyopia is commonly used to refer to amblyopia caused by astig- Possibility of amblyopia should be considered when in the first matism. Ametropias, therefore, reduce visual acuity(26), generating a stage of investigation a child presents with visual acuity less than mild visual deprivation that affects development of the visual system 20/30 or when the light reflexes in the two eyes are not symmetrical in childhood(26). The reported incidence of ametropia as a cause of and a visual difference between eyes is maintained after correcting amblyopia is quite high at 62.7%, with 9.4% due to myopia, 21.8% to refractive defects and organic visual defects. Suspicion for amblyopia hyperopia, and 31.3% to astigmatism(12,22). increases if, even after cycloplegic refraction, there is astigmatism greater than 2.5 D in both eyes or a ≥1.5 D difference between eyes, Anisometropia myopia greater than 5.0 D in both eyes or a ≥3.0 D difference between Anisometropia is an ophthalmic disorder in which optical measu eyes, as well as hyperopia greater than 4.5 D in both eyes or a ≥+1.5 D (36) rements differ between the eyes, which have myopia or hyperopia difference between eyes . of different degrees and which impairs binocular fusion(22). Variations In addition to using the Snellen chart, it is always important to greater than 1.0 diopter (D) in hypermetropic anisometropia or 2.0 D perform a cover test to evaluate ocular alignment. During the clinical in myopic anisometropia are associated with an increased incidence interview, noting whether the patient had congenital ptosis or cata- of amblyopia(27). Frequent coexistence of anisometropia and amblyo- racts and/or refractive defects during childhood is useful to aid in the pia in the first clinical test in the child and the persistence of reduced diagnosis of amblyopia. visual acuity after refractive correction strengthen the evidence that Strabismic amblyopia is most easily detected by parents. Teachers’ anisometropia is a cause of amblyopia(28). contribution is also important to detect amblyopia as early as possible(37). In Israel and Sweden, screening to detect amblyopia is perfor Strabismus med for school-age children. Ethical concerns have been raised re Strabismus, one of the principal ocular deficits in low-income garding this screening, however, as the results may subject children children(29,30), is characterized by dysfunction of the extraocular mus- to bullying, with an adverse impact on their mental health(38). cles, generating binocular misalignment. The strabismic eye may fail Researchers emphasize the importance of trying to discover the to receive visual stimuli onto the macular area(31), thus affecting various age of onset of abnormal visual experience, as this information is developmental stages of cortical processing(16). Identification of factors believed to be essential for choosing specific treatment, at least during that cause strabismus may be important for diagnosis and treatment each of the two sensitive periods of human visual development(17) of amblyopia(25). (Table 1).

Table 1. Differences in characteristics of amblyopia and response to treatment by time of onset Early sensitive period Late sensitive period Duration 4 to 18 months of agea(17) 18 months to 7 years of agea(17) Predominant mechanism in binocular connections Competitionb(21) Cooperationb(21) Ocular dominance columns Under developmentb(46,68) Already developedb(46,68) Occlusion Hypertrophy of LGNc cells of the non-occluded eye; Selective shrinkage of cells in the parvocellular shrinkage of LGN cells of the occluded eyeb(69-71) pathway in both non-occluded and occluded eyesb. Normal size of the magnocellular cellsb(69-71) Functional impairment Parvocellular-related function is more Parvocellular-related function is more diminished in diminished in both the amblyopic and the amblyopic eye of late-onset subjectsd(72) fellow eyes of early and late onsetd(72) a= the age ratio of 1:4 has been considered to compare the relative timing in monkey and man, so that 1 week in the monkey is approximately equivalent to 4 weeks in man; b= outcomes from studies in monkeys; c= LGN, lateral geniculate nucleus of the thalamus; d= outcomes from human studies.

Arq Bras Oftalmol. 2016;79(5):346-51 347 Amblyopi a: neural b asis adn ther apeutic a pproaches

Main treatments Another crucial aspect that deserves attention is that recovering visual acuity is only one of the goals of an amblyopia therapy program. Conventional treatment of amblyopia consists of occlusion of the Other aims are to restore stereoacuity and motor fusion and possibly fellow eye. This tends to augment visual acuity of the amblyopic eye to reverse suppression. Some researchers have warned that if suppression and to improve binocular function, as long as it is correctly perfor- is reversed but sensory and motor fusion are not restored, there will med(39). Treatment schedules vary from months to years(40) but last 3 be a risk of intractable diplopia. years on average(39). American and British guidelines both advise daily Pharmacological and behavioral forms of treatment in association occlusion for 2 h for moderate and 6 h for severe amblyopia. However, with occlusion therapy tend to reinforce neuroplasticity and ease vi- 10 or more hours have also been reported(40). Occlusion therapy (also sion recovery (Table 2). Patching combined with perceptual learning called patching) should be monitored frequently as to its results(41). achieves outcomes better than those with occlusion only(40). This asso- It can be used in association with other therapeutic modalities(19,40,42). ciation improves visual performance, mainly in binocular(52) and timing(49) Parents’ participation is essential for successful treatment; therefore, function and reduces or corrects spatial distortion of images(9). An they should be aware of the necessity, urgency, and potential effec- intrinsic difficulty of this treatment is that children must cooperate tiveness of the therapeutic program(43). and remain attentive. It is, however, a promising approach for patients Despite having been used for many years, occlusion therapy still who have not responded to occlusion alone(52). needs to be investigated as to the neural events responsible for rever- The following drugs have been used in association with occlusion: sal of the symptoms(39). Clarification is needed as to what is involved in gamma aminobutyric acid (GABA) synthesis inhibitors, citicoline, and the consolidation of visual neurophysiologic development driven by levodopa (Table 2). It has been shown in animal studies that a GABA the effects of visual processing using the amblyopic eye. It is believed synthesis inhibitor potentiates cortical plasticity(19). Citicoline, an in- that the neural basis of the treatment is associated with the pheno- termediate in acetylcholine and phospholipids biosynthesis, appears menon of neuroplasticity, an intrinsic capacity to adapt to diverse to ameliorate visual acuity by favoring action potential conduction, conditions to which the nervous system is submitted. Visual cortex but its long-term effects need to be evaluated(48). Levodopa, a dopa- plasticity occurs in response to changes in neuronal activity and is generated mainly by the action of neuromodulators that promote mine precursor used in treating Parkinson disease, ameliorates visual long-term synaptic changes(44). Patching of the fellow eye and visual function of patients with irreversible amblyopia. It is believed that (45) levodopa is capable of restoring visual neuroplasticity, although it is stimuli to the amblyopic eye appear to remodel cortical functions . (53) Besides functional alterations, patching also induces morphologic remains to be verified if this is a long-lasting effect . changes (indicating that there is morphologic plasticity) in cells of As a form of treatment independent of occlusion, some studies have (9,46) reported the use of atropine (Table 2), a parasympatholytic muscarinic the retina, lateral geniculate nucleus, and visual cortex (Table 1) . (29) In experimental studies in monkeys, it has been shown that eye antagonist. Atropine may help in treating moderate amblyopia , as it interferes with visual accommodation of the fellow normal eye, occlusion by lids suturing at birth and then removal of the sutures at (19) the third week of age caused a re-expansion of the ocular dominance thus indirectly forcing use of the amblyopic one . However, atropine treatment is not always effective(48). Less conventional treatments such columns in layer IVcβ of V1, where the afferents to parvocellular cells of the lateral geniculate nucleus synapse, and, conversely, a reduction as refractive therapy, acupuncture, and others have also been described(54). Randomized, controlled trials of treatment modalities for of the adjacent columns of magnocellular cells in layer IVcα(46). Hence, there is a dissociation between the magno- and parvocellular pathways, amblyopia are necessary. According to some authors, experimental evidence reveals that which may have some effect on visual function. Interestingly, such an (55,56) (57) effect was found only if deprivation and reversal were performed at abnormal visual experience can both extend and reduce plasti a specific period of visual development(46). These findings raise the city. This may be a significant observation for amblyopia treatment following question: Would this dissociation between the magno- and because such children had abnormal visual experiences before being treated. This may account for the variability and unpredictability of parvocellular pathways explain why patching is not successful in some (58) (59) children with amblyopia? the response to occlusion , positive response in some children , relati vely low incidence of amblyopic children with non-treated, early-onset As mentioned, plasticity in the visual pathways is substantially di (60) minished as children develop, yet the finding that treatment may be strabismus in comparison to those with congenital cataracts. partially effective in older subjects with late-onset amblyopia ind icates Neural basis that a certain residual plasticity is present that can reverse or attenuate the symptoms of amblyopia after the late sensitive period(17,40,47). As the Significant advances in understanding the neural basis of am- period of greater plasticity varies in different parts of the brain and blyopia are plausibly associated with development of more effective with distinct sensory functions, the period in which it is possible to re- therapeutic approaches. As of the middle of the last year (2015), gaps verse the symptoms caused by visual deprivation may vary as well(40). in science-based knowledge about the neural basis of amblyopia still Outcomes of treatment vary because of a number of factors. Even existed, and some aspects remained controversial and were a matter though there is not yet a consensus on the influence of age on treatment(48), of debate. studies indicate that treatment initiated after 6 to 8 years of age has Although it is not expected that the classical psychophysical de the lowest success rate(11,19,39,46). Thus, it has been recommended to ini ficits in amblyopia, such as loss of contrast sensitivity at high spatial tiate treatment as early as possible(48,49), even though 8- to 12-year-old frequencies , spatial distortion, mislocalization, and reduced sensitivity children may sometimes satisfactorily respond to therapy(39). The se- for form and motion, may be understood from a single model or ex- verity of amblyopia also significantly affects treatment outcome, with planation, some recent findings shed new light on the neural basis of the greatest rate of success found for mild amblyopia(47). Response to amblyopia. treatment is a function of initial visual acuity and treatment adheren An important aspect for understanding the cortical deficits in ce(39,50). For example, success in patients with mild amblyopia and patients with amblyopia is the possible reduction in the number of good adherence to treatment is higher than 80%, whereas it is only cortical neurons stimulated by foveal projections, which would induce about 15% in subjects with severe amblyopia and poor adherence(47). loss of contrast sensitivity and mislocalization. It is believed that the It is worth pointing out that occlusion treatment requires special visual impairment could therefore be explained at least partially by attention since occlusion of the fellow eye may reduce its visual acuity a reduced complement of cortical cells excited by the amblyopic and impair binocular vision. Beyond the visual effects, this may result projections(61) or because cortical magnification would be reduced(62) in disturbance of the child’s self-esteem(49) and disruption of the family (Table 3). routine. Hence, these factors should be evaluated in each case before Some intriguing questions have been raised in the literature: Would treatment is prescribed(51). V1 dysfunction be a consequence of loss of binocularity of cortical cells,

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Table 2. Main treatments for amblyopia: neurophysiologic effects and disadvantages Treatment Neurophysiologic effects Disadvantages Occlusion Stimulates amblyopic eye, improving its Reduces binocular function(32), changes family routine(49), visual acuity by plasticity(40) may induce psychological problems(32). Adherence varies(26,31) Occlusion + perceptual learning Improves binocular, spatial, and timing functions(32) Requires the child’s attentiveness and cooperation(50) Occlusion + levodopa Increases cortical plasticity(33) Long-term outcomes need to be monitored(33) Occlusion + citicoline Improves action potential conduction(33) Long-term outcomes need to be monitored(33) Atropine Prevents fellow normal eye accommodation, Occlusion outcomes are faster(45) stimulating the amblyopic one(45)

Table 3. Cortical deficits in amblyopia* the counterargument is supported by data revealing that a reduced Striate cortex Extrastriate cortex cortical sample alone would not induce changes in the size of popu (4) (V1) (V2 and V3) lation receptive fields and thus cannot be the only explanation. Interestingly, although subjects with amblyopia have a normal Complement of cells Normal Normal complement of cells, population receptive fields are enlarged in V1 Spatial resolution Reduced Reduced and even more so in V2 and V3. Enlarged population receptive field Cortical magnification factor Normal Normal might be consequence of unstable movement of the amblyopic eye(66), Topographical map Disordered Very disordered but such a possibility can be discarded due to the methodological (4) Population receptive field size Enlarged Very enlarged criteria adopted . Another possibility is that an enlarged population receptive field may be a result of a reduced contribution of smaller *= results from population receptive field functional magnetic resonance imaging analysis(4). population receptive fields for the amblyopic eye projections. Even though this last proposal sounds plausible, another relevant finding explains that enlarged population receptive fields is the disordered topographical map(4) derived from increased positional disarray of cells or would impairment of excitation-inhibition balance exist in binocular (Table 3). cells? Some researchers have speculated that cellular interactions in amblyopia are reduced in intensity, whereas others think that sensi There are important questions that have not yet been addressed. Is tivity and spatial resolution are both reduced in cortical neurons sti spatial resolution reduced in amblyopic cortical cells? Do subjects with mulated by foveal projections(63). Furthermore, it has been speculated amblyopia experience spatial distortions and reduced positional accu- that the cortical deficits would not necessarily occur in V1(64); perhaps racy as a function of reduced or lost spatial resolution? The response to this question seems to be indicated by findings that show greater posi- the problem might lie only in V2 and V3, with normal processing (4,67) in V1(65). The following hypothesis has also been proposed in the li tional variability is found in amblyopic population receptive fields . terature: The amblyopic projections are disordered, and there is a Taken together, the recent advances in understanding the neural significant reduction (or loss) of spatial resolution of cortical neurons basis of amblyopia reveal that patients with amblyopia exhibit a normal stimulated by projections from the fovea, which is thicker in subjects complement of cells whose spatial resolution is reduced and topo- with amblyopia when evaluated by optical coherence tomography(1). graphical map is disordered (Table 3). It remains to be investigated whether thickening of the fovea directly Final remarks influences visual acuity, whether it is associated with worse visual prognosis, and whether intensive early intervention is capable of Visual abnormalities vary with different types of abnormal visual controlling or preventing such thickening. experience and the age of onset. Children with amblyopia having si- Guided by simulations of how different types of cellular disturban milar visual acuity may exhibit very distinct morphophysiologic varia- ces (e.g., loss of cells’ spatial resolution, increased cellular disarray, and tions and distinct visual functions. These anatomical and psychophy- reduced cellular sampling) would affect the neuronal population sical differences, besides accounting for greater and longer-lasting receptive field, researchers have used functional magnetic resonance plasticity in some children, may require special treatment programs imaging to analyze population receptive fields in V1 (striate cortex), in order to improve therapeutic effectiveness. Therefore, combining V2 and V3 (extrastriate cortex) of humans with moderate-to-severe subjects with early- and late-onset amblyopia in research studies is amblyopia(4). The model regularly samples responses at the voxel le- not recommended. vel from a dense array of receptive fields. Hence, it forecast the effects Given that binocular function may affect plasticity, it is very im of the size of the population receptive field versus eccentricity and portant in the diagnosis and treatment of amblyopia to detect the also the effects of eccentricity versus cortical distance, which reflects presence or absence of binocularity. It should be investigated whether cortical magnification(4). the loss of binocular function was subsequently followed by a re Substantial evidence now supports the contention that the defi- duction of visual acuity or if abnormal monocular afferent signals first cits in visual processing are also found in V2 and V3, and that these are reduced visual acuity with a subsequent loss of binocularity. In many not a consequence of abnormal processing occurred in V1(4) (Table 3). children, amblyopia develops at an age in which the ocular domi- It is conceivable that patients with amblyopia possess an immature nance columns of V1(46,68) are no longer affected, i.e., after the early visual system with a normal complement of cells, i.e., the quality of sensitive period (Table 1). It has been documented that morphologic global cortical topographical representation of information from the changes occurring during the late sensitive period selectively affect amblyopic eye is preserved and, therefore, there is no reduction in cells of the parvocellular pathway(17,21,69-71). It seems reasonable to the number of cells excited(61). Moreover, cortical magnification is not recommend that treatment for amblyopia should be individualized, reduced as believed(62) but is normal(4) (Table 3). Although this last con- as some children with amblyopia may not respond to occlusion be- clusion may be contested by those who propose that the amblyopic cause of morphophysiologic dissociation between the magno- and eye would activate fewer neurons, hence generating a reduced sample, parvocellular pathways(72).

Arq Bras Oftalmol. 2016;79(5):346-51 349 Amblyopi a: neural b asis adn ther apeutic a pproaches

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Arq Bras Oftalmol. 2016;79(5):346-51 351 Letters to the Editor

early follicular and mid-luteal phases and by 2.64% between early folli- Retinal nerve fiber layer, ganglion cular and ovulatory phases(3). Although the effect of pregnancy on CT has been debated in the literature, some studies have demonstrated cell complex, and choroidal significantly increased CT during pregnancy, particularly during the second trimester(2). Accordingly, we would like to ask the authors thicknesses in migraine whether they considered the menstrual cycle and pregnancy status of the female participants. Additionally, we suggest that smoking, Espessuras da camada de fibras nervosas, alcohol consumption, drinking caffeinated beverages, body mass index, systemic blood pressure, and environmental lighting condi- do complexo de células ganglionares e da tions, which significantly affect CT, should be addressed in the paper. coroide na migrânea Finally, we suggest that the duration of the disease, frequency of migraine episodes, and the time passed after the latest episode as well as its severity may significantly affect the results, primarily Dear Editor, CT, in migraine patients with aura. We are curious about the authors’ We have read and reviewed the article titled “Retinal nerve fiber opinions on the aforementioned concerns. layer, ganglion cell complex, and choroidal thicknesses in migraine” by Çolak et al., with great interest(1). The authors investigated 45 mi- Salih Uzun1, graine patients with aura and peripapillary retinal nerve fiber layer Emre Pehlivan2 (RNFL), ganglion cell complex, and choroid thicknesses using optical coherence tomography. They found that RNFL was significantly thinner Submitted for publication: June 1, 2016 Accepted for publication: June 1, 2016 in the superior and inferior quadrants in the migraine group when 1 Department of Ophthalmology, Etimesgut Military Hospital, Ankara, Turkey. compared with that in the control group. Çolak et al. demonstrated 2 Department of Ophthalmology, Eskisehir Military Hospital, Eskisehir, Turkey. that the subfoveal, temporal, and nasal choroidal thickness (CT) at Funding: No specific financial support was available for this study. 500, 1000, and 1500 μm, respectively, were significantly thinner in Disclosure of potential conflicts of interest: None of the authors have any potential conflict of the migraine group as compared with those in the control group. We interest to disclose. Corresponding author: Salih Uzun. Etimesgut Asker Hastanesi Goz Hastaliklari Servisi. Etimes express our gratitude to the authors regarding this study. However, gut-Ankara, 06790 - Turkey - E-mail: [email protected] we would like to ask Çolak et al. to clarify some important points that might affect CT measurements(1). The choroid is one of the most vascularized regions of the human REFERENCES body. Therefore, any local, systemic, or environmental factor that 1. Colak HN, Kantarcı FA, Tatar MG, Eryilmaz M, Uslu H, Goker H, et al. Retinal nerve affects the vascular tract may have significant influences on CT. For fiber layer, ganglion cell complex, and choroidal thicknesses in migraine. Arq Bras instance, menstrual cycle and pregnancy may significantly affect (2)CT . Oftalmol. 2016;79(2):78-81. 2. Tan KA, Gupta P, Agarwal A, Chhablani J, Cheng CY, Keane PA, et al. State of science: The paper indicated that the mean age of the 45 participants was Choroidal thickness and systemic health. Surv Ophthalmol. 2016;S0039-6252:30010-2. 36.1 ± 6.5 years (ranging between 20 and 45 years), and 37 of them 3. Ulaş F, Doğan U, Duran B, Keleş A, Ağca S, Celebi S. Choroidal thickness changes during were female. Ulaş et al. showed that CT decreased by 6.47% between the menstrual cycle. Curr Eye Res. 2013;38(11):1172-81.

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354 Arq Bras Oftalmol. 2016;79(5):353-6 Committee of Medical Journal Editors (ICMJE), based on the exam- Supplemental files can have the following extensions: JPG, BMP, TIF, ples below. GIF, EPS, PSD, WMF, EMF or PDF. The titles of the journals should be abbreviated according to the 9. Abbreviations and Acronyms. Abbreviations and acronyms style provided by the List of Journal Indexed in Index Medicus of the should be preceded by the spelled-out abbreviation on first mention National Library of Medicine. and in the legends of tables and figures (even if they have been previously mentioned in the text). Titles and abstracts should not contain The names of all authors should be cited for references with up to abbreviations and acronyms. six authors. For studies with seven or more authors, cite only the first six authors followed by et al. 10. Units of Measurement: Values of physical quantities should be used in accordance with the standards of the International System Examples of references: of Units. Journal Articles 11. Language. Texts should be clear to be considered appropriate Costa VP, Vasconcellos JP, Comegno PEC, José NK. O uso da mitomicina for publication in a scientific journal. Use short sentences, written in C em cirurgia combinada. Arq Bras Oftalmol. 1999;62(5):577-80. a direct and active voice. Foreign words should be in italics. Thera- Books peutic agents should be mentioned by their generic names with the Bicas HEA. Oftalmologia: fundamentos. São Paulo: Contexto; 1991. following information in parentheses: trade name, manufacturer’s name, city, state and country of origin. All instruments or apparatus Book Chapters should be mentioned including their trade name, manufacturer’s Gómez de Liaño F, Gómez de Liaño P, Gómez de Liaño R. Exploración name, city, state and country of origin. The superscript symbol of del niño estrábico. In: Horta-Barbosa P, editor. Estrabismo. Rio de trademark ® or™ should be used in all names of instruments or trade Janeiro: Cultura Médica; 1997. p. 47-72. names of drugs. Whenever there are doubts about style, terminology, Annals units of measurement and related issues, refer to the AMA Manual of Höfling-Lima AL, Belfort R Jr. Infecção herpética do recém-nascido. Style 10th edition. In: IV Congresso Brasileiro de Prevenção da Cegueira; 1980 Jul 28-30, 12. Original Documents. Corresponding authors should keep the Belo Horizonte, Brasil. Anais. Belo Horizonte; 1980. v.2. p. 205-12. original documents and the letter of approval from the Research Dissertations Ethics Committee for studies involving humans or animals, the con- Schor P. Idealização, desenho, construção e teste de um ceratômetro sent form signed by all patients involved, the statement of agreement cirúrgico quantitativo [dissertation]. São Paulo: Universidade Federal with the full content of the study signed by all authors and the statement of conflict of interest of all authors, as well as the records of the de São Paulo; 1997. data collected for the study results. Electronic Documents Monteiro MLR, Scapolan HB. Constrição campimétrica causada por 13. Corrections and Retractions. Errors may be noted in published vigabatrin. Arq Bras Oftalmol. [online journal]. 2000 [cited 2005 manuscripts that require the publication of a correction. However, some errors pointed out by any reader may invalidate the results Jan 31]; 63(5): [about 4 p.]. Available at:http://www.scielo.br/scielo. or the authorship of a manuscript. If substantial doubt arises about php?script=sci_arttext&pid=S0004-27492000000500012&lng=pt& the honesty or integrity of a submitted manuscript, it is the editor’s nrm=iso responsibility to exclude the possibility of fraud. In these situations, 7. Tables. Tables should be numbered sequentially using Arabic nu- the editor will inform the institutions involved and the funding agen- merals in the order they are mentioned in the text. All tables should cies about the suspicion and wait for their final decision. If there is have a title and a heading for all columns. Their format should be confirmation of a fraudulent publication in ABO, the editor will act in simple, with no vertical lines or color in the background. All ab- compliance with the protocols suggested by the International Com- breviations (even if previously defined in the text) and statistical tests mittee of Medical Journal Editors (ICMJE) and by the Committee on should be explained below the table. The bibliographical source of Publication Ethics (COPE). the table should also be informed when the table is extracted from another study. Checklist Do not include tables in the main document of the manuscript, they Before submitting their manuscript, authors should make sure should be uploaded as supplementary documents that all the following items are available: 8. Figures (graphs, photos, illustrations, charts). Figures should □ Manuscript prepared in accordance with the instructions to be numbered sequentially using Arabic numerals in the order they authors. are mentioned in the text. ABO will publish the figures in black □ Maximum number of words, tables, figures, and references and white at no cost to the authors. Manuscripts with color figures according to the type of manuscript. will be published only after the authors pay a publication fee of □ Title page including the clinical trial registration number is not R$ 500.00 per manuscript. included in the main document Graphs should preferably be in shades of gray, on a white background □ No figures and tables are included in the main document of and without three-dimensional or depth effects. Instead of using pie the manuscript. charts, the data should be included in tables or described in the text. □ All figures and tables were uploaded separately as supple- Photos and illustrations should have a minimum resolution of mentary documents. 300 DPI for the size of the publication (about 2,500 x 3,300 pixels for □ Author Contribution Statement completed and saved as a a full page). The quality of the images is considered in the evaluation digital file to be sent as a supplementary document. of the manuscript. □ Form for Disclosure of Potential Conflicts of Interest of all authors completed and saved as digital files to be sent as The main document should contain all figure legends, typed double - supplementary documents. spaced and numbered using Arabic numerals. □ Digital version of the report provided by the Institutional Re- Do not include figures in the main document of the manuscript; they view Board containing the approval of the project to be sent should be uploaded as supplementary documents. as a supplementary document.

Arq Bras Oftalmol. 2016;79(5):353-6 355 List of WEBSITES U.S. National Institutes of Health Authorship Principles according to the ICMJE http://www.clinicaltrials.gov http://www.icmje.org/recommendations/browse/roles-and- responsibilities/defining-the-role-of-authors-and-contributors.html Australian and New Zealand Clinical Trials Registry http://www.anzctr.org.au Authors’ Participation Form http://www.cbo.com.br/site/files/Formulario Contribuicao dos International Standard Randomised Controlled Trial Number - Autores.pdf ISRCTN http://isrctn.org/ CONSORT (Consolidated Standards of Reporting Trials) http://www.consort-statement.org/consort-statement/ University Hospital Medical Information Network Clinical Trials Registry - UMIN CTR STARD (Standards for the Reporting of Diagnostic accuracy studies) http://www.umin.ac.jp/ctr/index.htm http://www.stard-statement.org/ PRISMA (Preferred Reporting Items for Systematic Reviews and Nederlands Trial Register Meta-Analyses) http://www.trialregister.nl/trialreg/index.asp http://www.prisma-statement.org/index.htm Registros Brasileiros de Ensaios Clínicos STROBE (Strengthening the Reporting of Observational studies http://www.ensaiosclinicos.gov.br/ in Epidemiology) http://www.strobe-statement.org/ MeSH - Medical Subject Headings http://www.ncbi.nlm.nih.gov/sites/entrez?db=mesh&term= Online interface for submission of manuscripts to ABO http://www.scielo.br/ABO DeCS - Health Sciences Keywords in Portuguese International Committee of Medical Journal Editors (ICMJE) http://decs.bvs.br/ http://www.icmje.org/ Format suggested by the International Committee of Medical Uniform requirements for manuscripts submitted to biomedical Journal Editors (ICMJE) journals http://www.nlm.nih.gov/bsd/uniform_requirements.html http://www.nlm.nih.gov/bsd/uniform_requirements.html List of Journal Indexed in Index Medicus Declaration of Helsinki http://www.ncbi.nlm.nih.gov/journals http://www.wma.net/en/30publications/10policies/b3/index.html AMA Manual of Style 10th edition Principles of the Association for Research in Vision and Ophthal- mology (ARVO) http://www.amamanualofstyle.com/ http://www.arvo.org/About_ARVO/Policies/Statement_for_the_ Protocols of the International Committee of Medical Journal Use_of_Animals_in_Ophthalmic_and_Visual_Research/ Editors (ICMJE) World Association of Medical Editors: Conflict of interest in peer- http://www.icmje.org/recommendations/browse/publishing-and- reviewed medical journals editorial-issues/scientific-misconduct-expressions-of-concern-and- http://www.wame.org/about/wame-editorial-on-coi retraction.html Form for Disclosure of Potential Conflicts of Interest Protocols of the Committee on Publication Ethics (COPE) http://www.icmje.org/coi_disclosure.pdf http://publicationethics.org/resources/flowcharts

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356 Arq Bras Oftalmol. 2016;79(5):353-6